Convenient preparation of chiral primary alcohols via catalytic asymmetric reduction of aldehydes using Bu3SnD

Full text of DOI:10.1021/jo961593s

7638
J . Org. Chem. 1996, 61, 7638-7639
Communications
Ta ble 1. Yield s a n d Ee’s for Ch ir a l P r im a r y Alcoh ols
Con ven ien t P r ep a r a tion of Ch ir a l P r im a r y
Alcoh ols via Ca ta lytic Asym m etr ic
Red u ction of Ald eh yd es Usin g Bu 3Sn D
Gary E. Keck* and Dhileepkumar Krishnamurthy
Department of Chemistry, University of Utah,
Salt Lake City, Utah 84112
reaction
time (h)
yielda
(%)
eeb
(%)
entry
aldehyde
Received August 19, 1996
1
2
3
4
5
6
benzaldehyde
furaldehyde
PhCH2CH2CHO
(E)-PhCHdCHCHO
geranial
2
2
20
20
24
24
92
80
90
83
81
75
94
97
95
93
95
90
Chiral primary alcohols have been used extensively in
the study of enzymatic mechanisms and as precursors
for other labeled compounds such as [1H,2H,3H]acetic
acid.1 Convenient methods for the incorporation of
isotopic labels can also assist investigations of complex
metabolic pathways, such as in vitro metabolism of drug
candidates. We describe herein a particularly convenient
method for the enantioselective introduction of deuterium
via catalytic asymmetric reduction of aldehydes,2 yielding
chiral primary carbinols RCHDOH. With minor modi-
fications, the method should be applicable to chiral
tritiated alcohols as well.
In a recent series of papers, we have documented the
utility of “BITIP” catalysts (acronymn denotes catalyst
preparation from BINOL and titanium tetraisopropoxide)
in catalytic asymmetric C-C bond-forming reactions such
as allylstannane additions3 and Mukaiyama aldol con-
densations,4 using aldehydes as substrates. Since stan-
nanes such as Bu3SnH are known to reduce aldehyde or
ketone carbonyl groups by either “one-electron” or “two-
electron” mechanisms,5 it was of interest to see if these
catalytic asymmetric reactions utilizing aldehydes as
substrates could be extended to encompass catalytic
asymmetric reductions.
Initial experiments using benzaldehyde as substrate
indicated that such reactions could in fact be accom-
plished catalytically. Of the procedures previously re-
ported, “method B” gave the best results in this instance.
Thus, reduction of benzaldehyde with Bu3SnD using 10
mol % (titanium relative to substrate PhCHO) of catalyst
prepared according to “method B” previously reported by
us afforded product of 94% ee (analysis via the corre-
sponding Mosher ester). Methods A and D afforded 84%
and 70% ee, respectively. In these reductions, little
BnOCH2CHO
All yields are isolated yields. ee was determined by 1H NMR
analysis of the corresponding MTPA ester.
a
b
difference was noted between reactions conducted in
ether vs those run using dichloromethane. The same
trends in enantiomeric excess obtained using methods
A, B, and D were also observed when 3-phenylpropional-
dehyde was used as substrate, indicating that method B
was probably the optimum procedure for these reduc-
tions.
Application of the method B protocol to several alde-
hydic substrates afforded the results summarized in
Table 1. In all cases, good yields of products with g90%
ee were obtained. Since analysis in all cases was via
NMR spectroscopy of the derived Mosher esters, it proved
difficult to assay ee’s in this range precisely, particularly
for ee’s g95%. Thus, both the precision and accuracy of
these measurements are not as high as those achievable
using chromatographic methods, but it is nonetheless
clear that the enantioselectivity of this process is excel-
lent and competitive with other known methods.
Perhaps the most commonly used method, developed
by Midland,6 for preparing such D-labeled alcohols utilizes
the reduction of RCDO with 3-pinanyl-9-BBN (prepared
from pinene and 9-BBN) or reduction of RCHO with the
deuterated borane prepared from pinene and 9-BBN-9-
d. These methods require either optically pure (+)- and
(-)-pinene or “correction” of the product ee for the % ee
of the pinene employed. The reductions of benzaldehyde,
cinnamaldehyde, and geranial reported by Midland with
9-BBN-9-d, after correction for the deuterium content of
the reagent and the % ee of pinene, proceed with 98, 84,
and 81% ee, respectively. Clearly, the simple catalytic
protocol described herein compares quite favorably (for
these cases) with the stoichiometric borane-based meth-
odology, and no such corrections are necessary.
(1) (a) Floss, H. G.; Lee, S. Acc. Chem. Res. 1993, 26, 116. (b) Parry,
R. J .; Trainor, D. A. J . Am. Chem. Soc. 1978, 100, 5243. (c) Kobayashi,
K.; J adhav, P. K.; Zydowsky, T. M.; Floss, H. G. J . Org. Chem. 1983,
48, 3510. (d) Shibuga, M.; Chou, H.-M.; Fountoulakis, M.; Hassam,
S.; Kim, S.-V.; Kobayashi, K.; Otsuka, H.; Rogalska, E.; Cassady, J .
M.; Floss, H. G. J . Am. Chem. Soc. 1990, 112, 297. (e) Mu, Y.; Omer,
C. A.; Gibbs, R. A. J . Am. Chem. Soc. 1996, 118, 1817.
(2) We are aware of only one previous report on the catalytic
asymmetric reduction of aldehydes: Corey, E. J .; Link, J . O. Tetrahe-
dron Lett. 1989, 30, 6275.
(3) (a) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J . Am. Chem. Soc.
1993, 115, 8467. (b) Keck, G. E.; Geraci, L. S. Tetrahedron Lett. 1993,
34, 7827. (c) Keck, G. E.; Krishnamurthy, D.; Grier, M. C. J . Org. Chem.
1993, 58, 6543.
(4) (a) Keck, G. E.; Krishnamurthy, D. J . Am. Chem. Soc. 1995, 117,
2363. (b) Keck, G. E.; Li, X.-Y.; Krishnamurthy, D. J . Org.Chem. 1995,
60, 5998. (c) Descriptions of catalyst preparations herein are used as
consistent with our previous reports.
Although the results described in Table 1 apply to Bu3-
SnD reduction of RCHO, it seems clear that Bu3SnH
reduction of RCDO could be accomplished equally well.
It also seems clear that chiral tritiated carbinols could
be prepared by this approach, using RC3HO with Bu3-
SnD or RCDO with Bu3Sn3H. In this context, it should
be noted that Bu3SnD is commercially available or can
be conveniently prepared from Bu3SnH by reaction with
LDA7 followed by quenching with D2O.8 A similar
(5) The literature on this subject is extensive. For representative
and leading references, see: (a) Tanner, D. D.; Singh, H. K. J . Org.
Chem. 1986, 51, 5182. (b) Shibata, I.; Yoshida, T.; Kawakami, T.; Baba,
A.; Matsuda, H. J . Org. Chem. 1992, 57, 4049. (c) Zelechonok, Y.;
Silverman, R. B. J . Org. Chem. 1992, 57, 5785. (d) Vedejs, E.; Duncan,
S. M.; Haight, A. R. J . Org. Chem. 1993, 58, 3046. (e) Hays, D. S.; Fu,
G. C. J . Org. Chem. 1996, 61, 4.
(6) (a) Midland, M. M.; Tramontano, A.; Zderic, S. A. J . Am. Chem.
Soc. 1977, 99, 5211. (b) Midland, M. M.; Greer, S.; Tramontano, A.;
Zderic, S. A. J . Am. Chem. Soc. 1979, 101, 2352.
(7) Still, W. C. J . Am. Chem. Soc. 1978, 100, 1481.
S0022-3263(96)01593-9 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 22, 1996 7639
protocol should serve to prepare Bu3Sn3H, perhaps by
nucleophilic addition to the re face of the aldehyde
substrate. The same appears true of the reduction
process described hereinsreduction of benzaldehyde us-
ing catalyst prepared from (S)-BINOL gave S product,
3
quenching with AcO3H (from Ac2O + H2O). Although
we have not prepared Bu3Sn3H or employed this reagent
in reductions due to the special regulations that are
involved for handling radioactive materials, we can see
no reason why such reactions should not proceed with
equally high enantiomeric excess as those described
herein.
1
as determined by H NMR experiments using Eu(hfc)3,
as previously reported by Midland.6 The same sense of
addition is assumed for the other substrates employed.
P r ep a r a tion of (S)-1-Deu ter ioger a n iol. A mixture
of (S)-(-)-BINOL (28.6 mg, 0.1 mmol), 1 M Ti(O-i-Pr)4
in CH2Cl2 (50 µL, 0.05 mmol), CF3CO2H (0.003 mL, 0.5
M in CH2Cl2), and oven-dried powdered 4 Å molecular
sieves (200 mg) in ether (2.0 mL) was heated at reflux
for 1 h. The red-brown mixture was cooled to rt, and
geranial (76 mg, 0.5 mmol) was added. The mixture was
stirred for 5 min and cooled to -78 °C, Bu3SnD (103 mg,
0.59 mmol) was added, and the contents were stirred for
10 min and then placed in a -20 °C freezer (without
stirring) for 24 h. Saturated NaHCO3 solution (0.5 mL)
was added, and the contents were stirred for 1 h and then
filtered through a plug of Celite. The organic layer was
separated, and the aqueous layer was extracted with
ether (3 × 2 mL). The combined organic layers were
dried over Na2SO4 and concentrated. The crude material
was purified by flash chromatography, eluting with 10%
acetone in hexanes, to afford 66 mg (85%) of geraniol-1-
d. The enantiomeric purity was determined to be 95%
Several features of these reactions are worthy of note.
First of all, the reducing agent employed possesses only
one transferable hydrogen that can come directly (Bu3-
SnD) or perhaps indirectly (Bu3Sn3H) from water via a
simple depronation/quenching protocol. Thus, the re-
agent is easily prepared from a convenient and inexpen-
sive source of label and can be stored indefinitely.
Secondly, both enantiomers of BINOL are commercially
available with essentially 100% enantiomeric excess.9
This ensures that any (R)/(S) pairs of labeled primary
alcohols prepared using this procedure will be of the same
enantiomeric excess (within experimental error) and can
be used without tedious corrections for the differing ee’s
of R and S enantiomers, a correction that is generally
necessary if the pinene based borane reduction is used
to prepare (R)/(S) pairs.10
In all of the reactions described to date, the use of
BITIP catalysts derived from (R)-BINOL results in
1
by 500 MHz H NMR analysis of corresponding MTPA
ester.
(8) The preparation of Bu3SnD from Bu3SnCl has also been de-
scribed: Ku¨hlein, K.; Neumann, W. P.; Mohring, H. Angew. Chem.,
Int. Ed. Engl. 1968, 7, 455.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health for financial support through Grant No.
GM28961. We also thank our colleague C. Dale Poulter
for helpful discussions regarding this chemistry and for
suggestions related to the potential application to tri-
tiated alcohols.
(9) Alternatively, resolution of racemic BINOL can be accomplished
by a number of procedures; the procedure developed recently at Merck
is particularly convenient: Cai, D.; Hughes, D. L.; Verhoeven, T. R.;
Reider, P. J . Tetrahedron Lett. 1995, 36, 7991.
(10) However, Brown and co-workers have reported procedures to
increase the optical purity of pinene to essentially 100%: (a) Brown,
H. C.; Yoo, N. M. Isr. J . Chem. 1977, 15, 12. (b) Brown, H. C.; Singaram,
B. J . Org. Chem. 1984, 49, 945.
J O961593S