The total synthesis of (-)-macrolactin A and (+)-macrolactin E / Gregory R. Ott.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Ott, Gregory R.

Contributor:

Smith, Amos B., III, advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Chemistry.

Chemistry--Penn dissertations.

Local Subjects:

Penn dissertations--Chemistry.

Chemistry--Penn dissertations.

Physical Description:

xvii, 297 pages : illustrations ; 29 cm

Production:

1997.

Summary:

This dissertation describes synthetic studies culminating in the first total synthesis of the potent cytotoxic and antiviral agent ($-$)-macrolactin A as well the related family member (+)-macrolactin E. The unified synthetic approach to these highly unsaturated, 24-membered macrocyclic lactones exploited the palladium-catalyzed Stille cross-coupling reaction as the cornerstone for the successful strategy.*

Retrosynthetically, disconnection of the macrocycle at the C(9,10) diene and at the lactone linkages (with inversion of the C(23) center) afforded the (+)-AB and (+)-CD fragments. Further simplification at the C(3,4) and C(16,17) diene linkages furnished the four major subtargets A-D, which were prepared in multigram quantities.

In the course of these synthetic investigations several unique discoveries were made with respect to diene as well as macrocycle formation. During construction of the AB fragment, it was observed that all attempts to cross-couple vinyl iodide 125* containing the terminal acetylene, failed to produce the desired diene. However, following interchange of the vinyl iodide and vinyl stannane moieties palladium catalyzed coupling led to clean formation of the Z,E-diene ($-$)-132 employing standard coupling conditions (Chapter 2).

Combined with previous investigations in the Smith Group toward the construction of large macrocyclic lactones several important insights have been discovered and reaffirmed.*

First, esterification of unsaturated carboxylic acids employing the Mitsunobu protocol, utilized in the Smith latrunculin syntheses, has proven quite reliable for esterification in the macrolactin studies, even with the sensitive vinyl stannanes (+)-AB and (+)-181 (Chapter 2). Second, Stille macrocyclization, as demonstrated by the Smith rapamycin efforts, proved more effective than the corresponding intermolecular coupling. Third, the macrolactin synthetic venture have revealed that the use of the more reactive trimethylvinyl stannane is necessary for expedient, reproducible macrocyclization (Chapters 2 and 3).

Finally, the efforts outlined in this dissertation have shown that the our unified strategy is effective for construction of other members of the macrolactin family (Chapter 3). In particular, we can effect selective deprotection of macrocycle ($-$)-176 employing TBAF/AcOH; we have demonstrated the viability of this tactic by completing the total synthesis of macrolactin E (+)-5. ftn*Please refer to the dissertation for diagrams.

Notes:

Supervisor: Amos B. Smith, III.

Thesis (Ph.D. in Chemistry) -- University of Pennsylvania, 1997.

Includes bibliographical references and index.

Local Notes:

University Microfilms order no.: 98-14899.

OCLC:

187457382