Rationalising the effect of reducing agent on the oxazaborolidine-mediated asymmetric reduction of N-substituted imines

Article abstract of DOI:10.1016/j.tetlet.2003.11.021

Comparing the effect of borane-based reducing agents on the stereochemical outcome of oxazaborolidine-mediated ketone and N-substituted imine reduction highlights the potential importance of reducing agent structure on the asymmetric sense of imine reduct

Full text of DOI:10.1016/j.tetlet.2003.11.021

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 853–855
Rationalising the effect of reducing agent on the oxazaborolidine-
mediated asymmetric reduction of N-substituted imines
Eirene H. M. Kirton,a,b Gary Tughan,c, Russell E. Morrisa and Robert A. Fielda,b,
*
aSchool of Chemistry, University of St. Andrews, North Haugh, St. Andrews KY16 9ST, UK
bSchool of Chemical Sciences and Pharmacy, University of East Anglia, Norwich NR4 7TJ, UK
cGlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG2 1NE, UK
Received 15 August 2003; revised 30 October 2003; accepted 6 November 2003
Abstract—Comparing the effect of borane-based reducing agents on the stereochemical outcome of oxazaborolidine-mediated
ketone and N-substituted imine reduction highlights the potential importance of reducing agent structure on the asymmetric sense of
imine reduction.
ꢀ 2003 Elsevier Ltd. All rights reserved.
Table 1. Oxazaborolidine-mediated asymmetric reduction of an imine
Chiral oxazaborolidines, typified by (S)-methyl-CBS-
oxazaborolidine 1 (CoreyÕs reagent), have found wide
Ph
Ph
application in the catalytic asymmetric reduction of
ketones.1;2 They have also been investigated, to a lesser
extent, for the reduction of imines,3 leading to the suc-
cessful asymmetric synthesis of Metolachlor, a widely
used herbicide.4 Studies by Sakai et al.,5 in connection
with the preparation of fluorinated amino acids, showed
that the enantiomer formed on oxazaborolidine-cata-
lysed reduction of imine 2 depended on the borane
reducing agent employed (Table 1). On moving from
borane–THF to the less reactive catecholborane, the
sense of the asymmetric reduction changed from S to R;
no explanation was given to account for this observa-
tion.
CO2Et
N
CO2Et
NH
N
O
F3C
F3C
B
H
1
Me
reducing
agent
OMe
OMe
2
3
Reducing agent
Ester 3
Borane–THF
Catecholborane
42% yield, 28% ee, S (see Ref. 6)
93% yield, 63% ee, R
In connection with a medicinal chemistry programme,
we had cause to investigate the asymmetric reduction of
imines. We were drawn to consider, and rationalise, the
impact of the choice of reducing agent on the stereo-
chemical outcome of such reactions; our observations
are presented herein.
For purposes of comparison, the oxazaborolidine-
catalysed reduction of acetophenone 5 and phenyl-
(1-phenylethylidene)amine 6 were carried out with
CoreyÕs reagent 1 in the presence of either borane–THF
or catecholborane.7 Several differences between ketone
and imine reduction were noted (Table 2).
The reduction of ketone 5 with borane–THF in the
absence of oxazaborolidine catalyst was sluggish; when
catecholborane alone was used, no reduction of 5 was
evident. In contrast, the uncatalysed reduction of imine
6 with either of these reducing agents was essentially
complete within 10 min. Clearly such an outcome pre-
sents problems for asymmetric imine reduction, since
* Corresponding author at present address: School of Chemical
Sciences and Pharmacy, University of East Anglia, Norwich NR4
7TJ, UK. Fax: +44-1603-592003; e-mail: r.a.field@uea.ac.uk
Present address: AstraZeneca-Charnwood, Bakewell Road, Lough-
borough LE11 5RH, UK.
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.021

854
E. H. M. Kirton et al. / Tetrahedron Letters 45 (2004) 853–855
Table 2. Oxazaborolidine-mediated reduction of acetophenone 5 and phenyl-(1-phenylethylidene)amine 6
Ph
B
Ph
XH
Me
X
N
O
Me
Me
reducing agent
7
8
X = O
X = NPh
5
6
Substrate
Oxazaborolidine
catalyst
Reducing agent
Conversion (%)a
ee (%)a
Product
configurationb
Acetophenone 5
None
S
Borane–THF
Borane–THF
Catecholborane
Catecholborane
40
>99
0
0
>99
0
––
Alcohol 7 R
––
Alcohol 7 R
None
S
90
80
Phenyl-(1-phenylethylidene)-amine 6
None
S
Borane–THF
Borane–THF
91
69
87
98
91
0
87
0
––
Amine 8 R
––
None
S
Catecholborane
Catecholborane
Catecholborane
47
49
Amine 8 S
Amine 8 R
R
a Determined by chiral HPLC––see general experimental protocol.7
b Absolute configurations were confirmed by comparison with literature data.8
the competing racemic background reaction may re-
duce the ee of the amine product, unless the rate of the
catalysed reaction is significantly faster than that of its
uncatalysed counterpart. With acetophenone 5, choice
of borane reducing agent did not affect the configura-
tion of the product, whereas with imine 6 a change in
the absolute configuration of the amine product was
evident on changing from borane–THF to cate-
cholborane, in keeping with the observations of Sakai
et al.5 To verify this observation, reduction of imine 6
with catecholborane and (R)-methyl-CBS-oxazaborol-
idine did indeed give rise predominantly to the (R)-
amine 8.
requires the oxazaborolidine to complex both the ketone
and borane in the least sterically demanding arrange-
ment, as outlined in Figure 1.10
With imines, the structure of the reducing agent appears
to play a role in the stereochemical outcome of the
oxazaborolidine-mediated reduction (Table 2). For
reaction of phenyl-(1-phenylethylidene)amine 6 with
borane–THF, a model analogous to that invoked to
explain the asymmetry of ketone reduction (Fig. 1)
cannot obviously account for the enantioselectivity
observed (i.e., Fig. 2, conformation A).11
On steric grounds, it seems likely that rotation of both
the imine and borane, such that B–H and C@N bonds
are aligned, better explains generation of the R-amine
product 8 (Fig. 2, conformation B). Rotation of both
reagents therefore gives the same stereochemical out-
come as for reduction of the corresponding ketone 5.
However, the analogous complex with catecholborane
(Fig. 2, conformation D) is untenable for steric reasons,
leading to alignment of imine C@N and borane B–H
bonds as for ketone reduction (Fig. 2, conformation C).
This in turn leads to the S-amine product 8, the opposite
outcome to that observed when borane–THF is used as
the reducing agent.
For ketone reduction, the chirality of the oxazaboro-
lidine is responsible for the stereocontrol. Supported by
crystallographic data,9 the proposed mechanism for
achieving asymmetric reduction with this system
O
Ph
Ph
Me
_
H
OH
Y
BH -THF
O
N
3
X
Y
+
B
+
X
Y
X
_
O
B H
H
X is small
Y is large
X is small
Y is large
H
In summary, in contrast to the corresponding reduction
of ketones, choice of reducing agent as well as catalyst
chirality can affect the sense of oxazaborolidine-medi-
ated asymmetric reduction of imines. Steric factors
provide a rationale for why, in conjunction with methyl-
CBS-oxazaborolidine, catecholborane gives rise pre-
dominantly to the opposite enantiomer to that formed
when borane–THF is employed.
Ph
Ph
N
O
B
Me
1
Figure 1. Model to account for asymmetry in oxazaborolidine-medi-
ated ketone reduction.

E. H. M. Kirton et al. / Tetrahedron Letters 45 (2004) 853–855
855
More hindered than
conformation B
A
B
Me
Me
_
B
_
B
O
O
+
+
N
N
+
+
N
H B
2
H B
2
H
N
Me
H
Me
HN
NH
Me
Me
R
S
D
C
Me
_
Me
_
B
O
O
+
N
B
+
O
N
O
+
+
B
H
B
H
N
N
O
Me
O
Me
More hindered than
conformation C
Figure 2. Model to account for asymmetry in oxazaborolidine-mediated imine reduction.12
6. The low yield of amino-ester 3 is accompanied by
formation of the corresponding amino-alcohol (49%
yield), albeit of the R-configuration (45% ee) (the change
in stereochemistry is not accounted for). On moving from
borane–THF to the less reactive catecholborane, forma-
tion of the amino-alcohol was no longer evident.
7. General procedure for oxazaborolidine-catalysed imine
reduction: reduction was achieved by a modification of the
procedure described by Cho and Chun.3b In THF
Acknowledgements
This study was supported by EPSRC and GSK (CASE
award to E.H.M.K.). We gratefully acknowledge
invaluable support form the EPSRC Mass Spectrometry
Service, Swansea.
References and notes
(1.5 mL), phenyl(1-phenylethylidene)amine
6
(25 mg,
130 lmol), (S)-methyl-CBS-oxazaborolidine 1, (13 lmol,
10 mol %) were stirred under nitrogen for 10 min. Reduc-
ing agent (150 lmol) was added and the reaction was
stirred at room temperature. Reactions were assessed by
HPLC after 1 h (250 · 4.6 mm Chiralcel OD-H column; 5%
ethanol in heptane; 0.5 mL/min; detection at 215/254 nm).
8. Morimoto, T.; Nakajima, N.; Achiwa, K. Tetrahedron:
Asymmetry 1995, 6, 23–26.
1. Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc.
1987, 109, 5551–5553; Reviewed in: Srebnik, M.; Deloux,
L. Chem. Rev. 1993, 93, 763–784; Corey, E. J.; Helal, C. J.
Angew. Chem., Int. Ed. 1998, 37, 1986–2012.
2. For selected recent examples of ketone reductions with
immobilised oxazaborolidines see: Price, M. D.; Sui, J. K.;
Kurth, M. J.; Schore, N. E. J. Org. Chem. 2002, 67, 8086–
8089; Schunicht, C.; Biffis, A.; Wulff, G. Tetrahedron
2000, 56, 1693–1699, and references cited therein.
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Wallbaum, S.; Martens, J. Bull. Korean Chem. Soc. 1994,
15, 53–57; (b) Cho, B. T.; Chun, Y. S. J. Chem. Soc.,
Perkin Trans. 1 1990, 3200–3201.
9. Corey, E. J.; Azimioara, M.; Sarshar, S. Tetrahedron Lett.
1992, 33, 3429–3430.
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1992, 33, 7107–7110; Jones, D. K.; Liotta, D. C.; Shinkai,
I.; Mathre, D. J. J. Org. Chem. 1993, 58, 799–801.
11. These models are based on the premise that only the trans
form of the imine is subject to oxazaborolidine-catalysed
reduction.
4. Cho, B. T.; Chun, Y. S. Tetrahedron: Asymmetry 1992, 3,
337–340.
12. The effect of imine structure, including N-substitution, on
the stereoselectivity of oxazaborolidine-catalysed imine
reduction has been noted (see Ref. 3).
5. Sakai, T.; Yan, F.; Uneyama, K. Synlett 1995, 753–754;
Sakai, T.; Yan, F.; Kashino, S.; Uneyama, K. Tetrahedron
1996, 52, 233–244.