Chiral Proton Catalysis: A Catalytic Enantioselective Direct Aza-Henry Reaction

Article abstract of DOI:10.1021/ja031906i

Despite Nature's longstanding ability to use a proton, the most prevalent Lewis acid, to both activate and orient a substrate during an enantioselective reaction, this work represents the first example of this phenomenon outside of a protein. A chiral, no

Full text of DOI:10.1021/ja031906i

Published on Web 03/02/2004
Chiral Proton Catalysis: A Catalytic Enantioselective Direct Aza-Henry
Reaction
Benjamin M. Nugent, Ryan A. Yoder, and Jeffrey N. Johnston*
Department of Chemistry, Indiana UniVersity, 800 East Kirkwood AVenue, Bloomington, Indiana 47405
Received December 23, 2003; E-mail: jnjohnst@indiana.edu
Scheme 1
Enzymes, nucleic acids, and other chiral biopolymers are charged
with the responsibility to sustain life. To fulfill this mandate, a
straightforward strategy is necessary to effect the basic chemical
reactions that synthesize organic molecules, often in enantiomeri-
cally enriched form. The proton (H+) is arguably the most common
Lewis acid found in Nature and exists in two forms classified by
the type of hydrogen bond that results: polar covalent and polar
Table 1. Chiral Proton-Catalyzed Aza-Henry Reactionsa
ionic (Scheme 1).1 It is therefore not surprising that this functionality
is believed to play a key role by both activating and orienting
substrates for chemical reaction within, for example, a peptide
cavity.2 Nonenzymatic, synthetically useful enantioselectiVe trans-
formations utilizing polar covalent hydrogen bonds (eq 1, RXH is
an enantiomerically pure catalyst) have recently emerged,3,4 whereas
the analogous use of a polar ionic hydrogen bond (eq 2) has
remained elusive.5,6 The latter was generally believed unattainable
through the use of chiral small-molecule ligands for two reasons.
First, the spherical nature of the proton’s empty 1s orbital challenges
the typical sensibilities regarding the design of a stereoisomerically
discrete coordination complex. Second, this same feature has led
to the perception that the nucleus is substantially more promiscuous
than most other Lewis acids, leading to the kinetic argument that
attempts to implement the chiral complex would succumb to achiral
catalysis by solvent-coordinated Brønsted acid (eq 2).7
We report here a highly enantioselective chiral proton-catalyzed
aza-Henry reaction (eq 3).8,9 Neither Brønsted base additive or
preactivation of the nucleophile is necessary. The success of this
new Lewis acid catalyst demonstrates that intervention of the achiral
solvent catalyst pathway (eq 2) can be minimized or avoided
entirely.10
Guided by the prejudices outlined above, we assumed that a
potentially bidentate ligand would be an important design element.11
The BisAMidine ligand in 1 (HQuin-BAM) was therefore syn-
thesized as a single enantiomer from commercially available (+)-
trans-cyclohexane diamine and 2-chloroquinoline in 86% yield
using palladium catalysis.12 Formation of the corresponding 1:1
Brønsted acid salt (1) was then accomplished by the addition of
trifluoromethane sulfonic acid, delivering a white crystalline bench-
stable solid.
An initial screen of aldimine electrophiles revealed that tert-
butoxy carbonyl (Boc) Schiff bases provide the necessary combina-
tion of reactivity and enantioselection. Less than 5% of the â-amino
nitroalkane 3a is formed at -20 °C after 5 days. When the same
reaction is executed in the presence of 10 mol % HQuin-BAM
catalyst 1, secondary amine 3a is formed in 60% ee and 57% yield
(Table 1, entry 1). Subsequent samarium(II) iodide reduction
provided in 92% yield the R-enantiomer of the derived Boc-
protected Vic-diamine reported previously.13 This degree of rate
acceleration concomitant with enantioselection illustrates the central
role of the proton; addition of 10 mol % HQuin-BAM alone also
failed to accelerate the aza-Henry reaction beyond the (slow)
background rate. Enantioselection and reactivity were further
1
2
c
entry
R
R
% yield
drb
%eeb
1
2
3
4
5
6
7
8
9
10
H
H
H
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
57
61
65
69
53
59
51
62
50
60
-
60
82
95
59
81
82
89
82
84
90
p-NO2
m-NO2
H
p-CF3O
p-Cl
m-NO2
o-NO2
p-CF3
p-NO2
-
-
CH3
CH3
CH3
CH3
CH3
CH3
CH3
14:1
19:1
17:1
11:1
7:1
19:1
7:1
3j
a All reactions were 0.25 M in substrate. Absolute and relative config-
uration for 3a and 3d assigned by chemical correlation (see Supporting
Information). Remaining products assigned by analogy. b Diasteromeric
ratios determined by GC. Enantiomeric excess determined by HPLC using
a chiral stationary phase. c Isolated yield after chromatography.
improved by implementation of more electrophilic aldimine deriva-
tives 2b-c, delivering secondary amines 3b and 3c in 82 and 95%
ee, respectively (Table 1, entries 2-3).
The opportunity to simultaneously control absolute and relative
stereochemistry was afforded by the use of nitroethane as the
pronucleophile. Benzaldehyde Schiff base 2d delivered the derived
secondary amine in 59% ee (Table 1, entry 4). Assignment of the
product as the cis-diastereomer and (R)-absolute configuration at
the benzylic carbon was made after reduction and Boc-deprotection
to the cis Vic-diamine.14 Further improvement in enantioselection
was made possible again through the use of electron-deficient Schiff
bases. p-Trifluoromethoxy- and p-chloro-benzaldehyde Schiff bases
2e and 2f furnished their aza-Henry products in 81 and 82% ee,
respectively, and with high (17-19:1) diastereoselectivity (Table
1, entries 5-6). Nitrobenzaldehyde derivatives provided the second-
ary amines in 82-90% ee (Table 1, entries 7, 8, 10). Finally, the
9
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J. AM. CHEM. SOC. 2004, 126, 3418-3419
10.1021/ja031906i CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
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Speculation about the exact nature of the stereochemical-
determining catalyst-substrate complex would be premature at this
time. However, it is clear from these initial experiments that the
proton plays a key role in both substrate activation and orientation
leading to asymmetric induction. To this point, the pseudo-C2-
symmetric coordination complex 1 has provided an effective
prospecting tool,15 and determination of the actual reactive inter-
mediate remains the subject of investigation.
In conclusion, we have demonstrated the use of a chiral proton
(a polar ionic hydrogen bond) alone as both the means of activation
(function) and control (structure) of absolute and relative stereo-
chemistry. That the small-molecule BAM ligand effectively se-
questers the proton from solvent without reliance on an enveloping
peptidic superstructure suggests that chiral proton coordination
complexes may ultimately find broad application in enantioselective
Lewis acid catalysis. The ease with which a Brønsted acid can be
removed from the final reaction via a base wash, coupled with its
significantly lower cost and toxicity compared to traditional Lewis
acid complexes, should further stimulate the development of new
Brønsted acid-catalyzed reactions.16
Acknowledgment. J.N.J. dedicates this paper to Professors
Robert Johnson, Leo Paquette, and David Evans for their mentorship
and innumerable scientific contributions. Financial support was
provided by Indiana University and the Young Investigator Award
programs of Boehringer-Ingelheim, Amgen, Yamanouchi, and Eli
Lilly. We are grateful to undergraduate Travis R. Smith for
assistance with the preparation of several substrates.
(10) Gobel’s use of an axially chiral amidinium ion delivered up to a 57:43
ratio of enantiomers (14% ee) from a Diels-Alder cycloaddition, thereby
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Supporting Information Available: General experimental proce-
dures and analytical data for all new compounds (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
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