Development of an organo alane/epoxide-based approach to the preparation of polypropionates: Application to the synthesis of the elaiophylin polypropionate subunit

The biomedical implications of polypropionates-containing natural products prompted the development of various strategies for the synthesis of polypropionates. Our recently-developed epoxide-based methodology for the construction of polypropionate has the potential for becoming a reliable method for the assembly of any polypropionate fragment, circumventing the major difficulties confronted by other approaches. In this work, we endeavored on the application of our strategy to the stereoselective construction of the elaiophylin C4-C12 polypropionate fragment. The diverse biological activity of elaiophylin and its array of contiguous stereogenic centers stimulated us to demonstrate the use of our epoxide-based strategy for the preparation of the elaiophylin polypropionate fragment 29. The proposed synthesis required the elaboration of the epoxide fragments C4-C10 (32) and C12-C16 (31) and their subsequent coupling via a dithiane reagent.; The construction of the terminal epoxide fragment 31 was planned through the application of an iodolactonization procedure. On the other hand, the preparation of the secondary epoxide 32 required two consecutives anti-epoxidation procedures of syn,trans-alkene precursors. The stereoselective epoxidation of trans-homoallylic alcohols represents a pivotal step to achieve the planned synthesis; however, the available methods do not afford the necessary epoxides in a stereoselective manner.; The iodolactonization of the unsaturated carboxylic acid precursor to produce the anti-epoxide 31 resulted unselective, producing a 1:1 mixture of syn- and anti-epoxides. Instead, we used a more effective and shorter preparative procedure for the non-stereoselective production of the terminal epoxide 31, which provided epoxides 52 and 53. Similarly, we applied several available epoxidation procedures for the stereoselective construction of the C4-C8 epoxide fragment 34 and for the subsequent C4-C10 epoxide fragment 32, but the methods were inefficient.; These inherent limitations encountered in our approach for the epoxidation of homoallylic alcohols were solved with the development of a second-generation strategy that incorporates the use of an allylic-controlled epoxidation procedure. The oxygenated functionality was incorporated using a derivatized alkynyl alane reagent for the epoxide cleavage step, which was transformed into the allylic moiety.; Different propargylic- and acetylenic-functionalized alkynyl derivatives were studied for the cleavage of several diastereoisomeric 3,4-epoxy alcohols (88a-88d), including our epoxide precursor 34. The TMS-acetylene alane reagent 84g demonstrated to be more suitable than the O-protected alane reagents, producing the epoxide cleavage product in moderate to high yields (45-87%). We incorporated this new strategy for the stereoselective synthesis of the elaiophylin C4-C10 polypropionate fragments. The introduction of a bulky group on the homoallylic alcohol combined with the high selectivity achieved in the epoxidation of allylic alcohols, afforded the required epoxide precursor 34 and the subsequent epoxide 32, with high stereo selectivity. These epoxides represent the elaiophylin C4-C8 and C4-C10 polypropionate fragments.; After many attempts, the secondary epoxide 32 could not be coupled to the terminal epoxide 31 via a dithiane dianion equivalent, for the final synthesis of the polypropionate fragment 29, due to the steric hindrance present in the secondary epoxide. An alternative approach to circumvent this limitation was proposed.