1092
J . Org. Chem. 1999, 64, 1092-1093
Tota l Syn th esis of th e Sp ir ok eta l
Na p h th oqu in on e (()-Diep oxin σ
Peter Wipf* and J ae-Kyu J ung
Department of Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260
Received December 3, 1998
Due to their extraordinary level of oxygenation and the
presence of highly electrophilic oxiranyl ketone functional-
ities, spiroketal naphthodecalins of the preussomerin, pal-
marumycin, and diepoxin type present challenging targets
for total synthesis (Figure 1). We have recently established
efficient approaches toward palmarumycin CP1 and (()-
deoxypreussomerin A (palmarumycin C2).1 Independently,
total syntheses of palmarumycin CP1, CP2, and the related
CJ -12,371 have also been disclosed by Barett et al. and
Taylor et al.2,3 The structure of the more highly oxygenated
diepoxin σ (Sch 49209) was reported in 1993 by Schlingmann
et al. from American Cyanamid and in 1994 by Chu et al.
from Schering-Plough.4,5 The absolute stereochemistry of
diepoxin σ was assigned in 1996 by exciton-coupled CD.6
Diepoxin σ shows considerable antifungal activity and MIC’s
against a panel of selected bacteria in the range of 4-32
µg/mL.4 The Schering group also reported potent in vitro
activity in the antitumor invasion assay, with an IC50 of 0.75
µM against HT 1080 human fibrosarcoma cells.5 Further-
more, in vivo this compound demonstrated a significant
reduction in the size of primary tumors and the number of
metastases.5
F igu r e 1.
Sch em e 1
Sch em e 2
As a continuation of our program toward the synthesis
and mechanistic evaluation of the reactivity pattern of
epoxyketone natural products such as aranorosin and manu-
mycins,7 we reported the first synthetic strategy toward
diepoxins in 1997.8 In a demonstration of the use of long-
range dipole effects in chiral auxiliary design, we were able
to obtain enantiomerically pure model compound 2 in eight
steps and 8.3% overall yield from 1 (Scheme 1).8 However,
after selective monohydrolysis of the trifluoromethyl acetal
and hydroxy-group directed bis-epoxidation followed by
removal of the chiral auxiliary from 3 to give diketone 4,
we were unable to introduce naphthodiol to gain access to
spiroketal 5. Therefore, we modified our retrosynthetic
strategy to diepoxin σ as shown in Scheme 2.
Introducing the naphthodiol acetal before enone epoxida-
tion by spirocyclization1 to quinone 6 was envisioned to solve
the problems encountered in the acetalization stage of our
first generation approach shown in Scheme 1. The biaryl
ether precursor to 6 could be conveniently derived by
Ullmann ether coupling of protected hydroquinone 8 with
8-iodo-1-methoxynaphthalene (7).1 During the entire course
of the synthesis, the enone alkene moiety in the target
molecule was going to be protected as the Diels-Alder
adduct with cyclopentadiene.9,10 Despite the risk involved
in a high-temperature retro Diels-Alder reaction on the
densely functionalized diepoxin core, this strategy proved
successful for the first preparation of this highly oxygenated
natural product.
[4 + 2] Cycloaddition between O-methylnaphthazarin (9)11
and cyclopentadiene followed by syn-reduction of naphtho-
quinone 10 readily provided the desired phenol 8 (Scheme
3). Ullmann coupling of this triol with iodide 712 in the
presence of stoichiometric copper(I) oxide13 led to the biaryl
ether 11 in 70% yield. Demethylation of 11 proved to be a
very challenging reaction due to the acid/base lability of the
two benzylic alcohols. After considerable experimentation
(1) Wipf, P.; J ung, J .-K. J . Org. Chem. 1998, 63, 3530.
(2) Barrett, A. G. M.; Hamprecht, D.; Meyer, T. Chem. Commun. 1998,
809.
(3) Ragot, J . P.; Alcarez, M.-L.; Taylor, R. J . K. Tetrahedron Lett. 1998,
39, 4921.
(9) In an earlier approach, we had failed to introduce this unsaturation
by Saegusa-Ito or related schemes: Wipf, P.; J ung, J .-K. Unpublished
results.
(4) Schlingmann, G.; West, R. R.; Milne, L.; Pearce, C. J .; Carter, G. T.
Tetrahedron Lett. 1993, 34, 7225.
(5) Chu, M.; Truumees, I.; Patel, M. G.; Gullo, V. P.; Puar, M. S.; McPhail,
A. T. J . Org. Chem. 1994, 59, 1222.
(10) For other applications of the Diels-Alder protective group strategy,
see: (a) Ichihara, A.; Kimura, R.; Oda, K.; Sakamura, S. Tetrahedron Lett.
1976, 4741. (b) Kamikubo, T.; Ogasawara, K. J . Chem. Soc., Chem.
Commun. 1996, 1679.
(6) Schlingmann, G.; Matile, S.; Berova, N.; Nakanishi, K.; Carter, G. T.
Tetrahedron 1996, 52, 435.
(7) (a) Wipf, P.; Kim, Y. J . Org. Chem. 1993, 58, 1649. (b) Wipf, P.; Kim,
Y.; Fritch, P. C. J . Org. Chem. 1993, 58, 7195. (c) Wipf, P.; Kim, Y. J . Org.
Chem. 1994, 59, 3518. (d) Wipf, P.; Kim, Y.; J ahn, H. Synthesis 1995, 1549.
(8) Wipf, P.; J ung, J .-K. Angew. Chem., Int. Ed. Engl. 1997, 36, 764.
(11) Compound 9 was prepared in 46% yield from 1,5-dimethoxynaph-
thalene by bisformylation with Cl2CHOCH3 and TiCl4, oxidative removal
of formyl groups with m-CPBA and LiOH, and oxidation with FeCl3. See
ref 8 and Laatsch, H. Liebigs Ann. Chem. 1990, 1151.
(12) Graybill, B. M.; Shirley, D. A. J . Org. Chem. 1966, 31, 1221.
(13) Moroz, A. A.; Shvartsberg, M. S. Russ. Chem. Rev. 1974, 43, 679.
10.1021/jo9823691 CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/28/1999