Total syntheses of (+)-zampanolide and (+)-dactylolide
Abstract
Chapter 1 of this dissertation describes synthetic efforts culminating in the first total synthesis and complete stereochemical assignment of (+)-zampanolide (3 ), the non-naturally-occurring antipode of a potent cytotoxic marine macrolide. Retrosynthetically, initial disconnections of zampanolide at the amide and N -acyl hemiaminal linkages gave rise to hexa-2( Z ),4(E )-dienoic acid chloride (fragment D ) and α-alkoxy acid 135 . Further simplification of 135 at the indicated locations led to fragments C(3-8) A , C(9-17) B , and (C18-20) C , all of which were prepared in multi-gram quantities.* The total synthesis of (+)-3 owes the success to the following cornerstone strategies: (1) The stereocontrolled assembly of fragment (-)-BHASH(0xa539c6c)via the modified Petasis-Ferrier rearrangement of vinyl acetal (+)-63 and subsequent elaboration of the derived pyranone (+)-86 . (2) The rapid and highly convergent assembly of macrocycle (+)-131HASH(0xa3428a8)via the efficient coupling of fragments (+)-A , (-)-B , and (+)-C . (3) Installation of the C(20) N -acyl hemiaminal moiety via a stereospecific Curtius rearrangement of α-alkoxy acid (-)-135 to carbamate (-)-136 .* Since the final step in the synthesis of (+)-zampanolide (3 ) inevitably led to erosion of stereogenicity at C(20), we were unable to assign the relative and absolute configuration at that center with certainty. However, successful PMB reprotection experiments of (+)-3 and (+)-C(20)- epi -3 , in conjunction with UV spectroscopic data, eventually enabled us to tentatively assign the configuration at C(20) as R . Chapter 2 of this thesis describes the first total synthesis and complete stereochemical assignment of a related cytotoxic macrolide, (+)-dactylolide (153 ). The structural similarity between the two natural products enabled us to exploit vinyl bromide (-)-AB , the intermediate from the total synthesis of (+)-zampanolide (3 ), as the point of departure and complete the total synthesis of (+)-dactylolide (153 ) in only 9 steps.* Our speculation that (+)-dactylolide (153 ) is either a biosynthetic precursor of (+)-zampanolide (3 ) [if the latter does exist in nature?] or a degradation product thereof led us to investigate the possibility of a direct conversion of (+)-3 to (+)-153 . To our delight, the desired transformation was cleanly achieved via thermolysis of (+)-zampanolide (3 ) in benzene at 85°C. *Please refer to dissertation for diagrams.
Subject Area
Organic chemistry
Recommended Citation
Igor Safonov,
"Total syntheses of (+)-zampanolide and (+)-dactylolide"
(January 1, 2002).
Dissertations available from ProQuest.
Paper AAI3043946.
http://repository.upenn.edu/dissertations/AAI3043946
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