Evidence for the structure, and for a non-chair conformation in ring F of two isomeric N-formylsolasodines

Abstract

Formylation of solasodine results in the formation of two different 3,N-diformylsolasodines whose isomerism is due to a difference in stereochemistry at C22 rather than restricted rotation about the C = N partial double bond of the amide or nitrogen inversion as previously proposed. Mass spectra, 'H and I3C n.m.r. spectra have shown the isomers to possess 22R,25R (major) and 22S,25R (minor) stereochemistry. The 22S,25R isomer is thermodynamically preferred at elevated temperatures while the 2212,2513 isomer is kinetically favoured upon recyclization of the ring-F opened intermediate which forms upon heating of either isomer. A non-chair ring-P conformation is proposed for each isomer on the basis of 13C and 'H n.m.r. spectra. mixture of the isomeric N-formylsolasodines. This study reports a detailed investigation of the isomeric (25R)-N-formyl-22N-spiroso1-5-en-3j3-y1 formates (3,Ndiformylsolasodines) by mass spectrometry, 13C and 'H n.m.r. spectroscopy which has led to assignment of structures (1) and (2) to these compounds. Results and DiscussionAddition of formic-acetic anhydride to a chloroform solution of solasodine yielded isomeric diformylsolasodines in a ratio of approximately 2 : 1. The major isomer (I) gave a 'H n.m.r. spectrum corresponding to that reported1 for isomer (B) while the minor isomer (2) afforded a 'H n.m.r. spectrum resembling that reported1 for isomer (A). Formylation of tomatidine under similar conditions yielded a single diformyl derivative (3). 'H and 13C N.M.R. SpectraDue to conflicting assignments reported by two groups of ~o r k e r s ' ,~ for 'H n.m.r. signals of the H21 and H27 [see structure (4) for numbering] methyl groups of (1) and (2), proton decoupling experiments were performed in order to unequivocally establish the position of the resonance for each methyl group (Table 1). Irradiation of (2), in CDCl,, at 6 2.30 (H20) collapsed only the downfield methyl doublet at 6 1.14 while irradiation at 6 1.80 (H 25) collapsed signals due to each of the H26 protons at 6 3.88 and 3.13 in addition to the upfield methyl doublet at 6 0.94. Similar results were obtained for (1) in C,D,, a solvent in which the upfield H26 resonance moved downfield relative to its position in CDCl, enabling it to be observed. These results confirm the assignments originally reported1 by Toldy and Radics and enable assignment of H 27 to the upfield methyl doublet. Furthermore, we have confirmed the report1 that the upfield H 26 has a trans (7-9 Hz) coupling to the H 25 proton in (1) and (2).

Revision of the Structure of N,O-Diacetylsolasodine. Unusual Epimerization at the Spiro Carbon Atom during Acetylation of Solasodine

“…In contrast to 22-epispirostane, 22-epispirosolane ( 2 ) proved resistant to acid conditions and seems to be thermodynamically stable. Two isomeric N -formyl derivatives of solasodine have been obtained by treatment of the alkaloid with acetic–formic anhydride. − However, physical data analyses ( 1 H and 13 C NMR, MS) of these compounds did not lead to consistent conclusions. The dominant view is that they are distinct rotamers resulting from a restricted rotation about the CN bond of the amide moiety [Figure (a)] .…”

“…The isomers were also suggested to result from nitrogen inversion (b), although it is difficult to understand how this could arise in view of the well-known partial double-bond character of the amide bond. There were also suggestions that the isomerism is due to a difference in configuration at C-22 (c) . A nonchair conformation (twist boat) has been proposed for both epimers.…”

“…There were also suggestions that the isomerism is due to a difference in configuration at C-22 (c). 26 A nonchair conformation (twist boat) has been proposed for both epimers.…”

Steroidal alkaloids

“…The electron-impact mass spectra of bifunctional steroids such as (2c) display characteristic fragment ions X+, e.g. 13) respectively, each with a twist-boat conformation for ring F. These conclusions were reached after detailed study of the diformyl derivatives (lob), (12), and ( 13) by lH and 13C n.m.r. When (1 2) or ( 13) was heated, a ring-opened amide ( 14) was observed;…”

Structure and Stereochemistry of Steroidal Amine Teratogens

“…If, on the other hand, the alkaloid bonds to the active site in the embryo through the formyl group, the biological activity of the two isomers might be the same or different. A factor complicating the interpretation of biological results of these compounds involves their ability to undergo facile isomerization under acidic conditions by means of a ring-opened intermediate (Gaffield et al, 1983). Similar susceptibility to electrophilic attack resulted in lessened teratogenicity in the rabbit of cyclopamine, relative to jervine, due to opening of ring-E by stomach acid with subsequent formation of the non-teratogenic alkaloid, veratramine (Keeler, 1970).…”