( ~ ) TETRAHEDRON LETTERS Tetrahedron Letters 39 (1998) 6099-6102 Pergamon Synthetic Studies Towards Phorboxazole A. A Convergent Synthesis of the C31-C46 Polyene Oxane-Hemiacetal Side Chain Gerald Pattenden*, Alleyn T. Plowright, James A. Tomos and Tao Ye Department of Chemistry, Nottingham University, Nottingham NG7 2RD, England Received 4 June 1998; accepted 15 June 1998 Abstract: A convergent and stereoselective synthesis of the C31-C46 side chain unit in the marine natural product phorboxazole A, which accommodates five asymmetric centres, three carbon-to-carbon double bonds and an oxane-hemiacetal unit, is described. © 1998 Elsevier Science Ltd. All rights reserved. Phorboxazole A 1 is a unique marine natural product which has been isolated from the Indian Ocean sponge Phorbas sp. 1 The molecule exhibits profoundly potent cytostatic activity against human tumour cell lines and it has an unprecedented structure based on a macrolactone core, four oxane and two oxazole rings, and accommodates fifteen asymmetric centres and five E- and one Z- olefinic bonds. The pronounced biological activity of this novel structure has aroused considerable interest in its total synthesis. 2 In recent work we have disclosed a synthesis of the 2,6-cis-oxane unit 3 in phorboxazole A. 3 In this communication we present a concise synthesis of the C31-C46 side chain portion 24 of the natural product which is appropriately functionalised for subsequent connection to the oxane unit 3 via an oxazole ring forming sequence. 5 OMe 9"""h ..... 0"~, 1 OMe OMe ~ O ~"" .'"" B r ~ ' v ~ ~ = O ~ ..... OPMB I -" H OMe OEt HO OTBS OH " 2 3 Me3Si"~,~ ~Me H OMe OMe o~ s ~--'~ I 6TBS 4 5 Our approach to the C31-C46 portion 2 in phorboxazo]e A was based on a convergent approach using an E-selective Julia benzothiazole sulfone olefination reaction 6 between the sulfone 4 and the cq~- unsaturated aldehyde 5 as a key step. Furthermore, we planned to syntbesise the sulfone 4 and the aldehyde 5 from the chiral pool compounds D-malic acid 6 and D-×ylose ]2 respectively, Thus, D-malic acid 6 was first converted into the differentially protected triol 7 using six straightforward steps in 43% overall yield as shown in Scheme 1.7 Deprotection of the PMB ether group in 7, using DDQ, 8 followed by oxidation of the resulting primary alcohol under Swern conditions next led to the 0040-4039/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved. PII: S0040-4039(98)01258-1