A 400-MHZ AND 600-MHZ H-1-NMR CONFORMATIONAL STUDY ON NUCLEOSIDE CYCLIC 3',5'-PV-TBP SYSTEMS - CONFORMATIONAL TRANSMISSION INDUCES DIEQUATORIAL ORIENTATION OF THE 3',5'-DIOXAPHOSPHORINANE RING IN A NONCHAIR CONFORMATION

The novel nucleoside cyclic 3′,5′ PV-TBP compounds 4 and 5 were studied as models for the proposed activated state of cyclic adenosine 3′,5′-monophosphate (cAMP). Compound 4 features equatorial-axial (e,a) orientation of the 3′,5′-dioxaphosphorinane ring. The design of compound 5, which incorporates OCH2CH2OMe as a conformational probe, was essentially tosed on our previous work on conformational transmission in PV-TBP compounds. 1H NMR analysis of compound 5 showed conformational transmission in the probe fragment, which indicates that the molecular structure with diequatorial (e,e) orientation of the 3′,5′-ring, and axial location of OCH2CH2OMe contribute significantly to the pseudorotational equilibrium. Conformational transmission in 5 was clearly established via comparison with the PV-TBP compounds 13, in which O-nBu replaces the OCH2CH2OMe group, 14, in which a trans-fused cyclopentane ring replaces the furanose ring of thymidine, and 15, in which the OCH2CH2OMe group is locked in an equatorial position of the PV-TBP. The results reveal that conformational transmission can help to stabilize diequatorial orientation of the 3′,5′-dioxaphosphorinane ring, which may be of relevance for the trigger function of cAMP with respect to protein kinases. The detailed conformational properties of 4 and 5 were investigated further on the basis of MNDO calculations on the models 22-24. Structural data as obtained from 1H NMR were used in the start of the optimizations. The calculations showed that axial-equatorial orientation of the 3′,5′-dioxaphosphorinane ring is favored by 3-4 kcal/mol over diequatorial orientation. The optimized structures show a twist conformation of the e,a-oriented 3′,5′-dioxaphosphorinane ring, whereas the e,e orientation corresponds with a half-chair geometry. © 1990, American Chemical Society. All rights reserved.