Synthesis of the C1–C20 and C15–C27 Segments of Aplyronine A

Abstract

The synthesis of C1-C20 and C15-C27 segments of Aplyronine A is described. Oxidative cleavage of cyclic vinyl sulfones has been used to prepare key fragments of Aplyronine A. Key precursors are united by Horner-Wadsworth-Emmons and Julia-Kociensky olefination for the respective elaboration of the C1-C20 and C15-C27 segments.

Mechanism-specified 5-exo termini differentiation of a C32-desmethyl C28–C34 aplyronine A analog segment

“…16 Transformation of vinyl sulfones 1 and 4 to lactones 2 and 5 and further on to termini-differentiated segments 3 and 6 was previously reported. 17,18 Unfortunately, base-mediated vinyl sulfone chemistry, established in several isomeric substrates, was uniformly unsuccessful for the preparation of allylic sulfone 7 from 4-ent. 19,20 Faced with a looming program deadline and encouraged by in silico modeling by Hirst, 21 which had previously calculated F-actin depolymerization ability, predicted pIC 50 values of 4.40, 4.08, and 4.05 for aplyronine A, aplyronine A C32 epi-methyl, and aplyronine A C32 desmethyl respectively.…”

“…Epoxidation of diene 9, 19 with dimethyldioxirane (DMDO) formed in situ from Oxone Ò and acetone provides enantiopure epoxide diastereomer 10. 18,19 Nucleophilic addition of sodium borohydride effects reduction of 10 to provide alcohol 11 in 82% yield. 2-Azido-2-methylpropanoic acid was prepared from 2-bromo-2-propionic acid and sodium azide using a simplification of the existing literature protocol.…”

Citric acid mediated catalytic osmylation/oxidative cleavage of electron deficient olefins: a vinyl sulfone study

“…In an effort to find an optimum procedure, cyclic vinyl sulfone 1, a pivotal aplyronine A intermediate, 6 was subjected to a variety of osmium catalyzed dihydroxylation conditions (Table 1). Entry 1 represents the results of the Upjohn 24 protocol as a point of departure.…”

“…Ozonolysis of seven-membered vinyl sulfones was more extensively studied for the synthesis of polypropionate fragments of apoptolidin and aplyronine A. [6][7][8] While ozonolysis of vinyl sulfones has been established as an effective method, it has limitations in the construction of polyketide fragments. Many frequently used protecting groups are incompatible with ozolytic cleavage conditions.…”

Recent Applications of the Horner-Wadsworth-Emmons Reaction to the Synthesis of Natural Products

“…For example, in the synthesis of the C1-C27 fragment of Aplyronine A, two different HWE reactions were used in a highly convergent way to establish the C1-C20 fragment of the 24-membered lactone (Scheme 11) [27].…”