Azasteroids, synthesis

Scheme 3.1 The Medicinal Chemistry synthesis of A -3-keto-4-azasteroids.

Scheme 1.28. Acyliminium ion-initiated domino cyclization in the synthesis of azasteroids.

Activation of a primary alcohol 174 by in situ mesylation and nucleophilic attack of a pyridine nitrogen atom was used in the last steps of a synthesis of cyclohexa[tf]quinolizidines 176. These compounds were obtained by direct NaBH4 reduction of intermediate pyridinium salts 175, and were proposed as tricyclic models containing the ABC-part of 8-azasteroids (Scheme 30) <1999T9269>. 

Novel steroidal pyridazines are readily prepared from ADC compounds and steroidal A2,4-dienes,163 A14,1 -dienes,164 and A16,20-dienes.165 ADC compounds are also commonly used in the protection of the steroid 5,7-diene system (see Section V,A). These Diels-Alder adducts of steroidal dienes and azo dienophiles should not be confused with the so-called azasteroids, which are also prepared from ADC compounds. Cyclic ADC compounds such as the pyrazole-3,5-diones (7), and the diazaquinones 12 and 13 readily add to dienes to give bicyclic pyridazine derivatives,166168 and these reactions have been adapted to the synthesis of 5,10-diazasteroids (106).42 Similarly, the 13,14-diaza- (107) and 13,14,16-triazasteroid (108) ring systems have been prepared.169... 

Consistently high levels of asymmetric induction have been achieved in the alkylation of tetrahydroisoquinolines using this methodology, as is demonstrated in the synthesis of chiral isoquinolinium alkaloids, e.g., (-)-salsolidine (61% yield, 95% ee)13, ( + )-homolaudanosine (48% yield, 96% op)14, ( —)-norcoralydine (37% yield, 98.5% op)15, some ben-zo[ ]quinolizidines (>99%ee), precursors of natural emetine16, corynantheine alkaloids17 and some azasteroids (93% ee)18. 

Tetrahydroisoquinolines have been oxidized to 3,4-dihydroisoquinolines using cerric ammonium nitrate <95SC(25)2591>, as well as by using molecular oxygen catalyzed by cuprous chloride <95H(41)773>. 3,4-dihydroisoquinolines have been used in the synthesis of l-substituted-2-aryltetrahydroisoquinolines <95SC(25)1817>, and in the synthesis of 1 -N-arylaminomethylene derivatives of 8-azasteroids (Scheme 41) <95KGS266>. 

Aromatic quinolizidines, advances in chemistry of 82AHC(31)1. 8-Azasteroids, total synthesis of 84UK1014. 

A convenient synthesis of 8-azasteroids by intramolecular alkylation of enaminoketones has been found . A new and efficient synthesis of pyrazoles through gem-dihalogenocyclopropyl acetates has been published . Tri-C-subst. imidazoles with 3 different substituents can be obtained in one step from a-acoxy-... 

In order to get experimental veiification of this proposal and also to interfere with sterol synthesis, we designed, first synthesized and evaluated novel azasteroid analogs of the presumptive carbocationic intermediate involved in the A -SR mechanism, based on the transition-state analog concept. These novel compounds were shown to be very powerful inhibitors of A -SR in vitro in a maize microsomal preparation (Figure 1)... 

Design, synthesis and biological evaluation of 6-substituted-4-azasteroids as tissue selective androgen receptor modulators... 

The route for the synthesis of steroid analogs with heteroatoms in positions 4 and 6 (Scheme 41) is analogous to that described in Schemes 38 and 39 for the carbocyclic steroids. The starting material used for the synthesis of 4-azasteroids was the quinolone (420) which with the performance... 

Azasteroids and their D-homo analogs have been obtained by Scheme 41 using as the starting material the quinolone (423), the tosylate or ben-zenesulfonate of which was converted via the vinyl carbinol (424), the diketone (425), and the tetracyclic ketone (427) into 6-aza-A -dehydroestrone (428) [535, 536]. However, the last stage of the synthesis, the hydrogenation of the 17-ketone (427), takes place unselectively in this case and in addition to the 14q -isomer of compound (428) C ield 26%), a predominating amount (yield 34%) of the unnatural 14/3 -isomer is formed. 

In its method of building up the skeleton, the last method for the synthesis of 8-azasteroids resembles the Robinson synthesis (see Scheme 24). Boiling the dihydroisoquinoline (451) with / -diketones in ethanol leads to the production, depending on the diketone used, of 12-oxo derivatives of the type of (450), 12,17a-dioxo derivatives of the lype of (453), or the 8,16-diaza-D-homo derivative (452) [555]. The 17-aza, 17-oxa-, and 17-thia-D-homo analogs of the estrogens (445 X =NH, O, S) have been obtained by Robinson s classical method using the condensation of the methoxytetralone (8) with the appropriate heterocyclic analogs of acelyl-cyclohexene (454 X =NH, O, S) [89, 556]. 

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