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I. Synthesis of an advanced Rottlerin intermediate. II. Development of a microwave-assisted methodology for the regioselective synthesis of 2,2-dimethyl-2H-chromenes

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I. SYNTHESIS OF AN ADVANCED ROTTLERIN INTERMEDIATE.
II. DEVELOPMENT OF A MICROWAVE-ASSISTED METHODOLOGY FOR THE
REGIOSELECTIVE SYNTHESIS OF 2,2-DIMETHYL-2ff-CHROMENES.
by
Marc Jordan Adler
Department of Chemistry
Duke University
Date: ^flN,') 0 /flOPS*
Approved:
Professor Steven W. Baldwin, Ph.D., Supervisor
Professor Stephen L. Craig, Ph.D.
Professor Cynthia M. Kuhn, Ph.D.
Dissertation submitted in partial fulfillment of
the requirements for the degree of Doctor
of Philosophy in the Department of
Chemistry in the Graduate School
of Duke University
2008
UMI Number: 3340967
Copyright 2008 by
Adler, Marc Jordan
All rights reserved.
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Copyright by
Marc Jordan Adler
2008
ABSTRACT
(Chemistry - Organic)
I. SYNTHESIS OF AN ADVANCED ROTTLERIN INTERMEDIATE.
II. DEVELOPMENT OF A MICROWAVE-ASSISTED METHODOLOGY FOR THE
REGIOSELECTIVE SYNTHESIS OF 2,2-DIMETHYL-2H-CHROMENES.
by
Marc Jordan Adler
Department of Chemistry
Duke University
Date:
fapU 1 1 ; ^ QOfe
Approved:
Professor Steven W. Baldwin, Ph.D., Supervisor
Professor Cynthia M. Kuhn, Ph.D.
An abstract of a dissertation submitted in partial
fulfillment of the requirements for the degree
of Doctor of Philosophy in the Department of
Chemistry in the Graduate School
of Duke University
2008
Abstract
I. The synthesis of an advanced intermediate of the biologically active
chromenochalcone natural product rottlerin was achieved. Beginning with starting
material phloroacetophenone, a convergent synthetic approach allowed for the
successfully construction of an unprecedented methylene-linked ketopolyphenol
heterodimer.
vV
OH
phloroacetophenone
H
MOM
ketopolyphenol
heterodimer
rottlerin
II. A novel, direct method to regioselectively synthesize 2,2-dimethyl-2£fOH
chromenes utilizing microwave irradiation was developed. This technique provides an
innovative approach to the synthesis of chromene containing compounds. By altering a
few of the reaction variables, a variety of chromenes were generated in good yield.
While optimization of the method is ideal for its application to novel substrates, the
conditions are generally applicable to a wide range of phenols.
microwave
OH
+
H
RT
CDCU
2,2-dimethyl2H-chromene
phenol
IV
To Mom, Dad, and Allison, for your love.
I couldn't possibly express my gratitude in words, only hugs.
To Tiffany, for holding my hand sometimes even though you don't like it.
v
Contents
Abstract
iv
List of Schemes
viii
List of Tables
x
List of Figures
xi
Definitions of Abbreviations and Commonly Used Terms
xiii
Acknowledgments
xiv
1. Introduction
2
1.1 History and Biological Activity of Rottlerin
2
1.2 Structural Features of Rottlerin
7
1.2.1 Rottlerin Subunit 1: 2 / 2-Dimethyl-2/f-chromene
9
1.2.2 Rottlerin Subunit 2: Chalcone
15
1.2.3 Rottlerin Subunit 3: Methylene-Bridged Biphenol
17
2. Synthesis of an Advanced Rottlerin Intermediate
20
2.1 Synthetic Approaches to Rottlerin
20
2.2 Rottlerin Epilogue
40
2.3 Experimental and Spectral Data
46
2.4 Selected NMR Spectra
90
2.5 Crystallographic Data for Chromenochalcone 16MOM
99
3. Microwave-Assisted Synthesis of 2,2-Dimethyl-2f/-chromenes
Ill
3.1 Results and Discussion of the Methodological Exploration
VI
Ill
3.2 Experimental and Spectral Data
124
3.3 Chromene Methodology Trials Data
132
3.4 Selected NMR Spectra
137
3.5 Crystallographic Data for Novel Chromene 35
141
References
152
Biography
162
vn
List of Schemes
Scheme 1: Rottlerin Retrosynthesis 1
20
Scheme 2: Synthesis of OQM Precursor 6
21
Scheme 3: Synthesis of Iodochromane 11
22
Scheme 4: Difficulties with HI Elimination of Iodochromane 11
24
Scheme 5: Synthesis of Chromenochalcone 16MOM
25
Scheme 6: Synthesis of Chromenochalcone 16TBS
26
Scheme 7: Failed Linkage Attempts of Advanced Intermediates
27
Scheme 8: Synthesis of Chromenyl OQM Precursor 19
27
Scheme 9: Retrosynthesis 2, from Advanced Intermediate 27
28
Scheme 10: Synthesis of OQM Precursor 26
29
Scheme 11: Successful Linkage of 15 and 26SEM
30
Scheme 12: Attempted Aldol Condensation of 27MS with Benzaldehyde
31
Scheme 13: Retrosynthesis 3, from Advanced Intermediate 32
32
Scheme 14: Synthesis of 31MOM, Attempted Linkage with 26SEM
32
Scheme 15: Retrosynthesis 4, from Advanced Intermediate 28
33
Scheme 16: Attempted Linkage of 13MOM and 26SEM
33
Scheme 17: Attempted Synthesis of 28MS via Ammonium 33
34
Scheme 18: Attempted Synthesis of 28HS via Chromene 34
34
viii
Scheme 19: Retrosynthesis 5, from Advanced Intermediate 40
35
Scheme 20: Synthesis of Chromenoaldehyde 37MOM
36
Scheme 21: Attempted Linkage of 25EOM and 37MOM
36
Scheme 22: Retrosynthesis 6, from Advanced Intermediate 45
37
Scheme 23: Synthesis of 41MOM, Attempted Mannich-Type Linkage with 25SEM
37
Scheme 24: Attempted Linkage of 25EOM and41MOM
38
Scheme 25: Synthesis of 44MOM, Attempted Linkage with 25EOM
38
Scheme 26: Retrosynthesis 7, from Advanced Intermediate 40
39
Scheme 27: Failed Acetylation of Model Compound 25MOM
39
Scheme 28: Rottlerin Retrosynthesis 8
41
Scheme 29: Synthesis of Unprecedented Ketopolyphenol Heterodimer 50
42
Scheme 30: Synthesis of Advanced Linked Chromene Intermediate 51
44
Scheme 31: Unsuccessful Aldol Condensation to Potentially Give Rottlerin
45
Scheme 32: Exemplary Mechanism for the Microwave Annulation Method
112
Scheme 33: Mechanism Emphasizing the Role of the Phenolic Proton
115
IX
List of Tables
Table 1: Standard, Best Chromene Yields; All Explored Phenols
113
Table 2: Optimization Trials for Series of 2,4-Dihydroxycarbonylbenzenes
120
Table 3: Optimization Trials for Series of Methoxyphenols
121
Table 4: Solvent Trials for the Synthesis of Octandrenolone (53)
122
Table 5: Complete Results of the Investigation of the Microwave-Assisted Synthesis of
2 / 2-Dimethyl-2H-chromenes in CDCb
132
x
List of Figures
Figure 1: Rottlerin
2
Figure 2: Structural Features of Rottlerin
8
Figure 3:2,2-Dimethyl-2ff-chromene
9
Figure 4: Some 2 / 2-Dimethyl-2ff-chromene Containing Bioactive Natural Products
10
Figure 5: Various Methods for Synthesizing 2,2-Dimethyl-2i^chromenes
11
Figure 6: Synthesis of 2,2-Dimethyl-2iLf-chromenes via an OQM Intermediate
12
Figure 7: Synthesis and Rearrangement of Phenyl Propargyl Ether
13
Figure 8: Oxidative Cyclization of ortho-Prenylated Phenol
14
Figure 9: Direct Synthesis of 2,2-Dimethyl-2icf-chromene from Parent Phenol
14
Figure 10: Chalcone
15
Figure 11: Flavonoid Subclasses
16
Figure 12: Synthetic Routes to Chalcones
17
Figure 13: Margaspidin, Desaspidin, and Albaspidin
18
Figure 14: OQM Precursors for Synthesis of Methylene-Bridged Biphenols
19
Figure 15: Non-Biomimetic Precursors to Methylene-Bridged Biphenols
19
Figure 16: Models of 27MS and32MS
30
Figure 17: J H NMR Spectrum of Dihydrobenzofuran 14
91
Figure 18:13C NMR Spectrum of Dihydrobenzofuran 14
92
xi
Figure 19: HMQC Spectrum of Dihydrobenzofuran 14
93
Figure 20: Pertinent Region of HMQC Spectrum of Dihydrobenzofuran 14
94
Figure 21: *H NMR Spectrum of Chromenochalcone 16MOM
95
Figure 22: 13 C NMR Spectrum of Chromenochalcone 16MOM
96
Figure 23: ! H NMR Spectrum of Methylene-Linked Biaryl 27MS
97
Figure 24: 13 C NMR Spectrum of Methylene-Linked Biaryl 27MS
98
Figure 25: Crystal Structure of Chromenochalcone 16MOM, View 1
99
Figure 26: Crystal Structure of Chromenochalcone 16MOM, View 2
99
Figure 27: Synthetic Targets Potentially Accessible Using Microwave Methodology.... 123
Figure 28: lU NMR Spectrum of Novel Chromene 13TBS
138
Figure 29: 13 C NMR Spectrum of Novel Chromene 13TBS
139
Figure 30: nOe Experiment to Determine the Structure of Chromene 55
140
Figure 31: Crystal Structure of Novel Chromene 35
141
xu
Definitions of Abbreviations and Commonly Used Terms
DMF:
N,N-Dimethylformamide
MeOH:
Methanol
EtOAc:
Ethyl acetate
EtOH:
Ethanol
TBS-:
terf-Butyldimethylsilyl-
MOM-:
Methoxymethyl-
EOM-:
Ethoxymethyl-
SEM-:
2-(Trimethylsilyl)ethoxymethyl-
Prenyl-:
(CH3)2C=CHCH2-
DBU:
l,8-Diazabicyclo[5.4.0]undec-7-ene
LiHMDS:
Lithium bis(trimethylsilyl)amide
Red-Al:
Sodium bis(2-methoxyethoxy)aluminum hydride
DIBAL:
Diisobutylaluminum hydride
Rochelle's salt:
Potassium sodium tartate
wet silica:
Silica gel pretreated with 0.3 weight equivalents of water
xiu
Acknowledgments
I would first and foremost like to thank Dr. Steven Baldwin, my advisor, who
served as not only a wonderful mentor, but a great friend as well. My decision to join
your group was based as much on the person you are as it was on the chemistry you do.
You granted me a personal and creative freedom that few graduate students get to
experience, and for that I am extremely grateful.
Hemraj (Raj) Juwarker and Louise (Lou) Charkoudian: I wouldn't have wanted
to do it without you. Between our loving friendships and shared passion for chemistry,
there is no part of my life I can't share with you. Raj, thank you for sharing a house,
watching basketball, talking chemistry, visiting Ganesh, eating (a lot), and laughing
(even more) with me. Lou, first year we dreamed of making and teaching our own class,
and you made it happen. Thanks for listening to me, for always seeking out my advice,
for coming to visit me, and for being a perpetual source of optimism even when I was
determined to be negative. Thank you both for being you.
I would not be a shadow of the chemist, or the man, that I am today if not for
Chris Beaudry. I learned more chemistry from you in a year than I did in my other three
years of college put together. You are a dedicated learner, a brilliant chemist, and most
importantly, a wonderful human being. You never gave up on me: you gave me more
attention and education than I deserved when I started working under you, and single-
xiv
handedly turned me from an underachiever with promising intellect to a scholar with
the initiative to achieve that promise. I hope that you know how thankful I am for the
knowledge and friendship you have given me.
Thank you to the Baldwin Group members past and present: Martin Mao,
Donghua Dai, Ben Rothstein, Scott Wilson, Vicky Hill, Victor Gonzalez and most
importantly, John Stanko. After sharing classes for a year, a lab for four years, a house
for two years, a whole bunch of IM teams, and socializing together, it's a wonder we
even have anything left to say to each other. It wasn't always ideal, but together we
made it work, and sometimes it was even pretty damn good. Thanks for teaching me
the art of beer pong: 24-0 against undergrads.
I am very thankful to my current and former committee members Stephen Craig,
Cynthia Kuhn, Katherine Franz, and Ross Widenhoefer. I sincerely appreciate the
respect that you all have given me. Steve and Ross, thank you for letting me participate
in your group meetings for periods of time when I felt my brain needed to be infused.
Dr. Kuhn, I am so grateful that you allowed me to serve as a TA for your Brain and
Behavior course instead of suffering through the cell signaling seminar. Dr. Franz,
thank you for all of our interactions over the years. I am especially thankful for your
willingness to support me in my post-doc search, and flattered that you would
sometimes direct your graduate students to me with their organic synthesis questions.
My mom loves to say that "you have different friends for different reasons".
Thank you to Bryce Dickinson, Sabah Oney, Tom McNicholas, Ryan Purcell, Chris
Bender, Jim Parise, Scott Sauer, Jared Heymann, and Charlotta Wennefors, for giving me
so many reasons to have friends.
Thank you to Holly Sebahar, Chris Roy, Dewey McCafferty, Christiana Conti,
George Dubay, Tony Ribeiro, Bill Day, Bozenna Krzyzanowska, Natasha Smith, Richard
MacPhail, Anne Langley, and Dr. James Bonk, who all helped me so much along the
way. I appreciate everything you all did to make my life at Duke that much better.
Thanks to the Duke Club Baseball Team, for giving me a chance to pitch one last
time. Thanks to the all of my intramural teammates for tolerating my competitiveness.
Thanks to the BCC: Chris, Dave, Nick, Ryan, Sean, Steve, Jill, Robyn, and Stacy,
for being my second family.
Although I do not know these people personally, they kept me going at times
when no one else could. Thank you to Talib Kweli, Kanye West, Jay-Z, Notorious B.I.G.,
Tupac Shakur, Dr. Dre, Bone Thugs-N-Harmony, Twista, Lupe Fiasco, The Roots,
Outkast, Timbaland and Magoo, Common, Mos Def, Little Brother, Wu-Tang Clan,
Crucial Conflict, Da Brat, Do or Die, 3XKrazy, Da Backwudz, Cam'ron, Canibus,
Pharoahe Monch, Gym Class Heroes, Gnarls Barkley, Damian Marley, Alicia Keys, John
Legend, Raphael Saadiq, Sublime, Incubus, Daft Punk, John Mayer, Muse, Maroon 5,
Norah Jones, Nirvana, Billy Joel, Nina Simone, Stevie Wonder, The Beatles, The Beach
xvi
Boys, Dan Hicks and his Hot Licks, Buena Vista Social Club, and all the classical
composers and performers featured on Tiffany's Classical Mix, Volumes 1, 3, and 4.
Thanks to the Duke men's basketball team, for all the hope, excitement, joy and pride
you've given me.
Finally, I would like to acknowledge the people to whom this dissertation is
dedicated. I am so lucky that I was born into such a loving and caring family. Mom,
Dad, and Alii, I am who I am only because of you. You have always encouraged and
supported me in whatever I do, and I am constantly motivated by the desire to make
you as proud of me as I am of all of you. I love you all so much. Thank you for
everything you have ever given to me.
The last thank you goes to Tiffany Dominique Perry, f.M.D. You inspire me to
work harder and be a better person by just being you. Thank you for laughing with me.
Thank you for teaching me. Thank you for sometimes reminding me I'm not as good as
I think I am, and when it's needed, reminding me I'm better than I think I am. Thank
you for always giving the perfect advice when it's needed and understanding when to
just listen. You are my love, my best friend, and so much more. I don't think you could
ever be as proud of me as I am of you, but that won't stop me from trying.
xvu
"Stay far from timid, only make moves when your heart's in it,
and live the phrase sky's the limit."
-Christopher Wallace, a.k.a. Notorious B.I.G.
'I see the forest through the trees, but only because I cut off the leaves
and left them blowing off into the breeze."
- Tsidi Ibrahim, a.k.a. Jean Grae
1
1. Introduction
1.1 History and Biological Activity ofRottlerin
OH
'
OH
Figure 1: Rottlerin
Rottlerin (I), also called mallotoxin, is a chromenochalcone which occurs
naturally in Mallotus philippensis (formerly Rottlera tinctoria), commonly known as the
kamala or monkey-faced tree. This evergreen tree of the spurge family Euphorbiaceae is
native to areas ranging from India, Sri Lanka, and South China to the West Pacific and
Australia. In India, where the tree grows throughout the deciduous forests up to 1500
meters, the fruit of the kamala tree has long been used as an herbal medicine for many
ailments.1-4 Generally, the fruit is crushed to make an intensely red powder, called
kamala, which is then assembled into a variety of preparations depending on the
intended use; these concoctions usually involve mixing into some oil or lipid. It is most
commonly used as an antihelminthic agent (drug which expels parasitic worms), and
specifically as a teniacide (drug which destroys tapeworms). Leprous or other minor
2
skin eruptions may be treated with kamala either topically or ingested. Ayervedic
medicine, which mentions kamala in all ancient scriptures (often referring to it as
kampillaka), has found this herb to be a valuable remedy for a variety of medical woes
including tumors, diabetes, flatulence, and chronically infected wounds. The drug has
also found use as an antifertility agent (contraceptive) when consumed orally.5 Finally,
the chromophoric nature of the powder makes it an effective dye, especially for silk
garments, which it turns a luminescent orange-brown color. 14
The constituents of the plant were first investigated in 1855 by Anderson, 6 who
was undoubtedly driven by the desire to determine what molecule or molecules in this
plant could possess such a wide variety of medicinal properties. He was able to isolate a
single crystalline compound, which he named rottlerin and assigned, based on
combustion analysis, the molecular formula of C11H10O3. Both Leube and Oettingen
independently devoted efforts towards the study of the chemical composition of kamala,
however neither could replicate the generation of the crystal which Anderson had
achieved. 7 In 1886, Perkin and Perkin,8 initially unaware of Anderson's studies,
analyzed the constituents of kamala and identified a crystalline substance which they
named mallotoxin. They determined the molecular composition to be either C11H10O3 or
CisHisOs, also based on combustion. The molecular formula was a point of contention in
the subsequent 50 years9-13 as interrogation of the compound continued until at last, in
1939, Brockmann and Maier not only unveiled the correct molecular composition of
3
rottlerin as C30H28O8, but also proposed the correct structure for rottlerin.14 While the
formulaic assignments of Anderson, Perkin, and Perkin were shown to be incorrect, it is
important to note that their combustion analyses were performed with remarkable
accuracy, revealing the by-weight percentages of carbon and hydrogen to within 0.5%;
their error was in succumbing to oversimplification when assigning the empirical
formula. While rottlerin was the initial compound isolated from kamala, other
structurally related molecules have subsequently been discovered, some even
possessing interesting biological activity.15-19
Rottlerin began to attract the attention of the Western scientific community as a
useful compound in 1994, when Gschwendt et al. showed it to be a specific inhibitor of
protein kinase C delta (PKCD).20 PKCD is one of twelve known mammalian subtypes of
the serine/threonine protein phosphorylating enzyme protein kinase C (PKC), which
may be activated by phosphatidylserine (PS) and diacylglycerol (DAG) in a Ca2+dependent manner. In addition, PKC can be activated by tumor-promoting phorbol
esters. PKCD belongs to the Ca2+-insensitive novel PKC (nPKC) subfamily, which retain
the ability to be activated by DAG or phorbol esters in the presence of PS.21 PKCD has
been shown to be an important enzyme for the growth and propagation of many
different types of cancer, including glioma,22 colon cancer,23 and breast cancer.24 Since
1994, rottlerin has been used as a standard in a large number (-500) of biological assays
4
for selectively blocking the activity of PKCD25; these studies have contributed greatly to
the elucidation of the important role this enzyme plays in many biological functions.
More recently, some dispute has arisen as to the legitimacy of rottlerin as a
selective PKCD inhibitor. 2528 The initial paper by Gschwendt et al. also states rottlerin
to be an effective inhibitor of calcium/calmodulin-dependent protein kinase kinase III
(CAMKK3),20 although this fact is generally ignored by those who use rottlerin to inhibit
PKCD. In addition, a 2000 study showed rottlerin to be a potent inhibitor of mitogenactivated protein kinase-activated protein kinase 2 (MAPKAPK2), p38regulated/activated kinase (PRAK), protein kinase A (PKA), and glycogen synthase
kinase 3-beta (GSK-3B); data divulged in the same publication in fact directly contradicts
the findings in the original Gschwendt paper by finding rottlerin to not be an inhibitor
of PKCD at all.28 Perhaps most interestingly, rottlerin has also been established as an
uncoupler of mitochondrial oxidative phosphorylation. 27 Some now believe that this
activity causes upstream or downstream effects which exhibit results indistinguishable
from those that would be caused by PKCD inhibition, leading early researchers to
incorrectly attribute the observed cellular phenomenon to direct inhibition of PKCD by
rottlerin.25 Furthermore, this study directly refutes these PKCD effects by proving
rottlerin to be effective in modulating cellular processes similarly in cells both with and
without PKCD. These findings have provoked some chemical suppliers to cease the
5
distribution of rottlerin for use as a PKCD inhibitor, yet some researchers continue its
use in this capacity undeterred.
Regardless of the mechanism of action, many reports have demonstrated that
rottlerin may be an effective drug against several different types of cancer. In 2003,
researchers were able to sensitize colon carcinoma cells to apoptosis using rottlerin.29
Two separate papers from 2005 show this drug to both inhibit the growth of
glioblastoma and sensitize glioma cells to apoptosis.30-31 Rottlerin was also shown, in
2006, to induce apoptosis in chronic lymphocytic leukemia cells.32
Additionally, acylphloroglucinols (structures derived from phloroacetophenone
(II)) as a class of molecules have been implicated as potential therapeutics for
neurodegenerative diseases,33 and rottlerin itself has been shown to be a neuroprotective
agent in cell culture and animal models. 34 Rottlerin has also been shown to inhibit T cell
activation35 and serve as a potassium channel activator.36
With specifically the antiglioblastoma effects demonstrated in his laboratory in
mind, 31 Dr. Madan Kwatra of the Duke University Pharmacology and Cancer Biology
Department brought this molecule to our attention, noting that it had not been
synthetically produced despite over 150 years of biological study. In fact, a March 3,
2008 SciFinder search of the word "rottlerin" yields 650 different journal articles and a
search for "mallotoxin" identifies an additional 4, yet not a single one of them is
dedicated to the synthesis of this much studied and little understood compound.
6
Currently, rottlerin is obtained by purification of the kamala fruit extract, resulting in
wide-ranging levels of purity, as many naturally occurring, structurally similar
compounds may persist as contaminants despite efforts to abolish them. Additionally,
rottlerin, even after isolation, has been shown to be somewhat unstable. 37 The isolation
process is also seemingly laborious and inefficient, as rottlerin is sold in small quantities
at high prices. For example, on March 3, 2008, Sigma-Aldrich offered 10 mg of rottlerin
at >85% purity for $93.40. This level of cost often makes rottlerin prohibitively expensive
for researchers wishing to speculatively investigate its potential therapeutic uses.
In addition to the potential financial and environmental advantages offered by
the synthetic production of rottlerin, structure/function analysis of this molecule has not
been pursued. The forging of a sufficiently malleable synthetic route would not only
allow for the commercial production of rottlerin, but also provide access to various
synthetic analogues; evaluation of the biological activity of these compounds compared
to rottlerin would not only provide valuable first insight into the relationship between
the structure of this drug and its cellular activity, but may also yield a more selective
and efficacious chemotherapeutic.
1.2 Structural Features of Rottlerin
Structurally, rottlerin (I) features many interesting facets. It possesses a psuedodimeric structure, as two phloroacetophenone (II) derived aryl cores are linked by a
methylene bridge. At its root, the foundation of rottlerin (I) is a polyketide, as
7
phloroacetophenone (II) is naturally derived from a tetraketide (III).38'39 One of the
rings is elaborated with chalcone (IV) functionality and also, perhaps most intriguingly,
contains a 2,2-dimethyl-2i ; f-chromene (V) moiety. While many natural products and
synthetic molecules containing these subunits have been synthesized, there is no
evidence of any previous synthetic inquiries pursued towards rottlerin (I) or any other
compound that possesses all three (III, IV, and methylene-linked biaryl cores derived
from II) of these features.
O
O
O
O
SR
III
IV
Figure 2: Structural Features of Rottlerin
Please note that in all schemes in this introductory section, the methods are
depicted using the simplest beginning phenol substrate theoretically required for the
transformation to simplify visualization. The actual methods were demonstrated with
variably substituted phenols to give a range of 2,2-dimethyl-2//-chromene, chalcone,
and methylene-linked biphenolic products.
1.2.1 Rottlerin Subunit 1: 2,2-Dimethyl-2H-chromene
v
Figure 3: 2,2-Dimethyl-21 : f-chromene
The structural attribute of rottlerin (I) that has historically garnered the most
attention is the 2,2-dimethyl-2H-chromene. This bicyclic molecular scaffold has been
classified as a "privileged structure", a designation used to describe structural motifs
which are observed in many naturally occurring organic compounds possessing varying
biological activity.40 This theme is indeed observed in many known biologically active
molecules, for example antibacterial drummondin A (VI),41-42 electron transport inhibitor
4-hydroxy-3-methoxylonchocarpin (VII),43'44 antitumor agents seselin (VIII)45 and (-)-3deoxy-MS-II (IX),46 and antijuvenile hormones precocene I (X) and II (XI), which are
used as pesticides.47
9
0
OH
Figure 4: Some 2 / 2-Dimethyl-2H-chromene Containing Bioactive Natural
Products
Over the years, a variety of methods have been used for the construction of 2,2dimethyl-2H-chromenes. The first route developed for assembly of these molecules was
the Grignard reaction of coumarins (XII), which proved effective for the synthesis of
several chromenes (V) of biological interest. It was also shown that chromenes (V)
could be obtained from chromanones (XIII) via reduction of the ketone followed by
dehydration of the corresponding a-hydroxy- (XIV) or a-methoxy-chromanes (XV).
Alternatively, oxidation of 2,2-dimethyl-chromanes (XVI) has also been used to afford
the desired chromene (V).48
The oxidative cyclization of ortfto-prenylated phenols (XVII) to give chromenes
(V) can be effected via epoxidation and autocyclization using meta-chloroperbenzoic
acid (mCPBA) followed by dehydration using methyltriphenoxyphosphonium iodide
(MTPI) in hexamethylphosphoramide (HMPA).48 A similar tactic has also been applied
in the solid phase, as the synthesis of a vast array of chromene containing compounds
10
was performed by Nicolaou et. al., who used a SeBr-functionalized bead to initiate the
cyclization of ort/20-prenylated phenols (XVII); after structural elaboration of the
resulting tethered chromanes (XIX), oxidative cleavage gave the target chromenes (V).
^ X / O ^ O
oJ
MeMgl
XII
NaBH4
»
or UAIH4
a?
H*
OH
XIV
O.
H4
NaBH,
CH 3 0"
OCH,
XV
nc°^
kXJ
/
DDQ
^
orNBS
-
XVI
/
Y°^
XJ
V
mCPBA
f Y°^1
k xj
MTPI
OH
HMPA
XVIII
XVII
BrSe.
( ^
O^ /
H,0.
2u2
Se
XVII
XIX
Q
Figure 5: Various Methods for Synthesizing 2,2-Dimethyl-2H-chromenes
11
XX
V
Figure 6: Synthesis of 2,2-Dimethyl-2H-chromenes via an OQM
Intermediate
Finally, another general way which 2,2-dimethyl-2ff-chromenes have been
synthesized is via a 67t-electrocyclization of a dimethylvinyl substituted (XX) orthoquinone methide (OQM). OQMs (XXI) are high energy species which are almost always
generated and then consumed in situ during the course of a reaction.50 Their existence
was first theorized by Fries in 1907, who hypothesized an OQM intermediate as an
explanation for the dimeric and trimeric products he was observing for a particular
reaction.51 It was not until 1959, however, when Gardner was able to provide the first
direct proof of their existence by spectroscopic analysis performed at -100°C.52 OQMs
serve as extremely good electrophiles, and their structure and electronic distribution
make them active components in both [4+2]-cycloadditions and 67t-electrocyclizations.
-JO
XXI
Figure 7: ortho-Quinone Methide
While OQMs can serve as valuable precursors to many desired compounds, their
widespread use as synthetic building blocks has been hampered by the difficulty in
controlling their reactivity. The most successful reactions involving OQMs are generally
12
either homodimerization or intramolecular processes (such as 671-electrocyclizations and
nucleophilic trapping), although researchers have successfully performed cycloadditions
with, intermolecular nucleophilic additions to, and hydride reductions of OQMs.50
The first reaction protocol used to generate chromenes (V) via transient OQM
intermediates (XX) was the thermal rearrangement of the corresponding phenyl
propargyl ether (XXIV).48 This method was first explored generally in 1969, and has
been used effectively in a number of examples since despite suffering as a viable option
for the synthesis of chromenes in a few ways. Firstly, it requires two separate reaction
setups to obtain the chromene from the parent phenol (XXII). Additionally, the
dimethylpropargyl halides (XXIII) necessary to make the phenyl propargyl ethers
(XXIV) are either quite costly to purchase or difficult to prepare, making their use on a
large scale impractical. Finally, the rearrangement step requires refluxing in highboiling solvents (e.g. N',N'-diethylaniline) that are often hazardous and/or difficult to
remove from the reaction mixture.
X
OH
sL
+
xxii
K2C03,
Kl,
xxiii
acetone
^y-°^L
heat
KJ
xxiv
v
Figure 7: Synthesis and Rearrangement of Phenyl Propargyl Ether
Another approach involves the oxidation of arf/jo-prenylated phenols (XVII)
with dichlorodicyanoquinone (DDQ). The employment of DDQ precludes this method
from use with molecules containing moieties susceptible to oxidation. A similar
13
technique employs Jones' reagent (OO3, H2SO4) as the oxidant, although this requires a
para-hydroxy phenol (XXV) precursor. After oxidation to the quinone (XXVI), the
OQM (and subsequently the chromene) is formed upon treatment with base.48
XXV
I
XXVI
I
V
Figure 8: Oxidative Cyclization of orffio-Prenylated Phenol
XXII
XXVII
V
Figure 9: Direct Synthesis of 2,2-Dimethyl-2if-chromene from Parent
Phenol
Several methods have been established to generate chromenes in a single step via
the direct condensation of an ot,f3-unsaturated aldehyde (XXVII) with a phenol (XXII).
Initiation of this reaction has been accomplished in a number of ways. The most
popular reaction conditions are base assisted; 5361 these reactions often necessitate the use
of high temperatures and/or long reaction times as well. This transformation has also
been accomplished thermally (140-150°C, neat) in the absence of catalyst,61 although this
requires a large (10-fold) excess of aldehyde and sustained high temperatures (6 hours).
14
Lastly, acid mediated protocols have been utilized to effect the conversion of these
starting materials to chromenes. 6264 Particularly elegant and concise phenylboronic acid
mediated syntheses of precocene I (X) and II (XI) were performed by Bissada et. al.62
using protocols which were developed in the same laboratory. 65
1.2.2 Rottlerin Subunit 2: Chalcone
IV
Figure 10: Chalcone
The chalcone (IV) structure is a subclass of the larger structural family called
flavonoids.66 This family of compounds has long been established to be biologically
active, as they naturally serve as plant antioxidants. 67 In addition to this endogenous
activity, a number of other biological applications have been elucidated 66 including antitumor activity.68
Chalcones (IV) are generated in vivo via chalcone synthase (CHS), an enzyme
discovered in 1970 which is the most biologically prevalent and well studied of the
functionally diverse type III polyketide synthases. 67 The therapeutic uses of chalcones
range from anti-inflammation and anti-infection69 to cytotoxicity and antioxidant
15
chemoprotection 70 to antibacterial and antifungal.71 Somewhat counterintuitively, a,|3unsaturated carbonyl compounds in general have been implicated in mutagenic and
carcinogenic pathways as well/ 2 although substitution at the P position with a benzene
ring (as seen in chalcones) seems to greatly attenuate this property. 73
chalcone
flavanone
flavone
iv
xxvm
xxix
isoflavanone
XXX
flavonol
XXXI
aurone
XXXII
Figure 11: Flavonoid Subclasses
Synthetic assembly of chalcones can most directly be effected through a ClaisenSchmidt condensation, which is a crossed aldol condensation involving an aryl ketone
(e.g. acetophenone (XXXIII)) and an aryl aldehyde (e.g. benzaldehyde (XXXIV)). This
is most directly accomplished by subjecting a mixture of the two carbonyl compounds to
a hydroxide base in an alcoholic solution/ 4-78 while variations of this method include the
use of ultrasound 79 or microwave irradiation. 80 Additionally, the Suzuki reaction of
aroyl chlorides (XXXV) and arylvinylboronic acids (XXXVI) can provide access to a
16
variety of substituted chalcones.81 It is also worthwhile to note that the interconversion
of orf/jo-hydroxychalcones and flavanones (XXVIII) may be readily accomplished by
varying the pH of the solution the substrate is subjected to; this phenomenon
undoubtedly occurs in natural settings as well.82
XXXIII
XXXIV
IV
OH
I
ci
XXXV
.B
HO-
D
^V^
cat. Pd
XXXVI
IV
Figure 12: Synthetic Routes to Chalcones
1.2.3 Rottlerin Subunit 3: Methylene-Bridged Biphenol
While a variety of methods exist for the construction of simple methylene-linked
biaryl compounds, including Friedel-Crafts-type benzylations 83 and palladium-catalyzed
couplings, 84 the situation becomes slightly more complicated when both of the aryls in
question are in fact phenols. For the purpose of this discussion, only methylene-linked
biphenols will be explored, as this literature is the most relevant to the investigation of a
synthetic route for the assembly of rottlerin (I).
17
Penttila et. al. elegantly showed in 1965 that the two aryl subunits of methylenelinked biphenol margaspidin (XXXVII), and related natural products desaspidin
(XXXVIII) and albaspidin (XXXIX), are fully assembled before the linking occurs.85
They concluded that the conjoining of the two rings occurs via an OQM (XXI) by
putative addition of a formaldehyde equivalent. This straightforward technique has in
fact been utilized synthetically, although it is effective exclusively when applied to the
synthesis of homodimers. 8687
OH XXXVIII
OCH3
OH
XXXIX
0H
Figure 13: Margaspidin, D e s a s p i d i n , and A l b a s p i d i n
A more selective way to perform this transformation is to first synthesize the
ortfiohydroxybenzyl alcohol (XL), which can be used to generate the OQM in situ,
followed by addition of the second phenol which acts as a nucleophile, attacking at the
position ortho to its hydroxyl substituent to give the linked product. 88 Application of
heat89 and/or acid (either Bronsted 9093 or Lewis94) have been utilized to initiate this
reaction. Equivalently functionalized OQM precursors such as benzodioxaborins
18
(XLI)65-95 and ortho-hydroxy benzyl amines96 (XLII) and ammoniums97 (XLIII) have
been used in this manner as well.
CC- CO
e
NR,
XLI
XL
OH
OH
XLII
NR3
XLIII
Figure 14: OQM Precursors for Synthesis of Methylene-Bridged Biphenols
Other, non-biomimetic synthetic techniques have been developed to obtain
methylene-linked biphenols as well; these include the deoxygenation of biphenolic
ketones98-100 (XLIV), the reduction of dibenzylamines101 (XLV), and the palladiumcatalyzed reductive coupling of hydroxybenzaldehydes (XLVI) and phenols (XXII).102
OH O
XLIV
OH
OH
NR2 OH
XLV
OH O
XLVI
OH
XXII
Figure 15: Non-Biomimetic Precursors to Methylene-Bridged Biphenols
19
2. Synthesis of an Advanced Rottlerin Intermediate
2.1 Synthetic Approaches to Rottlerin
Initial structural analysis of rottlerin (1) led us to believe that synthesis of the
biologically active molecule could be accomplished via an ortfio-quinone methide
(OQM) mediated linkage of two subunits (6 and 16), 5088 both of which could be derived
from phloroacetophenone (2). This route was attractive due to the delayed convergence
of the two phenolic rings, thus minimizing the number of linear steps. The late stage
linkage would also serve allow facile access to a wide range of structural derivatives of
rottlerin (1) which could then be biologically evaluated.
Scheme 1: Rottlerin Retrosynthesis 1
rottlerin
OR'
6
Aryl subunit 6 was prepared in four steps from phloroacetophenone (2).
Formylation of 2 afforded dicarbonyl 3, 103 which was selectively reduced by a
20
Clemmensen reduction to methylphloroacetophenone 4.104 To assist with solubility and
attenuate the reactivity of the aryl species, 4 was fully protected as the tris-TBS ether and
then selectively deprotected to yield the mono-TBS ether 5.105 This transformation was
performed using a method developed for selective deprotection of MOM-protected
phenols which are ortho to a carbonyl,106 but we fortuitously found it to be applicable to
the TBS protecting group as well. A Mannich reaction107 was then utilized to install the
amino-methylene substituent by refluxing either diethylamine (6Et2) or piperidine
(6PIP) with formaldehyde and 5.108
Scheme 2: Synthesis of OQM Precursor 6
OH
a
HCk_X^0H
H
- s^^y
b
HO
83%
HO^X^OH
76%
y ^ r
quant.
^ y ^ K ^ N R
OTBS
R2 = (CH2CH3)2 (6NEt2),
(CH2)5 (6PIP)
a. AICI3, CH(OEt)3, nitrobenzene; b. amalgamated Zn, aq. HCI, MeOH, reflux;
c. TBSCI, DBU, CH2CI2, then l2/MeOH; d. R2NH, H2CO, MeOH, reflux.
The synthesis of chromenochalcone 16 also began from 2, which was first
protected as the bis-MOM ether 7. 109no At this point, an interesting phenomenon began
to emerge: subjecting 2 to excess amine base (such as DBU) and MOMC1 afforded the
21
asymmetrically bis-protected 7 in vast preponderance, whereas exposure of 2 under
basic conditions to TBSC1 yielded the tris-protected species 17 exclusively. It is well
documented that the sp 2 hybridized oxygen of ortho-carbonylphenols engage in
significant hydrogen bonding with the phenolic proton. 111113 We believe that this
interaction precludes the reaction of the second ortho-phenol with MOMC1, while the
TBS group bonded to the first ortho-phenol allows for a coordination to exist between
the carbonyl oxygen and the silicon of that protecting group,114-117 maintaining the
energetically favorable planarity of the carbonyl and thus allowing deprotonation (and
subsequent reaction) of the second ortho-phenol. This association plays a large role in
the reactivity of these compounds, and was necessary to acknowledge and account for
when designing synthetic strategies for the construction of rottlerin.
Scheme 3: Synthesis of Iodochromane 11
OMOM
11
a. MOMCI, DBU, DMF; b. PrenylBr, NaH, DMF; c. N'.N'-diethylaniline, heat;
d. MeOH pretreated w/l 2 ; e. I2, DMF.
22
The next synthetic operation was the O-prenylation 118 of compound 7 to give
compound 8, which was followed by a para-Claisen rearrangement 119120 to afford 9. The
selective deprotection106 of 9 did not initially proceed as planned: when the substrate
was dissolved in methanol and then charged with iodine as outlined in the original
method for this selective deprotection, we observed not only deprotection but also
iodine (and methoxide) incorporation presumably via the nucleophilic attack of the
prenyl double bond on diatomic iodine. This adverse side reaction was able to be
avoided by allowing h to mix in methanol overnight, presumably consuming the iodine
to form the trace amounts of HI attributed as the active catalyst in this transformation,
and then adding substrate 9. In this manner, we were able to synthesize 10. The earlier
observation, however, led us to believe that the dihydropyranyl ring could be formed in
a similar fashion, by allowing 10 to react with I2 in a non-nucleophilic solvent; this
method indeed worked to generate compound 1 1 .
It was at this point that we reached an impasse, as conversion of 11 to the
desired chromene 13MOM proved difficult. Literature procedures for reactions of this
type rely on base initiated elimination of the homobenzylic iodide,118-121 but these
methods proved fruitless for our substrate. When exposed to sodium hydroxide in an
alkanol,121 spectroscopic analysis revealed complete conversion to an alkoxy containing
compound (shown to be 12) and no evidence of an alkene. This mystified us, as the
elimination of 11 should have proceeded much faster under these conditions than the
23
direct nucleophilic substitution of this substrate. Thus, in an effort to avoid any
substitution, a non-nucleophilic base (DBU) was used in anhydrous solvents;118 the
resulting product mixture contained two largely inseparable alkene products which
were identified using 2D J H NMR as 13MOM and 14. The unexpected product 14 (as
well as the previously obtained 12) could be the result of a base assisted rearrangement
of 11 which is not unanalogous to a Cope rearrangement.
Scheme 4: Difficulties w i t h HI Elimination of Iodochromane 11
°<Y^
RO
0^i^
0 H
YY
OMOM
12
R = CH 3 (12Me),
CH2CH3(12Et)
°^
a
HCX/L^O^/
°V^
b
y^-i
HCX^X^CU
y^
OMOM
11
OMOM
13MOM
^^°
p
OMOM
14
a. NaOH, ROH, reflux, 5h; b. DBU, toluene, 80°C.
This setback deemed that an alternative route to 13 be established. Utilizing a
phenylboronic acid mediated methodology, 6264 we were able to synthesize 13MOM,
albeit in relatively low yield. This substrate was easily converted into the chalcone
(16MOM),74"77 a watermelon Jolly Rancher red colored compound which we were able
to unambiguously identify by obtaining the crystal structure. The low yield of the
chromene forming reaction, however, rendered this route somewhat unacceptable in our
opinion, and thus other options were pursued.
24
Scheme 5: Synthesis of Chromenochalcone 16MOM
HO^/^/OH
a
H<X^L^OMOM
K^
b
H O ^ / ^ ^OH
53%
OMOM
OMOM
13MOM
OMOM
16MOM
a. MOMCI, DBU, DMF; b. I2, MeOH; c. PhB(OH)2, propionic acid, 3-methyl-2-butenal,
toluene, reflux; d. benzaldehyde, aq. NaOH, EtOH.
It was at this point that we began to explore the possibility of performing the
uncatalyzed, neutral, microwave-assisted condensation of 3-methyl-2-butenal with
phenols to form 2,2-dimethyl-2i1f-chromenes (specifically 13). Microwave irradiation
has seen an increased use in organic synthesis in recent years, as it can serve to excite
molecules which absorb at this frequency in a mixture without necessarily globally
affecting the thermal environment of the reaction.122125 While the reaction of 15 under
these conditions initially provided product in yields similarly low to the phenylboronic
acid protocol, we were able to obtain 13TBS from 18 (obtained in two steps from 2 in a
similar manner to the synthesis of 15) in a gratifyingly high yield. The aqueous base
sensitive nature of the TBS-protected phenol deemed that anhydrous conditions be
employed for the aldol condensation, which yielded 16TBS bountifully.
25
Scheme 6: Synthesis of Chromenochalcone 16TBS
OTBS
OTBS
16TBS
13TBS
a. TBSCI, DBU, CH2CI2; b. ultrasound, CCI4, MeOH;
c. 3-methyl-2-butenal, CDCI3, microwave; d. LiHMDS, benzaldehyde, THF.
Unfortunately, the linkage of either 16MOM or 16TBS with either 6Et2 or 6PIP
was not able to be initiated under a variety of conditions. Largely, no reaction at all was
instigated. An interesting observed product was 5, presumably formed via a reverse
Mannich reaction of the 6 compounds. The linkage of 5 with 19 (formed by a Mannich
reaction of 13TBS) was also attempted to no avail. A scouring of the literature was
unable to reveal a precedent for formation of OQMs when the aryl ring is also
substituted with an electron withdrawing orffro-ketone (or aldehyde), which led us to
believe that this moiety was potentially problematic in the formation of the requisite
OQM intermediate.
26
Scheme 7: Failed Linkage Attempts of A d v a n c e d Intermediates
HO.
HO^L^OH
I
a
+
OR
OTBS
HO
OTBS
R2 = (CH2CH3)2 (6NEt2),
(CH2)5(6PIP)
OR
R = TBS (16TBS),
MOM (16M0M)
OH
20
a
OTBS
HO^J^OTBS
^ *
'
OH
21
a. CDCI3, microwave.
Scheme 8: Synthesis of Chromenyl OQM Precursor 19
O^ s
O?
quant.
OTBS
OTBS
13TBS
19
a. Et2NH, CH 2 0, MeOH, reflux.
A revised retrosynthetic analysis led us to desire the assembly of 26 followed by
its linkage with 15 to give advanced methylene-bridged biphenol intermediate 27,
which could then be further elaborated to rottlerin (1). It was determined that the
conditions for installation of the methyl ketone126 could cause undesired decomposition
27
of the labile chromene ring, and thus 15 would be linked with 26 to form 27 before
incorporation of the chromene (followed by the aldol condensation).
Scheme 9: Retrosynthesis 2, from A d v a n c e d Intermediate 27
HO. ^ k
.OH
O^OH
R'O
°"Q _= "VV»
V
OH
22
Trihydroxybenzoic acid 22 was first protected to give acetonide ester 23, 127 and
subsequent masking of the two remaining free phenols was performed with a variety of
protecting groups. 128 Initially, a non-methylene oxyalkyl protecting group (TBS) was
investigated. We found the aldol condensation of phloroacetophenone (and related
structures) to occur much more quickly with each subsequent protection of the phenols.
Since two methyl ketones would be present at the time of chalcone formation, we sought
to gain selectivity in this reaction by liberating the phenols on the ring possessing the
ketone we did not wish to functionalize. Unfortunately, the conditions to reduce the
ester129130 effected almost complete liberation of the phenols as well. The SEM protecting
group, which can be selectively removed by fluoride,131 was then used, and provided
25SEM in good yield; subjecting this to Mannich conditions 108 afforded 26SEM.
28
Scheme 10: Synthesis of OQM Precursor 26
OH
a
HO^J^O
78%
\
j
b
^
RO^^A^O
61-98%
OH
23
R = TBS (24TBS), SEM (24SEM),
EOM (24EOM), MOM (24MOM)
0 H
58-100%
\
J
^
^ N
°luant-
OR
OR
25
26
R = SEM (25SEM), EOM (25EOM),
R = SEM (26SEM),
MOM (25MOM)
MOM (26MOM)
a. acetone, trifluoroacetic acid, trifluoroacetic anhydride; b. RCI, base;
c. Red-AI, toluene, reflux; d. CH 2 0, piperidine, MeOH, reflux.
Linkage of 15 and 26SEM was induced via microwave irradiation, producing
27MS. It was then frustrating when application of the previously developed chromene
forming method did not display any evidence of the formation of 28MS. Monte Carlo
conformational analysis of 27MS performed by Hemraj Juwarker 132 using
MacroModel 133 correlated with suspicions that a series of intramolecular hydrogen
bonds was rendering the phenolic -OH critical to chromene formation unavailable for
reaction, as it is involved in a hydrogen bond with the orfAo-ketone. The same
modeling parameters applied to 32MS, however, seemed to indicate that the steric bulk
of the conjugated phenyl ring would favor hydrogen bonding of the ketone to the other
cxrt/io-hydroxy substituent, thus freeing the desired phenol for chromenylation.
29
Scheme 11: Successful Linkage of 15 and 26SEM
SEMO
SEMO
OSEM
OS EM
27MS
28MS
a. microwave, CDCI3; b. 3-methyl-2-butenal, microwave, CDCI3.
b~y
,Si
o—
^^/O^-O.
CL ^O
Figure 16: Models of 27MS and 32MS
30
27MS
Attempted aldol condensation of 27MS progressed extremely slowly, most
likely due to the presence of two free phenols on the ring, which, especially after
deprotonation, adds a significant amount of electron density to the ring, thus decreasing
the electrophilicity of the carbonyl carbon.134 Additionally, the basic conditions of the
aldol resulted in the transformation of any formed chalcone products to the flavanone
(29),82 which was isolated, albeit in low yield.
Scheme 12: A t t e m p t e d A l d o l C o n d e n s a t i o n of 27MS w i t h B e n z a l d e h y d e
HO. J l .OH
OMOM
SEMO^L.OH
HO. A . . 0
a
^ SEMO
OSEM
OSEM
27MS
29
a. benzaldehyde, aq. NaOH, EtOH.
This led to the idea that perhaps installing the chalcone moiety prior to linkage
would be the optimal way to assemble 32MS. Chalcone 31 MOM was accessed in two
steps from previously synthesized 7 via aldol condensation followed by selective
deprotection, but all trials to link 31MOM with 26SEM were thwarted, as none of the
desired product was observed under the attempted conditions.
31
Scheme 13: Retrosynthesis 3, from Advanced Intermediate 32
R'O
Scheme 14: Synthesis of 31 MOM, Attempted Linkage with 26SEM
HCLxL/OMOM
50%
OMOM
31 MOM
OSEM
32MS
a. benzaldehyde, aq. NaOH, EtOH; b. I2, MeOH; c. 26SEM, microwave, CDCI3.
Attention was then focused back on 13MOM as a potential linking partner for
26SEM to give the ketone lacking rottlerin precursor 28. While classic installation of
the ketone would be incompatible with the chromene subunit, alternative routes were to
32
be pursued if 28MS could be obtained. But, once again, conditions could not be found
to enable the conjoining of these two compounds.
Scheme 15: Retrosynthesis 4, from Advanced Intermediate 28
HO.
^OH
I?
••>
i
OH
2
0,
R'O
0 H
V
R'O
HO.
s
J
1^r
Y
OR'
28
^OH
OH
9
Scheme 16: Attempted Linkage of 13MOM and 26SEM
0.
SEMO
a
SEMO
OSEM
26SEM
OMOM
13M0M
OSEM
28MS
a. Attempted conditions: microwave in CDCI3; K 2 C0 3 , acetone, reflux;
K 2 C0 3 , DMF, reflux; NaH, DMF, reflux.
Chromene 13MOM displayed a low level of aryl nucleophilicity, perhaps due to
the tight hydrogen bond between the phenolic hydrogen and the ketone oxygen.111113 In
an attempt to increase the electrophilicity of 26SGM the ammonium iodide salt (33) was
33
made; 97 linkage trials with this substrate were also unfruitful. In an effort to increase
the nucleophilicity of 13MOM, deprotection to give 34 was performed,135 but it
unsurprisingly decomposed under the linkage conditions, as chromenes with highly
electron rich aryl rings are known to be unstable. 136137
Scheme 17: Attempted Synthesis of 28MS via A m m o n i u m 33
o.
HO
SEMO
SEMO
b
SEMO
OSEM
26SEM
OSEM
28MS
a. Mel, MeCN; b. 13MOM, NaH, DMF.
Scheme 18: A t t e m p t e d Synthesis of 28HS via Chromene 34
O.
HO
^f
SEMO
OMOM
13MOM
OSEM
28HS
a. 3N HCI, MeOH, reflux; b. 26SEM, microwave, CDCI3.
Since it was eventually going to be necessary to tack on a ketone to one of the
aryl subunits of rottlerin (1) using our current approach, we felt that omitting the methyl
ketone from the other subunit could easily be rectified later, and that this approach
34
could perhaps lead to successful linkage of the two units with the chromene already
assembled. Additionally, we were now able to use traditional methylene oxyalkyl
protecting groups (EOM, MOM) on both rings: once the ketone installation on both rings
was performed, selective ortfjo-deprotection of these groups to give 40 would result in
the unmasking of all three phenols on the ring which we did not wish to perform the
aldol on; this would render the ketone on this ring unreactive to this method, allowing
for the selective aldol condensation of the desired ketone exclusively.
Scheme 19: Retrosynthesis 5, from A d v a n c e d Intermediate 40
40
39
OR'
25
Accordingly, 36 was synthesized in two steps from acetonide 23 by using the
previously developed chromene methodology followed by MOM protection of the free
phenol. Partial reduction of acetonide ester 36 to aldehyde 37MOM was
accomplished, 1 3 8 b u t a t t e m p t e d Mannich-type linkage 101 - 139 of 3 7 M O M w i t h 2 5 E O M
resulted disappointingly in irreversible decomposition of the chromene.
35
Scheme 20: Synthesis of C h r o m e n o a l d e h y d e 37MOM
0^0.
H./O
o^cx
.0
?
.0
H0X
a
b
MOMCl^/0
c
MOMO.
f l *
\
55%
OH
23
V
[1
87%
fi
20%
.0
35
36
37MOM
a. 3-methyl-2-butenal, CDCI3> microwave; b. NaH, MOMCI, DMF; c. DIBAL, CH2CI2.
Scheme 21: A t t e m p t e d Linkage of 25EOM and 37MOM
HO.
H./O
EOMO
OH
MOMO
+
EOMO
OEOM
25EOM
OEOM
37MOM
38
a. piperidine, MeOH, reflux.
Efforts were now directed towards linkage of the two aryl species (specifically 25
and 41) prior to assembly of the chromene, which would then be constructed at a later
time. Reduction of 24MOM to give 41 MOM was performed, but the attempted
Mannich style linkage of this substrate to 25EOM proved futile, as starting materials
were recovered in full; this reaction failed most likely due to the inability of the
relatively electron rich aldehyde to form the intermediate iminium species.
36
Scheme 22: Retrosynthesis 6, from A d v a n c e d Intermediate 45
R'O
1
i
OR'
Scheme 23: Synthesis of 41MOM, A t t e m p t e d Mannich-Type Linkage w i t h
25SEM
cca
HO.
a
—
99%
OMOM
24MOM
MOMCL/L.OH
TJ
\ ^
OMOM
41 MOM
b
-*~
OMOM
OMOM
,OH
SEMO
OSEM
42
a. DIBAL, CH2CI2; b. 25SEM, piperidine, MeOH, reflux.
Next, a literature encouraged palladium-catalyzed reductive tethering 102 of the
25EOM and 41MOM was investigated, but it did not provide 43ME, instead resulting
in a mixture of undesired products. The direct reduction of 24MOM to the benzyl
alcohol was regrettably unable to be performed, as only polymerized product
(presumably via the OQM formed in situ) was observed. Thus, a reductive amination 140
of 41MOM was performed, providing 44MOM in quantitative yield; this substrate,
however, proved impervious to linkage with 25EOM.
37
Scheme 24: A t t e m p t e d Linkage of 25EOM and 41MOM
HCX / ^
H
OH
EOMO
^o
MOMO./L/OH
+
| l j
OEOM
25EOM
^OMOM
a
X ' EOMO
OMOM
41 MOM
OMOM
OH
OEOM
43ME
a. Pd/C, H2, MeOH.
Scheme 25: Synthesis of 44MOM, A t t e m p t e d Linkage w i t h 25EOM
OMOM
MOMO^ ^
^OH
a
MOMO
b
EOMO
quant.
OMOM
41 MOM
OMOM
44MOM
OMOM
OH
OEOM
43ME
a. benzylamine, molecular sieves, MeOH, then LiBH4; b. 25EOM, microwave, CDCI3.
We then decided to reexplore the one successful linkage we were able to
perform, which was benzyl amine 26 with mono-protected phloroacetophenone 15 to
afford 27. While previously we attempted to install the chromene at this juncture, this
time we wished to attach the missing ketone moiety to give 45, which would be further
elaborated by first forming the chromene ring, and then selectively deprotecting the two
MOM-protected phenols ortho to the ketone to give 40.
38
Scheme 26: Retrosynthesis 7, from A d v a n c e d Intermediate 40
^OJ
.OH
R'O
OH
40
OR'
OR'
45
27
Before beginning the resynthesis of 27, the feasibility of this route was probed by
attempts to acetylate test compound 25MOM. Unfortunately, acetylation was not able
to be effected under relatively mild conditions, instead resulting in the decomposition of
the MOM group, and presumed subsequent polymerization due to the generation of a
formaldehyde equivalent from the MOM degradation. This finding effectively rendered
the idea of installing the ketone moiety after linkage of the two aryl subunits
unapplicable, which unfortunately meant that the only successful biphenolic linkage we
had performed could not serve as an intermediate for the first total synthesis of rottlerin.
Scheme 27: Failed Acetylation of Model C o m p o u n d 25MOM
OMOM
OMOM
a
OMOM
'
OMOM
25MOM
46
a. Bi(OTf)3, acetic anhydride, toluene OR ZnCI2, acetic acid.
39
2.2 Rottlerin Epilogue
The previous section details all work done towards the first total synthesis of
rottlerin up to April 7, 2008, when this dissertation was successfully defended. From the
following day until April 23, much effort was put forth towards the synthetic pursuit of
rottlerin. I was optimistic about one particular option: the reductive coupling of aryl
aldehydes with phenols to yield methylene-linked biphenols elucidated by Boyer and
Ducrot.102 My attraction to this method was rooted in the fact that the linkage is believed
to proceed not through an orfhoquinone methide intermediate (the formation of which
using ketone bearing phenols we had already abandoned), but rather by a palladium
assisted addition of the phenol to the aldehyde.
The paper by Boyer and Ducrot which unveiled this method of generating
methylene-linked biphenols did not utilize any ketone bearing substrates, but they did
mention, as almost an afterthought, that "the same conditions tested on various
acetophenones unfortunately gave no satisfactory results". While that statement could
be interpreted in a number of ways, I saw in it encouragement that perhaps a phenolic
ketone would be impervious to this reaction protocol despite the clear susceptibility of
phenolic aldehydes to this kind of manipulation.
My plan to utilize this methodology was to synthesize a protected
formylphloroacetophenone (48) and then use the Boyer-Ducrot method to reductively
link this compound with methylphloroacetophenone (4). After tethering the two aryl
40
subunits, the two orf/iophenols would be liberated through either the previously
utilized b/MeOH method 106 if MOM was the protecting group, or by the use of a
protecting group for R'/R" which could be orthogonally deprotected with respect to the
MOM group. From there, chromenylation would occur on the solitary unsubstituted
aryl carbon (and the corresponding ortho-phenol) to give 47. Aldol condensation with
benzaldehyde followed by MOM-deprotection would then yield rottlerin.
Scheme 28: Rottlerin Retrosynthesis 8
OMOM
HCL^k^OH
oJCX
OH
1
I
OH
"7
rottlerin
Several mono- (R"=H) and bis-protected (R'=R") variants of 48 were synthesized
and, frustratingly, an equal number of fruitless attempts at the linking reaction were
performed. My original thought was that by protecting as many phenols as possible I
would increase the electrophilicity of the aldehyde carbon, thus facilitating the addition
of 4 to it, the presumed first step in the desired reaction. Based on observed
phenomena, it would seem that this is faulty logic; thus I decided to try 48HH as a
participant in this reaction.
41
Scheme 29: Synthesis of U n p r e c e d e n t e d Ketopolyphenol Heterodimer 50
X
0
^
OH
OMOM
15
a
55%
H
HO./L.OH
N ^ ^
O
H0
- ^ -0H
°y^
HO^l/OH +
/ ^ ^
b
OMOM
48HH
OMOM
49
OMOM
HO^ J \ JDH
O^
45%
21%
a. POCI3, DMF, EtOAc; b. 4, Pd/C, H2, MeOH.
The initial step along this synthetic route was by no means a trivial one, as
formylation using the Vilsmeier-Haack reagent141 had long been an enigmatic reaction
for me. Nevertheless, 48HH was obtained in this manner in 55% yield from the
previously synthesized protected phloroacetophenone 15. On April 20, my remaining
96 mg of 48HH, which required a time consuming three steps to synthesize from the
commercially available phloroacetophenone (2), was exposed to these reaction
conditions for the first time. Much to my delight, the crude *H NMR seemed to indicate
the presence of three species only: 49 (isolated in 45%), 50 (21%), and unreacted
methylphloroacetophenone (4). The successful synthesis of 50 not only represented my
first successful attempt at the synthesis of a methylene-linked ketopolyphenol
heterodimer, but several searches on SciFinder correlated with my suspicions that a
substrate such as this (methylene-linked ortho and/or para polyoxygenated ketobenzene
heterodimer) had in fact never been previously synthesized. It is also important to note
42
that the Boyer-Ducrot paper clearly demonstrates that the ratio of the addition followed
by deoxygenation product {e.g. 50) to the straight deoxygenation product {e.g. 49) can
be easily tailored by manipulating the concentration of the solution, indicating that the
yield of this reaction is potentially ripe for optimization.
Using microwave irradiation to synthesize 2,2-dimethyl-2Jc/-chromenes had been
a bountiful endeavor for me with certain substrates, but the presence of a MOM
protecting group often proved problematic, resulting in the creation of undesired side
products I believed to be polymers forming from the decomposition of the MOM group,
yielding formaldehyde, which is well documented to polymerize with phenols.142
Accordingly, I decided to attempt a more traditional, hopefully less risky method for the
direct synthesis of 2,2-dimethyl-2ff-chromenes from phenols: refluxing the phenol in
pyridine with 3-methyl-2-butenal overnight. 58 This April 20 effort, however, resulted in
the complete irreversible decomposition of 20 of the 34 mg of advanced rottlerin
intermediate 50.
With 14 mg left on April 21,1 decided to try the microwave methodology. In
order to not volatilize the solvent completely and risk overheating of the precious
compound 50, the solvent volume was set to 1 mL and the amount of 3-methyl-2butenal was scaled up to keep the same effective concentration. While the crude J H
NMR indicated the presence of two distinct chromene products, the only compound I
was able isolate from this small scale reaction was unexpectedly a fully deprotected
43
chromene, either 5 1 A or 51B, in a quantity of approximately 2 mg. Given the small
amount of material, disambiguation of the product was not possible.
Scheme 30: Synthesis of A d v a n c e d Linked Chromene Intermediate 51
HCX J ^ .OH
HO
OMOM
OH
HO^ / L ^(X /
15%
OH
OH
HO.
I
OH
H(X ^
.OH
OR
51A
HO
I
OH
51B
a. 3-methyl-2-butenal, MeOH, microwave
While this put me possibly (if the product was 51 A) only one step away from the
first total synthesis of rottlerin, the potential for the success of that step was low. One
point of concern was that chromenes which contain free phenols on the same aryl ring
can be unstable compounds. 136137 A second worry was that the free phenol on the
chromene ring would be deprotonated under the basic conditions of the reaction and
inhibit the formation of the enolate needed for the aldol condensation by further
donating electron density to the carbonyl carbon.134 Finally, the amount of material was
minimal, so again I decided to increase the amount of solvent to a volume which would
not evaporate over the extended time required for the reaction, and appropriately
scaling the reagents. Nevertheless, I had not choice but to try; on April 22, try I did.
Spectroscopic and chromatographic analysis of the reaction mixture was
complicated by the fact that not only was there a 40-fold excess of benzaldehyde to start
44
with, but under the basic conditions of the reaction it undergoes a Cannizaro
disproportionate 1 4 3 to yield final reaction contaminants benzyl alcohol, benzoic acid,
and unreacted benzaldehyde. The reaction mixture was concentrated and then partially
purified by column chromatography. Selected fractions containing mixtures that
displayed promising peaks in crude 1H NMR spectra were concentrated and further
purified using preparative thin layer chromatography (TLC). Despite my best efforts, I
was unable to isolate any compound with chromenochalcone features.
Scheme 31: Unsuccessful A l d o l C o n d e n s a t i o n to Potentially Give Rottlerin
a. benzaldehyde, 20% aqueous NaOH, EtOH.
With no significant amount of any relevant intermediates, and this document
unfinished, the looming April 25 submission deadline meant the hope of completing
rottlerin in time for inclusion in this dissertation was not possible. The events in the
days preceding the final preparation of this document, however, provide significant
optimism for the use of this route to accomplish the first total synthesis of rottlerin.
45
2.3 Experimental and Spectral Data
General Experimental Considerations: ID NMR spectra were recorded on
a Varian Unity INOVA-400 or -300 spectrometer. Proton and carbon spectra were
acquired at 400 and 101 MHz, respectively, unless otherwise noted. Data for the nOe
experiment was collected at 500 MHz on a Varian Unity INOVA-500 spectrometer.
Chemical shifts are reported in ppm (8) relative to the solvent peak (CHCk in CDCb at
7.24 ppm for *H spectra, and 77.23 ppm for 13C spectra). Mass spectra were recorded on
a JEOL-SX102 mass spectrometer run as indicated under FAB (using xenon as the gas),
ESI (using nitrogen as the gas), or EI mode at 10 kV. Infrared spectra were determined
on a Nicolet Avatar 360 FT-IR spectrometer. Microwave reactions were run in 10 mL
sealed cap microwave reaction vessels in CEM Discover chemical synthesis microwaves
(S-Class and LabMate Series). Commercially available reagents and solvents were used
as purchased. For reactions which necessitated anhydrous conditions, solvent was
obtained from either a sealed anhydrous commercially available bottle or from an
automated still. Isolated compounds were purified using flash column chromatography
on silica gel (SiliCycle, 230-400 mesh).
46
Synthesis of 3-Acetyl-2,4,6-trihydroxy-benzaldehyde (3):
In an adaptation of the procedure of Yoneyama et al.,103 to 840 mg (4.5 mmol) of
phloroacetophenone (2) monohydrate in a 100 mL round-bottomed flask was added 35
mL of nitrobenzene and 2 g (5 mmol) of AlCb. This mixture was allowed to stir at room
temperature before being cooled in an ice bath to 0°C. Trimethyl orthoformate (2.7 mL,
15 mmol) was then added dropwise over 10 minutes, and the solution was allowed to
stir at 0°C for 1.5 hours. The reaction was then poured into 50 mL of 3M aqueous
NaOH. The aqueous mixture was washed with 30 mL of dichloromethane, and then
acidified using 3M aqueous HC1. This suspension was then extracted with three 50 mL
portions of EtOAc (and sparing amounts of acetone to assist with solubility), which were
combined, washed with 50 mL of brine, and finally dried over MgSCk. After filtration
and concentration, 815 mg of 3 (4.16 mmol, 92%) was obtained; J H NMR 6 9.89 (s, 1H),
5.78 (s, 1H), 2.53 (s, 3H).144
47
Synthesis of l-(2 / 4,6-Trihydroxy-3-methyl-phenyl)-ethanone (4):
HO.. J^
^OH
H(X ^
^OH
In an adaptation of the procedure of Hossain,104 a suspension of mossy zinc (300
mg) and HgCk (30mg) in HC1 (0.1 mL) and water (1 mL) in a 10 mL round-bottomed
flask was stirred at room temperature for 10 minutes. The acidic water was decanted
off, and the remaining solid was rinsed three times (via decanting) with 1 mL portions of
water. To the solid was then added 0.5 mL of water and 0.5 mL of HC1, followed by 147
mg (0.75 mmol) of 3 in 1.5 mL of MeOH. The reaction mixture was refluxed vigorously
for 15 minutes, and after cooling, filtered through a Buchner funnel using three 3 mL
portions of MeOH to rinse the solid. The filtrate was concentrated and purified via flash
column chromatography using 3:1 EtzO.hexane to obtain 113.7 mg (0.624 mmol, 83%) of
4 (Rf = 0.29); J H NMR 6 5.93 (s, 1H), 2.57 (s, 3H), 1.91 (s, 3H).145
48
Synthesis of l-[4-(terf-Butyl-dimethyl-silanyloxy)-2 / 6-dihydroxy-3-methylphenyl]-ethanone (5):
>rO^
%
-
H
0
^
0
H
T<
To a flame-dried 10 mL round-bottomed flask under an atmosphere of argon was
added 22 mg (0.122 mmol) of 4 and 1.5 mL of dichloromethane. The flask was cooled to
0°C, and then 0.055 mL (0.366 mmol) of DBU was added via syringe. After stirring for 5
minutes, 55 mg (0.366 mmol) of TBSC1 was added, and the resulting mixture was
allowed to stir to room temperature over a period of 2 hours. The solution was diluted
with 5 mL of dichloromethane and then washed with two 5 mL portions of water and
5mL of brine. The organic layer was dried over MgSCk, filtered, and concentrated. The
resulting solid was then dissolved in 1 mL of MeOH, and to this solution was added 1
chip of I2. After stirring at room temperature for 28.5 hours, the solution was treated
with 5 mL of a 1M aqueous solution of Na2S203. The mixture was extracted twice with 5
mL portions of dichloromethane. The combined organic layers were washed with 5 mL
of brine and then dried over MgSQi. After filtration and concentration, flash column
chromatography using 4:1 hexane:EtOAc gave 21.5 mg (0.0725 mmol, 65%) of 5 (Rf =
0.4); *H NMR 5 5.83 (s, 1H), 2.67 (s, 3H), 1.99 (s, 3H), 0.98 (s, 9H), 0.22 (s, 6H); 13C NMR 6
203.92,162.04,160.64,159.65,107.53,105.64, 98.77, 33.12, 25.85,18.50, 8.27, -3.96.
49
Synthesis of l-[4-(fer^Butyl-dimethyl-silanyloxy)-3-diethylaminomethyl-2,6dihydroxy-5-methyl-phenyl]-ethanone (6NEt2):
17 5
6NEtL
In an adaptation of the procedure of Omura et. al.,m to a 25 mL round-bottomed
flask was sequentially added 106.5 mg (0.36 mmol) of 5, 4 mL MeOH, 0.041 mL (0.4
mmol) of diethylamine, and 0.032 mL (0.4 mmol) of a 37% solution of formaldehyde in
water. The reaction mixture was refluxed under an atmosphere of argon for 2 hours,
and afforded 6NEt2 in quantitative yield after concentration; *H NMR 6 3.68 (s, 2H), 2.64
(s, 3H), 2.59 (q, / = 7.2, 4H), 1.92 (s, 3H), 1.06 (t,/= 7.2, 6H), 0.99 (s, 9H), 0.12 (s, 6H); 13C
NMR 5 204.67,162.95,162.83,158.22,106.94,106.41,102.96, 51.31, 50.60, 45.69, 33.06,
26.10,18.78,10.80, -2.94; LRMS (FAB) m/z calculated for C2oH35N04Si 381.2335 (M+),
found 381.24 (M+).
50
Synthesis of 1- [4-(
fer£-Butyl-dimethyl-silanyloxy)-2,6-dihydroxy-3-methyl-5-
piperidin-l-ylmethyl-phenyl]-ethanone (6PIP):
In an adaptation of the procedure of Omura et. al.,m to a 25 mL round-bottomed
flask was sequentially added 105 mg (0.35 mmol) of 5, 4 mL MeOH, 0.039 mL (0.39
mmol) of piperidine, and 0.031 mL (0.39 mmol) of a 37% solution of formaldehyde in
water. The reaction mixture was refluxed under an atmosphere of argon for 1 hour, and
afforded 6PIP in quantitative yield after concentration; *H NMR 5 3.62 (s, 2H), 3.10 2.79 (m, 2H), 2.67 (s, 3H), 1.94 (s, 3H), 1.62 (s, 6H), 1.01 (s, 9H), 0.13 (s, 6H); 13C NMR 6
204.66,163.04,162.18,158.23,106.93,106.78,102.76,56.22, 53.59, 33.21, 26.31, 25.74, 24.03,
18.88, 9.86, -2.84; LRMS (EI) m/z calculated for C2iH35N04Si 393.2335 (M+), found 393.26
(M+).
51
Synthesis of l-(2-Hydroxy-4 / 6-bis-methoxymethoxy-phenyl)-ethanone (7):
HO. A . ^
.0.
In an adaptation of the procedure of Kumazawa et. a/.,110 a 50 mL roundbottomed flask under an atmosphere of argon was charged with 250 mg (1.34 mmol) of
phloroacetophenone (2) monohydrate and 8 mL of DMF. To this was added 0.622 mL
(4.16 mmol) of DBU in 4 mL of DMF dropwise over 5 minutes via syringe, and the
solution was allowed to stir at room temperature for 2 hours. Then, 0.248 mL (3.28
mmol) of MOMC1 in 4 mL of DMF was added via syringe dropwise over 10 minutes,
and the reaction was stirred at room temperature for 14.5 hours, at which time it was
dumped into 25 mL of a saturated aqueous solution of NH4CI. This was then extracted
three times with 25 mL portions of EtOAc, and the combined organic layers were
washed with 25 mL of saturated aqueous NH4CI and then 25 mL of brine, and finally
dried over MgSCk. After filtration and concentration, flash column chromatography
using 9:1 CHCkEtOAc afforded 245 mg (1.16 mmol, 87%) of 7 (Rf = 0.65); »H NMR 6 6.21
(d, / = 2.4,1H), 6.20 (d, / = 2.4,1H), 5.21 (s, 2H), 5.12 (s, 2H), 3.48 (s, 3H), 3.43 (s, 3H), 2.61
(s, 3H).110
52
Synthesis of l-[2,4-Bis-methoxymethoxy-6-(3-methyl-but-2-enyloxy)-phenyl]ethanone (8):
H<X A^ 0 \^°\
^ ^^ -°- ^ -°- -°^
7
8
In an adaptation of the procedure of Vatele,118 to a flame-dried three-necked 100
mL round-bottomed flask fitted with two addition funnels under an atmosphere of
argon was added 167 mg (4.18 mmol) of NaH (60% in mineral oil) and then 10 mL of
DMF. The flask was cooled to 0°C, and 976.6 mg (3.8 mmol) of 7 in 15 mL of DMF was
then added dropwise over 10 minutes via one of the addition funnels. After allowing
the mixture to stir for 20 minutes, 0.482 mL (4.18 mmol) of prenyl bromide in 5 mL DMF
was added dropwise via the other addition funnel. The ice bath was then removed, and
the reaction mixture was allowed to stir for 3.5 hours, at which point it was dumped into
30 mL of ice water. The solution was extracted three times with 30 mL portions of
EtOAc, and the combined organic layers were washed with 30 mL of brine and then
dried over MgSC>4. After filtration and concentration, 8 was obtained in quantitative
yield, contaminated with mineral oil. This mixture was used without further
purification; ] H NMR 6 6.41 (d, / = 2.0,1H), 6.29 (d, / = 2.0,1H), 5.38 (t, / = 6.6,1H), 5.12
(s, 2H), 5.10 (s, 2H), 4.47 ( d , / = 6.6, 2H), 3.45 (s, 3H), 3.43 (s, 3H), 2.44 (s, 3H), 1.73 (s, 3H),
1.68 (s, 3H); 13C NMR 6 201.86,159.72,157.41,155.42,138.08,119.54,116.54, 96.21, 95.27,
94.98,94.64, 65.81,56.47, 56.31, 32.68, 25.88,18.39,146
53
Synthesis of l-[6-Hydroxy-2,4-bis-methoxymethoxy-3-(3-methyl-but-2-enyl)phenyl]-ethanone (9):
T
In an adaptation of the procedure of Raghavan et. al.,n9 a 50 mL round-bottomed
flask was charged with 974.4 mg (3 mmol) of 8 and 20 mL of N',N'-diethylaniline. The
solution was refluxed under an atmosphere of argon for 4 hours and then, after cooling
to room temperature, diluted with 50 mL of EtOAc. This mixture was washed with
three 50 mL portions of 2M aqueous HC1, which were combined and then extracted with
50 mL of EtOAc. The combined organic layers were washed with 25 mL of 10% aqueous
NaHCCfe and then 25 mL of brine, and finally dried over MgSCk. After filtration and
concentration, flash column chromatography using 9:1 hexane:EtOAc afforded 778 mg
(2.4 mmol, 80%) of 9 (Rf = 0.15); XH NMR 612.90 (s, 1H), 6.44 (s, 1H), 5.19 (s, 2H), 5.13 (t, /
= 6.5,1H), 4.93 (s, 2H), 3.49 (s, 3H), 3.43 (s, 3H), 3.28 (d, / = 6.5, 2H), 2.68 (s, 3H), 1.74 (s,
3H), 1.66 (s, 3H); 13C NMR 5 204.09,163.68,161.79,157.33,131.81,123.19,116.39,111.20,
101.59, 99.03, 94.07,58.55,56.51, 31.62, 25.89, 23.30,18.08.146
54
Synthesis of l-[2,6-Dihydroxy-4-methoxymethoxy-3-(3-methyl-but-2-enyl)phenyl]-ethanone (10):
HO^/L.O^/0^
HO
9
10
In an adaptation of the procedure of Keith,106 in a 100 mL round-bottomed flask
was placed two chips of L and 40mL of MeOH. The resulting mixture was stirred for 24
hours, at which point 936.1 mg (2.9 mmol) of 9 was added. After stirring at room
temperature for 26.5 hours, the solution was treated with 20 mL of a 1M aqueous
solution of Na2S203. This was then extracted twice with 40 mL portions of EtOAc. The
combined organic layers were washed with 25 mL of brine and then dried over MgSCX
Filtration and concentration afforded 819 mg (2.9mmol, 100%) of 10; XH NMR 5 6.14 (s,
1H), 5.16 (s, 2H), 5.16 (t, / = 7.1,1H), 3.44 (s, 3H), 3.30 (d, / = 7.1, 2H), 2.65 (s, 3H), 1.78 (s,
3H), 1.70 (s, 3H); 13C NMR 6 204.21,161.46,161.21,160.84,134.10,122.18,108.29,106.07,
94.13, 94.05,56.46, 33.16, 26.01, 21.83,18.01.147
55
Synthesis of l-(7-Hydroxy-3-iodo-5-methoxymethoxy-2,2-dimethyl-chroman-8yl)-ethanone (11):
To a flame-dried 25 mL round-bottomed flask under an atmosphere of argon was
added 36.8 mg (0.131 mmol) of 10, followed by 2.6 mL of DMF, and finally 33 mg (0.131
mmol) of I2. After stirring at room temperature for 22.5 hours, the solution was treated
with 5 mL of a 1M aqueous solution of Na2S2Q3. This was then extracted twice with 5
mL portions of EtOAc. The combined organic layers were washed with 5 mL of brine
and then dried over MgSCX After filtration and concentration, flash column
chromatography using 3:1 petroleum ether:EtOAc provided 14.5 mg (0.05 mmol) of
starting material 10 (Rf = 0.2) and 22.1 mg (0.054 mmol, 68% based on recovered 10) of
11 (Rf = 0.6); >H NMR & 6.19 (s, 1H), 4.34 (dd, / = 5.8, 9.6,1H), 3.45 (s, 2H), 3.32 (dd, / =
5.8,17.3,1H), 3.14 (dd, / = 9.6,17.2,1H), 2.58 (s, 3H), 1.61 (s, 3H), 1.51 (s, 3H); 13C NMR 6
203.14,165.52,160.07,155.37,106.60,101.16, 94.86, 94.19, 78.39, 56.61,33.36, 31.44, 30.72,
27.90, 23.49.
56
Synthesis of l-(6-Hydroxy-4-methoxymethoxy-2-methoxymethyl-3 / 3-dimethyl2,3-dihydro-benzofuran-7-yl)-ethanone (12Me)
HCX A . ,oJ
H 3 CO
In a 10 mL round-bottomed flask was placed 51.7 mg (0.127 mmol) of 11, which
was then dissolved in 5 mL of MeOH. After adding 15.3 mg of NaOH (0.382 mmol), the
solution was refluxed gently under an atmosphere of argon for 5 hours. The solution
was cooled, diluted with 10 mL of dichloromethane, and washed twice with 10 mL
portions of a saturated aqueous solution of NH4CI. The combined aqueous layers were
extracted with 10 mL of dichloromethane. The organic layers were combined, washed
with 10 mL of brine, and dried over MgSCk Filtration and concentration gave 12Me in
quantitative yield; *H NMR 6 6.11 (s, 1H), 5.17 (s, 1H), 5.16 (s, 1H), 3.75 (dd, / = 3.1, 9.7,
1H), 3.45 (s, 3H), 3.41 (t, / = 9.7,1H), 3.30 (s, 3H), 3.26 (dd, / = 3.1, 9.7,1H), 2.56 (s, 3H),
1.53 (s, 3H), 1.44 (s, 3H); LRMS (ESI) m/z calculated for GerfeOe 311.1495 (MH+), found
311.0 (MH+).
57
Synthesis of l-(2-Ethoxymethyl-6-hydroxy-4-methoxymethoxy-3 / 3-dimethyl-2 / 3dihydrobenzofuran-7-yl)-ethanone (12Et):
H3CH2CO
0 - ^ Y °
H
\^--^sjJ
11
12Et
In a 10 mL round-bottomed flask was placed 41 mg (0.10 mmol) of 11, which
was then dissolved in 4 mL of EtOH. After adding 16.8 mg of NaOH (0.30 mmol), the
solution was refluxed gently under an atmosphere of argon for 4.75 hours. The solution
was cooled, diluted with 10 mL of EtOAc, and washed twice with 10 mL portions of a
saturated aqueous solution of NH4Q and once with 10 mL of water. The combined
aqueous layers were extracted with 10 mL of EtOAc. The organic layers were combined,
washed with 10 mL of brine, and dried over MgSQi. Filtration and concentration gave
12Et in quantitative yield; ^ NMR 6 6.09 (s, 1H), 5.16 (s, 1H), 5.15 (s, 1H), 3.80 (dd, / =
3.2, 9.7,1H), 3.52 - 3.35 (m, 3H), 3.44 (s, 3H), 3.27 (dd, / = 3.1,10.1,1H), 2.55 (s, 3H), 1.53
(s, 3H), 1.45 (s, 3H), 1.16 (t, / = 7.0, 3H).
58
Synthesis of ^(Z-Hydroxy-S-methoxymethoxy^^-dimethyl^H-chromen-S-yl)ethanone (13MOM):
13MOM
In an adaptation of the procedure of Bissada et al.,62 to a 25 mL round-bottomed
flask fitted with a reflux condenser via a Dean-Stark trap (filled with benzene) under an
atmosphere of argon was sequentially added 255.8 mg (1.2 mmol) of 15, 5 mL of
benzene, 232 mg (2.4 mmol) of 3-methyl-2-butenal, 0.027 mL (0.36 mmol) of propionic
acid, and 234 mg (1.92 mmol) of phenylboronic acid. This solution was refluxed through
the Dean-Stark trap for 19 hours. The solution was then diluted with 10 mL of EtOAc
and washed twice with 10 mL of a saturated aqueous NH4CI solution. The aqueous
washes were combined and extracted with 10 mL of EtOAc. The organic solutions were
combined and washed with 10 mL of brine and then dried over MgSCk After filtration
and concentration, flash column chromatography using 4:1 hexane:Et20 provided 120.2
mg (0.43 mmol, 36%) of 13MOM (Rt = 0.36); J H NMR 5 6.56 (d, / = 10 Hz, 1H), 6.17 (s,
1H), 5.40 (d, / = 10 Hz, 1H), 5.17 (s, 2H), 3.45 (s, 3H), 2.64 (s, 3H), 1.47 (s, 6H); 13C NMR 8
203.57,166.09,158.63,156.63,125.02,116.74,106.74,103.44, 95.08, 94.42, 78.18, 56.67,
33.40, 28.10; IR (neat) 2974.54,1610.37,1589.96,1485.61,1426.80,1364.90,1265.90,
1217.26,1157.33,1117.53,1079.29,1057.51, 954.66, 877.55, 825.91, 687.82 cm"1.58
59
Synthesis of l-[5-(ferf-Butyl-dimethyl-silanyloxy)-7-hydroxy-2,2-dimethyl-2Jy1
chromen-8-yl]-ethanone (13TBS):
0-.
13TBS
A 10 mL microwave reaction vessel was charged with 282 mg (1 mmol) of 18. To
this was added 1 mL of CDCb and then 0.15 mL (1.5 mmol) of 3-methyl-2-butenal. The
reaction vessel was flushed with argon for a period of 30 seconds before being capped.
The tube was then placed into the microwave reactor and irradiated at 300 watts for 12
minutes. After cooling, the tube was removed and the reaction mixture was
concentrated. The resulting crude product was purified by flash column
chromatography using 10:1 hexane:Et20 to afford 327.6 mg (0.94 mmol, 94%) of 13TBS
(Rf = 0.50); *H NMR 5 6.50 (d, / = 10 Hz, 1H), 5.91 (s, 1H), 5.39 (d, / = 9.6 Hz, 1H), 2.64 (s,
3H), 1.47 (s, 6H), 0.98 (s, 9H), 0.24 (s, 6H); 13C NMR 5 203.6,165.6,158.2,157.2,124.9,
117.4,106.8,105.8, 99.9, 78.2, 33.4, 28.2, 25.9,18.5, -4.1; IR (neat) 2933.29, 2860.58,1611.25,
1580.12,1480.83,1416.78,1364.78,1286.45,1264.67,1172.21,1116.82,1075.17, 889.29,
833.67, 781.67, 731.80, 683.84 cm"1; HRMS (EI) m/z calculated for CwHzsCkSi 348.1757
(M+), found 348.1759 (M+).
60
Synthesis of l-(7-Hydroxy-5-methoxymethoxy-2,2-dimethyl-2ff-chromen-8-yl)ethanone (13MOM) and l-(6-Hydroxy-4-methoxymethoxy-3,3-dimethyl-2-methylene2,3-dihydro-benzofuran-7-yl)-ethanone (14):
11
13M0M
14
In an adaptation of the procedure of Vatele,118 to a flame-dried 100 mL roundbottom under an atmosphere of argon was added 100 mg (0.246 mmol) of 11, 5 mL of
toluene, and then 0.11 mL (7.38 mmol) of DBU. The reaction mixture was heated to 80CC
and stirred at this temperature for 4.5 hours. After cooling to room temperature, the
solution was diluted with 10 mL of EtOAc and then washed twice with 10 mL portions
of ice cold 1M aqueous HC1. The aqueous washes were combined and then extracted
with 10 mL of EtOAc. The organic layers were combined and washed first with 10 mL
of 10% aqueous NaHCQ3 and then with 20 mL of brine, and finally dried over MgSOi.
After filtration and concentration, flash column chromatography using 6:1
hexane:EtOAc yielded a largely inseparable mixture of 13MOM and 14 in a ratio of 3:1
(Rf = 0.32) in quantitative yield; 13MOM: see previous synthesis for spectral data; 14: lH
NMR 6 6.17 (s, 1H), 5.49 (s, 1H), 5.24 (s, 2H), 4.73 (s, 1H), 3.48 (s, 3H), 2.60 (s, 3H), 1.49 (s,
6H); 13C NMR 5 202.38,167.27,164.11,160.31,149.67,106.07,102.91,100.21, 94.97, 94.33,
91.96, 56.81, 31.66, 28.74.
61
Synthesis of l-(2,6-Dihydroxy-4-methoxymethoxy-phenyi)-ethanone (15):
O. . 0 .
HO. J^ .OH
In an adaptation of the procedure of Keith,106 to a 25 mL round-bottomed flask
was added 762.8 mg (2.98 mmol) of 7 was added. This was dissolved in 20 mL of
MeOH, and to this solution was added 64 mg (0.25 mmol) of L. After stirring at room
temperature for 25 hours, the solution was treated with 5 mL of a 1M aqueous solution
of Na2S2(D3. This was then extracted twice with 20 mL portions of EtOAc. The combined
organic layers were washed with 20 mL of brine and then dried over MgSCX After
filtration, concentration, and flash column chromatography using 9:1 CHCkEtOAc,
337.6 mg (1.59 mmol, 53%) of 15 (Rf = 0.26) was obtained; »H NMR 5 6.02 (s, 2H), 5.07 (s,
2H), 3.39 (s, 3H), 2.60 (s, 3H).58
62
Synthesis of l-(7-Hydroxy-5-methoxymethoxy-2,2-dimethyl-2H-chromen-8-yl)-3phenyl-propenone (16MOM):
To a 50 mL round-bottomed flask was sequentially added 118.6 mg (0.427 mmol)
of 13MOM, 2 mL of EtOH, and 0.432 mL (4.27 mmol) of benzaldehyde. The reaction
mixture was cooled to 0°C, and then 2 mL of a 20% aqueous solution of NaOH was
added dropwise. The ice bath was removed, and the reaction was stirred for 28 hours.
The reaction was diluted with 10 mL of Et20 and then washed twice with 10 mL
portions of ice cold 1M aqueous HC1. The aqueous washes were combined and
extracted twice with 10 mL of Et20. The combined organic layers were washed with 10
mL of brine and then dried over MgSCX After filtration and concentration, flash column
chromatography using 5:1 hexane:Et20 afforded 113.3 mg (0.308 mmol, 72%) of
16MOM (Rf = 0.21); this material was crystallized from Et20 by slow evaporation; lH
NMR 6 8.09 (d, / = 15.7,1H), 7.76 (d, / = 15.7,1H), 7.59 (dd, / = 1.7, 7.6, 2H), 7.44 - 7.35 (m,
3H), 6.60 (d, / = 9.9,1H), 6.24 (s, 1H), 5.47 (d, / = 9.9,1H), 5.20 (s, 2H), 3.47 (s, 3H), 1.54 (s,
6H); 13C NMR 6193.19,167.05,158.88,156.09,142.55,135.77,130.32,129.16,128.47,
127.65,125.09,116.95,107.16,103.80, 95.45, 94.50, 78.21,56.74, 28.22.
63
Synthesis of l-[5-(terf-Butyl-dimethyl-silanyloxy)-7-hydroxy-2/2-dimethyl-2i-fchromen-8-yl]-3-phenyl-propenone (16TBS):
13TBS
To a flame-dried 50 mL round-bottomed flask under an atmosphere of argon was
added 171.2 mg (0.49 mmol) of 13TBS and 10 mL of THF. After the solution was cooled
to -78°C, 1.13 mL of LiHMDS (1.0 M in THF, 1.13 mmol) was added via syringe, and the
reaction mixture was stirred for 15 minutes, at which time 0.5 mL of benzaldehyde (4.9
mmol) was added, also via syringe. The reaction was stirred at -78°C for 1.5 hours, and
then the dry ice/acetone bath was removed and stirring continued for another 25.5
hours. The crude mixture was diluted with 10 mL EfeO, and then washed twice with 10
mL of ice cold 1M aqueous HC1. These washes were combined and extracted with 10
mL of Et20. The combined organic layers were washed with 10 mL of brine and then
dried over MgSQt. After filtration and concentration, flash column chromatography
using 15:1 hexane:Et 2 0 gave 170 mg (0.39 mmol, 79%) of 16TBS (Rf = 0.4); *H NMR 6
8.09 (d, / = 15.7,1H), 7.75 (d, / = 15.7,1H), 7.59 (d, / = 7.8, 2H), 7.37 (m, 3H), 6.54 (d, / = 9.9,
1H), 5.97 (s, 1H), 5.44 (d, / = 9.9,1H), 1.53 (s, 6H), 1.00 (d, 9H), 0.26 (d, 6H).
64
Synthesis of l-[4-(ferf-Butyl-dimethyl-silanyloxy)-2,6-dihydroxy-phenyl]ethanone (18) via l-[2,4,6-Tris-(terf-butyl-dimethyl-silanyloxy)-phenyl]-ethanone (17):
HO^L/OH
OH
2
^v^
°^
ex Si
17
To a flame-dried 100 m l round-bottomed flask under an atmosphere of argon
was added 1 g (5.38 mmol) of phloroacetophenone (2) monohydrate and 60 mL of
dichloromethane. To this was added 4.4 mL (29.5 mmol) of DBU via syringe. After
stirring for 5 minutes, 3.56 mg (23.6 mmol) of TBSC1 was added, and the resulting
mixture was allowed to stir for 3.5 hours. The solution was washed with two 30 mL
portions of 1M aqueous HC1. These washes were combined and extracted with 30 mL of
dichloromethane. The combined organic layers were then washed with 20 mL of brine,
and dried over MgSCk. The resulting suspension was filtered, and the filtrate was
concentrated to afford 17, which used without further purification; XH NMR 6 5.93 (s,
2H), 2.41 (s, 3H), 0.95 (s, 9H), 0.92 (s, 18H), 0.17 (s, 18H), 105
In an adaptation of the procedure of De Groot et. al,105 the resulting solid was
placed in a 500 mL round-bottomed flask and dissolved in 30 mL of MeOH and 30 mL
of CCh. The reaction mixture was subjected to ultrasonic radiation at 50°C for 13.5
hours. After concentration and flash column chromatography using 4:1 hexane:EtOAc,
65
1.3 g (4.6 mmol, 86%) of 18 (Rf = 0.33) was obtained; mp = 111.2-113.0 °C; J H NMR 5 5.91
(s, 2H), 2.72 (s, 3H), 0.91 (s, 9H), 0.18 (s, 6H); 13C NMR 6 204.8,163.8,163.6,106.0,100.3,
32.8, 25.6,18.3, -4.3; IR (neat) 3255.82, 2933.77, 2860.13, 2360.77,1626.32,1579.09,1520.11,
1405.20,1365.57,1287.24,1251.19,1173.52,1065.42,1023.67, 965.05, 831.74, 781.79, 735.66,
670.81 cm-1; HRMS (EI) m/z calculated for Cwf^CUSi 282.1287 (M+), found 282.1281
(M+)105
Synthesis of l-[5-(terf-Butyl-dimethyl-silanyloxy)-6-diethylaminomethyl-7hydroxy-2,2-dimethyl-2/f-chromen-8-yl]-ethanone (19):
0>
13TBS
To a 25 mL round-bottomed flask was sequentially added 170 mg (0.49 mmol) of
13TBS, 5 mL of MeOH, 0.55 mL (0.54 mmol) of diethylamine, and 0.044 mL (0.54) of a
37% solution of formaldehyde in water. The resulting solution was refluxed under an
atmosphere of argon for 2 hours. The crude reaction mixture was concentrated
affording 19, which was taken on as a largely pure mixture; XH NMR 6 6.62 (d, / = 9.9,
1H), 5.39 ( d , / = 10.0,1H), 3.82 (s, 2H), 3.26 - 2.94 (m, 4H), 2.63 (s, 3H), 1.72 (s, 6H), 1.47 (s,
6H), 0.98 (s, 9H), 0.24 (s, 6H).
67
Synthesis of 5,7-Dihydroxy-2,2-dimethyl-benzo[l,3]dioxin-4-one (23):
HO^ J L .OH
YY Y
HO^X.
Y
OH
22
OH
23
In an adaptation of the procedure of Dushin et. al.,127 a 250 mL round-bottomed
flask was charged with 3 g (14.6 mmol) of trihydroxybenzoic acid 22 under an
atmosphere of argon and then cooled to 0°C. To this was sequentially added 24 mL of
trifluoroacetic acid, 10 mL of trifluoroacetic anhydride, and 8 mL of acetone. The
reaction was allowed to stir slowly to room temperature over 21 hours, and then
partially concentrated. The reduced-volume solution was diluted with 100 mL of
EtOAc, and washed carefully with aliquots of saturated aqueous NaHCCfe until
generation of CCh ceased, at which point the organic layer was washed with 30 mL of
brine and then dried over MgSCX Filtration and concentration of the resulting filtrate
afforded 2.4 g (11.46 mmol, 78%) of 23; »H NMR 6 10.07 (s, 1H), 5.80 (d, / = 2.1,1H), 5.69
(d, / = 2.1,1H), 1.44 (s, 6H).148
68
Synthesis of 5/7-Bis-(terf-butyl-dimethyl-silanyloxy)-2,2-dimethylbenzo[l,3]dioxin-4-one (24TBS):
HO
°^°OH
23
24TBS
To a 25 mL round-bottomed flask under an atmosphere of argon was
sequentially added 305 mg (1.45 mmol) of 23,10 mL of dichloromethane, and 0.5 mL
(3.3 mmol) of DBU (added dropwise). After stirring for 7 minutes, 481 mg (3.2 mmol) of
TBSC1 was added, and stirring continued for 3 hours. The reaction mixture was then
diluted with 10 mL of dichloromethane and twice washed with 10 mL of ice cold 1M
aqueous HC1. The aqueous washes were combined and extracted with 10 mL of
dichloromethane. The combined organic layers were washed with 10 mL of brine and
then dried over MgSCk. Filtration and concentration of the filtrate resulted in 626.5 mg
(1.42 mmol, 98%) of pure 24TBS (Rf = 0.35 in 6:1 hexane:Et 2 0); J H NMR 6 6.02 (d, / = 2.3,
1H), 6.01 ( d , / = 2.3,1H), 1.65 (s, 6H), 1.01 (s, 9H), 0.95 (s, 9H), 0.22 (s, 6H), 0.22 (s, 6H).
69
Synthesis of 2,2-Dimethyl-5,7-bis-(2-trimethylsilanyl-ethoxymethoxy)benzo[l,3]dioxin-4-one (24SEM):
To a flame-dried 25 mL round-bottomed flask under an atmosphere of argon was
added 143 mg (3.6 mmol) of NaH (60% in mineral oil) and 7 mL of dichloromethane.
After cooling to 0°C, 300 mg (1.43 mmol) of 23 in 3 mL of DMF was added dropwise.
This was stirred at 0°C for 1.5 hours, at which point 0.530 mL (2.99 mmol) of SEMC1 was
added via syringe. This was allowed to stir slowly to room temperature over 3.5 hours
and then carefully quenched with 10 mL of water and diluted with 25 mL of EtOAc. The
water was removed, and the organic solution was washed twice with 10 mL of water.
The aqueous washes were combined, and extracted with 20 mL of EtOAc. The
combined organic layers were washed with 10 mL of brine and then dried over MgSQi.
After filtration and concentration, flash column chromatography using in 2:1
hexanerEtaO provided 587.5 mg (1.25 mmol, 87%) of 24SEM (Rf = 0.25); *H NMR 5 6.53
(d, / = 2.3,1H), 6.27 (d, / = 2.3,1H), 5.31 (s, 2H), 5.19 (s, 2H), 3.83 - 3.77 (m, 2H), 3.75 - 3.69
(m, 2H), 1.67 (s, 6H), 0.98 - 0.89 (m, 4H), -0.02 (s, 6H), -0.03 (s, 6H).
70
Synthesis of 5,7-Bis-ethoxymethoxy-2,2-dimethyl-benzo[l,3]dioxin-4-one
(24EOM):
\j?
OH
23
To a flame-dried three-necked 100 mL round-bottomed flask fitted with an
addition funnel under an atmosphere of argon was added 1.37 g (6.5 mmol) of 23 and 16
mL of DMF. Using the addition funnel, 574 mg (14.35 mmol) of 60% NaH in mineral oil
in 10 mL of DMF was added dropwise, and the resulting mixture was allowed to stir at
room temperature for 1.5 hours, at which point 1.08 mL (11.54 mmol) of EOMC1 was
added dropwise. The reaction was stirred for 22.5 hours and then diluted with 50 mL of
Et20. This solution was then washed twice with 25 mL portions of ice cold 1M aqueous
HC1. The aqueous washes were combined and extracted with 25 mL of EbO. The
organic layers were combined, washed with 25 mL of brine, and dried over MgSCk
After filtration and concentration, flash column chromatography using 1:1 hexane:Et20
afforded 1.29 g (3.96 mmol, 61%) of 24EOM (Rf = 0.25); W NMR 5 6.47 (d, / = 2.2,1H),
6.20 (d, / = 2.2,1H), 5.24 (s, 2H), 5.14 (s, 2H), 3.74 - 3.67 (m, 2H), 3.67 - 3.59 (m, 2H), 1.60
(s, 6H), 1.17-1.10 (m, 6H); 13C NMR 5 163.99,160.56,158.90,157.97,105.05, 98.71, 98.17,
97.11, 93.77, 92.98, 64.89, 64.86, 25.61,15.09,15.06.
71
Synthesis of 5 / 7-Bis-methoxymethoxy-2 / 2-dimethyl-benzo[l / 3] dioxin-4-one
(24MOM):
tr°
OH
23
To a flame-dried 100 mL round-bottomed flask under an atmosphere of argon
was added 1 g (4.76 mmol) of 23. The flask was cooled to 0°C and then charged with 18
mL of diisopropylamine followed by 1.6 mL (19 mmol) of MOMC1 dropwise. The
reaction mixture was allowed to stir slowly to room temperature over 25.5 hours and
then partially concentrated. The resulting mixture was diluted with 50 mL of EtOAc
and then washed three times with 25 mL of ice cold 1M aqueous HC1. The aqueous
washes were combined and then extracted with 25 mL of EtOAc. The organic layers
were combined, washed with 25 mL of brine, and then dried over MgSCk Filtration and
concentration afforded 874.5 mg (2.9 mmol, 62%) of pure 24MOM (Rf = 0.23 in 2:1
hexane:EtOAc); J H NMR 6 6.50 (d, / = 2.3,1H), 6.28 (d, / = 2.3,1H), 5.26 (s, 2H), 5.15 (s,
2H), 3.52 (s, 3H), 3.47 (s, 3H), 1.68 (s, 6H).
72
Synthesis of 2-Methyl-3,5-bis-(2-trimethylsilanyl-ethoxymethoxy)-phenol
(25SEM):
; S i ^ O ^ O . / k
^ I
.OH
25SEM
In an adaptation of the procedure of Boers et. al.,129 to a flame-dried 100 mL
round-bottomed flask under an atmosphere of argon was sequentially added 673 mg
(1.43 mmol) of 24SEM, 15 mL of toluene, and 2.15 mL (7.05 mmol) of Red-Al (65% in
toluene). The reaction mixture was refluxed for 2.5 hours, and then allowed to cool to
room temperature. The reaction was then cooled to 0°C, and to this was added 4 g of
wet silica. The resulting slurry was stirred for 30 minutes at 0°C and then dried over
MgSCk The suspension was filtered through a pad of celite, which was washed
thoroughly with Et20. Concentration of the filtrate gave pure 25SEM in quantitative
yield (Rf = 0.33 in 2:1 hexane:Et 2 0); 1H NMR (300 MHz, CDCb) 6 6.40 (d, / = 2.0,1H), 6.25
(d, / = 2.1,1H), 5.18 (s, 2H), 5.14 (s, 2H), 3.79 - 3.69 (m, 4H), 2.04 (s, 3H), 1.01 - 0.90 (m,
4H), -0.01 (s, 6H), -0.01 (s, 6H); 13C NMR (75 MHz, CDCb) 6 157.03,156.53,155.06,106.97,
97.28, 96.54, 93.39, 93.20, 66.43, 66.38,18.24, 8.07, -1.22; LRMS (FAB) m/z calculated for
Ci9H3605Si2 400.2101 (M+), found 400.2 (M+).
73
Synthesis of 3,5-Bis-ethoxymethoxy-2-methyl-phenol (25EOM):
24EOM
25EOM
In an adaptation of the procedure of Boers et al.,129 to a flame-dried 100 mL
round-bottomed flask under an atmosphere of argon was sequentially added 1.29 g (3.96
mmol) of 24EOM, 40 mL of toluene, and 6.12 mL (20 mmol) of Red-Al (65% in toluene).
The reaction mixture was refluxed for 3 hours, and then allowed to cool to room
temperature. The reaction was then cooled to 0°C, and to this was added 10 g of wet
silica. The resulting slurry was stirred for 1 hour at 0°C and then dried over MgSCk
The suspension was filtered through a pad of celite, which was washed thoroughly with
Et20. Concentration of the filtrate gave pure 25EOM in quantitative yield; lH NMR 6
6.41 (d, / = 2.2,1H), 6.25 (d, / = 2.2,1H), 5.18 (s, 2H), 5.13 (s, 2H), 3.75 - 3.65 (m, 4H), 2.04
(s, 3H), 1.21 (m, 6H).
74
Synthesis of 3,5-Bis-methoxymethoxy-2-methyl-phenol (25MOM):
In an adaptation of the procedure of Boers et al.,129 to a flame-dried 100 mL
round-bottomed flask under an atmosphere of argon was sequentially added 398 mg
(1.34 mmol) of 24MOM, 14 mL of toluene, and 2.06 mL (6.75 mmol) of Red-Al (65% in
toluene). The reaction mixture was refluxed for 3 hours, and then allowed to cool to
room temperature. The reaction was then cooled to 0°C, and to this was added 2.5 g of
wet silica. The resulting slurry was stirred for 30 minutes at 0°C and then dried over
MgS04. The suspension was filtered through a pad of celite, which was washed
thoroughly with Et20. Concentration of the filtrate gave 175.5 mg (0.77 mmol, 58%) of
25MOM; JH NMR 5 6.38 (d, / = 2.2,1H), 6.24 (d, / = 2.3,1H), 5.14 (s, 2H), 5.08 (s, 2H),
3.46 (s, 3H), 3.44 (s, 3H), 2.05 (s, 3H).
75
Synthesis of 2-Methyl-6-piperidin-l-ylmethyl-3 / 5-bis-(2-trimethylsilanylethoxymethoxy)-phenol (26SEM):
- S i -^o^o
To a 10 mL round-bottomed flask was sequentially added 70.2 mg (0.175 mmol)
of 25SEM, 2 mL of MeOH, 0.1 mL of water, 0.021 mL (0.26 mmol) of formaldehyde
(37% in water), and 0.026 mL (0.26 mmol) of piperidine. The resulting solution was
refluxed for 3 hours. Concentration provided pure 26SEM in quantitative yield; J H
NMR (300 MHz, CDCb) 6 6.38 (s, 1H), 5.15 (s, 2H), 5.11 (s, 2H), 3.72 (m, 6H), 3.68 (s, 2H),
2.82 - 2.15 (m, 4H), 2.03 (s, 3H), 1.60 (m, 6H), 1.00 - 0.85 (m, 4H), -0.02 (s, 18H); 13C NMR
(75 MHz, CDCb) 6 157.99,155.83,153.60,108.22,104.28, 93.84, 93.73, 93.63, 66.38, 66.24,
55.02, 53.98, 26.00, 24.24,18.25, 8.16, -1.20; LRMS (FAB) m/z calculated for C25H48N05Si2
498.3071 (MH+), found 498.300 (MH+).
76
Synthesis of 3 / 5-Bis-methoxymethoxy-2-methyl-6-piperidin-l-ylmethyl-phenol
(26MOM):
.0. .0
26MOM
To a 50 mL round-bottomed flask was sequentially added 379 mg (1.6 mmol) of
25MOM, 8 mL of MeOH, 0.195 mL (2.4 mmol) of formaldehyde (37% in water), and
0.237 mL (2.4 mmol) of piperidine. The resulting solution was refluxed for 26 hours.
Concentration provided pure 26MOM in quantitative yield; lH NMR 5 6.36 (s, 1H), 5.13
(s, 2H), 5.09 (s, 2H), 3.74 (s, 2H), 3.47 (s, 3H), 3.43 (s, 3H), 3.03 - 2.32 (m, 4H), 2.06 (s, 3H),
1.70-1.55 (m,6H).
77
Synthesis of l-(2,6-Dihydroxy-3-(2-hydroxy-3-methyl-4 / 6-bis-(2-trimethylsilanylethoxymethoxy)-benzyl)-4-methoxymethoxy-phenyl)-ethanone (27MS):
In a 10 mL microwave vessel was placed 100 mg (0.2 mmol) of 26SEM, 197 mg
(0.93 mmol) of 15, and 2 mL of CDCk The tube was sealed and then irradiated at 300 W
for 2 minutes. After concentration, flash column chromatography using 2:1 hexane:EfeO
afforded 39.9 mg (0.06 mmol, 30%) of 27MS (Rf = 0.19); XH NMR (300 MHz, CDCb) 6
13.44 (s, 1H), 9.14 (s, 1H), 7.67 (s, 1H), 6.60 (s, 1H), 6.28 (s, 1H), 5.37 (s, 4H), 5.17 (s, 2H),
3.90 - 3.80 (m, 2H), 3.78 (s, 2H), 3.76 - 3.68 (m, 2H), 3.56 (s, 3H), 2.66 (s, 3H), 2.04 (s, 3H),
1.06 - 0.88 (m, 4H), 0.00 (s, 9H), -0.02 (s, 9H); 13C NMR (75 MHz, CDCb) 6 204.49,164.93,
159.42,155.75,154.33,152.16,118.50,118.46,109.86,107.79,107.23,105.59, 95.59, 95.10,
94.99, 94.75, 93.56, 67.71, 66.40, 57.46, 33.57,18.38,18.28, 8.66, -1.17, -1.19; LRMS (FAB)
m/z calculated for CsoHwOioSiz 625.2864 (MH+), found 625.31 (MH+).
Synthesis of l-(2-Hydroxy-4,6-bis-methoxymethoxy-phenyl)-3-phenylpropenone (30):
<X ^CX
To a 25 mL round-bottomed flask under an atmosphere of argon was added 1 g
(5.38 mmol) of phloroacetophenone (2) monohydrate and 10 mL of dichloromethane.
The suspension was cooled to 0°C and then 1.76 mL (12.5 mmol) of DBU was added.
This mixture was stirred at 0°C for 10 minutes, at which point 0.945 mL (12.5 mmol) of
MOMC1 was added via syringe. The reaction was allowed to stir slowly to room
temperature over 3 hours and then diluted with 10 mL of dichloromethane. This
organic solution was washed three times with 10 mL of ice cold 1M aqueous HC1. The
aqueous washes were combined and extracted with 20 mL of dichloromethane. The
combined organic layers were washed with 10 mL of brine and then dried over MgSOi.
The crude reaction mixture, containing 7 along with various side-products, was then
filtered and concentrated. To this oil was then sequentially added 40 mL of EtOH, 40
mL of a 20% aqueous solution of NaOH, and 6 mL of benzaldehyde. The reaction was
allowed to stir at room temperature for 39 hours and then slowly acidified with ice cold
3M aqueous HC1. The resulting suspension was extracted three times with 50 mL of
79
EtzO. The combined organic layers were washed with 30 mL of brine and then dried
over MgS04. After filtration and concentration, flash column chromatography using 3:1
hexane:Et 2 0 afforded 267.9 mg (0.6 mmol, 11% from 2) of 30 (Rf = 0.21); *H NMR 6 7.91
(d, / = 15.6,1H), 7.78 (d, / = 15.6,1H), 7.41 - 7.37 (m, 2H), 7.37 - 7.34 (m, 3H), 6.31 (d, / =
2.3,1H), 6.24 ( d , / = 2.3,1H), 5.28 (s, 2H), 5.18 (s, 2H), 3.52 (s, 3H), 3.46 (s, 3H).94
80
Synthesis of l-(2 / 6-Dihydroxy-4-methoxymethoxy-phenyl)-3-phenyl-propenone
(31MOM):
30
31 MOM
In an adaptation of the procedure of Keith,106 to a 100 mL round-bottomed flask
was sequentially added 267.9 mg (0.6 mmol) of 30,12 mL of MeOH, and 120 mg of h.
This solution was stirred at room temperature for 26.75 hours, at which point it was
quenched by addition of 10 mL of a 1M solution of aqueous Na2S203. This solution was
diluted with 30 mL of Et20 and washed twice with 10 mL of water. The aqueous washes
were combined and then extracted twice with 15 mL of Et20. The combined organic
layers were then washed with 10 mL of brine and then dried over MgSOt. After
filtration and concentration, flash column chromatography using 2:1 hexane: EfeO gave
83 mg (0.278 mmol, 46%) of 31MOM (Rf = 0.1); »H NMR 6 8.06 (d, / = 15.6,1H), 7.79 (d, /
= 15.6,1H), 7.57 - 7.52 (m, 2H), 7.34 - 7.30 (m, 3H), 6.13 (s, 2H), 5.13 (s, 2H), 3.42 (s, 3H).
81
Synthesis of 10-Hydroxy-2,2,7,7-tetramethyl-7H-l,3,8-trioxa-anthracen-4-one
(35):
OyO
s
V
OH
23
A 10 mL microwave reaction vessel was charged with 52.5 mg (0.25 mmol) of 23.
To this was added 1 mL of CDCb and then 0.08 mL (0.75 mmol) of 3-methyl-2-butenal.
The reaction vessel was flushed with argon for a period of 30 seconds before being
capped. The tube was then placed into the microwave reactor and irradiated at 300
watts for 1 hour. After cooling, the tube was removed and the reaction mixture was
concentrated. The resulting crude product was purified by flash column
chromatography using 5:1 hexaneiEfeO to afford 38 mg (0.138 mmol, 55%) of 35 (Rf =
0.41); !H NMR 5 10.61 (s, 1H), 6.57 (d, / = 10.4,1H), 5.88 (s, 1H), 5.48 (d, / = 10 Hz, 1H),
1.70 (s, 6H), 1.42 (s, 6H); 13C NMR 5 165.5,161.8,157.5,156.4,126.8,115.5,107.1,104.3,
96.5, 92.9, 78.5, 28.6, 25.9; IR (neat) 2977.74,1682.71,1638.75,1583.45,1497.06,1460.44,
1383.55,1324.43,1280.11,1206.65,1166.66,1121.28,1093.57,1052.53,985.47, 919.06,
884.34, 842.00, 799.46, 770.38, 737.97, 711.34, 658.01 cm-1; H R M S (EI) m/z calculated for
GsHieOs 276.0998 (M+), found 276.1003 (M+).
82
Synthesis of 10-Methoxymethoxy-2,2,7,7-tetramethyl-7i : i : l / 3 / 8-trioxa-anthracen4-one (36):
A flame-dried 25 mL round-bottomed flask fitted with an addition funnel under
an atmosphere of argon was charged with 14 mg (0.35 mmol) of NaH (60% in mineral
oil) and then cooled to -78°C. After the addition of 1.5 mL of DMF, 80 mg (0.29 mmol) of
35 in 1.5 mL of DMF was added drop wise over 5 minutes via the addition funnel. The
reaction was stirred at -78°C for 10 minutes, at which time 0.027 mL (0.35 mmol) of
MOMC1 in 1.5 mL of DMF was added dropwise over 5 minutes via the addition funnel.
The reaction was allowed to stir to room temperature over 22 hours. After dilution with
10 mL of Et2<D, the solution was carefully washed twice with 10 mL portions of a 1M
aqueous HC1 solution. The aqueous washes were combined and then extracted with 10
mL of Et20. The combined organic layers were washed with 5 mL of brine, and dried
over MgSCX After filtration and concentration, flash column chromatography using 2:1
hexane:EtOAc afforded 80.5 mg (0.25 mmol, 87%) of 36 (Rf = 0.46); J H NMR 6 6.66 (d, / =
10.1,1H), 6.14 (d, 1H), 5.58 ( d , / = 10.1,1H), 5.14 (s, 2H), 3.56 (s, 3H), 1.68 (s, 6H), 1.42 (s,
6H); HRMS (EI) m/z calculated for C17H20O6 320.1260 (M+), found 320.1259 (M+).
83
Synthesis of 7-Hydroxy-5-methoxymethoxy-2,2-dimethyl-2H-chromene-6carbaldehyde (37MOM):
HLX)
In an adaptation of the procedure of Bajwa et. a/.,138 to a flame-dried 10 mL
round-bottomed flask under an atmosphere of argon was added 176 mg (0.55 mmol) of
36 and 5.5 mL of dichloromethane. The solution was cooled to -78°C, and 1.65 mL (1.65
mmol) of a 1M solution of DIBAL in toluene was then added dropwise via syringe. The
reaction was stirred at -78°C for 4 hours, at which time it was quenched by careful
addition of 3 mL of a 1M aqueous HC1 solution. The resulting slurry was stirred to
room temperature and then diluted with 20 mL of EbO. This mixture was washed twice
with 10 mL of a 1M aqueous HC1 solution and once with 10 mL of saturated aqueous
Rochelle's salt. The aqueous washes were combined and extracted twice with 10 mL of
Et20. The combined organic layers were washed with 10 mL of brine and then dried
over MgSCk After concentration and filtration, flash column chromatography using 3:1
hexane:Et20 provided 28.6 mg (0.11 mmol, 20%) of 37MOM (Rf = 0.31); *H NMR 6 12.13
(s, 1H), 10.00 (s, 1H), 6.43 ( d , / = 10.1,1H), 6.14 (s, 1H), 5.58 ( d , / = 10.1,1H), 5.04 (s, 2H),
3.56 (s, 3H), 1.43 (s, 6H); 13C NMR 6 193.03,164.96,162.53,157.74,128.71,116.10,110.20,
107.19,101.71,101.04, 78.14, 58.39, 28.47.
84
Synthesis of 2-Hydroxy-4,6-bis-methoxymethoxy-benzaldehyde (41MOM):
24MOM
41 MOM
In an adaptation of the procedure of Bajwa et. al.,13S to a flame-dried 250 mL
round-bottomed flask under an atmosphere of argon was added 439 mg (1.47 mmol) of
24MOM and 10 mL of dichloromethane. The solution was cooled to -78°C, and to it
was then added 4.4 mL (4.4 mmol) of a 1M solution of DIBAL in toluene dropwise over
5 minutes. The reaction was stirred at -78°C for 2 hours, and then quenched with 5 mL
of MeOH. After allowing the solution to warm to room temperature, 20 mL of
dichloromethane was added and then this mixture was washed three times with 10 mL
of a 1M aqueous solution of HC1. The aqueous washes were combined and then
extracted twice with 15 mL of dichloromethane. The combined organic layers were
washed with 15 mL of brine and then dried over MgSCX Filtration and concentration
afforded 350 mg (1.45 mmol, 99%) of pure 41 MOM (Rf = 0.47 in 2:1 hexane:EtOAc); J H
NMR 6 12.25 (s, 1H), 10.13 (s, 1H), 6.22 ( d , / = 2.1,1H), 6.19 ( d , / = 2.1,1H), 5.21 (s, 2H),
5.15 (s, 2H), 3.48 (s, 3H), 3.44 (s, 3H); 13C NMR 5192.33,165.84,165.67,161.45,107.10,
96.78, 94.82, 94.32, 94.27,56.84,56.70; LRMS (EI) m/z calculated for CnHwOs 242.079
(M+), found 242.00 (M+).
85
Synthesis of 2-(Benzylamino-methyl)-3,5-bis-methoxymethoxy-phenol
(44MOM):
H
k^J
44MOM
In an adaptation of the procedure of Hayes et. a/.,140 to a 5 mL round-bottomed
flask under an atmosphere of argon containing molecular sieves was added 126 mg (0.52
mmol) of 41 MOM in 1 mL of MeOH via syringe followed by 0.085 mL (0.78 mmol) of
benzylamine, also via syringe. The reaction was stirred at room temperature for 2.75
hours and then cooled to 0°C. To this cooled reaction mixture was added 0.4 mL (0.8
mmol) of a 2M solution of LiBH4 in THF, and the solution was allowed to stir at 0°C for
2 hours, at which point it was quenched by the addition of 2 mL of water. The mixture
was brought to room temperature and then filtered through a pad of celite, washing the
solid thoroughly with 10 mL of EteO. The filtrate was washed twice with 8 mL of water,
and then the aqueous washes were combined and extracted with 10 mL of EbO. The
organic layers were combined, washed with 10 mL of brine, and then dried over MgSCk.
Filtration and concentration provided 176 mg (0.52 mmol) of pure 44MOM; *H NMR 5
7.27 - 7.12 (m, 5H), 6.25 (s, 1H), 6.11 (s, 1H), 5.10 (s, 2H), 5.04 (s, 3H), 4.53 (d, / = 5.6, 2H),
3.36 (m, 2H), 3.36 (s, 3H), 3.27 (s, 3H).
86
Synthesis of 3-Acetyl-2 / 4-dihydroxy-6-(methoxymethoxy)benzaldehyde (48):
In an adaptation of the procedure of Bharate et. al.,U9 to a flame-dried 25 mL
round-bottomed flask under an atmosphere of argon was sequentially added 106 mg
(0.5 mmol) of 15, 7.5 mL of EtOAc, 0.039 mL (0.5 mmol) of DMF, and 0.051 mL (0.55
mmol) of phosphorus oxychloride. After stirring for 2.5 hours, another 0.039 mL (0.5
mmol) of DMF and 0.051 mL (0.55 mmol) of phosphorus oxychloride were added to the
reaction mixture. This stirred for 45 minutes, at which point 0.039 mL (0.5 mmol) of
DMF and 0.051 mL (0.55 mmol) of phosphorus oxychloride which had been premixed in
a flame-dried 5 mL point-tipped flask under an atmosphere of argon was added via
syringe. The reaction stirred for another 5 minutes, at which point it was quenched by
the addition of 5 mL of water. After dilution with 10 mL of EtOAc, the solution was
washed twice with 5 mL portions of water. The aqueous washes were combined and
extracted with 5 mL of EtOAc and then twice with 10 mL portions of CHCL. The
combined organic layers were then washed with 10 mL of brine and dried over MgSCX
After filtration and concentration, flash column chromatography using 9:1 CHCkEtOAc
afforded 65.5 mg (0.273 mmol, 55%) of 48 (Rf = 0.6); J H NMR 510.06 (s, 1H), 6.12 (s, 1H),
5.27 (s, 2H), 3.50 (s, 3H), 2.70 (s, 3H).
87
Synthesis of l-(2 / 6-Dihydroxy-4-(methoxymethoxy)-3-methylphenyl)ethanone
(49) and Advanced Rottlerin Intermediate 50:
C^/
. y?
ex xx
I
nw
50
In an adaptation of the procedure of Boyer,102 to a 100 mL shaking vessel was
sequentially added 96 mg (0.4 mmol) of 48HH in 3.33 mL MeOH, 73 mg (0.4 mmol) of
4, and 80 mg (20 mol %) of Pd/C (5% by weight). The vessel was sealed and shaken
under an atmosphere of H2 for 14.5 hours. The suspension was filtered through a pad of
celite, which was thoroughly washed with 15 mL of Et20. Concentration of the filtrate
and flash column chromatography using 5:1 CHCtaEtOAc afforded 41 mg (0.18 mmol,
45%) of 49 (Rf = 0.50) and 34 mg (0.085 mmol, 21%) of 50 (Rf = 0.26); »H NMR (49) 6 6.12
(s, 1H), 5.15 (s, 2H), 3.44 (s, 3H), 2.66 (s, 3H), 2.00 (s, 3H); J H NMR (50) 6 6.15 (s, 1H), 5.26
(s, 2H), 3.60 (s, 2H), 3.42 (s, 3H), 2.57 (s, 3H), 2.56 (s, 3H), 1.89 (s, 3H); LRMS (50, ESI)
m/z calculated for C20H23O9 407.1342 (MH+), found 407.1 (MH+).
88
Synthesis of Advanced Rottlerin Intermediate Chromene 5 1 A or Regioisomeric
Chromene51B:
I
iH
50
I
nu
51B
Two separate microwave reaction tubes were charged with 7 mg (0.017 mmol x2)
in 1 mL of MeOH and 0.1 mL of 3-methyl-2-butenal (1.03 mmol). Both tubes were
irradiated at 100 W, with one being exposed for 10 minutes and the other being exposed
for 20 minutes. The two crude reaction mixtures were combined and concentrated.
Crude NMR showed the presence of two distinct chromene species. Flash column
chromatography using 9:1 CHCkEtOAc yielded a mixture of products near the baseline.
This material was again chromatographed, using 6:1 CHCl3:EtOAc, and the only isolable
compound was 2 mg (0.005 mmol, 15%) of either 5 1 A or 51B (Rf = 0.33); W NMR 5 6.61
(d, / = 10, IH), 5.42 (d, / = 10 Hz, IH), 3.75 (s, 2H), 2.68 (s, 3H), 2.66 (s, 3H), 2.05 (s, 3H),
1.45 (s, 6H); LRMS (ESI) m/z calculated for C23H25O8 429.1549 (MH+), found 429.2 (MH+).
89
2.4 Selected NMR Spectra
General Experimental Considerations: ID NMR spectra were recorded on
either a Varian Unity INOVA-400 (16MOM) or -300 (27MS) spectrometer. Proton and
carbon spectra for 16MOM were acquired at 400 and 101 MHz, respectively. Proton and
carbon spectra for 27MS were acquired at 300 and 75 MHz, respectively. Data for the
nOe experiment was collected at 500 MHz on a Varian Unity INOVA-500 spectrometer.
Chemical shifts are standardized to the solvent peak (CHCb in CDCb at 7.24 ppm for lH
spectra, and 77.23 ppm for 13C spectra).
90
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Figure 17: XH NMR Spectrum of Dihydrobenzofuran 14
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Figure 18: 13C NMR Spectrum of Dihydrobenzofuran 14
92
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Figure 19: HMQC Spectrum of Dihydrobenzofuran 14
93
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Figure 20: Pertinent Region of HMQC Spectrum of Dihydrobenzofuran 14
94
Figure 21: 1 H NMR Spectrum of Chromenochalcone 16MOM
95
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Figure 23: *H NMR Spectrum of Methylene-Linked Biaryl 27MS
97
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2.5 Crystallographic Data for Chromenochalcone 16M0M
Crystallographic data collected and analyzed by Dr. David Pham using a Bruker
Kappa Apex II spectrophotometer.
Figure 25: Crystal Structure of Chromenochalcone 16MOM, View 1
Figure 26: Crystal Structure of Chromenochalcone 16MOM, View 2
99
Table 1. Crystal data and structure refinement for 16MOM.
Empirical formula
C22 H22 05
Formula weight
366.40
Temperature
298(2) K
Wavelength
0.71073 A
Crystal system
Monoclinic
Space group
P21/c
Unit cell dimensions
a = 9.8357(9) A
a=90°.
b = 18.5469(17) A
0=115.84°.
c = 11.2832(10) A
Y = 90°.
Volume
1852.5(3) A3
Z
4
Density (calculated)
1.314 Mg/m3
Absorption coefficient
0.093 mm"1
F(000)
776
Crystal size
0.66x0.22x0.20 mm3
Crystal color and habit
Translucent Watermelon Jolly Rancher Red Prismatic Needle
Diffractometer
Bruker Kappa Apex U
Theta range for data collection
2.20 to 28.44°.
Index ranges
-13<=h<=13, -16<=k<=24, -10<=1<=14
Reflections collected
17494
Independent reflections
4572 [R(int) = 0.0191]
Observed reflections (I > 2o (I))
3360
Completeness to theta = 28.44°
98.1 %
Absorption correction
Semi-empirical from equivalents
Max. and min. transmission
0.9817 and 0.9414
Solution method
SHELXS-97 (Sheldrick, 1990)
Refinement method
SHELXL-97 (Sheldrick, 1997)
Data / restraints / parameters
Goodness-of-fit on F
2
4572 / 0 / 247
1.001
Final R indices [I>2o (I)]
Rl = 0.0406, wR2 = 0.1093
R indices (all data)
R l = 0.0602, wR2 = 0.1239
Largest diff. peak and hole
0.216 and-0.177 e.A"3
100
Table 2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (A2x 103)
for 16MOM. U(eq) is defined as one third of the trace of the orthogonalized U'J tensor.
x
y
z
U(eq)
0(1)
134(1)
1860(11
1729(1]
45(1
0(2)
3803(1)
1505(i;
1010(1]
69(1
0(3)
5422(1)
1469(i:
3466(1]
65(1
0(4)
3017(1)
1711(1]
6321(1]
54(1
0(5)
5144(1)
1066(1]
7748(1]
65(1
C(l)
-1269(1)
1751(1]
1873(1]
44(1
C(2)
-1071(2)
2017(1]
3196(1]
48(1
C(3)
266(1)
2012(1]
4221(1]
45(1
C(5)
3012(1)
1684(1]
5105(1]
44(1
C(6)
1589(1)
1788(1]
4049(1]
41(1
C(6A)
4283(1)
1574(1]
4897(1]
49(1
C(7)
4147(1)
1555(1]
3620(1]
48(1
C(8)
2728(1)
1591(1]
2513(1]
43(1
C(9)
1470(1)
1726(1]
2778(1]
40(1
C(10)
2647(2)
1446(1]
1202(1]
50(1
C(ll)
1264(2)
1165(1]
141(1]
51(1
C(12)
1067(2)
1149(1]
-1102(1]
53(1
C(13)
-204(2)
848(1]
-2229(1]
50(1
C(14)
-1453(2)
553(1]
-2143(2]
60(1
C(15)
-2602(2)
242(1]
-3224(2]
65(1
C(16)
-2528(2)
222(1]
-4413(2]
67(1
C(17)
-1313(2)
518(1]
-4525(2]
74(1
C(18)
-164(2)
829(1]
-3453(2]
64(1
C(19)
-1628(2)
952(1]
1732(2]
61(1
C(20)
-2423(2)
2187(1,
755(2]
63(1
C(21)
4424(2)
1724(1
7462(r
59(1
C(22)
4486(2)
551(1]
8274(2]
84(1
101
Table 3. Bond lengths [A] and angles [°] for 16MOM.
0(1)-C(9)
1.3551(14)
0(1)-C(1)
1.4723(14)
O(2)-C(10)
1.2507(16)
0(3)-C(7)
1.3487(15)
0(3)-H(lA)
0.8200
0(4)-C(5)
1.3709(16)
0(4)-C(21)
1.4211(16)
0(5)-C(21)
1.3769(19)
0(5)-C(22)
1.420(2)
C(l)-C(2)
1.5007(17)
C(l)-C(20)
1.5116(18)
C(l)-C(19)
1.5158(19)
C(2)-C(3)
1.3192(18)
C(2)-H(2A)
0.9300
C(3)-C(6)
1.4572(17)
C(3)-H(3A)
0.9300
C(5)-C(6A)
1.3836(18)
C(5)-C(6)
1.4008(17)
C(6)-C(9)
1.3920(17)
C(6A)-C(7)
1.3883(19)
C(6A)-H(6AA)
0.9300
C(7)-C(8)
1.4121(18)
C(8)-C(9)
1.4160(17)
C(8)-C(10)
1.4713(18)
C(10)-C(ll)
1.461(2)
C(ll)-C(12)
1.3308(19)
C(11)-H(11A)
0.9300
C(12)-C(13)
1.451(2)
C(12)-H(12A)
0.9300
C(13)-C(14)
1.387(2)
C(13)-C(18)
1.3994(19)
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n n o n n n n n n Q Q
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p p p p o p p p p p p
C(18)-C(13)-C(12)
119.35(13)
C(15)-C(14)-C(13)
120.85(14)
C(15)-C(14)-H(14A)
119.6
C(13)-C(14)-H(14A)
119.6
C(16)-C(15)-C(14)
120.28(16)
C(16)-C(15)-H(15A)
119.9
C(14)-C(15)-H(15A)
119.9
C(17)-C(16)-C(15)
119.86(15)
C(17)-C(16)-H(16A)
120.1
C(15)-C(16)-H(16A)
120.1
C(16)-C(17)-C(18)
120.25(15)
C(16)-C(17)-H(17A)
119.9
C(18)-C(17)-H(17A)
119.9
C(17)-C(18)-C(13)
120.95(15)
C(17)-C(18)-H(18A)
119.5
C(13)-C(18)-H(18A)
119.5
C(1)-C(19)-H(19A)
109.5
C(1)-C(19)-H(19B)
109.5
H(19A)-C(19)-H(19B)
109.5
C(1)-C(19)-H(19C)
109.5
H(19A)-C(19)-H(19C)
109.5
H(19B)-C(19)-H(19C)
109.5
C(1)-C(20)-H(20A)
109.5
C(1)-C(20)-H(20B)
109.5
H(20A)-C(20)-H(20B)
109.5
C(1)-C(20)-H(20C)
109.5
H(20A)-C(20)-H(20C)
109.5
H(20B)-C(20)-H(20C)
109.5
0(5)-C(21)-0(4)
113.24(12)
0(5)-C(21)-H(21A)
108.9
0(4)-C(21)-H(21A)
108.9
0(5)-C(21)-H(21B)
108.9
0(4)-C(21)-H(21B)
108.9
H(21A)-C(21)-H(21B)
107.7
0(5)-C(22)-H(22A)
109.5
0(5)-C(22)-H(22B)
109.5
H(22A)-C(22)-H(22B)
109.5
0(5)-C(22)-H(22C)
109.5
H(22A)-C(22)-H(22C)
109.5
H(22B)-C(22)-H(22C)
109.5
Symmetry transformations used to generate equivalent atoms:
106
Table 4. Anisotropic displacement parameters (A2x 103)for 16MOM. The anisotropic
displacement factor exponent takes the form: -2n2[ h 2 a* 2 U n + ... + 2 h k a* b* U 12 ]
u 11
u22
u33
u23
u13
u12
0(1)
34(1)
60(1}
4i(i;
7(1)
16(1)
5(1)
0(2)
51(1)
98(1}
70(i;
-4(1)
38(1)
-2(1)
0(3)
37(1)
87(i:
74(i;
5(1)
26(1)
4(1)
0(4)
44(1)
68(i;
42(i;
-4(1)
11(1)
0(1)
0(5)
57(1)
80(i;
57(i;
8(1)
23(1)
15(1)
C(l)
33(1)
54(i;
43(i;
2(1)
17(1)
2(1)
C(2)
40(1)
57(i;
50(i;
-2(1)
23(1)
5(1)
C(3)
44(1)
5i(i;
43(i;
-4(1)
20(1)
0(1)
C(5)
41(1)
42(i;
44(i;
-1(1)
14(1)
-4(1)
C(6)
36(1)
4i(i;
43(1]
0(1)
16(1)
-2(1)
C(6A)
34(1)
52(1;
52(i;
1(1)
11(1)
-3(1)
C(7)
36(1)
46(i;
63(i;
3(1)
23(1)
-KD
C(8)
38(1)
44(i;
50(i;
3(1)
21(1)
0(1)
C(9)
34(1)
39(i;
45(i;
3(1)
16(1)
0(1)
C(10)
48(1)
51(1]
58(i;
4(1)
30(1)
4(1)
C(ll)
50(1)
54(i;
56(i;
-1(1)
30(1)
2(1)
C(12)
52(1)
56(i;
58(i;
4(1)
32(1)
5(1)
C(13)
54(1)
48(i;
53(i;
5(1)
29(1)
10(1)
C(14)
67(1)
65(i;
60(i;
-8(1)
37(1)
-KD
C(15)
64(1)
60(i;
76(i;
-6(1)
35(1)
-3(1)
C(16)
71(1)
60(i;
58(i;
-1(1)
19(1)
7(1)
C(17)
84(1)
90(i;
46(1]
8(1)
28(1)
8(1)
C(18)
64(1)
80(i;
54(i;
13(1)
30(1)
5(1)
C(19)
64(1)
59(1]
66(i;
-9(1)
34(1)
-13(1)
C(20)
41(1)
85(i;
55(i;
13(1)
15(1)
13(1)
C(21)
5KD
65(i;
45(1]
-5(1)
7(1)
-4(1)
C(22)
99(1)
78(i;
83(i;
19(1)
48(1)
15(1)
107
Table 5. Hydrogen coordinates (x 104) and isotropic displacement parameters (A2x 103)
for 16MOM.
x
y
z
H(1A)
5206
1422
2681
78
H(2A)
-1904
2188
3294
57
H(3A)
362
2151
5046
55
H(6AA)
5223
1513
5609
59
H(11A)
500
993
341
61
H(12A)
1830
1354
-1268
63
H(14A)
-1516
565
-1344
72
H(15A)
-3431
45
-3150
78
H(16A)
-3302
8
-5139
80
H(17A)
-1266
507
-5330
88
H(18A)
653
1030
-3541
77
H(19A)
-807
691
2397
91
H(19B)
-1771
792
877
91
H(19C)
-2534
867
1834
91
H(20A)
-2144
2687
876
94
H(20B)
-3399
2128
742
94
H(20C)
-2458
2022
-65
94
H(21A)
5078
2076
7334
71
H(21B)
4256
1879
8208
71
H(22A)
5100
124
8523
125
H(22B)
3491
431
7622
125
H(22C)
4423
750
9034
125
108
U(eq)
Table 6. Torsion angles [°] for 16MOM.
C(9)-0(1)-C(l)-C(2)
40.43(14)
C(9)-O(l)-C(l)-C(20)
160.63(11)
C(9)-0(1)-C(l)-C(19)
-80.16(13)
0(1)-C(1)-C(2)-C(3)
-28.96(17)
C(20)-C(l)-C(2)-C(3)
-143.64(14)
C(19)-C(l)-C(2)-C(3)
90.17(16)
C(l)-C(2)-C(3)-C(6)
3.9(2)
C(21)-0(4)-C(5)-C(6A)
8.87(18)
C(21)-0(4)-C(5)-C(6)
-170.30(11)
0(4)-C(5)-C(6)-C(9)
-176.18(10)
C(6A)-C(5)-C(6)-C(9)
4.61(18)
0(4)-C(5)-C(6)-C(3)
8.71(17)
C(6A)-C(5)-C(6)-C(3)
-170.50(12)
C(2)-C(3)-C(6)-C(9)
12.90(18)
C(2)-C(3)-C(6)-C(5)
-172.03(13)
0(4)-C(5)-C(6A)-C(7)
179.83(11)
C(6)-C(5)-C(6A)-C(7)
-1.05(19)
C(5)-C(6A)-C(7)-0(3)
177.96(12)
C(5)-C(6A)-C(7)-C(8)
-4.73(19)
0(3)-C(7)-C(8)-C(9)
-176.32(11)
C(6A)-C(7)-C(8)-C(9)
6.45(18)
O(3)-C(7)-C(8)-C(10)
7.42(18)
C(6A)-C(7)-C(8)-C(10)
-169.80(12)
C(l)-0(1)-C(9)-C(6)
-26.94(16)
C(l)-0(1)-C(9)-C(8)
158.84(10)
C(5)-C(6)-C(9)-0(l)
-176.48(10)
C(3)-C(6)-C(9)-0(l)
-1.16(17)
C(5)-C(6)-C(9)-C(8)
-2.64(17)
C(3)-C(6)-C(9)-C(8)
172.69(11)
C(7)-C(8)-C(9)-0(l)
171.30(11)
C(10)-C(8)-C(9)-O(l)
-12.72(17)
C(7)-C(8)-C(9)-C(6)
-2.72(17)
C(10)-C(8)-C(9)-C(6)
173.26(12)
C(7)-C(8)-C(10)-O(2)
-21.34(19)
C(9)-C(8)-C(10)-O(2)
162.77(12)
C(7)-C(8)-C(10)-C(ll)
152.83(12)
C(9)-C(8)-C(10)-C(ll)
-23.06(19)
O(2)-C(10)-C(ll)-C(12)
-17.9(2)
C(8)-C(10)-C(ll)-C(12)
167.87(12)
C(10)-C(ll)-C(12)-C(13)
176.01(13)
C(ll)-C(12)-C(13)-C(14)
2.9(2)
C(ll)-C(12)-C(13)-C(18)
-175.01(14)
C(18)-C(13)-C(14)-C(15)
1.0(2)
C(12)-C(13)-C(14)-C(15)
-176.93(14)
C(13)-C(14)-C(15)-C(16)
-0.2(2)
C(14)-C(15)-C(16)-C(17)
-0.6(2)
C(15)-C(16)-C(17)-C(18)
0.5(3)
C(16)-C(17)-C(18)-C(13)
0.3(3)
C(14)-C(13)-C(18)-C(17)
-1.1(2)
C(12)-C(13)-C(18)-C(17)
176.96(15)
C(22)-0(5)-C(21)-0(4)
-73.54(17)
C(5)-0(4)-C(21)-0(5)
-74.75(16)
Symmetry transformations used to generate equivalent atoms:
Table 7. Hydrogen bonds for 16MOM [A and °].
D-H...A
0(3)-H(lA)...0(2)
d(D-H)
d(H...A)
d(D...A)
<(DHA)
0.82
1.79
2.5244(16)
147.7
Symmetry transformations used to generate equivalent atoms:
110
3. Microwave-Assisted Synthesis of 2,2-Dimethyl-2//-chromenes
3.1 Results and Discussion of the Methodological Exploration
While the variety of reaction conditions which exist for assembling 2,2-dimethyl2H-chromenes48'49'52"64150 offer synthetic chemists a number of options when confronted
with the desire to make such molecules, there is a lack of a single methodology which
can regioselectively generate such structures in a single step from the corresponding
phenol and a,|3-unsaturated aldehyde under neutral, mild conditions in a brief period of
time without excessive exposure to a thermally stressful environment. This, in turn,
precludes the use of a single methodology to efficiently convert a range of phenolic
substrates containing a wide array of other functionalities to their respective chromenes.
In light of the drug discovery community's current widespread tactic of
producing libraries of structurally similar compounds quickly, and synthetic chemists'
constant desire for new, broadly applicable tools for molecular construction, a new route
which allows for generation of a "privileged structure" 40 in a facile manner and under
mild conditions is seen as a valuable contribution to the chemical community. This,
coupled with our interest in the synthesis of the chromene containing biologically active
natural product rottlerin (1), inspired us to pursue the development of an efficient
process for the construction of 2,2-dimethyl-2H-chromenes that would be performed
under neutral, mild conditions. To this end, we began a detailed investigation of an
111
uncatalyzed, neutral, microwave-assisted 122125 condensation of 3-methyl-2-butenal (52)
with substituted phenols as a novel and direct route to access the family of compounds
possessing this privileged structure.
Scheme 32: Exemplary Mechanism for the Microwave A n n u l a t i o n Method
o
0H
a ^
2,2-dimethyl2AV-chromene
phenol
Microwave irradiation has seen an increased use in organic synthesis in recent
years, as it can serve to excite molecules which absorb at this frequency in a mixture
without necessarily globally affecting the thermal environment of the reaction.122"125
Inspired by a microwave induced para-Claisen rearrangement, 120 we believed that this
transformation would occur rapidly after the initial nucleophilic addition of the phenol
to the aldehyde, and that microwave irradiation could be the perfect way to initiate this
cascade.
In an effort to probe the relative reactivities of the selected phenols, each
substrate was initially subjected to a set of standard reaction conditions; the results of
these trials are labeled as trial type "standard" in Table 1. Each of the explored phenols
was chosen because its corresponding chromene product either is a natural product or
could be taken on to a biologically relevant natural product in short order.
112
Table 1: Standard/ Best Chromene Yields; All Explored Phenols
trial type
power
(W)
standard^est
150
2
standard
150
1
3
1
30
3
best
300
0.2
1.5
1
94
4
standard
150
1
3
1
0 b,<
5
best
300
0.5
1.5
0.5
60d
standard
150
1
3
1
16b'c
best
300
1
1.5
0.25
55
standard
150
21
best
150
48
10
standard
150
1
10
11
best
150
10
43
12
standard
150
1
4
13
best
150
10
15
14
standard
150
entry
phenol
D
$°
chromene product
time
(h)
equiv.
cone.
52
iML
yield
89
OH
2
OH
54
"Crude product mixtures consisted of >95% product and starting materials only unless otherwise indicated.
For 'standard' trial type, isolated yields are shown. Yields for trial type 'best' were determined by NMR
via comparison to an equimolar amount of 1,2-dimethoxyethane (based on starting phenol) added to the
crude reaction mixture after reaction completion and cooling. bCrude reaction mixture contained
significant amounts of undesired chromene side products. cCrude product mixture contained significant
amounts of uncharacterized compounds presumed to be polymeric material. dReaction ran in MeOH.
113
Table 1, continued: Standard, Best Chromene Yields; All Explored Phenols
entry
phenol
chromene product
trial type
power
(W)
none
standard
150
NR
none
standard
150
NR
none
standard
150
NR
""CCr-
standard
150
7
best
300
63
standard
150
5
best
300
88
standard
150
14
standard
150
44
15
time
(h)
equiv.
52
cone.
(M)
yield
%) a
OH
61
16
Cr"
62
17
18
63
19
20
21
65
H,00.
H3CO.
64
H.00
66
XT
22
23
70
a
Crude product mixtures consisted of >95% product and starting materials only unless otherwise indicated.
For 'standard' trial type, isolated yields are shown. Yields for trial type 'best' were determined by NMR
via comparison to an equimolar amount of 1,2-dimethoxyethane (based on starting phenol) added to the
crude reaction mixture after reaction completion and cooling.
Crude reaction mixture contained
significant amounts of undesired chromene side products. cCrude product mixture contained significant
amounts of uncharacterized compounds presumed to be polymeric material. dReaction ran in MeOH.
Several trends were noted, most markedly that increasing the electron density on
the aryl ring in general increased the effectiveness of this method.
Phloroacetophenone (2) initially displayed the most striking outcome, providing
the natural product octandrenolone (53) in 89% yield (Table 1, Entry 1). This is a
significant improvement on the previously highest reported yield (40%)151 of this
molecule. While there is a possibility for the formation of two different regioisomeric
114
dichromene products, 53 was the only product observed, the structure of which was
verified by comparison to previously reported spectral data.151 We believe that the
hydrogen bonding between the carbonyl and the ortfiophenol, 111113 which renders the
phenolic hydrogen unavailable, plays an important role in influencing the regioselective
reaction of this, and all, orf/johydroxycarbonylbenzenes using this method.
Scheme 33: Mechanism E m p h a s i z i n g the Role of the Phenolic Proton
Interestingly, selective protection of the 4-hydroxy substituent of
phloroacetophenone as either the feit-butyldimethylsilyl ether (18, Table 1, Entry 2) or
methoxymethyl ether (15, Table 1, Entry 4) resulted in a considerable drop in yield
under the standard reaction conditions. These findings, however, showed further
promise for the regioselectivity of this reaction, as none of the protected
dichromenylated products were observed. The structure of novel compound 13TBS
115
was determined by full spectroscopic characterization, and 13MOM was identified by
comparison to previously published spectral data.58
In the case of the MOM-protected phenol 15 (Table 1, Entry 4), the product
under the standard conditions was accompanied by significant levels of octandrenolone
(53) and also uncharacterized polymers, both attributed to the breakdown of the mixed
acetal protecting group. Decomposition was also seen in the reaction of the acetonide
containing phenol 23 under the standardized conditions (Table 1, Entry 6), although to a
lesser degree; the structure of the novel resulting chromene 35 was elucidated
unambiguously by x-ray crystallography.
All of the remaining investigated phenols presented the possibility for
regioisomeric products. In all cases where reaction occurred, the singular chromene
product indicated was the only one observed in any significant amount. The reactions
using phenols 5 4 , 5 6 , and 58 (Table 1, Entries 8-13) display remarkable regioselectivity.
While there are several products which could theoretically be produced in each case
(including dichromenylated products and a several regioisomeric mono-chromenes), the
shown products and starting materials were the only compounds detected in the crude
product mixtures. These isolated products were all identified based on comparison to
previously reported spectral data.56 The literature NMR data for chromene 55 was not
sufficiently diagnostic for us to state with certainty which isomer was synthesized, and
therefore a nOe experiment was performed to unambiguously establish the structure of
116
the product. Specifically, irradiation of the benzylic methyl protons resulted in
significant enhancement of the signal of the single adjacent aryl proton as well as the
aldehyde proton. No such enhancement of the a-vinyl hydrogen was observed, a result
consistent only with the indicated structure.
The difference in reactivity amongst phenols 5 4 , 5 6 , and 58 (Table 1, Entries 813) illustrate the impact a single methyl substitution can have on this method. A
comparison of the relative reactivity of phenols 58 (Table 1, Entry 12) and 54 (Table 1,
Entry 8) under the standard conditions shows that incorporation of the C-6 methyl
group resulted in a five-fold increase in yield. Similarly, going from an aldehyde (58,
Table 1, Entry 12) to a methyl ketone (56, Table 1, Entry 10) also improved the yield. It
is noteworthy that in both cases, the addition of the methyl group increases the electron
density in the aromatic ring.134
When the carbonyl was located meta to the hydroxyl substituents as in
compound 60 (Table 1, Entry 14), only uncharacterized polymer was observed after
microwave irradiation. The formation of this polymer apparently involves 3-methyl-2butenal (52), as irradiation of 60 without 52 provided full recovery of the starting
material. Notably, 4-hydroxybenzaldehyde (61) proved impervious to this annulation
method under a range of reaction conditions, including these standardized conditions
(Table 1, Entry 15).
117
Several non-carbonyl containing phenols were also attempted with varying
degrees of success. Although no reaction was observed with either phenol (62) itself or
with para-methoxyphenol (63) under several sets of reaction conditions including the
standardized conditions (Table 1, Entries 16 and 17), both mefa-methoxyphenol (64) and
3,4-dimethoxyphenol (66) gave low yields of chromene products when exposed to our
initial reaction conditions (Table 1, Entries 18 and 20). The low yields of the natural
products precocene I (65) and II (67) were subsequently improved dramatically by
altering some of the reaction variables (Table 1, Entries 19 and 21). These two materials
were identified as the products of the reactions of their respective parent phenols based
on previously published spectral data.60
Two dihydroxyaryl compounds not containing carbonyls were also investigated.
It is well documented that mono-chromenes derived from resorcinol (68) are unstable
compounds, 135 and thus not surprisingly chromene 69 was observed in only sparing
amounts (Table 1, Entry 22), as most of the material degraded during the course of the
reaction; this substrate was identified by the characteristic splitting in the *H NMR.
Orcinol (70) was a much more receptive substrate to the reaction conditions,
regioselectively providing exclusively chromene 71 (Table 1, Entry 23) in 44% yield
under the standard conditions; the remainder of the starting material was left
unaffected. The structure of chromene 71 was established based on comparison to
published NMR data.57
118
Although it was not possible to establish a single set of conditions that was
optimal for all substrates, by altering controllable experimental variables (time, power,
equivalents of 52, concentration) we were often able to significantly improve the yields
relative to our initial conditions. The results of this pursuit (the best yields for each
chromene produced with the conditions used) are also presented in Table 1. Of note,
this experimentation resulted in a drastic increase in the production of novel chromene
13TBS (30% to 94%, Table 1, Entries 2 and 3) and natural products precocene I (65, 7%
to 63%, Entries 18 and 19) and II (67, 5% to 88%, Table 1, Entries 20 and 21).
Phenol 15, under most reaction conditions in CDCb, resulted in the appearance
of significant amounts of unidentified compounds presumed to be polymeric material.
This phenomenon was attributed to the breakdown of the MOM protecting group,
followed by polymerization involving formaldehyde generated in situ. In an isolated
trial in methanol, chromene 13MOM was able to be produced from 15 cleanly in fairly
good yield (60%, Table 1, Entry 5), with the starting materials being the only other
compounds detected in the crude J H NMR. It is possible that in chloroform, where the
solubility of these compounds is poor, a phenolic proton is catalyzing the degradation of
the MOM group via intermolecular contacts prior to solvation; in methanol, which
readily solubilizes phenol 15, these intermolecular contacts in all likelihood do not exist
due to solvation. Additionally, reactions of 15 in CDCb were most successful when run
at the lowest investigated concentration (0.25 M).
119
The data reported as the best yield for each phenol was compiled from several
trials using each substrate; a discussion of illustrative findings from the investigations of
selected phenols accompanies the data shown in Tables 2 and 3, which track the impact
of changes in the controllable experimental variables. A complete table of the results of
all trials of all examined phenols can be seen in Chapter 3.3 of this document.
Table 2: Optimization Trials for Series of 2,4-Dihydroxycarbonylbenzenes
entry
phenol
time (h)
150
1
21
300
1
26
150
2
25
150
5
48
150
1
10
300
1
16
150
2
21
150
10
43
9
150
1
4
10
300
1
9
11
150
2
7
12
150
10
15
OH
56
equiv. 52
cone. (M)
yield (%)a
power (W)
OH
54
chromene product
"Crude product mixtures consisted of greater than 95% product and starting materials only. Yields were
determined by NMR via comparison to an equimolar amount of 1,2-dimethoxyethane (based on starting
phenol) added to the crude reaction mixture after reaction completion and cooling.
In the series of 2,4-dihydroxycarbonylbenzenes (Table 2), positive effects were
noted when either the power (entries 2, 6,10) or reaction time (entries 3, 7,11) was
doubled from the original standard conditions (entries 1, 5, 9). When exposed for yet
longer reaction times (entries 4, 8,12), even higher yields of the desired chromene
120
products ensued, although these effects do not appear to be linear. In all trials, no
significant amount of any other products was observed.
Table 3: Optimization Trials for Series of M e t h o x y p h e n o l s
entry
phenol
chromene product
cone. (M)
yield (%
150
1
7
300
1
39
300
1
63
300
2
27b
5
300
1
53
6
150
neat
19
150
1
5
300
1
39
300
1
88
300
2
41
11
300
1
44
12
150
neat
17
1
2
3
tr
H3CCX^,OH
4
H
10
3
C O ^
65
power (W)
time (h)
equiv. 52
HjCC
67
"Crude product mixtures consisted of greater than 95% product and starting materials only, unless
otherwise indicated. Yields were determined by NMR via comparison to an equimolar amount of 1,2dimethoxyethane (based on starting phenol) added to the crude reaction mixture after reaction completion
and cooling. bCrude product mixture contained greater than 5%, based on starting phenol, of
uncharacterized compounds presumed to be polymeric material.
Additional efforts were also put forth into the syntheses of the natural products
precocene I (65) and II (67) utilizing this method (Table 3). Doubling the power of the
microwave irradiation (Entries 2 and 8) from the standard conditions (Entries 1 and 7)
had a very favorable effect on the production of the desired 2,2-dimethyl-2iL/-chromenes,
and when coupled with a doubling of the amount of 52 added (Entries 3 and 9), yields
were even further increased. Trials at this elevated wattage run at twice the
concentration (Entries 4 and 10) displayed a minimal boost in the production of 67, but
121
the yield of 65 actually suffered due to decomposition of the materials. Increasing the
time of exposure (Entries 5 and 11) had a positive effect on the yield of both natural
products. Omitting solvent from the reaction mixture (Entries 6 and 12) did not prove
beneficial to the product output.
Table 4: Solvent Trials for the Synthesis of Octandrenolone (53)
HO^/L/OH
1M in solvent, 3 equiv. 52
V
300 W, 1 hour
HOv
(
OH
2
53
entry
1
solvent
hexane
dielectric constant (e)
2.0
yield(%)a
11
2
benzene
2.3
24
3
chloroform
4.8
60
4
tetrahydrofuran
7.5
9
5
acetone
21
17
6
ethanol
24
22
7
methanol
33
34
8
acetonitrile
37
5
9
N,N -dimethylformamide
38
4
10
water
80
3
11
none
na
21
12
CDC13 washed w/aq. NaOH
4.8
55
a
Yields were obtained by adding one equivalent (based on starting phenol 2) of naphthelene followed by
GCMS analysis.
While CDCb was chosen as the solvent for these reactions initially merely for
facility of NMR evaluation, further studies were performed to investigate the effect of
solvent choice on this reaction. While clearly the use of CDCk as the solvent provided
the maximum yield of the desired product, no trends regarding polarity or proticity
122
emerged from this investigation. In addition to a variety of solvents, the reaction was
also attempted in CDCb that had been washed several times with a 2M solution of
aqueous NaOH and subsequently dried over MgSOi (Entry 12); these conditions
afforded a yield comparable to the untreated CDCk This result shows that this reaction
is indeed truly uncatalyzed, since any trace DC1 (or HC1) in the solvent would have been
eliminated with the washing. The full results of these trials are reported in Table 4.
Since the goal of this exploration was to forge a new route to making 2,2dimethyl-2ff-chromenes exclusively, 2-methyl-3-butenal (52) was the only a,|3unsaturated aldehyde explored to any extent. However, differently substituted a,punsaturated carbonyls could potentially be utilized in this reaction to obtain a variety of
chromenes or related structures. The literature is rife with examples of natural products
which could potentially be constructed through use of this methodology, including A9tetrahydrocannabinol, 152154 smenochromene D,155 and daurichromenic acid.156
A9-tetrahydrocannabinol
O
smenochromene D
OH
daurichromenic acid
Figure 27: Synthetic Targets Potentially Accessible U s i n g Microwave
Methodology
123
3.2 Experimental and Spectral Data
General Experimental Considerations: ID NMR spectra were recorded on
a Variart Unity INOVA-400 spectrometer. Proton and carbon spectra were acquired at
400 and 101 MHz, respectively. Data for the nOe experiment was collected at 500 MHz
on a Varian Unity INOVA-500 spectrometer. Chemical shifts are reported in ppm (6)
relative to the solvent peak (CHCb in CDCb at 7.24 ppm for J H spectra, and 77.23 ppm
for 13C spectra). Mass spectra were recorded on a JEOL-SX102 high resolution mass
spectrometer run under EI mode at 10 kV. Infrared spectra were determined on a
Nicolet Avatar 360 FT-IR spectrometer. Microwave reactions were run in 10 mL sealed
cap microwave reaction vessels in CEM Discover chemical synthesis microwaves (SClass and LabMate Series). Isolated compounds were purified using flash column
chromatography on silica gel (SiliCycle, 230-400 mesh). Commercially available
reagents and solvents were used as purchased. Please note that an inert atmosphere is
not a requirement for this method: this step was performed merely to standardize all
reaction conditions.
124
Typical Experimental Procedure For Making 2,2-Dimethyl-2.H-chromenes;
Synthesis of Octandrenolone (53):
o
52
CDCI3, microwave
Phloroacetophenone (2) m o n o h y d r a t e (186 mg, 1 mmol) w a s w e i g h e d o u t a n d
placed in a 10 m L m i c r o w a v e reaction vessel. To this w a s a d d e d C D C k (1 mL), a n d t h e n
3-methyl-2-butenal (290 [xL, 3 m m o l ) . The reaction vessel w a s flushed w i t h argon for a
period of 30 seconds before being c a p p e d . The tube w a s then placed into the m i c r o w a v e
reactor a n d irradiated at 150 w a t t s for 1 hour. After cooling, the tube w a s r e m o v e d a n d
the reaction mixture w a s concentrated. The resulting crude p r o d u c t w a s purified b y
flash c o l u m n c h r o m a t o g r a p h y using 5:1 hexane:Et20 to afford 267 m g (89%) of
octandrenolone (53) as a pale yellow oil after concentration (Rf = 0.54); J H N M R 5 6.61
(d, / = 10 Hz, 1H), 6.54 (d, / = 9.6 Hz, 1H), 5.40 (t, / = 10 Hz, 2H), 2.62 (s, 1H), 1.45 (s, 6H),
1.40 (s, 6H); 13C N M R 5 203.3,160.7,156.8,155.1,125.4,124.8,116.5,116.3,105.6,102.4,
102.3, 78.4, 78.2, 33.3, 28.6, 28.1; IR (neat) 2975.13,1636.92,1596.46,1460.91,1425.75,
1363.89,1281.06,1193.62,1133.77,1119.15,1002.34, 938.39, 879.84, 727.66, 687.15, 623.07
cm"1
125
l-[5-(terf-Butyl-dimethyl-silanyloxy)-7-hydroxy-2 / 2-dimethyl-2/f-chromen-8-yl]ethanone (13TBS):
13TBS
Rf = 0.50 (10:1 hexane:Et 2 0); *H NMR 6 6.50 (d, / = 10 Hz, 1H), 5.91 (s, 1H), 5.39 (d,
/ = 9.6 Hz, 1H), 2.64 (s, 3H), 1.47 (s, 6H), 0.98 (s, 9H), 0.24 (s, 6H); 13C NMR 6 203.6,165.6,
158.2,157.2,124.9,117.4,106.8,105.8, 99.9, 78.2, 33.4, 28.2, 25.9,18.5, -4.1; IR (neat)
2933.29, 2860.58,1611.25,1580.12,1480.83,1416.78,1364.78,1286.45,1264.67,1172.21,
1116.82,1075.17, 889.29, 833.67, 781.67, 731.80, 683.84 cm-1; HRMS (EI) m/z calculated for
CioH2804Si 348.1757 (M+), found 348.1759 (M+).
l-(7-Hydroxy-5-methoxymethoxy-2,2-dimethyl-2H-chromen-8-yl)-ethanone
(13MOM):
Rf = 0.40 (2:1 hexane:Et20); »H NMR 5 6.56 (d, / = 10 Hz, 1H), 6.17 (s, 1H), 5.40 (d, /
= 10 Hz, 1H), 5.17 (s, 2H), 3.45 (s, 3H), 2.64 (s, 3H), 1.47 (s, 6H); 13C NMR 5 203.6,166.1,
126
158.7,156.6,125.0,116.8,106.8,103.5, 95.1, 94.4, 78.2, 56.7, 33.4, 28.1; IR (neat) 2974.54,
1610.37,1589.96,1485.61,1426.80,1364.90,1265.90,1217.26,1157.33,1117.53,1079.29,
1057.51, 954.66, 877.55, 825.91, 687.82 cm"1.58
10-Hydroxy-2,2,7,7-tetramethyl-7H-l,3,8-trioxa-anthracen-4-one(35):
OH
23
Rf = 0.56 (5:1 hexane:Et 2 0); *H NMR 5 10.61 (s, 1H), 6.57 (d, / = 10.4,1H), 5.88 (s,
1H), 5.48 ( d , / = 10 Hz, 1H), 1.70 (s, 6H), 1.42 (s, 6H); 13C NMR 6 165.5,161.8,157.5,156.4,
126.8,115.5,107.1,104.3, 96.5, 92.9, 78.5, 28.6, 25.9; IR (neat) 2977.74,1682.71,1638.75,
1583.45,1497.06,1460.44,1383.55,1324.43,1280.11,1206.65,1166.66,1121.28,1093.57,
1052.53, 985.47, 919.06, 884.34, 842.00, 799.46, 770.38, 737.97, 711.34, 658.01 cm-1; HRMS
(EI) m/z calculated for CisHieOs 276.0998 (M+), found 276.1003 (M+).
127
5-Hydroxy-2,2,74rimethyl-2H-chromene-6-carbaldehyde (55):
O^H
0_H
Rf = 0.37 (3:1 hexane:Et 2 0); J H NMR 5 12.62 (s, 1H), 10.03 (s, 1H), 6.63 (d, / = 10.4,
1H), 6.15 (s, 1H), 5.52 (d, / = 10.4 Hz, 1H), 2.46 (s, 3H), 1.42 (s, 6H); " C NMR 5 193.1,
160.7,160.7,143.8,127.7,115.5,113.4,111.4,107.4, 78.3, 28.6,18.51; IR (neat) 2974.72,
2928.23,1629.04,1566.69,1481.35,1428.86,1368.87,1325.19,1296.48,1254.30,1212.16,
1139.46,1061.52,1002.06, 881.00, 842.76, 808.43, 726.95, 664.31 cm-1.56
l-(5-Hydroxy-2,2-dimethyl-2f/-chromen-6-yl)-ethanone (57):
Rf = 0.50 (3:1 hexane:Et 2 0); J H NMR 5 7.49 (d, J = 8.8,1H), 6.69 (d, / = 10 Hz, 1H),
6.31 (d, / = 8.8 Hz, 1H), 5.56 (d, / = 9.6 Hz, 1H), 2.51 (s, 3H), 1.43 (s, 6H); 13C NMR 6 202.9,
159.9,159.8,131.8,128.4,116.0,114.0,109.4,108.5, 77.9, 28.5, 26.36; IR (neat) 2972.01,
2926.11,1619.97,1486.45,1427.84,1369.01,1329.79,1271.23,1210.72,1165.41,1114.58,
1073.15, 977.90, 895.26, 808.08, 730.76 cm-1.56
128
5-Hydroxy-2,2-dimethyl-2H-chromene-6-carbaldehyde (59):
O^M
O^M
Rf = 0.52 (3:1 hexane:Et 2 0); *H NMR 8 11.62 (s, 1H), 9.63 (s, 1H), 7.26 (d, / = 8.4 Hz,
1H), 6.66 (d, / = 10 Hz, 1H), 6.40 (d, / = 8.4 Hz, 1H), 5.58 (d, / = 10 Hz, 1H), 1.44 (s, 6H);
13
C NMR 5 194.7,160.7,158.9,134.9,128.8,115.4,115.3,109.6,109.0, 78.4, 28.6;
IR (neat) 2975.85,1641.54,1622.14,1579.16,1482.95,1430.42,1368.54,1326.50,1296.21,
1253.72,1212.53,1164.06,1109.85,1082.93, 940.66, 895.79, 848.02, 803.14, 729.35, 659.97,
609.43 cm 4 . 56
Precocene I (65):
H3CO
OH
H3CO
64
Rf = 0.48 (5:1 hexane:Et 2 0); *H NMR 8 6.86 (d, / = 8 Hz, 1H), 6.38 (dd, / = 8, 2.4 Hz,
1H), 6.35 (d, / = 2.4 Hz, 1H), 6.25 (d, / = 9.6 Hz, 1H), 5.45 (d, / = 9.6 Hz, 1H), 3.75 (s, 3H),
1.40 (s, 6H); 13C NMR 5 160.8,154.4,128.1,127.1,122.1,114.8,106.9,102.2, 76.6,55.5, 28.2;
IR (neat) 2972.53,1615.48,1568.51,1502.54,1458.87,1369.12,1317.63,1279.91,1195.63,
1158.77,1125.52,1034.06, 982.96, 838.63, 806.33, 755.01 cm 1 . 60
129
Precocene II (67):
H3CO
OH
H3CO
Oj
HgCO
H3CO
67
66
Rf = 0.21 (5:1 hexane:EhO); lH NMR 8 6.50 (s, 1H), 6.39 (s, 1H), 6.21 (d, / = 9.6 Hz,
1H), 5.45 ( d , / = 10Hz), 3.81 (s, 3H), 3.79 (S/ 3H), 1.38 (s, 6H); 13C NMR 8 149.8,147.4,
143.3,128.4,122.2,113.2,109.9,101.2, 76.2,56.7,56.1, 27.9; IR (neat) 2971.07, 2837.03,
1614.28,1505.47,1458.24,1362.48,1277.63,1196.02,1164.71,1133.70,1009.81, 903.09,
856.64, 754.65 cm"1.60
2,2-Dimethyl-2H-chromen-7-ol(69):
OH
HO
68
69
Rf = 0.26 (3:1 hexane:EbO); *H NMR 8 6.801 (d, / = 7.6 Hz, 1H), 6.296 (dd, / = 2.4
Hz, 8 Hz, 1H), 6.274 (d, / = 2.4 Hz, 1H), 6.230 (d, / = 10 Hz, 1H), 5.435 (d, / = 10 Hz, 1H),
1.385 (s, 6H); «C NMR 8 156.769,154.425,128.047,127.357,122.081,114.980,107,883,
103.927, 76.642, 28.181; IR (neat) 3371.68, 2974.51, 2927.93,1617.63,1502.58,1458.91,
1366.40,1302.66,1217.75,1156.04,1119.69, 990.51, 846.55, 809.18, 759.52, 701.77, 634.16
cm
•1 136
130
2,2,7-Trimethyl-2H-chromen-5-ol (71):
HO
OH
70
71
Rf = 0.25 (3:1 hexane:Et 2 0); J H NMR 5 6.402 (d, / = 10 Hz, 1H), 6.172 (s, 1H), 6.165
(s, 1H), 5.466 (d, / = 10 Hz), 2.185 (s, 3H), 1.372 (s, 6H); 13C NMR 5 156.083,154.398,
135.482,127.759,119.300,113.504,109.863,101.870, 75.978, 27.866,18.629; IR (neat)
3378.46, 2974.80,1608.00,1463.05,1364.82,1324.36,1245.13,1204.02,1137.88,1063.28,
990.28, 839.38, 765.73, 731.93, 702.64, 638.52 cm"1.57
131
3.3 Chromene Methodology Trials Data
Table 5: Complete Results of the Investigation of the Microwave-Assisted
Synthesis of 2 / 2-Dimethyl-2Jy r -chromenes in CDCb
power
(W)
time
(h)
equiv.
46
1
150
1
3
89
2
150
0.25
3
60
3
150
0.5
3
72
4
300
0.1
2.5
41
300
0.2
2.5
32
150
1
3
30
300
0.2
1.5
94
150
1
3
1 .
0 b,c
9
300
0.2
1.5
1
Qb,C
10
300
0.2
1.5
0.5
11
300
0.2
1.5
0.25
25
12
300
0.5
1.5
0.25
17 b ' c
300
1.0
1.5
0.25
300
0.2
3
0.25
25
15
150
0.5
1.5
0.25
29
16
150
1
1.5
0.25
21 c
entry
5
13
14
phenol
chromene product
53
OMOM
13MOM
cone.
(M)
yield
(%)a
5 b.c
1 4 b,o
"Crude product mixtures consisted of >95% product and starting materials only unless otherwise indicated.
For reactions run under the standardized set of conditions (150 W, 1 hour, 3 equivalents of 52, 1M in
CDCI3), isolated yields are shown. All other yields were determined by NMR via comparison to an
equimolar amount of 1,2-dimethoxyethane (based on starting phenol) added to the crude reaction mixture
after reaction completion and cooling. bCrude reaction mixture contained significant amounts of undesired
chromene side-products. cCrude product mixture contained significant amounts of uncharacterized
compounds presumed to be polymeric material.
132
Table 5, continued: Complete Results of the Investigation of the
Microwave-Assisted Synthesis of 2,2-Dimethyl-2H-chromenes in CDCb
chromene product
power
(W)
150
time
(h)
1
equiv.
46
3
0^0.
300
0.5
1
14c
300
0.5
2
23
300
0.1
1.5
35
y^r
300
0.2
1.5
35
\JQ
300
0.5
1.5
0.25
35
300
1
1.5
0.25
55
300
2
1.5
0.25
41°
300
1
3
0.25
30c
26
150
1
3
1
21
27
300
1
3
1
26
28
150
2
3
1
25
29
150
5
3
1
48
30
150
1
3
1
10
31
300
1
3
1
16
32
150
2
3
1
21
33
150
10
3
1
43
entry
phenol
17
18
19
22
u
23
OH
23
20
21
T
24
H
°YT
,0
35
25
CK M
cone.
(M)
yield
(%)a
16c
CU .H
a
Crude product mixtures consisted of >95% product and starting materials only unless otherwise indicated.
For reactions run under the standardized set of conditions (150 W, 1 hour, 3 equivalents of 52, 1M in
CDCI3), isolated yields are shown. All other yields were determined by NMR via comparison to an
equimolar amount of 1,2-dimethoxyethane (based on starting phenol) added to the crude reaction mixture
after reaction completion and cooling. bCrude reaction mixture contained significant amounts of undesired
chromene side products. cCrude product mixture contained significant amounts of uncharacterized
compounds presumed to be polymeric material.
133
Table 5, continued: Complete Results of the Investigation of the
Microwave-Assisted Synthesis of 2,2-Dimethyl-2H-chromenes in CDCh
entry
phenol
chromene product
power
(W)
time
(h)
equiv.
46
cone.
(M)
yield
(%)a
150
1
3
1
4
300
1
3
1
9
150
2
3
1
7
150
10
3
1
15
CK M
34
35
36
37
HOx
A
CT
OH
58
38
150
0C
150
NR
none
150
NR
none
150
NR
none
39
40
OH
41
62
"Crude product mixtures consisted of >95% product and starting materials only unless otherwise indicated.
For reactions run under the standardized set of conditions (150 W, 1 hour, 3 equivalents of 52, 1M in
CDCI3), isolated yields are shown. All other yields were determined by NMR via comparison to an
equimolar amount of 1,2-dimethoxyethane (based on starting phenol) added to the crude reaction mixture
after reaction completion and cooling. bCrude reaction mixture contained significant amounts of undesired
chromene side products. cCrude product mixture contained significant amounts of uncharacterized
compounds presumed to be polymeric material.
134
Table 5, continued: Complete Results of the Investigation of the
Microwave-Assisted Synthesis of 2,2-Dimethyl-21f-chromenes in CDCb
entry
phenol
42
O
43
power
(W)
chromene product
time
(h)
equiv.
46
cone.
(M)
yield
(%)a
OH
none
H3CO
63
44
150
NR
300
NR
150
300
1
1
3
1
7
3
1
39
300
1
6
1
63
300
1
3
2
27c
48
300
2
3
1
53
49
150
1
5
neat
19
50
150
1
3
1
5
300
1
3
1
39
300
0.5
6
1
37
300
1
3
2
41
300
2
3
1
44
55
150
1
5
neat
17
56
300
1
6
1
88
45
46
47
HgCO^/^^OH
XX
Ha CO
64
51
51
53
54
H3CO
OH
H3CO
H3CO
H3CO
66
67
"Crude product mixtures consisted of >95% product and starting materials only unless otherwise indicated.
For reactions run under the standardized set of conditions (150 W, 1 hour, 3 equivalents of 52, 1M in
CDCI3), isolated yields are shown. All other yields were determined by NMR via comparison to an
equimolar amount of 1,2-dimethoxyethane (based on starting phenol) added to the crude reaction mixture
after reaction completion and cooling.
Crude reaction mixture contained significant amounts of undesired
chromene side products. cCrude product mixture contained significant amounts of uncharacterized
compounds presumed to be polymeric material.
135
Table 5, continued: Complete Results of the Investigation of the
Microwave-Assisted Synthesis of 2 / 2-Dimethyl-2H-chromenes in CDCh
power
(W)
time
(h)
equiv.
46
cone.
(M)
yield
(%)a
150
1
3
1
14°
300
1
1
1
0C
300
1
2
1
0C
60
150
1
3
1
44
61
300
1
1
1
40
62
300
1
2
1
13c
phenol
entry
57
HO
chromene product
OH
58
59
68
69
71
"Crude product mixtures consisted of >95% product and starting materials only unless otherwise indicated.
For reactions run under the standardized set of conditions (150 W, 1 hour, 3 equivalents of 52, 1M in
CDC13), isolated yields are shown. All other yields were determined by NMR via comparison to an
equimolar amount of 1,2-dimethoxyethane (based on starting phenol) added to the crude reaction mixture
after reaction completion and cooling. bCrude reaction mixture contained significant amounts of undesired
chromene side products. cCrude product mixture contained significant amounts of uncharacterized
compounds presumed to be polymeric material.
136
3.4 Selected NMR Spectra
General Experimental Considerations: ID NMR spectra were recorded on
a Varian Unity INOVA-400 spectrometer. Proton and carbon spectra for were acquired
at 400 and 101 MHz, respectively. Data for the nOe experiment was collected at 500
MHz on a Varian Unity INOVA-500 spectrometer. Chemical shifts are standardized to
the solvent peak (CHCls in CDCk at 7.24 ppm for *H spectra, and 77.23 ppm for 13C
spectra).
137
8
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8
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8
8
8
^
^
S
0
"
|
(A
m
x
o
•-*
^
PI »
»
ifl
5 (<
Figure 28: *H NMR Spectrum of Novel Chromene 13TBS
138
»
«
ss*
*»
o
«a
o
a
«
a
a
s
a
3
8
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$
o
tr«-\
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I
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sm sul ato sr< s4 st<s>6 **
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t
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^ ^ S N f N f l T ^ f e u l gm
• "*• "1 - "*• H "• "*•
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0
.
O w N ( 1 T i f i « f j i O
Figure 29: 13C NMR Spectrum of Novel Chromene 13TBS
139
J-J
^
o
' 3 6.63 1.00
• 4 6.15 1.06
fl>
3*
3
rt>
Ul
3
3*
O
n
<-••
o
Ji
! 7 1.43 5.92
I 6 2.4S 3,26
' 5 5.51 1.00
2 10.02 1,0?
CD
«f
H
18.0
10,0
Is
d
s
s
It
10,04,
10.
Shft Integral Class J"<
i 112,62 0,81
'
t»
s
1,02
5 5.51
. 6 1.41 5,95
a
s
1,00
1,23
3 6.63
5
5 2 10.02 1,15
;4 6,1S
s
Shift Irrtegfal Class
ll 12.62 0,76
\
3
3
CD
a
o
d
n>
3
3
n>
W
x
ro
>•*
**•
o
w
o
3
a
It
1*1.
*1
7
«1{PSK>)
4
.1.1..I
enhanced
irradiated
enhanced
T
>
r-
3.5 Crystallographic Data for Novel Chromene 35
Crystallographic data collected and analyzed by Dr. David Pham using a Bruker
Kappa Apex II spectrophotometer.
Figure 31: Crystal Structure of Novel Chromene 35
141
Table 1. Crystal data and structure refinement for 35.
Empirical formula
C15H16 05
Formula weight
276.28
Temperature
298(2) K
Wavelength
0.71073 A
Crystal system
Monoclinic
Space group
P2,/c
Unit cell dimensions
a = 8.139(9) A
cc== 90°.
b = 6.957(8) A
(3== 98.71(2)°
c = 25.54(3) A
v == 90°.
Volume
1429(3) A3
Z
4
Density (calculated)
1.284 Mg/m3
Absorption coefficient
0.097 mm"1
F(000)
584
Crystal size
0.46x0.30x0.05 mm3
Crystal color and habit
Colourless Plates
Diffractometer
Bruker Kappa Apex II
Theta range for data collection
2.53 to 28.14°.
Index ranges
-10<=h<=10, -9<=k<=9, -33<=1<==33
Reflections collected
18686
Independent reflections
3475 [R(int) = 0.0235]
Observed reflections (I > 2o(I))
2461
Completeness to theta = 28.14°
99.0 %
Absorption correction
Semi-empirical from equivalents
Max. and min. transmission
0.9952 and 0.9569
Solution method
SHELXS-97 (Sheldrick, 1990)
Refinement method
SHELXL-97 (Sheldrick, 1997)
Data / restraints / parameters
Goodness-of-fit on F
2
3 4 7 5 / 0 / 185
1.041
Final R indices P>2o(I)]
R l = 0.0503, wR2 = 0.1291
R indices (all data)
R l = 0.0701, wR2 = 0.1450
Largest diff. peak and hole
0.349 and-0.322 e.A"3
142
Table 2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (A2x 103)
for 35. U(eq) is defined as one third of the trace of the orthogonalized U'J tensor.
x
y
z
U(eq)
0(1)
1183(1)
1392(2)
596(1)
61(1
0(2)
-343(1)
3400(2)
992(1)
78(1
0(3)
1062(1)
6496(2)
1482(1)
71(1
0(4)
6928(2)
6887(2)
1575(1)
101(1
0(5)
4088(1)
1769(2)
648(1)
54(1
CO)
1023(2)
3008(3)
879(1)
56(1
C(2)
2519(2)
4113(2)
1045(1)
47(1
C(3)
2499(2)
5787(2)
1354(1)
51(1
C(4)
3965(2)
6764(2)
1542(1)
54(1
C(5)
4024(3)
8506(3)
1858(1)
83(1
C(6)
5470(3)
9324(3)
2034(1)
92(1
C(7)
7101(2)
8562(2)
1928(1)
62(1
C(8)
8198(4)
7929(5)
2429(1)
117(1
C(9)
7987(3)
10010(3)
1633(1)
95(1
C(10)
5459(2)
6013(2)
1415(1)
56(1
C(ll)
5518(2)
4368(2)
1108(1)
54(1
C(12)
4046(2)
3440(2)
929(1)
46(1
C(13)
2739(2)
-826(3)
167(1)
71(1
C(14)
2582(2)
1262(3)
305(1)
55(1
C(15)
2277(3)
2578(3)
-172(1)
78(1
143
c
CS
"9
60
a
i
o
co
*
CN
•
*
R
i—l
CN
<N
U
CN
en
in
co
O
O
o
CN
<
CO
CN
NO
CN
/^i
rU
-=t
r-~
*
•
oo
co
o
K U
CN
s.^
ON
NO
CO
^H
CN
u
IN
OO
CO
• < *
*
CN
00
•
•<*
co
00
s_^
CN
CS
*
o
/
•
o
•<t
fN
co
^H
CN
<-> U
*
1-H
u
•
U
*
co
•
ON
CO
Tf
^^
u
co
co
co
U
NO
co
i—i
OS
•*t
o
o
CO
U
NO
U
NO
< ^^ <c
r- NO
ffi U ffi
in
^^ co o
NO
co
o m CN co
•* <tf CO
m
^
^H
U
o
U
o o o o o o o o o u u u u u u u u
0.9
CN
•
*
m
•
IT)
en
U
0.9
^ H ^ H C N c o c o ^ - ^ J - m i n — i c N t N c o ' ^ - ' ^ - i n i n
U
0.8
CO
s—^
NO
o
in
ON
CO
NO
ON
<
oo
o
*«* o
o
f-H
in
oo
o
o
NO
ON
w
oo
o
ON
o
NO
O
00
*w
u U X X «
r- r-- oo oo oo
U U U O
O
O
-H
CO
ON
O
—I
o
in
>n
CO
ON
CO
-H
r- o
c f? 3 q>
o
o
VO
ON
O
O
CO
^*
o
o
G
U
~*
o
o
ON
O
^-
r~
co
K
U
^H
NO
ON
ON
U
ON
NO
ON
X
U
ON
m
ON
<
U
C(13)-H(13A)
0.9600
C(13)-H(13B)
0.9600
C(13)-H(13C)
0.9600
C(14)-C(15)
1.514(3)
C(15)-H(15A)
0.9600
C(15)-H(15B)
0.9600
C(15)-H(15C)
0.9600
C(l)-0(1)-C(14)
118.07(12)
C(3)-0(3)-H(3A)
109.5
C(10)-O(4)-C(7)
122.85(14)
C(12)-0(5)-C(14)
116.13(12)
0(2)-C(l)-0(l)
118.46(15)
0(2)-C(l)-C(2)
124.55(18)
0(1)-C(1)-C(2)
116.94(14)
C(12)-C(2)-C(3)
118.75(14)
C(12)-C(2)-C(l)
119.59(16)
C(3)-C(2)-C(l)
121.52(14)
0(3)-C(3)-C(4)
117.72(16)
0(3)-C(3)-C(2)
121.33(15)
C(4)-C(3)-C(2)
120.94(14)
C(3)-C(4)-C(10)
117.70(16)
C(3)-C(4)-C(5)
123.55(16)
C(10)-C(4)-C(5)
118.75(16)
C(6)-C(5)-C(4)
120.00(18)
C(6)-C(5)-H(5A)
120.0
C(4)-C(5)-H(5A)
120.0
C(5)-C(6)-C(7)
123.79(19)
C(5)-C(6)-H(6A)
118.1
C(7)-C(6)-H(6A)
118.1
0(4)-C(7)-C(6)
112.85(15)
0(4)-C(7)-C(9)
103.43(17)
C(6)-C(7)-C(9)
111.03(19)
0(4)-C(7)-C(8)
106.17(19)
C(6)-C(7)-C(8)
112.3(2)
C(9)-C(7)-C(8)
110.7(2)
C(7)-C(8)-H(8A)
109.5
C(7)-C(8)-H(8B)
109.5
H(8A)-C(8)-H(8B)
109.5
C(7)-C(8)-H(8C)
109.5
H(8A)-C(8)-H(8C)
109.5
H(8B)-C(8)-H(8C)
109.5
C(7)-C(9)-H(9A)
109.5
C(7)-C(9)-H(9B)
109.5
H(9A)-C(9)-H(9B)
109.5
C(7)-C(9)-H(9C)
109.5
H(9A)-C(9)-H(9C)
109.5
H(9B)-C(9)-H(9C)
109.5
O(4)-C(10)-C(ll)
115.88(15)
O(4)-C(10)-C(4)
121.40(16)
C(ll)-C(10)-C(4)
122.70(15)
C(12)-C(ll)-C(10)
118.06(15)
C(12)-C(11)-H(11A)
121.0
C(10)-C(11)-H(11A)
121.0
0(5)-C(12)-C(ll)
118.89(14)
0(5)-C(12)-C(2)
119.20(13)
C(ll)-C(12)-C(2)
121.84(16)
C(14)-C(13)-H(13A)
109.5
C(14)-C(13)-H(13B)
109.5
H(13A)-C(13)-H(13B)
109.5
C(14)-C(13)-H(13C)
109.5
H(13A)-C(13)-H(13C)
109.5
H(13B)-C(13)-H(13C)
109.5
0(5)-C(14)-0(l)
109.56(15)
0(5)-C(14)-C(13)
106.52(14)
0(1)-C(14)-C(13)
106.28(14)
0(5)-C(14)-C(15)
111.26(15)
0(1)-C(14)-C(15)
109.17(15)
C(13)-C(14)-C(15)
113.88(17)
C(14)-C(15)-H(15A)
109.5
C(14)-C(15)-H(15B)
109.5
H(15A)-C(15)-H(15B)
109.5
C(14)-C(15)-H(15C)
109.5
H(15A)-C(15)-H(15C)
109.5
H(15B)-C(15)-H(15C)
109.5
Symmetry transformations used to generate equivalent atoms:
147
Table 4. Anisotropic displacement parameters (A2x 103)for 35. The anisotropic
displacement factor exponent takes the form: -2n2[ h 2 a* 2 U u + ... + 2 h k a* b* U 12 ]
Tjll
TJ22
033
TJ23
JJ13
U12
0(1)
44(1)
74(1)
65(1)
-9(1)
11(1)
-12(1)
0(2)
42(1)
101(1)
94(1)
-14(1)
21(1)
-7(1)
0(3)
47(1)
84(1)
87(1)
-14(1)
22(1)
7(1)
0(4)
50(1)
95(1)
161(2)
-74(1)
24(1)
-16(1)
0(5)
40(1)
59(1)
63(1)
-12(1)
4(1)
-2(1)
C(l)
42(1)
74(1)
53(1)
3(1)
9(1)
-4(1)
C(2)
38(1)
57(1)
46(1)
4(1)
9(1)
0(1)
C(3)
43(1)
61(1)
52(1)
4(1)
14(1)
6(1)
C(4)
50(1)
55(1)
60(1)
-5(1)
13(1)
2(1)
C(5)
64(1)
77(1)
113(2)
-37(1)
27(1)
KD
C(6)
76(1)
79(1)
124(2)
-50(1)
27(1)
-7(1)
C(7)
62(1)
55(1)
69(1)
-14(1)
8(1)
-7(1)
C(8)
156(3)
124(2)
69(1)
8(2)
11(2)
39(2)
C(9)
111(2)
66(1)
116(2)
7(1)
42(2)
7(1)
C(10)
44(1)
57(1)
70(1)
-11(1)
11(1)
-4(1)
C(ll)
37(1)
57(1)
70(1)
-10(1)
11(1)
0(1)
C(12)
41(1)
50(1)
48(1)
0(1)
8(1)
0(1)
C(13)
57(1)
74(1)
80(1)
-21(1)
4(1)
-11(1)
C(14)
42(1)
69(1)
53(1)
-7(1)
5(1)
-6(1)
C(15)
80(1)
99(2)
55(1)
5(1)
10(1)
3(1)
148
Table 5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (A2x 103)
for 35.
x
y
z
H(3A)
294
5770
1371
107
H(5A)
3046
9046
1937
100
H(6A)
5470
10440
2234
110
H(8A)
7644
6942
2599
175
H(8B)
8421
9007
2664
175
H(8C)
9226
7437
2342
175
H(9A)
7315
10302
1300
142
H(9B)
9032
9489
1570
142
H(9C)
8178
11163
1839
142
H(l 1A)
6523
3909
1026
65
H(13A)
2925
-1575
486
107
H(13B)
3658
-989
-24
107
H(13C)
1734
-1246
-49
107
H(15A)
2174
3879
-56
117
H(15B)
1270
2202
-395
117
H(15C)
3192
2487
-368
117
149
U(eq)
Table 6. Torsion angles [°] for 35.
C(14)-0(l)-C(l)-0(2)
158.60(15)
C(14)-0(1)-C(l)-C(2)
-23.9(2)
0(2)-C(l)-C(2)-C(12)
174.75(16)
0(1)-C(1)-C(2)-C(12)
-2.6(2)
0(2)-C(l)-C(2)-C(3)
-0.8(3)
0(1)-C(1)-C(2)-C(3)
-178.15(13)
C(12)-C(2)-C(3)-0(3)
-179.65(14)
C(l)-C(2)-C(3)-0(3)
-4.0(2)
C(12)-C(2)-C(3)-C(4)
-0.1(2)
C(l)-C(2)-C(3)-C(4)
175.56(15)
O(3)-C(3)-C(4)-C(10)
179.22(15)
C(2)-C(3)-C(4)-C(10)
-0.4(2)
0(3)-C(3)-C(4)-C(5)
-1.0(3)
C(2)-C(3)-C(4)-C(5)
179.40(17)
C(3)-C(4)-C(5)-C(6)
178.3(2)
C(10)-C(4)-C(5)-C(6)
-1.9(3)
C(4)-C(5)-C(6)-C(7)
-0.1(4)
C(10)-O(4)-C(7)-C(6)
-7.1(3)
C(10)-O(4)-C(7)-C(9)
-127.2(2)
C(10)-O(4)-C(7)-C(8)
116.3(2)
C(5)-C(6)-C(7)-0(4)
4.4(4)
C(5)-C(6)-C(7)-C(9)
120.0(3)
C(5)-C(6)-C(7)-C(8)
-115.6(3)
C(7)-O(4)-C(10)-C(ll)
-176.05(17)
C(7)-O(4)-C(10)-C(4)
5.7(3)
C(3)-C(4)-C(10)-O(4)
178.98(17)
C(5)-C(4)-C(10)-O(4)
-0.8(3)
C(3)-C(4)-C(10)-C(ll)
0.8(3)
C(5)-C(4)-C(10)-C(ll)
-178.99(18)
O(4)-C(10)-C(ll)-C(12)
-179.02(17)
C(4)-C(10)-C(ll)-C(12)
-0.8(3)
C(14)-0(5)-C(12)-C(ll)
-156.95(15)
C(14)-0(5)-C(12)-C(2)
25.85(19)
C(10)-C(ll)-C(12)-O(5)
-176.85(14)
C(10)-C(ll)-C(12)-C(2)
0.3(2)
C(3)-C(2)-C(12)-0(5)
177.23(13)
C(l)-C(2)-C(12)-0(5)
1.5(2)
C(3)-C(2)-C(12)-C(ll)
0.1(2)
C(l)-C(2)-C(12)-C(ll)
-175.58(15)
C(12)-0(5)-C(14)-0(l)
-49.31(18)
C(12)-0(5)-C(14)-C(13)
-163.87(13)
C(12)-0(5)-C(14)-C(15)
71.49(19)
C(l)-0(l)-C(14)-0(5)
49.11(19)
C(l)-0(1)-C(14)-C(13)
163.82(14)
C(l)-0(1)-C(14)-C(15)
-72.96(19)
Symmetry transformations used to generate equivalent atoms:
Table 7. Hydrogen bonds for 35 [A and °].
D-H...A
0(3)-H(3A)...0(2)
d(D-H)
d(H...A)
d(D...A)
<(DHA)
0.82
1.94
2.660(3)
145.8
Symmetry transformations used to generate equivalent atoms:
151
References
(1)
Thakur, R. S.; Puri, H. S.; Husain, A. Major Medicinal Plants of India; Central
Institute of Medicinal and Aromatic Plants: Lucknow, India, 1989.
(2)
Nair, C. K. N.; Mohanan, N. Medicinal Plants of India (with Special Reference to
Ayurveda); Nag Publishers: Jawahar Nagar, Delhi, 1998.
(3)
Joshi, S. G. Medicinal Plants; Oxford & IBH Publishing Co. Pvt. Ltd.: New Delhi,
2000.
(4)
Paranjape, P. Indian Medicinal Plants: Forgotten Healer: A Guide to
Herbal Medicine; Chaukhamba Sanskrit Pratisthan: Delhi, 2001.
(5)
Farnsworth, N. R.; Bingel, A. S.; Cordell, G. A.; Crane, F. A.; Fong, H. H. S. /.
Pharm. Sci. 1975, 64, 535-598.
(6)
Anderson Edin. New Phil. J. 1855, 1, 300.
(7)
McGookin, A.; Reed, F. P.; Robertson, A. /. Chem. Soc. 1937, 748-755.
(8)
Perkin, A. G.; Perkin, W. H. Chem. Ber. 1886, 19, 3109-3110.
(9)
Jawein, L. Chem. Ber. 1887, 20,182-183.
(10)
Perkin, A. G. /. Chem. Soc. 1893,975-990.
(11)
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Biography
marc Jordan
adler
PERSONAL
•
Parents Jacqueline and John Adler, sister Allison
EDUCATION
•
B.S., Chemistry, University of California, Berkeley, College of Chemistry; Berkeley, CA; May, 2003
•
Ph.D., Chemistry, Duke University; Durham, NC; May, 2008
TEACHING
•
Course Designer and Instructor, Chemistry 49S: Chemistry and Forensics (Spring 2006 and 2007).
•
Recitation Teaching Assistant, Chemistry 151/152: Organic Chemistry (Summer 2004, Fall 2006, 20072008 Academic Year)
•
Laboratory Teaching Assistant, Chemistry 151/152: Organic Chemistry (2003-2004 Academic Year).
•
Teaching Assistant, Pharmacology 160/Psychology 127: Drugs, Brain, and Behavior (Spring 2005 and
2006)
•
Supervised Undergraduate in Independent Study (Summer and Fall 2005, 2006-2007 and 2007-2008
Academic Years)
•
Tutor, The Science-Advancement Skills Program (2004-2005 Academic Year)
•
Tutor, Undergraduate Organic Chemistry (Spring 2004, Summer 2004, 2006, and 2007, and 2006-2007
Academic Year)
AWARDS
•
Dean's Award for Excellence in Teaching, Honorable Mention (2007, Teaching, Duke University)
•
Charles Bradsher Endowment (2007, Research, Duke University Department of Chemistry)
•
CR Hauser Fellowship (2007, Research, Duke University Department of Chemistry)
•
John Herbert Pearson Award (2007, Teaching, Duke University Department of Chemistry)
•
Stanley and Alice Thompson Summer Research Award (2002, Research, UC Berkeley, College of
Chemistry)
PUBLICATIONS
•
Charkoudian, L. K.; Heymann, J. J.; Adler, M. J.; Haas, K. L.; Mies, K. A.; Bonk, J. F. "Forensics as a
Gateway: Promoting Undergraduate Interest in Science and Graduate Student Professional
Development Through a First-Year Seminar Course"', Journal of'Chemical'Education. (Accepted)
162
PRESENTATIONS
•
Adler.M. J.: Baldwin, S. W. "First Total Synthesis of Rottlerin (In Progress...)", 120th Local ACS
Meeting (NCACS), Durham, NC, April 22, 2006. (Oral Presentation)
•
Adler. M. J.: Baldwin, S. W. "First Total Synthesis of Rottlerin (In Progress...)", 232nd National ACS
Conference, San Francisco, CA, September 13, 2006. (Poster)
•
Heymann, J. J.: Charkoudian, L. K.; Adler, M. J.; Haas, K. L.; Mies, K. A.; Bonk, J. F. "Inside CSL
Teaching Science in a Non-Majors Freshman Seminar Using Forensics", 121 st North Carolina
American Chemical Society Sectional Conference, April 21, 2007. (Poster)
•
Adler.M. J.: Baldwin, S. W. "First Total Synthesis of Rottlerin (In Progress...)", 40th National Organic
Symposium, Durham, NC, June 3, 2007. (Poster)
•
Heymann. J. J.: Charkoudian, L. K.; Adler, M. J.; Haas, K. L.; Mies, K. A.; Bonk, J .F. "CSI in the
Classroom: Teaching Science in a Non-Majors First-Year Seminar Using Forensics and
Chemistry", 234 th ACS National Meeting, Boston, MA, August 20, 2007. (Oral Presentation)
ORGANIZATION MEMBERSHIP
•
Phi Lambda Upsilon, Alpha Pi Chapter (May, 2004 - Present)
- Recruitment Co-Chair (June, 2004 - May, 2006)
- Webmaster (June, 2004 - May, 2006)
- Academic Speaker Coordinator (June, 2005 -June, 2007)
- Fundraising Activities (August, 2003 -June, 2007)
•
Pharmacology Student Training Program (August, 2004 - July, 2006)
•
American Chemical Society, Division of Organic Chemistry (February, 2005 - Present)
163
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