Craig Eugene Caufield

Base catalyzed degradations of rapamycin

Abstract The base catalyzed degradation of rapamycin was re-examined and a sequence of steps involving β-elimination, retro-aldol cleavage and benzilic acid rearrangement occur leading to several new products.

Convenient synthesis of functionalized terphenyls

A convenient synthetic methodology amenable for rapid synthesis of differentially functionalized terphenyls is described. Orthogonality requirements for the incorporation of phenoxy acetic acid and carboxamide function have been satisfied by utilization of hydroxyethoxy group as a precursor of the acid. Highly efficient and universal procedures have been developed for acid and amide formation.

Acid catalyzed functionalization of rapamycin

Abstract Rapamycin rapidly undergoes demethoxylation at C-7 in the presence of Lewis acids (BF 3 ·Et 2 O, SnCl 4 etc.) to give a highly stabilized carbocation. This intermediate gives a tetraene or is trapped by nucleophiles to give functionalized trienes. Several examples of the substitution reaction and elaboration of the reaction scheme are reported.

Chapter 21. Macrocyclic Immunomodulators

Publisher Summary The emergence of new novel chemical classes of macrocyclic immunomodulators may provide a greater understanding of the factors that control the immune system. The prototype for such emerging class of agents is cyclosporin A (CsA). This chapter discusses the mechanism of action of CsA with a summary of the chemistry; in vitro and in vivo immunopharmacology and the mechanism of action of the newer macrocyclic immunomodulators, such as FK-506, rapamycin, and didemnins. FK-506, RPM, and didemnin B (DB) may be found to be safer and more efficacious agents for transplantation rejection and autoimmune disease than CsA. FK-506 and CsA both act by inhibiting the production of growth promoting lymphokines, although FK-506 is effective at much lower doses. RPM, although structurally similar to FK-506, acts by inhibiting the response of T cells to lymphokines. The mechanism of the action of DB remains unknown, but seems to be more antiproliferative than either FK-506 or RPM. The importance and relevance of immunophilins needs to be delineated, but they may have a role in immunological signal transduction. In addition or alternatively, the immunophilins may be involved in the renal or vascular toxicity observed with this emerging class of novel macrocyclic immunomodulatory agents.