Organic Seminar Abstract (Postscript version)

May 27, 1997

The phorboxazoles A (1) and B (2) were isolated from the Indian Ocean marine sponge Phorbas sp in January 1993 near Western Australia.¹ The unique molecular framework of the phorboxazoles is comprised of a 21-member macrolide and a side chain which together embody two oxazole rings, four oxane rings and fifteen stereocenters in all. The overall structure of the phorboxazole macrolide was determined by extensive NMR experiments.¹ Initially, the relative stereochemistry of the C1-C26 macrolide and the C33-C37 oxane were determined, but because these domains are stereochemically insulated from one another and the configurations at C38 and C43 were undefined, considerable stereochemical ambiguity existed.

In more recent work,² by using a modification of Mosher's ester method on the natural product and synthesizing model compounds, Molinski et al. were able to establish both the relative and absolute configuration at C38 as well as the absolute configuration at C13. Eventually, by degradation of the natural product and derivatization of the relevant fragment, the configuration at C43, and hence the complete steroechemistry of the phorboxazoles, was assigned.³

Besides the unprecedented structural features, 1 and 2 also possess extraordinary antifungal and cytostatic properties and are among the most potent cytostatic compounds discovered to date. Testing of phorboxazoles A and B against the National Cancer Institute's panel of 60 tumor cell lines showed outstanding inhibition of cell growth with mean GI₅₀ values of less than 7.9 x 10^-10 M with most of the cell lines being inhibited 100% at this concentration.¹

Although the mechanism of action of 1 and 2 is unknown it has been established that they cause cell arrest in the S phase of the cell cycle and that they do not inhibit tubulin polymerization.³ Hence, the combination of unique stucture and intriguing cytostatic activities make the phorboxazoles an ideal focus of chemical and biological study.

Since full evaluation of the biomedical potential of the phorboxazoles will require reliable access to the natural products and structural variants, an initial research goal is to develop a versatile, efficient and convergent synthesis of phorboxazoles A and B. Strategic dissection of 1 (Figure 1) involves disconnections at three junctures, namely the two oxazoles and the C1-C3 acrylate to afford fragments 3, 4 and 5. A projected total synthesis of 1 and 2 involves the preparation of each individual fragment followed by their sequential couplings.

Fragment 4 (C18-C30) has been synthesized by Chi Sing Lee in our lab⁴ using a combination of asymmetric aldol chemistry and a stereoselective hetero-Michael addition to form the central oxane ring. More recently Russel Cink successfully completed the synthesis of fragment 5 (C3-C17). This work features a hetero Diels-Alder reaction to form the C11-C15 oxane followed by a facile intramolecular etherification to assemble the C5-C9 oxane.⁵

The majority of this seminar will focus on the unique synthetic challenges and opportunities associated with the synthesis of fragment 3 (C31-C46), the reterosynthesis of which is shown (Figure 2). A disconnection at C38-C39 leads to a vinyl iodide 6 and an aldehyde 7 which can be coupled by a Nozaki-Hiyama CrCl₂ /NiCl₂ mediated reaction⁶ (Figure 3) but the stereoselectivity of the C38 hydroxyl formation is an issue. Stereoselective synthesis of the aldehyde 7 and the iodide 6 allows this coupling to be studied in detail. The terminal vinyl bromide may be installed subsequent to C38-C39 bond formation via a Takai reaction⁷ (Figure 3). Finally C31 ester saponification liberates a carboxylic acid suitable for oxazole formation.

Once the three fragments have been synthesized, the next challenge will be the efficient step-wise coupling of 3, 4 and 5 via formation of the two oxazoles and the acrylate linkage. The sequence of stitching together the fragments shall begin by the synthesis of the macrolide oxazole followed by a Masamune-Roush modification⁸ of a Horner-Wadsworth-Emmons Wittig reaction to form the cis-olefin at C2-C3. Formation of the second oxazole formation to attach the side chain (C31-C46) followed by deprotection should result in the total synthesis of phorboxazole A (1). A simple Mitsunobu inversion of the secondary alcohol at C13 should furnish phorboxazole B (2).

References:

1. Searle, P.A.; Molinski, T.F. J.. Am. Chem. Soc. 1995, 117, 8126-8131.

2. Searle, P.A.; Molinksi, T.F.; Brzenski, L.J.; Leahy, J.W. J. Am. Chem. Soc. 1996, 118, 9422-9432.

3. Molinski, T.F. Tetrahedron Lett. 1996, 37, 7879-7880.

4. Lee, C.S.; Forsyth, C.J. Tetrahedron Lett. 1996, 37, 6449-6452.

5. Cink. R.D.; Forsyth, C.J. J. Org. Chem. ,1997, submitted.

6. Jin, H.; Uenishi, J.; Christ, W.J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 6048-6050.

7. Takai, K.; Yagashirs, M.; Kuroda, T.; Oshima, T.; Uchimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048-6050.

8. Blanchette, M.A.; Choy, W.; Davis, J.T.; Essenfeld, A.P.; Masamune, S.; Roush, W.R.; Sakai,T. Tetrahedron Lett. 1984, 25, 2183-2186.