Reiterative epoxide-based strategies for the synthesis of stereo-n-ads and application to polypropionate synthesis. A personal account

Abstract

The enantioselective synthesis of polypropionates continues to be an attractive realm for the synthetic chemists mostly due to the challenges presented by the number of consecutive stereogenic centers contained within the aliphatic chain. Over the years, our laboratory has developed an epoxide-based three-step reiterative methodology for the construction of these targets, with the ultimate goal that the approach could be extended to the synthesis of polypropionate-containing natural products. The key steps include the diastereoselective epoxidation of allylic and homoallylic alcohols, and the regioselective cleavage of 2-methyl-3,4-epoxy alcohols. The choice of the organometallic reagent, and the cis/trans geometry of the chiral epoxide can be used to control both the relative and absolute configuration of the resulting propionate unit, allowing our approach to be applied in the synthesis of advanced fragments. Additionally, the combination of our first- and second-generation methodologies permits the incorporation of different variations at the methyl moiety.

Effective In Situ Alkoxide Trapping by TMSX in the Presence of TPP Catalyst in Glycidol Acetal Rearrangements

“…11 However, our crossover experiments proved the exchange of alkoxide groups in the presence of an external acetal through rearrangement reactions. 10 Hence, it concludes that the strongly nucleophilic in situ-generated alkoxide is attacking the bicyclic epoxonium ion. This unpredicted outcome was further extended by exploring various epoxy polyenes and their glycidol acetals (18−21).…”

Epoxide-Based Synthetic Approaches toward Polypropionates and Related Bioactive Natural Products

“…To demonstrate the synthetic usefulness of this non-aldol approach for the elaboration of polypropionate-containing natural products, they applied a linear three-reaction sequence to the stereoselective construction of the stereohexads corresponding to the C15–C10 84 [ 158 ], C5–C12 85 [ 161 ], and C15–C8 86 [ 161 ] polypropionate chains of streptovaricin D 16b including the C10 carbomethoxy functionality needed for the elaboration ( Figure 13 ). Prieto also reported the C5–C10 87 [ 160 ] and triad C12–C16 88 [ 161 ] fragments of elaiophylin 5 , in addition to the stereotetrad C22–C27 89 [ 158 ] fragment of rifamycin S 15 ( Figure 13 ). In 2012, the linear, convergent, and enantioselective synthesis of the C14–C25 90 fragment of bafilomycin A 1 6 was reported in a 16% overall yield.…”

“…The process consisted of eight steps in its longest linear sequence (Figure 13) using a dithiane substitution reaction to the coupling of the corresponding linear fragments [ 162 ]. This group has reported the convergent synthesis of optically active and common precursors of the C1–C5/C15–C11 segment 91a,b of lankanolide 4b [ 157 ] ( Figure 13 ) and the convergent precursor for the C3–C9/C12–C18 fragments 92a,b of dolabriferol B 26b ( Figure 13 ) [ 161 ]. They also reported a second-generation methodology in 2014 to introduce the hydroxymethyl moiety found at the C16 of tedanolide 9 and C18 of myraporone 3/4 ( 24 ) [ 159 ].…”

“…Specifically, they constructed an optically active stereotetrad 92 that is a common intermediate for the elaboration of C6–C9 93a and C14–C7 93b aliphatic chains of tedanolide 9 and myraporone 3/4 ( 24 ), respectively ( Figure 13 ). The most recent paper reported by Prieto et al describes the enantioselective and stereoselective synthesis of several polypropionate chains, which include the C15–C20 segment 94 of crocacin 25 and the polypropionate chains of C22–C27 95 , mycalolide A 13 , and C19–C24 95 of the lobophorolide 12 natural products ( Figure 13 ) [ 161 ]. In summary, this reiterative, linear, and convergent methodology has demonstrated the versatility to synthesize stereotriads, stereotretrads, and stereohexads with regio-, enantio-, and diastereoselectivity in polypropionate natural products.…”

Highly Regio- and Stereoselective Intramolecular Rearrangement of Glycidol Acetal to Alkoxy Cyclic Acetals

“…In general, because of the high-energy HOMO lone pair and huge ring strain, a proton or a Lewis acid can easily activate the epoxide by enhancing the polarization of the C–O bond, resulting in a ring-opening reaction by nucleophiles. This mode of epoxide activation works effectively even when additional nucleophilic groups such as alcohols, esters, carbonates, carbamates, etc., are present in the molecule. , In fact, the proximal nucleophilic groups ease epoxide ring opening. The best examples of this class are Brønsted acid activation of epoxide in oxido squalene in cholesterol biosynthesis and biosynthesis of ladder polyether natural products.…”