On Cardioactive Steroids. XVI. Stereoselective β‐Glycosylation of Digitoxose: The Synthesis of Digitoxin

Abstract

Two methods for stereoselective b-glycosylation of digitoxose were developed. The first achieved stereocontrol by a 1,3-participation of a N-methylurethane group under acid catalysis. The second utilized mercuric-ion catalyzed cleavage of thioglycosides and a 1,3-participation of ap-methoxybenzoyl group in a neutral medium. The first highly stereoselective and quite eficient synthesis of digitoxin (C7) was achieved by a combination of these methods. The furyl-substituted precursor IV of digitoxigenin (Scheme I) was used as aglycone, and the furan group was converted to the unsaturated lactone of digitoxin by our known oxidation procedure ( M -chloroperbenzoic acid/NaBH,) after the assembly of the carbohydrate portion of the molecule and its deblocking was completed.Introduction. -In previous communications of this series, we have described a novel and efficient methodology for the synthesis of cardenolides, bufadienolides and their analogues. As a result of this technique, we were able to synthesize up to now some 50

Structural studies of digitoxin and related cardenolides by two-dimensional NMR

“…As far as the complete assignment of the proton NMR spectrum of digitoxin is concerned, our results are in complete agreement with a previously reported partial assignment (23). …”

The glycosylation of steroids

“…122 Ogura et al introduced the use of the (1-phenyltetrazol-5-yl)thio group as a new thio functional group activated by AgOTf under mild conditions (Scheme 63). 123 Some bioactive diosgenyl saponins such as dioscin, polyphyllin D or balanitin 7 have been prepared starting from ethyl thioglycosides activated by NIS-AgOTf or MeOTf and diosgenin.…”

Special Problems in Glycosylation Reactions: 2‐Deoxy Sugars

“…When applied to 2-deoxy-pyranosyl bromides, this procedure can lead to 2'-deoxy-P-disaccharides with a good stereoselectivity. Wiesner [92] introduced the concept of 1,3-participation of an axial 3-0-substituent (p-methoxy-benzoate or N-methylcarbamate) for the stereoselective P-glycosylation of digitoxose, a 2,6-dideoxy-~-riho-hexose. A 1,3-acyloxonium or a 1,3-bridging iminium ion was proposed as an intermediate species where the a-face of the donor would be blocked during the glycosylation step ( Figure 9).…”