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D. Sikriwal et al. / Tetrahedron 66 (2010) 6167e6173
dried (Na2SO4). Removal of the solvent in vacuo gave the product as
a pale yellow foam (0.73 g, 74%), which was purified by flash col-
umn chromatography on silica gel using ethyl acetate/hexane
(45:65) as eluant to give 14 (0.34 g, 35%) and 15 (0.33 g, 33.2%) as
viscous oils, which crystallised to white solid on standing
overnight.
minor isomer 17 could not be obtained pure but the spectrum was
obtained by subtraction from the mixture.
4.7.1.1. Methyl (2S,4S,6R)-N-tert-butoxycarbonyl-4-(N-para-tol-
uenesulonylamidobenzyl) pyroglutamate (16). 0White crystalline
solid; [found: C, 59.70; H, 5.99; N, 5.61. C25H30N2O7S requires C,
59.75; H, 6.02; N, 5.57%]; Rf (40% EtOAc/hexane) 0.32; mp
28
4.6.1.1. Methyl(2S,4S)-N-tert-butoxycarbonyl-4-(N-tert-butoxy-
carbonylaminomethyl)pyroglutamate (14). White solid; [found: C,
171e175 ꢁC; [
a]
D
þ77.5 (c 0.6, CHCl3); nmax (KBr) 2993, 1749, 1720,
1457, 1328, 1215, 1157, 1092 cmꢀ1
; dH (300 MHz, CDCl3) 7.46e7.49
54.88; H, 7.45; N, 7.61. C23H32N2O7 requires C, 54.83; H, 7.58; N,
(2H, d, J 8.1 Hz, ArH), 7.09e7.17 (7H, m, ArH), 6.45e6.47 (1H, d, JNH.6
4.0 Hz, NH), 4.40e4.44 (1H, d, J2,3S 9.5 Hz, H-2), 4.33e4.36 (1H, dd, J6,
NH 4.0 Hz, J6,4 6.9 Hz, H-6), 3.71 (3H, s, CO2CH3), 3.01e3.10 (1H, m, H-
4), 2.35 (3H, s, PhCH3), 2.00e2.12 (1H, m, H-3S), 1.78e1.85 (1H, m, H-
3R), 1.74 (9H, s, (CH3)3CO); dC (75 MHz, CDCl3) 173.0, 171.3, 148.8,
143.2, 137.2, 136.8, 129.3, 128.5, 128.1, 127.7, 127.4, 84.2, 59.0, 56.7,
52.7, 46.7, 27.9, 25.6, 21.5; MS (ESI) m/z: 525 [MþNa]þ; HRMS (DART):
[MꢀC5H10O2]þ, found 403.1281. C20H23N2O5S1 requires 403.1327.
22
7.52%]; Rf (70% EtOAc/hexane) 0.5; mp 95e97 ꢁC; [
a
]
ꢀ40.2 (c
D
0.28, CHCl3); nmax (KBr) 2928, 1772, 1707, 1520, 1459, 1374, 1313,
1258, 1217, 1158 cmꢀ1
;
dH (300 MHz, CDCl3) 5.15 (1H, br, NH),
4.56e4.60 (1H, dd, J2,3S 8.9 Hz, J2,3R 1.7 Hz, H-2), 3.78 (3H, s,
CO2CH3), 3.46e3.52 (1H, m, H-6), 3.30e3.36 (1H, m, H-6),
2.77e2.85 (1H, m, H-4), 2.06e2.23 (2H, m, H-3RþH-3S), 1.50 (9H, s,
(CH3)3CO), 1.42 (9H, s, (CH3)3CO); dC (75 MHz, CDCl3) 174.4, 171.6,
156.3, 83.9, 79.5, 57.0, 52.7, 42.7, 39.5, 28.3, 27.9, 25.6; MS (ESI) m/z:
395 [MþNa]þ; HRMS (DART): [MþH]þ, found 373.2010. C17H29N2O7
requires 373.1974.
4.7.1.2. Methyl (2S,4S,6S)-N-tert-butoxycarbonyl-4-(N-para-tol-
uenesulonylamidobenzyl)pyroglutamate (17 from 16þ17). Rf (40%
EtOAc/hexane) 0.32; nmax (KBr) 2933, 1749, 1720, 1457, 1327, 1263,
4.6.1.2. Methyl (2S,4R)-N-tert-butoxycarbonyl-4-(N-tert-butoxy-
carbonylaminomethyl)pyroglutamate (15). White solid; [found: C,
54.91; H, 7.53; N, 7.49. C23H32N2O7 requires C, 54.83; H, 7.58; N,
1214, 1156, 1092 cmꢀ1
; dH (300 MHz, CDCl3) 7.42e7.45 (2H, d, J
8.2 Hz, ArH), 7.00e7.17 (7H, m, ArH), 6.75e6.78 (1H, d, JNH.6 9.1 Hz,
NH), 4.63e4.68 (1H, dd, J6,NH 9.1 Hz, J6,4 4.8 Hz, H-6), 4.13e4.17 (1H,
dd, J2,3S 9.1 Hz, J2,3R 2.3 Hz, H-2), 3.73 (3H, s, CO2CH3), 3.16e3.24
(1H, m, H-4), 2.30 (3H, s, PhCH3), 1.79e2.12 (2H, m, H-3SþH-3R),
1.43 (9H, s, (CH3)3CO); dC NMR (75 MHz, CDCl3) 173.6, 171.2, 148.6,
142.9, 137.7, 136.4, 129.2, 128.6, 128.0, 127.9, 126.9, 84.1, 57.7, 57.0,
46.5, 27.8, 24.7, 21.4; MS (ESI) m/z: 525 [MþNa]þ.
7.52%]; Rf (70% EtOAc/hexane) 0.43; mp 105e107 ꢁC; [
a
]
23 ꢀ44.1 (c
D
0.2, CHCl3); nmax (KBr) 3020, 1786, 1748, 1710, 1511, 1369, 1308, 1216,
1156 cmꢀ1
; dH (300 MHz, CDCl3) 5.17 (1H, br, NH), 4.47e4.53 (1H,
dd (unresolved), H-2), 3.77 (3H, s, CO2CH3), 3.46e3.52 (1H, m, H-6),
3.30e3.38 (1H, m, H-6), 2.70e2.80 (1H, m, H-4), 2.46e2.56 (1H, m,
H-3S), 1.74e1.84 (1H, m, H-3R), 1.49 (9H, s, (CH3)3CO), 1.42 (9H, s,
(CH3)3CO); dC (75 MHz, CDCl3) 174.2, 171.7, 156.3, 149.2, 84.1, 79.6,
57.4, 52.6, 43.4, 40.3, 28.4, 27.9, 25.2; MS (ESI) m/z: 395 [MþNa]þ;
HRMS (DART): [MþH]þ, found 373.1982. C17H29N2O7 requires
373.1974.
Acknowledgements
D.S thank CSIR-UGC, New Delhi, India, for the financial support
in the form of Senior Research Fellowships. We thank SAIF, CDRI, for
the spectral and NOE data, Dr. P.K. Bharadwaj, IIT Kanpur for pro-
viding X-ray diffraction data and Prof. T. Naito for providing the
spectral data of compounds 10 and 1 (fully protected). CDRI com-
munication No. 7943.
4.6.2. Titanium enolate. TiCl4 (1.0 M in CH2Cl2, 3.3 ml, 3.3 mmol)
was added dropwise to a solution of 6 (0.35 g, 1.43 mmol) in an-
hydrous CH2Cl2 (10 ml) at ꢀ78 ꢁC under nitrogen atmosphere with
stirring followed after 5 min by dropwise addition of DIPEA
(0.62 ml, 3.59 mmol) resulting into a deep violet coloured solution.
The reaction mixture was stirred for 1.5 h at ꢀ78 ꢁC and a solution
of sulfone 13 (0.42 g, 1.58 mmol) in CH2Cl2 (10 ml) was added
(warm to dissolve). After stirring for 2 h at the same temperature,
the reaction was quenched with aqueous saturated ammonium
chloride solution (12 ml) and the mixture was allowed to warm to
room temperature. Water (15 ml) was added and the product was
extracted with dichloromethane (3ꢂ20 ml). The combined organic
extracts were washed with brine (10 ml), dried (Na2SO4) and con-
centrated in vacuo to yield the crude product 14 (0.43 g, 82%),
which was purified by flash column chromatography on silica gel,
using ethyl acetate/hexane (45:65) as eluant to give 14 (0.358 g,
67%) as clear oil, which crystallised on standing overnight.
Supplementary data
Supplementary data associated with this article can be found in
MOL files and InChIKeys of the most important compounds de-
scribed in this article.
References and notes
1. (a) Ikota, N. Tetrahedron Lett. 1992, 33, 2553; (b) Rosset, S.; Célérier, J. P.;
Lhommet, G. Tetrahedron Lett. 1991, 51, 7521.
2. (a) Baldwin, J. E.; Pritchard, G. J.; Williamson, D. S. Tetrahedron 2000, 57, 7991;
(b) Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K. J. Chem. Soc., PerkinTrans.12000,
3194; (c) Rubio, A.; Ezquerra, J.; Escribano, A. Tetrahedron Lett. 1998, 39, 2171.
3. Ohta, T.; Hosoi, A.; Nozoe, S. Tetrahedron Lett. 1988, 29, 329.
4. Ohfune, Y.; Tomita, M. J. J. Am. Chem. Soc. 1982, 104, 3511.
5. (a) Van Betsbrugge, J.; Van Den Nest, W.; Verheyden, P.; Tourwé, D. Tetrahedron
1998, 54, 1753; (b) Li, H.; Sakamoto, T.; Kikugawa, Y. Tetrahedron Lett. 1997, 38,
6677.
6. Hanessian, S.; McNaughton-Smith, G.; Lombart, H.; Lubell, W. Tetrahedron 1997,
53, 12789.
7. Welter, A.; Jadot, J.; Dardenne, G.; Marlier, M.; Casimir, J. Phytochemistry 1975,
14, 1347.
4.7. Methyl (2S,4S,6RS)-N-tert-butoxycarbonyl-4-(N-para-
toluenesulonylamidobenzyl)pyroglutamate (16 and 17)
Compounds 16 and 17 were obtained following the general
procedure for 7, 8 and 9.
8. Mbadiwe, E. I. Phytochemistry 1975, 14, 1351.
9. Isichei, M. O.; Achinewhu, S. C. Food Chem. 1988, 30, 83.
10. Akah, P. A.; Nwambie, A. I. J. Ethnopharmacol. 1994, 42, 179.
11. (a) Dupont, L.; Dideberg, O.; Welter, A. Acta Crystallogr. Sect. B: Struct. Sci. 1975,
31, 1018; (b) Welter, A.; Marlier, M.; Dardenne, G. Bull. Soc. Chim. Belg. 1975, 84,
243; (c) Welter, A.; Jadot, J.; Dardenne, G.; Marlier, M.; Casimi, J. Bull. Soc. Chim.
Belg. 1975, 84, 453.
4.7.1. Titanium enolate. Purification by flash column chromatog-
raphy on silica gel, using ethyl acetate/hexane (40:60) as eluant
separated mixture of 16 and 17 (0.526 g, 85%) together with
unreacted tosylamide. The major diastereoisomer 16 was separated
and purified by repeated recrystallisation from diethyl ether, which
provided distinct crystalline white solid 16 (0.142 g, 23%). The
12. Anwar, M.; Bailey, J. H.; Dickinson, L. C.; Edwards, H. J.; Goswami, R.; Moloney,
M. G. Org. Biomol. Chem. 2003, 1, 2364 and references cited therein.