TOTAL SYNTHESIS OF SALINOSPORAMIDE A AND ANALOGS THEREOF

摘要

Disclosed is a method of chemical synthesis comprising the steps of (a) reacting a 1, 3-dioxolane of formula (I) with a carboxylic acid of formula (II) to form an amide of formula (III) (b) deprotecting the compound of formula (III) to form a diketone compound of formula (IV) (c) performing an intramolecular aldol reaction on the compound of formula (IV) to form a bicyclic compound of formula (V) (d) cleaving the carbon-carbon double bond of the compound of formula (V) and cyclizing the cleaved double bond with the tertiary hydroxy group to form a tricyclic compound of formula (VI) (e) protecting the hemiacetal of the compound of formula (VI) to form a compound of formula (VII) (f) reducing the COOR2 group of the compound of formula (VII) to an alcohol to form a compound of formula (VIII) (g) oxidizing the alcohol of the compound of formula (VIII) to form a compound of formula (IX) (h) adding R4 to the compound of formula (IX) by reacting the compound of formula (IX) with an organometallic moiety containing at least one R4 to form a compound of formula (X) (i) removing PG1 on the compound of formula (X) and reductively opening the hemiacetal of the compound of formula (X) to form a compound of formula (XXIII): (j) protecting the primary hydroxy group of the compound of formula (XXIII) to form a compound of formula (XXIV) (k) cleaving the aminal group of the compound of formula (XXIV) to form a compound of formula (XXV) (l) protecting the secondary alcohol of the compound of formula (XXV) to form a compound of formula (XXVp): (m) converting the primary alcohol group and removing the PG2 protecting group moiety on the secondary alcohol of the compound of formula (XXVp) to form a compound of formula (XXVI) (n) removing the PG3 protecting group moiety on the primary alcohol of the compound of formula (XXVI) to form a compound of formula (XXVII) (o) protecting the primary alcohol of the compound of formula (XXVII) with the PG3 protecting group moiety to form a compound of formula (XXVI), wherein the PG3 can be same or different from the PG3 in step (m): (p) performing a lactonization reaction on the compound of formula (XXVI) to form a compound of formula (XXVIII) (q) removing the PG3 protecting group moiety on the compound of formula (XXVIII) to form a compound of formula (XV) (salinosporamide) wherein R1 - R6, RA and RB, Y, Z and PG1, PG2 and PG3 are defined in the specification.