Cryptophycins-309, 249 and other cryptophycin analogs: preclinical efficacy studies with mouse and human tumors.

Cryptophycins-1 and 52 (epoxides) were discovered to have in-vitro and in-vivo antitumor activity in the early 1990s. The chlorohydrins of these, Cryptophycins-8 and 55 (also discovered in the early 1990s) were markedly more active, but could not be formulated as stable solutions. With no method to adequately stabilize the chlorohydrins at the time, Cryptophycin-52 (LY 355073) entered clinical trials, producing only marginal antitumor activity.

(2S,1'S,2'R,3'R)-2-(2'-Carboxy-3'-hydroxymethylcyclopropyl) glycine is a highly potent group 2 and 3 metabotropic glutamate receptor agonist with oral activity.

The asymmetric synthesis and biological activity of (2S,1'S,2'R,3'R)-2-(2'-carboxy-3'-hydroxymethylcyclopropyl) glycine ((+)-3) is described. This novel C-3' substituted carboxy cyclopropyl glycine is a highly potent group 2 and group 3 mGluR agonist that has proven to be orally active in both fear potentiated startle (animal model for anxiety) and PCP-induced motor activation (animal model for psychosis) assays in rats.

Synthesis of cryptophycin 52 using the Shi epoxidation.

[reaction: see text] A synthesis of cryptophycin 52 is reported using a Shi epoxidation strategy to install the epoxide moiety in a diastereoselective fashion. Several epoxidation results for cryptophycin substrates are disclosed followed by a discussion of the details relating to the preparation of cryptophycin 52 in two synthetic steps from one of the intermediate epoxides.

Catalytic regioselective sulfonylation of alpha-chelatable alcohols: scope and mechanistic insight.

This paper describes a convenient protocol for the regioselective sulfonylation of alpha-chelatable alcohols. Typically, the reaction of alpha-heterosubstituted alcohols with 1 equiv of p-TsCl and 1 equiv of Et(3)N in the presence of 2 mol % of Bu(2)SnO leads to rapid, regioselective, and exclusive monotosylation. The pK(a) of the amine was correlated to the reaction rate.

Synthesis of Unit A of Cryptophycin via a [2,3]-Wittig Rearrangement.

The synthesis of unit A of the cryptophycins from (S)-trans-3-penten-2-ol and from (S)-trans-4-hexen-3-ol has been completed. The key stereodetermining step is a [2,3]-Wittig rearrangement of a propargyl ether. Elaboration of the rearrangement product was accomplished by means of a selective hydroboration-oxidation of a terminal alkyne, Horner-Emmons homologation of the derived aldehyde, followed by selective ozonolytic cleavage and Wittig olefination.