5672
J . Org. Chem. 1997, 62, 5672-5673
Sch em e 1
Ster eoselective Syn th esis of th e C3-C17
Bis-Oxa n e Dom a in of P h or boxa zole A
Russell D. Cink and Craig J . Forsyth*
Department of Chemistry, University of Minnesota,
Minneapolis, Minnesota 55455
The phorboxazoles are remarkable natural products
isolated recently from an Indian Ocean sponge Phorbas
sp.1 The structures of phorboxazole A (1) and its C13
epimer phorboxazole B have been established by a
combination of extensive NMR studies on the natural,
derived, and correlation products (Figure 1).1-3 In ad-
dition to an unprecedented structure, phorboxazole A (1)
has exceptionally potent cytostatic activity against the
complete NCI panel of 60 human tumor cell lines.1
Although the mode of cytostatic activity has not been
defined, the arrest of the cell cycle during S phase by 1
distinguishes it from antimitotic natural products.3 These
findings contribute to the recent emergence of the phor-
boxazoles as premiere synthetic targets. The conforma-
tionally rigid macrolide of the phorboxazoles, containing
three highly functionalized oxanes and one oxazole,
provides a variety of challenges and opportunities for
efficient and stereoselective heterocycle synthesis. The
C18-C26 portion of the macrolide bears a 2,6-diequato-
rially substituted oxane, whereas the C1-C17 region
contains two methylene-linked, trisubstituted oxanes
(C5-C15) that are alternately substituted in a 2,6-trans
and 2,6-cis fashion. A convergent synthesis of the central
C18-C30 phorboxazole core has been reported.4 De-
scribed here is a stereoselective synthesis of the comple-
mentary C3-C17 portion (2) of the phorboxazole mac-
rolide (Figure 1). This involves sequential assembly of
the C11-C15 and C5-C9 oxanes by hetero Diels-Alder
and intramolecular etherification processes, respectively,
to construct the unique methylene-linked bis-oxane
system of 1.
The bis-oxane portion of 1 joins the remainder of the
natural product through (Z)-acrylate and oxazole moi-
eties. Because this terminal functionalization could be
elaborated from aldehyde and vicinal amino alcohol
precursors at C3 and C16-C17, respectively, a stereo-
selective synthesis of intermediate 2 was targeted. The
synthetic design was to form the C5-C9 oxane by an
intramolecular SN2 displacement of an activated homoal-
lylic hydroxyl at C9. The etherification substrate would
derive conveniently from the convergent coupling of a
C3-C8 allylic nucleophile and a C9-C17 aldehyde. An
initial hetero Diels-Alder reaction between a C15-C17
R-chiral aldehyde and a C9-C14 diene would be relied
upon to provide the substituted C11-C15 oxane leading
to the C9 aldehyde.
enol ether 5 as the major diastereomer of a 16:4:1
mixture. Desilylation facilitated the separation of dia-
stereomers, which gave ketone 6 in 60% overall yield
from 4.8 Selective reduction of 6 to the corresponding
axial alcohol was accomplished with potassium tri-sec-
butylborohydride. Straightforward protecting and func-
tional group manipulations then gave â-pyranyl aldehyde
7 in 70% overall yield from 6. Initial attempts to form
the C5-C9 oxane using a cyclocondensation reaction
between 4 and 7 gave unsatisfactory results.9
Successful assembly of the C5-C9 oxane was initiated
by addition of the organochromium reagent10,11 derived
from allyic bromide 812 to aldehyde 7. Diastereomeric
homoallylic alcohols 9 (9S) and 10 (9R) were obtained in
a 3:2 ratio and 80% combined yield (Scheme 2).13 The
modest coupling diastereoselectivity was compensated for
by the ease of conversion of the chromatographically
separable 10 into 9 via a simple Mitsunobu14-saponifica-
tion protocol, as well as the overall synthetic convergency
of this direct coupling. Activation of the newly generated
hydroxyl toward intramolecular displacement was ac-
complished by mesylation of 9 to give 11. Selective mono-
desilylation followed by base treatment led to exception-
ally clean SN2 displacement of the mesylate by the C5
(6) (a) Danishefsky, S.; Kobayashi, S.; Kerwin, J . F., J r. J . Org.
Chem. 1982, 47, 1981-1983. (b) For a review see: Bednarski, M. D.,
Lyssikatos, J . P. In Comprehensive Organic Synthesis; Trost, B. M.,
Ed., Pergamon Press: New York, 1991; Vol. 2, pp 661-706.
(7) Diene 4 was prepared in five steps and 52% overall yield from
1,3-propanediol as described in the Supporting Information.
(8) The minor diastereomers were similarly converted into the
corresponding ketones, and analysis of the J H-H values of the R-keto
protons indicate that both are exo Diels-Alder adducts. Because
cyclocondensations of 3 have been shown previously to be highly Cram
selective (ref 6a), it is likely that the major byproduct is the Cram-exo
adduct and, hence, the overall Cram selectivity is ca. 20:1.
(9) Hydrolysis of the BF3‚OEt2-mediated silyl enol ether cyclocon-
densation products from 4 and 7 gave a mixture of ketones in a 2:1:
1:1 ratio and 68% combined yield.
Preliminary studies indicated that installation of the
C16 nitrogen atom was best deferred until after bis-oxane
formation was complete. Hence, the synthesis of 2 began
with an endo selective, BF3‚OEt2-mediated5 hetero Diels-
Alder reaction of (S)-glyceraldehyde acetonide (3)6 with
diene 47 (Scheme 1). This provided the C11-C15 pyranyl
(10) J in, H.; Uenishi, J .; Christ, W. J .; Kishi, Y. J . Am. Chem. Soc.
1986, 108, 5644-5646.
(1) Searle, P. A.; Molinski, T. F. J . Am. Chem. Soc. 1995, 117, 8126-
8131.
(2) Searle, P. A.; Molinski, T. F.; Brzezinski, L. J .; Leahy, J . W. J .
Am. Chem. Soc. 1996, 118, 9422-9423.
(3) Molinski, T. F. Tetrahedron Lett. 1996, 37, 7879-7880.
(4) Lee, C. S.; Forsyth, C. J . Tetrahedron Lett. 1996, 37, 6449-6452.
(5) (a) Mujica, M. T.; Afonso, M. M.; Galindo, A.; Palenzuela, J . A.
Tetrahedron 1996, 52, 2167-2176. (b) Mujica, M. T.; Afonso, M. M.;
Galindo, A.; Palenzuela, J . A. Synlett 1996, 983-984.
(11) Takai, K.; Yagashirs, M.; Kuroda, T.; Oshima, T.; Uchimoto,
K.; Nozaki, H. J . Am. Chem. Soc. 1986, 108, 6048-6050.
(12) Bromide 8 was prepared from (S)-4-[(4-methoxybenzyl)oxy]bu-
tane-1,2-diol as described in the Supporting Information.
(13) Stereochemical assignments for 9 and 10 were made on the
basis of Mosher ester analysis as described in the Supporting Informa-
tion.
(14) Martin, S. F.; Dodge, J . A. Tetrahedron Lett. 1991, 32, 3017-
3020.
S0022-3263(97)00875-X CCC: $14.00 © 1997 American Chemical Society
Cink, Russell D.
