The squalestatins: potent inhibitors of squalene synthase. The role of the tricarboxylic acid moiety.

Esterification of Carboxylic Acids and Etherification of Phenols with Amide Acetals

“…Further applications of 7e in the conversion of carboxylic acids 1 into tert-butyl esters can be found in the literature. [57][58][59][60][61][62][63][64][65][66][67][68] Di-tert-butyl acetal 7e can also be prepared in situ from tert-butyl alcohol in the presence of dineopentyl derivative 7d in boiling benzene in the conversion of L-trans-Nbenzoyl-4-hydroxyproline into its tert-butyl ester in 82% yield. 19 As a preparative alternative to di-tert-butyl acetal 7e, solutions of carboxylic acids 1, such as benzoic acid in dichloromethane, have been reacted with a cyclohexane solution of tert-butyl trichloroacetimidate [Me 3 COC(=NH)CCl 3 ], which is obtained on the addition of potassium tert-butoxide in tert-butyl alcohol-diethyl ether to trichloroacetonitrile.…”

“…the subsequently described alkylation of 4-nitrophenol (81) with 3a-hydroxy steroid 78, Scheme 18]. (56) reacts with acid-labile 4-methoxybenzyl alcohol (57) in the presence of DMF dineopentyl acetal 7d to give the corresponding 4-methoxybenzyl ester 58 in 74% yield, as well as small amounts of bis(4-methoxybenzyl) ether (59) and 4-methoxybenzyl neopentyl ether (60). 39 Likewise, hindered 2,6-dichlorobenzoic acid (61) and allylic alcohol 62 react in the presence of 7d to give ester 63 (Scheme 14).…”

The squalestatins: cleavage of the bicyclic core via the novel 6,8-dioxabicyclo[3.2.1]octane ring system

“…This process was repeated three times until all the water had been removed. The resulting yellow gum (400 mg) was chromatographed on silica gel eluting with ethyl acetate-cyclohexane 4 (s), 77.9 (d), 77.4 (s), 74.6 (d), 70.0 (d), 52.6 (q), 52.1 (q), 42.6 (t), 39.3 (t), 35.9 (d), 33.6 (d), 31 -4 (d), 30.1 (t), 29.2 (t), 24.6 (t), 20.8 (q), 20.0 (q), 18.7 (q), 13.6 (9) and 11.0 (9); m/z (DCT/NH,) 708 (M + NH,)+. 7, CHZCH,), 0.86 (3 H, d, J 7, CHCH,), 1.01 (3 H, d, J 7,…”

“…q), 53.1 (q), 43.1 (t), 40.0 (t), 36.9 (d), 34.5 (d), 32.0 (d), 29.7 (t), 29.6 (t), 24.9 (t), 21.1 (q), 19.9 (q), 19.1 (q), 14.0 (9) and 11.1 (9); m/z (DCI/NH,) 689 (M + H)+. CH=CHCO,), 5.99 (1 H, S, CHOCOCH=CH), 6.95 (1 H, dd, J…”

The Squalestatins: Inhibitors of Squalene Synthase. Enzyme Inhibitory Activities and in Vivo Evaluation of C3-Modified Analogues

“…As a part of our chemical program aimed at the modification of the complex squalestatin structure and the identification of the key structural features responsible for the biological activity, we have reported on the C1 chain-length requirements; on the role of the tricarboxylic acid moiety; on C6 and C7 modifications; on the C6,C7 dideoxy, C3 decarboxy, C4 deoxy, monocyclic, acyclic, , C3 hydroxymethyl and C3 heterocyclic analogues; and on modifications at the allylic center . In addition a detailed review bringing together all the published SAR of the squalestatins and the zaragozic acids has just been completed .…”