Plans for the concise total synthesis of the microbial product angelmicin B, a selective tyrosine protein kinase inhibitor, which has demonstrated the ability to inhibit the growth of src-transformed cancer cells, are described. The central focus of the proposal will be the expeditious construction of the AB- and A'B'-ring fragments of the natural product via an intramolecular Diels-Alder (IMDA) strategy. The novel incorporation of an oxasilacyclopentene ring in the IMDA substrate will be explored, and it is anticipated that the conformational constraint exerted by this structural motif will control the facial selectivity of the diene partner and, hence, the diastereoselectivity of cycloaddition. The use of an IMDA substrate containing an allenyl dienophile is expected to allow for the simultaneous introduction of both ring-junction stereocenters via an endo-selective IMDA reaction. Aromatic annulations of the AB- and A'B'-ring systems will give rise to two new polycyclic compounds, and union of these via catalytic asymmetric Suzuki coupling should provide the aglycone of angelmicin B as a single atropisomer. Attachment of the E- and FG-ring systems will be accomplished by stereoselective glycosidation to complete the synthesis.
| Lambert, William T; Roush, William R (2005) Synthesis of the A-B subunit of angelmicin B. Org Lett 7:5501-4 |
| Heitzman, Cheryl L; Lambert, William T; Mertz, Eric et al. (2005) Efficient protiodesilylation of unactivated C(sp3)-SiMe2Ph bonds using tetrabutylammonium fluoride. Org Lett 7:2405-8 |
