Enantioselective reduction of imines catalyzed by a rhenium(V)-oxo complex

Article abstract of DOI:10.1021/ja050831a

An air- and moisture-tolerant enantioselective hydrosilylation of N-phosphinyl imines employing a chiral Re(V)-oxo complex as a catalyst is described. The chiral catalyst is a cyanobis(oxazoline) (CNbox)-ligated rhenium-oxo complex of the general formula

Full text of DOI:10.1021/ja050831a

Published on Web 08/20/2005
Enantioselective Reduction of Imines Catalyzed by a
Rhenium(V)-Oxo Complex
Kristine A. Nolin, Richard W. Ahn, and F. Dean Toste*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
Received February 8, 2005; E-mail: fdtoste@berkeley.edu
The prevalence of chiral secondary amines in natural products
and pharmaceutical targets has fueled considerable research into
the asymmetric reduction of imines.1 These reductions generally
employ catalysts derived from transition metals in low-oxidation
states. For example, low oxidation state late metal catalysts2 or
titanocene3 complexes have dominated transition-metal-catalyzed
enantioselective hydrosilylation of imines. In contrast, we recently
described that the high-oxidation state Re-dioxo complex, (Ph3P)2-
Re(O)2I, serves as a catalyst for the hydrosilylation of ketones and
aldehydes.4 The high-oxidation state of the catalyst allows the
reaction to be carried out under “open-flask” conditions, without
the need for rigorous exclusion of air and moisture. Herein, we
describe the development of a novel Re(V)-oxo complex for the
catalytic enantioselective reduction of imines.
Figure 1. ORTEP drawing of X-ray structure of (R,R)-3. Representative bond
angles: C1-C27-C14 (121.0°), N1-Re-N2 (90.1°), O1-Re-O2 (174.7°).
Mechanistic studies5 on the (Ph3P)2Re(O)2I-catalyzed hydrosi-
lylation suggested that dissociation of a neutral ligand was essential
for the catalytic activity of Re(V)-oxo complexes. This constraint
precluded the use of neutral bidentate chiral ligands for the
development of a catalyst for enantioselective reductions; therefore,
we sought to prepare a Re(V)-oxo complex with monoanionic
bidentate ligands. We envisioned that monodeprotonated bis-
(oxazoline) (box) ligands might serve this purpose. While attempts
to prepare (box)Re(V)-oxo complexes were unsuccessful, we were
pleased to find that the increased acidity of the cyanobis(oxazoline)6
ligand (CNbox, 2) allowed for the facile synthesis of the (CNbox)-
Re(V)-oxo complex (3) by simply stirring Re(V)-oxo dimethyl
sulfide complex 17 in CH2Cl2 in the presence of 1.1 equiv of the
ligand (eq 1).
Table 1. Effect of Solvent, Temperature, and Silane on
Enantioselectivity
entry
silane
solvent
temp
% yield
% ee
1
2
3
4
5
6
DMPS-H
DMPS-H
DMPS-H
DMPS-H
DPMS-H
DMPS-H
CH2Cl2
THF
EtOAc
toluene
CH2Cl2
CH2Cl2
rt
rt
rt
rt
rt
40 °C
75
96
58
51
77
81
99
99
99
99
98
98
This catalyst system operates well with either dimethylphenylsilane
(DMPS-H) or diphenylmethylsilane (DPMS-H) as the hydride
source; however, DMPS-H generally provides the best enantiose-
lectivities (entries 1 and 5). Additionally, an increase in reaction
temperature to 40 °C had little impact on the enantioselectivity of
the reduction (entry 6).
Using these conditions, excellent enantioselectivities were ob-
tained in the Re(V)-oxo-catalyzed reduction of various N-
phosphinyl imines (Table 2). Reduction of phenyl methyl ketimine
6a afforded amine (R)-7a10 with greater than 99% ee (entry 1).
The enantioselectivity remained high in the reduction of ketimines
bearing electron-withdrawing and electron-donating groups on the
aromatic ring (entries 2 and 3). Heteroaromatic ketimines (entries
5 and 7) were also consistently reduced with excellent enantiose-
lectivity (99% ee). Five-, six-, and seven-membered ring ketimines
also reacted to give amines with excellent enantioselectivity (entries
8-10). Notably, contamination by the enamine tautomer does not
impact the reactivity or enantioselectivity of the hydrosilylation.
For example, reduction of benzosuberone-derived ketimine 6h,
which exists primarily in the enamine form, produced amine 7h in
71% yield and 96% ee. Furthermore, the reduction is not limited
to N-phosphinyl imines. Rhenium-catalyzed reduction of p-meth-
oxyphenyl (PMP) imine 6k proceeds with only slightly diminished
enantioselectivity compared to that of the phosphinyl imine 6j
(compare entries 10 and 11).3a On the other hand, rhenium-catalyzed
reduction of aliphatic imine 6l proceeded with poor enantiocontrol
(entry 12).
(CNbox)Re(V)-oxo complex 3 was isolated as a bright green
solid. Slow evaporation of a concentrated solution of (R,R)-3 in
dichloromethane at room temperature yielded X-ray quality, plate-
like crystals (Figure 1). The rhenium possesses distorted octahedral
geometry, in which the oxo ligand is trans to triphenylphosphine
oxide and the two chlorides are trans to the nitrogens of the CNbox
ligand. The short Re-oxo bond length (1.66 Å) indicates substantial
triple bond character.8
With this complex in hand, we set out to examine its potential
as a catalyst for enantioselective phosphinyl imine reduction. Our
choice of this imine nitrogen substituent was guided by the
requirement that the imine be tolerant to air and moisture that may
be present during the course of the reaction; however, once
reduction has taken place, the resulting phosphinyl amine can be
easily cleaved under acidic conditions.9 With this in mind, we
examined the reduction of imine 4 at room temperature using 2
equiv of silane and 3 mol % of 3 under ambient atmosphere (Table
1). Under these conditions, complex 3 catalyzed the reduction of
imine 4 to amine 5 with high selectivity in a range of solvents
(entries 1-4), with dichloromethane proving to be the most general.
9
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J. AM. CHEM. SOC. 2005, 127, 12462-12463
10.1021/ja050831a CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of the Enantioselective Imine Reductiona
and enantioselective reduction of R,â-unsaturated imines to allylic
N-phosphinyl amines, which can undergo further transformations.13
This reaction provides a rare example of a catalytic process
employing a chiral rhenium complex.14 While chiral metal-oxo
complexes are commonly employed as catalysts in asymmetric
oxidation reactions, this method highlights the potential for their
use in nonoxidative enantioselective transformations.15 Studies on
the development of this class of catalysts, including application of
the complexes described herein, are ongoing in our laboratories
and will be reported in due course.
Acknowledgment. We gratefully acknowledge the University
of California, Berkeley, the Camille and Henry Dreyfus Foundation,
Research Corporation and Merck Research Laboratories for finan-
cial support. K.A.N. thanks Novartis Pharma for a graduate
fellowship.
Supporting Information Available: Experimental procedures,
sample spectra, compound characterization data (PDF), and X-ray
structure data (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
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In conclusion, we have developed an “open-flask” enantiose-
lective reduction of imines and R-imino esters that employs a high
oxidation metal-oxo catalyst. Particularly noteworthy is the chemo-
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