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.
As the first non-peptide endothelin receptor antagonist from a higher plant, a new triterpenoid, myriceric acid A (50-235) (1) was isolated from the bayberry, Myrica cerifera. Myriceric acid A (1) inhibited not only an endothelin-1-induced increase in cytosolic free Ca2+ concentration (IC50 = 11 +/- 2 nM) but [125I]endothelin-1 binding in rat aortic smooth muscle cells (Ki = 66 +/- 15 nM). Two new related triterpenoids, myriceric acid C (6), and myriceric acid D (8), were also isolated. Furthermore, the chemical modification of these natural products led to the synthesis of sulfated derivatives (13, 14, 15) which showed 1.5 to 20 times higher affinity for endothelin receptors. The structure activity relationships of myriceric acids and their derivatives are discussed.
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