Stereoelectronic basis for the kinetic resolution of n-heterocycles with chiral acylating reagents

Article abstract of DOI:10.1002/chem.201402818

The kinetic resolution of N-heterocycles with chiral acylating agents reveals a previously unrecognized stereoelectronic effect in amine acylation. Combined with a new achiral hydroxamate, this effect makes possible the resolution of various N-heterocycles by using easily prepared reagents. A transition-state model to rationalize the stereochemical outcome of this kinetic resolution is also proposed.

Full text of DOI:10.1002/chem.201402818

DOI: 10.1002/chem.201402818
Communication
&
Synthetic Methods
Stereoelectronic Basis for the Kinetic Resolution of N-Heterocycles
with Chiral Acylating Reagents
Sheng-Ying Hsieh,[a] Benedikt Wanner,[a] Philip Wheeler,[b] Andrꢀ M. Beauchemin,[c]
Tomislav Rovis,*[b] and Jeffrey W. Bode*[a]
good selectivities (s) for the isolation of enantioenriched N-het-
Abstract: The kinetic resolution of N-heterocycles with
chiral acylating agents reveals a previously unrecognized
erocycles.[6]
The catalytic kinetic resolution of 3-benzylmorpholine 1 with
stereoelectronic effect in amine acylation. Combined with
a chiral hydroxamic acid proceeds with good selectivity (s=
a new achiral hydroxamate, this effect makes possible the
29).[5b] This is sufficient for isolating recovered starting material
resolution of various N-heterocycles by using easily pre-
in enantiopure form,[1b] but is not suitable for preparing the
pared reagents. A transition-state model to rationalize the
amides with sufficient enantioselectivity or for dynamic kinetic
stereochemical outcome of this kinetic resolution is also
resolutions. The use of other achiral acyl groups, such as 2-
proposed.
phenylacetate (2, Scheme 1) and 3-phenylpropanoate,[5c] gen-
The kinetic resolution of racemic small molecules remains a val-
uable method for the preparation of enantioenriched materi-
als, because it can always afford enantiopure materials by run-
ning the reactions to higher conversions.[1] The use of both
stoichiometric reagents and catalysts for the kinetic resolution
of alcohols, epoxides, and carboxylic acids is well established.[2]
In contrast, reagents for the kinetic resolution of amines—par-
ticularly secondary amines—are underdeveloped, and the state
of the art remains resolution by chromatography on chiral sup-
ports or diastereomeric salt formation and selective crystalliza-
tion.[3] The latter can be relatively effective, but often requires
the tedious screening of dozens or hundreds of salts and con-
ditions for successful resolution.[3a] Enzymatic resolutions are
highly developed for the resolution of alcohols, carboxylic
acids, and primary amines, but their utility for separating the
enantiomers of secondary amines is limited.[4]
We have recently documented a chiral hydroxamic acid ef-
fective for the resolution of piperidines, piperazines, diaze-
panes, morpholines, and tetrahydroisoquinolines.[5] The resolu-
tions, with either catalytic or stoichiometric amount of the
chiral hydroxamic acid, proceed at room temperature offering
Scheme 1. Kinetic resolution (KR) of amine 1 with stoichiometric acylating
agents.
erally gave somewhat inferior selectivities (s=13–25). To fur-
ther enhance the selectivity, we sought to identify an enantio-
merically enriched acyl group that could be combined with
the hydroxyamic acid catalyst, for example, a chiral acyl group
generated by the action of a N-heterocyclic carbene (NHC) cat-
alyst.[7] To establish whether such a strategy would be viable,
we chose first to examine the effect of readily available chiral
acyl groups on the kinetic resolution of secondary amines.
These studies revealed a surprising stereoelectronic effect on
the selectivity of amine acylation that has not been previously
documented, as well as an effective method for amine resolu-
tion using a chiral acyl donor.
[a] S.-Y. Hsieh, B. Wanner, Prof. Dr. J. W. Bode
Laboratorium fꢀr Organische Chemie
Department of Chemistry and Applied Biosciences, ETH Zꢀrich
Vladimir-Prelog-Weg 1–5, 8093 Zꢀrich (Switzerland)
Fax: (+41)44-633-1235
E-mail: bode@org.chem.ethz.ch
[b] Dr. P. Wheeler, Prof. Dr. T. Rovis
Department of Chemistry, Colorado State University
Fort Collins, Colorado 80523 (USA)
E-mail: rovis@lamar.colostate.edu
[c] Prof. Dr. A. M. Beauchemin
Department of Chemistry, University of Ottawa
Ottawa, Ontario K1N 6N5 (Canada)
For initial studies, we selected (S)-O-Me-mandelic acid, which
is readily prepared[8] or commercially available. The stoichio-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402818.
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metric reagent prepared with (4aR,9aS)-hydroxamic acid[5b]
gave a modest increase in selectivity (Table 1, entry 1). Surpris-
ingly, the reagent prepared from (R)-O-Me-mandelic acid and
epimerization during the amine resolutions, resulting in a
greater proportion of diastereomeric amide products. The poor
results from these examples may be an underlying reason for
the slow development of chiral reagents for amine resolution,
which despite some notable successes from Fu and co-work-
ers,[9] Krasnov and co-workers,[10] Mioskowski and co-workers,[11]
Seidel and co-workers,[12] Spivey and co-workers,[13] and
others,[14] has not kept pace with developments in other areas
of asymmetric synthesis.
Table 1. Screening of leaving groups on stoichiometric reagents.[a]
To differentiate the steric and electronic effects of the chiral
acyl group, we prepared a series of acyl donors by using the
achiral hydroxamic acid identified in Table 1 (entry 4). Replac-
ing of the OMe with an isosteric Et moiety led to almost com-
plete erosion of selectivity (Table 2, entry 2), suggesting an im-
[b]
Entry
1
Stoichiometric reagent
s
Conv. [%]
50
d.r.amide
e.r.amine
30
92:8
92:8
Table 2. Screening of chiral acyl groups (Acyl*) on stoichiometric re-
agents.[a]
2
3
1
9
50
32
50:50[c]
86:14[c]
50:50
67:33
Entry
1
Acyl*
s
Conv. [%]
40
d.r.amide
93:7
e.r.amine
79:21
4
5
24
8
40
40
93:7
79:21
73:27
24
84:16[c]
2
3
24
36
69:31
56:44
29:71
6
7
2
1
36
50
66:34[c]
50:50[c]
59:41
50:50
3[b]
11
12:88[c]
4
5
6
7
6
3
35
38
50
18
81:19
71:29
55:45
41:59
67:33
63:37
55:45
48:52
[a] Selectivity factor (s) and calculated conversion (conv.) were deter-
mined by Kagan’s equation (see Ref. [6]). [b] See the Supporting Informa-
tion for the determination of diastereomeric ratios (d.r.). [c] Epimerized
amide products were observed (<10% for entries 2, 3, and 5; >30% for
entries 6 and 7). See the Supporting Information for details.
1
À2[d]
the (4aR,9aS)-hydroxamic acid was completely unselective
(entry 2), prompting a further investigation into the nature of
the leaving group.
[a] Selectivity factor (s) and calculated conversion (conv.) were deter-
mined by Kagan’s equation (see Ref. [6]). [b] a-(R)-Fluoroacyl hydroxamate
(91% ee) was used. [c] See the Supporting Information for the determina-
tion of diastereomeric ratios. [d] Opposite relative diastereoinduction was
observed.
A series of activated (S)-mandelic acid reagents were pre-
pared, taking care to avoid epimerization in their formation.
The chiral acylating agents from achiral, cyclic hydroxamic
acids (Table 1, entries 3–5) were all effective for amine resolu-
tion. The bulky glycine derivative (Table 1, entry 4) gave a com-
parable selectivity to that of the chiral hydroxamic acid bearing
an achiral acyl group (s=24 vs. s=13–29).[5] The more
common activated carboxylates derived from N-hydroxysuccin-
imide (Table 1, entry 6) or imidazole (entry 7) were far less se-
lective. These reagents also suffered from a greater degree of
portant role for the electronegative substituent. Unfortunately,
the obvious substrate for probing this effect further, the re-
agent prepared from (S)-2-fluorophenylacetic acid, could not
be prepared in enantiopure form. Therefore, we compared hy-
drocinnamate esters with a-(R)-fluoro (Table 2, entry 3), (S)-me-
thoxy[15] (entry 4), (S)-azido[16] (entry 5), (S)-N-Cbz-[17] (entry 6),
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and (S)-N-phthaloyl[18] (entry 7) substituents. The fluorinated
compound (Table 2, entry 3) proved to be the most selective,
whereas the less electronegative amino acid derivative showed
no selectivity. These results point to a previously unexploited
stereoelectronic effect in diastereoselective acylations of chiral
amines.
The (S)-mandelic acid derived reagent 3 is suitable for the ki-
netic resolution of several classes of racemic N-heterocycles
(Table 3). Simply combining 3 and the amine in iPrOAc at room
Table 3. Kinetic resolutions using acyl hydroxamate 3.[a]
Scheme 2. Synthesis of acyl hydroxamate 3. DIC=N,N’-diisopropyl-carbodi-
imide.
[b]
Entry
1
Substrate
s
Conv. [%]
39
d.r.amide
e.r.amine
74:26
12
88:12[c]
2
3
22
24
43
40
92:8[c]
93:7
82:18
79:21
Figure 1. Proposed transition state model for kinetic resolution using 3. See
the Supporting Information for alternative approach trajectories.
4
5
27
18
38
36
94:6
77:23
74:26
92:8[c]
of amines with chiral hydroxamic acids implicate a hydrogen-
bonding interaction between the hydroxamate carbonyl and
the amine proton. This interaction constrains the number of
possible conformations to be considered, and the key alpha
stereocenter on the electrophile ensures the addition occurs
with high facial selectivity. The approach trajectory of the N-
heterocycle with an equatorial nitrogen lone pair minimizes
destabilizing steric interactions. The selectivity originates from
the ability of only one enantiomer to approach with minimal
destabilization due to its equatorial R group (Figure 1). Further
discussion and alternative representations are presented in the
Supporting Information.
[a] Selectivity factor (s) and calculated conversion (conv.) were deter-
mined by Kagan’s equation (see Ref. [6]). [b] See the Supporting Informa-
tion for the determination of diastereomeric ratios. [c] Epimerized amide
products were observed (<5%). See the Supporting Information for de-
tails.
temperature for 24 h gave good conversions and acceptable
selectivities for the resolution of 2-substituted piperidines
(Table 3, entries 1 and 2), morpholine (entry 3), diazepanone
(entry 4), and tetrahydroisoquinoline (entry 5). However, the se-
lectivities in most cases were inferior to those obtained under
catalytic conditions using a chiral hydroxamic acid derived
from either enantiomer of cis-(1,2)-aminoindanol.[5a] Neverthe-
less, the low cost of (S)-mandelic acid and the ease of prepar-
ing the achiral hydroxamic acid may make these stoichiometric
reagents preferable for certain applications (Scheme 2). In addi-
tion, the high selectivities and modular nature of the synthesis
bodes well for future developments.
In summary, we have developed a chiral acyl hydroxamate
reagent for kinetic resolutions of N-heterocycles. Optimization
of reagent structure and a survey of acyl donors revealed that
highly selective reactions can result from the stereoelectronic
preferences of a proximal alpha stereocenter. This feature had
not been previously exploited for enantioselective reactions of
amines, and led to the development of a simple, highly selec-
tive reagent (s=12 to 27) derived from (S)-mandelic acid. A
model featuring this key stereoelectronic effect also predicts
the stereochemical outcome. Collectively, this data provides
crucial understanding to further improve selectivities and
expand applicability of kinetic resolutions of amines.
The most surprising aspect of this work is the identification
of this unexploited stereoelectronic effect. Our stereochemical
model to rationalize the selectivities obtained is presented in
Figure 1. Ongoing mechanistic studies on the kinetic resolution
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Communication
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This work was supported by the European Research Council
(ERC Starting Grant No. 306793 - CASAA) and the National In-
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Keywords: hydroxamic acid
·
kinetic resolution
·
N-
heterocycles · stereoelectronic effects · synthetic methods
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Published online on && &&, 0000
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COMMUNICATION
&
Synthetic Methods
S.-Y. Hsieh, B. Wanner, P. Wheeler,
A. M. Beauchemin, T. Rovis,* J. W. Bode*
&& – &&
Stereoelectronic Basis for the Kinetic
Resolution of N-Heterocycles with
Chiral Acylating Reagents
Look both ways! Esters of chiral acids
and achiral hydroxyamic acids are just
as effective for the kinetic resolution of
N-heterocycles as those derived from
a chiral hydroxyamic acid and achiral
acids. The use of an inexpensive chiral
acylating agent highlights the unique
properties of hydroxyamic acids as leav-
ing groups and reveals a previously un-
recognized stereoelectronic effect in
amine acylation (see scheme).
Chem. Eur. J. 2014, 20, 1 – 5
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