Method for the production of mumbaistatin derivatives

A process for preparing a mumbaistatin derivative of formula (I) or a salt thereof

• wherein:
• R1 and R2 are independently H, (C1-C6)-alkyl or benzyl;
• R3, R4 and R5 are independently OH, O—(C1-C6)-alkyl, O-benzyl or O-acyl;
• R6 is OH, halogen, (C1-C6)-alkyl, O—(C1-C6)-alkyl, phenyl, benzyl, O-phenyl, O-benzyl, or O-acyl;
• X1 and X2 are independently O, NH, N(C1-C6)-alkyl or S;
• and
• m, n, q and r are independently 0 or 1;
• comprising
• (1) reacting a compound of formula (II)
• wherein Y is a leaving group selected from the group consisting of Hal, OTs, OTf and OMs, with a compound of formula (III),
• wherein X is an electron-pushing group and R′ is (C1-C6)-alkyl or [(C1-C6)-alkyl]3silyl, in a [2+4]cycloaddition, and subsequently reacting with a suitable acid to give a compound of formula (IV)
• wherein R″ is H or (C1-C6)-alkyl;
• (2) halogenating the compound of formula (IV), or an etherified or acylated compound thereof when q is 1 and R″ is H, to give a compound of formula (V), wherein the etherified compound is prepared by etherifying the compound of formula (IV) with a (C1-C6)-alkyl halide compound or a benzyl halide compound, and the acylated compound is prepared by esterifying the compound of formula (IV) with an acyl halide compound,
• (3) reacting the compound of formula (V) with an organometallic compound (VI)
• wherein M is Sn[(C1-C6)-alkyl]3, B(OH)2, B(OR)2, BF3−, ZnHal or MgHal, and (OR)2 is [O—(C1-C6)-alkyl]2 or a 1,2-vicinal diol, in the presence of a transition metal catalyst, to give a compound of formula (VII),
• and then oxidizing the compound of formula (VII) to give a compound of formula (VIII),
• or
• reacting the compound of formula (V) with an organometallic compound of formula (VI′)
• wherein M is as defined for compound (VI) and Z is O—(C1-C6)-alkylene-O, in the presence of a transition metal catalyst, to give a compound of formula (VII′),
• and then hydrolyzing the compound of formula (VII′) with a suitable acid to give a compound of formula (VIII),
• or
• when X2R2 is OH, esterifying the compound of formula (V) with the compound (VI) to give a compound of formula (VII″),
• converting the compound of formula (VII″), in the presence of a transition metal catalyst, into a compound of formula (VII′″),
• hydrolyzing the compound of formula (VII′″) under a basic or acidic condition to give a compound of formula (VII) wherein X2R2 is OH, oxidizing the compound formula (VII) to give a compound of formula (VIII) wherein X2R2 is OH, and optionally converting the compound of formula (VIII) wherein X2R2 is OH into a compound of formula (VIII) wherein X2 is O, NH, N(C1-C6)-alkyl or S, and R2 is H, (C1-C6)-alkyl or benzyl, provided that X2R2 is not OH;
• (4) reacting the compound of formula (VIII) with a compound of formula (IX)
• to give a compound of formula (X),
• (5) converting the compound of formula (X) into a compound of formula (XI) by hydrogenating the triple bond to a single bond and removing the [(C1-C6)-alkyl]3Si group,
• (6) optionally oxidizing the compound of formula (XI) to give a compound of formula (XII),
• (7) oxidizing the compound of formula (XI) or the compound of formula (XII) to give the compound of formula (I) wherein X1R1 is OH, and
• (8) optionally converting the compound of formula (I) wherein X1R1 is OH into the compound of formula (I) wherein X1 is O, NH, N(C1-C6)-alkyl or S, and R1 is H, (C1-C6)-alkyl or benzyl, or a salt thereof, provided that X1R1 is not OH.