Stereocontrolled syntheses of epimeric 3-aryl-6-phenyl-1-oxa-7-azaspiro[4.5]decane NK-1 receptor antagonist precursors

Article abstract of DOI:10.1021/ol006944a

Equation presented Complementary stereoselective syntheses of individual C3 epimers of the NK-1 receptor antagonist precursor 1 have been developed. Both diastereomers were derived from the common intermediate 3; introduction of the 3S stereocenter in 1a

Full text of DOI:10.1021/ol006944a

ORGANIC
LETTERS
2001
Vol. 3, No. 5
667-670
Stereocontrolled Syntheses of Epimeric
3-Aryl-6-phenyl-1-oxa-7-azaspiro[4.5]decane
NK-1 Receptor Antagonist Precursors
Janusz J. Kulagowski,* Neil R. Curtis, Christopher J. Swain, and
Brian J. Williams
Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories,
Neuroscience Research Centre, Terlings Park, Harlow, Essex, CM20 2QR, UK
janusz•kulagowski@merck.com
Received November 30, 2000
ABSTRACT
Complementary stereoselective syntheses of individual C3 epimers of the NK-1 receptor antagonist precursor 1 have been developed. Both
diastereomers were derived from the common intermediate 3; introduction of the 3S stereocenter in 1a was achieved through hydrogenation
of an arylated dihydrofuran, whereas the corresponding stereogenic center in 1b was installed using a stereo- and regioselective alkene
hydroarylation.
The search for clinically useful modulators of the neurokinin
NK-1 receptor has remained an active area of inquiry within
the pharmaceutical industry1 since disclosure of the first non-
peptide antagonist.2 Further interest has recently been
stimulated by the observation of antidepressant activity
through a novel mechanism of action during clinical trials
by Merck of an NK-1 antagonist.3
Our interest in the area led to a requirement for quantities
of both C3 epimers of the 6-phenyl-1-oxa-7-azaspiro[4.5]-
decane derivative 1 as precursors to a series of conforma-
tionally restricted ligands.4
(1) Swain, C. J. In Progress in Medicinal Chemistry; Ellis, G. P.,
Luscombe, D. K., Oxford, A. W., Eds.; Elsevier Science BV: Amsterdam,
1998; Vol. 35, p 57.
(2) Snider, R. M.; Constantine, J. W.; Lowe, J. A., III; Longo, K. P.;
Lebel, W. S.; Woody, H. A.; Drozda, S. E.; Desai, M. C.; Vinick, F. J.;
Spencer, R. W.; Hess, H.-J. Science 1991, 251, 435.
(3) Kramer, M. S.; Cutler, N.; Feighner, J.; Shrivastava, R.; Carman, J.;
Sramek, J. J.; Reines, S. A.; Liu, G.; Snavely, D.; Wyatt-Knowles, E.; Hale,
J. J.; Mills, S. G.; MacCoss, M.; Swain, C. J.; Harrison, T.; Hill, R. G.;
Hefti, F.; Scolnick, E. M.; Cascieri, M. A.; Chicchi, G. G.; Sadowski, S.;
Williams, A. R.; Hewson, L.; Smith, D.; Carlson, E. J.; Hargreaves, R. J.;
Rupniak, N. M. J. Science 1998, 281, 1640.
(4) (a) Elliott, J. M.; Cascieri, M. A.; Chicchi, G. G.; Curtis, N. R.;
Hargreaves, R.; Harrison, T.; Hollingworth, G. J.; Kulagowski, J.; Kurtz,
M. M.; Owen, S.; Rupniak, N. M. J.; Rycroft, W.; Sadowski, S.; Seward,
E.; Swain, C. J.; Tattersall, F. D.; Williams, B.; Williams, A. R. A New
Class of Spirocyclic NK1 Antagonists. Book of Abstracts, Tachykinins 2000;
Physiology, Drug Discovery and Clinical Applications, La Grande Motte,
France, 2000; poster P84. (b) Baker, R.; Curtis, N. R.; Elliott, J. M.;
Harrison, T.; Hollingworth, G. J.; Jackson, P. S.; Kulagowski, J. J.; Seward,
E. M.; Swain, C. J.; Williams, B. J. WO 97/49710, 1997; Chem Abstr.
1998, 128, 88921.
To ensure a sufficient supply of material for further
investigation, it was decided at the outset to develop separate,
but parallel, routes to both individual epimers. Under these
circumstances, introduction of the C3 stereocenter at a late
10.1021/ol006944a CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/16/2001

stage in the sequence would offer the most versatile and
efficient strategy. Retrosynthetic analysis (Figure 1) sug-
as the tert-butyl carbamate and oxidized to ketone 5 under
Swern conditions (Scheme 1).
Scheme 1
HPLC analysis of 5 (Chiralpak AD column with 99:1
isohexane/ethanol as mobile phase) indicated no loss in
optical purity relative to 4. Addition of the Grignard
derivative of trimethylsilyl propargyl ether proceeded ste-
reospecifically, anti to the 2-phenyl group as expected, giving
diol 3 in 82% yield from 4 after desilylation. The stereo-
chemical assignment was confirmed by the observation of
NOE interactions as indicated, and the enantiomeric integrity
of 3 was ascertained by HPLC (>99% ee; Chiralpak AD,
98:2 isohexane/ethanol). The presence of residual 5 in the
addition reaction, irrespective of the stoichiometry of Grig-
nard reagent used, suggested that some enolization of the
ketone had occurred under the reaction conditions. Recovered
ketone was determined to be racemic, indicating that
deprotonation had occurred at C2.
Figure 1. Retrosynthetic approach to individual C3 epimers of 1.
gested that control of this stereocenter could be achieved
through appropriate manipulation of the double bond in an
unsaturated spiro-piperidine (2).
Synthesis of the 3S epimer (1a) continued with palladium-
(0)-mediated hydrostannylation6 of 3 (Scheme 2), to provide
a mixture of vinyl stannanes (6a,b) with 7:1 selectivity for
the desired regioisomer (6a).
The N-Boc group and pseudoaxially disposed phenyl on
the piperidine would be expected to effectively shield the
underside of the dihydrofuran, thereby directing approach
of reactants to the opposite, â-face of the alkene. Thus,
hydrogenation of 2a, in which the double bond bears a
suitably substituted aryl group, would give rise to the 3S
epimer; conversely, the 3R diastereomer would be obtained
through addition of ArH to unsubstituted alkene 2b. Fur-
thermore, it was envisaged that the complementarity of the
two routes would result in convergence to a common
precursor, namely, propargyl diol 3. Here again, the phenyl
group might be expected to exert a controlling influence on
the emerging quaternary stereogenic center. In this Letter,
we describe the successful implementation of this strategy,
resulting in simple, stereocontrolled syntheses of the indi-
vidual epimers of 1.
Cyclodehydration of the mixture under Mitsunobu condi-
tions, followed by separation of isomers, proceeded unevent-
fully to afford 7 in 65% yield. Stille cross-coupling with
bromide 8a gave the key intermediate 2a. Subsequent
hydrogenation over Pearlman’s catalyst led to cleavage of
the benzyl ether with concomitant reduction of the double
bond, resulting in a 12:1 selectivity favoring the desired
diastereomer 1a as judged by NMR analysis.
Our retrosynthetic analysis for the construction of 1b called
for a formal hydroarylation of dihydrofuran 2b. Such
transformations have been reported for certain alkenes when
exposed to Heck-type carbopalladation under reductive
conditions.7 The success of this strategy rests with the
inability of the intermediate σ-palladium species to undergo
syn â-hydride elimination, instead being intercepted by
2-Phenylpiperidinol 4 has previously been resolved and
used to prepare a series of NK-1 ligands, demonstrating that
enantiospecific affinity for the receptor resides with the
antipode having the (2S) configuration.5 Accordingly, enan-
tiomerically enriched (>99% ee) (2S,3S)-(+)-4 was protected
(6) Miyake, H.; Yamamura, K. Chem. Lett. 1989, 981.
(7) (a) Burns, B.; Grigg, R.; Sarnhakumar, V.; Sridharan, V.; Stevenson,
P.; Worakun, T. Tetrahedron 1992, 48, 7297. (b) Veenstra, S. J.; Hauser,
K.; Betschart. Bioorg. Med. Chem. Lett. 1997, 7, 347. (c) Clayton, S. C.;
Regan, A. C. Tetrahedron Lett. 1993, 34, 7493.
(5) Harrison, T.; Williams, B. J.; Swain, C. J.; Ball, R. G. Bioorg. Med.
Chem. Lett. 1994, 4, 2545.
668
Org. Lett., Vol. 3, No. 5, 2001

the desired arylated material. Instead, only unchanged 2b
accompanied by anisole was observed, indicating that the
arylpalladium intermediate was being intercepted by hydride
prior to addition to 2b. In contrast, 2-iodoanisole did lead to
the desired coupling, giving 10a in a modest 10% yield,
although again accompanied by anisole as the major product.
An investigation of reaction parameters was undertaken with
the aim of optimizing the desired coupling reaction. While
turnover was very slow at ambient temperature, performing
the reaction at 80 °C resulted in rapid deposition of colloidal
palladium accompanied by termination of the reaction.
Different formate counterions, as well as tertiary amines,10
were evaluated as reductants. Additives such as triarylphos-
phines, triphenylarsine,11 or silver salts12 appeared to suppress
the reaction, while use of the corresponding aryl triflate failed
to give significant conversion. These studies eventually led
to adoption of the following optimized conditions: 0.1 equiv
of Pd(OAc)2, 1 equiv of n-Bu4NCl, 3 equiv of KO2CH, 3
equiv of 2-iodoanisole, 10 equiv of LiCl, DMF, 60 °C. The
inclusion of excess chloride ions, most conveniently as the
lithium salt, was found to be beneficial in suppressing
competing reduction of starting aryl iodide, although the
mechanism underlying this observation is presently unclear.13
Application of these conditions to the reaction of 2b with
8b gave 10b in 69% yield as a 20:1 mixture with the
corresponding 3S isomer. Hydrogenolysis provided 1b, which
was confirmed as having the 3R configuration by the
presence of an NOE interaction between the two benzylic
protons.
Scheme 2
hydride. In the case of 2b, steric considerations8 suggested
that cis addition of an arylpalladium complex across the
double bond would result in intermediate 9 (Scheme 3),
Scheme 3
A further product observed in the hydroarylation reaction
was the unsaturated regioisomer 11, isolated in 12% yield.
Formation of this material may be rationalized by initial
isomerization of 2b to the enol ether 12 followed by
R-arylation and subsequent â-elimination of the palladium
(Scheme 4).14
Scheme 4
containing the correct regio- and stereochemistry required
for 1b and lacking a syn hydrogen adjacent to the palladium.
Encouraged by the prospect of success, 2b was prepared
(Scheme 3) by partial hydrogenation of 3 over Lindlar
catalyst, followed by cyclization as before. Attempted
coupling with 2-bromoanisole as a model substrate under
conditions reported by Larock9 (cat. Pd(OAc)2, 1 equiv of
n-Bu4NCl, 3 equiv of KO2CH, DMF, rt) resulted in none of
In summary, we have developed simple, stereocontrolled
syntheses of both C3 epimers of 3-aryl-6-phenyl-1-oxa-7-
azaspiro[4.5]decane, 1a and 1b. The complementarity of the
(9) Larock, R. C.; Johnson, P. L. J. Chem. Soc., Chem. Commun. 1989,
1368.
(10) Stokker, G. E. Tetrahedron Lett. 1987, 28, 3179.
(11) Kojima, A.; Honzawa, S.; Boden, C. D. J.; Shibasaki, M. Tetrahe-
dron Lett. 1997, 38, 3455.
(8) Heck, R. F. In Organic Reactions; Dauben, W. G, Ed.; John Wiley
& Sons: New York, 1982; Vol. 27, p 345.
Org. Lett., Vol. 3, No. 5, 2001
669

two routes allows use of a common intermediate (3) to
provide multigram quantities of precursors to conformation-
ally restricted NK-1 antagonists.
Acknowledgment. We are indebted to Alan Watt, Laure
Hitzel, Steven Thomas, Derek Kennedy, and Dr. Richard
Herbert for analytical support, Prof. Istvan Marko for helpful
discussion, and Dr. Colin Leslie for preliminary experiments.
(12) Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52,
4130.
(13) For examples in which added halide ions affect the outcome of Heck
reactions, see: (a) Merlic, C. A.; Semmelhack, M. F. J. Organomet. Chem.,
1990, 391, C23. (b) Andersson, C.-M.; Hallberg. J. Org. Chem. 1988, 53,
2112.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 1a, 1b, 2a,
2b, 3, 5, 7, 8a, 8b, 10b, and 11. This material is available
free of charge via the Internet at http://pubs.acs.org.
(14) (a) Larock, R. C.; Gong, W. H. J. Org. Chem. 1990, 55, 407. (b)
Daves, G. D., Jr.; Hallberg, A. Chem. ReV. 1989, 89, 1433.
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