LETTER
Westley, J. W.; Potts, B. C. M. J. Org. Chem. 1995, 60,
Approach to the Left-Hand Side of Batzelladine A
2031
3.54–3.50 (2 H, m, CH2N), 3.42 (3 H, s, Me), 3.05 (1 H, ddd,
J = 16.8, 8.6, 6.9 Hz, one of CH2), 2.70 (1 H, ddd, J = 16.8,
8.8, 7.1 Hz, one of CH2C=C) and 2.00–1.94 (2 H, m, CH2).
13C NMR (62.5 MHz, CDCl3): d = 169.7 (C=O), 166.2
(C=O), 157.1 (C=CCO2Me), 143.2 (arom. C), 128.0 (arom.
CH), 126.3 (arom. CH), 125.8 (arom. CH), 90.1
(C=CCO2Me), 53.6 (CH), 52.0 (CH3), 50.1 (CH3), 47.5
(CH2), 31.5 (CH2), 21.7 (CH2). MS (TOF AP+): m/z (%) =
305 (22) [MH+], 230 (100), 195 (43).
1182. (b) Patil, A. D.; Freyer, A. J.; Taylor, P. B.; Cartre, P.
B.; Zuber, B.; Johnson, R.; Faulkner, D. J. J. Org. Chem.
1997, 62, 1814. (c) Braekman, J. C.; Daloze, D.; Tavares,
R.; Hajdu, E.; Van Soest, R. W. M. J. Nat. Prod. 2000, 63,
193. (d) Gallimore, W. A.; Kelly, M.; Scheuer, P. J. J. Nat.
Prod. 2005, 68, 1420. (e) Hua, H.-M.; Peng, J.; Dunbar, D.
C.; Schinazi, R. F.; de Castro Andrews, A. G.; Cuevas, C.;
Garcia-Fernandez, L. F.; Kelly, M.; Hamann, M. T.
Tetrahedron 2007, 63, 11179.
(16) (Z)-Ethyl 3-(Cyanoamino)-2-(pyrrolidin-2-ylidene)oct-
anoate (18)
(3) (a) Bewley, C. E.; Ray, S.; Cohen, F.; Collins, S. K.;
Overman, L. E. J. Nat. Prod. 2004, 67, 1319.
Cyanamide (16 mg, 0.4 mmol) was added to a solution of
hexanal (48 mL, 0.4 mmol) in dry CH2Cl2 (4 mL) under N2,
and the resulting suspension was stirred at 25 °C for 30 min.
A solution of (Z)-pyrrolidin-2-ylidene-acetic acid ethyl ester
(17, 60 mg, 0.4 mmol) in CH2Cl2 (2 mL) was added, and the
resulting mixture was stirred at 25 °C for 3 h. The solvent
was then removed in vacuo to afford the title compound as a
pale yellow gum (94 mg, 87% crude yield). 1H NMR (500
MHz, CDCl3): d = 8.26 (1 H, br s, NH), 4.37 (1 H, br s,
NHCN), 4.00–4.18 (2 H, m, CO2CH2), 3.75 (1 H, app. q, J =
7.4 Hz, CHNHCN), 3.50 (2 H, app. t, J = 7.0 Hz, CH2NH),
2.78 (1 H, ddd, J = 16.1, 9.1, 7.0 Hz, one of CH2C=C), 2.58
(1 H, ddd, J = 16.1, 9.2, 6.9 Hz, one of CH2C=C), 1.89–2.03
(2 H, m, pyrrolidine CH2CH2NH), 1.64–1.85 (2 H, m,
CH2CHNHCN), 1.14–1.26 [9 H, m, (CH2)3 and
(b) Shimokawa, J.; Iijima, Y.; Hashimoto, Y.; Chiba, H.;
Tanaka, H.; Nagasawa, K. Heterocycles 2007, 72, 145.
(c) Shimokawa, J.; Ishiwata, T.; Shirai, K.; Koshino, H.;
Tanatani, A.; Nakata, T.; Hashimoto, Y.; Nagasawa, K.
Chem. Eur. J. 2005, 11, 6878.
(4) (a) Shimokawa, J.; Shirai, K.; Tanatani, A.; Hashimoto, Y.;
Nagasawa, K. Angew. Chem. Int. Ed. 2004, 43, 1559.
(b) Arnold, M. A.; Day, K. A.; Durón, S. G.; Gin, D. Y.
J. Am. Chem. Soc. 2006, 128, 13255.
(5) (a) Cohen, F.; Overman, L. E.; Ly Sakata, S. K. Org. Lett.
1999, 1, 2169. (b) Nagasawa, K.; Ishiwata, T.; Hino, T.;
Koshino, H.; Hashimoto, Y.; Nakata, T. Org. Lett. 2002, 4,
2921. (c) Arnold, M. A.; Durón, S. G.; Gin, D. Y. J. Am.
Chem. Soc. 2005, 127, 6924. (d) Evans, P. A.; Qin, J.;
Robinson, J. E.; Bazin, B. Angew. Chem. Int. Ed. 2007, 46,
7417.
CO2CH2CH3], 0.81 (3 H, t, J = 6.9 Hz, CH3CH2-alkyl). 13
NMR (125 MHz, CDCl3): d = 169.0 (ester C=O), 166.0
(C=CCO2Et), 117.3 (NHC≡N), 88.3 (C=CCO2Et), 59.0
(CO2CH2), 47.3 (CHNHCN), 35.2 (CH2NH), 31.6
C
(6) Snider, B. B.; Chen, J.; Patil, A. D.; Faulkner, D. J.
Tetrahedron Lett. 1996, 37, 6977.
(7) (a) Cohen, F.; Overman, L. E. J. Am. Chem. Soc. 2001, 123,
10782. (b) Cohen, F.; Overman, L. E. J. Am. Chem. Soc.
2006, 128, 2604.
(8) Collins, S. K.; McDonald, A. I.; Overman, L. E.; Rhee, Y. H.
Org. Lett. 2004, 6, 1253.
(CH2C=C), 31.5 (CH2CHNHCN), 26.6 (CH2CH2NH), 22.5
(CH2) 22.4 (CH2), 21.6 (CH3CH2-alkyl), 14.6
(CO2CH2CH3), 13.9 (CH3CH2-alkyl).
(17) Methyl (5S)-1,2,3,5,6,7-Hexahydro-3-(9-tert-butyl-
diphenylsilyloxynonyl)-5-hydroxy-1-thioxo-
(9) For related work, see: (a) Black, G. P.; Murphy, P. J.;
Thornhill, A. J.; Walshe, N. D. A.; Zanetti, C. Tetrahedron
1999, 55, 6547. (b) Louwrier, S.; Ostendorf, M.; Tuynman,
A.; Hiemstra, H. Tetrahedron Lett. 1996, 37, 905.
(10) (a) Elliott, M. C.; Long, M. S. Tetrahedron Lett. 2002, 43,
9191. (b) Elliott, M. C.; Long, M. S. Org. Biomol. Chem.
2004, 2, 2003.
(11) (a) Tanino, H.; Nakata, T.; Kaneko, T.; Kishi, Y. J. Am.
Chem. Soc. 1977, 99, 2818. (b) Taguchi, H.; Yazawa, H.;
Arnett, J. F.; Kishi, Y. Tetrahedron Lett. 1977, 17, 627.
(c) Hong, C. Y.; Kishi, Y. J. Am. Chem. Soc. 1992, 114,
7001.
(12) Elliott, M. C.; Kruiswijk, E. J. Chem. Soc., Perkin Trans. 1
1999, 3157.
(13) Davies, C. D.; Elliott, M. C.; Wood, J. L. Tetrahedron 2006,
62, 11158.
(14) Nishiyama, K.; Oba, M. Bull. Chem. Soc. Jpn. 1987, 60,
2289.
(15) (Z)-Methyl [3-Methoxycarbonylamino)-3-phenyl-2-
pyrrolidin-2-ylidene]propionate (16)
pyrrolo[1,2-c]pyrimidine-4-carboxylate (25)
Trimethylsilyl isothiocyanate (62 mL, 0.45 mmol) was added
to a solution of aldehyde 26 (183 mg, 0.45 mmol) in dry
CH2Cl2 (3 mL) under N2, and the resulting brown solution
was stirred for 30 min at 25 °C. A solution of alkylidene-
pyrrolidine 24 (70 mg, 0.45 mmol) in CH2Cl2 (2 mL) was
then added, and the reaction was stirred for 3 h. The reaction
was quenched with ca. 0.1 M aq NaOH solution (20 ml) and
the layers separated. The aqueous layer was washed with
CH2Cl2 (3 × 25 mL), the combined organic layers dried with
Na2SO4, and the solvent removed in vacuo. The resulting
orange gum was purified by column chromatography
(eluent: hexane–EtOAc, 2.5:1; Rf = 0.55) to give the title
compound (79 mg, 29%) as a yellow gum. HRMS: m/z calcd
for C34H49N2O4SiS [M]: 609.3182. Found: 609.3196 [MH+].
IR (CH2Cl2): nmax = 3401, 3205, 2883, 1675, 1629, 1531,
1462, 1416, 1324 and 1255 cm–1. 1H NMR (500 MHz,
CDCl3): d = 7.70–7.55 (4 H, m, arom. CH), 7.41–7.28 (6 H,
m, arom. CH), 6.99 (1 H, br s, NH), 5.20 (1 H, br s, OH),
5.10 (1 H, app. t, J = 8.0 Hz, CHOH), 4.24 (1 H, app. dt, J =
7.8, 3.8 Hz, CHNH), 4.06 (1 H, ddd, J = 11.6, 8.8, 3.3 Hz,
one of CH2NCS), 3.89 (1 H, ddd, J = 11.6, 9.0, 8.0 Hz, one
of CH2NCS), 3.65 (3 H, s, CO2CH3), 3.58 (2 H, t, J = 6.5 Hz,
CH2OTBDPS), 2.40–2.33 (1 H, m, one of CH2CHOH),
2.00–1.95 (1 H, m, one of CH2CHOH), 1.54–1.40 (6 H, m,
3 × CH2) and 1.36–1.10 [19 H, m, 5 × CH2 and ((CH3)3C].
13C NMR (125 MHz, CDCl3): d = 175.3 (C=S), 166.2
(C=O), 153.2 (C=CCO2Me), 139.8 (arom. C), 134.6 (arom.
CH), 128.5 (arom. CH), 126.6 (arom. CH), 99.6
Methyl N-phenylmethylenecarbamate (15, 62 mg, 0.38
mmol) was added to a solution of (Z)-pyrrolidin-2-ylidene-
acetic acid methyl ester (11, 54 mg, 0.38 mmol) in CH2Cl2
(5 mL). The resulting solution was stirred at r.t. overnight,
concentrated in vacuo, and purified by flash column
chromatography (eluent: hexane–EtOAc, 2:1; Rf = 0.4) to
give the title compound (78 mg, 67%) as a colourless oil.
HRMS: m/z calcd for C16H21N2O4 [M]: 305.1501. Found:
305.1515 [MH+]. 1H NMR (400 MHz, CDCl3): d = 8.27 (1
H, br s, NH), 7.21–7.18 (4 H, m, J = 4.2 Hz, arom. CH),
7.14–7.08 (1 H, m, arom. CH), 5.91 (1 H, app. br d, J = 9.4
Hz, NH), 5.11 (1 H, d, J = 10.0 Hz, CHPh), 3.65 (3 H, s, Me),
(C=CCO2Me), 71.2 (CHOH), 63.0 (CH2OTBDPS), 51.2
(CO2CH3), 50.9 (CH-alkyl), 48.7 (CH2NC=S), 36.1
(pyrrolidine CH2CHOH), 31.6 (CH2CH-NH), 28.8 (CH2),
Synlett 2008, No. 13, 2028–2032 © Thieme Stuttgart · New York