STUDIES ON LACTONES RELATED TO THE CARDIAC AGLYCONES. I. SYNTHESIS OF β-SUBSTITUTED Δ^α,β-BUTENOLIDES FROM ι-METHOXYMETHYL KETONES

Abstract

The group of naturally occurring substances known as the cardiac drugs forms an interesting division of the large group of steroids. These substances have been grouped together on the basis of a common pharmacodynamic action on the heart. The investigations, chiefly of Jacobs, Windaus, Tschesche, and Stoll, have provided ample evidence, which has been adequately reviewed in numerous publications (1), for assigning structures to the more important members of the group. With the exception of the toad venoms and a few other substances of alkaloidal nature, the drugs are all non-nitrogenous glycosides which on hydrolysis with acid break with greater or less ease into the aglycones and constituent sugars. The major portion of the physiological action of the glycosides has been found to reside in the aglycone portion of the molecule, although the nature of the sugar moiety plays a definite but relatively minor part in determining the quantitative action of the drugs (2). For purposes of chemical classification it is convenient to subdivide the group of aglycones on the basis of the structure of the side chain. Thus one finds a large group of aglycones, which can be called the "digitalis-strophanthus group," characterized by a side chain consisting of the lactone of an enolized |8-aldehydo acid carrying the cyclopentanophenanthrene ring system as a substituent on the /3-carbon atom (type formula I), and a second and smaller group, which may be designated the "squill-toad venom group," in which the side chain is an -pyrone substituted in the 5-position (type formula II).

STUDIES ON LACTONES RELATED TO THE CARDIAC AGLYCONES. IV. PREPARATION OF β-PHENYL-Δα,β-BUTENOLIDE FROM PHENYLGLYOXAL AND FROM ETHYL β-METHYLCINNAMATE

“…In order to circumvent the difficult dehydration of the hydroxy acetal ester, II, ethyl /3-methylcinnamate (VIII) was oxidized with selenium dioxide, with the object of taking advantage of the activation of the hydrogens of the methyl group by the double bond and thus proceeding directly to the unsaturated aldehydo ester III. However, the oxidation proceeded only to the alcohol stage (IX), and the only product isolated was the ® ^-lactone V. This experiment is of significance, however, in that it provides rigid confirmatory evidence for the structure assigned to this lactone both in this paper and in a preceding one (1).…”

“…Better success attended the application of the Reformatzky reaction to the acetal of phenylglyoxal, although in comparison with the methods presented in earlier papers (1,2) this scheme possesses serious disadvantages. Nevertheless, it seems of interest to present at this time our experiences dealing with phenylglyoxal and its derivatives, in view of the experiments along the same line recently reported by Shemyakin and Red'kin (7).…”

STUDIES ON LACTONES RELATED TO THE CARDIAC AGLYCONES. III. THE PROPERTIES OF β-SUBSTITUTED Δα,β-BUTENOLIDES AND A SUGGESTED REVISION OF THE STRUCTURE OF THE SIDE CHAIN OF THE DIGITALIS-STROPHANTHUS AGLYCONES

“…In a preceding paper (19) the synthesis of model ß-substituted Aa '0-butenolides has been described. A study of the properties of ß-cyclohexyl-" -M)utenolide has revealed information which has led us to consider more seriously the question of a "'^-formulation for the unsaturated lactones of the natural cardiac drugs.…”

STUDIES ON LACTONES RELATED TO THE CARDIAC AGLYCONES. II. SYNTHESIS OF β-SUBSTITUTED Δα,β-BUTENOLIDES FROM ι-ACETOXYMETHYL KETONES

“…A small test portion of the crystalline material was removed and the accompanying oil was drained off on a porous plate. The remaining crystalline material gave a strong nitroprusside reaction and was identified as /3-phenyl-A">s-butenolide by mixed melting point (4). It was impossible to isolate the oily hydroxy lactone in a pure state since this lost water very easily on manipulation.…”

“…A small portion of the crystalline material was removed from the mixture, freed from accompanying oil by pressing on a porous plate, and recrystallized from water. The crystalline material melted at 112°and gave no depression with /3-cyclohexyl-(3-hydroxybutyrolactone prepared from methoxymethylcyclohexyl ketone (4). It was neutral, saturated towards catalytically activated hydrogen and gave negative Tollens' and nitroprusside color tests.…”