Strained silacycles in organic synthesis: A new reagent for the enantioselective allylation of aldehydes

Article abstract of DOI:10.1021/ja0264908

A new reagent for the enantioselective allylation of aliphatic aldehydes has been developed. The reagent is easily prepared in a single step from commercially available materials and may be stored without significant decomposition. The reactivity of the r

Full text of DOI:10.1021/ja0264908

Published on Web 06/17/2002
Strained Silacycles in Organic Synthesis: A New Reagent for the
Enantioselective Allylation of Aldehydes
James W. A. Kinnaird, Pui Yee Ng, Katsumi Kubota, Xiaolun Wang, and James L. Leighton*
Department of Chemistry, Columbia UniVersity, New York, New York 10027
Received April 10, 2002
Scheme 1
The asymmetric allylation of aldehydes remains one of the most
important and fundamental carbonyl addition reactions for the
synthesis of optically active chiral building blocks. Many moder-
ately to highly enantioselective chiral reagents1 and catalytic
systems2 have been developed, yet a general solution that meets
every condition for true convenienceseasily and inexpensively
prepared and stable/storable reagent/catalyst, no toxic reagents/
byproducts, and easy separation/purification of the homoallylic
alcohol productssremains elusive. We now report significant
progress toward this goal in the form of a new reagent that meets
Scheme 2
all of these criteria, while providing good to excellent enantio-
selectivities for a range of aliphatic aldehydes.
Ample precedent3 and prior experience4 alerted us to the fact
that silicon, when constrained in a four- or five-membered ring,
exhibits substantial Lewis acidity that may be harnessed for
uncatalyzed aldol and allylation reactions. This led to the proposal
that allyltrichlorosilane might simply be treated with various 1,2-
diols, 1,2-amino alcohols, and 1,2-diamines, to give actiVe allylation
reagents without need for any additional catalysts or reagents. If
so, the rapid evaluation of chiral diols, amino alcohols, and diamines
could ensue. Conceptually, this would represent an interesting class
of chiral auxiliarysone that induces not only chirality but also
reactivity.
To evaluate this hypothesis, allyltrichlorosilane was treated with
pinacol and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in CH2Cl2
to provide allylsilane 1 in 72% yield. Gratifyingly, when 1 was
treated with benzaldehyde in toluene at room temperature, a smooth
uncatalyzed allylation took place to afford alcohol 2 in an
unoptimized 52% yield (Scheme 1). In related studies involving
the use of diisopropyltartrate as the diol component, Wang5
employed Lewis bases for activation, and Kira6 proposed that the
ester groups themselves provide activation by acting as a Lewis
base for silicon. The present work clearly establishes that Lewis
base activation of this type is not necessary.7 Indeed, that ring strain
is at least partially responsible for the reactivity of allylsilane 1 is
supported by the fact that related allylsilanes 1a, 1b, and 1c do not
react with benzaldehyde even at 50 °C.
Screening of chiral, nonracemic 1,2-diols, 1,2-amino alcohols.
and 1,2-diamines commenced. and amino alcohols were chosen for
initial study due to the diverse array of inexpensive amino alcohols
that are readily available. Indeed, both enantiomers of pseudoephe-
drine are available and inexpensive, and we began our investigation
with this amino alcohol. Reaction of (1S,2S)-pseudoephedrine with
allyltrichlorosilane and Et3N in CH2Cl2 allowed the isolation of
allylsilane 3 (as a 2:1 mixture of diastereomers) in 88% yield
(Scheme 2). Reaction of 3 with benzaldehyde in benzene at room
temperature gave alcohol 2(S) with 66% enantiomeric excess (ee).
Optimization of the reaction variables (solvent, concentration, and
temperature) led to an increase in selectivity to 81% ee. Toluene
proved the best solvent among those screened (THF, DMF, EtOAc,
CH2Cl2, hexane, t-BuOMe, Et2O, CH3CN, benzene), while 0.2-
0.4 M silane concentration provided the best results. Lower
temperatures did provide higher enantioselectivity, as expected, but
only to about -10 °C. Below this temperature the ee decreased,
suggesting a complex mechanism.
A survey of several different aldehydes (Table 1) revealed that
while reagent 3 is only moderately effective with aromatic and
conjugated aldehydes (entries 1 and 2), it is generally effective for
a range of aliphatic aldehydes (entries 3-8). Thus, dihydrocinna-
maldehyde may be allylated in 84% yield and 88% ee (entry 3),
isovaleraldehyde in 79% yield and 87% ee (entry 4), and cyclo-
hexanecarboxaldehyde in 70% yield and 87% ee (entry 5).
Pivaldehyde is allylated with superior enantioselectivity (96% ee,
80% yield, entry 6), and benzyloxyacetaldehyde and tert-butyldim-
ethylsilyloxyacetaldehyde proceed in 85% and 71% yield and 88%
and 89% ee respectively (entries 7 and 8), demonstrating tolerance
for potentially Lewis basic functionality.
Reagent 3 offers several advantages in terms of practicality and
convenience: (1) reagent 3 (and its enantiomer) may be prepared
in bulk quantities in a single step from commercially available and
inexpensive materials. (2) reagent 3 is stable and may be stored
* To whom correspondence should be addressed: E-mail: leighton@
chem.columbia.edu
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J. AM. CHEM. SOC. 2002, 124, 7920-7921
10.1021/ja0264908 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Enantioselective Allylation of Aldehydes with (S,S)-3
While optimization will be required for greater reaction efficiency,
these results establish that diamines may allow for the highly
enantioselective allylation of a broad range of aldehydes.
We have described the development of a new chiral reagent for
the enantioselective allylation of aliphatic aldehydes. While the
search for other auxiliaries that give higher selectivities will
continue, and the performance of reagent 3 with more complex
(chiral) aldehydes remains to be investigated, the convenience and
practicality associated with reagent 3 recommend it for immediate
use with simple aliphatic aldehydes. In addition, it has been shown
that simply by constraining silicon in a five-membered ring with
1,2-diols, 1,2-diamines and 1,2-amino alcohols, sufficient Lewis
acidity for uncatalyzed aldehyde allylation reactions obtains. The
use of this discovery for the development of other reactions should
prove possible and will be reported in due course.10
Acknowledgment. The National Institutes of Health (National
Institute of General Medical Sciences: R01 GM58133) is acknowl-
edged for financial support of this work. We thank the Sumitomo
Corp. for postdoctoral support to K.K. J.L.L. is a recipient of a
Bristol-Myers Squibb Unrestricted Grant in Synthetic Organic
Chemistry and a Pfizer Award for Creativity in Organic Chemistry.
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.
a Reactions run with silane 3 (1.5 mmol) and aldehyde (1.0 mmol) in
toluene (5 mL) at -10 °C for 2 h. b Isolated yield. c Determined by chiral
HPLC analysis or by the Mosher ester method. d Reaction time ) 24 h.
e Due to product volatility, an alternative workup and purification was
employed. See the Supporting Information.
References
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(2) For a recent review of enantioselective Lewis acid-catalyzed allylmetal
additions, see: (a) Yanagisawa, A. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-
Verlag: Heidelberg, 1999; Vol. II, Chapter 27. Enantioselective Lewis
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for long periods of time (several weeks, at least) obviating the need
to freshly prepare 3 for each use. (3) The workup and purification
consist of the addition of 1 N HCl and EtOAc, separation of the
layers, and concentration, to give the homoallylic alcohol product
in typically >90% purity.
Mechanistically, we envision that complexation of the aldehyde
to the silane to give a trigonal bipyramidal intermediate is followed
by allyl transfer. Whether the two diastereomers of reagent 3 react
identically or differently remains an open question as a complex-
ation-pseudorotation-decomplexation sequence could lead to
interconversion. Experiments designed to elucidate this issue are
in progress.8
Finally, we note that 1,2-diamines also may serve as effective
auxiliaries. Reaction of (1R,2R)-N,N′-dibenzylcyclohexane-1,2-
diamine9 with allyltrichlorosilane and DBU in CH2Cl2, and filtration
of the resulting ammonium salts gave allylsilane 4 in >95% yield
and sufficient purity (>95%) for use in allylation reactions (eq 1).
(6) Zhang, L. C.; Sakurai, H.; Kira, M. Chem. Lett. 1997, 129.
(7) For a discussion of this type of Lewis base activation and lead references,
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(8) Preliminary attempts to separate the diastereomers or to obtain a mixture
with a ratio different than 2:1 have failed.
(9) Denmark, S. E.; Stadler, H.; Dorow, R. L.; Kim, J. H. J. Org. Chem.
1991, 56, 5063.
(10) We have preliminarily examined crotylation reactions in this context and
found the enantioselectivities to be moderately lower. Details of our
attempts to optimize these reactions will be reported as indicated.
Treatment of 4 with benzaldehyde in benzene resulted in a slow
allylation to give alcohol 2(S) in 46% yield and 90% ee, and under
identical conditions dihydrocinnamaldehyde could be allylated in
58% yield and 95% ee (eq 2).
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