Communications
DOI: 10.1002/anie.201007210
Synthetic Methods
Rapid Total Syntheses Utilizing “Supersilyl” Chemistry**
Brian J. Albert, Yousuke Yamaoka, and Hisashi Yamamoto*
Although more than 100 years of study have demonstrated
that the aldol reaction is one of the most fundamental and
effective methods for the construction of complex molecules,
in particular natural products, its full potential has not been
realized.[1] Polyketides, a family of natural products, have
provided chemists with a rich source of molecular architec-
tures and biologically significant compounds.[2] Polyketides
often contain the 1,3-polyol motif, and unsurprisingly the
aldol reaction has been the preferred method to access these
structures.[1,2] Unfortunately, however, the most selective
aldol products afford ketones or esters[3] and not aldehydes.
Thus, the reported biomimetic routes require additional
protection and redox steps for each iteration, thus making
Scheme 1. Supersilyl-directed aldol reactions. HMDS=1,1,1,3,3,3-hexa-
the preparation of long-chain polyketides excessively lengthy
(poor redox economy).[4] Therefore, interest in one-pot
polyaldol cascade reactions has increased.[5] Although, sev-
eral elegant stereoselective approaches have been reported,
all the methods inevitably stop after the second aldol reaction
because of the cyclization of the hydroxyaldehydes or
-ketones. This cyclization could be blocked if the pendant
hydroxy groups were rendered non-nucleophilic by an in situ
generated blocking variant, which, importantly, would afford
aldehydes 2 as products. We recently reported the first high-
yielding triple aldol reaction (Scheme 1A).[6] This cascade
results in high 1,3-stereoinduction, generated from the
extreme bulk of the tris(trimethylsilyl)silyl (supersilyl)
group, which also retards undesired polymerization.[7]
methyldisilazane, TES=triethylsilyl, Tf=trifluoromethanesulfonyl,
TMS=trimethylsilyl.
cancer xenograft in mice with no observable side effects.[9c]
The structure and absolute stereochemistry of EBC-23 was
determined by the Williams research group (in their 15-step
total synthesis, 11 steps for the longest linear sequence).[9b]
Our retrosynthetic analysis of EBC-23 relies on supersilyl-
directed aldol methods (Scheme 2A). Hydrolytic opening of
the spiroketal reveals polyhydroxy ketone 6, which could be
rapidly generated from tetradecanal, two equivalents of
acetaldehyde silyl enol ether 1, acetone, an a-hydroxyalde-
hyde, and acryloyl chloride.
The use of the bulky b-silyloxy methyl ketones 3 in 1,5-
stereoselective aldol reactions with aldehydes produces 4 or 5
with high diastereoselectivity (Scheme 1B).[8] Importantly, all
three 1,3,5-triol stereoisomers can easily be prepared from 4
and 5.[8] The utilization of both of these strategies would allow
for the facile synthesis of complex 1,3-polyols and spiroketals.
Herein we report the rapid total syntheses of EBC-23 and
polymethoxy-1-alkene 13 by these approaches.
As part of a screening program to identify new anticancer
agents, spiroketal EBC-23 (Scheme 2A) was isolated from
the fruit of Cinnamomum laubatii.[9a] This natural product was
active in vitro against several human cancer cell lines, and
more importantly, inhibited the growth of a human prostate
With this strategy in mind, ketone (ꢀ )-9 was prepared as
shown in Scheme 2B. Tetradecanal[10] was treated with 1 and
[11]
Tf2NAlMe2
to give aldehyde (ꢀ )-7 in 85% yield. This
aldehyde was treated with silyl enol ether 8 in the presence of
Tf2NH and 1-iodo-2-phenylacetylene[6] to furnish (ꢀ )-9 in
75% yield and a diastereomerically pure form after column
chromatography. The preparation of alkoxyaldehyde 11
commenced with our asymmetric epoxidation of 3-hydroxy-
1,4-pentadiene.[12] This epoxy alcohol was converted into 10 in
90% yield according to a literature procedure.[13] Aldehyde 11
was prepared from 10 by a hydrolysis/oxidative cleavage
sequence in ꢁ 84% (yield over two steps).
The endgame for the synthesis of EBC-23 commenced
with the coupling of (ꢀ )-9 and 11 under standard condi-
tions,[8] which produced 12 in only 6% yield, presumably
because of the low solubility of (ꢀ )-9 in DMF (Table 1,
entry 1). The addition of 10% (v/v) THF improved the yield
slightly, but the solubility of (ꢀ )-9 and its putative lithium
enolate was still insufficient (entry 2). When the reaction was
performed with THF as the lone solvent, 12 was obtained in
good yield but poor diastereoselectivity (entry 3). Therefore,
the use of DMF as a cosolvent in the aldol reaction was
explored (entries 4–8), since we postulate that two molecules
coordinate to the lithium atom in the closed transition state.[8]
The optimal result was obtained by using toluene as the major
[*] Dr. B. J. Albert, Dr. Y. Yamaoka, Prof. Dr. H. Yamamoto
Department of Chemistry, The University of Chicago
5735 S Ellis Avenue, Chicago, IL 60637 (USA)
Fax: (+1)773-702-0805
E-mail: yamamoto@uchicago.edu
[**] This work was made possible by the generous support of the NIH
(P50GM086 145-01) and a Uehara Foundation fellowship (Y.Y.). We
would additionally like to thank Antoni Jurkiewicz for his NMR
expertise and Chang-Jin Qin for his assistance with mass spec-
trometry.
Supporting information for this article is available on the WWW
2610
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 2610 –2612
Albert, Brian J.
