Three-Component Synthesis of Prostaglandins

Despite their fascinating pharmacological properties, prostaglandins are difficult drugs to administer because, in addition to their natural scarcity, they are rapidly inactivated by enzymatic degradation and interact nonselectively with tissues and cells. Despite these difficulties, biosynthetic production of PGs has not met increasing demand. Biosyn- 

SCHEME 4. Problem in the three-component coupling synthesis. 

SCHEME 5. One-pot synthesis of prostaglandin framework (organolithium/or-ganozinc procedure). 

SCHEME 7. One-pot synthesis of protected PGE2 and 5,6-didehydro-PGE2 (organo-cuprate/organotin procedure). 

The synthesis just described is the most direct, general three-component synthesis of PGs. Because researchers are attracted to its simplicity, a number of related syntheses have been accomplished 14). Some syntheses are achieved by using cyclopentenones with full or partial side-chain structures. 

---

The challenge of three-component synthesis of prostaglandines has been met by Ryoji Noyori et /. with extraordinary success. The assembly of the "lower" ((d) and the "upper" (a) side chain is accomplished in a "one-pot" protocol. The (D-side chain is attached by addition of (5)-/raiw-3-terr-butyldimethylsiIyIoxy-l-octenyllithium complexed with one equivalent of dimethylzinc or, alternatively, with copper iodide and tributylphosphine. To install the a-chain, the zinc enolate formed in the preceding step is directly condensed with the functionalized cts-allylic or propargylic part, whereas the copper enolate has to be added in the presence of triphenyltin chloride and hexamethylphosphoric acid triamide (HMPA). ... 

---