9,10-seco-Steroids, synthesis

A total synthesis of functionalized 8,14-seco steroids with five- and six-membered D rings has been developed (467). The synthesis is based on the transformation of (S)-carvone into a steroidal AB ring moiety with a side chain at C(9), which allows the creation of a nitrile oxide at this position. The nitrile oxides are coupled with cyclic enones or enol derivatives of 1,3-diketones, and reductive cleavage of the obtained cycloadducts give the desired products. The formation of a twelve-membered ring compound has been reported in the cycloaddition of one of the nitrile oxides with cyclopentenone and as the result of an intramolecular ene reaction, followed by retro-aldol reaction. 

A new, general method is developed for preparation of various 3-substituted carbonyl compounds of high enantiomeric purity. Application of this method is made to asymmetric synthesis of either enantiomer of 3-methylalkanoic acids, of enantiomerically pure 3-methylcyclopentanone, 3-methyl-cyclohexanone, 3-naphthylcyclopentanone and 3-vinylcyclopentanone 18. 9,11-Seco steroid 3 6... 

Cases exist, such as the natural or commercial preparation of provitamin D from provitamin D (Sect. 1) or the ring opening of cycIohexa-2,4-dienones to their dieneketene seco-isomers (Sect. 2), in which the photoreaction has the advantage. There are other instances such as the preparation of reactive or//(o-quinodimethane derivatives as intermediates in steroid synthesis ) (Sect. 3), in which either pliotoenoKzation or thermal seco-isomeriza-tions of appropriate benzocyclobutene derivatives may be used equally weU. 

The 9,11-seco steroid (68) was formed with the desired natural (135,145) absolute stereochemistry. Conversion of a racemic sample of (68) into racemic steroidal equilenin (69) was used to demonstrate the potential of this methodology for the total synthesis of enantiomerically pure steroidal material of natural configuration, although an enantiomerically pure synthesis was not performed [46]. 

A number of other synthetic approaches to the steroid skeleton are discussed in the following sections, which are devoted more specifically to the synthesis of oestrane, androstane, and pregnane derivatives, as well as to seco-compounds and steroidal alkaloids. 

Because of its flexibility, the Torgov synthesis (see Scheme 6) is still used quite frequently for the preparation of modified steroids. Acid cyclization of 3-methoxy-8,14-seco-oestra-l,3,5(10),9(1 l)-tetraene-14,17-dione (96) gave a mixture of the A -bisdehydro-oestrone (97) and A -dehydro-14/8-hydroxy-8a-oestrone (98). Catalytic hydrogenation of (98) afforded 3-methoxy-14 -hydroxy-8a,9)8-oestrone (99a) and 79% of 3-methoxy-14)S-hydroxy-8a,9a-oes-trone (99b). Treatment of (99b) with thionyl chloride in pyridine provided, after hydrolysis, 59% of 3-methoxy-A -dehydro-8a-oestrone (100), which on hydrogenation yielded the 8a,14)S-oestrone analogue (101). 

Treatment of the steroid (146 Scheme 48) with LTA and TMS-N3 gives the 5,6-seco-5-oxo-7-carboni-trile steroid (147) useful for the synthesis of ring b homoazasteroids. ZbiraF explains the mechanism as an aza analog of the Eschenmoser fragmentation via formation of the azido epoxide. 

Zbiral, E., Nestler, G., Kischa, K. Transfer reactions with lead(IV) acetate. IV. General single stage synthesis of seco-oxonitrile forms of steroids with iead(iV) acetate-trimethyisiiyi azide. New type of fragmentation principle. Tetrahedron 1970, 26, 1427-1434. 

The asymmetric synthesis of optically active 6-thiaoestrogens has been described. This work followed previously reported total synthetic schemes in which the asymmetric conversion was effected with 8,14-seco-intermediates. In addition, the synthesis of variously modified 6-thia-steroids by the classical route has also been reported. ... 

Stereochemistry of Cyclization. Until now, we have been dealing with the formation of centers of asymmetry in compounds with an already-formed carbon skeleton. We must also consider the stereochemistry of the formation of such centers in the very process of the formation of the steroid skeleton, i.e., in cyclization reactions. In the majority of known methods of cyclization (see Table 4), adjacent to the newly formed ring there is a pre-existing or newly formed double bond, which raises the question of the stereochemistry of the reaction. Only comparatively rarely in the total synthesis of steroids does cyclization lead directly to the production of new centers of asymmetry. As an example we may mention the cyclization of 13,17-seco-16-carboxy-A -steroids of the type of... 

Migliuolo, A., Piccialli, V., and Sica, D. (1992) Two new 9,11-secosterols from the marine sponge Spon officinalis. Synthesis of 9,ll-seco-3p,6a,ll-trihydroxy-5a-cholest-7-en-9-one. Steroids, 57, 344-347. 

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