An epoxide- and organoalane-based methodology for the iterative construction of polypropionate units: Application to the synthesis of streptovaricin D and U ansa chains

Since the 1980s, synthetic chemists have been challenged by the stereoselective construction of polypropionates. Many different approaches have been developed for the synthesis of these chains, the aldol reaction being the most widely used technology. Although some of these approaches present high stereoselectivities, they lack generality in terms of chain length and the stereochemical combinations allowed. For instance, contiguous anti polypropionate units are the most arduously accessible through aldol or aldol-related methodologies.; Our contribution to this area is the development of a new and alternative methodology for the stereoselective construction of polypropionates. We propose a reiterative epoxide- and organoalane-based method that, in theory, is general, enabling the assembly of any polypropionate array regardless of its stereochemical requirements.; The diastereoselective epoxidation of homoallylic alcohols and the regioselective cleavage of 2-methyl-3,4-epoxy alcohol derivatives represent the key steps in this approach. Although success have been achieved, some problems in both steps have been observed, which hinder the scope and generality of our methodology. To seek solutions to these limitations, we investigated the factors that influence these key chemical transformations. We found that the outcome of these reactions depends on the stereochemical disposition of the substituents on the corresponding substrates. For the cleavage of epoxides, the nature of the organometallic reagent also plays a crucial role. Besides, for the diethylpropynyl alane reagent, we demonstrated that we can revert the inherent C3 regioselectivity observed for some diastereomers by protecting the secondary alcohol with the MEM group. For attaining better diastereos electivities in the epoxidations, the indirect strategies described herein were developed.; To further demonstrate the synthetic potential of our methodology we engaged on the synthesis of the C5-C15 polypropionate chains of streptovaricins D and U. Streptovaricins are important members of the ansamycin family of antibiotics and the synthetic challenge stems from the large number of adjacent stereogenic centers. Indeed, the daunting all-anti stereopentad between C5-C10 makes streptovaricins D and U ideal, but demanding candidates for ascertaining the versatility of our approach for the stereoselective construction of polypropionates. For streptovaricin D, the introduction of the carbomethoxy functionality at C10 is also an intricate task. Interestingly, these polypropionate chains are common to other streptovaricin related compounds such as damavaricin, awamycin, and protostreptovaricins I and II. Thus, the synthesis of our target ansa chains would facilitate the total synthesis of all these attractive biologically active compounds. Furthermore, the successful application of our epoxide-based methodology would open the door to the elaboration of synthetic analogues that may have increased therapeutic properties.; Two complementary linear syntheses (C5-C15 and C15-C5) were performed and eight stereogenic centers were assembled in thirteen synthetic steps and 5% overall yield from commercially available inexpensive materials. The advanced epoxides 175 and 201 comprise the C5-C12 polypropionate fragment of streptovaricin U. On the other hand, epoxides 184 and 239 comprise the C5-C12 and C15-C8 polypropionate fragments of streptovaricin D, respectively. These epoxides were synthesized from the alkynyl alane cleavage products of the 2-methyl-3,4-epoxy alcohols 84c and 84f after two additional 3-step reaction cycles. An additional iteration must be achieved to attain our goal. Although the intended syntheses remain to be completed, our reiterative methodology allowed for the efficient and stereoselective construction of an all-anti stereohexad, and also for the incorporation of the C10 oxygenated functionality by means of functionalized alkynyl alane reagents.