Application of Complex Aldol Reactions to the Total Synthesis of Phorboxazole B

Abstract

The synthesis of phorboxazole B has been accomplished in 27 linear steps and an overall yield of 12.6%. The absolute stereochemistry of the C4−C12, C33−C38, and C13−C19 fragments was established utilizing catalytic asymmetric aldol methodology, while the absolute stereochemistry of the C20−C32 fragment was derived from an auxiliary-based asymmetric aldol reaction. All remaining chirality was incorporated through internal asymmetric induction, with the exception of the C43 stereocenter which was derived from (R)-trityl glycidol. Key fragment couplings include a stereoselective double stereodifferentiating aldol reaction, a metalated oxazole alkylation, an oxazole-stabilized Wittig olefination, and a chelation-controlled addition of the fully elaborated alkenyl metal side chain.

Catalytic, Enantioselective, Vinylogous Aldol Reactions

“…[28] Because this catalyst requires a potentially chelating substrate for high selectivity, the reaction remains somewhat limited in terms of aldehyde scope. Nevertheless, this method affords the products in high yields and selectivities and has been applied in successful syntheses of phorboxazole B [29] and bryostatin 2. [30] To demonstrate the versatility of the acetoacetate aldol adduct 48, Evans and co-workers constructed two different pyran rings in phorboxazole B from this product of a vinylogous aldol addition (Scheme 15).…”

“…Application of the vinylogous aldol reaction catalyzed by the Cu II /pybox complex (R,R)-45 in the total synthesis of phorboxazole B. [29] Asymmetric Catalysis Angewandte Chemie dienol ether 25 (Scheme 16). [31] The enantioselectivity of these reactions is highly sensitive to both the rate of addition of the silyl dienol ether and the solvent used.…”

Indução assimétrica 1,5-Anti na adição de enolatos de boro de metilcetonas beta-oxigenadas a aldeídos

“…Evans e colaboradores descreveram a aplicação da reação aldólica 1,5-anti em um processo de dupla estereodiferenciação, que foi utilizado em uma das etapas chave da síntese total do macrolídeo forboxazol B 50 . Nesta reação, a indução assimétrica promovida pelo centro β-alcóxi do enolato de boro da metilcetona 65 foi primeiro investigada utilizando-se o diidrocinamaldeído (Esquema 17 -entrada 1).…”

The Vinylogous Mukaiyama Aldol Reaction in Natural Product Synthesis

“…Evans' building block 84 was further used in the total synthesis of (+)-dactylolide (239) (chemical structure reported in Scheme 2.63, stereocenter C19) exploiting exactly the same strategy (82% yield, 95% ee) [43]. (83) in the total synthesis of (−)-callipeltoside A. A rationale for the stereochemical outcome of that reaction was given based on the examination of the X-ray crystal structure of benzyloxyacetaldehyde (192) bound to the chiral (S,S)-bis-oxazoline-copper complex ent-193.…”