Mild and practical reductions of prochiral ketones to chiral alcohols using the chiral boronic ester TarB-H

Article abstract of DOI:10.1055/s-0028-1083605

Chiral alcohols are prepared under mild conditions in high enantiomeric excesses using the tartaric acid derived chiral boronic ester TarB-H. The phenylboronic acid was quantitatively recovered and recycled using a simple extraction with sodium hydroxide and diethyl ether. Aromatic and aliphatic secondary alcohols were prepared in up to 99% ee. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083605

3874
PRACTICAL SYNTHETIC PROCEDURES
Mild and Practical Reductions of Prochiral Ketones to Chiral Alcohols Using
the Chiral Boronic Ester TarB-H
R
eductions of
c
P
rochiral
K
o
etone
s
to Ch
t
iral
A
l
t
Using
E
TarB-
H
agon, Jinsoo Kim, Bakthan Singaram*
Department of Chemistry and Biochemistry, University of California, Santa Cruz,
1156 High Street, Santa Cruz, CA 95064, USA
Fax +1(831)4592935; E-mail: Singaram@chemistry.ucsc.edu
PSP
Received 29 July 2008; revised 6 August 2008
No140
Abstract: Chiral alcohols are prepared under mild conditions in high enantiomeric excesses using the tartaric acid derived chiral boronic
ester TarB-H. The phenylboronic acid was quantitatively recovered and recycled using a simple extraction with sodium hydroxide and di-
ethyl ether. Aromatic and aliphatic secondary alcohols were prepared in up to 99% ee.
Key words: boron, reductions, asymmetric synthesis, chiral alcohols
COOH
O
O
OH
RS
NaBH4 (2.0 equiv)
THF, 30 min
B
+
O
RL
RS
RL
COOH
up to 99% yield
up to 99% ee
TarB-H
Scheme 1 Reduction of prochiral ketones with TarB-H
Chiral secondary alcohols are key intermediates in a large TarB-X is easily prepared by mixing the desired isomer of
number of biologically active compounds.1,2 A number of tartaric acid with the phenylboronic acid in refluxing tet-
boron containing reducing agents such as CBS3 and B- rahydrofuran over calcium hydride for one hour
chlorodiisopinocampheylborane (DIP-Cl)4 have been (Scheme 2). The solution is filtered through a fritted filter
used to synthesize chiral alcohols in excellent yields and and stored as a molar solution in an ampoule.
enantiomeric excesses. Both CBS and DIP-Cl use BH3:L
Computer modeling and 11B NMR data supports our the-
in stoichiometric amounts, which is in turn prepared from
ory that reduction proceeds via a chiral acyloxyborohy-
sodium borohydride. Consequently, direct reductions of
dride intermediate species, which is formed when the
ketones using sodium borohydride are more desirable.
carboxylic acid group on TarB-X reacts with sodium
We have reported that the tartaric acid derived reagent borohydride (Scheme 3).7
TarB-X mediates the asymmetric reduction of various ke-
Most boron-derived reducing agents, including CBS and
tones using lithium borohydride.5 Since lithium borohy-
DIP-Cl, are extremely susceptible to hydrolysis and thus
dride is soluble in tetrahydrofuran , the hydride can give
either achiral reduction in solution or complex with the
HOOC
COOH
TarB-X reagent and give chiral reduction. Initial screen-
ings revealed that the meta-nitro derivative TarB-NO2
gave the best results when used concomitantly with lithi-
um borohydride. We later replaced lithium borohydride
with sodium borohydride and found that it gave superior
results. We concluded that this increase in induction was
due to the fact that only the acyloxyborohydride, which is
formed when sodium borohydride reacts with the carbox-
ylic acid moiety of TarB-X, is soluble in tetrahydrofuran
and thus direct reduction of the ketone in solution is min-
imized.6,7 TarB-NO2 proved adept in the reduction of var-
ious ketones at room temperature, but required a dry and
inert atmosphere to maintain high enantioselectivities.
COOH
COOH
OH
B
O
O
HO
OH
B
L-(+)-tartaric acid
OH
CaH2, THF
reflux 1 h
X
X
TarB-X
phenylboronic
acid derivative
Scheme 2 Synthesis of TarB-X
Rs
H
B
RL
H
H
O
O
OH
RS
NaBH4
O
O
+
TarB-H
THF
RL
RS
RL
B
O
O
COOH
SYNTHESIS 2008, No. 23, pp 3874–3876
x
x.
x
x
.
2
0
0
8
Advanced online publication: 06.11.2008
DOI: 10.1055/s-0028-1083605; Art ID: Z18008SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 3 Asymmetric reduction of a prochiral ketone via the pro-
posed acyloxyborohydride intermediate

PRACTICAL SYNTHETIC PROCEDURES
Prochiral Ketones to Chiral Alcohols Using TarB-H
3875
are usually used under an inert atmosphere.8,9 In order to
make the TarB-X system more amenable to large-scale
synthesis, we conducted various experiments to find a de-
rivative that could give the same results as TarB-NO2
without the need for a dry and inert atmosphere.10 Our re-
sults indicated that by using two equivalents of TarB-H
we could achieve the same induction as TarB-NO2 in a
closed flask. Although we have to use a superstoichiomet-
ric amount of TarB-H, the parent phenylboronic acid can
be easily recovered and recycled. Phenylboronic acid is
also significantly less expensive than the 3-nitrophenyl-
boronic acid used to synthesize TarB-NO2.11
Table 1 Reduction of Various Ketones with TarB-H in an Open
Flask (continued)
Entry Ketone
Yielda (%) eeb (%)
Configc
O
10
88
89
R
O
11
92
88
R
O
12
89
68
85
67
R
R
Using two equivalents of TarB-H and sodium borohyride
in an open flask, we reduced a variety of aromatic and al-
iphatic ketones to chiral secondary alcohols at room tem-
perature on a 5 mmol scale (Scheme 1, Table 1).10
O
13
Table 1 Reduction of Various Ketones with TarB-H in an Open
Flask
O
14
99
85
61
61
R
R
Entry Ketone
1
Yielda (%) eeb (%)
Configc
O
15
O
83
80
90
99
99
96
R
a All reactions gave 100% conversion according to GC and NMR.
b Determined by GC analysis of the acetylated alcohols on a Supelco
Beta-Dex 120 column.
O
c Determined by optical rotation values in comparison to the literature
values.
2
3
R
R
Our results were excellent with aromatic ketones (entries
1–5), all of which we were able to reduce with greater than
95% ee excepting 2-bromoacetophenone and propio-
phenone (entries 6 and 7). Tertiary alkyl ketones all gave
excellent results as well (entries 8 and 9), with good to
moderate results for secondary and n-alkyl ketones (en-
tries 10–15). In order to control the reactions at larger
scales we cooled the reaction over ice water and entrained
the evolving hydrogen gas through a bubbler to prevent
buildup.
O
O
4
81
95
R
O
5
6
7
97
80
86
95
86
64
R
R
R
TarB-H is an extremely mild boron-based reducing agent
that can be used to synthesize a variety of aromatic and
aliphatic chiral secondary alcohols with exceptional enan-
tiomeric excesses without the need for rigorous exclusion
of water. TarB-H also used sodium borohydride as its hy-
dride source instead of the more expensive and reactive
BH3:L species. Additionally, the phenylboronic acid used
in the synthesis of TarB-H can be easily recovered and re-
cycled for further use.
O
O
Br
All alcohols obtained in Table 1 were characterized by GC, optical
rotation, and 1H and 13C NMR.10
O
8
80
89
99
96
R
R
(R)-1-Phenylethanol; Gram-Scale Synthesis
A 500-mL oven dried round-bottom flask was equipped with a stir-
rer bar and allowed to cool to r.t. in air. The flask was charged with
acetophenone (1.63 mL, 14 mmol) and 0.5 M TarB-H in THF (56
mL, 28 mmol) and subsequently cooled in an ice bath. The ketone
and TarB-H were stirred for 15 min. after which NaBH4 (1.06 g, 28
mmol) was added directly to the soln. The flask was then immedi-
O
9
Synthesis 2008, No. 23, 3874–3876 © Thieme Stuttgart · New York

3876
S. Eagon et al.
PRACTICAL SYNTHETIC PROCEDURES
References
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The mixture was allowed to stir for 2 h. The soln was quenched
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The solution was extracted with pentane (3 × 50 mL) and the com-
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°C, Tcolumn = 120 °C, He carrier gas, 45 cm3/min): tR = 16.0 (minor),
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Recovery of the Boronic Acid
The basic aqueous layer was placed in a 250-mL flask and acidified
with concd HCl to pH £1. The aqueous layer was then extracted
with Et2O (3 × 40 mL). The combined ether layers were dried
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white powder (2.88 g, 85%).
Synthesis 2008, No. 23, 3874–3876 © Thieme Stuttgart · New York