Strained silacycles in organic synthesis: The tandem aidol-allylation reaction

Article abstract of DOI:10.1021/ja027655f

Allyl(crotyl)enolsilanes, when constrained in a five-membered ring with a 1,2-diol, react with aldehydes in a tandem aldol-allylation reaction to give polyketide fragments. These experimentally trivial and efficient reactions establish two new carbon-carb

Full text of DOI:10.1021/ja027655f

Published on Web 08/15/2002
Strained Silacycles in Organic Synthesis: The Tandem Aldol-Allylation
Reaction
Xiaolun Wang, Qinglin Meng, Andrew J. Nation, and James L. Leighton*
Department of Chemistry, Columbia UniVersity, New York, New York 10027
Received July 11, 2002
A common structural theme in polyketide/macrolide natural
products is one or more (1,3,5...)-polyol chains derived from the
biosynthetic coupling of acetate and propionate units. In devising
stereocontrolled approaches to the synthesis of such structures,
chemists have relied heavily on aldol addition reactions. Enolate
fragments derived from aldehydes have been little-used in this
Scheme 1
1
chemistry, principally because the product is itself an aldehyde,
and oligomerization may occur. However, if such oligomerization
could be controlled, in terms of both chain length and stereoselec-
tivity, a single step synthesis of polyketide chains with four, six,
eight, or more stereocenters would result (eq 1). The key to such
a process is the discovery of a method to halt the oligomerization
at the desired chain length. To achieve this, we envisioned an
Scheme 2
n
intramolecular allylation as the termination event. The metal (ML )
would thus bear the desired number of enolate fragments as well
as an allyl group. Upon completion of the aldol cascade, intramo-
lecular allylation of the terminal aldehyde would halt chain
propagation (eq 2). As a first step toward the development of such
a process, and as a useful reaction in its own right, we report herein
the tandem aldol-allylation reaction.2
of diastereomers along with a small amount of the direct allylation
product. Optimization of the reaction variables (solvent, concentra-
tion, and temperature) led to the identification of 0.5-1 M [silane]
in toluene at 40 °C as the optimal conditions. Shown in Scheme 3
are the results for both benzaldehyde and cyclohexanecarboxalde-
hyde under these conditions. That the strain induced in the silacycle
by the 1,2-diol is essential for reactivity was demonstrated by the
observation that the 2,4-dimethyl-2,4-pentanediol-derived analogue
of 2 is unreactive under identical reaction conditions.
Scheme 3
n
In considering possibilities for the ML fragment, we quickly
focused on silicon for the following attributes: (1) enol- and
allylsilanes are both readily prepared and stable, and (2) our recent
discovery that silicon, constrained in a five-membered ring by 1,2-
diols, 1,2-amino alcohols, and 1,2-diamines, possesses Lewis acidity
3
sufficient for clean, uncatalyzed allylation of aldehydes. We thus
envisioned the synthesis (and reaction) of an allylenolsilane, with
the remaining two valences used to constrain the silicon in a five-
membered ring (Scheme 1).
In an effort to expand the scope of the process, (E)-crotylenol-
silane 5 and (Z)-crotylenolsilane 6 were prepared from (E)- and
4
(
Z)-crotyltrichlorosilane, respectively, using the method outlined
The reaction of pinacol with allyltrichlorosilane and 1,8-
in Scheme 2. Reaction of 5 with cyclohexanecarboxaldehyde in
toluene at 40 °C gave a mixture of two tandem reaction products
with 8:1 diastereoselectivity from which diol 7 could be isolated
in 60% yield (Scheme 4). Under the same conditions, 6 produced
a 10:1 mixture of diol diastereomers from which diol 8 could be
isolated in 71% yield. In both reactions, the simple aldehyde
crotylation product could be detected, but was produced in only
diazabicyclo[5.4.0]undec-7-ene (DBU) in CH
tion of allylchlorosilane 1 in 72% yield (Scheme 2). Treatment of
with the lithium enolate of acetaldehyde (prepared by treatment
of CH dCHOSiMe with MeLi) then gave allylenolsilane 2 in 70%
2 2
Cl led to the forma-
1
2
3
yield. Silane 2 may be distilled to purity and is stable to storage
for at least several months.
When allylenolsilane 2 was treated with benzaldehyde in benzene
at 50 °C, a smooth reaction occurred to give diol 3 as an 8:1 mixture
∼
5% yield. That the cis-crotyl group gives an anti propionate unit
and trans gives syn is easily rationalized by the illustrated
stereochemical model (pinacol omitted for clarity) and is similar
*
To whom correspondence should be addressed. E-mail: leighton@
5
chem.columbia.edu.
to observations recorded by Kira and Sakurai et al. and Roush
1
0672 J. AM. CHEM. SOC. 2002, 124, 10672-10673
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10.1021/ja027655f CCC: $22.00 © 2002 American Chemical Society

C O MMU N I C A T I O N S
Scheme 4
Scheme 6
(86:11:3:1 dr) in 71% overall yield along with 26% of the simple
crotylation product (eq 3). The major diastereomer was identified
as 18 and was isolated in 60% yield. It is noteworthy that in this
case the use of benzene as solvent led to significantly improved
selectivity and yield relative to the use of toluene.
6
and Chemler during studies of intramolecular crotylsilylations of
â-hydroxy ketones and aldehydes.
To investigate the effects of similar substitution on the enolate
fragment, allyl-(Z)-enolsilane 9 and allyl-(E)-enolsilane 10 were
prepared from allylsilane 1 and (Z)- and (E)-propenyloxytrimeth-
7
ylsilane, respectively, using the method outlined in Scheme 2.
Reaction of 9 with cyclohexanecarboxaldehyde in toluene at 40
°
C produced four tandem products (65:18:12:5 dr) in 59% overall
yield, along with a small amount (15%) of simple allylation product
Scheme 5). The major product, identified as diol 11, could be
We have described a new tandem aldol-allylation reaction that
allows the highly efficient single-step synthesis of stereochemically
complex polyketide fragments in an experimentally trivial manner
employing easily prepared reagents. Further study will focus on
optimization of chemo- and diastereoselectivity and on enantiose-
lective variants.
(
isolated in 38% yield. Conversely, reaction of 10 gave principally
two tandem products (2:1 dr) in 30% yield, along with ∼30% of
the simple allylation product. While these reactions will require
optimization in terms of selectivity and efficiency to be as useful
as the reactions described in Schemes 3 and 4, it is noteworthy
that the aldol reactions of 9 and 10 apparently proceed primarily
Acknowledgment. The National Institutes of Health (National
Institute of General Medical Sciences - R01 GM58133) is
acknowledged for financial support of this work. J.L.L. is a recipient
of a Pfizer Award for Creativity in Organic Chemistry.
through boatlike transition structures.8
,9
Scheme 5
Supporting Information Available: Experimental procedures,
characterization data, and stereochemical proofs (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
References
(
(
(
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(
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