Yangzhi Ling

Synthesis of 20α- and 20β-acetamido, amino, nitro and hydroxy derivatives of 14-hydroxy-5β,14β-pregnane 3β-glycosides: pregnanes that bind to the digitalis receptor

Synthesis of 20α- and 20β-acetamido-, amino-, nitro- and hydroxy-3β-glycoside (α-L-rhamnopyranoside and tris-β-D-digitoxoside) and genin derivatives of 14-hydroxy-5β,14β-pregnane together with the C-20 oxime, hydrazone and amidinohydrazone is described from digitoxin. Ortho esters were also isolated. Structures were established by NMR measurements. These compounds have been shown to bind to the digitalis receptor of heart muscle. The 20β derivatives were consistently more potent than are the corresponding 20α compounds. The 20β-nitro α-L-rhamnoside derivative proved to be the most potent. Receptor binding data are given and structure-activity relationships are presented.

Synthesis of 3β,14-dihydroxy-5β,14β-pregnan-20-one C-3 derivatives: ozonolysis of digitoxin and digitoxigenin and their derivatives followed by zinc–acetic acid reduction to the C-21 methyl ketone

Ozonolysis of digitoxin, digitoxin tetraacetate, digitoxin tetrakis-(2,2,2-trichloroethyl carbonate), digitoxigenin, digitoxigenin acetate, digitoxigenin hemisuccinate and digitoxigenin 2,2,2-trichloroethyl carbonate followed by treatment with excess of zinc in acetic acid gave either the corresponding 21-hydroxy ester after 5 min or the 21-methyl ketone after 20 h. This procedure is more efficient than methods previously reported for the conversion of the α,β-unsaturated γ-lactone into an acetyl group and is applicable to the cardiac glycosides directly to give 14β-hydroxypregnan-20-one derivatives. Acidic hydrolysis of 14,21-dihydroxy-and 14-hydroxy-3β-tris(digitoxosyloxy)-5β,14β-pregnan-20-one is reported. Structures are based on 1H and 12C NMR assignments.

Synthesis and structure-activity relationships of 14β-hydroxy-5α-pregnanes: pregnanes that bind to the cardiac glycoside receptor

Abstract 5α-pregnane-3β,14β,20β-triol 3-α- l -rhamnopyranoside (8) and 3β-(α- l -rhamnopyranosyloxy)-5α-pregn-14-en-20-one (14) were prepared from uzarigenin by ozonolysis followed by zinc and acetic acid reduction and glycosidation. During the glycosidation reaction leading to (8) the corresponding ortho ester (9) was also obtained. Uzarigenin α- l -rhamnopyranoside (15) also was prepared. Synthesis of 5α-pregnane-3β,14β,20β-triol (20) is described. Structures were established by analysis of their NMR spectra. The binding affinity of 5α and 5β cardenolide and pregnane derivatives as a measured in a radioligand binding assay was determined and their structure-activity relationships compared. The receptor binding affinity of the 5α derivatives is les than that of the corresponding 5β derivatives.

Synthesis and isomerization of 19-hydroxy-5β,19-cyclosteroids

Abstract Synthesis of 19(R/S)-hydroxy-5β,19-cycloandrostane-3,17-dione by reductive cyclization of the steroid 4-en-3-one 19-aldehyde with zinc in aqueous acetic acid is reported. On either acid or base treatment the R-isomer is converted to the S-isomer through an intermediate 3-hydroxy-3,5-cyclosteroid.

Synthesis of 19-hydroxy-1β,19-cyclosteroids

19(R/S)-Substituted 1β,19-cyclo-5α-steroids have been synthesized by reductive cyclization of 3,17-dioxo-5α-androst-1-en-19-al with zinc in aqueous acetic acid or lithium in ammonia. The major product from the zinc reaction, the 19(R)-cyclopropanol, exists in equilibrium with the 3-hemiketal; the minor product, the 19(S)-alcohol, is isolated as the silyl ether and deprotected to give the 19(S)-cyclopropanol. The major product from the lithium–ammonia reaction is the 19(S)-cyclopropanol. Neither acid nor base treatment of the 19(R)- and 19(S)-alcohols gives evidence of their interconversion. Structures are established by NMR measurements.

Pregnane and 21-norpregnane derivatives of ouabain that bind to the digitalis receptor

Abstract 14β-Hydroxy-5β-pregnane and 14β-hydroxy-21-nor-5β-pregnane derivatives of ouabain were synthesised and their structures established by NMR measurements. Binding affinity in an [ 3 H]ouabain radioligand binding assay was determined. Pregnane derivatives of ouabain are more polar than pregnane rhamnoside derivatives of digitoxigenin. Whereas ouabain binds similarly to digitoxigenin rhamnoside, the pregnane derivatives of ouabain have significantly weaker binding affinity than their congeners from digitoxigenin.

19-Hydroxy-5β,19-cyclosteroids: synthesis, isomerization and ring opening

19(R/S)-Hydroxy-5β,19-cyclosteroids have been synthesised from the 19-formyl 4-en-3-one by reductive cyclization with zinc in aqueous acetic acid. Treatment of the aldehyde with lithium in liquid ammonia also gave the 19(R)-hydroxy-5β,19-cyclosteroid together with the 17β-hydroxy analogue. The 19(R)-alcohol is isomerized to the 19(S)-alcohol in either dilute acidic or basic media via the 3-hydroxy-3,5-cyclosteroid. The 19(S)-alcohol is in equilibrium with its 3-hemiketal. Treatment of the 19(R)-alcohol with methanolic HCl gave the 19(R)- and 19(S)-methyl ethers, the 3-methyl ether 19-ketal and the 3α-methoxy-3β,5β- cyclosteroid. Further rearrangements of the 19(R)- and 19(S)-alcohols take place on more vigorous treatment with acid or base to give cyclopropanol ring-opened aldehydes including a 5β-methyl-A-norsteroid. Metal hydride reduction of the 3-ketone in the 19(R)-alcohol gave only the 3β-alcohol whereas the 19(S)-alcohol gave both the 3α- and 3β-alcohols. Acid treatment of the 3β-alcohols gave products with retention of configuration at C-5 and C-19 while base-catalysed ring opening gave inversion at C-5. Ring opening mainly involved breaking of the 5,19-bond, however, the 19(S)-alcohol also resulted in 10,19-bond cleavage. Structures were established by NMR measurements.