3
530
J . Org. Chem. 1998, 63, 3530-3531
Tota l Syn th esis of P a lm a r u m ycin CP
()-Deoxyp r eu ssom er in A
1
a n d
(
Peter Wipf* and J ae-Kyu J ung
Department of Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260
Received March 30, 1998
Since the isolation of the spiroketal MK3018 by Ogishi et
al. in 19891 and the bis-ketal decalin preussomerin A by
F igu r e 1. Representative spiroketal naphthodecalin natural
products.
2
Weber et al. in 1990, many structurally related fungal
3
metabolites have been reported (Figure 1). In addition to
Sch em e 1
3
general antitumor and antibiotic activities, selective inhibi-
tion of Ras farnesyl-protein transferase with an IC50 of g1.2
µM has been detected with these compounds.4
Recently, Krohn et al. reported the first semisynthetic
generation of the palmarumycin spiroacetal framework by
oxidative cyclization of a fungal metabolite.5 As a part of
our program toward the synthesis and mechanistic study of
6
,7
epoxy ketone natural products, we have recently embarked
on the total synthesis of diepoxin σ.8 In this paper, we
describe our progress toward a general route for the con-
struction of the spiroketal naphthodecalins and, specifically,
the first total syntheses of palmarumycin CP1 and (()-
deoxypreussomerin A. These natural products were isolated
3
f
from Coniothyrium palmarum and an unidentified ceolo-
4
mycetes (MF 5916), respectively, and are representative for
the structural features of many naturally occurring naph-
thoquinone dimers. Deoxypreussomerin A was also isolated
(
and named palmarumycin C2) from C. palmarum, and the
3
g
structure was further confirmed by X-ray analysis.
We
envisioned that both compounds as well as ultimately
diepoxin σ could be derived from p-quinone ketal 1, which
(
1) Ogishi, H.; Chiba, N.; Mikawa, T.; Sasaki, T.; Miyaji, S.; Sezaki, M.
J P 01,294,686, 1989; Chem. Abstr. 1990, 113, 38906q.
2) Weber, H. A.; Baenziger, N. C.; Gloer, J . B. J . Am. Chem. Soc. 1990,
12, 6718.
should be available by Ullmann ether coupling of phenol 2
and iodide 3 followed by oxidative spirocyclization (Scheme
(
1
).
1
9
(
3) (a) Preussomerins A-F: Weber, H. A.; Gloer, J . B. J . Org. Chem.
Our first attempts for an Ullmann coupling between the
1
991, 56, 4355. (b) Diepoxins: Schlingmann, G.; West, R. R.; Milne, L.;
10
readily available tetralone 4 and 8-iodo-1-methoxynaph-
thalene (3)11 failed, possibly due to the lack of nucleophilicity
of the deactivated tetralone under the standard Ullmann
reaction conditions. After protection of the carbonyl group
in 4 with ethylene glycol, the resulting acetal was now
successfully converted to the biaryl ether 5 in 78% yield in
refluxing pyridine in the presence of 0.2 equiv of Cu2O and
Pearce, C. J .; Carter, G. T. Tetrahedron Lett. 1993, 34, 7225. (c) Schling-
mann, G.; Matile, S.; Berova, N.; Nakanishi, K.; Carter, G. T. Tetrahedron
996, 52, 435. (d) SCH 49210, SCH 53514, and SCH 53156: Chu, M.;
Truumees, I.; Patel, M. G.; Gullo, V. P.; Blood, C.; King, I.; Pai, J .-K.; Puar,
M. S. Tetrahedron Lett. 1994, 35, 1343. (e) SCH 49211 and SCH 49212:
Chu, M.; Truumees, I.; Patel, M. G.; Gullo, V. P.; Pai, J .-K.; Das, P. R.;
1
Puar, M. S. Bioorg. Med. Chem. Lett. 1994, 4, 1539. (f) Palmarumycins CP
CP : Krohn, K.; Michel, A.; Fl o¨ rke, U.; Aust, H.-J .; Draeger, S.; Schulz, B.
Liebigs Ann. Chem. 1994, 1093. (g) Palmarumycins C Krohn, K.;
1
-
4
1
-C16:
1
equiv of K2CO3 (Scheme 2). When 1 equiv of Cu2O was
Michel, A.; Fl o¨ rke, U.; Aust, H.-J .; Draeger, S.; Schulz, B. Liebigs Ann.
Chem. 1994, 1099. (h) CJ -12,371 and CJ -12,372: Sakemi, S.; Inagaki, T.;
Kaneda, K.; Hirai, H.; Iwata, E.; Sakakibara, T.; Yamauchi, Y.; Norcia, M.;
Wondrack, L. M.; Sutcliffe, J . A.; Kojima, N. J . Antibiot. 1995, 48, 134. (i)
SCH 49209: Chu, M.; Truumees, I.; Patel, M. G.; Gullo, V. P.; Puar, M. S.;
McPhail, A. T. J . Org. Chem. 1994, 59, 1222. (j) Cladospirone bisepoxide:
Thiergardt, R.; Rihs, G.; Hug, P.; Peter, H. H. Tetrahedron 1995, 51, 733.
k) SCH 50673 and SCH 50676: Chu, M.; Truumees, I.; Patel, M.; Blood,
C.; Das, P. R.; Puar, M. S. J . Antibiot. 1995, 48, 329. (l) SCH 53823 and
SCH 53825: Chu, M.; Patel, M. G.; Pai, J .-K.; Das, P. R.; Puar, M. S. Bioorg.
used, the coupling yield dropped to <60%.
O-Demethylation in the presence of the dioxolane protec-
tive group was not clean; however, stepwise cleavage of the
acetal in aqueous acetone with TsOH followed by double
demethylation with BBr3 gave 7 in 95% overall yield. After
considerable experimentation, we found that the oxidative
spirocyclization of phenol 7 was best performed after reduc-
(
5
Med. Chem. Lett. 1996, 6, 579. (m) Palmarumycin CP4a and CP : Krohn,
K.; Beckmann, K.; Fl o¨ rke, U.; Aust, H.-J .; Draeger, S.; Schulz, B.; Buse-
mann, S.; Bringmann, G. Tetrahedron 1997, 53, 3101.
tion of the tetralone with LAH by treatment with PhI(OAc)2
in trifluoroethanol for 10 min.6
,8,12
The linchpin spiroketal
(4) Singh, S. B.; Zink, D. L.; Liesch, J . M.; Ball, R. G.; Goetz, M. A.;
intermediate 1 was thus obtained in high overall yield.
For the preparation of palmarumycin, spiroketal 1 was
oxidized with Dess-Martin reagent,13 followed by aromati-
Bolessa, E. A.; Giacobbe, R. A.; Silverman, K. C.; Bills, G. F.; Pelaez, F.;
Cascales, C.; Gibbs, J . B.; Lingham, R. B. J . Org. Chem. 1994, 59, 6296.
(
5) Krohn, K.; Beckmann, K.; Aust, H.-J .; Draeger, S.; Schulz, B.;
Busemann, S.; Bringmann, G. Liebigs Ann./ Recueil 1997, 2531.
6) Aranorosin: Wipf, P.; Kim, Y. J . Org. Chem. 1993, 58, 1649. Wipf,
(
P.; Kim, Y.; Fritch, P. C. J . Org. Chem. 1993, 58, 7195. LL-C10037R: Wipf,
P.; Kim, Y. J . Org. Chem. 1994, 59, 3518. Wipf, P.; Kim, Y.; J ahn, H.
Synthesis 1995, 1549. Asukamycin and manumycin A: Wipf, P.; Xu, W.;
Takahashi, H.; J ahn, H.; Coish, P. D. G. Pure Appl. Chem. 1997, 69, 639.
Wipf, P.; Coish, P. D. G. Tetrahedron Lett. 1997, 38, 5073.
(9) Moroz, A. A.; Shvartsberg, M. S. Russ. Chem. Rev. 1974, 43, 679.
(10) Newhall, W. F.; Harris, S. A.; Holly, F. W.; J ohnston, E. L.; Richter,
J . W.; Walton, E.; Wilson, A. N.; Folkers, K. J . Am. Chem. Soc. 1955, 77,
5646.
(11) Graybill, B. M.; Shirley, D. A. J . Org. Chem. 1966, 31, 1221.
(12) Pelter, A.; Elgendy, S. Tetrahedron Lett. 1988, 29, 677.
(13) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.
(7) Wipf, P.; J eger, P.; Kim, Y. Bioorg. Med. Chem. Lett. 1998, 8, 351.
8) Wipf, P.; J ung, J .-K. Angew. Chem., Int. Ed. Engl. 1997, 36, 764.
(
S0022-3263(98)00576-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/12/1998