Total Synthesis of Myxovirescins, 1 Strategy and Construction of the “Southeastern” Part [O(1)–C(14)

Abstract

AbstractIn this and the following two papers the synthesis of myxovirescins A1, A2 and M2, 28‐membered macrocyclic lactam‐lactones with antibiotic acitivity, is described. A retrosynthetic analysis of the myxovirescin family of ca. 30 target molecules leads to a strategy which could be applied to approximately half of them by slight variations of the building blocks used (Schemes 1–3 and following paper). The southeastern part of the molecule, containing the atoms O(1)–C(14) of myxovirescins A and M is described in this first paper (Scheme 3). The assembly is achieved by using the following appropriately protected units: (S)‐2‐hydroxy‐pentanoic acid, ([1,3]dithian‐2‐ylmethyl)‐amine (Scheme 4), the triflate of (S,R)‐2,2‐dimethyl‐5‐vinyl‐[1,3]dioxolan‐4‐ylmethanol, (E)‐3‐bromo‐2‐buten‐1‐ol, and (E)‐2‐bromo‐2‐buten‐1,4‐diol (Scheme 5), the starting materials for these being malic acid, aminoacetaldehyde, ribose, crotyl alcohol and butyne‐1,4‐diol. The building blocks are put together by using the following key steps: Kolbe electrolysis, amide formation, lithiodithiane alkylation, and Suzuki coupling (Schemes 6 and 8). The only newly created chirality center [C(6) of the target molecules] is generated stereoselectively by a Li‐selectride reduction/Mitsunobu inversion (Table 1, Scheme 7). The termini of the O(1)–C(14) fragment (2 in Scheme 8) carry a (protected) hydroxy acid and an aldehyde group for the Julia coupling and lactonization, respectively, in the final steps of the synthesis. All intermediates are fully characterized. The X‐ray crystal structures of two compounds prepared for incorporation as N(4)–C(11) and as C(12)–C(14) of the target molecules are also described (Figures 1 and 2). magnified image