Enantioselective Syntheses of (S)-Ketamine and (S)-Norketamine

Article abstract of DOI:10.1021/acs.orglett.9b02575

An efficient asymmetric synthesis of (S)-ketamine (esketamine) based on catalytic enantioselective transfer hydrogenation of cyclic enone and [3,3]-sigmatropic rearrangement of allylic cyanate to isocyanate is described. The catalytic asymmetric route afforded esketamine (99.9% ee) in 50% overall yield over four steps and forms the basis for the future development of the drug substance. Furthermore, the route was applicable to the synthesis of (S)-norketamine via simple hydrolysis of isocyanate penultimate.

Full text of DOI:10.1021/acs.orglett.9b02575

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Syntheses of (S)‑Ketamine and (S)‑Norketamine
Cheng-yi Chen*,† and Xiaowei Lu‡
†Janssen R&D, API Small Molecule Development, Discovery Product Development & Supply, Hochstrasse 201, 8205 Schaffhausen,
Switzerland
‡Porton (Shanghai) R&D Center, 1299 Ziyue Road, Zizhu Science Park, Minhang District, Shanghai 200241, China
S
* Supporting Information
ABSTRACT: An efficient asymmetric synthesis of (S)-ketamine (esketamine) based on catalytic enantioselective transfer
hydrogenation of cyclic enone and [3,3]-sigmatropic rearrangement of allylic cyanate to isocyanate is described. The catalytic
asymmetric route afforded esketamine (99.9% ee) in 50% overall yield over four steps and forms the basis for the future
development of the drug substance. Furthermore, the route was applicable to the synthesis of (S)-norketamine via simple
hydrolysis of isocyanate penultimate.
etamine and its (S)-enantiomer (esketamine) have
scale production. Toste and Yang recently disclosed use of a
Krecently been studies for rapid-onset antidepressant effect chiral organophosphoric acid catalyst for the direct asymmetric
electrophilic amination of α-substituted ketones with di-tert-
butyl azodicarboxylates.10 Though the amination step proceeds
in high enantioselectivity (99% ee) in 78% yield, elaboration of
the advanced amino ketone intermediate to esketamine called
for the three-step transformation with deprotection of the Boc
group, N−N bond cleavage and methylation, affording
esketamine in 30% overall yield. More recently, Gohari et al.
reported two asymmetric syntheses of esketamine using
Ellman’s (S)-tert-butanesulfinamide as chiral auxiliary. The
imine addition step proceeded in modest diastereoselectivity
(75−85%).11 The limited success in these asymmetric
syntheses of esketamine may stem from the lack of efficient
synthetic method for the installation of the α-tertiary amine
center.12 We envisioned that esketamine (1) could be prepared
from penultimate trichloroacetamide 2 via methylation and
deprotection (Scheme 1). The trichloroacetamide, in turn,
could be prepared via an Overman rearrangement13 of a chiral
allylic alcohol 4. This synthetic design takes advantage of the
methyl vinyl ethers as latent protecting group for the ketone
moiety. Furthermore, the allylic alcohol can be prepared from
enantioselective reduction of enone 5.
and has been advanced as a new treatment for major depressive
disorder including treatment-resistant depression.1 (S)-Ket-
amine (esketamine) displays approximately 3- to 4-fold greater
affinity for the glutamate N-methyl D-asparate (NMDA)
receptor in vitro than (R)-ketamine.2 With acceptable
tolerability in short-term treatment, esketamine has drawn
greater attention for the development as an antidepressant
drug. With superior antidepressant efficacy in novel intranasal
spray formulation, esketamine for the treatment of treatment-
resistant depression was granted by the US FDA with
“breakthrough therapy” designation.3 Recently, the U.S. FDA
has approved Spravato (esketamine) nasal spray as a rapidly
acting antidepressant for adults with treatment-resistant
depression (TRD), which represents one of the most
significant milestones for depression treatment in decades.4
The drug substance, however, has been produced since the
discovery of ketamine5 via a racemic synthesis and classical
resolution.6 Giving the importance of the drug, we herein wish
to disclose an efficient asymmetric synthesis of esketamine
based on catalytic enantioselective transfer hydrogenation of
enone and [3,3]-sigmatropic rearrangement of allylic cyanate
to set the sole stereocenter. Furthermore, hydrolysis of
isocyanate penultimate led to (S)-norketamine.
As shown in Scheme 2, we started our work with the
preparation of enone 5 according to the published method
whereby Suzuki−Miyaura coupling of bromo enone 614 with
2-Cl-phenyl boronic acid under conventional coupling
conditions afforded enone 5 in 88% yield. CeCl3-mediated
1,2-reduction of enone 5 with NaBH4 afforded racemic alcohol
7. Heating of this imidate intermediate 8 under Overman
The structural uniqueness of esketamine and importance of
the compound has prompted several asymmetric syntheses
over the years.7 Kiyooka and co-workers reported the synthesis
of esketamine in high enantioselectivity over 10 steps in 21%
yield.8 To achieve high enantioselectivity (97% ee), this route
used excess BINAL-H (3.4 equiv)9 for the reduction of an
enone and relied on ozonolysis of an olefin to install the ketone
functionality, both of which may not be convenient for large-
Received: July 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02575
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Scheme 1. Retrosynthetic Analysis of Esketamine
Scheme 3. Racemic Ketamine via [3,3]-Rearrangement of
Allylic Cyanate
Scheme 2. Overman Rearrangement of Racemic Allylic
Alcohol
the asymmetric version of esketamine and its enantiomer if the
requisite chiral intermediates could be produced.
We next explored the asymmetric reduction of enone 5 to its
alcohol 4 as shown in Scheme 4. Among many protocols for
a
Scheme 4. Asymmetric Transfer Hydrogenation of Enone
rearrangement conditions13a did not render a clean reaction
profile. Similar results were obtained using alternative Pd-
catalyzed conditions.13c A brief literature survey revealed that
Overman rearrangement of such fully substituted allylic alcohol
was less precedented.13 We speculated that the steric
interaction between the trichloromethyl and methoxy groups
prevented the molecule from adopting a boat-transition state
prior to rearrangement. The chair-transition state is also not
feasible due to A1,3 interaction.
a
All reactions were run under nitrogen in HCO2H/Et3N (2/3 v/v)
b
(10 mL/g substrate) at 80 °C for 3 h. Enantioselectivity was assayed
by chiral HPLC.
The allyl cyanate/isocyanate transposition15 has been
reported as an attractive alternative to the Overman rearrange-
ment of allylic trichloroacetimidates. The success is generally
believed to result from the mild reaction conditions and the
high degree of stereocontrol. As illustrated in Scheme 3, we
were delighted to find that rearrangement allylic alcohol 7 can
be facilitated via cyanate/isocyante strategy.8 Treatment of
allylic alcohol 7 with Cl3CCONCO afforded carbamate 10 in
85% yield. Dehydration of carbamate 10 afforded cyanate
intermediate 11, which smoothly rearranges at 0 °C to
isocyanate 12 in good yield for the two steps. We
demonstrated this isocyanate can be converted to ketamine
via a two-step transformation: reduction and hydrolysis to
afford ketamine in 42% unoptimized yield. The enablement of
this racemic synthesis of ketamine opened the possibility for
the asymmetric reduction of ketone to alcohol, we chose the
asymmetric transfer hydrogenation due to its reliability, mild
reaction conditions, and easy operation in the laboratory.16 We
initially screened four Ru-based chiral catalysts for the enone
reduction. We were delighted to find that all four catalysts
reduced ketone to alcohol in >97% ee with full conversion at 1
mol % catalyst loading. At 0.1 mol % catalyst loading, however,
only [(S,S)-Teth-TsDPEN]RuCl gave full conversion in 97−
98% ee; the rest three catalysts only reached 45−50%
conversion at this lower catalyst load. After selecting [(S,S)-
Teth-TsDPEN]RuCl as the optimal catalyst for the enantio-
selective reduction of enone 5, we advanced the chiral product.
The cyanate rearrangement worked equally well to afford
isocyanate 16 in 98% ee in 88% yield.17 A complete chirality
B
DOI: 10.1021/acs.orglett.9b02575
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
transformation without any erosion of ee was observed as
shown in Scheme 5.
integrity of chirality. This asymmetric route to esketamine
(99.9% ee) forms the basis for the future development of the
compound and could be extended to the synthesis of (S)-
norketamine and esketamine-d3. The simplicity and high
efficiency of this synthesis renders it attractive when compared
to the others reported in the literature. We hope this work will
prompt others to explore application of the milder cyanate
rearrangement chemistry in the synthesis of important chiral
pharmaceutical agents.
Scheme 5. [3,3]-Sigmatropic Rearrangement of Chiral
Allylic Imidate
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02575.
Experimental details, characterization data, and NMR
spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: cchen117@its.jnj.com.
ORCID
Having successfully installed of α-tertiary isocyanate chiral
center with a total transfer of chirality, we shifted our attention
to the end game for the synthesis of esketamine. As shown in
Scheme 6, reduction of isocyanate using LiAlH4 afforded
Cheng-yi Chen: 0000-0001-7666-3087
Notes
The authors declare no competing financial interest.
Scheme 6. Synthesis of Esketamine and S-Norketamine
ACKNOWLEDGMENTS
■
We acknowledge Mrs. Huawei Ma and Mrs. Huan Dong at
Porton (Shanghai) R&D Center for analytical support and Mr.
Zhaobing Wang and Mrs. Wei Liu at the Porton (Shanghai)
R&D Center for the preparation of enone 5 according to
literature procedures. We also acknowledge Drs. Christopher
Teleha and Qinghao Chen of Janssen R&D, Spring House, PA,
for helpful discussions during the preparation of this
manuscript.
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■
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C
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Letter
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D
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