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Elisabethin A A Marine Diterpenoid Yet To Surrender to Total Synthesis.

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Natural Product Synthesis
Elisabethin A: A Marine Diterpenoid Yet To Surrender
to Total Synthesis**
Giuseppe Zanoni* and Maurizio Franzini
biomimetic synthesis · Diels–Alder reaction ·
secondary metabolites · terpenoids · total synthesis
Gorgonian corals have attracted con-
[**] We thank Prof. Giovanni Vidari, Prof.
Pierluigi Caramella, and Prof. Remo Gandolfi for helpful discussions.
thetic challenge for organic chemists. Its
structure was elucidated by exhaustive
spectroscopic studies and X-ray diffraction analysis, which did not allow the
establishment of the absolute configuration of the natural compound.[1] The
tricyclic cis,trans-fused 5,6,6 ring system
of elisabethin A embodies a fully substituted enedione functionality and six
contiguous stereogenic centers, of which
one, at the junction of the three rings, is
quaternary. To date, only two research
groups, those led by Mulzer[2] and Rawal,[3] have tackled the task of the total
synthesis of this unusual molecule. For
the reader3s convenience, the absolute
configuration of the final product described in Mulzer3s work is tentatively
assumed to be that of the natural
In Mulzer3s approach, two stereogenic centers were established in a
convergent fashion through the condensation of two chiral units (Scheme 1).
The first of these units, iodide 2, was
prepared in five steps and 55 % overall
yield from the known aldehyde 3,[4]
which was obtained in turn from (S)(+)-3-hydroxy-2-methylpropionic acid
methyl ester, an expensive commercially
available nonnatural chiral-pool compound.[5]
The dienyl system in iodide 2 was
secured through a classical Horner–
Wadsworth–Emmons reaction, followed
by a salt-free Wittig ethenylation. The
aromatic intermediate 4 was then assembled by means of a finicky diastereoselective alkylation of imide 5 (the
second of the above-mentioned chiral
units) with iodide 2, followed by a
straightforward four-step manipulation.
Imide 5 was prepared from the com-
Angew. Chem. Int. Ed. 2004, 43, 4837 –4841
DOI: 10.1002/anie.200460570
siderable attention as a result of their
wealth of bioactive secondary metabolites, such as acetogenins, sesquiterpenoids, diterpenoids, prostanoids, and
steroids. Specifically, the West Indian
sea whip Pseudopterogorgia elisabethae,
collected in deep waters near San Andrs Island (Colombia), has been a
goldmine for novel diterpenoids with
rare carbon-skeleton architectures. Elisabethanes stand out among these diterpenoids for their interesting anti-inflammatory, antibacterial, analgesic, and cytotoxic activities. The intricate structure
of elisabethin A (1), a representative
member of this family whose biological
properties have not been fully investigated,[1] constitutes a formidable syn-
[*] Dr. G. Zanoni
Dipartimento di Chimica Organica
Universit di Pavia
Viale Taramelli, 10, 27100 Pavia (Italy)
Fax: (+ 39) 0382-507-323
M. Franzini
Department of Chemistry
Stanford University
Stanford, CA 94305-5080 (USA)
mercially available aldehyde 6 in 11
steps, the last of which consisted of a
modified Evans oxazolidinone condensation with the mixed pivaloyl anhydride 7. The product of the ensuing
doubly stereodifferentiating alkylation
was obtained with a satisfying 93:7 d.r.
and in 69 % yield after recycling of the
starting material.
The other four contiguous stereogenic centers present in the natural
product were installed by means of a
unique Diels–Alder reaction performed
on the quinoidal system 8. After removal of the phenolic silyl ether protecting
groups, an oxidation reaction promoted
by aqueous ferric chloride afforded the
desired cycloadduct via a transient quinonic intermediate. The surmised quinoidal system 8 was never isolated, but it
was detected by TLC and by NMR
spectroscopy. The subsequent intramolecular Diels–Alder (IMDA) reaction
was monitored by TLC.
The comments of the authors about
the IMDA reaction deserve additional
mention. Although rare, there are indeed a few reported examples of the
participation of acyclic terminal
Z dienes in IMDA reactions.[6] Because
of their proclivity to preferentially undergo a thermally induced [1,5] H shift[7]
and/or thermal Z to E isomerization,[8, 6a]
terminal Z dienes have been avoided in
total synthesis. There are many more
reports on failed attempts to carry out
IMDA reactions with E,Z and
Z,Z dienes than reports of successful
cases.[8a, 9]
Secondly, the tenfold excess of iron
chloride, employed as the oxidizing
agent for hydroquinone 9, might also
act as a Lewis acid to catalyze the
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Scheme 1. The Mulzer approach to elisabethin A. Bn = benzyl, TBS = tert-butyldimethylsilyl, Piv = pivaloyl, Tr = trityl.
subsequent IMDA reaction through polarization of the carbonyl p bonds in the
transient quinone.[10] Moreover, the observed high substrate-dependent diastereoselectivity, as confirmed by the
HPLC detection of less than 3 % of an
alleged minor epimer, would rule out
the necessity for a Diels–Alderase in a
hypothetical biosynthetic pathway to
elisabethin A.[11] Both of these points
raise some reservations about the “virtually biomimetic” mode of this IMDA
reaction, which was referred to in this
way by the authors by virtue of the
otherwise very mild reaction conditions
(aqueous medium at room temperature).
The moot point in the synthesis
described stems, however, from the
proposed structure for the product of
the cycloaddition, and therefore for the
transition state leading to it. Although in
principle an IMDA reaction can proceed through either an exo or an endo
transition state (TS), the latter is known
to generally be highly preferred under
conditions of Lewis acid catalysis, at low
reaction temperatures, and in the presence of an electron-withdrawing group
in close proximity to the dienophile.[12, 6b]
Not only are these conditions met in this
case, but minimization of the allylic
strain between the isopropenyl group
at C9 (elisabethin A numbering) and
one of the quinone carbonyl groups
would also favor an endo approach.
Recent work on the IMDA reaction of
masked p-benzoquinones generated in
situ indeed showed that endo transition
states largely prevail, almost independent of the substitution pattern of the
dienyl unit.[13]
Upon the realization that the initially proposed endo TS would give a
different product from the obtained
compound 10, in a correction the authors proposed an exo TS (R1 = Me,
R2 = H, Scheme 2) to account for the
relative and absolute stereochemistry
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
assigned to compound 10.[14] Unfortunately, a cursory inspection of molecular
models seems to hint at a lack of the
required overlap and alignment of the
E,Z diene and quinoid dienophile, as a
result of severe steric constraints. However, a Z to E isomerization of the
terminal olefin could take place in the
presence of the excess FeCl3 ; Lewis acid
mediated olefin isomerization reactions
are well documented in the literature.[15, 12a] If such an isomerization was
combined with an exo IMDA reaction
(R1 = H, R2 = Me), the C3 epimer 10 a
would clearly form (Scheme 2). Conversely, in a third, more plausible scenario, a Z to E isomerization in combination with an endo TS (R1 = H, R2 =
Me) would lead to 10 b, with the opposite configuration at the three contiguous centers C1, C2, and C3 with respect
(Scheme 2).
Angew. Chem. Int. Ed. 2004, 43, 4837 –4841
close examination of the work
published by Rawal and discussed below in the spectroscopic and chemical characterization of the alleged common
intermediate 10 (and its enantiomer), the identity of natural
elisabethin A and of Mulzer3s
synthetic compound 1 can
hardly be reaffirmed at this
For the attempted total
enantioselective synthesis of
elisabethin A by Rawal and
acid was selected from the
natural chiral pool as the initial source
of chirality (Scheme 3). The construction of the other stereogenic centers was
based on a sequence of internal asymmetric induction steps and a highly
stereoselective chirality transfer step
with quite a high degree of atom economy. The C7 stereogenic center was
installed with a satisfying 8:1 d.r. by
methylation of the enolate anion of
lactone 11, which was eventually converted into alkyne 12 through a onecarbon homologation. The configuration at C9 was established first through
a Negishi coupling of acyl chloride 13,
followed later by a clever, underutilized
Scheme 2. Possible stereoisomeric products from the
IMDA cyclization.
Despite the extensive NOESY spectroscopic studies reported, the correct
structure for intermediate 10, which was
prepared in 16 linear steps and a remarkable 25 % overall yield, can not be
validated at this stage. Comparison of
the 13C NMR data of natural elisabethin A[1] with those of the final synthetic
product, obtained from 10 by hydrogenation of the C4–C5 endocyclic alkene, base-induced epimerization, and
demethylation in modest overall yield,
reveals several significant divergences in
the chemical shifts (up to 0.5 ppm).
Furthermore, the two 1H NMR spectra
are not completely superimposable. In
light of the incongruities revealed by a
Angew. Chem. Int. Ed. 2004, 43, 4837 –4841
Scheme 3. The Rawal approach to elisabethin A. NBS = N-bromosuccinimide.
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
pinacol-like rearrangement to furnish
the methyl ester intermediate 14. The
anchimeric assistance provided by the
electron-rich aromatic counterpart in
the migration dictates the overall retention of configuration observed at C9,
which bears a methoxycarbonyl group in
the product 14 as a precursor to the
isopropenyl unit in the natural product.
The Z bromovinyl group in 14 was readily elaborated from the terminal alkyne
derived from alcohol 12.
After constructing the Z,E dienyl
moiety by means of a Negishi coupling
of Z-bromoalkene 14 with (E)-1-bromopropene, Rawal and co-workers also
relied on the high stereospecificity of
an IMDA reaction to define the configuration of the remaining four stereogenic centers. The quinoidal functionality in 15, the substrate for the IMDA
addition, was formed in moderate yield
by an O2-induced oxidation catalyzed by
salcomine. In the IMDA reaction, the
endo TS, which avoids 1,3-allylic strain
between the methyl group at C7 and the
propenyl substituent on the cis double
bond, delivered 16 as a single stereoisomer, whose carbon skeleton is epimeric at C2 with ent-elisabethin (ent-1).
Scheme 4. a) Pd/C, H2, EtOAc, room temperature, 1 h;
b) Wilkinson catalyst, H2 ; c) NaOH, MeOH/H2O, 80 8C,
5 h; d) NaOEt, EtOH, reflux.
Unfortunately, the synthesis of
ent-elisabethin could not be completed. After the selective hydrogenation of 16 with the Wilkinson
catalyst to form the tricyclic intermediate 17 (Scheme 4), which
was obtained in a total of 16
linear steps and 1.7 % overall
yield, it was found that it was
not possible to epimerize the C2
center under a variety of experimental conditions. Dreiding
models seem to suggest that the
C2 H bond is locked in an almost coplanar orientation with
respect to the adjacent carbonyl
group as a result of the rigidity of
the polycyclic frame, in stereoelectronic misalignment for deprotonation.
The putative enantiomer of
17 prepared by Mulzer by the
hydrogenation of 10, however,
underwent successful epimerization under basic aqueous conditions (Scheme 4). This discrepancy between the two alleged enantiomers can be attributed to in- Scheme 5. a) 1. LiI, 2,6-lutidine, 80 8C, 99 %; 2. CAN,
accuracy in the stereochemical MeCN, 0 8C, then pyridine, Et3N, 50 8C, 84 %. CAN =
assignment of 10, as alluded to
above. The structure of the cycloadduct 16 was further confirmed by tion analysis of crystals of a key interNOE studies reported by Rawal,[3] and mediate in Mulzer3s route and the use of
by chemical correlation after derivatiza- nonnatural d-pyroglutamic acid as chition into ent-elisapterosin B,[16] another ral-pool source in Rawal3s approach will
natural diterpene of the same family, defuse any remaining doubts about the
recently synthesized by Kim and Rych- structure of the synthetic elisabethin A
novsky.[17] The conversion of ent-b-eli- and the absolute configuration of the
sabethin (ent-1b), formed by demethy- natural product.
Cases of the incorrect assignment of
lation of 17, into ent-elisapterosin 18
was inspired by a hypothetical biomi- the configuration of IMDA products are
metic pathway. Thus, a CeIV-mediated in fact known in the literature.[19] For
oxidative cyclization was followed by example, in a Communication on the
base-induced tautomerization of the preparation of the core carbon frameresulting diketone fragment. The former work of elisabethin A by an IMDA
step probably proceeds by an oxidative reaction involving an o-imidoquisingle-electron transfer (SET) from ent- none,[20] Nicolaou et al. initially assigned
1b, which triggers the C C bond for- this unit the configuration I shown in
mation (Scheme 5).[18] Further oxida- Scheme 6. However, after the collection
tion by CeIV would generate the tertiary of crystallographic data, the same aucarbocation proposed by Rawal as an thors reassigned the configuration of
intermediate in his synthesis. Stereo- this compound as II in a full paper a year
electronic constraints would favor de- later.[13a]
protonation from one of the methyl
In conclusion, further work is regroups, thus leading to the less substi- quired before elisabethin A can be
tuted alkene as the product.
placed in the basket of natural products
It would be premature to claim that whose synthesis has been completed.
a complete synthesis of elisabethin A
has been achieved. Only X-ray diffrac- Published Online: September 3, 2004
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2004, 43, 4837 –4841
Scheme 6. a) Dess–Martin periodinane (4.0 equiv), H2O (2.0 equiv), CH2Cl2, 25 8C, 25 %.
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[3] N. Waizumi, A. R. Stankovic, V. H.
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2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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