Catalytic Kinetic Resolution of Disubstituted Piperidines by Enantioselective Acylation: Synthetic Utility and Mechanistic Insights

Article abstract of DOI:10.1021/jacs.5b07201

The catalytic kinetic resolution of cyclic amines with achiral N-heterocyclic carbenes and chiral hydroxamic acids has emerged as a promising method to obtain enantio-enriched amines with high selectivity factors. In this report, we describe the catalytic kinetic resolution of disubstituted piperdines with practical selectivity factors (s, up to 52) in which we uncovered an unexpected and pronounced conformational effect resulting in disparate reactivity and selectivity between the cis- and trans-substituted piperidine isomers. Detailed experimental and computational studies of the kinetic resolution of various disubstituted piperidines revealed a strong preference for the acylation of conformers in which the α-substituent occupies the axial position. This work provides further experimental and computational support for the concerted 7-member transition state model for acyl transfer reagents and expands the scope and functional group tolerance of the secondary amine kinetic resolution.

Full text of DOI:10.1021/jacs.5b07201

Article
pubs.acs.org/JACS
Catalytic Kinetic Resolution of Disubstituted Piperidines by
Enantioselective Acylation: Synthetic Utility and Mechanistic Insights
Benedikt Wanner,† Imants Kreituss,† Osvaldo Gutierrez,‡ Marisa C. Kozlowski,*,‡ and Jeffrey W. Bode*,†
†Laboratorium fur Organische Chemie, Department of Chemistry and Applied Biosciences, ETH-Zurich, 8093 Zurich, Switzerland
̈
̈
̈
‡Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, Pennsylvania 19104,
United States
S
* Supporting Information
ABSTRACT: The catalytic kinetic resolution of cyclic amines
with achiral N-heterocyclic carbenes and chiral hydroxamic
acids has emerged as a promising method to obtain enantio-
enriched amines with high selectivity factors. In this report, we
describe the catalytic kinetic resolution of disubstituted
piperdines with practical selectivity factors (s, up to 52) in
which we uncovered an unexpected and pronounced
conformational effect resulting in disparate reactivity and
selectivity between the cis- and trans-substituted piperidine
isomers. Detailed experimental and computational studies of
the kinetic resolution of various disubstituted piperidines
revealed a strong preference for the acylation of conformers in
which the α-substituent occupies the axial position. This work
provides further experimental and computational support for the concerted 7-member transition state model for acyl transfer
reagents and expands the scope and functional group tolerance of the secondary amine kinetic resolution.
of a chiral hydroxamic acid, employed in either catalytic or
stoichiometric amounts, as highly enantio- and chemoselective
acylating agent, which operates by a unique mechanism
involving concerted acyl and proton transfer via a seven-
member transition state.11,12 To date, our studies on the kinetic
resolution of chiral N-heterocycles using chiral hydroxamic
acids have been limited to mono-, α-substituted N-heterocyclic
substrates. In contrast to the resolution of α-monosubstituted
N-heterocycles, the resolution of disubstituted piperidines
requires an enantioselective catalyst that is not affected by the
additional ring substituents (Scheme 1).
In this report, we examine the reactivity and selectivity of
disubstituted piperidines in the kinetic resolution by means of
enantioselective acylation with a chiral hydroxamic acid. Kinetic
resolution studies and density functional theory (DFT)
calculations exposed remarkable conformational preferences
in both reactivity and selectivity, revealing a requirement for
axial-α substitution on the reactive form of the N-heterocycle
for effective resolution. This preference extends even to
substitution patterns where the substituents must occupy bis-
axial positions. This work provides, (1) access to valuable
enantioenriched disubstituted piperidines, (2) general guide-
lines for selecting suitable N-heterocycles as substrates for the
kinetic resolution via chiral hydroxamic acids, and (3)
affirmation of the transition state model involving a high
INTRODUCTION
■
Disubstituted piperidines are increasingly attractive platforms
for drug development, as the precise placement of substituents
about the basic, low-molecular weight, three-dimensional
scaffold is ideally suited for structure−activity relationship
studies.1 Although the synthesis of such saturated N-hetero-
cycles remains challenging,2 recent advances including diaster-
eoselective metalation/cross-coupling,3 conjugate additions of
dihydropyridinones,4 hydrogenation of disubstituted pyridines,5
and cyclization methods6 are bringing these once exotic
building blocks into the mainstream. Unfortunately, most of
the available methods for the preparation of multisubstituted
N-heterocycles deliver racemic products, and prospects for
enantioselective approaches to many substitution patterns are
limited.7
For such challenging cases, kinetic resolution can be an
efficient and powerful alternative to enantioselective synthesis
of chiral N-heterocycles.8 Although kinetic resolution has the
disadvantage of a maximum yield of 50% of a desired
stereoisomer, for early stage applications it can be a reliable,
effective, and easily implemented tool for the production of
enantiopure material. Provided that selectivity factors (s)
greater than 20 can be obtained, kinetic resolution can be
used to separate enantiomers with acceptable yield and
outstanding enantiopurity.9
In 2011, our group reported a new approach to the catalytic,
kinetic resolution of saturated N-heterocycles consisting of two
catalysts working synergistically.10 Our key advance was the use
Received: July 10, 2015
© XXXX American Chemical Society
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Scheme 1. Four Possible Positional Isomers of Disubstituted
Piperidines That Serve as Targets for Our Study
Table 1. Catalytic Kinetic Resolution of Disubstituted
Piperidines
energy conformation of the substrate that we had previously
developed on the basis of DFT calculations.
RESULTS AND DISCUSSION
■
As depicted in Scheme 1, there are four types of disubstituted
piperidines that could serve as target substrates for our study.
Piperidines without α-substituents, such as 3,5-disubstituted
piperidines, undergo acylation in an unselective manner.
Further, 2,6-disubstituted substrates were found to be
unreactive and were excluded from further studies.
Our work therefore targeted the six isomers arising from 2,3-,
2,4-, and 2,5-disubstitution of piperidine, with cis and trans
stereoisomers in each case. Further disubstituted compounds
with an exocyclic 4-methylene group were also prepared and
evaluated. The results of the catalytic kinetic resolution are
summarized in Table 1. Surprisingly, we observed substantial
differences in the reactivity and selectivity between the cis
isomer and trans isomer of the otherwise identical positional
isomers. For the 2,3-disubstituted piperidines (Table 1, entries
1 and 2, entries 7 and 8) and 2,5-disubstituted piperidines
(Table 1, entries 5 and 6) the cis isomer underwent faster
reactions with higher selectivity, while the trans isomer gave rise
to superior outcomes for the 2,4-disubstituted compounds
(Table 1, entries 3 and 4). The decahydroquinoline isomers
were particularly interesting, as the trans isomer is conforma-
tionally locked. These results already hinted at strict stereo-
chemical requirements for effective enantioselective acylation.
In light of these initially confusing results, we undertook an
extensive study to assess the role of the positional isomers and
their stereoisomers. Our goal was to reliably predict whether a
given substrate would undergo a selective kinetic resolution.
We elected to evaluate at least three substrate pairs (cis/trans)
for each of the three positional isomers, giving 20 substrates in
total. Considerations for compound selection included
synthetic accessibility, the presence of groups for further
functionalization of the products, and ready access to
diastereomerically pure forms of the targets (see Supporting
Information for experimental procedures and characterization
data).
a
b
c
Calculated selectivity.15 Calculated conversion.15 Reaction time
d
until the α-hydroxyenone is fully consumed. Determined by SFC or
HPLC on a chiral support. Isolated as the Cbz-derivative. Yield after
column chromatography. Opposite sense of induction observed.
RMesClO4 = (2,4,6-trimethylphenyl)-2,5,6,7-tetrahydro-pyrrolo[2,1-c]
e
f
[1,2,4]triazol-4-ylium perchlorate.
disubstitution series (Table 2). The data presented in Table 1
implied that substrates with a cis configuration undergo faster
reaction with much higher selectivities than those observed for
the trans isomers. With cis-2-phenylpiperidin-3-ol (Table 2,
entry 1) an s-factor of 24 and a conversion of 33% could be
obtained after 48 h, whereas the trans diastereomer (Table 2,
entry 2) reached only 14% conversion after 72 h with
essentially no selectivity. This trend could also be observed
To rule out selectivity arising from the NHC-catalyst in the
kinetic resolution, we used our previously reported stoichio-
metric variant in the resolution of these N-heterocycles.10
Slightly higher reaction rates and selectivities are observed with
this reagent and a recyclable, resin-supported variant makes it
an attractive option for practical amine resolution.13 We first
examined the kinetic resolution of the compounds in the 2,3-
B
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Table 2. Kinetic Resolution of 2,3-Disubstituted Piperidines
with Stoichiometric Reagent 1
Table 3. Kinetic Resolution of 2,4-Disubstituted Piperidines
with Stoichiometric Reagent 1
a
b
c
Calculated selectivity. Calculated conversion. Reaction time until
d
stoichiometric reagent is fully consumed. Determined by SFC or
HPLC on a chiral support. Isolated as the Cbz-derivative. Yield after
column chromatography. Stochiometric reagent 1 (0.6 equiv) was
used. Opposite sense of induction observed.
e
f
a
b
c
Calculated selectivity. Calculated conversion. Reaction time until
g
d
stoichiometric reagent is fully consumed. Determined by SFC or
HPLC on a chiral support. Isolated as the Cbz-derivative. Yield after
column chromatography. Stochiometric reagent 1 (0.6 equiv) was
e
f
for the other two sets of substrates (Table 2, entries 3 and 4,
entries 5 and 6). Decahydroquinolines showed a similar
behavior in terms of reaction rate, although acceptable
selectivity was obtain in both cases. In the resolution of cis-
decahydroquinoline (Table 2, entry 7), 65% conversion was
obtained after 15 h, whereas the conformationally locked trans-
decahydroquinoline (Table 2, entry 8) reacted much slower.
Notably, the opposite sense of induction was observed with this
substrate, which contradicted a simple stereochemical model
based only on the stereochemistry of the acyl transfer reagent
(vide infra). The kinetic resolution reactions were stopped once
the stoichiometric reagent was fully consumed.14
For the 2,4-disubstituted piperidines (Table 3), the trend was
reversed in comparison to that observed for the 2,3-
disubstituted examples in Table 2. For this series, the cis
diastereomers exhibit poor selectivities (s = 3−7) and low
reactivity with reaction times between 72 and 120 h (Table 3,
entries 1, 3, and 5). In contrast, the trans diastereomers reached
full conversion in 20 h or less with high selectivities (s = 10−
29) (Table 3, entries 2, 4, and 6).
used.
corresponding trans diastereomers. The biggest contrast with
regards to s factors can be noticed in entry 5; for cis-6-
propylpiperidin-3-ol an s factor of 52 was obtained while the
trans isomer (Table 4, entry 6) afforded an s factor of only 4.
Such large differences in selectivity were not evident in entries
1−4; however, the data supports the conjecture that cis isomers
in this series are superior to the trans isomers. These substrates
also demonstrate the chemoselectivity of the kinetic resolution
for N-heterocycles bearing a variety of functional groups
suitable for further functionalization.
The divergent reactivity of the diastereomeric pairs in the
different series can be rationalized on the basis of our recent
DFT calculations of the transition states of α-methylpiperidine
reacting with the chiral acylating agent.12 These studies
concluded that acylation occurred via a concerted seven-
membered transition state with concomitant proton transfer
guided by the hydroxamic acid and with the α-substituent
placed in the axial position. In contrast, other work from our
group on the resolution of morpholines with stoichiometric
chiral acyl donors and achiral hydroxamic acids was most
consistent with a stereochemical model featuring an equatorial
In the case of the 2,5-disubstituted piperidines (Table 4) we
observed a similar trend as with the 2,3-disubstituted substrates.
Namely, higher s-factors were observed for the cis diaster-
eomers as well as higher reaction rates compared to the
C
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a
Table 4. Kinetic Resolution of 2,5-Disubstituted Piperidines
with Stoichiometric Reagent 1
Scheme 2. Relative Acyl Transfer Reaction Barriers
a
Relative acyl transfer reaction barriers (free energies are in kcal/mol;
gas phase energetics calculated using B3LYP/6-31G(d,p)//(in
parentheses IEPCM-CH2Cl2-M06-2X/6-311+G(d,p)) for the compet-
ing diastereomeric transtion states between cis- and trans-2,3-dimethyl
substituted piperidines and the acyl transfer agent.
a
b
c
Calculated selectivity. Calculated conversion. Reaction time until
d
stoichiometric reagent is fully consumed. Determined by SFC or
HPLC on a chiral support. Isolated as the Cbz-derivative. Yield after
column chromatography.
e
faster rates and superior s factors (s = up to 24) in comparison
to the trans 2,3-disubstituted piperidines. For example, the
lowest transition state free energy for the II-cis (25.8 kcal/mol
gas phase) is approximately 3 kcal/mol lower in energy than
the lowest for II-trans (29.1 kcal/mol gas phase), which is
consistent with the relative rates of these two amine
diastereomers.
substituent of a morpholine.16 However, no computational
studies were performed on this system and significant
conformational differences between morpholine and piper-
idines can be expected. Both models suggest that the
stereoselective step involves a seven-membered transition
state with the lone pair of the nitrogen in the equatorial
position. This mechanism of acyl transfer was found to be
general for a variety of widely used acyl transfer reagents
including N-hydroxysuccinimide, and HOAt.
To reconcile these two models with the results obtained for
the resolution of disubstituted piperidines, we undertook
detailed DFT studies on the relevant transition states using
the cis and trans geometric isomers of 2,3-dimethylpiperidine as
a model system and the chiral hydroxamic acid.17 All
calculations were carried out using the same computational
methods previously employed in related systems using
Gaussian 09.18 Structures were optimized with B3LYP/6-
31G(d).19,20 Single-point energy calculations in the condensed
phase (CH2Cl2; ε = 8.93) were undertaken using the IEPCM
solvation model with M06-2X/6-311+G(d,p).21 Scheme 2
shows the lowest energy transition states for acyl transfer to
each enantiomer of cis- and trans-2,3-dimethylpiperidine. As
anticipated from our previous work, the concerted seven-
membered transition states feature an intramolecular proton
shuttle between the secondary amine and the hydroxamate
carbonyl. The calculations are in agreement with experimental
rates and selectivity trends listed in Table 2 (entries 1−6) in
which the cis 2,3-disubstituted piperidines showed significantly
This finding is in line with our postulate that the lower
energy transition states for acyl transfer feature an axial α-
substituent, which requires the trans-2,3-dimethylpiperidine to
adopt an unfavorable diaxial conformation. In contrast, the
chair conformation of the cis-2,3-dimethylpiperidine with an α-
axial substituent is the preferred ground state conformation.
Further, our calculations correctly predict the fastest reacting
enantiomer via II-trans-TS and II-cis-TS, respectively. In
agreement with experiment, the quantum mechanical calcu-
lations indicate a larger gap between the cis-1,2-disubsituted
systems (here modeled as 2,3-dimethylpiperidine II-cis and ent-
II-cis) than the trans-1,2-disubsituted systems, which reflects
the significant difference in selectivity between cis and trans
diastereomers.22 Notably, the lowest energy diastereomeric
transition states place the α-substituent away from both the
aromatic ring of the acyl transfer agent and the acyl chain.
Exhaustive conformational analysis, including other chair
conformations, revealed that all other transition states are
much higher in energy (see Figure 1 and Supporting
Information). For kinetic resolution, the energy difference
between the diastereomeric acylation transition states deter-
mines the selectivity. As shown in Figure 1, the significant
energy difference (3.7 kcal/mol, s = 19−24) between II-cis-TS
and ent-II-cis-TS arises from the additional unfavorable gauche
D
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Figure 1. Proposed reaction pathways for possible conformers/enantiomers in the kinetic resolution. Relative acyl transfer reaction barriers (free
energies are in kcal/mol; gas phase energetics calculated using B3LYP/6-31G(d,p)//(in parentheses IEPCM-CH2Cl2-M06-2X/6-311+G(d,p)) for
the competing diastereomeric transtion states between cis and trans 2,3- dimethyl substituted piperidines and the acyl transfer agent.
interactions between the α-substituent in the equatorial
position and the carbonyl group. In addition, ent-II-cis-TS
has a further interaction between the axial β-methyl group and
the hydroxamate carbonyl.
In contrast, the energy difference between II-trans-TS and
ent-II-trans-TS is small at 0.5 kcal/mol, which is consistent
with the poor s factors (s = 1−4) observed for the trans
substituted systems. It is remarkable, however, that the
preferred conformation for the lowest energy transition state
is the trans-2,3-bis-axial, which demonstrates again the strong
preference for α-axial substituents in the acylation step and
offers an excellent example of the Curtin-Hammett principle
(Figure 1, bottom). The dimethyl groups are in the axial
position in II-trans-TS and in the equatorial position in ent-II-
trans-TS; in this case, the additional 1,3-diaxial interactions in
II-trans-TS raise its energy leading to a smaller energy gap
between the two enantiomers and smaller selectivity values.
The disparate results seen for the decahydroquinolines serve
to further confirm this model. The trans-decahydroquinoline
leads to the opposite sense of induction relative to the cis-
decahydroquinoline even though the same configuration of the
chiral acylating reagent is employed. Since the trans-
decahydroquinoline cannot react in the conformation where
the α-substituent is axial, the only transition states that are
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acessible have the α-substituent in the equatorial position
(Figure 1, lower right). When only these two transition states
are considered, selectivity is expected for the opposite
enantiomer owing to the large calculated energy gap. Further,
the reaction rate of trans-decahydroquinoline is expected to be
slower, as observed experimentally, since the overall energy of
this pathway is higher.
The same results can be applied to 2,5-disubstituted
piperidines. Just as with the 2,3-disubstituted compounds, the
cis diastereomer consists of two conformers that differ only
slightly in energy, whereas the trans diastereomer exists
primarily in the diequatorial conformer rather than the higher
energy diaxial conformation. An analogous situation occurs for
the 2,4-disubstituted compounds; however, it is the trans
isomer that always has one axial substituent in the lowest
energy conformations, and is more selective. The cis-2,4-
disubstituted isomers, in contrast, exist almost exclusively in the
more favorable diequatorial conformation and give rise to lower
selectivity.
This analysis suggests that disubstituted piperdines with a
single chiral center and no large conformational preferences
between the axial and equatorial α-substituents should be good
substrates for the resolution. This hypothesis is confirmed by
the excellent results obtained with substrates bearing an
exocyclic 4-methylene and a single α-substituent (Table 5,
entries 1−3). In addition 2,4,4-trisubstituted piperidines
containing a cyclic ketal were also resolved with modest
selectivity (Table 5, entries 4 and 5). All five substrates
evaluated show fast reaction rates and useful selectivity,
indicating no adverse effect on the resolution of substrates
containing additional achiral substitution. The alkene or
protected carbonyl in the products provides a means for
postresolution derivatization.
In summary we have examined the kinetic resolution of
disubstituted piperidines using a chiral hydroxamic acid catalyst
and its corresponding stoichiometric reagent. For most cases,
synthetically useful relative rates and outstanding functional
group tolerance were observed. The exceptionsstereo-
isomeric substrates that gave poor reactivity and selectivity
revealed a pronounced conformational preference in which the
lowest energy transition states require that the α-substituent
populates the axial position. This conjecture was fully
supported by DFT calculations on the transition states for all
of the relevant stereoisomers and ring conformations. These
findings rationalized the initially unexpected differences in
reactivity and selectivity between cis and trans stereoisomers
and strengthen our stereochemical model.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b07201.
■
S
Experimental procedures and spectroscopic data for all
new compounds. Transition state structures of all
minimized TSs (PDF)
Table 5. Kinetic Resolution of 2,4,4-Trisubstituted
Piperidines with Stoichiometric Reagent 1
AUTHOR INFORMATION
■
Corresponding Authors
*bode@org.chem.ethz.ch
*marisa@sas.upenn.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the European Research Council
(ERC Starting Grant No. 306793-CASAA) and National
Institutes of Health (GM-112684 to M.C.K.) and the National
Science Foundation (CHE1464778 to M.C.K.). Computational
support was provided by XSEDE on SDSC Gordon (TG-
CHE120052). We thank LOC MS Service (ETH Zurich) for
̈
analyses and Dr. Nils Trapp and Dr. Bernd Schweizer for the
acquisition of X-ray structures. We are also grateful to Dr.
Kimberly Geoghegan, Sheng-Ying Hsieh, and Dr. Hidetoshi
Noda for helpful discussions.
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(14) For the purposes of method development and study, we
performed the kinetic resolutions under conditions that allow for
accurate calculations of the relative rates. At longer reaction times, the
hydroxyenone and stochiometric reagent can undergo side reactions.
This protocol explains the low conversion even with full consumption
of the reagent with slow-reacting substrates. For preparative work, the
resolutions are allowed to proceed to higher conversion, which affords
virtually enantiopure recovered amines. As a guideline, s = 20 can
deliver > 99% ee at 62% conversion. See Vedejs, E.; Jure, M. Angew.
Chem. 2005, 117, 4040−4069; Angew. Chem., Int. Ed. 2005, 44, 3974−
4001 for a discussion.
(15) Calculated according to: Kagan, H. B.; Fiaud, J. C. Top.
Stereochem. 1988, 18, 249−330.
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(17) All calculations were carried out using Gaussian 09, revision
D.01.
(18) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci,
B.; Petersson, G. A. et al. Gaussian 09, revision D.01; Gaussian, Inc.:
Wallingford CT, 2013.
G
DOI: 10.1021/jacs.5b07201
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX