General Light-Mediated, Highly Diastereoselective Piperidine Epimerization: From Most Accessible to Most Stable Stereoisomer

Article abstract of DOI:10.1021/jacs.0c11911

We report a combined photocatalytic and hydrogen atom transfer (HAT) approach for the light-mediated epimerization of readily accessible piperidines to provide the more stable diastereomer with high selectivity. The generality of the transformation was explored for a large variety of di- to tetrasubstituted piperidines with aryl, alkyl, and carboxylic acid derivatives at multiple different sites. Piperidines without substitution on nitrogen as well as N-alkyl and aryl derivatives were effective epimerization substrates. The observed diastereoselectivities correlate with the calculated relative stabilities of the isomers. Demonstration of reaction reversibility, luminescence quenching, deuterium labeling studies, and quantum yield measurements provide information about the mechanism.

Full text of DOI:10.1021/jacs.0c11911

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General Light-Mediated, Highly Diastereoselective Piperidine
Epimerization: From Most Accessible to Most Stable Stereoisomer
Zican Shen,§ Morgan M. Walker,§ Shuming Chen, Giovanny A. Parada, Duc M. Chu, Sun Dongbang,
James M. Mayer,* K. N. Houk,* and Jonathan A. Ellman*
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ABSTRACT: We report a combined photocatalytic and hydrogen atom transfer (HAT) approach for the light-mediated
epimerization of readily accessible piperidines to provide the more stable diastereomer with high selectivity. The generality of the
transformation was explored for a large variety of di- to tetrasubstituted piperidines with aryl, alkyl, and carboxylic acid derivatives at
multiple different sites. Piperidines without substitution on nitrogen as well as N-alkyl and aryl derivatives were effective
epimerization substrates. The observed diastereoselectivities correlate with the calculated relative stabilities of the isomers.
Demonstration of reaction reversibility, luminescence quenching, deuterium labeling studies, and quantum yield measurements
provide information about the mechanism.
We sought to more broadly apply light-mediated, highly
diastereoselective epimerization to piperidines with a range of
substitution patterns. The most extensively used methods for
piperidine synthesis as well as some of the most exciting new
methods often proceed with high selectivity for the contra-
thermodynamic diastereomer.3b,5 We speculated that epimeri-
zation through an α-amino radical intermediate might provide
rapid access to the more stable isomer.6 However, few
examples of stereoselective light-mediated epimerization have
been reported.7
Herein, we describe a combined photocatalytic and
hydrogen atom transfer (HAT) approach to furnish
thermodynamically more stable piperidine derivatives by
epimerization of the corresponding readily accessible but less
stable stereoisomers. The approach was first demonstrated by
highly diastereoselective epimerization of di- to tetrasubsti-
tuted contra-thermodynamic piperidines 1-syn (Scheme 1B, eq
1), prepared by syn selective hydrogenation of pyridines, which
is one of most extensively used methods for piperidine
synthesis.5 The approach was then extended to the highly
diastereoselective epimerization of di- to trisubstituted contra-
thermodynamic derivatives 2-anti (Scheme 1B, eq 2), which
can be obtained by Seidel and co-workers’ powerful approach
for diastereoselective α-substitution of free piperidines.3b
Epimerization was effective for piperidines with aryl, alkyl,
amino, aniline, ester, and primary or tertiary amide
substituents. Additionally, piperidines without substitution on
nitrogen as well as N-alkyl and aryl derivatives were effective
iperidines represent the most prevalent class of hetero-
Pcycles found in U.S. Food and Drug Administration
approved pharmaceuticals,1 and due to the importance of this
motif a variety of strategies have been developed for their
stereoselective synthesis and functionalization.2,3 Recently, our
group reported the photoredox catalyzed diastereoselective α-
amino C−H arylation of densely functionalized piperidine
derivatives (Scheme 1A).4 Key to the high diastereoselectivity
of this transformation was an in situ, reversible photoredox-
mediated α-amino epimerization reaction.
Scheme 1. Photoredox-Mediated Piperidine Epimerization
Received: November 17, 2020
Published: December 29, 2020
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© 2020 American Chemical Society
126

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a
Table 1. Scope for Conversion of 1-syn to 1-anti
a
Isolated yields on 0.3 mmol scale; dr was determined by 1H NMR analysis. Crude yields and dr are noted in parentheses and were determined by
b
c
d
e
1H NMR analysis with an external standard. MeCN as solvent. CySH instead of PhSH. 40 h reaction time. 1d-syn was an 88:12 mixture of
diastereomers. Isolated yield on 0.1 mmol scale. Reaction performed at 0.03 M due to poor solubility. Isolated yield on 0.2 mmol scale. 1p-syn
was a 63:37 syn/anti mixture of diastereomers. 1q-syn was a 60:40 syn/anti mixture of diastereomers. 1r-syn was a 66:34 syn/anti mixture of
f
g
h
i
j
k
diastereomers.
epimerization substrates. The experimentally observed diaster-
eomer ratios are generally in reasonable agreement with the
calculated relative stability of the two diastereomers, which is
helpful for predicting epimerization selectivity. Moreover,
quantum yield determination, luminescence quenching, and
deuterium labeling studies provide insight into the mechanism
for epimerization.
We began our investigation by exploring photocatalytic
epimerization of 1a-syn (see Tables S1 and S2 for optimization
experiments). High diastereoselectivity for 1a-anti was
achieved by employing 1 mol% [Ir{dF(CF3)ppy}2(dtbpy)]PF6
photocatalyst and 1.0 equiv of PhSH as an HAT8 reagent in
acetonitrile or methanol under blue light irradiation, with
methanol providing slightly higher selectivity. Control experi-
ments revealed that photocatalyst, light, and PhSH are all
necessary reaction components, with minimal (<5%) 1a-anti
obtained in their absence. A variety of hydrogen atom donors
were evaluated with aromatic thiols determined to provide the
highest selectivity for this substrate (Table S2). To
demonstrate the scalability of this transformation, the reaction
of 1a-syn was set up on 1 mmol scale to afford 1a-anti in 96%
isolated yield and with >99:1 dr, which compares favorably to
the standard 0.3 mmol reaction scale (Table 1).
After identifying the optimal reaction conditions, we next
evaluated the scope of epimerization (Table 1). In addition to
the 2-phenyl-derivative 1a-syn, which provided the anti isomer
as determined by X-ray crystallography, different substituents
could also be incorporated on the phenyl ring. Piperidines with
both electron-rich (1b-anti) and electron-deficient (1c-anti)
para substituents were obtained with high diastereoselectiv-
ities. Epimerization of piperidine 1d-syn with an ortho-
substituted phenyl group gave only modest diastereoselectivity
under the standard reaction conditions (data not shown),
perhaps because steric interactions with the ortho-methyl
group9 prevent resonance stabilization of the α-amino radical
intermediate (vide infra). In contrast, use of CySH10 and a
longer reaction time provided 1d-anti in 95:5 dr.
Piperidine derivatives with various functionalities at the 3-
position were also explored. Piperidines displaying esters at this
site epimerized to the anti product in high yields and with high
diastereoselectivities (1e-anti and 1f-anti). Notably, 1f-syn,
which incorporates an N-cyclopentyl aniline, is a late stage
intermediate in the synthesis of the phase III clinical candidate
avacopan.11 A homologated ethyl ester (1g-anti), the
corresponding tertiary amide (1h-anti), and the primary
amide (1i-anti) all epimerized in high yields and with excellent
diastereoselectivities.
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a,b
When alkyl substituents were present at the 2-position, the
products were obtained with good anti selectivity, including for
cyclohexyl (1j-anti) and methyl (1k-anti) groups. However,
CySH rather than PhSH was necessary to promote
epimerization of these 2-alkyl substituted piperidines, presum-
ably because its S−H bond dissociation energy matches with
the C−H bond dissociation energies for those piperidines that
do not provide aromatic stabilization for the α-amino radical.10
In contrast, PhSH with a weaker S−H bond dissociation
energy resulted only in recovery of 1j-syn.
Table 2. Representative Conversion of 2-anti to 2-syn
We further extended the substrate scope by evaluating more
highly substituted piperidines that also incorporated nitrogen
substituents (Table 1). N-Alkyl substituted piperidines bearing
methyl, ethyl, and isopropyl groups afforded products 1l-anti,
1m-anti, and 1n-anti, respectively, in good yields and with
consistently high diastereoselectivities. Epimerization of N-
phenyl-substituted piperidine 1o-syn proceeded in 95% yield,
albeit with only moderate diastereoselectivity for the anti
isomer. Extending the reaction time for this substrate did not
improve the anti/syn isomer ratio.
a,b
Importantly, α-epimerization is not limited to 2,3-
disubstituted piperidines. For 2,5-disubstituted piperidines
with aryl and alkyl substituents at the 2-position, epimerization
also proceeded in high yields and stereoselectivities as
demonstrated for 1p-anti and 1q-anti, respectively. Addition-
ally, products were obtained in good yields and high
diastereoselectivities for N-methyl (1r-anti) and N-isopropyl
(1s-anti) piperidines with the 2,5-disubstitution pattern.
Piperidines with even higher levels of substitution also
epimerized efficiently. For example, the all syn 2,3,5-
trisubstituted piperidine 1t-syn equilibrated with high
selectivity and yield to 1t-anti. The corresponding tetrasub-
stituted N-methyl (1u-anti) and N-ethyl (1v-anti) derivatives
were similarly obtained with very high selectivity. Moreover,
the 2,3,5-trisubstituted piperidine 1w-syn, which incorporated
an ester at the 3-position, also efficiently epimerized to give
1w-anti.
To this point, only syn contra-thermodynamic piperidines
had been investigated. To demonstrate the potential generality
of α-amino epimerization for contra-thermodynamic anti
stereoisomers, we evaluated a number of 2,4- and 2,6-
disubstituted piperidines 2-anti (Table 2), prepared by an
efficient new method developed by Seidel and co-workers.3b
Under the standard reaction conditions, epimerization with
greater than 95:5 diastereoselectivity for the syn isomer was
observed for both unsubstituted and N-alkyl 2,4-disubstituted
(2a−2c) and 2,6-disubstituted (2e and 2f) piperidines. Only
the N-phenyl substituted piperidine epimerized with modest
diastereoselectivity to give 2d-syn, consistent with that
observed for N-phenyl 2,3-disubstituted piperidine 1o (see
Table 1).
See footnotes a and b for Table 1.
Table 3. Experimental and Calculated Relative Energies
exptl dr
entry substrate anti/syn
exptl ΔGsyn − ΔGanti calcd ΔGsyn − ΔGanti
a
(kcal/mol)
(kcal/mol)
1
2
3
4
5
6
7
1a
1j
1k
1l
1p
1o
2e
98:2
83:17
97:3
97:3
97:3
78:22
4:96
2.3
0.9
2.1
2.1
2.1
2.2
1.3
3.6
2.8
1.6
1.9
−2.4
0.8
−1.9
a
ωB97X-D/6-311++G(d,p), SMD (MeOH or MeCN)//ωB97X-D/
6-31G(d), SMD (MeOH or MeCN). Exptl = experimental.
6), while epimerization to the most stable diastereomer
occurred, the relatively modest diastereoselectivity did not
correlate that well with the calculated energy difference
between the two diastereomers. For 2e with a different
substitution pattern (entry 7), reasonable agreement between
the calculated energy difference and experimentally observed
ratio was observed.
In the photoredox-mediated arylation of piperidines, we had
previously observed that the distribution of piperidine isomers
resulted from reversible light-mediated in situ epimerization of
the initially formed α-arylated piperidines.4 To probe the
reversibility of photoredox-mediated epimerization in our
current study, we subjected stereoisomerically pure 1o-anti
1
to the reaction conditions (Figure 1a). By crude H NMR
analysis, we observed a 76:24 syn/anti diastereomer ratio
favoring 1o-anti, in very close agreement to the ratio obtained
starting with 1o-syn (see Table 1). Having each diastereomer
converge to the same syn/anti ratio is consistent with a
thermodynamically controlled process under the photoredox
conditions of the reaction.
To gain further information on the mechanism of
epimerization, we investigated deuterium incorporation for
several piperidines with the reaction performed in methanol-d4,
which results in rapid exchange of PhSH to PhSD (Figure 1b−
d).12 For 1a-syn (Figure 1b) and 1p-syn (Figure 1c), the
diastereomeric products were obtained with complete
deuterium incorporation at the 2- and 3-positions, but without
To compare the diastereomer ratios obtained under
photoredox conditions with the relative stabilities of the
corresponding syn and anti isomers, we used density functional
theory (DFT) to calculate the relative free energies of a
representative set of piperidine diastereomers (Table 3). The
relative energies for piperidine diastereomers for derivatives 1
with a range of different substituents correlated well with the
observed high diastereomer ratios (entries 1−5). For these
piperidines, the lower energy anti isomer displays both
substituents in equatorial positions and the higher energy syn
isomer displays one group axial, causing unfavorable 1,3-diaxial
interactions. For the N-phenyl substituted piperidine 1o (entry
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Figure 1. (a) Thermodynamic equilibration of 1o. (b) Deuterium incorporation for the conversion of 1a-syn to 1a-anti in methanol-d4. (c)
Deuterium incorporation for the conversion of 1p-syn to 1p-anti in methanol-d4. (d) Deuterium incorporation for the conversion of 2e-anti to 2e-
syn in methanol-d4. (e) Unexpected products observed for 1x-syn. (f) Luminescence quenching data. (g) Possible mechanism. aSee footnote a for
Table 1.
deuterium incorporation at any other sites. We hypothesize
that an enamine intermediate could explain the observed
deuterium incorporation at the 3-position. For 2e-anti (Figure
1d), complete deuterium incorporation was likewise observed
at the 2- and 3-positions; however, a small amount of
deuterium was also incorporated at the 6-position.
The formation of an enamine intermediate is further
supported by the photoredox-mediated reaction of hydroxy-
methylpiperidine 1x-syn, which provided 1a-anti and 1y-anti,
instead of the expected 1x-anti (Figure 1e). We postulate that
following enamine formation, hydroxide could be eliminated to
form an α,β-unsaturated iminium that would serve as a
common intermediate to both 1a-anti and 1x-anti (see Figure
S1 for mechanism).
To probe whether a closed-loop photoredox mechanism is
plausible,13 we used Scaiano’s method14 to determine the
quantum yield of the reaction for 1a-syn. The quantum yield
was calculated to be Φ = 0.1 at early conversions, indicating
that a photoredox catalyzed cycle is likely though a radical
chain mechanism cannot be ruled out. UV−vis titrations
confirmed that the major species in the reaction mixture is
thiophenolate, which is generated in situ by deprotonation of
PhSH by piperidine 1a-syn (see Figures S2 and S3, and Table
S4). Luminescence quenching revealed that thiophenolate
quenched the photocatalyst excited state more than 2 orders of
magnitude faster than either PhSH or piperidine 1a-anti did,
with a bimolecular dynamic constant of 6.6 × 109 M−1 s−1
(Figure 1f, also see Figures S4−S9 and Tables S5−S7).15
A mechanistic hypothesis is depicted in Figure 1g that is
consistent with the mechanistic experiments. Excitation of the
iridium(III) photocatalyst produces the strongly oxidizing
excited state *IrIII,16 which is reduced by the in situ generated
thiophenolate, consistent with the more rapid quenching by
the mixture of PhSH and piperidine 1a-syn relative to either
compound alone (Figure 1f).17 The resulting thiophenyl
radical can then undergo reversible polarity matched HAT8
with piperidines 1a-syn/anti (α-amino, α-methylbenzylic C−
H BDE = 79−88 kcal/mol,10a,18 versus PhS−H BDE = 79.0
kcal/mol19) to furnish α-amino radical 3 and PhSH. Significant
to this step, Bertrand et al. reported radical-mediated
racemization of benzylic amines with arylthiol radicals initiated
with AIBN.10a HAT between the α-amino radical 3 and PhSH
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Communication
Author Contributions
then regenerates piperidines 1a-syn/anti along with thiophenyl
radical. Electron transfer from Ir(II) to the thiophenyl radical
(or PhSSPh20) provides ground state Ir(III) to complete the
photocatalytic cycle. The product deuteration patterns
depicted in Figure 1b−d can be explained by reversible
oxidation of the α-amino radical intermediate 3 to iminium 4
with subsequent reversible tautomerization to enamine 5.21
We have described the highly diastereoselective photo-
catalytic light-mediated epimerization of readily accessible, but
contra-thermodynamic piperidines to give more stable
diastereomers. Piperidines bearing a variety of substituents
and substitution patterns, including substituents on the
piperidine nitrogen, were effective substrates. The epimeriza-
tion proceeds by a reversible process wherein either
diastereomer gives the same diastereomer ratio. The observed
distribution of isomers correlates reasonably well with their
calculated relative stabilities, which should facilitate application
of the method. In future work, we will apply this approach to
the diastereoselective epimerization of other classes of
heterocycles.
§Z.S. and M.M.W. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NIH Grant R35GM122473 (to
J.A.E.), NSF Grant CHE-1764328 (to K.N.H.), and NIH
Grant R01GM050422 (J.M.M.). We thank Dr. Brandon Q.
Mercado (Yale) for solving the crystal structure of 1a-anti and
Dr. Fabian Menges (Yale) for assistance with mass
spectrometry. Calculations were performed on the Hoffman2
cluster at UCLA, and the Extreme Science and Engineering
Discovery Environment (XSEDE), which is supported by the
NSF (Grant OCI-1053575).
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c11911.
Experimental procedures, characterization data, crystal-
lographic data, deuterium studies, and Cartesian
coordinates of all computed structures (PDF)
Crystallographic data for the picrylsulfonic acid salt of
1a-anti (CIF)
AUTHOR INFORMATION
■
Corresponding Authors
James M. Mayer − Department of Chemistry, Yale University,
New Haven, Connecticut 06520, United States; orcid.org/
0000-0002-3943-5250; Email: james.mayer@yale.edu
K. N. Houk − Department of Chemistry and Biochemistry,
University of California, Los Angeles, California 90095,
United States; orcid.org/0000-0002-8387-5261;
Email: houk@chem.ucla.edu
Jonathan A. Ellman − Department of Chemistry, Yale
University, New Haven, Connecticut 06520, United States;
orcid.org/0000-0001-9320-5512;
Email: jonathan.ellman@yale.edu
Authors
Zican Shen − Department of Chemistry, Yale University, New
Haven, Connecticut 06520, United States
Morgan M. Walker − Department of Chemistry, Yale
University, New Haven, Connecticut 06520, United States
Shuming Chen − Department of Chemistry and Biochemistry,
University of California, Los Angeles, California 90095,
United States; orcid.org/0000-0003-1897-2249
Giovanny A. Parada − Department of Chemistry, Yale
University, New Haven, Connecticut 06520, United States
Duc M. Chu − Department of Chemistry, Yale University, New
Haven, Connecticut 06520, United States
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Cation Cascade to Aryltetralin Cyclic Ether Ligands Under Visible-
Light Photoredox Catalysis. Angew. Chem., Int. Ed. 2020, 59, 21195−
21202. (b) Kim, J.; Kang, B.; Hong, S. H. Direct Allylic C(sp3)−H
Thiolation with Disulfides via Visible Light Photoredox Catalysis.
ACS Catal. 2020, 10, 6013−6022. (c) Patehebieke, Y. An Overview
on Disulfide-Catalyzed and -Cocatalyzed Photoreactions. Beilstein J.
Org. Chem. 2020, 16, 1418−1435. (d) Nguyen, T. M.; Nicewicz, D. A.
Anti-Markovnikov Hydroamination of Alkenes Catalyzed by an
Organic Photoredox System. J. Am. Chem. Soc. 2013, 135, 9588−
9591.
(21) (a) Leitch, J. A.; Rossolini, T.; Rogova, T.; Maitland, J. A. P.;
Dixon, D. J. α-Amino Radicals via Photocatalytic Single-Electron
Reduction of Imine Derivatives. ACS Catal. 2020, 10, 2009−2025.
(b) Trowbridge, A.; Reich, D.; Gaunt, M. J. Multicomponent
synthesis of tertiary alkylamines by photocatalytic olefin-hydro-
aminoalkylation. Nature 2018, 561, 522−527. (c) Beatty, J. W.;
Stephenson, C. R. J. Amine Functionalization via Oxidative
Photoredox Catalysis: Methodology Development and Complex
Molecule Synthesis. Acc. Chem. Res. 2015, 48, 1474−1484.
(d) Hager, D.; MacMillan, D. W. C. Activation of C−H Bonds via
the Merger of Photoredox and Organocatalysis: A Coupling of
Benzylic Ethers with Schiff Bases. J. Am. Chem. Soc. 2014, 136,
16986−16989.
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