Enantioselective, biocatalytic reduction of 3-substituted cyclopentenones: Application to the asymmetric synthesis of an hNK-1 receptor antagonist

Article abstract of DOI:10.1021/ol1030348

A convergent and enantioselective route to the hNK-1 receptor antagonist (1) is described, which sets all six stereogenic centers with high diastereoselectivity and delivers 1 in only 11 steps and 23% overall yield. The process was enabled by the developm

Full text of DOI:10.1021/ol1030348

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1004–1007
Enantioselective, Biocatalytic Reduction
of 3-Substituted Cyclopentenones:
Application to the Asymmetric Synthesis
of an hNK-1 Receptor Antagonist
Kevin R. Campos,* Artis Klapars, Yoshinori Kohmura, David Pollard,
Hideaki Ishibashi, Shinji Kato, Akihiro Takezawa, Jacob H. Waldman,
Debra J. Wallace, Cheng-yi Chen, and Nobuyoshi Yasuda
Department of Process Chemistry, Merck Research Laboratories, P.O. Box 2000,
Rahway, New Jersey 07065, United States
kevin_campos@merck.com
Received December 14, 2010
ABSTRACT
A convergent and enantioselective route to the hNK-1 receptor antagonist (1) is described, which sets all six stereogenic centers with high
diastereoselectivity and delivers 1 in only 11 steps and 23% overall yield. The process was enabled by the development of the enantioselective
enzymatic reduction of 3-functionalized cyclopentenones and stereospecific Pd-catalyzed etherification coupling of fragments 6 and 7.
Human neurokinin-1 (hNK-1) is a G-protein-coupled
receptor, which is concentrated in the central nervous
system and gastrointestinal tissue.1 The neuropeptide sub-
stance P (SP) isthe preferredligand for the hNK-1 receptor
and engages in the moderation of many biological
processes.2 Mostnotably, hNK1receptorantagonistshave
been developed as therapeutic agents for treatment of
chemotherapy-induced nausea and vomiting (CINV) and
postoperative nausea and vomiting (PONV).3 Aprepitant
(Emend)4 is currently the only hNK1 antagonist on the
market and is approved for the treatment of both CINV
(1) Nicoll, R. A.; Schenker, C.; Leeman, S. E. Annu. Rev. Neurosci.
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(2) (a) Guard, S.; Watson, S. P. Neurochem. Int. 1991, 18, 149. (b)
Takeuchi, Y.; Shands, E. F. B.; Beusen, D. D.; Marshall, G. R. J. Med.
Chem. 1998, 41, 3609 and references cited therein.
(4) Hale, J. J.; Mills, S. G.; MacCoss, M.; Finke, P. E.; Cascieri,
M. A.; Sadowski, S.; Ber, E.; Chicchi, G. G.; Kurtz, M.; Metzger, J.;
Eiermann, G.; Tsou, N. N.; Tattersall, F. D.; Rupniak, N. M. J.;
Williams, A. R.; Rycroft, W.; Hargreaves, R.; MacIntyre, D. E. J.
Med. Chem. 1998, 41, 4607.
(5) (a) Bao, J.; Lu, H.; Huagang, Morriello, G. J.; Carlson, E. J.;
Wheeldon, A.; Chicchi, G. G.; Kurtz, M. M.; Tsao, K.-L. C.; Zheng, S.;
Tong, X.; Mills, S. G.; DeVita, R. J. Bioorg. Med. Chem. Lett. 2010, 20,
2354. (b) Owen, S. N.; Seward, E. M.; Swain, C. J.; Williams, B. J. U.S.
Patent 6,458,830 B1, 2001. (c) Finke, P. E.; MacCoss, M.; Meurer, L. C.;
Mills, S. G.; Caldwell, C. G.; Chen, P.; Durette, P. L.; Hale, J.; Holson, E.;
Kopka, I.; Robichaud, A. PCT Int. Appl. WO9714671, 1997.
(3) (a) Tattersall, F. D.; Rycroft, W.; Cumberbatch, M.; Mason,
G.; Tye, S.; Williamson, D. J.; Hale, J. J.; Mills, S. G.; Finke,
P. E.; MacCoss, M.; Sadowski, S.; Ber, E.; Cascieri, M.; Hill, R. G.;
MacIntyre, D. E.; Hargreaves, R. J. Neuropharmacology 2000, 39, 652.
(b) Rupniak, N. M. J.; Tattersall, F. D.; Williams, A. R.; Rycroft, W.;
Carlson, E. J.; Cascieri, M. A.; Sadowski, S.; Ber, E.; Hale, J. J.; Milles,
S. G.; MacCoss, M.; Seward, E.; Huscroft, I.; Owen, S.; Swain, C. J.;
Hill, R. G.; Hargreaves, R. J. Eur. J. Pharmacol. Med. Chem. 1997,
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10.1021/ol1030348
Published on Web 02/08/2011
2011 American Chemical Society

and PONV. As a result, there is ongoing pharmaceutical
research to identify potent, selective, and orally bioavail-
able hNK-1 receptor antagonists as potential therapeutic
agents.5 Recently, structure 1 was identified as a potent,
selective hNK-1 receptor antagonist, which warranted fur-
ther development;6 however, the reported synthesis was
unsuitable to the large scale preparation of 1, which was
required to support the program. The development of a
concise, stereoselective, and scalable synthesis of this struc-
turally complex target constituted a considerable synthetic
challenge. Herein we wish to report a convergent, stereo-
controlled asymmetric synthesis of 1.
Scheme 2. Synthesis of Allylic Ether 10a
reduction of 3-cyanocyclopentenone (8)8 afforded 6 in
variable yields and moderate enantioselectivities.9 This is a
historic problem with the enantioselective reduction of
2-unsubstituted cyclopentenones, presumably due to the
lack of any functionality in these substrates that would
interact with a chiral reagent or catalyst to offer significant
enantiofacial discrimination. Although there was no pre-
cedent forthe asymmetric, biocatalyticreduction ofenones
similar to 8,10 a ketoreductase library was screened. We
discovered that alcohol dehydrogenase from Rhodococcus
erythropolis (ADH RE) efficiently reduced enone 8 to (S)-
allylic alcohol 6 in high yield (93%) and excellent enantios-
electivity (>99% ee) (Scheme 2). In order to probe the
scope of this novel biocatalytic transformation, two other
3-substituted cyclopentenones were also subjected to the
same reaction conditions and afforded the (S)-allylic alco-
hol in good yield and >99% ee (Table 1). The extension of
this method to other substrates suggests that broader
application may be possible.
Scheme 1. Retrosynthetic Analysis
The structural complexity of 1 could be divided into
three distinct synthetic challenges: (1) the sterically con-
gested ether which contained stereochemistry at both
secondary stereogenic termini, (2) the trans,trans-1,2,
3-trisubstituted cyclopentane core, and (3) the pyrrolidinone
ring containing two stereogenic centers, one of which was
a tertiary branched alkyl amine (Scheme 1). In order to
address the stereochemistry of the remote, quaternary ste-
reogenic center, we devised a strategy to produce 1 from
ketone 2, which would be acquired through diastereose-
lective alkylation of oxazolidinone 3 with iodoketone 4.
The most effective method to control the relative stereo-
chemistry of the cyclopentane core in 4 would be via
substrate-controlled conjugate addition of an aryl-metal
species on allylic ether 5, followed by isomerization of the
ketone to the thermodynamically favored diastereomer.
We envisioned that the most elegant approach to construct
both secondary stereogenic centers in allylic ether 5 would
be via convergent, stereospecific coupling of allylic alcohol
6 and alcohol 7, both of which would need to be prepared
in enantiomerically pure form.
Table 1. Enantioselective, Biocatalytic Reduction of 3-Substi-
tuted Cyclopentenones
entry
EWG
conditions
% yield
% ee
1
2
3
CO2Me
CN
ADH RE, NADH, FDH
ADH RE, NADH, FDH
ADH RE, NADH, FDH
83
92
87
>99
>99
>99
SO2Ph
Alcohol 7 is a common structural motif that exists in
several hNK-1 antagonists reported by Merck4,5 and is
readily available via asymmetric reduction of the corre-
sponding aryl methyl ketone.7 In contrast, the enantiose-
lective synthesis of allylic alcohol 6 has not been reported.
Application of existing methodologies to the asymmetric
(8) Zimmerman, H. E.; Pasteris, R. J. J. Org. Chem. 1980, 4864–4876.
For an improved synthesis of 8, please refer to the Supporting Informa-
tion.
(9) (a) Ohkuma, T.; Koizumi, M.; Doucet, H.; Pham, T.; Kozawa,
M.; Murata, K.; Katayama, E.; Yokozawa, T.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1998, 120, 13529. (b) Corey, E. J.; Guzman-Perez, A.;
Lazerwith, S. E. J. Am. Chem. Soc. 1997, 119, 11769. (c) Yun, J.;
Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 5640. (d) Brown, H. C.;
Ramachandran, P. V. Acc. Chem. Res. 1992, 25, 16–24. (e) Midland,
M. M.; Tramontano, A.; Kazbubski, A.; Graham, R. S.; Tsai, D. J. S.;
Cardin, D. Tetrahedron 1984, 40, 1371. (f) Noyori, R.; Suzuki, M.
Angew. Chem., Int. Ed. Engl. 1984, 23, 847.
(6) Campos, K. R.; Chen, C-y; Ishibashi, H.; Kato, S.; Klapars, A.;
Kohmura, Y.; Pollard, D. J.; Takezawa, A.; Waldman, J. H.; Wallace,
D. J.; Yasuda, N. PCT Int. Appl. 2008021029, 2008.
(7) Hansen, K. B.; Chilenski, J. R.; Desmond, R.; Devine, P. N.;
Grabowski, E. J. J.; Heid, R.; Kubryk, M.; Mathre, D. J.; Varsolona, R.
Tetrahedron: Asymmetry 2003, 14, 3581.
(10) (a) For an excellent review of enzymatic reduction of ketones,
see: Moore, J. C.; Pollard, D. J.; Kosjek, B.; Devine, P. N. Acc. Chem.
Res. 2007, 1412–1419. (b) Fonteneau, L.; Rosa, S.; Buisson, D. Tetra-
Org. Lett., Vol. 13, No. 5, 2011
1005

With alcohols 6 and 7 prepared in high optical purity, we
sought a method to couple these partners without epimer-
ization at either center. The documented stereospecificity
of transformations which proceed via η3-allylmetal inter-
mediates made the Pd-catalyzed allylic etherification an
attractive choice.11,12 Although alcohol 7 was an unlikely
candidate to participate in this coupling due to its steric
congestion and poor nucleophilicity, we were able to
develop conditions which effectively coupled 7 with allylic
naphthoate ester 9 in goodyield withoutcompromisingthe
integrity of either stereogenic center (Scheme 2). Under
optimized conditions, 9 and 7 were coupled using Pd(OAc)2
and dppp in the presence of 0.5 equiv of Et2Zn to afford
allylic ether 10 in 83% yield with net retention of config-
uration at both stereogenic centers.
(95%) and exceptional diastereoselectivity (>99:1
β-center) after isomerization of the ketone to the thermo-
dynamically preferred diastereomer (NaOMe/MeOH,
98:2 R-center). Due to the improved diastereoselectivity,
robustness, and improved cost the latter transformation
was employed.
Scheme 3. Synthesis of trans,trans-1,2,3 Cyclopentane Corea
Figure 1. Synthesis and X-ray crystal structure of 4.
Selective iodination of 12 with ICl in MeOH produced
iodoketone 4 in 90% isolated yield (eq 2, Figure 1). An
X-ray crystal structure of 4 verified both the relative and
absolute chemistry of the four stereogenic centers as-
sembled in this process.
Scheme 4. Convergent Coupling and Rearrangement to Lactama
Attempts to accomplish a cuprate conjugate addition on
R,β-unsaturated nitrile 10 were unsuccessful; however
we were able to demonstrate a Rh-catalyzed conjugate
addition (3 mol % [CODRh(OH)]2, EtOH, reflux) using
5.0 equiv of arylboronic acid or 1.5 equiv of aryl tri-
fluoroborate (K salt).13 Both procedures afforded 11 in
93% assay yield and high diastereoselectivity (>99:1
β-center, 90:10 R-center) after isomerization of the ketone
to the thermodynamically favored diastereomer (NaOMe/
MeOH). The nitrile was readily converted to the methyl
ketone via treatment with MeLi in MTBE, delivering 12
in 90% assay yield (Scheme 3). Alternatively, methyl
ketone 13 was readily produced from nitrile 10 (MeLi,
MTBE), and as expected, Cu-catalyzed conjugate addi-
tion of an aryl Grignard delivered 12 in excellent yield
With a convergent and highly selective process to as-
semble iodoketone (6 steps, 58% yield), we focused our
attention on the development of a stereocontrolled method
to assemble the pyrrolidinone ring (Scheme 4). Alkylation
of oxazolidinone 3 with iodoketone 4 was accomplished
with LiHMDS at low temperature to afford 2 in 90% yield
and >99:1 diastereoselectivity.14 Aminolysis of oxazolidi-
none 2 with ammonium hydroxide resulted in formation of
hedron: Asymmetry 2002, 13, 579. (c) Attolini, M.; Bouguir, F.; Iacazio,
G.; Peiffer, G.; Maffei, M. Tetrahedron 2001, 57, 537.
(11) (a) Kim, H.; Lee., C. Org. Lett. 2002, 4369. (b) Leahy, D. K.;
Evans, P. A. Modern Rhodium-catalyzed Organic Reactions 2005, 191–
214. (c) Muzart, J. Tetrahedron 2005, 5955–6008 and references cited
therein.
(12) Both the acetate and benzoate esters afforded similar yields, but
the crystalline naphthoate ester was chosen for isolation purposes.
(13) (a) Wang, H.; Yang, D.-Q.; Mo, H.-H. Youji Huaxue 2007, 806–
818. (b) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 2829–2844. (c)
Batey, R. A.; Thadani, A. N.; Smil, D. V. Org. Lett. 1999, 1683. (d)
Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16, 4229.
(14) (a) Seebach, D.; Sting, A. R. Angew. Chem., Int. Ed. 1996, 2708–
2748 and references cited therein. (b) Karady, S.; Amato, J.; Weinstock,
L. Tetrahedron Lett. 1984, 25, 4337. (c) Szumigala, R. H., Jr.; Onofiok,
E.; Karady, S.; Armstrong, J. D., III; Miller, R. A. Tetrahedron Lett.
2005, 4403.
1006
Org. Lett., Vol. 13, No. 5, 2011

Scheme 5. Mechanism of Lactam Hydrolysis/Rearrangement
Figure 2. PM3-minimized structure of acyliminium 18.
intermediate 14, which underwent spontaneous cyclization
to aminal 15 as a 1:1 mixture of diastereomers (Scheme 5).
structure of intermediate 4. Deprotection of the CBz-
protected amine in 17 was accomplished with HBr/HOAc,
and the hNK-1 antagonist, 1, was isolated in 85% yield as
the benzenesulfonate salt.
Scheme 6. Endgame Chemistry
In conclusion, a convergent, highly selective route has
been developed for the synthesis of the potent hNK-1
receptor antagonist 1. Assembly of this highly functiona-
lized candidate was accomplished with exceptional stereo-
control of all six stereogenic centers, in a total of 11 steps
and 23% overall yield. The highlights of this synthesis are
the discovery of an enantioselective, biocatalytic reduction
of 3-substituted cyclopentenones and the development of a
convergent and stereospecific Pd-catalyzed allylic etherifi-
cation. The application of these two unique synthetic
transformations in sequence, followed by substrate-con-
trolled, diastereoselective conjugate additions, has general
application to the enantioselective synthesis of highly func-
tionalized cyclopentanoids with a high degree of stereo-
control. A detailed description of the generality of these
methods will be disclosed shortly.
Dehydration of 15 with methanesulfonic acid affor-
ded a 3:1 mixture of enamide isomers, favoring 16, in
94% yield.15 Reduction of the mixture of enamides with
Et3SiH/MeSO3H afforded 17 in excellent yield as a 90:10
mixture of diastereomers (Scheme 6). The unusually high
diastereoselectivity achieved in the reduction could be
rationalized through analysis of the PM3 minimized struc-
ture of acyliminium intermediate 18, which suggests a
less-hindered (Re) face (Figure 2). This conformation is
further supported by analogy to that observed in the crystal
Acknowledgment. We thank J. Chilenski (Merck & Co.)
for determination of absolute stereochemistry by single crystal
X-ray diffraction as well as R. Reamer and L. DiMichele
(Merck & Co.) for structural elucidation by NMR.
Supporting Information Available. Experimental details.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Direct reduction of 15 to 17 generates 1 equiv of water which
negatively impacts the yield and selectivity of the Et3SiH reduction.
Org. Lett., Vol. 13, No. 5, 2011
1007