Phorboxazole synthetic studies: The C3-C15 bis-oxane segment

Article abstract of DOI:10.1016/S0040-4039(00)00530-X

The enantioselective synthesis of the C3-C15 bis-oxane segment of the phorboxazoles has been accomplished from 3-t-butyldiphenylsilyloxypropanal in 9 steps (>90% ee). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00530-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3801–3803
Phorboxazole synthetic studies: the C3–C15 bis-oxane segment
Patrick B. Greer and William A. Donaldson ∗
Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, Wisconsin 53201-1881, USA
Received 23 February 2000; revised 28 March 2000; accepted 30 March 2000
Abstract
The enantioselective synthesis of the C3–C15 bis-oxane segment of the phorboxazoles has been accomplished
from 3-t-butyldiphenylsilyloxypropanal in 9 steps (>90% ee). © 2000 Elsevier Science Ltd. All rights reserved.
The phorboxazoles A and B (1a and b) are isomeric macrolides isolated from the marine sponge
Phorbas sp.1a In addition to exhibiting antifungal activity against Candida albicans, both phorboxazoles
gave mean GI50s<8×10−10 M against most of the 60 tumor cell lines in the NCI panel. The complex
structure of 1 consists of four oxane rings, two oxazole rings, 15 asymmetric centers, and a conjugated
diene segment. The complete structure was assigned on the basis of NMR spectral studies, Mosher ester
data, degradation, and model synthesis.1 The outstanding biological activity of 1, combined with its
complex structural architecture, has led to significant activity by a number of research groups,2 and a total
synthesis by Forsyth’s group.3 Recent reports by Hoffmann,2c Smith2d and Pattenden2e have prompted
us to report our own efforts on the synthesis of the C3–C15 bis-oxane segment 2.
Lewis acid catalysed diene-aldehyde cyclocondensation4 of 3 with 4 in the presence of BF3·Et2O,
followed by brief treatment with CF3CO2H gave dihydropyrone rac-5 (Scheme 1). In our hands
attempted asymmetric cyclocondensation by a number of literature procedures proved capricious.5 For
this reason, establishment of optical activity was deferred to a later stage. Oxymercuration/reduction
of 5 followed by reduction [LiAlH(OtBu)3] and acylation gave 6. Reaction of 6 with allyl
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00530-X
tetl 16809

3802
trimethylsilane/TMSOTf/CH3CN6 gave the α-C-glucoside 7, which upon ozonolysis gave the aldehyde
rac-8. The synthesis of a similar aldehyde was reported by Hoffmann’s group2c beginning from
8-oxabicyclo[3.2.1]octan-3-one (11 steps), and by Smith’s group2d beginning from 2,4-pentandione (12
steps); our route to 8 is significantly shorter (six steps).
Scheme 1. (P=TBDPS)
Chiral allylation of rac-8 with B-allyldiisopinocampheylborane (prepared from (−)-(IPC)2BOMe),7
followed by oxidative work up with NaBO3, gave a separable mixture of the diastereomers (+)-9 and
(−)-10 (41 and 42%, respectively). The absolute stereochemistry of each alcohol at C11 was assigned as
(S) on the basis of the relative chemical shifts of their (R)- and (S)-Mosher’s esters (>90% de each).
Ring closing metathesis8 has recently found utility in the preparation of unsaturated δ-lactones.9 To
this end, esterification of (−)-10 with acryloyl chloride gave (−)-11, which upon treatment with with
Grubbs’ catalyst (0.3 equivalents) gave the unsaturated pyrone (−)-2.10
In summary, the C3–C15 bis-oxane segment of the phorboxazoles has been prepared in nine steps.
Studies directed toward the preparation of other portions of the phorboxazoles continues in our laboratory.
Acknowledgements
The authors are grateful to the Marquette University Graduate School and the Marquette University
Research Incentive Fund for financial support. P.B.G. is the recipient of a Johnson Wax research
fellowship. Partial financial support was provided by the National Institutes of Health (GM-42641). The
high resolution mass-spectral determinations were made at the Washington University Resource for Mass
Spectrometry.
References
1. (a) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117, 8126–31; (b) Searle, P. A.; Molinski, T. F.; Brzezinski, L. J.;
Leahy, J. W. J. Am. Chem. Soc. 1996, 118, 9422–23; (c) Molinski, T. F. Tetrahedron Lett. 1996, 37, 7897–80.
2. C3–C15 bispyran segment: (a) Cink, R. D.; Forsyth, C. J. J. Org. Chem. 1997, 62, 5672–73; (b) Williams, D. R.; Clark,
M. P.; Berliner, M. A. Tetrahedron Lett. 1999, 40, 2287–90; (c) Wolbers, P.; Hoffmann, H. M. R. Tetrahedron 1999, 55,
1905–14; (d) Smith III, A. B.; Verhoest, P. R.; Minbiole, K. P.; Lim, J. J. Org. Lett. 1999, 1, 909–12; (e) Pattenden, G.;
Plowright, A. T. Tetrahedron Lett. 2000, 41, 983–86. For other references see Ref. 2e.

3803
3. Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem. Soc. 1998, 120, 5597–98.
4. Danishefsky, S.; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1380–1419.
5. On one occasion asymmetric LACDAC using the Keck procedure gave (−)-5 (ca. 90% ee, 19% yield). Numerous attempts
to repeat this result were unsuccessful. (a) Keck, G. E.; Li, X.-Y.; Krishnamurthy, D. J. Org. Chem. 1995, 60, 5998–99; (b)
Bednarski, M.; Danishefsky, S. J. Am. Chem. Soc. 1986, 108, 7060–67; (c) Togni, A. Organometallics 1990, 9, 3106–13;
(d) Ghosh, A. K.; Mathivanan, P.; Cappiello, J.; Krishnan, K. Tetrahedron: Asymmetry 1996, 7, 2165–68.
6. Hosomi, A.; Sakata, Y.; Sakurai, H. Tetrahedron Lett. 1984, 25, 2383–86.
7. Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092–93.
8. Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2037–56; Grubbs, R. H.; Chang, S. Tetrahedron 1998,
54, 4413–50.
9. Nicolaou, K. C.; Rodriguez, R. M.; Mitchell, H. J.; van Delft, F. L. Angew. Chem., Int. Ed. Engl. 1998, 37, 1874–76; Ghosh,
A. K.; Cappiello, J.; Shin, D. Tetrahedron Lett. 1998, 39, 4651–54; Cossey, J.; Bauer, D.; Bellosta, V. Tetrahedron Lett.
1999, 40, 4187–88; Ramachandran, P. V.; Reddy, M. V. R.; Brown, H. C. Tetrahedron Lett. 2000, 41, 583–86.
10. Compound (−)-2: [α]D −38 (c 1.0, CHCl3); 1H NMR (CDCl3) δ 7.68–7.61 (m, 4H), 7.46–7.32 (m, 6H), 6.77 (ddd, J=3.3,
5.3, 9.6 Hz, 1H), 5.97 (br d, J=10.1 Hz, 1H), 5.06 (tt, J=4.5, 9.0 Hz, 1H), 4.52 (m, 1H), 4.24 (dq, J=4.6, 9.1 Hz, 1H), 3.97
(tt, J=4.2 Hz, 8.4 Hz, 1H), 3.81–3.63 (m, 2H), 2.36 (m, 2H), 2.28 (ddd, J=5.5, 9.3, 15.3 Hz, 1H), 2.03 (s, 3H), 1.97 (td,
J=3.1, 12.7 Hz, 1H), 1.86–1.62 (m, 5H), 1.39 (td, J=9.2, 12.9 Hz, 1H), 1.02 (s, 9H); 13C NMR (CDCl3) δ 170.3, 164.1,
144.9, 135.5, 133.8, 129.6, 127.7, 121.4, 75.0, 67.2, 66.4, 65.9, 60.2, 38.1, 36.8, 36.2, 34.4, 28.7, 26.8, 21.2, 19.2.