Expanded substrate scope and catalyst optimization for the catalytic kinetic resolution of N-heterocycles

Article abstract of DOI:10.1039/c2cc34907h

The scope, reactivity, and selectivity of the chiral hydroxamic acid-catalyzed kinetic resolution of chiral amines are improved by a new catalyst structure and a more environmentally friendly reaction protocol. In addition to increasing selectivity across all substrates, these conditions make possible the resolution of N-heterocycles containing lactams or other basic functional groups that can inhibit the catalyst.

Full text of DOI:10.1039/c2cc34907h

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COMMUNICATION
Expanded substrate scope and catalyst optimization for the catalytic
kinetic resolution of N-heterocyclesw
Sheng-Ying Hsieh, Michael Binanzer, Imants Kreituss and Jeffrey W. Bode*
Received 9th July 2012, Accepted 13th July 2012
DOI: 10.1039/c2cc34907h
The scope, reactivity, and selectivity of the chiral hydroxamic
acid-catalyzed kinetic resolution of chiral amines are improved
by a new catalyst structure and a more environmentally friendly
reaction protocol. In addition to increasing selectivity across all
substrates, these conditions make possible the resolution of
N-heterocycles containing lactams or other basic functional
groups that can inhibit the catalyst.
that increase selectivity and make possible resolutions of
substrates unreactive under our prior conditions (Scheme 1).
Chiral hydroxamic acid catalyst 1 is prepared from (1R, 2S)-
aminoindanol in two steps.9,12 Our first task was therefore to
identify a variant of this catalyst that improved the selectivity
of substrates such as 2-ethyl piperidine. Substitution of the
aromatic ring provided the most easily executed route to
catalyst tuning. Using standard protocols we prepared 6-bromo,
6,7-dibromo, and 6-nitro-substituted variants 2–4 (Table 1).13
A different route, beginning from the amino indanol, was used to
prepare N-hydroxycarbamate 5.14 Upon screening these catalysts
for the resolution of 2-ethyl piperidine (Table 1), we were pleased
to find that 6-bromo-substituted catalyst 2 led to a marked
increase in selectivity.
Enantiopure amines are important components of pharmaceuticals
and other biologically active molecules.1 Synthetic methods for the
preparation of enantioenriched primary amines include nucleophilic
addition to substrates bearing a chiral auxiliary,2 asymmetric
hydroamination,3 asymmetric hydrogenation,4 and kinetic
resolution.5 Acyclic chiral secondary amines can often be
prepared from the corresponding primary amines by alkylation.
In contrast, enantiopure cyclic secondary amines such as
piperidines, morpholines, diazepanes and piperazines are often
difficult to obtain by enantioselective synthesis;6 classical
resolution by diastereomeric salt formation and chromatography
on chiral supports remain the state of the art.7,8 In seeking to
address this well-known deficiency in asymmetric synthesis, we
have developed a new catalytic kinetic resolution of N-heterocycles
by the combination of a chiral hydroxamic acid acylation catalyst
coupled with the catalytic generation of an acylating agent with an
achiral N-heterocyclic carbene.9
Our original conditions were not suitable for the resolution of
substrates bearing lactam or N-carbamate groups. Diazepanones
and others (6–8, Scheme 2a and b) showed poor reactivity. We
speculated that these substrates form hydrogen bonds to the
hydroxamic acid, thereby deactivating the catalyst. To test this
hypothesis we conducted the resolution of 2-methylpiperidine –
an excellent substrate under normal conditions – in the presence
of 1 equiv. of d-valerolactam (9, Scheme 2c). We observed
significantly lower conversion and reaction rate, pointing to
an unproductive interaction between the chiral catalyst and
the added lactam. NMR titration of hydroxamic acid 1 with
d-valerolactam 9 proved informative. Upon addition of 9 to a
CDCl3 solution of 1, we observed a significant change of the
chemical shift of the OH proton of the hydroxamic acid in the
NMR spectra, indicative of a hydrogen bonding interaction of
During the course of our studies, we identified three limitations
of our original conditions to the resolution of chiral N-heterocycles.
First, some substrates gave unexpectedly poor selectivity. Although
enantiopure recovered starting material can be obtained from any
selectivity level, S-factors of 20 or higher are desired for practical
use.11 Some of our most important substrates, for example 2-ethyl
piperidine (S = 12), fell slightly short of this goal. Second,
N-heterocycles containing lactam substructures or pendant amines
with carbamate protecting groups or bulky substituents gave poor
conversions. Third, the use of chlorinated solvents and relatively
high catalyst loadings diminished the appeal of these conditions. In
this communication we report optimized catalyst 2 and improved
reaction conditions (0.2 M iPrOAc, K2CO3, 5 mol% chiral catalyst)
Laboratorium fur Organische Chemie, Department of Chemistry and
¨
¨
Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
¨
E-mail: bode@org.chem.ethz.ch; Web: http://www.bode.ethz.ch
w Electronic supplementary information (ESI) available: Experimental
data, NMR titration, and NMR spectra. See DOI: 10.1039/c2cc34907h
Scheme 1 New hydroxamic acid catalyst 2 and reaction conditions
for catalytic kinetic resolution of secondary cyclic amines.
c
8892 Chem. Commun., 2012, 48, 8892–8894
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Table 1 Screening of catalysts 1–5 in CH2Cl2 vs. iPrOAca
reaction workup; the DBU used in our original procedure was
sometimes difficult to separate from the recovered, enantio-
enriched amine. The improved reactivity offered by Br-substi-
tuted catalyst 2 and these alternative reaction conditions also
allowed us to reduce the loading of chiral hydroxamic acid
catalyst 2 to 5 mol% (Table 1, entry 8).
These new conditions were applied to the resolution of a
number of valuable amines that were unreactive or not effectively
resolved with our original procedure (Table 2). Most importantly,
the use of iPrOAc allowed us to resolve substrates containing a
lactam, including 3-alkyl-piperazinones (entry 1) and 7-substituted
1,4-diazepanones (entries 2–4). Furthermore, it also significantly
improved both the reactivity and selectivity of piperazines bearing
N-carbamate protecting groups. These valuable substrates had
proven to be problematic under our original conditions.
We have also evaluated these improved conditions for the
resolution of piperidines, morpholines, tetrahydroisoquinolines,
and azepanes, including both previously tested substrates
as well as new examples (Table 3). In comparison to our
original conditions, we obtained better selectivity in all cases
examined.
Entry Condition Catalyst Sb
Conv.c (%) er amined er amided
1
2
3
4
5
6
7
8
A
A
A
A
A
1
2
3
4
5
12
25
9
12
1
16
>23 59
21 57
53
52
51
47
20
37
88 : 12
93 : 7
83 : 17
82 : 18
51 : 49
74 : 26
84 : 16
90 : 10
82 : 18
86 : 14
54 : 46
91 : 9
B, CH3CN 2
B, THF
B, iPrOAc
2
2
>99 : 1 84 : 16
97 : 3 86 : 14
Table 2 Kinetic resolutions of substrates containing lactam and
carbamate functional groups
a
RMesClO4
=
2-(2,4,6-trimethylphenyl)-2,5,6,7-tetrahydro-
b
pyrrolo[2,1-c] [1,2,4]triazol-4-ylium perchlorate. Calculated selectivity.10
c
d
Calculated conversion. Determined by SFC on a chiral support.
Conv.b er aminec
(%)
er amidec
Entry Substrate
Sa
9
yieldd (%)
yieldd (%)
1e
58
90 : 10 (42) 79 : 21 (56)
2
3
22
54
95 : 5 (43)
88 : 12 (54)
>20 64
>99 : 1 (34) 78 : 22 (48)
Scheme 2 (a) Substrates that show good conversion and selectivity in
CH2Cl2. (b) Substrates with lactam or carbamate substructures that
show low conversion in CH2Cl2. (c) The addition of 1 equiv. of
d-valerolactam inhibits the catalytic amine resolution.
4e
30
41
81 : 19 (39) 94 : 6 (40)
the lactam with the cyclic hydroxamic acid 1. Standard methods
were used to calculate an association constant of 100 MÀ1 15
.
This finding suggested that a more polar solvent could
disrupt this interaction and free the hydroxamic acid to
participate in the synergistic catalytic cycle. This theory was
tested by performing the same titration experiment in CD3CN.
We observed a linear relationship indicating very little hydrogen
bonding interaction and no association was detected within
experimental error.
5e
23
21
45
57
84 : 16 (55) 92 : 8 (44)
6
97 : 3 (35)
86 : 14 (21)
A screen of alternative solvents for the catalytic kinetic
resolution revealed iPrOAc as a suitable alternative (Table 1,
entries 6–8). Furthermore, we found that these conditions
allowed the use of K2CO3 as the base, which simplified the
a
b
c
Calculated selectivity. Calculated conversion. Determined by
supercritical fluid chromatography or HPLC on a chiral support. d Isolated
yield after column chromatography. e 10 mol% hydroxamic acid.
c
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Table 3 Kinetic resolution of piperpidines, piperazines, morpholines,
isoquinolines, and azepanes with 5 mol% 2 in iPrOAca
Kind gifts of racemic amines were made by Bioblocks, Inc. and
Sigma-Aldrich.
Conv.c er amined
(%)
er amided
Entry Substrate
Sb
yielde (%)
yielde (%)
Notes and references
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71 : 29 (61)
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9
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55
46
51
46
99 : 1 (27)
87 : 13 (45)
98 : 2 (36)
90 : 10 (51)
93 : 7 (43)
97 : 3 (51)
29
127
16
9
83 : 17 (45)
79 : 21 (24)
89 : 11 (43)
84 : 16 (35)
10
46
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In summary, we have identified improved conditions and
catalysts for the catalytic kinetic resolution of cyclic secondary
amines. A remote substituent on the chiral hydroxamic acid
catalyst improved selectivities of 6- and 7-membered N-hetero-
cycles in the range needed for practical resolutions and the use
of iPrOAc allowed us to expand the substrate scope to
piperazinones and diazepanones, which were unreactive under
our prior conditions.
This work was supported by ETH-Zurich. We are grateful to
Yuta Murakami and Yuma Umezaki for preliminary studies.
15 Y. Cao, X. Xiao, R. Lu and Q. Guo, J. Mol. Struct., 2003, 660, 73–80.
c
8894 Chem. Commun., 2012, 48, 8892–8894
This journal is The Royal Society of Chemistry 2012