Highly enantioselective and regioselective carbonyl reduction of cyclic α,β-unsaturated ketones using TarB-N02 and sodium borohydride

Article abstract of DOI:10.1021/ol901677b

Asymmetric 1,2-reduction of α,β-unsaturated ketones using TarB-NO₂ and NaBH₄ Is reported. Simple cycloalkenones give products In low enantiomeric excess. However, cycloalkenones with a-substituents, such as halides, alkyl, and aryl, have been enantioselectively reduced with this system to yield chiral allylic alcohols In enantiomeric excess up to 99%. The starting materials for TarB-N0₂ are inexpensive, and the boronlc acid can be easily recovered In high yield by a simple acid extraction.

Full text of DOI:10.1021/ol901677b

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4358-4361
Highly Enantioselective and
Regioselective Carbonyl Reduction of
Cyclic r,ꢀ-Unsaturated Ketones Using
TarB-NO2 and Sodium Borohydride
Jinsoo Kim, John Bruning, Kevin E. Park, David J. Lee, and Bakthan Singaram*
Department of Chemistry and Biochemistry, UniVersity of California Santa Cruz,
1156 High Street, Santa Cruz, California 95064
singaram@chemistry.ucsc.edu
Received July 22, 2009
ABSTRACT
Asymmetric 1,2-reduction of r,ꢀ-unsaturated ketones using TarB-NO2 and NaBH4 is reported. Simple cycloalkenones give products in low
enantiomeric excess. However, cycloalkenones with r-substituents, such as halides, alkyl, and aryl, have been enantioselectively reduced
with this system to yield chiral allylic alcohols in enantiomeric excess up to 99%. The starting materials for TarB-NO2 are inexpensive, and the
boronic acid can be easily recovered in high yield by a simple acid extraction.
The asymmetric carbonyl reduction of R,ꢀ-unsaturated
ketones is a direct and simple method to synthesize chiral
allylic alcohols. Enantioselective 1,2-reduction of these
ketones is a valuable technique in the synthesis of allylic
alcohols of synthetic interest.1 However, selective 1,2-
reduction is hampered by the competing 1,4-reduction and
literature describing enantioselective 1,2-reduction is far
surpassed by literature on asymmetric 1,4-additions.2 Luche
reported that the use of CeCl3 and NaBH4 in methanol
exclusively gave 1,2-reduction products.3 However, this
method was never applied toward the asymmetric synthesis
of allylic alcohols from the corresponding ketone. Modern
syntheses that incorporate Luche reduction typically rely on
nonreagent controlled factors to achieve enantioselectivity
in their reductions.4 Nutaitis reported the use of sodium
triacetoxyborohydride (NaBH(OAc)3) for the 1,2-reduction
of 2-cyclohexen-1-one.5 Although it proved effective for
selective 1,2-reduction, it had not been applied for the
asymmetric synthesis of chiral allylic alcohols. Modern
methods describing the asymmetric 1,2-reduction of R,ꢀ-
unsaturated ketones still remain scarce and often are limited
to transfer hydrogenation.6 Oxazaborolidines in stoichiomet-
(4) (a) Hayashi, N.; Suzuki, T.; Usui, K.; Nakada, M. Tetrahedron 2009,
65, 888. (b) Gollner, A.; Mulzer, J. Org. Lett. 2008, 10, 4701. (c) Veitch,
G. E.; Boyer, A.; Ley, S. V. Angew. Chem., Int. Ed. 2008, 47, 9402. (d)
Pragani, R.; Roush, W. R. Org. Lett. 2008, 10, 4613.
(1) Vorogushin, A. V.; Wulff, W. D.; Hansen, H. -J. Tetrahedron 2008,
64, 949.
(5) Nutaitis, C. F.; Bernardo, J. E. J. Org. Chem. 1989, 54, 5629.
(6) (a) van Innis, L.; Plancher, J. M.; Marko, I. E. Org. Lett. 2006, 8,
6111. (b) Shirahata, T.; Sunazuka, T.; Yoshida, K.; Yamamoto, D.; Harigaya,
Y.; Kuwajima, I.; Nagai, T.; Kiyohara, H.; Yamada, H.; Omura, S.
Tetrahedron 2006, 62, 9483. (c) Garanger, E.; Boturyn, D.; Coll, J. -L.;
Favrot, M. -C.; Dumy, P Org. Biomol. Chem. 2006, 4, 1958. (d) Peach, P.;
Cross, D. J.; Kenny, J. A.; Mann, I.; Houson, I.; Campbell, L.; Walgrove,
T.; Wills, M. Tetrahedron 2006, 62–1864.
(2) (a) Kanai, M.; Shibasaki, M. In Catalytic Asymmetric Synthesis, 2nd
ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000; Chapter 8D, pp 569. (b)
Prakash, G. S. K.; Wang, F.; Stewart, T.; Mathew, T.; Olah, G. A. Proc.
Nat. Acad. Sci. U.S.A. 2009, 106, 4090. (c) Rabalakos, C.; Wulff, W. D.
Synlett 2008, 2826. (d) Rabalakos, C.; Wulff, W. D. J. Am. Chem. Soc.
2008, 130, 13524.
(3) Luche, J. -L. J. Am. Chem. Soc. 1978, 100, 2226.
10.1021/ol901677b CCC: $40.75
Published on Web 08/27/2009
 2009 American Chemical Society

ric amounts have been used in 1,2-reduction to prevent alkene
hydroboration.7 DIP-chloride was reported in 1,2-reduction
of 2-cyclohexen-1-one, but after 7 days the alcohol was
isolated in only 36% ee.8 Biotransformations using enzymes
are perhaps the most common methods used in asymmetric
1,2-reduction of enones. Unfortunately, this method typically
requires long reaction times and large excess of the enzyme
performing the reduction.9,10 Additionally, the R,ꢀ-unsatur-
ated ketone must be soluble in water and usually only one
enantiomeric alcohol can be synthesized by enzyme route.
Chiral deprotonation of epoxides has been explored as an
alternative route toward chiral allylic alcohols, but this
method is also highly substrate limited.11 Our interest in the
asymmetric reduction of prochiral ketones using the chiral
boronic ester TarB-NO2 (Figure 1) and NaBH4 prompted us
to explore the asymmetric reduction of R,ꢀ-unsaturated
ketones as a potential route to chiral allylic alcohols.
method did favor 1,2-reduction in TarB-NO2 mediated
reaction with 2-cyclohexen-1-one, the amount of 2 was still
significant and very little asymmetric induction was observed
(entry 4). Previous research in our laboratory had demon-
strated the ability of lithium aminoborohydride (LAB)
reagents to selectively reduce the carbonyl of both R,ꢀ-
unsaturated aldehydes and ketones.14 However, in TarB-NO2-
mediated reduction lithium pyrrolidinoborohydride yielded
a 75:25 mixture of 1 and 2 and nearly racemic alcohol (entry
5).
Table 1. TarB-NO2-Mediated Reduction of 2-Cyclohexen-1-onea
reaction
temp (°C)/time
entry
hydride
NaBH4
NaBH(OAc)3
NaBH(OPh)3
NaBH4/B(OH)3
LiBH3(pyrrolidine)
1:2b
% ee 1c
1
2
3
4
5
25/30min
25:75
100:0
80:20
87:13
75:25
33
33
17
6
0/12
0/12
h
h
Figure 1. L-TarB-NO2.
25/30min
25/3
h
6
a General reaction conditions: 1 mmol of ketone dissolved in 2 mL of
0.5 M TarB-NO2 (1 mmol) followed by 2 mmol of hydride. b Ratio
determined by GC. c Enantiomeric excess determined by chiral GC
Our initial studies utilized NaBH(OAc)3 as a stoichiometric
reducing agent as this reagent had been reported to give
predominantly allylic alcohol products.12 We expected that
substituting NaBH4 with NaBH(OAc)3 in TarB-NO2 medi-
ated reduction would allow us to enantioselectively reduce
R,ꢀ-unsaturated ketones to the corresponding chiral allylic
alcohols. We also included other reducing agents, such as
NaBH4, NaBH(OPh)3, and LiBH3(pyrrolidine). Accordingly,
TarB-NO2 was mixed in equimolar amounts with 2-cyclo-
hexen-1-one and 2 equiv of the hydride source (Table 1).
Initial reduction of 2-cyclohexen-1-one with TarB-NO2 and
NaBH4 at room temperature gave a mixture of 2-cyclohexen-
1-ol (1) and 2-cyclohexan-1-one (2) in a 25:75 ratio (entry
1) and the desired allylic alcohol was obtained in 33% ee.
Reduction of the same ketone using NaBH(OAc)3 at 0 °C
for 12 h showed complete regioselectivity in the reduction,
but the asymmetric induction was similar to that obtained
with NaBH4 (entry 2). Substitution of NaBH(OAc)3 with
NaBH(OPh)3 led to a decrease in asymmetric reduction and
a 80:20 mixture of 1 and 2 (entry 3). A recent publication
described the use of NaBH4 and boric acid in the selective
1,2-reduction of R,ꢀ-unsaturated ketones.13 Although this
The low enantioselectivity in TarB-NO2-mediated reduc-
tion of 2-cyclohexen-1-one led us to consider substrate
modification to enhance asymmetric induction. Our compu-
tational modeling predicted that the transition state was
lowest in energy when the carbonyl carbon was proximal to
the carboxylic acid moiety of TarB-NO2.15 However, our
model was unclear in delineating the influence of electronics
and sterics in the asymmetric induction involving TarB-NO2
mediated asymmetric reduction. Our recent work on asym-
metric reduction of aliphatic ketones suggested that steric
requirements of the alkyl groups attached to the carbonyl
functionality were key in achieving high induction.16 For
example, the TarB-NO2 mediated asymmetric reduction of
2-octanone gave the product alcohol in 60% ee whereas
pinacolone, a ketone containing two sterically distinct alkyl
groups, gave the product in 95% ee. We also noted that
2-methyl-3-pentanone gave product alcohol in 62% ee,
similar to the results obtained with 2-octanone. Apparently,
TarB-NO2 reagent does not significantly distinguish an
isopropyl group from an ethyl group.
(7) Cho, B. T. Tetrahedron 2006, 62, 7621.
(8) Brown, H. C.; Ramachandran, P. V. Acc. Chem. Res. 1992, 25, 16.
In a recent report on the synthesis of allocolchicine
analogues, TarB-NO2-LiBH4 was used in the reduction of
ketone 3.1 However, the product alcohol 4 was obtained in
(9) Pollard, D. J.; Telari, K.; Lane, J.; Humphrey, G.; McWilliams, C.;
Nidositko, S.; Salmon, P.; Moore, J. Biotechnol. Bioeng. 2006, 93, 674
.
(10) Zagozda, M.; Plenkiewicz, J. Tetrahedron: Asymmetry 2006, 17,
1958
.
(11) (a) Oxenford, S. J.; Wright, J. M.; O’Brien, P.; Panday, N.; Shipton,
M. R. Tetrahedron Lett. 2005, 46, 8315. (b) Gayet, A.; Andersson, P. G
AdV. Synth. Catal. 2005, 347, 1242.
(14) Pasumansky, L.; Goralski, C. T.; Singaram, B. Org. Process Res.
DeV. 2006, 10, 959.
(12) Gribble, G. W. Chem. Soc. ReV. 1998, 27, 395.
(13) Cho, B. T.; Kang, S. K.; Kim, M. S.; Ryu, S. R.; An, D. K.
Tetrahedron 2006, 62, 8164.
(15) Cordes, D. B.; Nguyen, T. M.; Kwong, T. J.; Suri, J. T.; Luibrand,
R. T.; Singaram, B. Eur. J. Org. Chem. 2005, 5289.
(16) Kim, J.; Singaram, B. Tetrahedron Lett. 2006, 47, 3901.
Org. Lett., Vol. 11, No. 19, 2009
4359

42% ee (Scheme 1). It is possible that use of NaBH4 would
improve the asymmetric induction in this reduction as its
insolubility in THF would minimize achiral reduction. It
should be pointed out that neither the use of stoichiometric
CBS catalyst in this reduction nor kinetic resolution of the
alcohol with (-)-sparteine yielded the product allylic alcohol
of higher optical purity.17
Table 2. TarB-NO2-Mediated Reduction of Cyclic R-Substituted
R,ꢀ-Unsaturated Ketones (5)a
Scheme 1
.
Asymmetric Reduction of R,ꢀ-Unsaturated Ketones
in the Synthesis of Allocolchinoids
These results suggested that the reactions mediated by
TarB-NO2 are sensitive to steric requirements of the alkyl
groups of the prochiral ketone. We envisioned that adding
steric bulk to one of the R-carbons of a cyclic enone would
improve the enantioselectivity of TarB-NO2 mediated reduc-
tions. Initially we envisioned that 2-alkyl- or 2-arylcycloalk-
enones possess different steric requirements. However, these
2-substituted cyclohexenones are not available commercially,
and their synthesis was not trivial. Consequently, we looked
into 2-halocyclohexenones as possible substrates for TarB-
NO2/NaBH4 system.
It is known that bromination of 2-cyclohexen-1-one
followed by elimination with an amine base yields 2-bromo-
2-cyclohexen-1-one 5a.18 The corresponding iodo analogue
5b can be synthesized under Baylis-Hillman conditions with
DMAP and molecular iodine.19 We were gratified that the
reduction of 5a with TarB-NO2 and NaBH(OAc)3 yielded
6a exclusively in 92% ee (Table 2, entry 1). Similarly, TarB-
NO2-NaBH4 reduction of 5a showed superb selectivity (99%
ee) and excellent regioselectivity (entry 2). Typically these
reductions were carried out by mixing 1 equiv of the enone
with one equivalent of TarB-NO2 followed by addition of
1.2 equiv of solid NaBH4 in a single portion and stirring the
reaction for 1 h at 25 °C. Results from the reduction of
various cyclic R-substituted R,ꢀ-unsaturated ketones using
TarB-NO2 and NaBH4 are summarized in Table 2. Both 5a
and 5b showed exceptional enantioselectivity of 99% ee
(entries 2 and 3). Suzuki coupling of phenylboronic acid with
5b furnished 2-phenyl-2-cyclohexen-1-one (5c), which was
reduced to the corresponding alcohol 6c in 99% ee (entry
4).20 High enantioselectivity was also observed with 5d,
which was reduced in 88% ee (entry 5). The cyclopentenone
5e was reduced in excellent 94% ee (entry 6), and the
ꢀ-substututed 5g was reduced to afford the product alcohol
in 92% ee (entry 9).
a General reaction conditions: 4 mmol of ketone dissolved in 8 mL of
0.5 M TarB-NO2 (4 mmol) followed by 4.8 mmol of hydride. b Isolated
yield. c Enantiomeric excess determined by chiral GC. Absolute configu-
ration assigned by chiroptical comparison to literature values. d Reduction
performed at 1 mmol scale using 2 equiv of NaBH(OAc)3 as hydride. e 0.25
mmol scale reaction. f Configuration assigned by analogy. g Reduction
performed at 0 °C.
(17) Stoichiometric CBS-mediated reduction of the R-bromo-R,ꢀ-
unsaturated ketone gave very high enantioselection.
(18) Kowalski, C. J.; Weber, A. E.; Fields, K. W. J. Org. Chem. 1982,
47, 5088.
(19) Krafft, M. E.; Cran, J. W. Synlett 2005, 1263.
(20) Felpin, F. -X. J. Org. Chem. 2005, 71, 8575.
4360
Org. Lett., Vol. 11, No. 19, 2009

One of the attractive aspects of TarB-NO2-mediated
reduction is the easy accessibility of either enantiomer of
the product alcohol by simply switching (S,S)-tartaric acid
for the (R,R)-isomer in the synthesis of TarB-NO2. This is
especially attractive since both isomers of tartaric acid are
commercially available and are inexpensive. This is evi-
denced by the TarB-NO2 mediated reduction of 5f to either
(R)- or (S)-6f in extremely high ee (entries 7 and 8).
Additionally, the arylboronic acid of TarB-NO2 can be easily
recovered in high yield by a simple acid extraction.21
We also examined R-alkyl cyclic enone reductions with
TarB-NO2-NaBH4. We were pleased to see that 5h was
reduced in high enantioselectivity, yielding alcohol 6h in
80% ee (entry 10). Even the acyclic substrate 5i yielded chiral
alcohol in very good 88% ee (entry 11).
by the steric difference of the R-carbons of the ketone rather
than electronic effects. One of the more appealing aspects
of TarB-NO2 is the simplicity in generating either enantiomer
alcohol, the opposite isomer of tartaric acid can simply be
used to synthesize TarB-NO2. The synthesis of (R) alcohols
from L-TarB-NO2 and (S)-alcohols from D-TarB-NO2 strongly
suggests that these reactions occur according to our previ-
ously proposed reaction mechanism. Reaction conditions are
mild, and reduction is typically complete in just 1 h. The
starting materials are very inexpensive, and the boronic acid
used to make TarB-NO2 is easily recovered in high yield by
an acidic extraction. Additionally, very little consideration
needs to be taken with respect to the reagents; most can
simply be weighed and added to a flask under inert
atmosphere. The facile reaction conditions and high enan-
tioselectivity make TarB-NO2 a strong competitor in the field
of asymmetric reduction.
The asymmetric reduction of cyclic R-substituted R,ꢀ-
unsaturated ketones shown in this report further demonstrates
the versatility of TarB-NO2. This challenging class of
substrates was not only reduced with excellent regioselec-
tivity, but the enantioselection was also very high. Appar-
ently, TarB-NO2 mediated reductions are highly controlled
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(21) Eagon, S.; Kim, J.; Singaram, B. Synthesis 2008, 3874.
OL901677B
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