Method for the Direct Enantioselective Synthesis of Chiral Primary α-Amino Ketones by Catalytic α-Amination

Article abstract of DOI:10.1021/acs.orglett.8b03733

A useful catalytic enantioselective approach has been developed for the synthesis of chiral ketamine analogs using Rh(II)-catalyzed amination of triisopropylsilyl enol ethers to form α-amino ketones with O-(4-nitrophenyl)hydroxylamine as nitrogen donor in 81-91% ee.

Full text of DOI:10.1021/acs.orglett.8b03733

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Method for the Direct Enantioselective Synthesis of Chiral Primary
α‑Amino Ketones by Catalytic α‑Amination
Yixin Han and E. J. Corey*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
S
* Supporting Information
ABSTRACT: A useful catalytic enantioselective approach has been
developed for the synthesis of chiral ketamine analogs using Rh(II)-
catalyzed amination of triisopropylsilyl enol ethers to form α-amino ketones
with O-(4-nitrophenyl)hydroxylamine as nitrogen donor in 81−91% ee.
Scheme 1. Kurti−Falck Amination of 3 to 4
̈
he recent finding that ketamine (1; Figure 1), a long-used
1
Tinjectable general anesthetic, can also promptly relieve
treatment-resistant depression2 has provided synthetic chem-
istry with a unique opportunity to help with one of the world’s
most pressing problems. Amine 1 is far from an ideal
therapeutic agent. Although a subanesthetic dose of ketamine
can sometimes lift refractory depression in as little as 1 h, the
response rate is moderate and side effects may be significant. It
has been suggested that a metabolite of ketamine 2R,6R-
hydroxy norketamine (2; Figure 1) may possibly be superior to
it,3−5 but this has not been tested by in vivo clinical studies.
The mechanism by which ketamine lifts depression is unclear,
but there is evidence that inhibition of the N-methyl-D-
aspartate (NMDA) subtype of glutamate activated synaptic
receptor is involved. In addition, recent evidence indicates that
the lateral habenula region in the brain may be a key site of
NMDA receptor inhibition by ketamine.6 We describe in this
Letter a study aimed at development of a new enantioselective
route to ketamine and a variety of structural analogs by direct
α-amination of suitable cyclic ketones. This area of synthetic
methodology is relatively undeveloped. The most actively
studied approach to the enantioselective synthesis of α-amino
ketone derivatives involves the Michael addition of a ketone
enolate or equivalent to an azodicarboxylic ester.7−10 In our
previous work on the enantioselective synthesis of ketamine, its
metabolites, and its analogs, the α-amino ketone subunit was
accessed via a chiral epoxide and an α-azido ketone.10−12
At the outset the best option for a direct attachment of NH2
alpha to the ketonic carbonyl function appeared to be the use
of a transition metal nitrene complex, especially with rhodium
as metal.13,14 Of special relevance was the Ku
̈
rti−Falck
process14 for the amination of olefins by Rh(II) carboxylate
catalyzed transfer of NH from O-(2,4-dinitrophenyl)-
hydroxylamine (2,4-DNPONH2), for example, as illustrated
by the reaction in Scheme 1. Although the report that the
reaction did not occur with useful enantioselectivity using
several chiral Rh(II) complexes was not encouraging,14a we
decided to investigate this approach with the trimethylsilyl enol
ether of 2-phenylcyclohexanone as the test substrate by
screening of a set of chiral Rh(II) complexes under essentially
the conditions used by Kurti et al. (CF3CH2OH as solvent at
̈
ambient temperature of 23 °C). The results of these early
studies are summarized in Scheme 2, which shows the
structures of the chiral ligands attached to Rh(II). The Rh(II)
1
complexes were homogeneous by chromatographic and H
NMR analysis and are likely to have the sequential NNOO
arrangement about each rhodium of the Rh2 complex.15 The
yield of the product 2-amino-2-phenylcyclohexanone (5) was
determined by isolation, and the ee values were measured by
HPLC analysis using a Chiral Technologies AD-H column. On
the basis of the yields and ee values shown in Scheme 2, it was
decided to advance the Rh(II) complex 2115 (Figure 2)
derived from ligand 16 (an ester of (+)-menthol) for further
study.
The ligand 16 can readily be synthesized from (+)-menthol
and (S)-pyroglutamic acid by coupling with DCC and DMAP
in CH2Cl2/DMF (8:1). The complex 21 was prepared by
Figure 1. Structure of ketamine (1) and 2R,6R-hydroxynorketamine
(2).
Received: November 21, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03733
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Chiral Ligands Used in the Screening of Rh2
Complexes for Enantioselectivity
Table 1. Enantioselective Amination of Various Silyl Enol
Ether of 2-Phenylcyclohexanone16
b
c
R3Si
yield (%)
ee (%)
TMS
TES
TBS
Ph3Si
TIPS
35
44
40
30
46
44
46
52
55
58
a
b
Reactions conducted on a 0.1 mmol scale. Isolated yield.
c
Determined by HPLC.
Table 2. Effect of Additives on the Enantioselective
Amination
b
c
additives
yield (%)
ee (%)
none
HOAc
K2CO3
2,6-lutidine
pyridine
DMAP (2 equiv)
DMAP (3 equiv)
DBU
imidazole
dabco
41
40
30
56
60
76
70
56
53
48
40
63
56
56
58
40
51
69
74
81
81
64
78
74
80
73
76
82
N-Me-imidazole
1,1,3,3-tetramethylguanidine
TMEDA
4-pyrrolidinopyridine
a
b
Reactions conducted on a 0.1 mmol scale. Isolated yield.
c
Determined by HPLC.
Scheme 3. Yield and Enantioselectivity vs. RONH2
Figure 2. Structure of Rh complex 21.
of 21 was carried out by flash column chromatography on silica
gel; for details, see Supporting Information.
A definite improvement in the enantioselectivity of the α-
amination process with 2-phenylcyclohexanone was found by
reaction of Rh2(OAc)4 and excess ligand 16 in chlorobenzene
at reflux using a Soxhlet extraction apparatus with a mixture of
Celite 545 and CaH2 to remove HOAc as formed. Purification
B
DOI: 10.1021/acs.orglett.8b03733
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
phenylcyclohexanone is not noticeably accelerated by DMAP
or the other bases.
Scheme 4. Simple Enantioselective Synthesis of (R)-Nor-
and (R)-Homoketamine
We were pleasantly surprised to find that the replacement of
O-(2,4-dinitrophenyl)hydroxylamine by O-(4-nitrophenyl)-
hydroxylamine (4-NPONH2) under the optimized conditions
shown in Table 2 with the TIPS enol ether and DMAP as base
provided even higher enantioselectivity, as summarized in
Scheme 3 (data from repeated experiments). It is noteworthy
that O-phenylhydroxylamine and O-pivaloylhydroxylamine
were unreactive under the same conditions (Scheme 3). The
rate of disappearance of the starting enol ether was somewhat
slower with the O-(4-nitrophenyl)hydroxylamine reagent than
with O-(2,4-dinitrophenyl)hydroxylamine. The rate of reaction
of TIPS enol ether decreases markedly as the ratio of
CF3CH2OH to THF is lowered from 4:1, becoming very
slow below 1:1. Because ethanol is not an effective replacement
for trifluoroethanol, it seems likely that the role of the latter is
to assist amino transfer to rhodium by solvation of or hydrogen
bonding to the aryloxide leaving group. Neither N-amino-4-
(dimethylamino)pyridinium 2,4-dinitrophenolate nor N-ami-
nopyridinium iodide were reactive as a nitrogen donor to
rhodium of 21 under the conditions that worked with the 2,4-
DNPONH2 or 4-NPONH2 reagents.
Scheme 5. Aziridination of 26 to 27 Using Catalyst 21
When the conditions indicated in Scheme 3 were applied to
the five- and seven-membered homologues of the TIPS enol
ether of 2-phenylcyclohexanone (22 and 23) using O-(4-
nitrophenyl)hydoxylamine as reagent, the desired products,
nor- and homo-ketamine analogs 24 and 25, were obtained
enantioselectively as shown in Scheme 4.
Scheme 6. One Route to 28, a Possible Amination
Intermediate (Ligands Not Shown)
When we applied catalyst 21, O-(4-nitrophenyl)-
hydroxylamine, and DMAP to the Kurti−Falck amination of
̈
1-phenylcyclohexene (26), we found that aziridine 27 was
formed in good yield (80%), but with poor enantioselectivity
(32% ee), as summarized in Scheme 5. The rate of reaction
was approximately one-third that with the TIPS enol ether of
2-phenylcyclohexanone.
In summary, we have described a useful new method for the
direct enantioselective conversion of certain silyl enol ether of
cyclic ketones to α-amino ketones using the chiral Rh(II)
catalyst 21 with O-(4-nitrophenyl)hydroxylamine as amine
donor in the presence of 4-N,N-dimethylamino pyridine
(DMAP). The reaction is highly accelerated when trifluor-
oethanol is utilized as the reaction medium, which appears to
indicate that hydrogen bonding of CF3CH2OH to the O-
arylhydroxylamine and transfer of NH2 to the Rh(II) catalyst
21 is likely to be the rate-limiting step. The favorable effects of
DMAP and O-(4-nitrophenyl)hydroxylamine on enantioselec-
tivity may be due to their presence in the active amination Rh
complex, such as expressed by formula 28,17−19 wherein 28
may be either a hydrogen bonded or contact ion pair. A
possible route to 28 is depicted in Scheme 6. Further
discussion of the mechanistic basis of enantioselectivity
requires a more detailed study.
examining the reaction of a series of silyl enol ethers with
varying steric properties, as shown in Table 1. The
triisopropylsilyl (TIPS) enol ether provided the best
combination of yield and ee.
We next examined the effect of added amine bases on the α-
amination reaction of the TIPS enol ether of 2-phenyl-
cyclohexanone. The results of these experiments are
summarized in Table 2 , which reveals a beneficial effect of
certain amines, especially 4-N,N-dimethylamino pyridine
(DMAP) on both the yield and enantioselectivity of the
enantioselective Kurti−Falck amination process with the TIPS
̈
ASSOCIATED CONTENT
■
enol ether of 2-phenylcyclohexanone, even though the rate of
amination is a little slower when DMAP is present. 1,8-
Diazabicyclo[5.4.0]undec-7-ene (DBU), a considerably stron-
ger base than DMAP, is definitely less effective in terms of the
enhancement of yield and enantioselectivity. Imidazole and N-
methyl imidazole markedly improve enantioselectivity, but not
yield. The rate of amination of the TIPS-enol ether of 2-
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03733.
Synthetic procedures, NMR, and HPLC (PDF)
C
DOI: 10.1021/acs.orglett.8b03733
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(18) The Lewis acid character of Rh in complexes such as 21 is clear
from catalysis (ref 15) and numerous studies of such coordination
compounds.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: corey@chemistry.harvard.edu.
ORCID
(19) The 1H NMR spectrum of the complex 21 undergoes change in
the presence of DMAP (see SI).
Yixin Han: 0000-0002-4941-092X
E. J. Corey: 0000-0002-1196-7896
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to Pfizer Inc. for a research grant and to Prof.
■
́
́
Laszlo Ku
̈
rti for a gift of 2,4-DNPONH2.
REFERENCES
■
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DOI: 10.1021/acs.orglett.8b03733
Org. Lett. XXXX, XXX, XXX−XXX