Karl Bischofberger

Synthesis of C-glycosyl compounds. Part 1. Reaction of ethyl isocyanoacetate with 2,3:5,6-di-O-isopropylidene-D-mannono-1,4-lactone

Formylaminomethylenation of 2,3:5,6-di-O-isopropylidene-D-mannono-1,4-lactone (1) with ethyl isocyanoacetate (2) gave, as the major product, (E)-ethyl 3,6-anhydro-2-deoxy-2-formylamino-4,5:7,8-di-O-isopropylidene-D-manno-oct-2-enonate (3)(58%), which on hydrogenation gave ethyl 3,6-anhydro-2-deoxy-2-formylamino-4,5:7,8-di-O-isopropylidene-D-erythro-L-gluco-octonate (17), in almost quantitative yield. Base-catalysed equilibration of the D-erythro-L-gluco-octonate (17) gave a mixture of the L-allo-, L-altro-, L-gluco-, and L-manno-epimers [(23), (22), (17), and (19), respectively]. The configurations at C-2 and C-3 of these epimers were established by chemical and physical methods.The D-erythro-L-gluco-epimer (17) and the D-erythro-L-manno-epimer (19) were degraded to ethyl 3,6-anhydro-2-deoxy-2-formylamino-4,5-O-isopropylidene-D-glycero-L-gluco-heptonate (37) and its D-glycero-L-manno-epimer (39), respectively. Acidic hydrolysis of compounds (17), (19), (37), and (39) gave the free amino-acids, L-2-(β-D-mannofuranosyl)-glycine (41), the analogous D-amino-acid (42), L-2-(β-D-lyxofuranosyl)-glycine (43), and the analogous D-amino-acid (44), in moderate yields.In the presence of base, alcohols and thiols readily attacked the double bond of the oct-2-enonate (3) to give, for example, ethyl (ethyl 2-deoxy-2-formylamino-4,5:7,8-di-O-isopropylidene-α-D-manno-D-glycero-oct-3-ulo-3,6-furanosid)onate and its D-manno-L-glycero-epimer [(9) and (10)].

Cycloaddition of phenyl vinyl sulphone to 3-methoxy-16-methylestra-1,3,5(10),14,16-pentaen-17-yl acetate: synthesis of 14-functional ised 19-norpregnane derivatives

Diets–Alder reaction of 3-methoxy-16-methylestra-1,3,5(10),14,16-pentaen-17-y1 acetate 3 with phenyl vinyl sulphone affords three 14,17-cycloadducts; the two major products (ca. 37% each) are the regioisomers derived from endo addition on the β-face, whereas the minor product (ca. 14%) is the endo isomer of meta-directed attack on the α-face. Sequential reductive desulphonylation, hydroxylation, and oxidative cleavage of the major products is described, and the derived 14-hydroxymethyl-3-methoxy-19-norpregna-1,3,5(10)-trien-20-one 16 is converted into 14α-hydroxymethyl and 14α-formyl analogues of 19-norprogesterone. A route to 3-methoxy-1.4-methyl-19-norpregna-1,3,5(10)-trien-20-one 27 is described.

Total synthesis of (±)-14α-methyl-19-norsteroids

Trans-1,6-Dimethylbicyclo[4.3.0]nonane-2,7-dione was converted, in six steps, into a mixture of (±)-3-methoxy-14-methyl-14α-estra-1,3,5(10),9(11)-tetraen-17-one and the corresponding Δ8-isomer.

Acid-mediated rearrangements of 14,17-ethenoestra-1,3,5(10)-trien-17-ols: synthesis of 14,16-ethano-19-norsteroids

3-Methoxy-171-methyl-l 4,17α-ethenoestra-1,3,5(10)-trien-17β-ol 1 undergoes a 16(17 → 171)abeo-rearrangement in the presence of boron trihalides, to give the corresponding 16α-methyl-14β,16β-ethano 17-ketone. Similar rearrangements are described for epimeric 14,17-bridged estradiol analogues, leading to 16β-methyl-14α,16α-ethano 17-ketones. By contrast, acid-mediated reactions of 3-methoxy-14,17α-ethenoestra-1,3,5(10)-trien-17β-ol 11 display reagent dependence, leading to products of competing 16(17 →r;171)abeo-and 15(14 → 172)abeo-rearrangements. Conversion of certain rearrangement products into 14,16-ethano analogues of estradiol and 19-nortestosterone are described, and X-ray crystallographic structure determinations are reported for three ring-D-bridged compounds, and a novel spiro compound arising from rearrangement of the 14α,17α-etheno 17β-alcohol 11.

Cycloaddition route to 14-hydroxymethyl-19-norprogesterone

Diels–Alder reaction of 3-methoxy-16-methylestra-1,3,5(10),14,16-pentaen-17-yl acetate with phenyl vinyl sulphone affords three 14,17-cycloadducts, two of which are efficiently converted into 14-hydroxymethyl-19-norprogesterone.

Preparation of analogues of the carbohydrate moiety of the polyoxins.

Syntheses of 2-C-[ethoxycarbonyl(formylamino)methylene] carbohydrate derivates by formylaminomethylenation of two pentofuranosulosides and a pentopyranosuloside are described. Hydrogenation of the unsaturated branched-chain compounds gave glycosides bearing protected amino-acid moieties as substituents at C-2. Hydrolysis and reduction experiments that establish the structures of the branched-chain compounds are described.

14-Methyl steroids. Part 5. Structural features influencing stereoselectivity of 14-methylation of 15-oxo-19-norsteroids: synthesis of 14α-methyl-19-norprogesterone

Methylation of 3-methoxy-14β-estra-1,3,5(10),8-tetraen-15-one (5) in the presence of base affords a ca. 5 : 1 mixture of the corresponding 14α- and 14β-methyl compounds (6) and (7) respectively, whereas similar treatment of 20,20-ethylenedioxy-3-methoxy-19-norpregna-1,3,5(10)-trien-15-one (15) results in exclusive formation of the 14α-methyl product (18). The latter compound (18) has been converted into 14α-methyl-19-norprogesterone (23). The stereoselectivity of 14-methylation of 15-ketones is correlated with the propensity of ring D to adopt a quasi-trans or quasi-cis conformation in the derived enolate, leading to preferred 14α-or 14β-methylation respectively.

14-Methyl steroids. Part 2. Total synthesis of (±)-14α-methyl-19-norsteroids

trans-1,6-Dimethylbicyclo[4.3.0]nonane-2,7-dione (1) is converted, via regiospecific homologation at C-2, into trans-1,6-dimethyl-2-methylenebicyclo[4.3.0]nonane-3,7-dione (6). Conjugate alkylation of (6) with m-methoxybenzylmagnesium chloride followed by acid treatment, affords a mixture of (±)-3-methoxy-14-methyl-14α-estra-1,3,5(10),9(11)-tetraen-17-one (8) and the corresponding Δ8-isomer (9). The stereoselectivity of reductions of the Δ9(11)- and Δ8-bonds in (8) and (9) and the derived 17-acetals is examined, and an efficient synthesis of (±)-3-methoxy-14-methyl-14α-estra-1,3,5(10)-trien-17-one (13) is described.

Synthesis of fluorinated branched-chain sugars

Treatment of (E)-3-deoxy-3-C-ethoxycarbonyl(formylamino)methylene-1,2 : 5,6-di-O-isopropylidene-α-D-glucofuranose with trifluoro(fluoro-oxy)methane gives branched-chain sugars bearing a fluorine atom at the branch point. Some reactions of these fluorinated sugars are described.

Cyano-sugars. Part 3. Synthesis of 2-C-cyano-2-deoxy-sugars from 2-C-cyano-galactals and attempts to prepare pentofuranosyl cyanides from aldonic acid lactones with tosylmethyl isocyanide

1,5-Anhydro-2-C-cyano-2-deoxy-D-lyxo-hex-1-enitol (2) reacted with sodium methoxide in methanol to give, after acetylation, methyl 3,4,6-tri-O-acetyl-2-C-cyano-2-deoxy-β-D-galactopyranoside (6) as the main product. Similar treatment of 1,5-anhydro-2-C-cyano-2-deoxy-1,2-O-isopropylidene-D-lyxo-hex-1-enitol (3) gave methyl 4,6-di-O-acetyl-2-C-cyano-2-deoxy-3-O-methyl-α-D- and -β-D-galactopyranoside (11) and (7), respectively, as the main products. Compounds (6), (7), and (11) were converted into their 2-C-acetamidomethyl analogues (8), (9), and (12), respectively, in high yield by catalytic hydrogenation in ethanol–acetic anhydride.The formylaminomethylenation of 2,3 : 5,6-di-O-isopropylidene-D-mannono-1,4-lactone with tosylmethyl isocyanide gave (E)- and (Z)-2,5-anhydro-1-deoxy-1-formylamino-3,4 : 6,7-di-O-isopropylidene-1-tosyl-D-manno-hept-1-enitol [(17) and (18)]. The reaction of the main isomer (17) with 2 equiv, of sodium ethoxide in ethanol, gave ethyl [(1R)-O-ethyl-1-formylamino-3,4 : 6,7-di-O-isoproyplidene-aldehydo-α-D-manno-heptafuranos]uloside and its (1S)-epimer [(21) and (22)], and not 2,3 : 5,6-di-O-isopropylidene-α,β-D-mannofuranosyl cyanide, as expected. 2,3 : 5,6-Di-O-isopropylidene-D-gulono-1,4-lactone behaved similarly.