The asymmetric syntheses of phyllanthocin and breynolide by means of a novel furanone ring construction are proposed. Phyllanthocin, the aglycon of the potent anti-cancer agents phyllanthoside and phyllanthostatin, and breynolide, the aglycon of the hypocholesterolemic agent breynin A and B, are remarkably similar in structure. Each contains a hexahydrobenzofuran ring and a spirocyclic ketal moiety while breynolide is somewhat more structurally complex and contains a tetrahydrothiophene ring. A synthetic scheme for both molecules is proposed in which the hexahydropenzofuran portion of the molecule is constructed using an electrophilic carbonyl ylide synthon. The ylide synthon achieves the synthesis of a furanone by means of regiospecific and stereoselective carbon-carbon bond forming reactions. The initial step involves an intramolecular directed Mukaiyama type aldol reaction of a ketene silyl acetal and a stannyl substituted mixed acetal. The stannyl substituent not only serves as the masked anionic portion of the ylide, but also serves to direct the stereochemistry of the aldol process. Subsequent transmetalation of the stannane permits an intramolecular condensation reaction of an alpha-alkoxyorganolithio species with an amide to provide the furanone. The spirocyclic ketal portion of both phyllanthocin and breynolide is derived from an alpha- alkoxyorganostannane prepared from glutamic acid. The spirocyclic ketal portion of phyllanthocin and breynolide is then derived from enolate oxidation chemistry. The chemistry proposed herein not only provides a route for the synthesis of two specific compounds of considerable pharmacological interest, but is also designed to be amenable to the synthesis of analogs. Basic chemistry in the area of the directed aldol reaction and the novel construction of oxacyclic rings will also be probed.
| Honari, S; Patterson, D R; Gibbons, J et al. (1997) Comparison of pain control medication in three age groups of elderly patients. J Burn Care Rehabil 18:500-4 |
