Sarett’s ketone

The synthesis of the 19-nor analog (83) of Sarett s ketone also takes place via nonaromatic intermediates, being carried out in accordance with Scheme 63 [663, 664]. The cyclic diene (77) required for the synthesis was obtained from the ethyl enol ether of 1,3-cyclohexanedione (76) by the Normant reaction and transketalization with ethylmethyldioxolan. Conden-... 

The synthesis of aldosterone from Sarett s ketone (67) has been carried out successfully by three groups of workers Wettstein s group (of the firm of "Ciba," Basle, Switzerland), by Reichstein s group (Basle University), and by SzpilfogePs group (the firm of "Organon, Oss, Holland). A common feature of all these syntheses is the use of the center of asymmetry already present in Sarett s ketone to form the C13 center of asymmetry. 

The reduction of the lactone grouping of compound (119) required the preliminary protection of the two keto groups. Reaction with ethylene glycol formed the diketal, the controlled reduction of which with lithium aluminum hydride enabled the cyclohemiacetal (118) to be obtained. In itself, the reduction takes place with a high yield and the main difficulty is the deketalization of the extremely unstable compound (118). Consequently, the products of lithium aluminum hydride reduction were immediately acetylated with acetic anhydride to a mixture of the 21-mono-and 18,21-diacetates. Hydrolysis of this mixture with 90% acetic acid at 100 C led to the 21-acetate of dl -aldosterone (123). Deacetylation of the latter with potassium carbonate gave not only dl -aldosterone (124) with a yield of 50%, but also its 17o -epimer. Natural -aldosterone was obtained by the same route from the tZ-enantiomer of (119). By Wettstein s first method (Scheme 66), cZZ-aldosterone (124) was formed from Sarett s ketone (67) in 22 stages with an over-all yield of 1.7%. 

The second group of total syntheses of aldosterone and its analogs from Sarett s ketone is characterized by the formation of ring D by Stork s method using intramolecular crotonic cyclization of 14,16-diketones (Schemes 68 and 69). The key stereochemical question of these syntheses is the formation of the C14 center of asymmetry in the hydrogenation of the A-bond. 

The synthesis of compound (158) completes the solution of three problems in the passage from Sarett s ketone (67) to aldosterone the stereospecific formation of the C13 and C14 centers of asymmetry and of the cy-c lohem iac etal grouping. 

An attempt has also been made to form ring D from Sarett s ketone (67) by cyclizing 14,16-diketones to D-homo derivatives [761] (Scheme 69). On undergoing the Michael reaction in an anhydrous medium, the oxalyl and formyl derivatives (168) R = C02Et and R = H, respectively) of the initial ketone (67) formed, with the axial entry of the side chain, compounds with the 13q -configuration of the angular substituent (169) which shows the unsuitability of these products for the formation of 11,18-cyclohemiacetals. The cyclization of (169) under mild conditions gave the spirane derivatives... 

Lead tetraacetate oxidation (63) of oxodelcosine (LXXXV) gave LXXXVII, presumably arising from the expected diketone LXXXVI. Evidence favoring structure LXXXVII was the further oxidation of one of the two hydroxyls to a five-membered ketone (LXXXVIII) with Sarett s reagent. Thus, the unreacted hydroxyl of LXXXVII must be tertiary this can be explained if the C-1 hydroxyl reacted with the C-8 ketone to form a hemiketal. Furthermore, the hemiketal formation as... 

Oxidation with Sarett s reagent gave two products (1) the azomethine CCXCVIII which formed the ethiodide CCXCIX, convertible to chasmanine by reduction with sodium borohydride, and (2) the neutral V-acetyl-A-desethyl-14-dehydrochasmanine (CCC). The stereospecific course of the reduction of the five-membered ketone is indicative of the ketone carbonyl being at C-14 rather than C-12 and is consistent with the stereochemistry of these skeletons which have free access to the C-12 position, whereas the C-14 position is hindered by ring D, leaving only one side open for attack. 

The building up of ring D by Sarett s method with the successive introduction of amethallyl group at C 2 and an ethoxycarbonylmethylene group at Ci4 led via ketone (173) to compound (174), from which compound (176) was obtained by reduction of theCi4 chain, oxidation of the C13 side chain, and cyclization via the intermediate (177) the cis-C/D linkage in compound (176) was shown by its oxidation to the ketone (178) [762]. 

The mechanism of the Sarett oxidation, Collins oxidation, with Corey s PCC and with PDC, follows a similar mechanism as shown in Scheme 7.1. The alcohol reacts with CrOs to give a chromate ester. Either a base (Py) removes a proton from the chromate ester to give an oxidized product (aldehyde or ketone) and HCrOs" or a proton is transferred by the intramolecular mechanism to give an aldehyde or ketone and H2Cr03. 

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