Total syntheses of (+)-zampanolide and (+)-dactylolide.

Format:

Book

Thesis/Dissertation

Author/Creator:

Safonov, Igor.

Contributor:

Smith, Amos B., III, advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Chemistry, Organic.

0490.

Penn dissertations--Chemistry.

Chemistry--Penn dissertations.

Local Subjects:

Penn dissertations--Chemistry.

Chemistry--Penn dissertations.

0490.

Physical Description:

365 pages

Contained In:

Dissertation Abstracts International 63-02B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

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 alpha-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 (-)-B 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 (+)-131 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 alpha-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.

Notes:

Thesis (Ph.D. in Chemistry) -- University of Pennsylvania, 2002.

Source: Dissertation Abstracts International, Volume: 63-02, Section: B, page: 0808.

Supervisor: Amos B. Smith, III.

Local Notes:

School code: 0175.

ISBN:

9780493578439

Access Restriction:

Restricted for use by site license.