New Synthetic Approach to the Bicyclo[3.1.0]hexane Ring System from (+)-(1R,4R)-4-(Benzyloxymethyl)-4-(hydroxymethyl)cyclopent-2-enol.

Abstract

A methanocarba approach to conformationally constrain the sugar ring in nucleosides and nucleotides was introduced by Marquez and co-workers. Thus, a bicyclo[3.1.0]hexane system has been constrained in a North ((N), 2'-exo) or South ((S), 2'-endo) conformation, according to the pseudorotational cycle. In many studies of the ribose ring conformation of nucleosides and nucleotides binding to G proteincoupled receptors (GPCRs), novel (N)-ligands for adenosine receptors and P2Y receptors provided favorable receptor affinity and/or selectivity compared to their corresponding (S)-conformers. In addition, (N)-bicyclo[3.1.0]hexane nucleosides, -tides and oligonucleotides, including 2'-deoxy analogues, were good candidates for the development of a potent antiherpes agent, as an inhibitor of (cytosine C5)methyltransferase, for using in oligonucleotides and as a mechanistic probe of base flipping by Hhal DNA methyltransferase. Since the biological relevance of (N)-bicyclo[3.1.0]hexane derivatives is so high, additional effort is warranted to overcome the drawbacks of the previous synthetic pathways described in earlier publications. Those methods involved two or three operationally demanding steps and gave unexpectedly low yields when applied to a gram-scale synthesis (Figure 1). The preparation of (N)-bicyclo[3.1.0]hexanes in quantity is crucial to progress in the related research fields; thus, improving the yield of existing synthetic steps or developing novel synthetic pathways is desirable. In this letter we describe the conversion of (+)(1R,4R)-4-(benzyloxymethyl)-4-(hydroxymethyl)cyclopent2-enol into a key intermediate (+)-bicyclo[3.1.0]hexane alcohol 1. The starting material 2 contains a quaternary carbon, which eliminates the need for harsh conditions usually associated with the construction of a quaternary carbon center. Although there remain aspects for further refinement, this work provides a novel route to obtain the crucial intermediate (+)-bicyclo[3.1.0]hexane 1. The synthesis of (+)-(1R,4R)-4-(benzyloxymethyl)-4(hydroxymethyl)cyclopent-2-enol 2 was done according to the previously reported method. The versatility of diol 2 was demonstrated previously with the synthesis of the (N)locked bicyclo[2.2.1]heptane system. Preparation of silyl acetonide 3 from 2 followed a well-established method. The published report gave a synthetic method to a silyl triol, which was protected as the acetonide to afford silyl acetonide 3 (Scheme 1). Removal of the benzyl group with Pd/C in the presence of hydrogen in a variety of conditions was also accompanied by the unexpected deprotection of the silyl group. Treatment of silylated acetonide 3 with Pd black