Jerzy Wicha

The lead structure in cardiac glycosides is 5 β,14 β-androstane-3 β,14-diol

SummaryThe purpose of the present study was to determine the lead structure in cardiac glycosides at the receptor level, i.e. the minimal structural requirement for specific and powerful receptor recognition. Accordingly 73 digitalis-like acting steroids were characterized as to the concentration effecting half-maximum inhibition of Na,K-ATPase from human cardiac muscle under standardized turnover conditions. Since the Ki value equaled the apparent KD value, K′D was expressed in terms of the apparent standard Gibbs energy change ΔGo′ of steroid interaction with Na,K-ATPase. This allowed the use of the extrathermodynamic approach as a rational way of correlating in a quantitative manner, the potency and structure of the various steroidal compounds.The results of the present analysis taken in conjunction with relevant findings reported in the literature, favour the following conclusions.1.Cassaine, canrenone, prednisolone- and progesterone-3,20-bisguanylhydrazone, and chlormadinol acetate are compounds that are not congeneric with digitalis.2.The butenolide ring of cardenolides or the analogous side-chains at C17β of 5β,14β-androstane-3β,14-diol are not pharmacophoric substructures, but merely amplifiers of the interaction energy of the steroid lead.3.All modifications of the structure, geometry and spatial relationship between the steroid nucleus and butenolide side chain of digitoxigenin all at once weaken the close fit interaction with the steroid and butenolide binding subsites of the enzyme in such way that the cardenolide derivatives interact with the receptor binding site area in whatever orientation that will minimize the Gibbs energy of the steroid-receptor-solvent system.4.The “butenolide carbonyl oxygen distance model” (Ahmed et al. 1983) for the interpretation of the differences in potency of the cardenolide derivatives describes the change in interaction energy through structural modification as a function of the entire molecule.5.5β,14β-androstane-3β,14-diol, the steroid nucleus of cardiac glycosides of the digitalis type, is the minimum structure for specific receptor recognition and the key structure for inducing protein conformational change and thus Na,K-ATPase inhibition. It is also the structural requirement for maximum contributions of the butenolide substituent at C17β and the sugar substituent at C3β-OH to the overall interaction energy, i.e. this steroid nucleus is the lead structure.6.The tridigitoxose side-chain at C3β-OH of digitalis glycosides can be more than isoenergetically replaced by glucose, 2′,3′-O-isopropylidene-rhamnose, digitoxose, rhamnose and 4′-deoxy-4′-amino-rhamnose (increasing order of interaction energy increments) indicating a remarkable degree of conformational adaptability of the sugar binding subsite.

BF3-mediated reaction of a sulphone with aldehydes: A method for sterospecific construction of prostaglandin ω-chain

Abstract A new method for stereospecific construction of the allylic alcohol moiety of prostaglandins, based on application of optically active α-hydroxy aldehydes, is described. In the presence of BF3 .Et2O, lithiated sulphones 1 prepared from Corey aldehyde, and carbonyl compounds 2 give t or only their traces were formed. The addition products 3 , in the form of benzoates, mesylates or free alcohols, were subjected to reductive elimination by means of sodium amalgam to give the alkenes 4 . Compounds 4d and 4f were transformed into racemic and natural PGF2α, respectively, in line with the known method.

The reaction of α,β-epoxysilanes with metallated alkylaryl sulphones. A novel approach to allylic alcohols

Abstract Lithiated alkylaryl sulphones ( 2a - c ) react with α,β-epoxysilane ( 1 ) to yield O-trimethylsilyl allylic alcohols ( 3a - c ), predominantly as Z isomers. The BF3-assisted reaction followed by treatment of the adduct with nBu4NF affords allylic alcohols.

A novel approach to prostaglandins from the corey lactone involving BF3-mediated reactions of a sulphone and aldehydes

Abstract Transformation of the diol 1 via epimeric sulphones 7 to PGF 2α , is described. Alkylation of lithiated sulphones 7 with aldehydes 8a, 8b or 8c in the presence of BF 3 efficiently gives corresponding adducts.

Enantioselective synthesis of the methylenecyclopropane derivative related to hypoglycine, from malic acid

Abstract Synthesis of (S)-methylenecyclopropaneacetic acid starting from L-(−)-malic acid, via (2S)-O-tert-butyldimethylsilyl-1,2-epoxybutan-4-ol and 1-O-tert-butyldiphenylsilyl-5-benzenesulfonyl-6-trimethylsilylhexane-1,3-diols as the key intermediates, is described.

Steric Control of α- and β-Alkylation of Azulenone Intermediates in a Guanacastepene A Synthesis

The origins of different stereoselectivities observed experimentally in the alkylations of azulenone precursors in the guanacastepene A synthesis have been determined through density functional theory investigations. The optimized transition structures of methylation of two different guanacastepene A precursors show that steric effects, rather than torsional factors that often determine such stereoselectivities, dictate the preferred products observed.

Catalytic enantioselective annulation using phenylsulfanylmethyl vinyl ketone. An approach to trans-hydrindane building blocks for ent-vitamin D3 synthesis

Abstract An enantioselective synthesis of the ent -vitamin D 3 northern portion building block is presented. The key step involves phenylalanine-catalyzed annulation of 2-methylcyclopent-2-en-1-one with phenylsulfanylmethyl vinyl ketone.

Enantioselective synthesis of the methylenecyclopropane derivative related to hypoglycine, starting from malic acid

The methylenecyclopropane derivative 11 was synthesized from (S) malic acid via epoxide 5 and β-trimethylsilyl sulfone 6.

Methylation and hydroxymethylation involving free radicals: an application to stereoselective construction of 20(S) sterol side-chain

Abstract Reductive radical cyclization of bromomethyl-silyl-ethers 1b and 2b was found to proceed in 5-exo-mode. Epimeric cyclic siloxanes 3 were transformed stereoselectively into 20(S) 25-hydroxycholesterol. Unsaturated (E) ester 4 was converted to its (Z) isomer 7 via saturation and selective dehydrogenation.

Synthesis of 21-hydroxycholesterol and 25-hydroxycholesterol from 3β-hydroxyandrost-5-en-17-one. A method for the stereospecific construction of sterol side-chains

Alkylation of lithium derivatives of the ethyl and methyl esters of 3β-tetrahydropyran-2-yloxypregn-5-en-21-oic acid (3a) and (3c) with 1-bromo-4-methylpentane gave corresponding derivatives of cholest-5-en-21-oic acid, which were converted into 21-hydroxycholesterol (5e) by reduction of the alkoxycarbonyl groups and acid hydrolysis of the ether group. Alkylation of lithium derivatives of esters (3a) and (3c) with 2-(3-bromopropyl)-2-methyl-1,3-dioxolan (8) followed by conversion of the alkoxycarbonyl groups into a methyl group and removal of the protecting groups gave 3β-hydroxy-27-norcholest-5-en-25-one (7a) which was converted into 25-hydroxycholesterol (7c). Alkylation of the lithium derivative of the ester (3c) with methyl iodide gave methyl (20R)-3β-hydroxy-24,25-bisnorchol-5-en-22-oate (4b).