S. Raghavan, V.S. Babu / Tetrahedron 67 (2011) 2044e2050
2049
305 [MþNa]þ; HRMS(ESI) calcd for C14H22N2O4Na [MþNa]þ
J¼9.5 Hz, 1H), 4.19 (q, J¼7.3 Hz, 2H), 4.07e3.94 (m, 2H), 3.80e3.68
(m, 1H), 3.40e3.31 (m, 1H), 2.72 (dd, J¼17.6, 5.1 Hz, 1H), 2.35e2.23
(m, 1H), 1.96 (s, 3H), 1.55e1.45 (m, 4H), 1.41 (s, 9H), 1.29 (t, J¼7.3 Hz,
305.1604, found 305.1610.
4.1.17. (1S,5S,6S)-Ethyl-5-(tert-butoxycarbonylamino)-7-azabicyclo
[4.1.0]hept-3-ene-3-carboxylate [24]. The inseparable mixture of
azido alcohols 22 and 23 upon treatment with triphenylphosphine
as detailed above for the preparation of 18 yielded a separable
mixture of compounds 18 and 24. The crude product was purified
by column chromatography (eluent 40% EtOAc/hexane) to afford
initially compound 18 and then compound 24 (23 mg, 71%) isolated
3H), 0.92e0.84 (m, 6H); dC (75 MHz, CDCl3): d 170.7, 165.7, 156.3,
137.6, 129.3, 82.1, 79.4, 75.7, 60.8, 54.4, 49.2, 30.9, 28.4, 26.2, 25.8,
23.3, 14.3, 9.6, 9.3; m/z (MS-ESI) 413 [MþH]þ; HRMS(ESI) calcd for
C16H25N2O5 [MþH]þ 413.2666, found 413.2651.
4.1.21. Ethyl-(3R,4R,5S)-4-acetamide-5-amino-3-(1-ethylpropoxy)
cyclohexene-1-carboxylate phosphate [1]. To a stirred solution of 19
(62 mg, 0.15 mmol) in CH2Cl2 (1 mL), TFA (0.22 mL) was added at rt.
The resulting solution was stirred for 1 h at the same temperature.
After removing solvent under reduced pressure, the residue was
dissolved in CH2Cl2 (3 mL), and saturated NaHCO3 aq solution was
added at 4 ꢁC. The aq layer was extracted with CH2Cl2 (10 mL) and
the combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated. To a stirred solution of crude
product in EtOH (2.4 mL), a solution of H3PO4 in EtOH (1 M, 0.3 mL,
0.3 mmol) was added at room temperature. After the resulting
solution was warmed to 50 ꢁC, crystallization commenced. The
mixture was slowly cooled down to 4 ꢁC. The crystals were col-
yield as a gummy liquid. Rf (60% EtOAc/hexane) 0.3; [
a
]
25 ꢀ38 (c 1,
D
CHCl3); nmax (KBr) 3259, 2977, 2929, 1706, 1437, 1176, 1119,
722 cmꢀ1
; dH (300 MHz, CDCl3) 6.74e6.64 (m, 1H), 4.70e4.59 (m,
1H), 4.56e4.47 (m, 1H), 4.16 (q, J¼6.8 Hz, 2H), 2.91e2.79 (m, 1H),
2.54e2.33 (m, 3H), 1.45 (s, 9H), 1.28 (t, J¼6.8 Hz, 3H); dC (75 MHz,
CDCl3) 166.6, 155.1, 139.2, 132.8, 79.9, 60.7, 45.4, 37.2, 28.3, 24.1,
22.6, 14.1.
4.1.18. Compound 18 from 24. To a solution of the aziridine 24
(23 mg, 0.08 mmol) in toluene (1 mL) was added DBU (5
mL,
0.02 mmol) at rt. After 24 h of stirring at rt, toluene was removed
under reduced pressure and the residue was purified by column
chromatography (eluent 40% EtOAc/hexane) to afford aziridine 18
(13 mg, 58%) as a gummy liquid. 15% of aromatized compound
lected and washed with acetone and hexane to afford 1 (32 mg, 71%
25
yield) as white crystals. Mp 205e206 ꢁC; [
a
]
D
ꢀ26.4 (c 1, H2O);
(Reported [
a
]
29 ꢀ27.1 (c 0.97, H2O));4q nmax (KBr) 3422, 2362, 2342,
D
observed; Rf (50% EtOAc/hexane) 0.3; [
a]
25 ꢀ44.9 (c 1, CHCl3); nmax
1715,1658,1248 cmꢀ1
;
dH (400 MHz, CDCl3) 6.81 (m,1H), 4.33e4.26
D
(KBr) 3259, 2977, 2929, 1706, 1437, 1176, 1119, 722 cmꢀ1
;
dH
(m, 1H), 4.26e4.17 (m, 1H), 4.06e3.98 (m, 1H), 3.60e3.47 (m, 2H),
2.97e2.88 (m, 1H), 2.54e2.42 (m, 1H), 2.04 (s, 3H), 1.58e1.46 (m,
3H), 1.45e1.36 (m, 1H), 1.24 (t, J¼7.3 Hz, 3H), 0.84 (t, J¼7.7 Hz, 3H),
0.80 (t, J¼7.7 Hz, 3H); dC (75 MHz, CDCl3) 175.9, 168.0, 138.5, 128.2,
84.9, 75.7, 63.0, 53.2, 49.7, 28.8, 26.1, 25.6, 23.0, 13.9, 9.1, 9.0; m/z
(MS-ESI) 313 [MþH]þ; HRMS(ESI) calcd for C16H29N2O4 [MþH]þ
313.2132, found 325.2127.
(300 MHz, CDCl3) 7.25e7.13 (m, 1H), 4.52e4.32 (m, 2H), 4.17 (q,
J¼6.8 Hz, 2H), 2.89e2.70 (m, 1H), 2.68e2.47 (m, 2H), 2.44e2.24 (m,
1H), 1.42 (s, 9H), 1.28 (t, J¼6.8 Hz, 3H); dC (75 MHz, CDCl3) 166.6,
155.0, 137.6, 132.9, 79.4, 60.5, 42.7, 36.8, 28.2, 26.3, 25.4, 14.0.
4.1.19. (1S,5S,6R)-Ethyl-7-acetyl-5-(tert-butoxycarbonylamino)-7-
azabicyclo[4.1.0]hept-2-ene-3-carboxylate [2]. To a solution of the
aziridine 18 (70 mg, 0.25 mmol) in anhydrous CH2Cl2 (1.25 mL)
Acknowledgements
cooled at 0 ꢁC were added Et3N (67
and acetic anhydride (28
m
L, 0.5 mmol), DMAP (1 mg),
m
L, 0.28 mmol) successively and the
S.R. is thankful to Dr. J.M. Rao, Head, Org. Div. I and Dr. J.S. Yadav,
Director, IICT for constant support and encouragement. V.S.B is
thankful to the CSIR, New Delhi for fellowship. Financial assistance
from DST (New Delhi) is gratefully acknowledged. We thank Dr. A.C.
Kunwar for the NMR spectra and Dr. R. Srinivas for the mass spectra.
mixture was stirred for 30 min at ambient temperature. The re-
action mixture was diluted with CH2Cl2 (3 mL) and washed with
10% aq citric acid solution, water, brine, and dried over Na2SO4.
Evaporation of the solvent under reduced pressure afforded the
crude product, which was purified by column chromatography
(eluent 1% Et3N, 19% EtOAc, 80% hexane) to afford 2 (71 mg, 87%) as
References and notes
25
a pale yellow liquid. Rf (30% EtOAc/hexane) 0.3; [
a
]
D
ꢀ101.2 (c 1,
29
ꢀ102.4 (c 0.92, CHCl3));4q nmax (KBr) 3346,
1. (a) Kim, C. U.; Lew, W.; Williams, M. A.; Wu, H.; Zhang, L.; Chen, X.; Escarpe, P.
A.; Mendel, D. B.; Laver, W. G.; Stevens, R. C. J. Med. Chem. 1998, 41, 2451; (b)
Schmidt, A. C. Drugs 2004, 64, 2031.
CHCl3); (Reported [
a
]
D
2977, 2927, 1708, 1524, 1367, 1253, 1169 cmꢀ1
; dH (300 MHz, CDCl3)
7.23e7.14 (m, 1H), 4.58e4.47 (m, 1H), 4.41 (d, J¼8.3 Hz, 1H), 4.20 (q,
J¼7.5 Hz, 2H), 3.15e3.03 (m, 2H), 2.79e2.67 (m, 1H), 2.42e2.28 (m,
1H), 2.14 (s, 3H), 1.43 (s, 9H), 1.31 (t, J¼7.5 Hz, 3H); dC (75 MHz,
CDCl3) 181.2, 165.7, 154.9, 133.6, 130.2, 79.9, 60.9, 41.9, 40.9, 31.8,
28.2, 26.6, 23.0, 14.1; m/z (MS-ESI) 325 [MþH]þ; HRMS(ESI) calcd
for C16H25N2O5 [MþH]þ 325.1772, found 325.1763.
2. (a) Moscona, A. N. Engl. J. Med. 2005, 353, 1363; (b) Russell, R. J.; Haire, L. F.;
Stevens, D. J.; Collins, P. J.; Lin, Y. P.; Blackburn, G. M.; Hay, A. J.; Gamblin, S. J.;
Skehel, J. J. Nature (London) 2006, 443, 45.
3. (a) Rohloff, J. C.; Kent, K. M.; Postich, M. J.; Becker, M. W.; Chapman, H. H.; Kelly,
D. E.; Lew, W.; Louie, M. S.; McGee, L. R.; Prisbe, E. J.; Schultze, L. M.; Yu, R. H.;
Zhang, L. J. Org. Chem. 1998, 63, 4545; (b) Federspiel, M.; Fischer, R.; Hennig, M.;
Mair, H.-J.; Oberhauser, T.; Rimmler, G.; Albiez, T.; Bruhin, J.; Estermann, H.;
Gandert, C.; Gockel, V.; Gotzo, S.; Hoffmann, U.; Huber, G.; Janatsch, G.; Lauper,
S.; Rockel-Stabler, O.; Trussardi, R.; Zwahlen, A. G. Org. Process Res. Dev. 1999, 3,
266; (c) Karpf, M.; Trussardi, R. J. Org. Chem. 2001, 66, 2044 and references
therein; (d) Harrington, P. J.; Brown, J. D.; Foderaro, T.; Hughes, R. C. Org. Process
Res. Dev. 2004, 8, 86.
4. (a) Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.; Swaminathan, S.;
Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai, C. Y.; Laver, W. G.; Stevens, R.
C. J. Am. Chem. Soc. 1997, 119, 681; (b) Karpf, M.; Trussardi, R. J. Org. Chem. 2001,
66, 2044; (c) Cong, X.; Yao, Z.-J. J. Org. Chem. 2006, 71, 5365; (d) Yeung, Y.-Y.;
Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 6310; (e) Fukuta, Y.; Mita, T.;
Fukuda, N.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 6312; (f) Shie, J.-
J.; Fang, J.-M.; Wang, S.-Y.; Tasi, K.-C.; Cheng, Y.-S. E.; Yang, A.-S.; Hsiao, S.-C.; Su,
C.-Y.; Wong, C.-H. J. Am. Chem. Soc. 2007, 129, 11892; (g) Satoh, N.; Akiba, T.;
Yokoshima, S.; Fukuyama, T. Angew. Chem., Int. Ed. 2007, 46, 5734; (h) Ya-
matsugu, K.; Kamijo, S.; Suto, Y.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2007,
48, 1403; (i) Bromfield, K. M.; Graden, H.; Hagberg, D. P.; Olsson, T.; Kann, N.
Chem. Commun. 2007, 3183; (j) Mita, T.; Fukuda, N.; Roca, F. X.; Kanai, M.;
Shibasaki, M. Org. Lett. 2007, 9, 259; (k) Kipassa, N. T.; Okamura, H.; Kina, K.;
Hamada, T.; Iwagawa, T. Org. Lett. 2008, 10, 815; (l) Zutter, U.; Iding, H.; Spurr, P.;
Wirz, B. J. Org. Chem. 2008, 73, 4895; (m) Matveenko, M.; Willis, A. C.; Banwell,
4.1.20. (3R,4R,5S)-Ethyl-4-acetamido-5-(tert-butoxycarbonylamino)-
3-(pentan-3-yloxy)cyclohex-1-enecarboxylate [19]. To a stirred so-
lution of 2 (71 mg, 0.22 mmol) in 3-pentanol (4.2 mL), a solution of
BF3$Et2O in 3-pentanol (1 M, 0.32 mL, 0.32 mmol) was added at
ꢀ20 ꢁC. After 30 min, the reaction was diluted with EtOAc and
quenched with saturated NaHCO3 solution. The aq layer was
extracted with EtOAc. The combined organic layers were washed
with brine, dried over Na2SO4, and filtered. After removal of the
solvent under reduced pressure the crude product was purified
through column chromatography (eluent 40% EtOAc/hexane) to
afford 19 (62 mg, 70%) as a colorless solid. Mp 139e140 ꢁC; Rf (50%
EtOAc/hexane) 0.3; [
a]
25 ꢀ95.8 (c 1, CHCl3); (Reported [
a]
29 ꢀ97.1 (c
D
D
0.92, CHCl3));4q nmax (KBr) 3422, 2925, 1715, 1688, 1658, 1248 cmꢀ1
;
dH (300 MHz, CDCl3) 6.74 (m, 1H), 6.17 (d, J¼8.1 Hz, 1H), 5.30 (d,