Asymmetric synthesis of unsaturated α-benzyloxyaldehydes: An enantioselective synthesis of (+)-exo-brevicomin

Article abstract of DOI:10.1016/j.tetasy.2005.10.035

Enantioselective synthesis of α-hydroxy aldehydes with an alkene tether was accomplished from l-(+)-tartaric acid, employing stereoselective reduction of a 1,4-diketone with L-selectride as the key step. Synthetic utility of these aldehydes was demonstrat

Full text of DOI:10.1016/j.tetasy.2005.10.035

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3951–3953
Asymmetric synthesis of unsaturated a-benzyloxyaldehydes:
an enantioselective synthesis of (+)-exo-brevicomin
Kavirayani R. Prasad* and Pazhamalai Anbarasan
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 12 October 2005; accepted 24 October 2005
Available online 28 November 2005
Abstract—Enantioselective synthesis of a-hydroxy aldehydes with an alkene tether was accomplished from L-(+)-tartaric acid,
employing stereoselective reduction of a 1,4-diketone with L-selectride as the key step. Synthetic utility of these aldehydes was dem-
onstrated in the synthesis of pine beetle pheromone (+)-exo-brevicomin.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The synthesis of bio-active natural products with the aid
of building blocks derived from chiral pool sources is an
attractive method in organic synthesis.1 In this context,
naturally occurring a-hydroxy carbonyl compounds
have been explored extensively in natural product syn-
thesis.2 However, their higher homologues bearing a
longer carbon chain with or without further functional-
ities are scarce from chiral pools. These types of car-
bonyl compound serve as excellent building blocks for
the synthesis of chiral 1,2-difunctional compounds, for
example, 1,2-amino alcohols and 1,2-diols, which have
numerous applications in the enantioselective synthesis
of natural products. We were interested in the synthesis
of a-hydroxy aldehydes/acids having an alkene tether,
which could be further applied to the synthesis of a
number of oxygen-containing heterocycles. Although
there are a few examples of the synthesis3 of such types
of compounds, a general approach is essential. Herein,
we report a general method for the synthesis of a-hydr-
oxy aldehydes having an alkene tether starting from
chiral pool tartaric acid. The further synthetic utility
of these aldehydes is demonstrated by application to
the synthesis of the pine beetle pheromone (+)-exo-
brevicomin.
Recently, we reported the synthesis of a-methoxyaryl-
acetic acid derivatives from L-(+)-tartaric acid, involv-
ing a very highly diastereoselective reduction of a
C2-symmetric 1,4-diaryl diketone with K-selectride4
(Scheme 1).
Encouraged by this strategy, we anticipated that reduc-
tion of the C2-symmetric 1,4-alkenyl diketones 2, should
furnish the C2-symmetric 1,4-diols 3, precursors for the
title compounds. Thus, diketones 2a and 2b were
prepared by the addition of the respective Grignard
reagents to bis-Weinreb amide5 1 of tartaric acid. Subse-
quent reduction of diketone with L-selectride resulted in
a single diastereomer of diols 3a and 3b in very high
yields. The formation of the other possible two diaste-
reomers (C1-symmetric diastereomer and the other C2-
symmetric diastereomer) was not observed within
1
detectable limits by H NMR (Scheme 2).
Protection of the diols as benzyl ethers 4a–b was effected
with sodium hydride and benzyl bromide in almost
quantitative yield. Facile deprotection of the acetonide
of the benzyl ethers was executed with ferric chloride6
to furnish the corresponding 1,2-diols 5a and 5b 94%
and 89% yield, respectively, which upon treatment with
lead tetra acetate in benzene resulted in the quantitative
formation (2 mol) of aldehydes 6a and 6b (Scheme 3).
Stereochemical integrity was preserved all through the
transformations. The configuration at the newly formed
stereogenic center was further established by comparing
specific rotation of alcohols 7a and b {[a]D for
*
Corresponding author. Fax: +91 80 23600529; e-mail: prasad@
orgchem.iisc.ernet.in
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.10.035

3952
K. R. Prasad, P. Anbarasan / Tetrahedron: Asymmetry 16 (2005) 3951–3953
Ar
Ar
Ar
Ar
Ar
HO
HO
OMe
OMe
O
O
O
O
OH steps
OH
K-Selectride/18-C-6
O
O
or
O
THF, -78 C, 87-93%
˚
Ar
Scheme 1. Asymmetric synthesis of a-methoxyarylacetic acid derivatives.
Me
OMe
O
N
OH
OH
MgBr
(4 eq)
O
O
O
O
n
O
O
L
-Selectride (4 eq)
n
n
n
THF, -78 C, 2.5 h
THF, 0 C,1 h
˚
˚
O
O
n
O
N
Me
OMe
2a: n = 2, 94%
2b: n = 3, 96%
3a: n = 2, 91%
3b: n = 3, 94%
1
Scheme 2. Stereoselective reduction of 1,4-diketones derived from L-(+)-tartaric acid.
OH
OBn
O
O
O
O
FeCl3.6H2O
DCM, rt, 2 h
NaH,DMF
n
n
n
n
BnBr, 0 C-rt, 2h
˚
OH
OBn
3a: n = 2
3b: n = 3
4a: n = 2, 94%
4b: n = 3, 97%
OBn
n
OBn
OBn
HO
HO
Pb(OAc)4,benzene
rt, 1.5 h
O
NaBH4 /MeOH
0 C, 1 h
n
n
˚
OH
H
n
OBn
7a: n = 2, 93%
7b: n = 3, 95%
6a: n = 2, 96%
6b: n = 3, 98%
5a: n = 2, 94%
5b: n = 3, 89%
Scheme 3. Synthesis of enantiopure a-benzyloxyaldehydes.
7b = À11.8 (c 1.9 CHCl3), lit.3e À12.2 (c 1.8 CHCl3)}
obtained from the reduction of aldehydes 6a and 6b.
western pine beetle, which is a principle pest in the tim-
ber regions of the west coast of North America. The syn-
thesis of (+)-exo-brevicomin is outlined in Scheme 4.
Aldehyde 6b was treated with ethylmagnesium bromide
in the presence of magnesium bromide in dichlorometh-
ane to yield the corresponding threo alcohol 8 as a single
diastereomer in 78% yield.8 Wacker oxidation9 of alco-
hol 8 with PdCl2/CuCl produced ketone 9 (85% yield,
[a]D = À12.8 (c 1.3, CHCl3), lit.10 +13.0 (c 1.7, CHCl3)
for the corresponding enantiomer). Simultaneous
debenzylation and intramolecular acetalization with
Pd/C in MeOH and a trace of 3 M HCl transformed 9
The synthetic potential of these hydroxy aldehydes 6a
and 6b is widespread, and they serve as excellent precur-
sors for a number bio-active oxygen containing com-
pounds. To demonstrate the utility of these chiral
aldehydes, the synthesis of pine beetle pheromone (+)-
exo-brevicomin7 was undertaken.
The pheromone exo-brevicomin 10 is an aggregation
pheromone produced by Dendroctonus brevicomis, the
O
OH
EtMgBr, MgBr2
H
PdCl2/CuCl/O2
DCM, -78 C, 4.5 h
˚
DMF-H2O,
OBn
OBn
78%
rt, 2.5 h, 85%
6b
8
OH
O
O
10% Pd/C, MeOH
3N HCl, rt, 2.5 h, 72%
OBn
O
(+)-exo-brevicomin 10
9
Scheme 4. Synthesis of (+)-exo-brevicomin.

K. R. Prasad, P. Anbarasan / Tetrahedron: Asymmetry 16 (2005) 3951–3953
3953
3. (a) Vettel, S.; Lutz, C.; Diefenbach, G.; Haderlein, G.;
into (+)-exo-brevicomin {[a]D = +66.6 (c 0.3, Et2O),
lit.8 = +66.7; (c 1.40 Et2O)} in 72% yield.
Hammerschmidt, S.; Kuhling, K.; Mofid, M.-R.; Zim-
¨
mermann, T.; Knochel, P. Tetrahedron: Asymmetry 1997,
8, 779; (b) Macritchie, J. A.; Silcock, A.; Willis, C. L.
Tetrahedron: Asymmetry 1997, 8, 3895; (c) Agami, C.;
Mathieu, H. Tetrahedron Lett. 1998, 39, 3505; (d) McNe-
ill, A. H.; Thomas, E. J. Tetrahedron Lett. 1993, 34, 1669;
(e) Servi, S. Tetrahedron Lett. 1983, 24, 2023.
3. Conclusion
In summary, a high yielding approach for the synthesis
of a-hydroxy aldehydes tethered to an alkene was
accomplished by stereoselective reduction of a 1,4-di-
ketone derived from tartaric acid. The synthetic utility
of this methodology was illustrated by applying it to
the enantioselective synthesis of (+)-exo-brevicomin.
Synthesis of further functionalized hydroxy aldehdyes/
acids and their potential use as building blocks in oxy-
gen containing heterocycles is in progress.
4. Prasad, K. R.; Chandrakumar, A. Tetrahedron: Asymme-
try 2005, 16, 1897.
5. Nugiel, D. A.; Jakobs, K.; Worley, T.; Patel, M.;
Kaltenbach, R. F., III; Meyer, D. T.; Jadhav, P. K.; De
Lucca, G. V.; Smyser, T. E.; Klabe, R. M.; Bacheler, L. T.;
Rayner, M. M.; Seitz, S. P. J. Med. Chem. 1996, 39, 2156.
6. Sen, S. E.; Roach, S. L.; Boggs, J. K.; Ewing, G. J.;
Magrath, J. J. Org. Chem. 1997, 62, 6684.
7. Recent asymmetric synthesis of brevicomin: (a) Kumar,
D. N.; Rao, B. V. Tetrahedron Lett. 2004, 45, 2227; (b)
Raghavan, S.; Joseph, S. C. Tetrahedron Lett. 2003, 44,
8237; (c) de Sousa, A. L.; Resck, I. S. J. Braz. Chem. Soc.
2002, 13, 233; (d) Mayer, S. F.; Mang, H.; Steinreiber, A.;
Saf, R.; Faber, K. Can. J. Chem. 2002, 80, 362; (e) Gallos,
J. K.; Kyradjoglou, L. C.; Koftis, T. V. Heterocycles 2001,
55, 781; (f) Burke, S. D.; Muller, N.; Beudry, C. M. Org.
Lett. 1999, 1, 1827; (g) Hu, S.; Jayaraman, S.; Oehlsch-
lager, A. C. J. Org. Chem. 1999, 64, 2524; For a review on
the synthesis of pheromones see: (h) Mori, K. Eur. J. Org.
Chem. 1998, 1479.
Acknowledgements
We thank Department of Science and Technology
(DST), New Delhi, for funding of this project. P.A.
thanks IISc, Bangalore for a research fellowship.
References
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