LETTER
Simple Protocol for Enantioselective Reduction of Aromatic Ketones
1129
The use of an authentic standard of ( )-3, obtained by con- Encouraged by these results and in order to further test the
ventional reduction of 2 with sodium borohydride in catalytic performance of the so generated catalysts, a set
methanol, allowed the proper qualification of the HPLC of aromatic ketones carrying various substituents was
separation, employed for assessment of the optical yields submitted to this enantioselective reduction under stan-
of product.
darized conditions. In a typical and representative proce-
dure, a flame-dried 10 mL flask was charged with toluene
(1 mL) and a 2 M solution of BH3 SMe2 in SMe2 (0.075
mL, 0.15 mmol) under an argon atmosphere. This was
dropwise treated with dry n-octanol (0.063 mL, 0.40
mmol) and the reaction mixture was stirred for 1 hour at
34 ºC, when a solution of (–)-114 (28 mg, 0.11 mmol) in
anhydrous toluene (1 mL) was added to the thus formed
borate ester. After stirring for 1 hour at 34 ºC, more
BH3 SMe2 in SMe2 (0.55 mL, 1.1 mmol) was added, fol-
lowed by slow injection (1 h) via syringe pump of a solu-
tion of ketone 2 (200 mg, 1.1 mmol) in toluene (1 mL).
When judged completed by TLC analysis, the reaction
was quenched with 1 N HCl (5 mL) and extracted with
EtOAc (3 15 mL). The extracts were successively
washed with saturated NaHCO3 (5 mL) and brine (5 mL),
dried with Na2SO4, concentrated under reduced pressure
and chromatographed furnishing (+)-3 (198 mg, 98%;
ee = 97%, by chiral HPLC), as a colorless oil.
All of the evaluated alcohols showed good to excellent
performances. Reaction conditions, however, required
fine tuning for the best performance to be achieved; a tem-
perature of 34 ºC was found to be optimal for the reduc-
tion and no significant differences were observed between
toluene and THF as solvents. Repeated tests indicated that
in small scale reactions, lower alcohols (entries 1 and 2)
were outperformed by their higher molecular weight con-
geners, which furnished better and more repeatable re-
sults. This seems to be in line with a previous publication
in which MeOH and EtOH as additives gave comparative-
ly poorer results.9a On the other hand, the catalyst derived
from n-octanol showed one of the best performances; un-
fortunately, however, its exact structure could not be un-
veiled because in agreement with a previous report,
attempts to isolate this catalyst met with failure due to its
unstability.11
Interestingly, in spite of Brown’s report indicating that the
reaction of secondary alcohols with borane does not
achieve completion at room temperature,13 reductions car-
ried out with catalysts derived from cyclohexanol and 2-
propanol (entries 3 and 6) were almost quantitative, pro-
vided (+)-3 with excellent enantiomeric excesses and
were not appreciably slower than those which employed
OABs derived from primary alcohols.
The results, summarized in Table 2, evidence that regard-
less of the nature of the functional group or the substitu-
tion pattern, the reactions were highly enantioselective for
the tested acetophenones. The secondary alcohol obtained
in entry 3 was recently employed as a key intermediate for
an enantioselective total synthesis of 1-S-(–)-salsolidine.15
As expected, in the case of 3,4-dimethoxy phenylacetone
(entry 9), very low induction was observed.9b
In conclusion, this work demonstrated the efficiency and
usefulness of a simplified protocol for the one pot catalyt-
ic enantioselective reduction of prochiral ketones, featur-
ing a facile in situ preparation of oxazaborolidines by
reaction of BH3 SMe2, an alcohol and (–)-1.
Table 1 Reduction of 3,4-Dimethoxyacetophenone (2) with Cata-
lysts Derived from (–)-1, Formed in the Presence of Various Alcohols
The protocol is simple, versatile, easy to be carried out in
small scale and isolation of air and moisture sensitive ox-
azaborolidine species is not required. The use of readily
available chemicals constitutes an additional attractive fa-
voring the adoption of this methodology.
Entry
Alcohola
Yield (%)b
ee (%)c
90
Acknowledgement
1
2
3
4
5
6
MeOH
100
90
The authors gratefully acknowledge CONICET, ANPCyT and SE-
CyT-UNR for financial support. V.L.P. thanks CONICET for a fel-
lowship.
MeCH2OH
MeCH(OH)Me
Me(CH2)3OH
Me(CH2)7OH
Cyclohexanol
90
90
97
100
98
96
References
97
(1) Hirao, A.; Itsuno, S.; Nakahama, S.; Yamazaki, N. J. Chem.
Soc., Chem. Commun. 1981, 315.
93
96
(2) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc.
1987, 109, 5551.
a 10 mol% of (–)-1 were employed.
b Isolated yield after flash column chromatography.
(3) (a) Singh, V. K. Synthesis 1992, 605. (b) Martens, J.;
Wallbaum, S. Tetrahedron: Asymmetry 1992, 3, 1475.
(c) Deloux, L.; Srebnik, M. Chem. Rev. 1993, 93, 763.
(d) Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37,
1987.
c Determined by HPLC with a Chiralcel OD column; mobile phase:
hexane/2-propanol (9:1) at 0.5 mL/min.
Synlett 2002, No. 7, 1128–1130 ISSN 0936-5214 © Thieme Stuttgart · New York