Stereoselective total synthesis and enantioselective formal synthesis of the antineoplastic sesquiterpene quinone metachromin A

Abstract

A primeira síntese total da substância antitumoral de origem marinha metacromina-A (1) foi alcançada através de uma abordagem sintética convergente e aplicável a preparação de análogos para estudos biológicos. A síntese envolveu doze etapas na sua sequência mais longa e dezesseis no total, apresentando como destaques (1) a eficácia na síntese da quinona intermediária 11; (2) a preparação eficiente dos fragmentos chaves 5 e 6; (3) uma reação de acetoxilação do tipo ThieleWinter altamente regiosseletiva e (4) uma reação de acoplamento do tipo Horner-Wadsworth-Emmons empregando o fragmento 6 como fosfonato não estabilizado capaz de atuar como um agente produtivo no acoplamento. Uma síntese formal e enantiosseletiva da metacromina-A também é descrita a partir da síntese assimétrica do fragmento 5, utilizando as metodologias desenvolvidas por Simpkins (desprotonação assimétrica com bases nitrogenadas quirais) e d'Angelo (alquilações desracemizantes). Este último processo forneceu o fragmento 5 com um excesso enantiomérico dẽ 85%, determinado por espectroscopia de RMN 1 H.The first total synthesis of the antineoplastic marine natural product metachromin-A (1) was accomplished through a convergent synthetic approach amenable to the preparation of analogues for biological studies. The synthesis involved twelve steps in its longest sequence and sixteen steps overall. The total synthesis of the racemic metachromin-A features: (1)

Insecticidal activity of menthol derivatives against mosquitoes

“…The methoxy derivative of L ‐menthol, menthyl methyl ether, was synthesized by reaction with dimethyl sulfate and anhydrous potassium carbonate under reflux in dry acetone 19. The glyceryl acetal derivative of L ‐menthol was synthesized by reaction with glycerol and p ‐toluenesulfonic acid under reflux in toluene 20. Reactions were monitored by thin‐layer chromatography, using a mixture of hexane and ethyl acetate, and compounds were visualized by vanillin‐sulfuric acid spray, heat and under UV light.…”

Unusual cyclic terpenoids with terminal pendant prenyl moieties: from occurrence to synthesis

“…Almeida and Correia reported on the total synthesis, 25 as well as enantioselective formal synthesis of this compound. 26 Hoppe and collaborators have also reported the enantioselective total synthesis of both (+)and (À)-metachromin-A. 27…”

“…The synthesis of metachromin A 26a pendant prenylated sesquiterpene with the quinone functional group attached to the lateral chain, was realized according to a convergent strategy. 25,26 Connection of the terpenic and aromatic fragments was based on a HWE olenation of the monocyclic ketone 260 with the aromatic phosphonate 261 (Scheme 13). In order to attach the lateral chain in the monocyclic fragment of 260, the Michael addition of trimethylsilylenolether derived from 2,5dimethylcyclohexanone 262 to methylvinyl ketone was applied.…”

Synthesis and Antitumor Activity of Diterpenylhydroquinone Derivatives of Natural Ent-Labdanes

“…The crucial step is the attachment of the aromatic synthon to the terpenyl skeleton. There are many publications that report different methods for accomplishing these coupling reactions in the synthesis of sesquiterpenyl-quinones [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. On the other hand, isolation of natural diterpenylquinones has not been reported and only one work has reported the synthesis of diterpenylnaphthoquinones, which showed an important activity in the inhibition of the growth of cancerigenous cells [ 1 , 2 ].…”