A Unified Strategy toward the Synthesis of Acerogenin-Type Macrocycles: Total Syntheses of Acerogenins A, B, C, and L and Aceroside IV
A general strategy for the synthesis of acerogenin-type diarylheptanoids contg. an endocyclic biaryl ether bond has been developed, and convergent total syntheses of acerogenin A, B, C, and L and aceroside IV have been accomplished. Cycloetherification of the linear diarylheptanoid 1-(4-fluoro-3-nitrophenyl)-7-(3-hydroxy-4-methoxyphenyl)heptan-3-one (I) under mild conditions (CsF, DMF, 0.01 M, rt, 5 h) gave the macrocycle 4-methoxy-17-nitro-2-oxatricyclo[13.2.23,7]eicosa-1(18),3,5,7(20),15(19),16-hexaen-12-one (II) in 95% yield. Removal of the nitro group followed by O-demethylation gave acerogenin C (III), whose redn. afforded acerogenin A. Glucosidation of III with 2,3,4,6-alpha -D-tetrabenzoylglucopyranosyl bromide followed by sapon. gave aceroside IV in excellent overall yield. Acerogenins B and L were synthesized in a similar fashion featuring a key intramol. SNAr reaction of linear compd. 7-(4-fluoro-3-nitrophenyl)-1-(3-hydroxy-4-methoxyphenyl)heptan-3-one. The entropy driving force resulting from the preorganization of cyclization precursors in favor of the bent conformation was proposed to contribute significantly to the efficiency of this cyclization. Both computational studies and spectroscopic data (NOE) supported this hypothesis. Exptl., it was obsd. that even at high concn. (1 M of 18 in DMF) the anal. pure macrocycle II could still be obtained in 45-50% isolated yield. Furthermore, when the cyclization of I was carried out in the presence of an external nucleophile (4-methoxyphenol) or an electrophile (4-fluoro-3-nitrotoluene), only the 15-membered cyclophane II was isolable. This provides exptl. evidence that compd. I is indeed preorganized in such a way that intramol. reaction was highly competitive with the alternative intermol. process. [on SciFinder (R)]
Keywords: Glucosylation; Macrocyclization (total syntheses of acerogenins A ; B ; C ; and L and aceroside IV) ; acerogenins A B C L aceroside IV synthesis; cycloetherification intramol nucleophilic aryl addn
Biomolecules and Their Synthetic Analogs
Institut de Chimie des Substances Naturelles,CNRS,Gif-sur-Yvette,Fr.
written in English.
105-45-3 (Methyl acetoacetate); 105-53-3 (Diethyl malonate); 1071-46-1 (Monoethyl malonate); 15017-52-4; 61403-85-8 (alpha -D-Glucopyranosyl bromide); 129150-61-4; 221123-51-9; 221123-53-1 Role: RCT (Reactant), RACT (Reactant or reagent) (total syntheses of acerogenins A, B, C, and L and aceroside IV); 60432-34-0P; 74174-21-3P; 87425-32-9P (Acerogenin C); 160877-38-3P; 160877-40-7P; 177262-58-7P (Acerogenin L); 197382-92-6P; 197382-94-8P; 197382-96-0P; 197382-99-3P; 221123-48-4P; 221123-49-5P; 221123-50-8P; 221123-52-0P; 221123-54-2P; 221123-55-3P; 221123-56-4P; 221123-57-5P; 221123-58-6P; 221123-59-7P; 221123-60-0P; 221123-61-1P; 221123-62-2P; 221123-63-3P; 221123-64-4P; 221123-65-5P; 221123-67-7P Role: RCT (Reactant), SPN (Synthetic preparation), PREP (Preparation), RACT (Reactant or reagent) (total syntheses of acerogenins A, B, C, and L and aceroside IV); 60503-28-8P (Acerogenin A); 74174-17-7P (Acerogenin B); 74390-30-0P (Aceroside IV); 221123-66-6P; 221132-11-2P; 221132-52-1P Role: SPN (Synthetic preparation), PREP (Preparation) (total syntheses of acerogenins A, B, C, and L and aceroside IV)
Record created on 2010-11-25, modified on 2016-08-08