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CO2Me
CO2Bn
c,d
CO2Bn
b
O
S
N
N
N
3. Sphingosine-1-phosphate receptor agonists: (a) Bolli, M.;
Lehmann, D.; Mathys, B.; Mueller, C.; Nayler, O.; Velker,
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Ghosh, S.; Elder, A. M.; Mattia, K. M. U.S. Patent Appl.
Publ. 2,005,070,549, 2005; EDG receptor agonists: Chen,
W.; Hale, J. J.; Li, Z.; Lynch, C. L.; Mills, S. G.; Neway,
W. E., III. PCT Int. Appl. WO 2,003,105,771, 2003;
GABA uptake inhibitors: Hoeg, S.; Greenwood, J. R.;
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F.; Groneberg, R. D.; Harvey, D. M.; O’Sullivan, M. F.;
Zetterberg, F. PCT Int. Appl. WO 2,006,073,361, 2006;
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Qasem, A. R.; Sgarzi, F.; Spampinato, S. J. Med. Chem.
2002, 45, 2571–2578; Agonists at the strychnine-sensitive
glycine receptor: Johnson, G.; Drummond, J. T.; Boxer, P.
A.; Bruns, R. F. J. Med. Chem. 1992, 35, 233–241.
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2007, 72, 2030–2039.
Ph
10
Me
Ph
Me
18
Ph
Me
19
R = Me
R = Bn
a
17
CO2H
e
19
N
H
(S)-1
Scheme 4. Optimized method: (a) BnOH, APTS, toluene, reflux, 18 h,
98%; (b) Lawesson’s reagent, toluene, 95 °C, 2 h, 98%; (c) MeI,
CH2Cl2, rt, 24 h; (d) NaBH4, MeOH, 0 °C, 1 h, 75% yields from 14; (e)
Pd/C, H2, MeOH, rt, 24 h, 100%.
Previous results associated with the use of a large excess
of a pyrophoric reagent, led us to envisage the reduction
of the thiolactam via its methyl thioiminium salt.23 Benz-
ylic ester 1724 was prepared from 10 in order to release
b-proline 1 after a single hydrogenolysis step in the final
optimized route (Scheme 4). Thiolactam 1825 reacted
with an excess methyl iodide in dichloromethane quan-
titatively to afford the thioiminium salt intermediate as
a colorless foam, which was immediately treated with
NaBH4 in methanol to afford amino ester 19 with a
reproducible 75% overall yield.26 Finally, palladium
mediated debenzylations released pure (S)-b-proline 1
quantitatively.27 Under similar conditions, the lactam
diasteromer 9 afforded (R)-1 with comparable yields
for each steps (72% overall yield from 9).
In conclusion, we have reported the shortest synthesis of
b-proline 1 starting from easily available lactams 9 or 10
prepared from the cheap methyl itaconate and (R)-a-
methylbenzylamine. The key step involved the chemo-
selective reduction of a methyl thioiminium salt in the
presence of a benzylic ester. This high yielding practical
synthesis can be carried out on a multigram scale and
provides in a single four step procedure both enantio-
mers of b-proline 1 in 72% overall yield.
8. Thomas, C.; Orecher, F.; Gmeiner, P. Synthesis 1998,
1491–1496.
9. Mazzini, C.; Lebreton, J.; Alphand, V.; Furstoss, R. J.
Org. Chem. 1997, 62, 5215–5218.
10. Klein, S. I.; Czekaj, M.; Molino, B. F.; Chu, V. Bioorg.
Med. Chem. Lett. 1997, 7, 1773–1778.
11. Kim, Y. J.; Kaiser, D. A.; Pollard, T. D.; Ichikawa, Y.
Bioorg. Med. Chem. Lett. 2000, 10, 2417–2419.
12. Stoncius, A.; Nahrwold, M.; Sewald, N. Synthesis 2005,
1829–1837.
13. b-Proline: 265 €/g (Interchim) compared to a-proline: 0.56
€/g (Aldrich).
Acknowledgments
`
The authors acknowledge the ‘Ministere de la Recherche
et des Nouvelles Technologies’ ‘PunchOrga’ Network
(Poˆle Universitaire Normand de Chimie Organique),
CNRS (Centre National de la Recherche Scientifique),
the ‘Region Basse Normandie’, and the European
Union (FEDER) for funding.
´
14. Wu, Y.-H.; Feldkamp, R. F. J. Org. Chem. 1961, 26,
1519–1524.
References and notes
15. Felluga, F.; Pitacco, G.; Prodan, M.; Pricl, S.; Visintin,
M.; Valentin, E. Tetrahedron: Asymmetry 2001, 12, 3241–
3249.
1. Kim, Y. J.; Kaiser, D. A.; Pollard, T. D.; Ichikawa, Y.
Bioorg. Med. Chem. Lett. 2000, 10, 2417–2419.
2. (a) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem.
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16. Methyl-5-oxo-1-((R)-1-phenylethyl)pyrrolidine-3-carbox-
ylate 9 and 10. To a solution of (R)-1-phenylethylamine
(1.16 g, 9.57 mmol, 1.3 equiv) in methanol (1.5 mL) was
added methyl itaconate 8 (1.16 g, 7.33 mmol). The mixture