H. T. Andrew Cheung

Stereochemistry of the hexosulose in cardenolide glycosides of the asclepiadaceae

The 4,6-dideoxyhexosulose moiety of gomphoside (1) and afroside (2) has been shown to have the 1′S,2′S,3′R,5′R configuration, Formation of 2′,3′-OO-isopropylidene derivatives establishes that the hydroxy-group at C-3′, which is axial, is cis to that at C-2′. The latter group is cis to the anomeric C-1′ hydrogen, as shown by nuclear Overhauser enhancement measurements. Chemical and 1H and 13C n.m.r. data have been used to show that the same chirality at carbons 1′, 2′, and 5′ is present in the following glycosides from plants of the Ascepiadaceae family: calactin (3), syriobioside (10), desglucosyrioside (11), syrioside (12), uscharidin (5), calotoxin (9), uscharin (7), and voruscharin (8).

Cardenolide glycosides of the asclepiadaceae. New glycosides from asclepias fruticosa and the stereochemistry of uscharin, voruscharin and calotoxin

Eight new cardenolide glycosides, 19-deoxyuscharin (1b), 4′β-hydroxygomphoside (1k), 3′-didehydrogomphoside (1d), 3′-epigomphoside (1e), 3′-epiafroside (2e), 3′-epigomphoside 3′-acetate (1f), 3′-didehydroafroside (2d), and 3′-epiafroside 3′-acetate (2f), have been isolated from Asclepias fruticosa R. Br. The structures of all new compounds were established by spectral comparisons with known compounds. The chirality at C-3′ of uscharin (3b), voruscharin, and 19-deoxyuscharin (1b) is proposed to be S. By comparison with 4′β-hydroxygomphoside (1k), the β configuration of the 4′-hydroxy group of calotoxin (3k)(from Calotropis procera) has been established.

7β,8β-Epoxycardenolide glycosides of Asclepias eriocarpa

The identity of eriocarpin with desglucosyrioside (1) has been established by comparison of their triacetates. 13C and 1H N.m.r. spectra show that the conversion of labriformidin into desglucosyrioside involves solely the reduction of a 3-keto-function in the carbohydrate portion (B) which is identical (in structure and stereochemistry) with that in uscharidin (7). Structures are proposed for labriformidin and labriformin. 13C N.m.r. data establish the β-configuration of the 7,8-epoxide in labriformidin, desglucosyrioside, and in the 5β-cardenolide sarverogenin (11).

Ring c aromatic steroids. Part 2. Rearrangement of 16α,17α-epoxy-and 17α-hydroxy-5,7-dienes

Epoxide-opening in 3β-acetoxy-16α,17α-epoxypregna-5,7-dien-20-one (3) and its Δ6,8(14)-isomer (7), as induced by boron trifluoride–acetic anhydride is accompanied by C-13 methyl migration. The product, 3β,16α-diacetoxy-17β-methyl-18-norpregna-5,7,13-trien-20-one (4) was converted in two steps into the c-aromatic steroid 3β,16α-diacetoxy-17β-methyl-18-norpregna-8,11,13-trien-20-one (6) as a mixture of C-5-epimers. A D-homo-product (17) resulted from acid-catalysed rearrangement of 3β,20ξ-diacetoxy-17α-hydroxypregna-5,7-diene (16).

Cardenolide glycosides with 5,6-unsaturation from Asclepias vestita

Asclepias vestita from Commatti Canyon in California has yielded nine new 19-oxo cardenolide glycosides and one genin, all with the 5(6) double-bond, viz 5,6-dehydrocalactin, 5,6-dehydrocalotropin, 5,6-dehydroasclepin, 5,6-dehydrouscharidin, 5,6-dehydrocalatoxin, 16α-hydroxy-5,6-dehydrocalotropin, 16α-acetoxy-5,6-dehydrocalotropin, 16α-hydroxy-5,6-dehydroasclepin, 16α-acetoxy-5,6-dehydroasclepin, and the genin, 5,6-dehydrocalotropagenin. Most of these Δ5-cardenolide glycosides were accompanied by the known 5α(H) analogues. Also found were two 5α-cardenolides with a 19-hydroxy group, viz. the glycoside 19-dihydrocalotropin and the known genin coroglaucigenin. The position of the unsaturation in the Δ5-cardenolides was located by comparison of the 400 MHz n.m.r. data with those of the 5α-analogues, with consideration of the anisotropy effect of the Δ5 double-bond. A pair of model Δ5-19-oxo and 5α(H)-19-oxo steroids have also been studied for comparison.

Afroside, a 15β-hydroxycardenolide

Afroside (2) has the same carbohydrate as gomphoside (1), namely a 4,6-dideoxyhexosulose doubly linked to the aglycone at the 2α and 3β positions. It differs from gomphoside in having a 15β-hydroxy-group, the location of which is shown by n.m.r. (1H and 13C) and mass spectra, and is established by the formation of a 14,15-cyclic carbonate derivative (2e). The 14β,15β-diol group shows unusual inertness to glycol cleavage and to OO-isopropylidene derivative formation, in contrast with the behaviour of the 2′,3′-diol in the carbohydrate, and the 2α,3β-diol in the genin, afrogenin (4). Degradation of the carbohydrate in afroside gave afrogenin (4), and ‘anhydroafrogenin’(9) which is a 15-ketone with 14α-H. The conformation of the highly crowded ring D is studied using 1H and 13C n.m.r.

Ring-A oxygenated derivatives of 5α- and 5β-cardenolides

The introduction of an hydroxy-group α to the 3-keto-function of the 5α- and the 5β-cardenolides uzarigenone (4) and digitoxigenone (15) was carried out in three steps in good overall yield. The dimethyl acetals (5) and (16) of uzarigenone and digitoxigenone were pyrolysed to the respective Δ2- and Δ3-enol ethers (6) and (17). Epoxidation followed by spontaneous rearrangement led to respectively 2α-hydroxyuzarigenone (8) and 4β-hydroxydigitoxigenone (18). Sodium borohydride reduction of 2α-acetoxyuzarigenone (9) gave the 2- and 3-monoacetates (10) and (11) of gomphogenin (12)(2α-hydroxyuzarigenin), the latter monoacetate by acyl migration. On hydrolysis each formed gomphogenin (12). Reduction of the keto-function of 4β-acetoxydigitoxigenone (19) by lithium tri-t-butoxyaluminium hydride proceeded without rearrangement to yield the corresponding 3α-alcohol (20). The 13C n.m.r. data of 18 members of the title compounds are analysed.

New glucoside conjugates and other cardenolide glycosides from the monarch butterfly reared on Asclepias fruticosa L.

Eight cardenolide glycosides and one genin, including two new glucoside conjugates, have been isolated from adult monarch butterflies (Danaus plexippus L.) the larvae of which were reared on Asclepias fruticosa L. leaves. The glycosides calactin, calotropin (major components), calotoxin, and afroside were identified by comparison with authentic samples. The remaining compounds, after conversion into peracetates, have been shown by 400 MHz 1H n.m.r. and mass spectra (and for the first two compounds by direct comparison) to be the genin calotropagenin and the glycosides frugoside, gofruside, gomphogenin 3-β-D-glucopyranoside, and calotropagenin 3-β-D-glucopyranoside. The relationship between these compounds from monarch butterflies and those previously isolated from the food plant A. fruticosa is discussed.

In vitro metabolism of the cardiotonic steroids gomphogenin and calactin

The metabolism of gomphogenin and calactin was studied in vitro using respectively microsomes and the S9 fraction of homogenates from rat liver. These two substrates were previously shown to be in vitro and in vivo metabolites of gomphoside, a cardiotonic steroid belonging to a class of 5 alpha-cardenolide glycosides with doubly-linked hexosulose sugars. Structures of new metabolites were elucidated using 400 MHz 1H-NMR and chemical ionization mass spectrometry, while known compounds were identified by direct comparison. The major metabolite isolated from gomphogenin (2 alpha-hydroxyuzarigenin) metabolism was the oxidation product 2-oxo-uzarigenin which was further oxidized metabolically to 4 alpha-hydroxy-2-oxo-uzarigenin. Other metabolites were 2 alpha-hydroxyuzarigenone and its reduction product 3-epigomphogenin. Calactin was oxidized in vitro to 10-carboxyl-19-norgomphoside, the predominant metabolite, and underwent cleavage of the doubly-linked sugar to yield calotropagenin.

Structure of aspecioside from the monarch butterfly larvae foodplants Asclepias speciosa and A. syriaca

Aspecioside, a 7β,8β-epoxycardenolide glycoside isolated from Asclepias speciosa(Asclepiadaceae), has been shown by 400 MHz 1H n.m.r., 13C n.m.r., mass spectrometry, and biogenetic considerations to be 12β-hydroxy-5α-tanghinigenin-3-(6-deoxy-β-D-allopyranoside). It is also found in A. syriaca.