Practical methods for the preparation of spiro[benzo[c]thiophene- 1(3H),4'-piperidine]-(2S)-oxide by resolution and asymmetric sulfoxidation

Article abstract of DOI:10.1016/S0957-4166(98)00257-2

We report simple and efficient methods for the preparation of enantiomerically pure spiro[benzo[c]thiophene-1(3H),4'-piperidine]-(2S)- oxide (S)-1, a key intermediate for the synthesis of tachykinin receptor antagonist, by resolution and asymmetric sulfoxidation. Racemic (RS)-1 can be resolved with (S)-(+)-mandelic acid in acetonitrile to give (S)-1 of >99% ee. We also describe the asymmetric sulfoxidation of sulfide 5 in excellent enantiomeric excess and high chemical yield by the use of the Davis reagent.

Full text of DOI:10.1016/S0957-4166(98)00257-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2567–2570
Practical methods for the preparation of spiro[benzo[c]thiophene-
1(3H),40-piperidine]-(2S)-oxide by resolution and asymmetric
sulfoxidation
Takahide Nishi,∗ Katsuyoshi Nakajima, Yukiko Iio, Koki Ishibashi and Tetsuya Fukazawa
Medicinal Chemistry Research Laboratories, Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
Received 29 May 1998; accepted 24 June 1998
Abstract
We report simple and efficient methods for the preparation of enantiomerically pure spiro[benzo[c]thiophene-
1(3H),40-piperidine]-(2S)-oxide (S)-1, a key intermediate for the synthesis of tachykinin receptor antagonist, by
resolution and asymmetric sulfoxidation. Racemic (RS)-1 can be resolved with (S)-(+)-mandelic acid in acetonitrile
to give (S)-1 of >99% ee. We also describe the asymmetric sulfoxidation of sulfide 5 in excellent enantiomeric
excess and high chemical yield by the use of the Davis reagent. © 1998 Elsevier Science Ltd. All rights reserved.
Chiral sulfoxides are important compounds both as subunits in a number of natural products and
medicines, and as chiral auxiliaries in asymmetric syntheses.1 For this reason, it is of great benefit
to develop efficient methods for the preparation of chiral sulfoxides with high enantiomeric purity.
Spiro[benzo[c]thiophene-1(3H),40 -piperidine]-(2S)-oxide (S)-1 is one of the key constituents of biologic-
ally active compounds such as tachykinin receptor antagonists.2 Since the (S)-configuration of sulfoxide
has been shown to be an essential requirement for more potent binding affinities in one of our recent
studies,2a we have relied on the use of large amounts of enantiomerically pure (S)-1 in various phases of
our program to design potent, orally active tachykinin receptor antagonists.
At first, we investigated the resolution of racemic sulfoxide (RS)-1. Racemic sufoxide (RS)-1 was
prepared in 50–60% yield from (2-bromophenyl)methanethiol 2 in five steps via a modified version of
Parham’s method (Scheme 1).3 Compound 2 was converted to a dianion with n-BuLi in THF at −78°C,
and then converted to compound 4 by treatment with N-Boc-piperidin-4-one 3. Compound 4 was treated
with aqueous H2SO4 at 100°C to cyclize, and then converted to sulfide 5 by treatment with Boc2O and
∗
Corresponding author. E-mail: takahi@shina.sankyo.co.jp
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00257-2

2568
T. Nishi et al. / Tetrahedron: Asymmetry 9 (1998) 2567–2570
triethylamine. Racemic sulfoxide (RS)-1 was cleanly provided by oxidation of 5 via treatment with m-
chloroperbenzoic acid (mCPBA) or Oxone® followed by deprotection of the amine.
Scheme 1.
In conducting the resolution, we initially examined various combinations of resolving reagent (man-
delic acid, tartaric acid, dibenzoyltartaric acid and camphorsulfonic acid) and solvent. The optically
active sulfoxide (S)-1 was most efficiently prepared by resolution of (RS)-1 with (S)-(+)-mandelic acid in
acetonitrile. Treatment of an acetonitrile solution of racemic (RS)-1 with 0.5 equiv. of (S)-(+)-mandelic
acid resulted in 60–70% yield (based on mandelic acid) of (S)-1/(S)-(+)-mandelic acid salt with >99% ee
(Scheme 2). Recrystallization from acetonitrile or ethanol gave white crystals (mp 197.0–200.0°C, [α]24
D
+78.3 (c 1, MeOH)), and a subsequent base treatment gave (S)-1 of 99.8% ee in 75–85% recovery.4
Scheme 2.
The ee-value of 1 could be determined by HPLC analysis. The sulfoxide 1 was converted to the N-Boc
derivative with Boc2O and triethylamine in CH2Cl2, and the resulting N-Boc-1 was analyzed by chiral
HPLC (column, Chiralcel OD (4.6φ×250 mm); eluent, n-hexane:2-propanol (80:20) mixture; flow rate,
0.8 ml/min; tR of (S)-isomer, 21.9 min; tR of (R)-isomer, 17.8 min). The stereochemistry of (S)-1 was
confirmed by X-ray analysis of the α-methoxy-α-trifluoromethylphenylacetic acid (MTPA) amide of
(S)-1. A single-crystal X-ray structure determination of the (R)-MTPA amide of (S)-1 unambiguously
established the relative configuration, and hence, the absolute stereochemistry of sulfoxide is S, as shown
in Fig. 1.5 This synthesis also led, of course, to the synthesis of (R)-1 with the opposite configuration
by using (R)-(−)-mandelic acid. Thus, (RS)-1 could be efficiently resolved with mandelic acid with high
enantiomeric purity and a good yield.
On the other hand, asymmetric oxidation of prochiral sulfide 5 is a straightforward route to chiral
sulfoxide (S)-1. To date, there are relatively few general methods for the preparation of chiral sulfoxide
Fig. 1.

T. Nishi et al. / Tetrahedron: Asymmetry 9 (1998) 2567–2570
2569
Table 1
Asymmetric sulfoxidation of 5
with high enantiomeric purity. The most successful methods for asymmetric sulfoxidation include the
modified Sharpless procedure,6 and much progress has been made through the use of enzymes,7 or the
use of chiral complexes with titanium,8 manganese,9 and vanadium10 as catalysts, or the use of the
chiral oxaziridines of Davis.11 However, among these approaches to enantiomerically pure sulfoxide,
the applicable sulfides are still limited mainly to aryl alkyl sulfides, and a significant decrease in
enantioselectivity is seen for oxidation of dialkyl sulfides. In the present study, we examined several
of the approaches for asymmetric sulfoxidation of 5. The data in Table 1 summarize the results obtained
in different oxidation conditions.
Attempts at titanium-mediated oxidation using diethyl tartarate (DET)8f or binaphthol8d
as chiral ligands were unsatisfactory with diminished yield and enantioselectivity (run 1
and 2). Attempts at manganese-catalyzed9 c and vanadium-catalyzed10b oxidation procedures
resulted in moderate ee and yield (run 3 and 4). In the course of this investigation, we
examined both [(3,3-dimethoxycamphoryl)sulfonyl]oxaziridine 811a and N-(phenylsulfonyl)-(3,3-
dichlorocamphoryl)oxaziridine 911b, two Davis reagents which have been reported to be useful for
asymmetric sulfoxidation (runs 5–8). These oxidations were carried out by treating the sulfide 5
with an equivalent amount of the oxaziridines in the appropriate solvent at 25°C. In particular, N-
(phenylsulfonyl)(3,3-dichlorocamphoryl)oxaziridine 9 yielded much better ees than the other reagents.
A screening of appropriate solvents for oxidation showed a dramatic solvent effect, and the best solvents

2570
T. Nishi et al. / Tetrahedron: Asymmetry 9 (1998) 2567–2570
were dichloromethane and toluene. The major advantages of these stoichiometric reagents are that they
can oxidize substrates under neutral, aprotic conditions, and that they can be recycled as chiral species.
Recrystallization of the resulting N-Boc-(S)-1 (94–96% ee) from diisopropyl ether gave N-Boc-(S)-1 of
24
99.8% ee as white crystals (mp 129.0–130.5°C), [α]D +57.1 (c 1, MeOH). Following deprotection of
the Boc group with 4 N HCl/dioxane in ethanol, recrystallization from a mixture of methanol:diethyl
ether (1:2) gave (S)-1 HCl salt in quantitative yield (mp 209.5–210.5°C, [α]D24 +63.8 (c 1, MeOH)).
In conclusion, the methods described above greatly simplify the preparation of 1 in both enantiomeric
forms with high enantiomeric purity.
Acknowledgements
We are grateful to Mr. Yoji Furukawa for the X-ray analysis.
References
1. (a) Carreño, M. C. Chem. Rev. 1995, 95, 1717–1760. (b) Kagan, H. B. In Catalytic Asymmetric Synthesis, Ojima, I. Ed;
VCH: New York, 1993; Chapter 4.3, pp. 203–226. (c) Anderson, K. K. In The Chemistry of Sulfones and Sulfoxides, Patai,
S., Rappoport, Z., Stirling, C. J. M., Eds; John Wiley and Sons: Chichester, England, 1988; Chapter 16, pp. 823–849 and
references cited therein.
2. (a) Nishi, T.; Fukazawa, T.; Kurata, H.; Ishibashi, K.; Nakajima, K.; Yamaguchi, T.; Ito, K. EP-776893-A1 (1996), Sankyo
Co., Ltd. (b) Kubota, H.; Kakefuda, A.; Nagaoka, H.; Yamamoto, O.; Ikeda, K.; Takeuchi, M.; Shibanuma, T.; Isomura, Y.
Chem. Pharm. Bull. 1998, 46, 242–254.
3. Parham, W. E.; Egberg, D. C.; Sayed, Y. A.; Thraikill, R. W.; Keyser, G. E.; Neu, M.; Montgomery, W. C.; Jones, L. D. J.
Org. Chem. 1976, 41, 2628–2633.
4. All new compounds are fully characterized by their spectroscopic and analytical data.
5. Crystal data: C22H22NO3F3S, MW=437.5, T=298 K, CuKα radiation, λ=1.5418 Å; monoclinic, space group P21,
a=9.994(2) Å, b=10.870(1) Å, c=20.569(1) Å, β=103.24(1)°, V=2175.0(5) Å3, Z=4, Dc=1.34g/cm3, R=0.066. Full X-
ray crystallographic data will be deposited with the Cambridge Crystallographic Data Centre.
6. (a) Bendazzoli, P.; Di Furia, F.; Licini, G.; Modena, G. Tetrahedron Lett. 1993, 34, 2975–2978. (b) Kagan, H. B.; Rebier,
F. Synlett. 1990, 643–650 and references cited therein.
7. (a) Colonna, S.; Gaggero, N.; Casella, L.; Carrea, G.; Pasta, P. Tetrahedron: Asymmetry 1992, 3, 95–106. (b) Fu, H.;
Kondo, H.; Ichikawa, Y.; Look, G. C.; Wong, C.-H. J. Org. Chem. 1992, 57, 7265–7270. (c) Madesclaire, M.; Fauve, A.;
Metin, J.; Carpy, A. Tetrahedron: Asymmetry 1990, 1, 311–314.
8. (a) Superchi, S.; Rosini, C. Tetrahedron: Asymmetry 1997, 8, 349–352. (b) Brunel, J.-M.; Kagan, H. B. Bull. Soc. Chim.
Fr. 1996, 133, 1109–1115. (c) Di Furia, F.; Licini, G.; Modena, G.; Motterle, R.; Nugent, W. A. J. Org. Chem. 1996, 61,
5175–5177. (d) Komatsu, N.; Hashizume, M.; Sugita, T.; Uemura, S. J. Org. Chem. 1993, 58, 4529–4533. (e) Sasaki, C.;
Nakajima, K.; Kojima, M.; Fujita, J. J. Bull. Chem. Soc. Jpn 1991, 64, 1318–1324. (f) Beckwith, A. L. J.; Boate, D. R. J.
Chem. Soc., Chem. Commun. 1986, 189–190.
9. (a) Halterman, R. L.; Jan, S.-T.; Nimmons, H. L.; Standlee, D. J.; Khan, M. A. Tetrahedron 1997, 53, 11257–11276. (b)
Nagata, T.; Imagawa, K.; Yamada, T.; Mukaiyama, T. Bull. Chem. Soc. Jpn 1995, 68, 3241–3246. (c) Noda, K.; Hosoya,
N.; Irie, R.; Yamashita, Y.; Katsuki, T. Tetrahedron 1994, 50, 9609–9618. (d) Palucki, M.; Hanson, P.; Jacobsen, E. N.
Tetrahedron Lett. 1992, 33, 7111–7114.
10. (a) Vetter, A. H.; Berkessel, A. Tetrahedron Lett. 1998, 39, 1741–1744. (b) Bolm, C.; Bienewald, F. Angew. Chem. Int. Ed.
Engl. 1995. 34, 2640–2642. (c) Nakajima, K.; Kojima, M.; Toriumi, K.; Saito, K.; Fujita, J. Bull. Chem. Soc. Jpn 1989,
62, 760–767.
11. (a) Davis, F. A.; Kumar, A.; Chen, B.-C. J. Org. Chem. 1991, 56, 1143–1145. (b) Davis, F. A.; Reddy, R. T.; Han, W.;
Carroll, P. J. J. Am. Chem. Soc. 1992, 114, 1428–1437.