Preparation and use of enantioenriched Allenylsilanes for the stereoselective synthesis of homopropargylic ethers

Article abstract of DOI:10.1021/ol070936d

Equation Presented A convenient procedure for the synthesis of highly enantioenriched allenylsilanes by Johnson orthoester Claisen rearrangement of 1-silyl propargylic alcohols is described. Allenylsilanes are then used as carbon nucleophiles in three-com

Full text of DOI:10.1021/ol070936d

ORGANIC
LETTERS
2007
Vol. 9, No. 14
2689-2692
Preparation and Use of Enantioenriched
Allenylsilanes for the Stereoselective
Synthesis of Homopropargylic Ethers
Ryan A. Brawn and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment, Metcalf Center for Science and Engineering, 590 Commonwealth
AVenue, Boston UniVersity, Boston, Massachusetts 02215
panek@bu.edu
Received April 20, 2007
ABSTRACT
A convenient procedure for the synthesis of highly enantioenriched allenylsilanes by Johnson orthoester Claisen rearrangement of 1-silyl
propargylic alcohols is described. Allenylsilanes are then used as carbon nucleophiles in three-component, Lewis acid mediated additions to
in situ generated oxonium ions, resulting in enantioenriched homopropargylic ethers.
In recent years, allenes have emerged as an important
functional group and have been used in a variety of organic
transformations, including ionic additions,1 cycloadditions,2
cyclizations,3 and sp2-sp2 and sp2-sp cross-coupling pro-
cesses.4 Despite these important contributions, the chemistry
of allenes remains underdeveloped. One important class of
allenes that has proven to be useful is enantioenriched
allenylstannanes, which have been used as carbon nucleo-
philes for the diastereo- and enantioselective synthesis of
homopropargylic alcohols.5
As a complement to allenylstannane chemistry, an efficient
synthesis of highly enantioenriched allenylsilanes is a desir-
able synthetic objective and a potentially useful contribution
to the field. Like allenylstannanes, the related silanes can
be used to synthesize homopropargylic alcohols.6 These
reagents share the ability to convert axial chirality into central
chirality in the resulting product, by addition to carbon-
heteroatom π-bonds. Chiral allenylsilanes have been prepared
using Fleming’s SN2′ displacement strategy;7 the majority
of the reports have used racemic reagents. The lack of general
synthetic pathways to highly enantioenriched allenylsilanes
may have hindered their development, and a convenient
(1) Ma, S. In Modern Allene Chemistry; Krause, N., Hashmi, A. S. K.,
Eds.; Wiley-VCH: Weinheim, Germany, 2004; pp 595-699.
(2) Murakami, M.; Matsuda, T. In Modern Allene Chemistry; Krause,
N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, Germany, 2004,
pp 727-815. (b) Mandai, T. In Modern Allene Chemistry; Krause, N.,
Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, Germany, 2004; pp 925-
972.
(3) (a) Tius, M. A. In Modern Allene Chemistry; Krause, N., Hashmi,
A. S. K., Eds.; Wiley-VCH: Weinheim, Germany, 2004; pp 817-845.
(b) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2000, 39, 3590-3593.
(c) Zimmer, R.; Reissig, H.-U. In Modern Allene Chemistry; Krause, N.,
Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, Germany, 2004; pp 877-
923.
(5) (a) Marshall, J. A.; Wang, X.-J. J. Org. Chem. 1990, 55, 6246-
6248. (b) Marshall, J. A.; Wang, X.-J. J. Org. Chem. 1992, 57, 1242-
1252. (c) Marshall, J. A.; Perkins, J. J. Org. Chem. 1994, 59, 3509-3511.
(d) Marshall, J. A.; Perkins, J. F.; Wolf, M. A. J. Org. Chem. 1995, 60,
5556-5559. (e) Marshall, J. A.; Palovich, M. R. J. Org. Chem. 1997, 62,
6001-6005.
(6) (a) Danheiser, R. L.; Carini, D. J. J. Org. Chem. 1980, 45, 3925-
3927. (b) Danheiser, R. L.; Carini, D. J.; Kwasigroch, C. A. J. Org. Chem.
1986, 51, 3870-3878. (c) Marshall, J. A.; Maxson, K. J. Org. Chem. 2000,
65, 630-633.
(7) (a) Fleming, I.; Terrett, N. K. J. Organomet. Chem. 1984, 264, 99-
118. (b) Fleming, I.; Newton, T. W. J. Chem. Soc., Perkin Trans. 1 1984,
1805-1808.
(4) Zimmer, R.; Reissig, H.-U. In Modern Allene Chemistry; Krause,
N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, Germany, 2004; pp
847-876.
10.1021/ol070936d CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/09/2007

stereoselective route to the synthesis of chiral allenylsilanes
remains a desirable objective.
Scheme 2. Lipase Resolution
In that regard, a convenient, straightforward pathway has
been developed for the preparation of highly enantioenriched
allenylsilanes. We began the synthesis with commercially
available 3-butyn-2-ol (1), which was deprotonated using
n-butyllithium (2 equiv) to generate a dianion. C-Silylation
with phenyldimethylchlorosilane resulted in alkyne 2,
in high yield (86.3% after purification, >35 g scale).
Selective C-silylation was observed, and the addition
of lithium chloride resulted in nearly exclusive
C-silylation. Trace amounts of bis-silylated product
(<10%) were observed (1H NMR analysis) in the absence
of LiCl.8
The ee’s of the allenes have been determined by HPLC
and, as anticipated, are nearly identical to the ee’s of the
starting propargylic alcohols.13 The optimal conditions for
the Claisen rearrangement were found using refluxing
xylenes, while the use of toluene or other lower boiling
hydrocarbon solvents resulted in low conversion. The
absolute configuration of the allenylsilane is based on the
concerted nature of the sigmatropic rearrangement using a
pseudo-chair transition state, and accordingly, (R)-2 afforded
(Sa)-4 and (S)-2 afforded (Ra)-4.14
Scheme 1. Silylation of 3-Butyn-2-ol
Racemic propargylic alcohol 2 was subjected to a kinetic
resolution using Amano lipase AK.9 The advantages of
employing a biocatalytic resolution are several fold: the
procedure is operationally simple; both enantiomers are
obtained in high ee; the reagents are readily available and
inexpensive; and the enzyme can be recycled for multiple
uses without losing catalytic efficiency. The resolution
afforded the enantioenriched propargylic alcohol (S)-2 (49%
yield, >95% ee) and acetate (R)-3 (48% yield) after
purification over silica gel. Acetate (R)-2 was hydrolyzed
when re-exposed to the lipase in pH 7 aqueous buffer to
afford propargylic alcohol (R)-3 (77% yield, >99% ee) after
purification over silica gel.10
Scheme 3. Johnson Orthoester Claisen Rearrangement
Having established a reliable protocol for the production
of enantioenriched allenylsilanes, we used the silanes in
three-component, Lewis acid catalyzed SE2′ reactions to form
homopropargylic ethers.15 By examining a series of Lewis
acids that were likely to effect this reaction, we found that
BF3•OEt2 was the most efficient catalyst. A solution of
aldehyde and TMSOMe was exposed to BF3•OEt2, followed
by addition of a solution of the allenylsilane. After perform-
ing a solvent screen, it was found that the optimal solvent
for the reaction was acetonitrile (Table 1).16
The individual propargylic alcohols (S)-2 and (R)-2 were
then subjected to an orthoester Claisen rearrangement9b,11 to
afford the enantioenriched allenylsilanes (Ra)-4 and (Sa)-4.12
The (Sa)-allene is obtained in 81% yield and 98% ee, and
the complementary (Ra)-allene is obtained in 79% yield and
98% ee.12
(8) Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624-
1654.
(9) (a) Sparks, M. A.; Panek, J. S. Tetrahedron Lett. 1991, 32, 4085-
4088. (b) For assignment of absolute configuration, see: Panek, J. S.; Clark,
T. D. J. Org. Chem. 1992, 57, 4323-4326 and references found therein.
(c) Lipase AK available from Amano Enzyme Inc.
(10) HPLC analyses were performed using a ChiralCel OD-H column,
isocratic 1% isopropanol/hexane eluent at 1mL/min flow rate.
(11) (a) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T.
J.; Li, T.-T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1970, 92,
741-743. (b) Mori, K.; Nukanda, T.; Ebata, T. Tetrahedron 1981, 37,
1343-1347.
(12) For other examples of orthoester Claisen rearrangements to access
allenes, see: (a) Allenylstannanes: Marshall, J. A.; Wang, X.-j. J. Org.
Chem. 1991, 56, 3211-3213. (b) Racemic allenylsilanes: Yun, S.-J.; Chung,
K. H.; Yu, B.-C. J. Korean Chem. Soc. 2004, 48, 439-442.
(13) Ziegler, F. E. Acc. Chem Res. 1977, 10, 227-232. HPLC analyses
were performed after conversion of the methyl ester to a carboxylic acid
(LiOH in H2O/MeOH) using a ChiralPak AD column, isocratic 1%
isopropanol/hexane eluent at 1mL/min flow rate.
(14) See Supporting Information for a detailed description.
(15) Panek, J. S.; Yang, M.; Xu, F. J. Org. Chem. 1992, 57, 5790-
5792.
(16) No product was observed in THF, diethyl ether, or DMF; -20 °C
was found to be the best temperature for the reaction, as lower temperatures
resulted in an incomplete reaction, with recovered staring materials.
2690
Org. Lett., Vol. 9, No. 14, 2007

Table 2. Three-Component Reactions with TMSOMe
Table 1. Solvent Screen
solvent
temp
yielda
drb
MeCN
MeNO2
DCM
Toluene
MeCN
-20 °C
-20 °C
-20 °C
-20 °C
-45 °C
78%
49%
11%
<5%
44%
>20:1
>20:1
>20:1
>20:1
>20:1
a Isolated yield after chromatographic purification over silica gel.
1
b Diastereomeric ratios (dr) were determined by H NMR analysis.
The observed syn stereochemistry can be explained by
either an antiperiplanar or a synclinal transition state
(Scheme 4), where the (Ra)-allenylsilane adds to the Re
Scheme 4. Transition State Models
face of the oxonium ion. While either transition state
will result in the observed stereochemistry, the antiperi-
planar transition state, where the interaction between
the R group on the oxonium ion and the methyl on the
allene is minimized, may be the best illustration of this
reaction.
a Isolated yields reported as a diastereomeric mixture after purification
1
over silica gel. b Diastereomeric ratios (dr) were determined by H NMR
analysis.
select secondary ethers (entries 7-10). The latter cases are
illustrative of examples of double stereodifferentiation, where
the magnitude of diastereoselectivity is either enhanced
(matched cases) or attenuated (mismatched cases). In general,
the yields for these reactions were similar to those using
TMSOMe, but the diastereoselectivities tended to be slightly
lower.
Aromatic aldehydes afforded the highest yields and
selectivities in the three-component reactions using
TMSOMe as the oxonium ion precursor (Table 2, entries
1-6), with yields as high as 78%, and a single diastereomer
observed for many of the systems. Branched aliphatic
aldehydes (entries 8 and 9) also gave the homopropargylic
ethers in high selectivity, albeit in moderate yield. Straight
chain aliphatic systems typically gave low yields and
selectivities (entries 10 and 11). Thiophenecarboxaldehyde
(entry 7), a heteroaromatic system, showed reactivity and
good yield (54%), but the diastereoselectivity was low (2.7:
1).
In conclusion, an efficient procedure for the prepara-
tion of highly enantioenriched allenylsilanes (>97% ee) with
high yields on a multigram scale is reported. The allenylsi-
lanes were used as carbon nucleophiles in three-component,
Lewis acid catalyzed additions to in situ generated oxonium
ions for the asymmetric synthesis of a range of structurally
diverse homopropargylic ethers. The use of these reagents
in complex molecule synthesis will be reported at a later
time.
More complex trimethylsilyl ethers were also effective in
generating oxonium ions for these reactions (Table 3). These
include primary allylic and benzylic ethers (entries 1-6) and
Org. Lett., Vol. 9, No. 14, 2007
2691

Table 3. Three-Component Reactions with Other TMS Ethers
a Isolated yields reported as a diastereomeric mixture after purification over silica gel. b Diastereomeric ratios (dr) were determined by 1H NMR analysis.
Acknowledgment. Financial support was obtained
from NIH CA 53604. J.S.P. is grateful to Amgen, Johnson
& Johnson, Merck Co., Novartis, Pfizer, and GSK for
financial support. The authors are grateful to Prof. Scott E.
Schaus, Dr. Sarathy Kesavan, and Jason Lowe for helpful
discussions.
Supporting Information Available: Experimental details
and selected spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL070936D
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Org. Lett., Vol. 9, No. 14, 2007