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Explorations into New Reaction Chemistry.

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Reviews
T. Mukaiyama
Synthesis Planning
Explorations into New Reaction Chemistry
Teruaki Mukaiyama*
Keywords:
aldol reaction · glycosylation ·
nucleophilic substitution ·
oxidation · synthetic methods
Angewandte
Chemie
5590
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200300641
Angew. Chem. Int. Ed. 2004, 43, 5590 – 5614
Angewandte
Chemie
Synthetic Methods
This Review describes the basic concepts that have guided our
From the Contents
exploration of new chemical reactions by giving examples of results
from my research group. Our strategy of carrying out research is to
investigate three to four different topics at a time so we can gather as
many results as possible. These may at first appear unrelated to each
other but may have the potential to be united into a greater hypothesis
after repeated feedback. Three scenarios from our research are
presented: the “oxidative–reductive condensation reaction” devised in
1960, which after an interval of nearly 40 years brought forth the new
concept of using compounds of structure Ph2POR as reducing
reagents; the “TiCl4-aldol reaction” of 1973 that eventually led to the
present “base-promoted aldol reaction” through a chain of ideas; and
the “glycosylation reaction using fluorosugars” from 1984 which
recently bloomed into “stereocontrolled glycosylation”. Thus, it can be
said that by reviewing what we had done before, we were able to
expand on it to achieve new outcomes.
1. Oxidative–Reductive Condensation Reactions
1.1. Introduction
The fundamental concept of the oxidative–reductive
condensation is to perform a dehydration condensation by
removing H2O as 2[H] and [O] by the use of a combination of
a weak reductant and oxidant. The characteristic feature of
these reactions is that they proceed under “mild and neutral”
conditions without any assistance from added acids or bases.
The first example of this type of condensation in regard to
acylation reactions was reported from our laboratory in
1963.[1] Treatment of diphenyl- or bis(p-methoxyphenyl)mercury with tri-n-butylphosphane in the presence of two
equivalents of carboxylic acid leads to formation of the
corresponding acid anhydride in high yield together with
mercury and tri-n-butylphosphine oxide (Scheme 1).[1] In this
1. Oxidative–Reductive
Condensation Reactions
5591
2. Crossed Aldol Reactions via
Boron and Silicon Enolate
Intermediates
5597
3. Stereoselective Glycosylation
with Glycosyl Fluorides
5607
4. Concluding Remarks
5610
a conjugated dicarbonyl compound
such as trans-1,2-dibenzoylethylene
were
used
as
the
acceptors
(Scheme 2).[2]
Furthermore, it was also shown
that treatment of Bz-l-Leu-OH (Bz =
benzoyl) with H-Gly-OEt in the presence of triphenylphosphane (reductant) and di(2-pyridyl)disulfide (oxidant) lead to the formation of Bz-l-Leu-Gly-OEt
in high yield (Scheme 3),[3] and Corey et al. have developed
an efficient method for the synthesis of macrocyclic lactones
by treating hydroxycarboxylic acids with di(2-pyridyl)disul-
Scheme 2. Oxidative–reductive condensation in the presence of a
conjugated dicarbonyl compound as the oxidant.
Scheme 1. Principle of the oxidative–reductive condensation of carboxylic acids to carboxylic acid anhydides in the presence of diarylmercury
and tri-n-butylphosphane.
Scheme 3. Oxidative–reductive condensation of two amino acid derivatives in the presence of a disulfide as the oxidant.
reaction two molecules of carboxylic acid undergo condensation with the help of a hydrogen acceptor (diaryl mercury)
and an oxygen acceptor (tri-n-butylphosphane) to give the
anhydride. A similar dehydration condensation reaction of
acids also took place successfully when tributylphosphane and
[*] Prof. T. Mukaiyama
Center for Basic Research
The Kitasato Institute
6-15-5 (TCI), Toshima, Kita-ku, Tokyo 114-0003 (Japan)
Fax: (+ 81) 3-3911-3111
E-mail: mukaiyam@abeam.ocn.ne.jp
Angew. Chem. Int. Ed. 2004, 43, 5590 – 5614
DOI: 10.1002/anie.200300641
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5591
Reviews
T. Mukaiyama
fide in the presence of triphenylphosphane [Eq. (1); THP =
tetrahydropyran-2-yl, py = pyridine].[3b] This method leads to
the efficient synthesis of medium to large rings (7–16,[3c] 12–
21[3d]), and has been applied to the synthesis of a number of
important macrocyclic targets including monensin,[3b] erythronolide B [Eq. (2)],[3e] ( )-11-hydroxy-trans-8-dodecenoic
acid lactone,[3f] ( )-vermiculine [Eq. (3)],[3g] enterobactin,[3h]
and prostaglandins.[3b,i]
concept into an efficient alkylation method by using a
combination of triphenylphosphane and DEAD (Mitsunobu
reaction) [Eq. (5)].[5] Shi et al. used this reaction for the
stereospecific synthesis of chiral tertiary alkylaryl ethers in
about 50 % yield and with complete invertion of configuration.[6] Tsunoda et al. reported an alkylation reaction using
alcohols and cyanomethylenetributylphosphorane [Eq. (6)][7]
or
N,N,N’,N’-tetramethylazodicarboxamide
(TMAD)
[Eq. (7)][7] which works in a similar manner.
In 1967 phosphoric esters were also prepared by using
allyl diethyl phosphite and diethyl azodicarboxylate (DEAD)
in the presence of alcohols [Eq. (4)].[4] Later, Mitsunobu, a
former student from my research group, developed this
Teruaki Mukaiyama was born in 1927. He
received his B.Sc. from the Tokyo Institute of
Technology (T.I.T.) in 1948, and Ph.D. from
the University of Tokyo in 1957. He first
became Assistant Professor at Gakusyuin
University in 1953 and then at T.I.T. in
1958. He was appointed Full Professor at
TIT in 1963 and moved to the University of
Tokyo in 1974. In 1987 he became Professor
of Chemistry at the Science University of
Tokyo. Since 2002 he has been Professor at
the Kitasato Institute; as well as Emeritus
Professor at the University of Tokyo, the
T.I.T., and the Science University of Tokyo. He is a recipient of many major
awards and is currently a member of the Japan Academy as well as a foreign member of the Academy of Sciences in France and Poland.
5592
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
The search for new combinations of weak reductant and
oxidant for the oxidative–reductive condensation has been a
matter of continued interest for us ever since the reaction was
first reported. We have long expected that quinone compounds could be used as effective oxidants in this type of
condensation; however, no successful examples have been
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Angew. Chem. Int. Ed. 2004, 43, 5590 – 5614
Angewandte
Chemie
Synthetic Methods
reported to date. It was then considered that the interaction of
alkoxydiphenylphosphane with weak oxidants such as quinone would provide a key intermediate, the phosphonium
salt, more smoothly than triphenylphosphane because the
former is a stronger reductant. In addition, the alkoxydiphenylphosphane formed by introducing an alkoxy group into a
trivalent phosphorus compound worked more effectively in
the formation of the alkoxyphosphonium salt, an important
key intermediate.
1.2. Preparation of tert-Alkyl Carboxylates with Inverted
Configuration from Chiral tert-Alcohols
Oxidative–reductive condensation using a combination of
2,6-dimethyl-1,4-benzoquinone and alkoxydiphenylphosphanes, formed in situ from alcohols and chlorodiphenylphosphane or (N,N-dimethylamino)diphenylphosphane,
affords alkyl carboxylates in high yields from the corresponding alcohols and carboxylic acids by a one-pot procedure
under neutral and mild conditions (Scheme 4).[8] The ester-
Scheme 5. Esterification of carboxylic acids with secondary alcohols
such as (l)-menthol.
Scheme 6. Esterification of bulky secondary or tertiary carboxylic acids
with bulky tertiary alcohols.
Scheme 4. Esterification of carboxylic acids by oxidative–reductive
condensation with alcohols.
ification of various secondary alcohols proceeded in a similar
manner in high yields with complete inversion of the stereochemistry at the C-OH atom. For example, benzoic acid and
l-menthol afforded the corresponding alkyl carboxylate with
inverted configuration in yields of 86 % (Scheme 5).[8]
Furthermore, it was shown that the reactions of various
carboxylic acids with tertiary alkoxydiphenylphosphanes
formed in situ proceeded very smoothly; for example, 2,2dimethylpropionic acid and 2-methyl-1-phenylpropan-2-ol or
2-phenylbutyric acid and 1-adamantanol afforded the corresponding tert-alkyl carboxylates in yields of 85 to 96 %
(Scheme 6).[8] The stereochemistry in the above ester-forming
reaction was examined, and indeed this oxidative–reductive
method worked effectively in converting tertiary alcohols into
their corresponding esters with almost complete inversion of
configuration (Scheme 7).[9] The method involves initial
introduction of the alcohol to diphenylphosphinite ester,
followed by treatment with a carboxylic acid and 2,6dimethyl-1,4-benzoquinone.
The results for the condensation of carboxylic acids with
various chiral tertiary alcohols are shown in Table 1. EsterAngew. Chem. Int. Ed. 2004, 43, 5590 – 5614
Scheme 7. Preparation of tert-alkyl carboxylates from chiral tert-alcohols with inversion of configuration by oxidative–reductive condensation using 2,6-dimethy-1,4-benzoquinone.
ification of carboxylic acids proceeded smoothly in dichloromethane at room temperature to afford the corresponding
tert-alkyl carboxylates in good yields and with almost
complete inversion of configuration. In contrast, treatment
of a solution of 1-adamantanol with benzoic acid in dichloromethane for 15 h afforded an ester in 83 % yield with
retention of configuration. The esterifications of various
chiral tertiary alcohols with benzoic acid or p-methoxybenzoic acid (which contains an electron-donating group) proceeded within 18 h at room temperature to give the alkyl
www.angewandte.org
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5593
Reviews
T. Mukaiyama
Table 1: Esterification of carboxylic acids with chiral tertiary alcohols.
Entry R1OH[c]
R/S[d] R2
Yield [%] R/S[e]
1[a]
–
83
2[a]
3[a]
86:14 Ph
78
PhCH2CH2 76
16:84
66:34
4
5
95:5
6
7
8
9
2:98
10
11
Ph
–
Ph
p-MeOC6H4
p-Cl-C6H4
PhCH2CH2
85
86
7:93
5:95
83
76
20:80
24:76
Ph
p-MeOC6H4
p-Cl-C6H4
PhCH2CH2
90
88
98:2
98:2
86
86
70:30
69:31
A condensation using readily available 1,4-benzoquinone
instead of the above-mentioned 2,6-dimethyl-1,4-benzoquiInversion [%] none was studied to enable a practical and convenient
synthetic reaction to be established. The desired alkyl
–
carboxylates were obtained in good to high yields by
combined use of 1.7 equivalents of alkoxydiphenylphos98
phanes (with primary, bulky secondary, or tertiary alkoxy
40
groups), 1.7 equivalents of 1,4-benzoquinone, and a carboxylic acid.[10] The corresponding carboxylates with inverted
configuration were also obtained in high optical purity and
98
chemical yields in the case of chiral secondary or tertiary
> 99
alcohols. Esterification of various in situ formed alkoxydiphenylphosphanes with various carboxylic acids were
84
80
attempted under the conditions shown in Table 2. Benzylation
of benzoic acids having electron-donating or electron-with> 99
drawing groups and of saturated or unsaturated aliphatic
> 99
carboxylic acids proceeded smoothly to afford the corresponding benzyl carboxylates in high to excellent yields under
71
mild conditions (Table 2, entries 1–6). Treatment of a primary
70
alcohol such as n-butanol, an aromatic alcohol with an
electron-donating group such as p-methoxybenzyl alcohol, or
> 99
a secondary alcohol such as diphenylmethanol with benzoic
12
1:99
Ph
86
99:1
13
91:9
Ph
83
9:91
14
22:78 Ph
81
77:23 99
15[b]
–
Ph
> 99
Table 2: Esterifications of carboxylic acids with alcohols.
nd
[a] The reaction mixture was refluxed for 15 h. [b] The corresponding olefin
was obtained in 81 % yield. [c] Entries 2–7: ()-Terpinen-4-ol (Acros
Organics) and ()-linalool (Fulka Chemika) were used. Entries 8–15: The
chiral alcohols were prepared according to Walsh’s procedure. [d] The
enantiomeric ratios of tert-alcohols were determined by preparing the
corresponding esters with the carboxylic chlorides.
carboxylates in good yields (81–90 %) with almost complete
inversion of configuration (98 to > 99 %; Table 1, entries 4, 5,
8, 9, and 12–14). However, the desired esters were obtained in
76–86 % yields with 70–84 % inversion when an aliphatic
carboxylic acid or p-chlorobenzoic acid, which contains an
electron-withdrawing group, was used (Table 1, entries 6, 7,
10, and 11). Heating a solution of ()-terpinen-4-ol and
benzoic acid or 3-phenylpropionic acid in dichloromethane at
reflux for 15 h afforded the corresponding esters in 78 % yield
with 98 % inversion or 76 % yield with 40 % inversion,
respectively (Table 1, entries 2 and 3). In contrast, 2-(4methoxyphenyl)-2-butanol afforded an olefin in 81 % yield,
with none of the desired ester detected (Table 1, entry 15).
Thus, oxidative–reductive condensation using alkoxydiphenylphosphanes generated in situ (namely, diphenylphosphinite ester) with 2,6-dimethyl-1,4-benzoquinone and carboxylic acids provided a new and efficient method for the
preparation of tert-alkyl carboxylates from various chiral
tertiary alcohols with inversion of the configuration at the COH atom.
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2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1.3. Preparation of Primary, Secondary, and Tertiary Alkyl
Carboxylates from Alcohols and Carboxylic Acids
t [h] Yield [%]
Entry R’OH
RCOOH
1
2
PhCOOH
p-MeOC6H4COOH
p-NO2C6H4COOH
PhCH2CH2COOH
PhCH=CHCOOH
CH3(CH2)3COOH
PhCOOH
BnOH
Yield [%][a]
1
1
98
95
98
95
1
96
95
92
98
90
93
93
92
93
91
8
p-MeOC6H4CH2OH
CH3(CH2)3OH PhCOOH
1
1
1
1
1
90
88
9
PhCOOH
3
90
94
10[b]
PhCOOH
3
91
86
(> 99.9 %) (> 99.9 %)
11[b]
p-NO2C6H4COOH
3
96
95
(> 99.9 %) (> 99.9 %)
12
PhCOOH
3
4
5
6
7
15
75
69
13
15
95
96
14
15.0 95
96
15[b]
PhCOOH
15
95
(> 99 %)
96
(> 99.9 %)
[a] See ref. [5b]: Esterification of carboxylic acids with alcohols by using
2,6-dimethyl-1,4-benzoqinone. (alcohols: 1.1–1.2 equiv, carboxylic acids:
1.0 equiv, 2,6-dimethyl-1,4-benzoqinone: 1.0 equiv). [b] Yields in parenthesis are inversion yields.
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Angew. Chem. Int. Ed. 2004, 43, 5590 – 5614
Angewandte
Chemie
Synthetic Methods
acid for 1–3 h gave the corresponding esters in high yields
(Table 2, entries 7–9). Similarly, the reaction of tert-butyl
alcohol and benzoic acid under the same conditions afforded
the desired ester in 75 % yield (Table 2, entry 12). The
condensation of tertiary alcohols and carboxylic acids such
as 1-adamantanol and 2-phenylbutyric acid or 1-methylcyclopentanol and triphenylacetic acid also proceeded smoothly to
afford the corresponding carboxylates in excellent yields
(Table 2, entries 13 and 14). In addition, it was noted that the
corresponding alkyl carboxylates were obtained in excellent
yields with perfect inversion of configuration when a chiral
secondary alcohol such as l-menthol was used (Table 2,
entries 10 and 11). In the case of the chiral tertiary alcohol
(S)-2-phenyl-2-butanol, the corresponding ester was obtained
in 95 % yield with 99 % inversion.
1.4. Preparation of Symmetrical or Unsymmetrical Ethers by
Oxidative–Reductive Condensation
The O-alkylation of 2.0 equivalents of 2-phenylethanol in
dichloromethane with 1.0 equivalent of 2,6-dimethyl-1,4-benzoquinone and 1.0 equivalent of benzyloxydiphenylphosphane (formed in situ from nBuLi-treated benzyl alcohol
and chlorodiphenylphosphane) was investigated, but the
desired ether was not obtained (Scheme 8). It was considered
Scheme 9. Preparation of symmetrical or unsymmetrical ethers from
two alcohols by oxidative–reductive condensation using tetrafluoro-1,4benzoquinone.
mary, secondary, or tertiary alcohols were used (Table 3,
entries 1–5). The etherification at room temperature of
alkoxydiphenylphosphanes formed in situ from several
nBuLi-treated bulky secondary or tertiary alcohols with 2phenylethanol or 2-methyl-1-phenyl-2-propanol also proceeded smoothly to afford the corresponding unsymmetrical
ethers in high yields after 3 h (Table 3, entries 6 and 7).
The desired ether was obtained in 83 % yield without
racemization when alkoxydiphenylphosphanes formed in situ
from nBuLi-treated p-methoxybenzyl alcohol was treated
with alcohols having a hydroxy group at the a-position of a
carboxylic ester (such as methyl (R)-()-mandelate). Reac-
Table 3: Etherification of alcohols and alkoxydiphenylphosphanes (formed in situ
from alcohols, Ph2PCl, and nBuLi) using fluoranil.
Scheme 8. Etherification of 2-phenylethanol with BnOH. nd = not
detected.
that an important intermediate phosphonium salt had likely
been formed, since an alkoxy group had previously been
introduced into a phosphane by the use of oxidants such as
2,6-dimethyl-1,4-benzoquinone. However, it appeared that
the intermediate phosphonium salt had not in turn been
converted smoothly into a pentavalent phosphorus compound
after abstraction of a hydrogen atom from the alcohol. Thus,
to extend the scope of the oxidative–reductive reaction to this
ether formation, a more powerful oxidant such as fluoranil
(tetrafluoro-1,4-benzoquinone) was considered, and the reaction of this derivative with alcohols and alkoxydiphenylphosphanes (formed in situ from nBuLi-treated alcohols and
chlorodiphenylphosphine) was attempted. It was found that
the intermediate phosphonium salt was converted smoothly
into the pentavalent phosphorus compound by abstracting
one hydrogen atom from a molecule of alcohol, and that the
corresponding symmetrical or unsymmetrical ethers could be
prepared successfully in good to high yields by starting from
two free alcohols (Scheme 9).[11] For example, the corresponding symmetrical or unsymmetrical ethers were obtained
in good to high yields when benzyl alcohols having either
electron-donating or electron-withdrawing groups and priAngew. Chem. Int. Ed. 2004, 43, 5590 – 5614
Entry ROH
R’OH
Product
Yield [%]
1
90
2
94
3
92
4
94
5
75
6
90
7
92
8[a]
83
9[b]
89
[a] 1.0 equivalent of fluoranil was used. No racemization was observed by HPLC
(Daicel Chiralcel OD). [b] The ether was obtained with 95 % inversion.
www.angewandte.org
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5595
Reviews
T. Mukaiyama
tion of alkoxydiphenylphosphanes formed in situ from
nBuLi-treated methyl (R)-()-mandelate and p-methoxybenzyl alcohol under the above conditions gave the corresponding ethers in 89 % yield with 95 % inversion (Table 3,
entries 8 and 9). Thus, efficient methods for the etherification
of chiral alcohols with either retention or inversion of the
configuration were established: namely, treatment of a chiral
alkoxydiphenylphosphane with an achiral alcohol afforded
the ether with inversion of the configuration while the
reaction of an achiral alkoxydiphenylphosphane and a chiral
alcohol afforded the ether with retention of configuration.
1.5. Oxidation with Organosulfur Compounds
Divalent sulfur compounds are known to exist as three
relatively stable species in different oxidation states (thiolate
RS , sulfenyl radical RSC, and sulfenyl cation RS+). Interconversions between these species take place relatively easily,
and are expected to participate in oxidation or reduction
processes. Based on this concept, a sulfenylation of carbonyl
compounds was developed in 1970 in which sulfenamides
were used as new sulfenylating agents.[12] Sulfur compounds
having a sulfur–boron bond later led to a crossed aldol
reaction (1971). The concept of using two elements in
combination (one being sulfur) was further applied in 2000
to develop a new method for the oxidation of alcohols.
1.5.1. Stoichiometric Oxidation of Alcohols by Using Sulfinimidoyl
Chloride
The oxidation of primary and secondary alcohols to the
corresponding carbonyl compounds is one of the most
fundamental and important transformations in organic synthesis.[13] There are many useful methods for the stoichiometric oxidation of alcohols by using, for example, chromium(vi) compounds,[14] manganese dioxide,[15] activated
dimethylsulfoxides,[16, 17] and hypervalent iodine compounds[18, 19] as oxidants. During our total synthesis of taxol
it was noticed that a more useful and widely applicable
oxidation method was still needed. Our experience in the
study on organosulfur compounds having a sulfur–nitrogen
bond led to the idea that sulfinimidoyl chloride would be a
suitable oxidizing agent for alcohols. In fact, various primary
and secondary alcohols are effectively oxidized under mild
conditions to the corresponding aldehydes and ketones by
using N-tert-butylbenzenesulfinimidoyl chloride and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) [Eq. (8)].[20, 21] The sulfinimidoyl chloride mediated oxidation of alcohols proceeds at
readily controllable reaction temperatures (78 8C–RT) by
simply adding this oxidizing agent to the mixture of alcohol
and DBU. In contrast, Swern oxidation[17b] requires strictly
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2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
controlled cooling (< 20 8C) to generate the thermally
unstable key intermediate, chlorodimethylsulfonium chloride,
from oxalyl chloride and dimethylsulfoxide. It should be
further noted that trimethylsiloxy bonds remain intact during
the sulfinimidoyl chloride mediated oxidation, while they are
cleaved under Swern oxidation conditions. Polymer-supported sulfinimidoyl chloride is a particularly convenient
reagent for the oxidation of alcohols because the oxidation
products are easy to isolate.[22, 23]
1.5.2. Catalytic Oxidation of Alcohols with Sulfenamide
The oxidation of alcohols with a stoichiometric amount of
sulfinimidoyl chloride has been modified to a more-convenient catalytic method. The oxidation of various alcohols is
successfully performed by using a stoichiometric amount of
N-chlorosuccinimide (NCS) and a catalytic amount of N-tertbutylbenzenesulfenamide in the presence of potassium carbonate and 4-E molecular sieves [Eq. (9)].[24, 25] The key
oxidizing agent, sulfinimidoyl chloride, is generated in situ by
chlorination of the sulfenamide with NCS. Oxidation of the
alcohols then proceeds smoothly to afford carbonyl compounds, thus regenerating the catalyst. The catalytic oxidation
tolerates various kinds of functional groups in the alcohols;
thus, silyl ethers, benzyl ethers, epoxides, urethanes, esters,
and double bonds are not damaged during this catalytic
oxidation, and the corresponding carbonyl compounds are
obtained in high yields. Labile or highly epimerizable
aldehydes can also be prepared efficiently by this catalytic
oxidation, and the carbonyl compounds are isolated more
easily than when a stoichiometric amount of sulfinimidoyl
chloride is used. The oxidation of diols having both a primary
and a secondary hydroxy group in the same molecule results
in the primary hydroxy group being selectively oxidized. The
usefulness of this catalytic oxidation has been shown in the
total syntheses of natural products.[26]
1.5.3. Dehydrogenation of Saturated Ketones to a,b-Unsaturated
Ketones
Ketones can be directly dehydrogenated to a,b-unsaturated ketones in one pot. Firstly the ketones are converted
into the corresponding lithium enolates by LDA. The lithium
enolates thus formed are then allowed to react with sulfinimidoyl chloride at 78 8C and dehydrogenation immediately
takes place to afford a,b-unsaturated ketones [Eq. (10)].[27]
The less-hindered positions of unsymmetrical ketones are
selectively oxidized by kinetic deprotonation of the ketones
with LDA. Compared to other methods for the dehydrogen-
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Synthetic Methods
ation of saturated ketones to a,b-unsaturated ones,[28–31] the
above dehydrogenation takes place at a much lower temperature (78 8C) and in a single pot, and has been applied to a
key step in the total synthesis of natural products.[32]
1.5.4. Oxidation of Amines to Imines and Oxidation of
Hydroxylamines to Nitrones
A variety of oxidants for the oxidation of secondary
amines to the corresponding imines have been developed to
date.[33] Examples include hypervalent iodine reagents,[34]
phenylselenic anhydride,[35] manganese dioxide,[36] and
others.[37] The oxidation of amines was also carried out using
a catalytic amount of ruthenium catalysts,[34c, 38] a cobalt–Shiff
base complex,[39] or NiSO4[40] in the presence of an appropriate co-oxidant. Most of these methods have only been
applied to the oxidation of benzylic and allylic amines, which
afford conjugated imines at room temperature or above, and a
limited number of examples were reported for the oxidation
of aliphatic amines to nonconjugated imines.
Similar to the oxidation of alcohols to carbonyl compounds, various secondary amines are dehydrogenated to
imines under very mild conditions (at 78 8C) by using
sulfinimidoyl chloride and DBU [Eq. (11)].[41] The benzylic or
the less-hindered positions are selectively oxidized in the case
of unsymmetrical secondary amines,. Primary amines are also
oxidatively deaminated[42] to afford the corresponding carbonyl compounds in one pot. In this procedure linear or
nonlinear primary amines are first converted into their Ncyclohexyl or N-mesyl derivatives. These derivatives are then
oxidized using sulfinimidoyl chloride and DBU and the
imines formed are hydrolyzed to give carbonyl compounds
(Schemes 10 and 11).[43] N,N-Disubstituted hydroxylamines
Scheme 11. Conversion of primary amines into aldehydes in the
presence of sulfinimoyl chloride and DBU.
are smoothly oxidized to the corresponding nitrones[44] at
78 8C by using sulfinimidoyl chloride and DBU in dichloromethane [Eq. (12)].[45]
2. Crossed Aldol Reactions via Boron and Silicon
Enolate Intermediates
2.1. Introduction
Metal enolates play an important role in organic synthesis.
In particular, aldol-type reactions mediated by metal enolates
are very useful synthetic methods for the stereoselective
formation of carbon–carbon bonds. During the last thirty
years the generation and reaction of various metal enolates
have been extensively studied, and successful applications to
the controlled formation of carbon–carbon bonds has been
realized under mild conditions. However, under the classical
aldol reaction conditions in which basic media are employed,
dimers, polymers, self-condensation products, or a,b-unsaturated carbonyl compounds are invariably formed as byproducts. The lithium enolate mediated aldol reaction is
considered to be a useful synthetic method for solving the
above problems. In addition to the well-studied aldol reaction
based on lithium enolates, very useful and versatile regio- and
stereoselective carbon–carbon bond-forming aldol-type reactions have been established in our laboratory by the use of
boron enolates (1971),[46] silicon enolates/Lewis acids
(1973),[47, 48] and tin(ii) enolates (1982).[49]
2.2. Crossed Aldol Reactions with Boron Enolates
2.2.1. Discovery of the Aldol Reaction Mediated by Boron
Enolates
Scheme 10. Conversion of an aromatic primary amine into an aldehyde
in the presence of sulfinimoyl chloride and DBU.
Angew. Chem. Int. Ed. 2004, 43, 5590 – 5614
Firstly, the background of how the idea of using boron
enolates (vinyloxyboranes) in aldol reactions arose should be
described. At the beginning of the 1970s the development of
several new reactions was being studied that utilized the
characteristics of alkylthioboranes based on the concept of
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“elements in combination”. In this concept two types of
elements are used in tandem to create a novel reactivity that is
different from that which can be achieved when using them
separately. For example, treatment of ketene (1) with two
equivalents of butylthioborane 2 was expected to give the
ketene thioacetal 3, but instead afforded S-butyl-3-hydroxy-3methylbutanethiolate (4, Scheme 12).
Scheme 12. Unexpected formation of b-hydroxy thioester 4 by the
reaction of ketene (1) and thioborane 2.
It was difficult at first to figure out the mechanism of the
above reaction, but identification of the product soon
indicated the participation of acetone in this reaction (in
this process ketene (1) is generated by the degradation of
acetone under irradiation, and hence a small amount of
acetone is introduced into the reaction mixture. Thus, bhydroxy thioester 4 is generated by the reaction of the three
components, acetone, ketene (1), and alkyl thioborane 2.
Introduction of gaseous ketene (1) free form acetone into a
mixture of alkyl thioborane 2 and a carbonyl compound
affords the corresponding b-hydroxy thioesters 5 in high yield,
as expected [Eq. (13)].[46] Investigation of the mechanism
reveals that the key intermediate of this reaction is the boron
enolate 7 generated form ketene (1) and alkyl thioborane 6
(Scheme 13).[47] Thus, our original study on organothioboranes accidentally led us to discover the widely utilized aldol
reactions via boron enolate intermediates.[50]
2.2.2. Direct Generation of Boron Enolates
A method for the direct generation of boron enolates
from the parent carbonyl compounds was desirable to expand
the synthetic utility of the boron enolate mediated aldol
reaction. Although several synthetic methods for generating
boron enolates had been reported,[50–52] none useful for the
direct generation of boron enolates from their parent
carbonyl compounds were known until 1976. After the
discovery of the aldol reaction via boron enolate intermediates, we made an extensive search for such a useful method
together with Inoue. It was thought then that increasing the
Lewis acidity of the boron atom by introducing an excellent
leaving group would facilitate the coordination of carbonyl
compounds. The corresponding boron enolate could then be
formed by abstraction of the a-proton of the carbonyl
compound with a weak base such as a tertiary amine.
The trifluoromethanesulfonyloxy (triflate, TfO) group
was chosen as the leaving group. Dibutylboryl triflate 8 was
found to generate boron enolates 9 by reacting with ketones
in the presence of a weak base such as N-diisopropylethylamine or 2,6-lutidine (Scheme 14).[53] The subsequent addi-
Scheme 14. Preparation of the boron enolate from dibutylboryl triflate
and reaction with aldehydes to form aldol compounds.
tion of aldehydes afforded the corresponding aldols 10 in
good yields. This was the first example of using triflate salts in
synthetic chemistry; various triflate salts are now known to be
versatile Lewis acids in organic synthesis. Thus, the crossedaldol reaction of a ketone and an aldehyde in the presence of
dialkylboryl triflate can be performed easily under mild
reaction conditions.
Since our first report, this aldol reaction has been
investigated in detail by many research groups.[50] It is
currently understood that the boron enolate mediated aldol
reaction proceeds via a more-rigid chairlike six-membered
transition state (12 or 15) than those obtained with alkali
metal enolates because of the shorter bond between the
boron and oxygen atoms (Scheme 15). Therefore, aldol
reactions via boron enolates give aldol adducts more stereoselectively than those via alkali metal enolates such as lithium
enolates. This stereoselective aldol reaction now provides an
outstanding method for the stereoselective synthesis of
acyclic compounds.
2.2.3. Application of Crosssed Aldol Reactions Mediated by Boron
Enolates to the Synthesis of Natural Products
Scheme 13. The reaction of ketene (1) with alkylthioborane 6 affords
the boron enolate 7.
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Boron enolates are prepared under mild and essentially
neutral conditions and react readily and stereoselectively with
carbonyl compounds to form aldols. The stereocontrolled
synthesis of acyclic molecules by the boron enolate mediated
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Scheme 15. Steteoselective aldol reaction of (Z)- and (E)-boron
enolates with aldehydes.
aldol reaction is now applied frequently to the synthesis of
natural products.
Toshima and co-workers reported the synthesis of concanamycin F, an 18-membered macrolide antibiotic, by using
a PhBCl2-mediated aldol reaction (Scheme 16).[54] Shioiri and
Scheme 17. Total synthsis of antillatoxin. Bn = benzyl.
idea immediately came to mind that titanium(iv) chloride
would effectively generate active electrophilic species
through its strong interaction with carbonyl compounds and
that this complex would react easily even with relatively weak
carbon nucleophiles to form a new carbon–carbon bond.
Next, by analogy with enol boronates, the use of stable and
isolable silyl enol ethers[58] was investigated as the weak
nucleophile, and, just as expected, the aldol reaction between
the silyl enol ether of acetophenone 16 and benzaldehyde in
the presence of titanium(iv) chloride afforded the aldol
product 17 in high yield [Eq. (14)].[48]
Scheme 16. Total synthesis of concanamycin F. TBAF = tetrabutylammonium fluoride.
co-workers reported the total synthesis of the cyclic lipopeptide antillatoxin. The stereochemistry at C4 and C5 was
determined by using a syn- and anti-selective boron enolate
mediated aldol reaction, respectively (Scheme 17).[55]
2.3. Crossed Aldol Reactions with Silicon Enolates
2.3.1. Discovery of Silicon Enolate mediated Crossed Aldol
Reactions
The driving force in the above-mentioned aldol reaction
involving a boron enolate is considered to be the interconversion of the enol forms of the ketones (boron enolates) into
their more stable keto form (b-boryloxy ketones).[56] While we
were studying the boron enolate mediated aldol reaction, our
investigation was also continuing on developing new chemical
reactions with titanium(iv) chloride.[57] A new and important
Angew. Chem. Int. Ed. 2004, 43, 5590 – 5614
It was known that enol ethers react with acetals or ketals
in the presence of a Lewis acid to give aldol-type adducts;
however, these reactions are often accompanied by undesired
side reactions.[59] Furthermore, it had also been difficult to
perform crossed-aldol reactions selectively since conventional
aldol reactions are carried out under equilibrium conditions
in which either a basic or an acidic catalyst is used in protic
solvents.[60] Detailed studies of this new aldol reaction of
silicon enolates, however, revealed a number of advantatges
over conventional methods. Firstly, this reaction not only
gives a variety of aldol adducts in high yields, but also gives a
regioselective aldol adduct when the silyl enol ether of an
unsymmetrical ketone is used. This latter result means that
the aldol reaction proceeds with retention of the regiochemical integrity of the starting silyl enol ethers to afford the
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corresponding aldol regiospecifically. The starting silyl enol
ethers themselves can be conveniently prepared regioselectively under kinetic or thermodynamically controlled conditions.
Secondly, functional group selectivity is observed: namely,
the reactions with aldehydes proceed at 78 8C while those
with ketones proceed at elevated temperatures (ca. 0 8C).
Chemoselectivity is observed with acceptors having two
different kinds of carbonyl functions, such as aldehyde and
ketone or ester, in the same molecule. Treatment of phenylglyoxal with silyl enolate 18 at 78 8C affords a-hydroxy-gdiketone 19 [Eq. (15)].[60b] The reaction of ketoesters 20 with
silyl enolate 18 gives hydroxy ketoesters 21 as the sole
products [Eq. (16)].[60]
pared by a TiCl4-promoted reaction of a-halo acetals 26 with
silyl enolates (Scheme 19).[62]
In the presence of titanium(iv) chloride, silyl dienolate 29
derived from an a,b-unsaturated aldehyde reacts with acetal
Scheme 19. Synthesis of furans through a TiCl4-mediated reaction of ahaloacetals with silyl enolates.
28 selectively at the g-position to give d-alkoxy-a,b-unsaturated aldehydes 30. The yield of the reaction is low since
titanium(iv) chloride is strongly acidic and the silyl dienolate
29 polymerizes. However, addition of tetraisopropoxytitanium(iv) to titanium(iv) chloride improves the yield dramatically.[63] Vitamin A has successfully been synthesized by use
of silyl dienolate 29 under the above conditions
(Scheme 20).[64]
A crossed-aldol reaction between two ketones affords
thermodynamically unfavorable aldols in high yields as a
result of the stabilization of the aldol adducts by their
intramolecular chelation with a titanium center 22 or by their
conversion into silyl ethers 23 (Scheme 18). The syn/anti ratio
Scheme 20. Synthesis of vitamin A by an aldol reaction of acetal 28
with silyl dienol ether 29.
Silyl ketene acetals 31 derived from carboxylic esters are
more nucleophilic than silyl enol ethers and also react with
ketones and aldehydes in the presence of titanium(iv)
chloride to give b-hydroxy esters 32 in high yields
[Eq. (18)].[65, 66] Although the Reformatsky reaction is well-
Scheme 18. Formation of the thermodynamically unfavorable aldol
through stabilization of the intermediate.
of the aldol product is influenced both by steric factors of the
aldehyde and silyl enolate, and by the properties of the Lewis
acid catalyst.[61]
As an extension of this new protocol for carbon–carbon
bond formation, the reaction between silyl enolates and
acetals 24 has been performed in the presence of titanium(iv)
chloride to afford b-alkoxy carbonyl compounds 25
[Eq. (17)].[62] Various substituted furans 27 are readily pre-
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known as a good synthetic method for synthesizing b-hydroxy
esters, the titanium(iv) chloride mediated reaction is a milder
and more versatile method for synthesizing a-substituted bhydroxy esters.
Since this discovery of aldol reactions of silyl enolates with
carbonyl compounds or acetals, silyl enolates have become
one of the most popular carbon nucleophiles in organic
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synthesis and are also employed in other reactions such as
Michael reactions,[67] Mannich reactions,[68] and others.[69] Silyl
enolates are superior to other metal enolates in terms of their
isolation, regioselectivity of formation, and their unique
reactivities under mild conditions.
2.3.2. Lewis Acid Catalyzed Aldol Reactions of Silicon Enolates
The first titanium(iv) chloride mediated aldol reaction of
silyl enolates with aldehydes was carried out with a stoichiometric amount of titanium(iv) chloride.[48] Other Lewis acids
were also tried, and it was found that a catalytic amount of a
triphenylmethyl (trityl) salt 33 (for example, trityl perchlorate) is sufficient to effectively promote the aldol reaction
[Eq. (19)].[70] In fact, 5–10 mol % of the trityl salt is sufficient
to drive the aldol reaction to completion. An interesting finding in
this catalytic reaction is that the
silicon enolate reacts with aldehydes to give the corresponding
aldol adducts as their silyl ethers 34.
The aldol reaction of silyl enolates and acetals in the presence of a
catalytic amount (1–10 mol %) of
trityl pechlorate proceeded effectively to afford b-methoxy ketones
in high yield. The reaction of
dithioacetal 35 with silyl enolates
in the presence of a trityl
tetrafluoroborate catalyst affords
b-ethylthio ketones 36 [Eq. (20)].[71]
Since the stereoselectivity of silyl enolate mediated aldol
reactions varies with the Lewis acids employed, these aldol
reactions provide useful synthetic methods in stereoselective
and asymmetric carbon–carbon bond formation and have
been applied to the total synthesis of natural products by
many research groups.
The stereoselective aldol reaction of the trimethylsilyl
enolate of methyl 2-benzyloxyacetate (37) with enantiomerically pure trialkoxy aldehyde 38 is performed by using three
equivalents of MgBr2·Et2O as an activator to afford an aldol
adduct 39 in high yield and exellent diastereoselectivity
(Scheme 21). In contrast, the conventional Lewis acids such as
TiCl4 and SnCl4 give the desired aldol product 39 in only low
Scheme 21. Diastereoselective aldol reaction for preparing an acyclic polyoxy molecule 39. Ac = acetyl,
PMB = 4-methoxybenzyl, TBS = tert-butyldimethylsilyl.
A combination of the two weak acids tin(ii) chloride and
chlorotrimethylsilane is also found to serve as an effective
catalyst for the aldol reaction.[72] Neither chlorotrimethylsilane nor tin(ii) chloride alone shows any accelerating effect at
78 8C, even when added in excess. However, the aldol
reaction carried out in the presence of catalytic amounts of
both chlorotrimethylsilane and tin(ii) chloride gives the
desired product in more than 90 % yield [Eq. (21)]. It is
presumed that the cationic silyl species generated by coordination of the chloride ion to the tin(ii) atom catalyzes the
aldol reaction.
Angew. Chem. Int. Ed. 2004, 43, 5590 – 5614
2.3.3. Application of Silicon Enolate Mediated Crossed Aldol
Reactions to the Synthesis of Natural Products
yields.[73, 74] This method has been applied in our total synthesis of the antitumor agent taxol as a key step in constructing the B ring system of the target molecule.[75]
In the total synthesis of antifungal antibiotic tautomycin, a
potent protein phosphatases inhibitor, Ichihara and co-workers reported the TiCl4-mediated aldol coupling of two large
subunits (Scheme 22).[76] Evans et al. reported the total
synthesis of the 14-membered macrolide antibiotic 6-deoxyerythronolide B by using a BF3·OEt2-mediated aldol reaction
involving fragment coupling (Scheme 23).[77] A fragment
coupling reaction promoted by Sn(OTf)2 was employed in
the total synthesis of zaragozic acid C by Hashimoto and coworkers (Scheme 24).[78] Carreira and co-workers reported
the total synthesis of macrolactin A, a 24-membered polyene
macrolide antibiotic, by using an enantioselective dienolate
aldol addition catalyzed by a chiral Ti complex
(Scheme 25).[79]
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Scheme 22. Total synthesis of tautomycin. DEIPS = diethylisopropylsilyl, TES = triethylsilyl.
Scheme 25. Total synthesis of macrolactin A.
2.3.4. Asymmetric Aldol Reactions with Chiral Tin(ii) Lewis Acid
Catalysts
The asymmetric aldol reaction is one of the most powerful
tools for the construction of new carbon–carbon bonds with
control over the absolute configurations of newly formed
chiral centers.[80] Of this class of reaction, one that is mediated
by silicon enolates has been extensively studied by many
research groups over the past two decades.
2.3.4.1. Stoichiometric Enantioselective Aldol Reactions
Scheme 23. Total synthesis of 6-deoxyerythronolide B.
Scheme 24. Total synthesis of zaragozic acid C. MEM = methoxyethoxymethyl.
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2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
A wide variety of aldehydes react with the (E)-silicon
enolate[81] 40 derived from propionic acid thioester to give
syn-aldol adducts in high yields and with perfect stereochemical control by the combined use of tin(ii) triflate, chiral
diamine 41, and dibutyltin acetate (Scheme 26).[82–84] It is
thought that an active complex 42 consisting of three
components, tin(ii) triflate, chiral diamine 41, and dibutyltin
acetate, is formed during these aldol reactions. This threecomponent complex would activate both the aldehyde and
silyl enolate (double activation); it is proposed that the chiral
diamine-coordinated tin(ii) triflate activates the aldehyde
while oxygen atoms of the acetoxy groups of the dibutyltin
acetate interact with the silicon atom of the silicon enolate.
Since optically active molecules containing 1,2-diol units
are often observed in nature (carbohydrates, macrolides,
polyethers), the asymmetric aldol reaction of the silyl enolate
of a-benzyloxythioacetate 43 with aldehydes has been investigated with the aim of introducing two vicinal hydroxy groups
and stereoselective formation of a carbon–carbon bond.
Interestingly, it is found that the anti-a,b-dihydroxy thioester
derivatives 44 are obtained in high yields with excellent
diastereo- and enantioselectivities by the combined use of
tin(ii) triflate, chiral diamine 45, and dibutyltin acetate
[Eq. (22)].[85] These results are unusual because the aldol
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Scheme 26. Enantioselecive synthesis of syn-aldol adducts from
aldehydes and a (E)-silyl enolate.
reaction of simple silyl enolate 40 with aldehydes
generally affords syn-aldol adducts as mentioned above
(see Scheme 26). Consideration of the transition states of
these aldol reaction leads us to postulate that coordination of an oxygen atom of the silyl enolate 43 to the tin
atom of tin(ii) triflate occurs, which is essential for the
anti selectivity. To prove the hypothesis the silicon
enolate 46, which has a bulky tert-butyldimethylsilyl
group, was prepared to prevent the coordination of the aoxygen atom to the tin(ii) center. As expected, syn-aldol
47 is obtained in high stereoselectivity by the reaction
using the sterically hindered silicon enolate 46 in the
presence of tin(ii) triflate, a chiral diamine 48, and
dibutyltin acetate [Eq. (23)].[86]
Scheme 27. Stereoslective synthesis of 6-deoxy-l-talose. DIBAL = diisobutylaluminum
hydride, NMO = N-methylmorpholine N-oxide.
It is thus possible to prepare either the syn or anti aldols
selectively by choosing the appropriate protecting group on
the alkoxy group. This methodology has been applied to the
synthesis of several monosaccharides including branched,
deoxy, and amino sugars.[87] One example is shown in
Scheme 27).[87c]
Angew. Chem. Int. Ed. 2004, 43, 5590 – 5614
2.3.4.2. Catalytic Enantioselective Aldol Reactions
As described above, optically active aldol adducts are
easily obtained by using a stoichiometric amount of chiral
diamine, tin(ii) triflate, and dibutyltin acetate. An essential
step in an enantioselective aldol reaction with only a catalytic
amount of the chiral catalyst system is transmetalation of the
initially formed tin(ii) alkoxide 51 to silyl alkoxide 52 with
silyl triflate (Scheme 28). Carrying out the aldol reaction with
smaller amounts of the chiral catalyst resulted in the
formation of aldol adducts with low stereoselectivities,
because Sn–Si exchange occurs slowly and an undesired
Me3SiOTf-promoted aldol reaction also occurs which affords
racemic aldol adducts. A solution of silyl enolate and
aldehyde in dichloromethane was added slowly to a solution
of the catalyst 45 (20 mol %) to keep the concentration of
trimethylsilyl triflate as low as possible during the reaction
[Eq. (24)]. This resulted in the aldol product 53 being
obtained in good yields and with high enantioselectivities.[88]
The selectivities are improved by using propionitrile as the
solvent instead of dichloromethane because the rate of Sn–Si
exchange is faster in propionitrile than in dichloromethane.[89]
After these first reports on the highly efficient catalytic
enantiolesective aldol reaction, the catalytic symmetric aldol
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smoothly by generating an activated TMS enolate
through formation of a hypervalent silicate.[97]
An aldol adduct was obtained in 15 % yield when
the aldol reaction of TMS enolate 1 with benzaldehyde (PhCHO) was carried out in THF using
20 mol % of the Lewis base LiNPh2 (Scheme 29).
This result indicated that a stoichiometric amount of
LiNPh2 was required for the completion of the
reaction. The aldol adducts formed after quenching
were a mixture of the aldol (R = H, 55) and the Osilyl ether (R = TMS, 56), which suggested the
concurrent formation of the lithium aldolate and
O-silyl ether. In addition, it was noted that the
amount of O-silyl ether formed in THF was less in all
cases than that of the aldol, irrespective of the kind of
lithium amide employed. To achieve a catalytic aldol
reaction the lithium aldolate formed must be trans-
Scheme 28. A proposed catalytic cycle for the enantioselective aldol reaction.
Scheme 29. Lithium amide mediated aldol reaction of TMS enolate 54
and benzaldehyde.
reactions of silicon enolates with aldehydes using chiral
boron,[90] titanium,[91] zirconium,[92] and copper Lewis acids,[93]
as well as by transmetalation to chiral PdII enolates[94] have
been independently reported by other research groups.
formed rapidly to its O-silyl ether by the coformed silylamide.
Since the silylamide is a good silylating reagent, it was
expected that by careful choice of the reaction conditions
would result in formation of the O-silyl ether and simultaneous regeneration of the lithium amide (Scheme 30).
2.3.5. Base-Catalyzed Crossed Aldol Reactions with Trimethylsilyl
Enolates
Recently, several aldol reactions of silyl enolates with
aldehydes have been demonstrated in which the silyl enolates
are activated with Lewis bases instead of conventionally used
Lewis acids: Denmark and Stavenger introduced a Lewis base
catalyzed aldol reaction of trichlorosilyl enolates with aldehydes by using phosphoramides as a Lewis base[95] and
Hosomi and co-workers have reported an aldol reaction that
uses a combination of dimethylsilyl enolate and CaCl2 in an
aqueous DMF solvent.[96] Silyl enolates in which the Lewis
acidity of the silicon atom has been enhanced were employed
in these Lewis base catalyzed aldol reactions to facilitate
interaction with the base.
The use of other Lewis base catalysts was investigated for
the activation of silyl enolates to enable simple and popular
silyl enolates such as trimethylsilyl (TMS) enolates to be
employed. These catalytic aldol reactions of TMS enolates
with aldehydes in the presence of a Lewis base proceeded
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2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Scheme 30. Silyl transfer of silylamide to lithium aldolate.
Since the solvents were considered to influence this silyl
transfer from the silylamide to the lithium aldolate, various
solvents were further screened to obtain higher yields and
higher ratios of the O-silyl ether over the aldol. This process
led to the discovery that DMF (55:56 = 1:35) and pyridine
(55:56 = 1:6) were both excellent solvents for the generation
of the aldol adducts in quantitative yields.
The catalytic aldol reaction was investigated with 5 mol %
of LiNPh2 added to a solution of the substrate in DMF at
45 8C, and the desired aldol was obtained in 80 % yield along
with recovery of 18 % of the starting material. Similarly, the
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aldol adduct was obtained in quantitative yield when the
reaction was carried out with 20 mol % of LiNPh2 at 0 8C in
pyridine (Scheme 31). In the absence of the catalyst, the aldol
adduct was not obtained at either 45 8C in DMF or at 0 8C in
Table 4: Lithium 2-pyrrolidone catalyzed aldol reaction of TMS enolate
54 with aldehydes.
Solvent
T [8C]
t [h]
Yield[a] [%]
1
DMF
45
2
92
2
pyridine
0
3
95
3
DMF
45
3
92
4
pyridine
0
30
88
5
DMF
45!RT
3 days
57
6
DMF
45
4
55[b]
Entry
Scheme 31. LiNPh2-catalyzed aldol reaction of TMS enolate 54 and
benzaldehyde.
pyridine. These results indicate that LiNPh2 itself apparently
behaves as an effective catalyst in promoting the aldol
reaction in DMF or in pyridine.[97a,c]
In the next development, 2-pyrrolidone was chosen as a
precursor of the catalyst[97b,c] because it is easy to dissolve in
water, is readily available, and is inexpensive. In addition, the
pKa value of the NH bond is relatively close to that of
diphenylamine (measured in DMSO).[98] Reaction of TMS
enolate 54 and PhCHO in the presence of 5 mol % of lithium
2-pyrrolidone either at 45 8C in DMF or at 0 8C in pyridine
gave the desired aldol in 95 % yield in DMF or 78 % yield in
pyridine [Eq. (25)]. These results indicate that the lithium 2pyrrolidone does indeed catalyze the aldol reaction of the
TMS enolates with aldehydes in DMF or pyridine by acting as
a Lewis base.
Aldehyde
[a] Yield was determined by 1H NMR analysis (270 MHz) using 1,1,2,2tetrachloroethane as an internal standard. [b] Yield of the isolated
product.
Table 5: Lithium 2-pyrrolidone catalyzed aldol reaction of TMS enolate
54 with aldehydes.
t [h]
Yield[a] [%]
1
1
97
2
2
91
3
3
97[b]
Entry
Aldehyde
[a] Yield was determined by 1H NMR analysis (270 MHz) using 1,1,2,2tetrachloroethane as an internal standard. [b] Yield of the isolated
product.
Trimethylsilyl enolate 54 reacted smoothly with various
aromatic aldehydes to afford the corresponding aldols in high
yields. Aromatic aldehydes having an electron-withdrawing
group such as p-nitrobenzaldehyde or aliphatic aldehydes also
afforded the aldol adducts in moderate yields (Table 4).
The Lewis base catalyzed aldol reaction has some
characteristic advantages, especially when aldehydes with
basic groups are used. To show the utility of this Lewis base
catalyzed aldol reaction TMS enolate 54 and aldehydes with
basic groups were allowed to react in DMF at 45 8C in the
presence of 10 mol % of lithium 2-pyrrolidone. The reaction
proceeded smoothly and the corresponding aldol adducts
were obtained in high yields (Table 5).
Several other silyl enolates were also employed in this
lithium 2-pyrrolildone catalyzed aldol reaction. Initially TMS
Angew. Chem. Int. Ed. 2004, 43, 5590 – 5614
enolates prepared from (S)-ethyl ethanethioate or acetophenone were employed and the corresponding aldol adducts
were obtained in high yields. The two isomeric trimethylsilyl
enolate derived from methyl propionate were both found to
give aldols with moderate syn diastereoselectivity (Table 6).
The use of a Lewis base catalyst weaker than the former
one was next considered to further extend the utility of this
Lewis base catalyzed aldol reaction. The carboxylate anion
was tried on the expectation that this weakly basic ion may
also have an affinity toward the silicon atom. Furthermore,
silylation of the lithium aldolate by TMS carboxylate was
expected to establish a catalytic cycle since the silyl carboxylates were also silylating reagents. So a readily available
lithium acetate (AcOLi) was chosen as a milder Lewis base in
place of the above-mentioned lithium salts. The reaction of
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Table 6: Lithium 2-pyrrolidone catalyzed aldol reaction of TMS enolates
with benzaldehyde.
Entry
Silyl enolates
E/Z
t [h]
Yield[a] [%]
Table 7: LiOAc-catalyzed aldol reaction of TMS enolate 54 with aldehydes.
syn:anti
t [h]
Yield[a] [%]
1
3
97[b] (69)
2
3
94 (63)
Entry
1
–
2
95
–
2
–
3
77
–
3
5:1
3
42
63:37
3
16
78 (84)
4
1:9
3
88
73:27
4
17
62 (94[b])
5
18
84[b] (65[b])
[a] Yield was determined by 1H NMR analysis (270 MHz) using 1,1,2,2tetrachloroethane as an internal standard.
PhCHO and TMS enolate 54 in the presence of 10 mol % of
AcOLi at 45 8C in DMF afforded the aldol adduct in 83 %
yield. This result confirmed the capability of AcOLi to play a
role as an effective Lewis base catalyst in this aldol
reaction.[97d]
Aldol reactions in water or water-containing organic
solvents have attracted much attention in the sense that they
are economical and environmentally benign synthetic methods. Although several methods for carrying out aldol reactions with silyl enolates in water or water-containing organic
solvents have been reported,[96, 99] there are few that use silyl
enolates derived from carboxylic esters as a consequence of
their extreme sensitivity toward water.
The reaction of PhCHO and TMS enolate 54 was
performed in the presence of 10 mol % of AcOLi at 45 8C
in DMF/H2O (10:1), and afforded the aldol adduct in 71 %
yield. The reaction conditions were then carefully screened to
improve the yields. The corresponding aldol was obtained in
highest yield when the reaction was carried out with two
equivalents of 54 in DMF/H2O (50:1).[99]
Reactions of TMS enolate 54 with various aldehydes were
then tried under these conditions, and the aldol adducts were
obtained in high yields in every case (Table 7). It is
remarkable that 4-chloro- and 4-nitrobenzaldehyde as well
as 3-phenypropionaldehyde reacted smoothly to afford the
desired aldols in higher yields than in non-aqueous solvents.
2-Pyridinecarboxaldehyde afforded the aldol adduct in high
yield, even though the reaction does not generally proceed in
the presence of Lewis acids. One of the particular characteristics of this base-catalyzed aldol reaction carried out in a
water-containing DMF solvent is that the desired aldols are
formed in moderate to high yields even with aldehyde
substrates having free amide, hydroxy, or even carboxylic
groups—such groups are incompatible when metal enolates
or Lewis acids are employed.
Lithium aldolate is formed via a hexacoodinate hypervalent silicate similar to that formed under non-aqueous
conditions (Scheme 32).[97c] The initially formed lithium
aldolate and silyl acetate were hydrolyzed rapidly to produce
LiOH and acetic acid when the reaction is carried out in
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6
2.5
7
14
8
3
9
24
97 (84)
84
92[b]
52
[a] Yield was determined by 1H NMR analysis (270 MHz) using 1,1,2,2tetrachloroethane as an internal standard. Numbers in parentheses are
yields under non-aqueous conditions. [b] Yield of the isolated product.
Scheme 32. The catalytic cycle of a Lewis base catalyzed aldol reaction
of TMS enolates and aldehydes.
water-containing DMF. Subsequent neutralization should
afford AcOLi, thus establishing a catalytic cycle (Scheme 33).
This catalytic aldol reaction can also be performed
smoothly with other TMS enolates. For example, TMS
enolates derived from (S)-tert-butyl isobutanethioate and
acetophenone afforded the corresponding aldols in high
yields (Scheme 34).
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stannous chloride (SnCl2) and silver perchlorate (AgClO4) in
diethyl ether (Et2O; Scheme 35). In the following, the
historical development of the chemistry of glycosyl fluoride
as a glycosyl donor, and recent stereoselective glycosylation
using glycosyl fluoride is described.
Scheme 33. Regeneration of the catalyst in water-containing DMF.
Scheme 35. First example of glycosylation with glycosyl fluoride.
Scheme 34. Lithium acetate mediated aldol reaction of TMS enolates
and aldehydes in water-containing DMF.
This is the first example of a Lewis base catalyzed aldol
reaction that tolerates silyl enolates derived from carboxylic
esters. This method is applicable to the synthesis of various
aldols since the reaction does not need strictly anhydrous
conditions and can be performed with a mild, readily
available, and inexpensive Lewis base catalyst.
3. Stereoselective Glycosylation with Glycosyl
Fluorides
3.1. Introduction
The development of useful methods for stereoselective
glycosylation is one of the most fundamental and important
aspects for the syntheses of various types of glycosides and
oligosaccharides. In general, the stereoselective synthesis of
1,2-cis-glycosides is more difficult than that of 1,2-transglycosides, which can normally be synthesized by utilizing
neighboring-group participation from the 2-acyloxy group.
The Koenigs–Knorr reaction,[100] which employs glycosyl
chlorides and bromides, has for a long time been the most
commonly employed method; however, it requires a stoichiometric amount of troublesome heavy-metal salts and the
reaction conditions are rather drastic. Over the last two
decades various types of glycosyl donors, such as thioglycosides, glycosyl trichloroacetimidates, glycosyl acetate, selenoglycosides, glycosyl sulfoxides, 1-OH sugars, glycosyl donors
with phosphorus-containing leaving groups, glycals, and
pentenyl glycosides, have been developed[101] and employed
in the syntheses of saccharide chains. In 1981 we reported the
first use of glycosyl fluoride as a glycosyl donor.[102] In these
syntheses a-glucosides were obtained with good stereoselectivities when glucosyl fluoride and various glycosyl acceptors
were treated in the presence of a promoter generated from
Angew. Chem. Int. Ed. 2004, 43, 5590 – 5614
As described above, glycosyl chlorides and bromides are
used frequently in glycosylation reactions. However, in these
cases, the carbon–halogen bond is readily cleaved and
successful results cannot always be expected in regard to
both yields and stereoselectivities. A glycosyl fluoride was
chosen as the glycosyl donor on the basis that the carbon–
fluorine bond would be expected to have a high bond energy
and, consequently, that would lead to selective SN2 replacement provided that smooth activation could be achived.
Glycosyl fluorides had not been employed before since the
presence of a strong CF bond at the anomeric carbon atom
would make them more stable than other similar halides
because their high bond-dissociation energy (CF:
552 kJ mol1, CCl: 397 29 kJ mol1, CBr: 280 21 kJ mol1)[103] was believed to make them hard to activate.
At that time (the 1980s), the synthesis of the glycosyl
fluoride starting material was a problem because simple
preparative methods usually included the use of hazardous
anhydrous hydrogen fluoride. However, a facile method for
the synthesis of glycosyl fluorides from 1-hydroxy sugars using
2-fluoropyridinium salts had been found by accident
(Scheme 36).[104] This finding opened the way for using these
fluorides as glycosyl donors.
During the course of examining various Lewis acids for
activating glycosyl fluoride we encountered an extremely
interesting phenomenon, namely, that the desired reaction
Scheme 36. Preparation of glycosyl fluoride. Ts = p-toluenesulfonyl.
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T. Mukaiyama
proceeded with tin(ii) chloride, which is considered to be a
fairly weak Lewis acid, in the coexistence of silver perchlorate
in diethyl ether to give the corresponding 1,2-cis glycoside
stereoselectively.[102] After the above-mentioned combinedcatalyst system was reported, the fluorides became widely
recognized as useful glycosyl donors. The notable advantage
of a glycosyl fluoride as a glycosyl donor is its higher thermal
and chemical stability relative to glycosyl chlorides, bromides,
and iodides; it is possible to purify glycosyl fluorides by
column chromatography on silica gel. Many methods for the
preparation of glycosyl fluorides[105] have been developed by
using various fluorinating reagents such as HF[106] 2-fluoro-1methylpyridinium tosylate,[107] diethylaminosulfur trifluoride
(DAST),[108–110] HF/pyridine,[111–113] CF3ZnBr/TiF4,[114] DEAD/
PPh3/Et3O·BF4,[115] selectfluor,[116] deoxofluor,[117] N,N-diisopropyl(1-fluoro-2-methyl-1-propenyl)amine,[118] HF/MeCN/
Ac2O,[119] AgF,[120] ZnF2,[121] Et3N/HF,[122] CF3ZnBr,[114]
DAST/N-bromosuccinimide (NBS)/NIS,[123, 124] 4-methyl(difluoroiodo)benzene,[125] TBAF,[126] and PhI(OAc)2/SiF4.[127]
Of these, DAST, HF/pyridine, and DAST/NBS are most
frequently used. Moreover, Lal and co-workers recently
developed an attractive nonexplosive reagent, deoxofluor,[117]
which can be used on a kilogram scale.
Activating reagents for glycosylations with glycosyl fluoride have been studied intensively and various types of
reagents have been developed such as SnCl2/AgClO4,[102]
SnCl2/TrClO4,[107] SnCl2/AgOTf,[128] SiF4,[129] Me3SiOTf,[129]
BF3·OEt2,[130] TiF4,[131] SnF4,[131] [Cp2MCl2]/AgClO4 (M = Ti,
Zr, Hf; Cp = cyclopentadiene),[132] [Cp2ZrCl2]/AgBF4[133]
[Cp2HfCl2]/AgOTf,[133, 134] Bu2Sn(ClO4)2,[135] Me2GaCl,[136]
Tf2O,[137] LiClO4,[138] Yb(OTf)3,[139] La(ClO4)3·n H2O,[140]
La(ClO4)3·n H2O/Sn(OTf)2,[141] Yb/Amberlyst 15,[142] sulfated
zirconia,[143] TrB(C6F5)4,[144, 145] TfOH,[145–147] HClO4,[147]
HB(C6F5)4,[147] carbocations (B(C6F5)4 and TfO salts),[148]
SnCl2/AgB(C6F5)4,[149] SnCl4/AgB(C6F5)4,[150] Ce(ClO4)3.[151]
Our original activator, SnCl2/AgClO4, was effectively applied
in the synthesis of several types of glycosphingolipids
(Scheme 37)[152, 153] and of cyclodextrin (Scheme 38).[154]
Suzuki and co-workers applied their original activators
[Cp2MCl2]/AgClO4 (M = Zr, Hf) to the total synthesis of
mycinamicin IV (Scheme 39),[155] and Yamada and Nishizawa
employed Me3SiOTf in their synthesis of baiyunoside
(Scheme 40).[156]
Scheme 37. Total synthesis of the trimeric Lex glycosphingolipid.
3.2. Effect of Counteranions and Solvents on the Stereoselectivity
Recently, we found that a number of protic acids activated
glycosyl fluoride, and that various glycosyl acceptors reacted
to form the corresponding disaccharides in good to excellent
yields with either high a or b selectivities.[145–147] According to
the concept of hard and soft acids and bases (HSAB),[157] a
proton (H+) is considered to be fluorophilic because of its
hard character, and the dissociation energy of the HF bond
is higher than those of HCl, HBr, or HS (HF:
570 kJ mol1, HCl: 432 kJ mol1, HBr: 366 kJ mol1, HS:
344 12 kJ mol1).[103] In fact, glycosyl fluoride was activated
with TfOH, while glycosyl bromide and chloride were not
effectively activated by TfOH (Table 8, entries 1–4). Interest-
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2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Scheme 38. Total synthesis of a-cyclodextrin.
ingly, a thioglycoside, which is frequently employed in
glycosylation, was not activated at all by a TfOH catalyst
(entry 8),[158] which indicated that the chemoselective synthesis of oligo- and polysaccharides should be possible by
proper choice of the donor glycosyl fluoride and thioglycoside
(see Table 10).
During our study on the protic acid catalyzed glycosylation of glycosyl fluoride we found that the stereochemistry of
the resulting glycosides is influenced by the combination of
both the catalyst and the solvent. For example, an a-glycoside
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Synthetic Methods
Table 9: Effect of the solvent and the counterion of the protic acid[a] .
Scheme 39. Total synthesis of mycinamicin IV.
Entry
Cat.
Yield [%] (a/b)
(Et2O, RT, 4 h)
Yield [%] (a/b)
(BTF/tBuCN (5:1), O 8C, 2 h)
1
2
3
4
5
6
7
8
HOTf[b]
HOTf[c]
HClO4[c]
HOSO2C4F9[d]
HNTf2[b]
HNTf2[d]
HSbF6[d]
HB(C6F5)4[e]
98 (88:12)
96 (88:12)
98 (92:8)
99 (88:12)
quant. (49:51)
quant. (50:50)
99 (56:44)
95 (55:45)
quant. (47:53)
99 (49:51)
quant. (60:40)
96 (47:53)
99 (9:91)
quant. (9:91)
quant. (12:88)
99 (7:93)
[a] with HBF4·OMe2, p-toluenesulfonic acid, methanesulfonic acid, or
TFA as the catalyst. [b] Commercial substrate. [c] The protic acid was
generated from a silver salt and tBuCl in toluene and the supernatant
was used. [d] The protic acid was generated from a silver salt and tBuBr
in toluene and the supernatant was used. [e] The protic acid was
generated from [AgB(C6F5)4] and tBuBr in toluene/Et2O (1:1) and the
supernatant was used.
Scheme 40. Total synthesis of baiyunoside.
Table 8: Trifluoromethansulfonic acid catalyzed glycosylation with various glycosyl donors.
Entry
X
Yield [%]
a/b[a]
1
2
3
4
5
6
7
8
F (b)
F (a)
Br (a)
Cl (a)
OH (mix)[b]
OAc (a)
OCOOPh (b)
SEt (b)
83
87
9
6
51
75
61
0
67:33
66:34
45:55
52:48
73:27
68:32
72:28
–
[a] The a/b ratios were determined by HPLC analysis. [b] a/b = 7:3.
was obtained as the major product when the glycosylation was
carried out in diethyl ether with a catalytic amount of TfOH,
HClO4, or C4F9SO3H (Table 9, entries 1–4). On the other
hand, b stereoselectivity was observed when a catalytic
amount of HNTf2, HSbF6, or HB(C6F5)4 was used in BTF/
tBuCN (5:1, BTF = benzotrifluoride; Table 9, entries 5–8).
Angew. Chem. Int. Ed. 2004, 43, 5590 – 5614
These observations were very important because they demonstrated that the stereoselectivity of the reaction[147] is
strongly dependent on both the nature of the catalyst
counteranion as well as on the solvent and could be varied
by careful combination of the catalyst and solvent. This
phenomenon is observed in the glycosylation of various
glycosyl acceptors (Table 10).
Quite recently, an “armed” glycosyl fluoride was
employed as a glycosyl acceptor in the glycosylation of a
novel glycosyl donor 57 having a thioformimidate group at an
anometric position. The disaccharide obtained may be used
for the next one-pot glycosylation by suitable choice of the
reaction conditions (Scheme 41).[159]
3.3. Total Synthesis of Natural Origosaccharides by One-Pot
Sequential Glycosylation
The one-pot sequential glycosylation strategy was applied
to the convergent total synthesis of the F1a antigen
(Scheme 42).[160] First, glycosyl fluoride 58 was treated with
thioglycoside 59 in the presence of a catalytic amount of
TfOH to afford disaccharide 60 in situ. The b stereoselectivity
of the reaction was controlled by neighboring-group participation of the p-MeBz group at the C2 position. Next, the
second glycosylation of glycopeptide 61 with this disaccharide
62 was attempted by subsequently adding NIS in a one-pot
operation, and fully protected F1a 62 was obtained stereoselectively in high yield (89 %). Several transformations of the
thus obtained trisaccharide 62 gave the F1a antigen
(63).[161, 162] Moreover, the one-pot sequential glycosylation
method was also applied successfully to the rapid assembly of
a branched heptasaccharide (Scheme 43).[163, 164]
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T. Mukaiyama
Table 10: Protic acid catalyzed stereoselective glycosylation.
Additive[a]
t [h]
T 8C
Yield [%] (a/b)[b]
1
2
3
TfOH
HClO4
HB(C6F5)4
8
6
6
0
0
20
95 (89:11)
94 (93:7)
97 (4:96)
4
5
6
TfOH
HClO4
HB(C6F5)4
12
7
11
0
0
20
97 (84:16)
89 (88:12)
92 (8:92)
7
8
9
TfOH
HClO4
HB(C6F5)4
20
7
11
0
0
20
88 (81:19)
95 (83:17)
95 (8:92)
10
11
12
TfOH
CHlO4
HB(C6F5)4
12
4
2
0
0
20
quant. (86:14)
92 (98:11)
89 (5:95)
13
14
15
TfOH
CHlO4
HB(C6F5)4
12
6
2
0
0
20
quant. (80:20)
87 (85:15)
87 (5:95)
16
17
18
TfOH
CHlO4
HB(C6F5)4
2
19
10.5
0
0
20
90 (87:13)
82 (82:18)
78 (15:85)
Entry
Acceptor
Scheme 42. Total synthesis of the F1a antigen.
[a] Glycosylation was carried out in Et2O when TfOH or HClO4 was used
as the catalyst. The glycosylation was carried out in BTF/tBuCN (5:1)
when HB(C6F5)4 was used as the catalyst. [b] The a/b ratios were
determined by HPLC analysis.
Scheme 41. Glycosylation using glycosyl fluoride as an acceptor.
4. Concluding Remarks
In basic science it is critical to find the first approach
(“seeds-oriented” work), but it is equally important to
optimize the approach and to develop new systems (“needs
oriented”). In either case, ample time and energy need be
invested before a chemist can garner anything useful. Once
the fundamental target is reached, however, the whole
process appears so easy that anyone else could have done it,
like the episode of “ColumbusO egg”. However, to win
through to the result, a researcher must go through unrewarding months and years of making hypotheses and repeating experiments, and this is exactly what makes a chemist. The
most important thing here is “not to imitate others”. If
someone has already been involved with the topic, dare not to
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2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Scheme 43. One-pot synthesis of a branched heptasaccharide.
stick to the same topic, but find something of your own. This is
our code, which should never be forgotten.
Experience and the accumulation of experiences play a
very important role in pursuing research work. If a mature
hypothesis does not lead you to a satisfactory result, just try
once more from the beginning and continue to do the
experiments. You will then eventually find an interesting clue,
unless you give up half way. Chemistry is still more or less
unpredictable. Wisdom learned not from books or what
others said but from oneOs own experience—which I call
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Angew. Chem. Int. Ed. 2004, 43, 5590 – 5614
Angewandte
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Synthetic Methods
“chemical wisdom”—will become a motivating force for
associating problems with questions that give you a different
idea. Those who have accumulated a lot of such “chemical
wisdom” should be able to formulate a seminal hypothesis by
the association of small clues. By overcoming difficulties
without compromise, hard and steady work done (especially
at the time of oneOs youth) will give you love for your work
and will furnish you with “chemical wisdom”, and consequently will lead you to successful later development.
The fun of chemistry is in its unexpectedness. There are
times when you come to face-to-face with an unexpected
phenomenon while carrying out experiments. You simply
have to be sufficiently aware and open to accept the
seemingly unbelievable. There are still many more valuable
ideas remaining to be discovered. The question is how to find
them and how to develop them into new possibilities.
The author thanks Dr. Taichi Shintou, Dr. Hidehiko Fujisawa,
and Dr. Jun-ichi Matsuo for their contributions to the current
research and also in preparing this manuscript. These studies
were supported in part by the Grant-in-Aid of the 21st Century
COE Program from the Ministry of Education, Culture,
Sports, Science, and Technology (MEXT), Japan.
Received: November 24, 2003
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2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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