Enantioselective organocatalytic reductive amination

Article abstract of DOI:10.1021/ja057222n

The first enantioselective organocatalytic reductive amination reaction has been accomplished. The development of a new chiral phosphoric acid catalyst has provided a convenient strategy for the enantioselective construction of protected primary amines an

Full text of DOI:10.1021/ja057222n

Published on Web 12/14/2005
Enantioselective Organocatalytic Reductive Amination
R. Ian Storer, Diane E. Carrera, Yike Ni, and David W. C. MacMillan*
DiVision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125
Received October 23, 2005; E-mail: dmacmill@caltech.edu
The reductive amination reaction remains one of the most
powerful and widely utilized transformations available to practi-
tioners of chemical synthesis in the modern era.1 A versatile
coupling reaction that enables the chemoselective union of diverse
ketone and amine containing fragments, reductive amination can
also provide rapid and general access to stereogenic C-N bonds,
a mainstay synthon found in natural isolates and medicinal agents.
While a variety of protocols have been described for the asymmetric
reduction of ketimines (a strategy that requires access to preformed,
bench stable imines),2 it is surprising that few laboratory methods
are known for enantioselective reductive amination.1b,3 Moreover,
the use of this ubiquitous reaction for the union of complex
fragments remains unprecedented in the realm of asymmetric
catalysis, a remarkable fact given the widespread application of
both racemic and diastereoselective variants. In this communication,
we report the first organocatalytic reductive amination, a biomimetic
reaction that allows the asymmetric coupling of complex fragments
using chiral hydrogen-bonding catalysts and Hantzsch esters.4,5
ketone and amine coupling partners to a chiral hydrogen-bonding
catalyst8 would result in the intermediate formation of an iminium
species that in the presence of a suitable Hantzsch ester would
undergo enantioselective hydride reduction, thereby allowing asym-
metric reductive amination in an in vitro setting.9 This proposal
was further substantiated by the significant advances in hydrogen-
bonding catalysis, arising from the pioneering studies of Jacobsen,10
Corey,11 Takemoto,12 Rawal,13 Johnston,14 Akiyama,15 and Terada.16
An initial evaluation of the proposed reductive amination was
performed with acetophenone, p-anisidine, ethyl Hantzsch ester
(HEH), and several classes of established hydrogen-bonding
catalysts (eq 1, Table 1). While thiourea 1 and taddol 2 did not
induce reductive amination, the binol phosphoric acid catalysts
3a-d (introduced by Terada and Akiyama) did indeed provide the
desired amine adduct, albeit with moderate conversion and stereo-
induction (entries 1-5, 7-65% ee). To our great delight, we found
that an unprecedented ortho-triphenylsilyl variant of the Terada-
Akiyama catalyst 5 facilitates the desired coupling in high conver-
sion and with excellent levels of enantiocontrol at 40 °C (entry 8,
94% ee).17 Importantly, preliminary studies have revealed that water,
generated in the initial condensation step, has a deleterious impact
on both iminium formation and the hydride reduction step. As such,
the introduction of 5 Å sieves was found to be critical to achieve
useful reaction rates and selectivities.
Having established the optimal conditions for hydrogen bond
catalysis, we next examined the scope of the ketone component in
this organocatalytic reduction. As revealed in Table 2, a variety of
substituted acetophenone derivatives can be successfully coupled
(eq 2), including electron-rich, electron-deficient, as well as ortho,
meta, and para substituted aryl ketone systems (Table 2, entries
1-9, 60-87% yield, 83-95% ee). Moreover, cyclic aryl ketones
(entry 10, 75% yield, 85% ee) and R-fluoromethyl ketones (entry
11, 70% yield, 88% ee) are also tolerated in this process without
loss in reaction efficiencies or enantiocontrol.
It has long been established that nature has perfected reductive
amination as an in vivo chemical tool for the enantioselective
synthesis of essential biomonomers. As a preeminent example,
transferase enzymes utilize hydrogen bonding to selectively activate
pyruvate-derived ketimines toward hydride delivery from NADH,
thereby ensuring the enantiocontrolled formation of naturally
occurring amino acids.6 With this in mind, we recently questioned
whether the conceptual blueprints of biochemical amination might
be translated to an enantioselective reductive coupling wherein
enzymes and cofactors are replaced by small organic catalysts and
NADH analogues.7 Specifically, we proposed that exposure of
Pleasingly, the pyruvic acid-derived cyclic imino ester (eq 3)
also underwent facile reduction to yield the corresponding cyclic
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J. AM. CHEM. SOC. 2006, 128, 84-86
10.1021/ja057222n CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Evaluation of Phosphoric Acid Catalyst Architecture
tion wherein the CdN Si-face is exposed to hydride addition
(MM3-7, green dot ) H). In contrast, the ethyl-containing
substrate (R2 ) Et, MM3-7, green dot ) Me) is conformationally
required to position the terminal CH3 of the ethyl group away from
the catalyst framework, thereby ensuring that both enantiofacial
sites of the iminium π-system are shielded (MM3-7, green dot )
Me). As shown in Figure 1 (Supporting Information), we have
recently obtained a single-crystal X-ray structure of a catalyst-bound
aryl imine that exhibits a remarkable correlation to MM3-7 in
terms of both hydrogen bond orientation and the specific architec-
tural elements that dictate iminium enantiofacial discrimination.18
entry
cat.
cat. substitution (R)
additive
temp (
°
C)
% conva
% eeb
1
2
3
4
5
6
7
8
3a
3a
3b
3c
3d
4
2-naphthyl
2-naphthyl
H
3,5-NO2-phenyl
3,5-CF3-phenyl
SitBuPh2
SiPh3
none
80
80
80
80
80
80
80
40
6
41
43
45
39
35
70
85
37
45
7
16
65
61
87
94
5 Å MS
5 Å MS
5 Å MS
5 Å MS
5 Å MS
5 Å MS
5 Å MS
5
5
SiPh3
a Conversion determined by GLC analysis. b Enantiomeric excess de-
termined by chiral GLC analysis (Varian CP-chirasil-dex-CB).
Table 2. Organocatalytic Reductive Amination of Aromatic
Ketones
Both these X-ray and calculated structures suggest that catalyst
5 should be generically selective for the reduction of iminium ions
derived from methyl ketones. To test this hypothesis, we next
examined the amination of para substituted aryldiketone 8. In accord
with our torsional-control hypothesis, diketone 8 underwent chemo-
selective reduction to yield monoaminated 9 with a 18:1 preference
for coupling at the methyl ketone site (eq 4, 85% yield, 96% ee).
a Absolute stereochemistry determined by chemical correlation. b Enan-
tiomeric excess determined by chiral GLC or SFC-HPLC analysis.
c Performed at 5 °C. d Reduction of preformed cyclic imine.
We next proposed to test this methyl versus ethyl chemoselec-
tivity in a productive fashion via the amination of butanone, a
prochiral ketone that contains both such alkyl substituents on the
same carbonyl (eq 5). In the event, the corresponding 2-amino
butane product 10 was furnished with notable levels of enantio-
control (83% ee), thereby revealing that ketones that contain dialkyl
substituents of similar steric and electronic character are viable
substrates for this process (e.g., A values: Me )1.7 vs Et ) 1.75).
Indeed, the capacity of catalyst 5 to selectively function with a
broad range of methyl alkyl substituted ketones has now been
established (Table 3, entries 1-4, 49-75% yield, 83-94% ee). In
alanine amino ester with excellent enantioselectivity (Table 2, entry
12, 82% yield, 97% ee). However, implementation of the corre-
sponding ethyl substituted imine 7 resulted in a dramatic decrease
in efficiency (82 vs 27% yield). Computational studies reveal that
this remarkable change in reaction rate as a function of alkyl
substituent likely arises from catalyst imposed torsional constraints
on substrate conformation. More specifically, imines that incorporate
a methyl group are predicted to undergo selective catalyst associa-
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C O M M U N I C A T I O N S
Table 3. Organocatalytic Reductive Amination of Alkyl-Alkyl
Ketones
simple fragment coupling has been accomplished with a wide range
of ketones in combination with aryl and heterocyclic amines. Further
mechanistic studies of this amination reaction will be reported
shortly.
Acknowledgment. Financial support was provided by the
NIHGMS (R01 GM66142-01) and kind gifts from Amgen and
Merck. This research was supported by a Marie Curie International
Fellowship (to R.I.S.) within the 6th European Community
Framework Programme. Joe Carpenter is thanked for catalyst
preparation.
Supporting Information Available: Experimental procedures,
structural proofs, and X-ray and spectral data. This material is available
free of charge via the Internet at http://pubs.acs.org.
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a Enantiomeric excess determined by chiral SFC-HPLC.
this context, it is important to underscore a key benefit of reductive
amination versus imine reduction. Specifically, imines derived from
alkyl-alkyl ketones are unstable to isolation, a fundamental
limitation that is comprehensively bypassed using direct reductive
amination.
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(17) Catalysts 1 and 3 were prepared using procedures outlined in refs 8 and
12. Catalyst 5 was first prepared and applied to this catalytic protocol on
October 13, 2004, to furnish the amine in Table 2, entry 1, in 94% ee.
(18) The crystallographic data have been deposited at the CCDC, 12 Union
Road, Cambridge, CB2 1EZ, UK, and copies can be obtain on request,
free of charge, by quoting the publication citation and the deposition
number 287655.
Last, a central tenet of this investigation was to develop an
enantioselective reductive amination that can be employed in
complex fragment couplings (eq 7). As revealed in Table 4, this
goal has now been accomplished using a variety of electronically
diverse aryl and heteroaromatic amines in combination with aryl
ketones (entries 1-5, 91-95% ee) as well as alkyl-alkyl carbonyls
(entry 6, 90% ee).
In summary, we have developed the first enantioselective
organocatalytic reductive amination. This mild and operationally
JA057222N
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