44 PMR Measurements of Chair-Twist Conforma tional Equilibria for Diastereomeric P-Derivatives of Thymidine Cyclic 3',5'-Monophosphate Downloaded via TUFTS UNIV on July 11, 2018 at 10:41:30 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
Possible Implications for Naturally Occurring Cyclic Nucleotides ALAN E. SOPCHIK, GURDIP S. BAJWA, KEITH A. NELSON, and WESLEY G. BENTRUDE Department of Chemistry, University of Utah, Salt Lake City, UT 84112
The factors influencing the unusually exothermic hydrolysis of cAMP to 5'-AMP (1) have been considered worthy of considerable investigation. A recent estimate (2) is that 4-5 kcal/mol of strain is imparted to cAMP by the trans nature of the phosphate -ribose ring fusion. Also of interest in such molecules is an understanding of how such strain may affect the conformational properties of the phosphate ring including the energetics of the conversion of that ring from its normal chair conformation into the twist form. We have examined by PMR the conformational properties of certain P-derivatized thymidine cyclic nucleotides, I, and have compared them to those for the model compounds, II (3, 4). The
derivatives (III-VI) were prepared by methods we reported ear lier (5-9) and separated into individual diastereomers of MPLC. Configurations at phosphorus were assigned on the basis of the well-known Ρ NMR chemical shift criterion (10) and confirmed by C NMR (6). X-ray crystallography was applied to VIb (8). 3 1
1 3
IIIa IIIb IVa IVb
X = MeO, Y = O Va X = Me N, Y = O X = O, Y = MeO Vb X = O, Y = MeN X = MeO, Y = S VIa X = Me, Y = O X = S, Y = MeO VIb X = O, Y = Me 2
2
0097-6156/81/0171-0217$05.00/0 © 1981 American Chemical Society
Quin and Verkade; Phosphorus Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
218
PHOSPHORUS
CHEMISTRY
Table I contains the proton coupling constants (300 MHz) for the individual diastereomers of I(III-VI). In the chair confor mation, J should be small (0.5-2.0 Hz) and J large (20-22 Hz) as they are in various nucleoside cyclic 3',5'-monophosphates. (11) Ring reversal can give only one twist form of relatively low energy(because of the trans ring fusion (Dreiding models)) in which the values of J and J are essentially interchanged. It is clear that IIIa and IVa are almost entirely in the chair conformation with MeO axial as it prefers to be in II (3). The same is true for Vb and VIb with bulky Me and Me Ν groups equatorial. However, Va, IIIb and IVb cannot be entirely in chair conformations since J 5 and J y , are, respectively, too large and too small in each case. By using J 5 tp and J^itp values from Vb for those of the chair conformer of Va along with reasonable estimates of 19 Hz and 0.5 Hz for J 5 »p and Jyip, respectively, in the twist structure, one can estimate that Va is about 65-75% in this twist conformation depending on solvent and temperature (7). The sterically large size of MeN (3, 12) results in destabilization of the chair conformation causing the twist structure to be highly populated. If one uses a similar approach for Illb, it is estimated that about 30-35% of Illb is in the twist conformation with MeO pseudoaxial in accordance with its usual preference. The twist population for IVb is probably about the same. Derivative Via shows only a small increase in J 5 tp and de crease in J5»»p, and the sum of the couplings is somewhat lower than expected. Whether conformational averaging or only ring distortion occurs here is not certain. The percentage of twist conformation populated by Va is similar to that for cis II with Ζ = MeN (_t-Bu and Ζ cis) (4). We have argued elsewhere (7) that this means that unless the synaxial repulsions are unusually high for chair-form Va, the VII VIII chair-twist component of the conformational change depicted by eqn. 1 (X = Me N, Y = 0) is probably only about 1 kcal/mol as it is for the model systems (4, 13). 5'P
5"P
5'P
5"P
2
t p
p
2
2
2
VIII
Further support for the idea that the accessibility of twist conformations is similar in the cyclic nucleotide derivatives to what it is for II comes from the results for phosphate Illb. In similar solvents, the àGzs for the equilibrium IX t X is ^1.5 kcal/mol in favor of X with MeO axial (14). In the case of Illb, relief of steric interactions involving the small axial P=0 is not a factor in the isoraerization of eqn. 1. The 33% population of twist conformation is an indication that AG?5 for the XI XII
Quin and Verkade; Phosphorus Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
44.
SOPCHIK E T A L .
IX
IIIa IVa Va Va VIa IIIb IVb Vb VIb
a
a
a
b
c
a
a
a
c
j aeetone-d, b
J
_ ^
219
Equilibria
\ ^ ο \ ρ
Constants (Hz) f o r I I I - IV at 300
Coupling
Compounds
Conformational
/
J >
Table I.
a
Chair-Twist
J
5'P
0.9 ^1.0 12.2 14.4 2.5 7.0 7.4 0.9 4.7
5"P
J
21.5 22.4 8.4 6.0 17.2 14.8 17.4 21.6 20.2
toluene-
"8
f
5 5"
-9.4 -9.3 -9.2 -9.1 -9.2 -9.4 -9.6 -9.3 -9.4
C
J
3'P
•V5
