1′,6′-methano carbocyclic thymidine: Synthesis, x-ray crystal structure, and effect on nucleic acid duplex stability

A ring-closing metathesis based synthesis of bicyclic nucleosides locked in S-type conformations by hydroxyl functionalised 3′,4′-trans linkages

“…6,7 Oligonucleotides containing the monomer 3 (R 1 ¼H, R 2 ¼OH), however, demonstrated slightly decreased recognition of DNA and RNA complements. 21 Similar results have been obtained with other bicyclic nucleoside monomers that are strongly restricted in S-type conformations due to a 1 0 ,3 0 -cis linkage 22 or a 2 0 ,3 0 -trans linkage. 18 destabilisation might, in all three cases, be steric influence from the additional ring structures or distortion of duplex hydration patterns.…”

The Properties of Locked Methanocarba Nucleosides in Biochemistry, Biotechnology, and Medicinal Chemistry

“…This structural demand rules out convergent approaches, and the synthesis must proceed from a suitably protected bicyclic amine. Altmann et al [34] also reported the first synthesis of S-methanocarbathymidine (S-MCT, 75; Scheme 12.11).…”

“…These difficulties were not encountered with the hydrogen phosphonate protocol during the synthesis of a phosphorothioate 15-mer ODN containing 10 modified 2 0 -exo N-thymidine units [20]. Surprisingly, the same phosphoramidite chemistry when used with locked, 3 0 -exo (S) bicyclo[3.1.0]hexane units presented no such problems [34]. This contrasting chemical behavior between locked 2 0 -exo and 3 0 -exo units was later found to be related to a concept already discussed in Sections 12.3.3 and 12.3.4, whereby the rigid bicyclo[3.1.0]hexane scaffold controls the outcome of sharply different pathways [47].…”

Bicyclic nucleosides and conformational restriction of oligonucleotides

“…32 X-Ray crystallography showed the carbonucleoside derivative 37 to adopt a conformation in which the pseudosugar moiety is puckered in a south type (C3Ј-exo, 3 E) conformation. 30 In the crystal, the nucleobase displayed a syn orientation with its 2-oxygen atom involved in intramolecular Scheme 5 30 Reagents and conditions: i) TMSBr, MeOH, ZnBr 2 (cat. ), 0 ЊC (70%); ii) N-tert-butyldimethylsilyl-N-methylacetamide, DMF, 0 ЊC to rt (64%); iii) KOBu t , Bu t OH, rt (76%); iv) KOH, EtOH, 80 ЊC (78%); v) a. DPPA, Et 3 N, toluene, 0 ЊC to rt, then 80 ЊC, b. BnOH, 80 ЊC, then 100 ЊC (85%); vi), H 2 , 10% Pd-C, toluene (84%); vii) hydrogen bonding with the 5Ј-hydroxy group.…”