(3S,6R)-3-Propyl-8-methylene-1,4-diazabicyclo[4.3.0]nonane-
2,5-dione 38
(1H, m), 1.86–2.08 (4H, m), 2.41–2.45 (1H, m), 3.52 (1H, m),
3.74 (1H, m), 3.81 (1H, m), 4.10 (1H, m), 6.37 (1H, br, NH);
δC(CDCl3, 50 MHz) 11.3, 15.3, 22.0, 24.5, 29.4, 39.7, 45.6,
58.3, 62.9, 165.2, 169.2; m/z (APCIϩ, M ϩ 1), 211 (100%);
C11H18N2O2 requires 211.1447. Found 211.1443.
Mono-lactim ether 35 (150 mg, 0.72 mmol) was dissolved in
0.1 HCl (2 ml) and left to stand for 5 min and the solvent
removed in vacuum. The gummy residue was immediately dis-
solved in a solution of N-methylmorpholine (200 mg) in butan-
2-ol (10 ml) and acetic acid (1 ml) and the reaction mixture
heated under reflux for 8 h. The solvent was removed in
vacuum to afford a crude oil which was purified by chroma-
tography (silica, ethyl acetate) to afford the desired compound
as a crystalline solid (131 mg, 0.63 mmol, 88% yield); mp
138 ЊC; [α]D23 ϩ85.0 (c 0.5, CH3OH); νmax(KBr)/cmϪ1 3480 (NH),
Acknowledgements
We thank Oxford Asymmetry International (S. D. B.) and the
Ministerio de Educación y Ciencia de España (F. S. S.) for
funding.
1669 (C᎐O), 1636 (C᎐O); δ (CD OD, 500 MHz) 0.97 (3H, t,
᎐
᎐
H
3
J 7.4, CH3), 1.39–1.51 (2H, m, CH2CH2CH3), 1.73–1.78 (2H,
m, CH2CH2CH3), 2.74 (1H, m, 7-Ha), 2.94 (1H, ddd, J 15.6, 7.3,
1.2, 7-Hb), 3.85 (1H, t, J 6.6, 3-H), 3.90 (1H, dq, J 16.0, 2.0,
9-Ha), 4.36 (1H, d, J 16.0, 9-Hb), 4.41 (1H, dd, J 10.8, 7.3,
References and notes
1 C. Prasad, Peptides, 1995, 16, 151; S. Johne and D. Groeger,
Pharmazie, 1977, 32, 1; K. Yoshida, M. Okamota, N. Shimazaki,
N. Norihiko and K. Hemmi, Prog. Biochem. Pharmacol., 1988, 22,
66.
2 A. J. Birch and R. A. Russell, Tetrahedron, 1972, 28, 2999.
3 R. M. Williams, T. Glinka, E. Kwast, H. Coffman and J. K. Stille,
J. Am. Chem. Soc., 1990, 112, 808 and references contained
therein.
6-H), 5.11 (1H, d, J 1.6, 8-C᎐CH H ), 5.14 (1H, dd, J 2.0,
᎐
a
b
1.0, 8-C᎐CH H ); δ (CD OD, 50 MHz) 13.9 (CH ), 19.5
᎐
a
b
C
3
3
(CH2CH2CH3), 36.7 and 37.4 (CH2CH2CH3 and 7-CH2), 50.9
(9-CH ), 58.2 (3-CH), 59.1 (6-CH), 109.4 (8-C᎐CH ), 142.3
᎐
2
2
(8-C), 168.4 (C᎐O), 170.8 (C᎐O); m/z (APCIϩ, M ϩ 1), 209
᎐
᎐
4 Based on a Chemical Abstract search on a parent Pro-Xxx skeleton.
5 R. D. Stipanovic, H. W. Schroeder and H. Hein, Lloydia, 1976,
39, 158; R. D. Stipanovic, H. W. Schroeder and H. Hein, J. Chem.
Soc., Perkin Trans. 1, 1973, 950.
6 J. Dittmann, A. Lawen, R. Zocher and H. Kleinkauf, Biol. Chem.
Hoppe-Seyler., 1990, 371, 829.
(100%); C11H17N2O2 requires 209.1290. Found 209.1295.
(3S,6R,8R)-3-Propyl-8-methyl-1,4-diazabicyclo[4.3.0]nonane-
2,5-dione [cyclo-L-norvaline-(4R)-methyl-D-proline] 26
Palladium on carbon (20%, 15 mg) was added to a solution of
DKP 38 (35 mg, 0.17 mmol) in methanol (5 ml) and stirred
under an atmosphere of hydrogen overnight. The reaction
mixture was filtered, and the solvent removed in vacuum to
yield a crude gum [31 mg, 0.15 mmol, 89% yield, 85% de
judged from integration of signals at δ 2.28 (minor) and δ 2.36
(major)]. The reaction mixture was purified by fractional
recrystallisation (ethyl acetate) of the minor diastereoisomer
43 and concentration of the mother liquor to afford the desired
compound 26 as a white crystalline solid (23 mg, 0.11 mmol,
65% yield); mp 231 ЊC (EtOAc); [α]D23 ϩ168.0 (c 0.52, EtOH);
δH(CDCl3, 500 MHz) 0.97 (3H, t, J 7.4, CH3), 1.16 (3H, d, J 6.2,
8-CHCH3), 1.41–1.56 (2H, m, CH2CH2CH3), 1.68 (1H, q,
J 10.8, 7-Hendo), 1.71–1.87 (2H, m, CH2CH2CH3), 2.36 (1H, m,
8-H), 2.46 (1H, m, 7-Hexo), 3.18 (1H, dd, J 11.8, 9.7, 9-Hendo),
3.68 (1H, dd, J 11.8, 3.0, 9-Hexo), 3.92 (1H, td, J 7.4, 5.5, 3-H),
4.28 (1H, dd, J 10.8, 5.6, 6-H), 7.30 (1H, br d, J 4.8, NH); NOE
enhancements (CDCl3, 500 MHz) δ 1.16 (8-C-CH3) enhances
resonances at δ 1.68 (7-Hendo, 2.5%), δ 2.36 (8-H, 3.9%) and
δ 3.18 (9-Hendo, 2.2%); δ 1.68 (7-Hendo) enhances resonances at
7 J. Su, Y. Zhong, L. Zeng, H. Wu, X. Shen and K. Ma, J. Nat. Prod.,
1996, 59, 504.
8 J. Baldas, A. J. Birch and R. A. Russell, J. Chem. Soc., Perkin Trans.
1, 1974, 50; P. S. Steyn, Tetrahedron, 1973, 29, 107; C.-B. Cui,
H. Kakeya, G. Okada, R. Onose, M. Ubukata, I. Takahasi, I.
Kiyoshi and H. Osada, J. Antibiot., 1995, 48, 1382; K. Arai, K.
Kimura, T. Mushiroda and Y. Yamamoto, Chem. Pharm. Bull.,
1989, 37, 2937; H. Fujimoto, Chiba Daigaku Seibutsu Kassei
Kenkyusho Hokoku, 1977, 5, 9 (Chem. Abstr., 1979, 91, 69 306a).
9 K. Kanoh, S. Kohno, T. Asari, T. Harada, J. Katada,
M. Muramatsu, H. Kawashima, H. Sekiya and I. Uno, Bioorg. Med.
Chem. Lett., 1997, 22, 2847.
10 T. Ostenfeld Larsen, J. C. Frisvad and S. Rosendal Jensen,
Phytochemistry, 1992, 31, 1613.
11 This class of -proline derived DKP natural products includes (a) the
tryprostatins (mammalian cell-cycle inhibitors) C. Cui, H. Kakeya
and H. Osada, Tetrahedron, 1997, 53, 59; C. Cui, H. Kakeya and
H. Osada, Tetrahedron, 1996, 52, 12 651; C. Cui, H. Kakeya and
H. Osada, J. Antibiot., 1996, 49, 534; C. Cui, H. Kakeya and H.
Osada, J. Antibiot., 1996, 49, 534; C. Cui, H. Kakeya and H. Osada,
J. Antibiot., 1996, 49, 527; C. Cui, H. Kakeya, G. Okada, R. Onose,
M. Ubukata, I. Takahasi, I. Isami, K. Isono and H. Osada,
J. Antibiot., 1995, 48, 1382; (b) the verrucologens (mycotoxins)
H. Hayashi, S. Murao and M. Arai, Chem. Express, 1991, 6, 989;
R. P. Hodge, C. M. Harris and T. M. Harris, J. Nat. Prod., 1988,
51, 66; M. Uramoto, M. Tanabe, K. Hirotsu and J. Clardy,
Heterocycles, 1982, 17, 349; (c) the epicorazines (antibiotics)
G. Deffieux, M.-J. Filleau and R. Baute, J. Antibiot., 1978, 31, 1106;
G. Deffieux, M. A. Baute, R. Baute and M.-J. Filleau, J. Antibiot.,
1978, 31, 1102; (d) the gliotoxins (immunomodulators) F. Seigle-
Murandi, S. Krivobok, R. Steiman and D. Marzin, J. Agric.
Food Chem., 1990, 38, 1854; P. Waring, R. D. Eichner,
A. Mullbacher and A. Sjaarda, J. Biol. Chem., 1988, 263, 18 493;
P. Waring, R. D. Eichner, U. Tiwari-Palni and A. Mullbacher, Aust.
J. Chem., 1987, 40, 991; (e) leptosins (antitumour) C. Takahashi,
A. Numata, Y. Ito, E. Matsumura, H. Araki, H. Iwaki and
K. Kushida, J. Chem. Soc., Perkin Trans. 1, 1994, 1859.
12 C. J. Barrow and H. H. Sun, J. Nat. Prod., 1994, 57, 471.
13 H. Izumida, N. Imamura and H. Sano, J. Antibiot., 1996, 49, 76;
H. Izumida, M. Nishijima, T. Takadera, A. M. Nomota and
H. Sano, J. Antibiot., 1996, 49, 829; H. Izumidi, N. Imamura, H.
Sano, M. Yamagishi, K. Ooishi, M. Suzuki and A. Katsuyama,
Patent, Chem. Abstr., 1997, 126, 30 385.
14 S. Murao, H. Hayashi, K. Takiuchi and M. Arai, Agric. Biol. Chem.,
1988, 52, 885; H. Hayashi, T. Fujiwara, S. Murao and M. Arai,
Agric. Biol. Chem., 1991, 55, 3134; H. Hayashi, K. Takiuchi,
S. Murao and M. Arai, Agric. Biol. Chem., 1989, 53, 461.
15 See D. Gröger and H. G. Floss, in The Alkaloids: Chemistry
and Biology, ed. G. A. Cornell, Academic Press, London, 1998,
pp. 172–218, and references contained therein.
δ 1.16 (8-C-CH3, 3.8%); δ 2.36 (8-H, 2.2%), δ 2.46 (7-Hexo
,
14.6%) and δ 3.18 (9-Hendo, 2.0%); δ 4.28 (6-H) enhances
resonances at δ 2.36 (8-H, 4.0%) and δ 2.46 (7-Hexo, 5.8%);
δC(CDCl3, 50 MHz) 13.5 (CH3), 17.4 (CH2CH2CH3), 18.6
(8-C-CH3), 30.7, 36.1 and 37.1 (CH2CH2CH3 and 7-CH2 and
9-CH2), 52.4 (8-CH), 57.7 and 58.7 (6-CH and 3-CH), 166.2
(C᎐O), 169.6 (C᎐O); m/z (APCIϩ, M ϩ 1); 211 (100%),
᎐
᎐
C11H19N2O2 requires 211.1447. Found 211.1447.
cyclo-L-Ile-D-Pro 45
Triethylamine (1.3 ml) was added to a solution of -Pro-
OMeؒHCl (720 mg, 4.3 mmol) in CHCl3 (20 ml) and the
reaction mixture cooled to Ϫ78 ЊC. Isoleucine-NЈ-carboxy-
anhydride41 (682 mg, 4.3 mmol) in THF (10 ml) was added
dropwise and the reaction mixture stirred at Ϫ78 ЊC for 4 h.
The reaction mixture was concentrated in vacuum to a volume
of 10 ml, filtered through Celite with washing (ether), and the
solvent removed in vacuum to afford a crude oil. This oil
was dissolved in ethanol (20 ml), heated at reflux for 36 h,
the solvent removed in vacuum, and the crude oil purified by
chromatography (ethyl acetate) to afford the desired compound
as an amorphous white powder (611 mg, 2.9 mmol, 67%);
[α]D23 ϩ98 (c 0.1, EtOH); δH(CDCl3, 500 MHz) 0.95 (3H, t,
J 7.4, CH3), 1.04 (3H, d, J 6.9, CH3), 1.21–1.31 (1H), 1.55–1.62
J. Chem. Soc., Perkin Trans. 1, 1998
2319