Sintese total e enantiosseletiva da aglicona do antibiotico (+)-10-desoximetimicina

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DATA DE PUBLICAÇÃO

1998

RESUMO

This work describes the enantioselective total synthesis of (+)-10-Deoxymethynolide (2c), the aglycon of the 12-membered macrolide antibiotic 10-Deoxymethymycin, through the esterification of the C1-C7 and C8-C13 fragments ((-)-339 and (+)-346, respectively) and macrocyclization of the corresponding vinylic iodide-aldehyde via an intramolecular Nozaki- Hiyama reaction. Studies aiming the use of the Horner- Wadsworth-Emmons reaction to accomplish the macrocyclization were also undertaken. The C1-C7 fragment (+)-152a was prepared by an unprecedented aldol reaction of the boron enolate from (R)-4-benzyl-3-propionyl-2-oxazolidinone and a b-O-tosyl aldehyde, followed by an intramolecular alkylation which afforded (+)-152a a synthetic equivalent of the Prelog-Djerassi lactonic acid (112a) (Scheme 61). Lactone (+)-152a was then transformed to the corresponding carboxilic acid (-)-339, after LiAlH4 reduction, 1,3-diol protection, reductive openning and Jones oxidation (Scheme 80). The C8-C13 fragment (+)-346 was also assembled by an enantioseletive aldol reaction followed by iodoolefination of the corresponding aldehyde under Takai s conditions (Scheme 81). The carboxylic acid (-)-339 was esterified with vinilic iodide (+)-346 using Yamaguchi protocol. Deprotection of the primary alcohol in (+)-362, followed by Dess-Martin oxidation afforded vinylic iodide-aldehyde 367 which was submitted to the planned macrocyclization mediated by CrCl2/ NiCl2 to afford the corrresponding 12-membered macrolactone in 74% yield as a 1:1 mixture of epimeric alcohol at C7. Oxidation of the these allylic alcohols and deprotection of the secondary alcohol afforded macrolide (+)-2c (Scheme 98). The convergent total synthesis of the (+)-10-Deoxymethynolide (2c) was therefore accomplished in 19 steps and 9,5% yield considering its longest route, starting from the (S)-3-hydroxy-2-methyl methylpropionate.

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