Stereoselective arylation of substituted cyclopentenes by substrate-directable Heck-Matsuda reactions: a concise total synthesis of the sphingosine 1-phosphate receptor (S1P(1)) agonist VPC01091.

We describe herein an efficient and diastereoselective substrate-directable Heck-Matsuda reaction with nonactivated five-membered olefins. The carbamate acts as the main directing group in the arylation process allowing the synthesis of several functionalized aryl cyclopentenes in good to excellent diastereoselectivities (>85:15) and in isolated yields ranging from 41 to 90%. No double bond isomerizations were observed in these Heck reactions, and the newly created benzylic centers were preserved in all cases examined. The substrate directable Heck arylation approach was successfully applied in a straightforward total synthesis of the sphingosine 1-phosphate receptor-subtype 1 (S1P(1)) agonist VPC01091 by a concise and practical route involving 5 steps in 40% overall yield.

Chemo-, regio- and stereoselective Heck arylation of allylated malonates: mechanistic insights by ESI-MS and synthetic application toward 5-arylmethyl-γ-lactones.

We describe herein a general method for the controlled Heck arylation of allylated malonates. Both electron-rich and electron-poor aryldiazonium salts were readily employed as the aryl-transfer agents in good yields and in high chemo-, regio-, and stereoselectivity without formation of decarboxylated byproducts. Reaction monitoring via ESI-MS was used to support the formation of chelated Pd species through the catalytic cycle. Additionally, some Heck adducts were successfully used in the total synthesis of pharmacologically active γ-lactones.