A Direct Synthesis of Nucleoside Analogs Homologated at the 3′‐ and 5′‐Positions

Abstract

A new route is presented to prepare analogs of nucleosides homologated at the 3'-and 5'-positions. This route, applicable to both the d-and l-enantiomeric forms, is suitable for the preparation of monomeric bishomonucleosides needed for the synthesis of oligonucleotide analogs. It begins with the known monobenzyl ether 3 of pent-2-yne-1,5-diol, which is reduced to alkenol 4. Sharpless asymmetric epoxidation of 4, followed by opening of the epoxide 5 with allylmagnesium bromide, gives a mixture of diols 6 and 7. Protection of the primary alcohol as a silyl ether followed by treatment with OsO 4 , NaIO 4 , and mild acid in MeOH, followed by reduction, yields (2R,3R) {{[(tert-butyl)diphenylsilyl]oxy}methyl}tetrahydro-2-(2-hydroxyethyl)-5-methoxyfuran ( methyl 3-{{[(tert-butyl)diphenylsilyl]oxy}methyl}-2,3,5-trideoxy-a/b-d-erythro-hexafuranoside; 10) (Scheme 1). Protected nucleobases are added to this skeleton with the aid of trimethylsilyl triflate (Scheme 2). The o-toluoyl (2-MeC 6 H 4 CO) and p-anisoyl (4-MeOC 6 H 4 CO) groups were used to protect the exocyclic amino group of cytosine. The bis-homonucleoside analogs 11 and 14a are then converted to monothiol derivatives suitable for coupling (Schemes 3 and 4) to oligonucleotide analogs with bridging S-atoms. This synthesis replaces a much longer synthesis for analogous nucleoside analogs that begins with diacetoneglucose ( 1,2 : 5,6-di-Oisopropylideneglucose), with the stereogenic centers in the final products derived from the Sharpless asymmetric epoxidation. The new route is useful for large-scale synthesis of these building blocks for the synthesis of oligonucleotide analogs.

Primitive Genetic Polymers

“…The results from these studies were intriguing, but less than straightforward to interpret. Although short sulfone-linked DNA analogs (sNAs) were shown to support Watson-Crick base pairing (Roughton et al 1995), longer oligosulfones appeared to have somewhat compromised pairing abilities (Huang et al 1991;Richert et al 1996) and small changes in nucleobase oligosulfone sequence resulted in appreciable changes in oligomer solubility, folding and aggregation Schmidt et al 2003). These authors interpreted the results of these studies as evidence that (1) charged linkages are important for molecular recognition by providing a repulsive energetic term between the two backbones of a duplex, ensuring molecular recognition is largely a function of the nucleobases, (2) that the regular repeating charge limits intramolecular folding of oligomers, thereby allowing these polymers to function well as linear duplexes and as templates for the same during replication, and (3) that, given the dominance of charge in governing the physical properties of these nucleic acids in aqueous solution, changes in DNA/RNA nucleobase sequence have only a second-order effect on polymer properties (i.e., sequence exerts more effect on the molecular recognition of a complementary strand and less effect on helical parameters), thereby allowing the use of virtually any possible nucleotide sequence .…”

Synthesis and Properties of Oligodeoxynucleotide Analogs with Bis(methylene) Sulfone Bridges

“…Further, the degree to which physical and chemical properties of large molecules are changed by small changes in sequences, first suggested in an SNA matrix, needs to be further explored. Given the availability of substantial amounts of building blocks (see the preceding paper [27]), we have explored in detail the synthesis of octameric dSNAs and tested their molecularrecognition properties. The details of the synthesis provide insights into the change in reactivity as one proceeds from small molecules to large molecules.…”

“…This problem was circumvented by addition of a secondary educt by Richert, who added greater than stoichiometric amounts of a 6'-OH uridine analog to his tetramer to enhance the absolute alcohol concentration in the bromination reaction (turnover rate 80%, yielding 60% brominated monomer and 40% brominated tetramer [30]). Following this strategy, tetramer 21 and monomer 25 (compound 11 of the preceding paper [27]) were brominated with PPh 3 and CBr 4 in 1,2-dichloroethane/MeCN 4 : 1 (Scheme 5). TLC Monitoring showed the complete turnover of starting material after 90 min.…”

“…in the preceding paper [27]; 278 mg, 0.546 mmol) was coevaporated 3 Â with pyridine and dissolved in pyridine/CH 2 Cl 2 4 : 1 (5 ml). The soln.…”

“…'-trideoxy-b-d-erythro-hexofuranosyl}thy-mine (compound 11 in the preceding paper [27]; 50 mg, 98 mmol) and PPh 3 (51 mg, 196 mmol) were coevaporated 3 Â with toluene, dried overnight under high vacuum at r.t., and then dissolved in 1,2-dichloroethane/MeCN 4 : 1 (10 ml). A soln.…”