The total synthesis of (-)-rapamycin

John Angelo McCauley, University of Pennsylvania


This dissertation describes synthetic studies culminating in the total synthesis of the macrocyclic immunomodulaor ($-$)-rapamycin (1). Retrosynthetically, the molecule was divided into the fully functionalized intermediates 144 and 145. From these subtargets, rapamycin was completed in four steps: (1) union of the fragments via acylation at C(34); (2) intramolecular Stille coupling to form the triene and close the rapamycin macrocycle; (3) selective deprotection of the C(10) hemiketal hydroxyl; and (4) removal of the two remaining silyl protective groups. Disconnection of the major subtargets generated the five building blocks (A-E) each of which could be prepared on multi-gram scale (Chapters 2 and 3). Independent couplings of the five intermediates were performed with the ultimate goal of developing the most efficient methods for their union. In the course of these investigations, extensive studies of the coupling of B and C subtargets and the formation of the rapamycin C(27) center were performed. These studies led to the development of efficient protocols for the generation of dithiane anions and their additions to iodohydrins, epoxides and aldehydes as well as the conclusion that the trisubstituted olefin $\alpha$ to a C(27) aldehyde was the stereochemical controlling group in nucleophilic addition reactions of dithiane anions. The next subunit could then be appended by alkylation of the BC dithiane. Alternatively, the A and B subunits could be joined first, elaborated to aldehyde 215 followed by the addition of the C subunit. The stereochemical outcome of the dithiane anion addition reactions were proven using a combination of X-ray crystallographic analysis and, subsequently, synthetic intersection with previously prepared intermediates. Elaboration of the C(27)-(R) intermediate for rapamycin (Chapter 3) and the (S)-isomer for epi-27-rapamycin (Chapter 4) to their respective vinyl stannanes proceeded along similar lines. Performing this sequence of reactions on the C(27) epi series demonstrated that this small change had a profound effect on substrate reactivity. Of note are the efficient dithiane group removal and the regio- and stereoselective palladium-catalyzed hydrostannylation. The use of natural rapamycin in a semi-synthetic investigation allowed us to develop and implement a successful protecting group strategy for the rapamycin hydroxyl groups (Chapter 3). Uncovered in this investigation was the dramatic effect of solvent and silylating reagent on the silylation reaction of the C(10) hemiketal hydroxyl. Finally, the addition of dithiane 206 to D-glyceraldehyde acetonide was shown to give the desired (R) configuration of the C27 alcohol; this stereochemical result was proven by intersection with a known intermediate. Attempts were made to use this intermediate in a stereoselective synthesis of rapamycin (Chapter 5).$\sp*$ ftn$\sp*$Please refer to the dissertation for diagrams.

Subject Area

Organic chemistry|Pharmacology

Recommended Citation

McCauley, John Angelo, "The total synthesis of (-)-rapamycin" (1996). Dissertations available from ProQuest. AAI9627963.