Practical Partial Synthesis of Myriceric Acid A, an Endothelin Receptor Antagonist, from Oleanolic Acid

Myriceric acid A ( 1 ) is an oleanane triterpene that is a potent and specific endothelin A receptor antagonist. A practical procedure for large-scale synthesis of myriceric acid A ( 1 ) has been developed starting from oleanolic acid 4 . The conversion of oleanolic acid 4 to the key intermediate myricerone 3 was achieved in an efficient manner employing a photochemical reaction (the Barton reaction) of nitrite 7 . Our synthetic procedure alleviated several difficulties of the original Barton's procedure with regard to yields and large-scale operation. Myricerone 3 afforded Horner−Wadsworth−Emmons (HWE) type phosphonate 2 which has proved to be a versatile precursor of 1 . The preparation of phosphonate 2 on a scale of several hundred grams is described. The synthesis was completed by condensation of 2 with 3,4-bis[(diphenylmethyl)oxy]benzaldehyde ( 21 ), giving α,β-unsaturated ester 22, which was deprotected to afford 1 . The whole synthetic sequence is efficient (14 steps, 31% yield) and requires no chromatographic purification except to obtain the final product 1 .