ity of phorbol to acid, base, heat, and light and its hazardous
nature.6,7 We describe herein the synthesis of the first
members of a new and simplified class of phorbol ester
skeletal analogues and their binding to PKC and η-C1B, a
surrogate of the regulatory domain of η-PKC.8
We previously reported an analysis of all pharmacophoric
triads of phorbol. The best correlation between atom type/
position with activity was found with the oxygens at C4,
C9, and C20. The C3 oxygen was noted as a possible
surrogate of the C4 oxygen.9 To obtain further information
on the role of these oxygen atoms in the binding and the
activities of the phorbol esters, we have now developed a
procedure for the concise removal of the A ring from readily
available phorbol derivatives. This procedure entails initial
conversion of phorbol (1) to its triacetate 2 and treatment of
the latter with NBS/NaOAc in aqueous DME [Scheme 1] in
wide range of novel phorbol ester analogues of biochemical,
synthetic, and medicinal interest.
While the above degradative sequence was developed
initially with the acetate derivatives, the C12 and C13
dibutyrates were selected for affinity and functional assays.12
Tributyrate 5 was thus prepared in a fashion analogous to
that of 4. Reduction of ketone 5 with NaBH4 (MeOH, 0 °C)
provided two epimeric C4 alcohols (1:1), which were
separated chromatographically. Since reduction of 5 with
NaBH(OAc)3 provided only one of these epimers, resulting
presumably from coordination to the C9 alcohol and delivery
of hydride from the R-face of the carbonyl, this alcohol is
assigned as the C4-âÃΗ isomer.13 Selective hydrolysis
(HClO4/ MeOH, rt, 48 h) of the C20 butyrate of each epimer
afforded the epimeric triols 7a and 7b, respectively [Scheme
2].
Scheme 1a
Scheme 2a
a (a) Ac2O, pyridine, rt, 18 h, 90%; (b) NBS/NaOAc, DME/H2O,
rt, 20 h, 70%; (c) O3, CH2Cl2, -78 °C f rt, then, Zn/NaOAc/
HOAc, rt, 1 h, 48%.
a (a) Butyric anhydride, pyridine, rt, 18 h, 82%; (b) NBS/NaOAc,
DME/H2O, rt, 20 h, 78%; (c) O3, CH2Cl2, -78 °C f rt, then, Zn/
NaOAc/HOAc, rt, 1 h, 45%; (d) NaBH4, MeOH, 0 °C, 30 min,
then, HClaq, 5 min, 6a, 37%; 6b, 37%; (e) HClO4, MeOH, rt, 48 h,
7a, 67%; 7b, 75%.
order to protect the B ring double bond as the dibromide.10
Ozonolysis of the resultant dibromide is followed by in situ
treatment of the intermediate ozonide with Zn/HOAc/
NaOAc, which serves both to reduce the ozonide and to
cleave the dibromide, delivering ketone 4 in 48% yield.11
The efficiency and brevity of this remarkably facile retro-
annelation make it a highly useful strategy for accessing a
Attempts to prepare the C4 carbonyl analogue [compound
11, Scheme 3] by deprotection of the C20 alcohol in 5 under
(5) For examples of structure-activity studies, see: (a) Kazanietz, M.
G.; Araces, L. B.; Bahador, A.; Mischak, H.; Goodnight, J.; Mushinski, J.
F.; Blumberg, P. M. Mol. Pharmacol. 1993, 44, 298-307. (b) Zhang, G.;
Kazanietz, M. G.; Blumberg, P. M.; Hurley, J. H. Cell 1995, 81, 917-924.
(c) Irie, K.; Ishii, T.; Ohigashi, H.; Wender, P. A.; Miller, B. L.; Takeda,
N. J. Org. Chem. 1996, 61, 2164-2173. (d) Sodeoka, M.; Arai, M. A.;
Adachi, K.; Uotsu, K.; Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 457-
458. (e) Winkler, J. D.; Kim, S.; Harrison, S.; Lewin, N. E.; Blumberg, P.
M. J. Am. Chem. Soc. 1999, 121, 296-300.
(6) (a) Wender, P. A.; Lee, H. Y.; Wilhelm, R. S.; Williams, P. D. J.
Am. Chem. Soc. 1989, 111, 8954-8957. (b) Wender, P. A.; Kogen, H.;
Lee, H. Y.; Munger J. D. Jr.; Wilhelm, R. S.; Williams, P. D. J. Am. Chem.
Soc. 1989, 8957-8958. (c) Wender, P. A.; McDonald, F. E. J. Am. Chem.
Soc. 1990, 112, 4956-4958. (d) Wender, P. A.; Rice, K. D.; Schnute, M.
E. J. Am. Chem. Soc. 1997, 119, 7897-7898.
(7) For other approaches to the synthesis of phorbol or phorbol analogues,
see: (a) Tokunoh, R.; Tomiyama, H.; Sodeoka, M.; Shibasaki, M.
Tetrahedron Lett. 1996, 37, 2449-2452. (b) Sugita, K.; Sawada, D.;
Sodeoka, M.; Sasai, H.; Shibasaki, M. Chem. Pharm. Bull. 1996, 44, 463-
465. (c) Sugita, K.; Neville, C. F.; Sodeoka, M.; Sasai, H.; Shibasaki, M.
Tetrahedron Lett. 1995, 36, 1067-1070. (d) Sugita, K.; Shigeno, K.; Neville,
C. F.; Sasai, H.; Shibasaki, M. Synlett 1994, 325-329. (e) Brickwood, A.
C.; Drew, M. G. B.; Harwood, L. M.; Ishikawa, T.; Marais, P.; Morisson,
V. J. Chem. Soc., Perkin Trans. 1 1999, 913-921. (f) Page, P. C. B.;
Jennens, D. C.; McFarland, H. Tetrahedron Lett. 1997, 38, 5395-5398.
(g) McMills, M. C.; Zhuang, L.; Wright, D. L.; Watt, W. Tetrahedron Lett.
1994, 35, 8311-8314. (h) Paquette, L. A.; Sauer, D. R.; Edmondson, S.
D.; Friedrich, D. Tetrahedron 1994, 50, 4071-4086. (i) Dauben, W. G.;
Dinges, J.; Smith, T. C. J. Org. Chem. 1993, 58, 7635-7637. (j) Rigby, J.
H.; Kierkus, P. C. J. Am. Chem. Soc. 1989, 111, 4125-4126.
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