Nucleosteroids: Synthesis of Purinyl‐Steroid Derivatives under Mitsunobu Reaction Conditions.

Abstract

The feasibility of using the Mitsunobu reaction for coupling of purines with steroids to obtain nucleosteroids was investigated in the particular case of 6-chloropurine and cholesterol. Three principal products were obtained: 3β-(6-chloropurin-9-yl)-5-cholestene (1), 3α-(6-chloropurin-9-yl)-5-cholestene (2), and 6β-(6-chloropurin-9-yl)-3,5-cyclocholestane (3), isolated with 10.5%, 22.7%, and 12.6% yield, respectively. The stereochemical and structural diversity of the coupling products are explained by the formation of a homoallylic carbocation through participation of the double bond of cholesterol.J. Heterocyclic Chem., 42, 1 (2005).The synthesis of carbocyclic nucleoside analogs covers a wide range of substances in which an ample variety of carbocyclic moieties has been displayed [1][2][3]. The development of this type of compound points to the search for new perspectives for antiviral, antibiotic, or antitumoral applications, in which the use of nucleoside analogs has been significant [3][4].We already investigated the synthesis of several steroidpurine coupling products [5,6] through an approach based on nucleophilic reactions, as was previously described by van Lier et al. [7]. To broaden the range of steroids potentially useful as starting materials for coupling with nitrogenated bases, we studied the feasibility of the conditions of the Mitsunobu reaction applied to the particular case of cholesterol. The mildness and simplicity of the procedure is an important aspect of this reaction. The biologic importance of cholesterol made it an attractive substrate to develop related nucleosteroids potentially useful in the above mentioned therapeutic fields.In this report, we describe the coupling of 6-chloropurine with cholesterol through substitution of the hydroxyl group by employing conditions of the Mitsunobu reaction. The experiment was conducted at room temperature, and 3β-(6-chloropurin-9-yl)-5-cholestene (1), 3α-(6-chloropurin-9-yl)-5-cholestene (2), and 6β-(6-chloropurin-9-yl)-3,5-cyclocholestane (3) were isolated in 10.6%, 22.8%, and 12.6% yields, respectively (total yield, 46.0%). The course and products of the reaction are shown in Scheme 1, which is similar to the results by Aneja et al. [8] dealing with the Mitsunobu reaction of cholesterol [9].The interaction of diethyl azodicarboxylate, triphenylphosphine, and 6-chloropurine with cholesterol would form intermediates I-III [8]. The nucleophilic attack of the purinyl anion I to intermediates II, and III, gives the 3α-(9-purinyl)-5-cholestene 2, 3β-(9-purinyl)-5-cholestene 1, and 6β-(9-purinyl)-3,5-cyclocholestane 3, respectively.