Practical enantioselective reduction of ketones using oxazaborolidine catalyst generated in situ from chiral lactam alcohol and borane

Article abstract of DOI:10.1016/j.tet.2003.08.064

Reduction intermediate prepared in situ from chiral lactam alcohol 3 and borane at room temperature was found to catalyze the borane reduction of various prochiral ketones with high enantioselectivity up to 98% ee.

Full text of DOI:10.1016/j.tet.2003.08.064

Tetrahedron 59 (2003) 8411–8414
Practical enantioselective reduction of ketones using
oxazaborolidine catalyst generated in situ from chiral
lactam alcohol and borane
b
a
a
Yasuhiro Kawanami,a Shinichi Murao, Takahiko Ohga and Nobuyo Kobayashi
,
*
aDepartment of Biochemistry and Food Science, Faculty of Agriculture, Kagawa University, Miki-cho, Kagawa 761-0795, Japan
bDepartment of Chemistry, Faculty of Education, Kagawa University, Takamatsu, Kagawa 760-8522, Japan
Received 7 July 2003; accepted 26 August 2003
Abstract—Reduction intermediate prepared in situ from chiral lactam alcohol 3 and borane at room temperature was found to catalyze the
borane reduction of various prochiral ketones with high enantioselectivity up to 98% ee.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
reaction of 1 with excess borane–methyl sulfide complex
(BMS) generated the oxazaborolidine 2a at room tempera-
ture for 10 h (Scheme 1). Shioiri et al.6 also reported that
trimethyl borate could improve the reactivity and enantio-
selectivity of BMS reduction using 1 via the B–OMe
oxazaborolidine 2d (Fig. 1).
Since Itsuno et al.1 and Corey et al.2 reported oxazabor-
olidine-catalyzed asymmetric borane reduction of achiral
ketones (CBS reduction), an enormous number of borane
reduction using b-amino alcohol have been extensively
investigated.3 The most effective chiral amino alcohol was
reported to be 1 derived from (S)-proline, providing the
efficient method for the synthesis of optically active
secondary alcohols with predictable absolute stereochem-
istry. However, the preparation of oxazaborolidine 2a
requires extended heating with excess BH3 under increased
pressure due to ring strain in the [3.3.0] ring system.4 To
overcome this disadvantage, the B–Me oxazaborolidine 2b
formed by reaction of 1 with methylboronic acid has been
developed as an easily prepared and stable catalyst which
mediates the borane reduction of ketones with excellent
enantioselectivity.5 Quallich et al.4 described that the
As an alternative method, we suppose that chiral lactam
alcohol 3,7 (S)-5-(diphenylhydroxymethyl) pyrrolidin-2-
one, should be easily reduced with borane to the
corresponding imine and would be further reduced by the
neighboring alkoxyborane to generate the oxazaborolidine
2a (Scheme 2). This is suggested by the fact that racemic 1
was synthesized from racemic 3 by reduction with borane in
THF.5 Therefore, we expected that the reduction intermedi-
ate generated in situ from 3 and borane would comparably
catalyze borane reduction of prochiral ketones with high
enantioselectivity. In this communication, we report a
Figure 1.
Keywords: borane; reduction; asymmetric synthesis; enantioselective;
lactam alcohol.
*
Corresponding author. Tel.: þ81-87-891-3088; fax: þ81-87-891-3021;
e-mail: kawanami@ag.kagawa-u.ac.jp
Scheme 1. Preparation of oxazaborolidine.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.08.064

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Y. Kawanami et al. / Tetrahedron 59 (2003) 8411–8414
Scheme 3.
Table 1. Asymmetric reduction of ketones using chiral lactam alcohol 3
Entry
Ketone
Yield (%)
% eea
Configurationb
Scheme 2. A possible pathway to the oxazaborolidine 2a.
practical and excellent method for the enantioselective
borane reduction of ketones using chiral lactam alcohol 3.
1
97
97 (97)c
R
2. Results and discussion
2
3
4
80
96
82
91 (90)c
R
R
S
The lactam alcohol 3 was easily prepared by Grignard
reaction (PhMgBr) of methyl (S)-pyroglutamate which was
formed via esterification of inexpensive (S)-pyogultamic
acid, as described previously.7 The reduction of chiral
lactam alcohol 3 (10 mol%) with 1 equiv. of BH3–THF
smoothly proceeded at room temperature within 5 min. The
resulting oxazaborolidine catalyst was found to catalyze the
borane reduction of a variety of ketones, providing chiral
secondary alcohols in high enantiomeric excess (ee) and
good yield. The results are summarized inTable 1 (Scheme 3).
97
–
98 (97)c
Reduction of aryl methyl, ethyl, and chloromethyl ketone
with borane and 10 mol% of 3 proceeded with excellent
enantioselectivity (91–98% ee, entries 1–4). Reduction of
cyclic aryl ketone, a-tetralone afforded the corresponding
(R)-alcohol with slightly lower enantioselectivity (85% ee,
entry 5). Alkyl methyl ketones having a tertiary, secondary,
and primary alkyl group were reduced with good to
moderate ee (entries 6–8). Thus, the enantioselectivities
of borane reduction using the lactam alcohol 3 were
comparable to those reported in the literature for the
isolated 2a (entries 1, 2, 4–6). These results suggest that the
lactam alcohol 3 was actually reduced by borane to generate
the oxazaborolidine 2a in situ at room temperature for a
short time. Furthermore, 2-(diphenylhydroxymethyl)pyrro-
lidine 1 was recovered in good yield by neutralization and
extraction from aqueous acidic solution after quenching.
This result also supports the generation of oxazaborolidine
2a as shown in Scheme 2, although the isolation of 2a from
the reaction mixture of 3 and borane and the NMR analysis
have not been succeeded yet may be due to its instability.
5
6
7
84
86
87
85 (89)c
R
R
R
89d (92)c
81d
–
–
8
89
50
R
All reactions were carried out with 10 mol% of 3 at room temperature.
Determined by HPLC analysis using chiralcel OD column.
a
To improve the enantioselectivity in reduction of aliphatic
ketones with moderate enantioselectivities, we investigated
thetemperatureeffectonthe enantioselectivity. Theresultsare
summarized in Table 2. When the reaction temperature was
increased from 210 to 608C, ee of the resulting alcohol
produced from aliphatic ketones gradually increased up to
94% ee (entries 2–4), while that of aromatic ketone slightly
decreased (entry 1). This is in agreement with the observations
reported in the borane reduction catalyzed by B–Bu
oxazaborolidine 2c8 (508C), 1,3-amino alcohol derived from
ketopinic acid9 (508C), and (S)-proline10 (1108C).
b
Determined by comparison of the sign of specific rotation with the
literature value.
Isolated oxazaborolidine catalyst 2a.2
Determined by HPLC analysis using chiralcel OD column after
4-nitrobenzoylation.
c
d
3. Conclusion
We have demonstrated that the chiral oxazaborolidine
catalyst generated in situ from the lactam alcohol 3 and
borane catalyzed the enantioselective reduction of ketones

Y. Kawanami et al. / Tetrahedron 59 (2003) 8411–8414
8413
Table 2. Temperature effect on the enantioselectivity of asymmetric
reduction
acetate (50/1) and then chromatographed (hexane–AcOEt,
4/1) to give a white solid (695 mg, 65%); mp 194–1958C,
[a]2D5¼286.8 (c 0.74, CHCl3); IR (KBr) 3300, 1680 cm21
;
Entry
Ketone
Temperature (8C)
% ee
1H NMR (CDCl3) d 1.94–2.05 (1H, m), 2.09–2.18 (1H, m),
2.23–2.38 (2H, m), 2.66 (1H, s), 4.75 (1H, dd, J¼5.4,
8.3 Hz), 5.41 (1H, br s), 7.21–7.52 (10H, m); 13C NMR
(CDCl3) d 21.6, 30.2, 60.6, 78.7, 125.6, 125.8, 127.1, 127.5,
128.3, 128.8, 143.2, 145.2, 179.3; EI MS (Mþ) 267.
210
25
60
97
97
95
1
4.2. Typical procedure for enantioselective reduction of
ketones: (R)-1-phenylethanol
210
25
60
88
89
94
2
3
To a solution of chiral lactam alcohol 3 (26.6 mg,
0.1 mmol, 10 mol%) in THF (2 ml) was added 1 M BH3–
THF solution (1 ml, 1 mmol) and the mixture was stirred
under Ar at room temperature for 5 min. A solution of
acetophenone (116.6 ml, 1 mmol) in THF (1.5 ml) was
added dropwise. The reaction mixture was stirred until
the ketone was disappeared on a TLC (10 min). The
reaction was quenched with 2N HCl (4 ml), extracted
with ether, and dried over MgSO4. Flash-chromatography
of the crude mixture (hexane–AcOEt, 4/1) provided (R)-
1-phenylethanol (119 mg, 97%); [a]2D5¼þ49.8 (c, 2.10,
CH2Cl2) (lit.,11 [a]D23¼252.5 (c, 2.27, CH2Cl2) for S-
isomer). The ee was determined to be 97% by HPLC
analysis using a Chiralcel OD column, hexane–i-
PrOH¼97/3, 0.8 ml/min. For 1-phenylpropan-1-ol, 1-(4-
chlorophenyl)ethan-1-ol, 2-chloro-1-phenylethan-1-ol,
1,2,3,4-tetrahydronapht-1-ol, 4-phenylbutan-2-ol, hexane–
i-PrOH¼97/3, 0.8 ml/min. For 4-nitrobenzoate of 1-cyclo-
hexylethan-1-ol, 3,3-dimethylbutan-2-ol, hexane–i-
PrOH¼200/1, 0.3 ml/min.
210
25
60
64
81
82
210
25
60
28
50
64
4
with high enantioselectivity. Thus the new methodology
made the enantioselective reduction more practical because
it is easier to handle, the preparation of catalyst is less time
consuming, and no expensive reagents are involved. Further
study of this asymmetric catalytic reduction is now in
progress.
To establish the absolute configuration of the produced
alcohol, its sign of optical rotation was compared with
the reported value; (S)-(2)-1-phenylpropan-1-ol,12 (R)-
(þ)-1-(4-chlorophenyl)ethan-1-ol,13 (R)-(2)-2-chloro-1-
phenylethan-1-ol,14 (R)-(2)-1,2,3,4-tetrahydronapht-1-ol,15
(R)-(2)-1-cyclohexylethan-1-ol,16 (R)-(2)-3,3-dimethyl-
butan-2-ol,16 (R)-(2)-4-phenylbutan-2-ol.17
4. Experimental
4.1. General
IR spectra were determined using a Shimadzu IR-435
1
spectrophotometer. H NMR and 13C NMR spectra were
recorded at 400 and 100 MHz using JNM-A400 spec-
trometer, respectively. Mass spectra were recorded on a
JEOL JMS-SX102A mass spectrometer. Optical rotations
were taken with a JASCO P-1010 polarimeter. The HPLC
analysis was carried out using a DAICEL Chiralcel OD
column (0.46£25 cm) with a Shimadzu LC6A. Tetrahy-
drofurane (THF) was distilled from sodium benzophenone
ketyl before use. TLC was carried out on Merck glass plates
precoated with silica gel 60F-254 (0.25 mm) and column
chromatography was performed using Merck 23–400 mesh
silica gel. BH3–THF solution was purchased from the
Aldrich Chemical.
Acknowledgements
We are grateful to Professor Tsutomu. Katsuki (Kyushu
University) for helpful discussion.
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