Tandem aldol-allylation and aldol-aldol reactions with ketone-derived enolsilanes: Highly diastereoselective single-step synthesis of complex tertiary carbinols

Article abstract of DOI:10.1021/ja053593s

A new tandem aldol-allylation reaction employing ketone-derived enolates has been developed that leads to the rapid, diastereoselective synthesis of tertiary carbinol containing fragments with relevance to polyketide natural product synthesis. In addition

Full text of DOI:10.1021/ja053593s

Published on Web 08/27/2005
Tandem Aldol-Allylation and Aldol-Aldol Reactions with Ketone-Derived
Enolsilanes: Highly Diastereoselective Single-Step Synthesis of Complex
Tertiary Carbinols
Xiaolun Wang, Qinglin Meng, Nicholas R. Perl, Yue Xu, and James L. Leighton*
Department of Chemistry, Columbia UniVersity, New York, New York 10027
Received June 1, 2005; E-mail: leighton@chem.columbia.edu
As part of a program dedicated to the development of tandem
reactions for the rapid synthesis of polyketide natural products, we
have reported a new tandem aldol-allylation reaction that can
deliver polyketide fragments with up to four stereocenters in a
remarkably simple reaction that owes its success to the Lewis acidity
induced in the silane by the strained pinacolate ring (Scheme 1).1
In analyzing ways to expand the scope of this reaction, we noted
the occurrence of tertiary carbinols in important polyketide natural
the synthesis of stereochemically complex diols (4 f 5 and 6 f
7). A methallyl fragment was also found to be a viable participant
in the tandem reaction (8 f 9), leading to a significantly faster
and highly diastereoselective reaction, although in this case, a
significant amount (19%) of the simple aldehyde methallylation
product was also observed. Finally, the methallyl and cis-crotyl
substitutions may be combined as in silane 10, leading to the highly
diastereoselective synthesis of diol 11 in 74% yield. The illustrated
chairlike transition state (pinacol omitted for clarity) for the allyl-/
crotylation step correctly rationalizes the simple diastereoselectivity
of crotylation products 5, 7, and 11 and is similar to a model
advanced by Chemler and Roush in their detailed examination of
2
products (e.g., the spongistatins ), which suggested the use of
ketone-derived enolates as the enol component of the tandem
3
reagents (e.g., 1, Scheme 1). Type I allyl- and crotylsilane additions
4
to ketones are known but have not previously been described as
5
part of a tandem reaction of the type proposed here. Herein we
report the realization of this idea, as well as a new, related reaction
involving ketone-derived enolates, the tandem aldol-aldol reaction.
In all cases, stereochemically and structurally complex polyketide-
like tertiary carbinols may be obtained from aldehydes in an
operationally trivial and highly diastereoselective tandem reaction.
intramolecular crotylsilylations. However, the observed preference
for the allyl-/crotylation to occur cis to the cyclohexyl group leading
to syn-1,3-diols is not well-understood and, indeed, stands in
6
contrast to the corresponding intramolecular allylborations.
Scheme 3
Scheme 1
Our studies began with the synthesis of allylenolsilane 1 (Scheme
2). Chlorosilane 2 was treated with the lithium enolate derived from
acetone to give 1 in 61% yield. Treatment of CyCHO with 1.5
equiv of 1 in toluene at 60 °C for 48 h gave diol 3 in 82% yield
and with 8:1 diastereoselectivity favoring the syn-diol diastereomer.
As expected, and unlike some of the previously described aldehyde-
1
derived allylenolsilanes, <2% of the product resulting from direct
allylation of the aldehyde was observed.
Scheme 2
Extensive investigations have revealed that tandem aldol-
allylation reagents constructed from 1,2-N-alkylamino alcohols or
1,2-N,N′-dialkyldiamines, as opposed to 1,2-diols as above, provide
little or no diol (tandem) products in reactions with aldehydes.
Reasoning that the basic amine group is the source of the problem,
we have investigated less basic N-aryl amino alcohols. After
considerable experimentation, allylenolsilane 12 was prepared (as
a 3:1 mixture of diastereomers), and we were delighted to find not
only that it participated in a smooth tandem aldol-allylation
A survey of the scope with respect to substitution on the allyl
fragment was undertaken (Scheme 3). Both cis- and trans-crotyl
fragments participated smoothly in the tandem reaction, allowing
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10.1021/ja053593s CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4
Scheme 6
reaction with benzaldehyde but also that the 1,3-anti diol 13 was
the major product with 8:1 diastereoselectivity (Scheme 4).
Although the fact that 12 is prepared as a 3:1 mixture of
diastereomers is a complicating feature of this silane design, this
experiment nevertheless demonstrates that the design of tandem
aldol-allylation reagents that give stereochemical flexibility is
possible.
to be competitive with an aldehyde for the attentions of reagent
14, it may reasonably be posited that such a sequestering mechanism
could become important in the design of a tandem aldol-aldol
reaction with aldehyde-derived dienolsilane reagents.
These successes with ketone-derived enolates within the strained
silacycle paradigm raised the possibility of a tandem aldol-aldol
reaction using a dienolsilane. While several groups have success-
fully and elegantly orchestrated one-pot sequential aldol reactions,7
and one group has reported tandem aldol-aldol reactions using
New tandem aldol-allylation reactions have been described,
employing enolsilanes derived from ketones, leading to the dia-
stereoselective synthesis of complex tertiary carbinols. In addition,
a new and highly efficient and diastereoselective tandem aldol-
aldol reaction has been described. These operationally simple
reactions provide remarkably efficient access to complex structures
with relevance to biologically important polyketide natural products.
Current efforts are focused on the development of enantioselective
and/or diastereoselective (using chiral aldehydes) variants of these
powerful reactions.
8
various metal dienolates, the scope of these reactions is quite
narrow and the development of a more general system remains an
elusive and enticing goal. Thus, to investigate the ability of our
silane system to participate in a smooth tandem aldol-aldol
reaction, we prepared dienolsilane 14 as outlined in Scheme 5. The
use of bicyclohexyl-1,1′-diol instead of pinacol was due to the
success of the former (and failure of the latter) in the reaction with
4
SiCl . With 14 in hand, the reactions with three aldehydes were
investigated. As shown, the reactions proceeded smoothly, deliver-
ing hemiketals 15a-c in high yields and with excellent diastereo-
selectivity. These efficient and selective reactions have potential
relevance to the synthesis of tetrahydropyrans, such as are found
in polyketide natural products.
Acknowledgment. This work was supported by a grant from
the National Institutes of Health (NIGMS GM58133). We gratefully
acknowledge research support from the Astellas USA Foundation,
Amgen, and Merck Research Laboratories.
Supporting Information Available: Experimental procedures,
characterization data, and stereochemical proofs. This material is
available free of charge via the Internet at http://pubs.acs.org.
Scheme 5
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6
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9
to structure 17. In principle, this rearrangement provides a built-
(
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