Hecogenin acetate

The seminal work on steroid analyses using chiroptical detection was done by Djerrasi by the determination of hecogenin acetate in the presence of tigonenin acetate.Every steroid is chiral and therefore amenable to polarimetric detection after chromatographic separation. Chromophores are fairly uncommon, and analysis by ORD or CD is therefore less suitable. The only unsaturation in the cholesterol molecule, for example, is the isolated A -double bond, which has an absorbance maximum at 205 nm. Unsaturation coupled with chirality provides some selectivity, as ably demonstrated by the work of Potapov for analogs of progesterone Even simpler than that is the direct discrimination between the ketosteroids testosterone and dihydrotestosterone, which have opposite signs in methylene chloride solution (Fig. 6). 

The preparation of 12-oxygenated conanine derivatives and a partial synthesis of dihydroholarrhenine (4) have been reported. 3/3-Acetoxy-5a-pregnan-12,20-dione ethylene acetal (5 a), prepared from hecogenine acetate by published procedures, was transformed to the oxime (5b) which was reduced by sodium in propanol to the epimeric 20-amino-derivatives, with hydrolysis of the 3-acetoxy-group. Separation of the 20o -epimer (6a) was effected by crystallization and column chromatography. Reduction of the cathylate (6b) gave (6c) which was oxidized to the... 

A re-investigation " of the decomposition of the 12-tosylhydrazone (529) of hecogenin acetate by bases shows that aprotic media lead to formation of the 11-ene (530), probably via a carbene intermediate. Hydroxylic solvents protonate the intermediate diazo-compound, leading to the olefinic product (531) by rearrangement of a C-12 carbonium ion. The related solvolysis of the 12/9-tosylate (532) gives the stable 13(17a)-olefinic compound (531) at high temperatures, and... 

Scheme 13. Introduction of the C-14,15 alkene into hecogenin acetate.

Scheme 16. Jeong and Fuchs synthesis of diene 38 from hecogenin acetate.

Introduction of asymmetry into a homodimer was demonstrated [9] by Winterfeldt and coworkers at Hannover (Scheme 5). Commercially available hecogenin acetate was transformed [10] to 5 and dimerized to symmetrical diketone 6. The two carbonyls could be statistically differentiated by controlled reduction or trapping of the dienolate to yield hydroxy ketone 7. Compounds 6 and 7 were evaluated at the NCI. The symmetrical 6 affects 32 of the 58 cell lines tested, while a saturated version lacking the D ring alkene shows weak activity. Meanwhile, unsymmetrical 7 is significantly cytotoxic against all 58 cell lines, being approximately 4,000 times weaker than cephalostatin 1. 

The synthesis began with a derivative of hecogenin acetate, which already contains all the carbons needed. Classical Marker sa-pogenin spiroketal ring-opening gave 11 (Scheme 7) which was carried forward to 12. 

The Fuchs group has also prepared [15] dihydrocephalostatin 1 . In this synthesis (Scheme 9), the angular methyl group of keto alcohol 20 (obtained from hecogenin acetate) was functionalized by Meystre s hypoiodite method and oxidized to yield 21. Further reactions via intermediates 22 and 23 afforded 24, which was coupled with a-amino oxime ether 25 (prepared from 18) to give dihydrocephalostatin 1 after deprotection. This dihydro derivative had biological activity comparable to cephalostatin 1. 

The determination of the precise biological target of these alkaloids requires larger amounts of material. Thus, it is particularly exciting that Winterfeldt s synthetic dimer 7, prepared in 10 steps from hecogenin acetate, displays high activity. According to Pettit,... 

Due to the common occurrence of steroids in Nature, there is not much need to synthesize the steroid skeleton from simple substrates. Therefore, the use of phosphonates in syntheses involving this class of compounds, concerns mostly modifications of the steroid pool, like in the case of the conversion of 17-oxo-steroids to 20-ketosteroids and progesterone as well as construction of the South steroid subunit of cephalostatin 1 from hecogenin acetate. 

A soln. of hecogenin acetate in dioxane UV-irradiated until after 9.25 hrs. the optical activity has become constant lumihecogenin acetate. Y 80%. P.Bladon, W. McMeekin, and I. A. Williams, Soc. 1963, 5727. 

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