THE QUESTION OF CHAIR TWIST EQUILIBRIA FOR THE PHOSPHATE RINGS OF NUCLEOSIDE CYCLIC 3',5'-MONOPHOSPHATES - H-1-NMR AND X-RAY CRYSTALLOGRAPHIC STUDY OF THE DIASTEREOMERS OF THYMIDINE PHENYL CYCLIC 3',5'-MONOPHOSPHATE
THE QUESTION OF CHAIR TWIST EQUILIBRIA FOR THE PHOSPHATE RINGS OF NUCLEOSIDE CYCLIC 3',5'-MONOPHOSPHATES - H-1-NMR AND X-RAY CRYSTALLOGRAPHIC STUDY OF THE DIASTEREOMERS OF THYMIDINE PHENYL CYCLIC 3',5'-MONOPHOSPHATE
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DOI：
10.1021/ja00247a036
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发表时间：
1987-06-24
影响因子：
15
通讯作者：
HUTCHINSON, JP
中科院分区：
文献类型：
--
作者：
NELSON, KA;BENTRUDE, WG;HUTCHINSON, JP
The diastereomeric cis and trans forms of thymidine phenyl cyclic 3'',5''-monophosphate triesters 5 were synthesized starting with the corresponding cycle N,N-dimethyl phosphoramide. X-ray crystallography unequivocally identified the trans diastereomer (PhO and 1-thyminyl, trans). 1H NMR analysis shows the phosphate ring of cis-5 to be in the chair conformations with the PhO axial. trans-5 features a chair .dblarw. twist phosphate ring equilibrium (acetone-d6) with J5''aP (11.6 Hz) > J5''bP (9.6 Hz). Use of reasonable assumed values of 3JHP for the protons on C-5'' in the chair and twist forms leads to the conclusion that about 60% of trans-5 is in the twist conformation 6b in acetone-d6, and a little over 40% of trans-5 populates 6b in CDCl3. Careful dissection of the free-energy components which contribute to the observed chair .dblarw. twist equilibrium for trans-5 gives an estimated value for .DELTA.Goc.fwdarw.t of only 2.2 kcal/mol. This represents the intrinsic resistance of the chair-form ring to conversion to the twist conformation with the PhO pseudoaxial and gives an upper limit value for the cyclic 3'',5''-monophosphate itself. This very low value of .DELTA.G0c.fwdarw.t is found in spite of the 5 kcal/mol of strain energy associated with the transoid fusion of the phosphate and deoxyribose rings. Clearly, .DELTA.G0 for the chair .fwdarw. twist interconversion for a nucleoside cyclic 3'',5''-monophosphate can be readily supplied by binding interactions within the active site of a phosphodiesterase or protein kinase. The apparent ease of chair-twist interconversion is reflected also in the X-ray structure in which the phosphate ring about phosphorus is flattened into a near half-chair conformation which approximates the barrier geometry from the chair .fwdarw. twist interconversion. This appears to be a response to the propensity of the PhO to be axial (or pseudoaxial) and the intermolecular NH.cntdot..cntdot..cntdot.O.dbd.P H-binding interaction noted in the unit cell. (The internuclear N(3)-O(7) distance between the symmetry related molecules is only 3.004 .ANG.). The conformation of the deoxyribose ring of both cis- and trans-5, as determined from proton-proton coupling constants, is close to that of cTMP itself, 4E-4T3.
