Kited in Great Britain 0040-4039191 $3.00 +.Oa Pergamon Pless plc Carbocyclic Analogs of Nucleosides via Modified Mitsunobu Reactions

Abstract: A set of carbocyclic nucleoside analogs have been prepared using a novel modilication of the Mitsunobu reaction. This approach helps solve an important synthetic problem in the preparation f carbocyclic an.llogs of nucleosides. Analogs of oligonucleotides having dimethylene sulfide, sulfoxide, and sulfone units replacing the phosphate diester groups in the backbone, compounds that are potential antisense reagents, have been synthetic targets in these laboratories for some time 2,3,4. As a part of this work, we wished to have a variant of these analogs with the ring oxygen replaced by a-CH2- group (e.g., 1). Efforts to prepare building blocks for these analogs encountered several synthetic problems that are common in the synthesis of carbocyclic analogs of nucleosides generally.5 Attachment of cyclopentane or other substituents to a purine via direct alkylation often yields both N7 and @ substituted derivative&, while alkylation of pyrimidines (e.g., with tosylates and mesylates)7 is generally low yielding. Alkylation of purines using epoxides has successfully yielded carbocyclic analogs of nucleosides 8~,10+11,12. However, this approach necessarily gives ring systems that are hydmxylatcd in an inconvenient position. Further, stepwise construction of purine and pyrimidine ring systems around a carbccyclic amine13 proved in our hands to be tedious and low-yielding, and involved reaction conditions that were incompatible with groups used in our systems to protect functionality on the side chains of the cyclopenryl ringsId. We therefore have extended Mitsunobu-type procedures’s to append the heterocyclic rings 6-chloropurin