Conformational restraints

Substitution of a dipeptide unit by a cychc dipeptide derivative within a peptide chain can induce certain conformational restraints that may alter the biological response via changing receptor selectivity. A facile procedure for synthesis of pyrazinone ring-containing opioid mimetics [21] has been elaborated, based on the cycHzation of readily available dipep-tidyl chloromethyl ketones [22] (Scheme 6). This method affords 2(IH)-pyrazinone derivatives containing substituents with desired functional groups at positions 3 and 6 in high yield. 

Several studies have been reported on the application of conformational restraint to the 1,5-diaryl-pyrazole series in an attempt to provide compounds with modified properties. In one approach, a Sanofi-Synthelabo patent application claimed a series of conformationally restrained compounds, exemplified by compound (391). Compounds of the invention were stated to be CBi receptor antagonists with K[ values below 5 x 10 M and selectivity over CB2 receptors of at least 10-fold [274]. 

Because of the conformational restraints imposed on the cycloamyloses by their looped arrangement, it is reasonable to assume that the structural features derived for the crystalline state will be retained in solution. This has been confirmed in recent years by means of a variety of spectroscopic techniques. Nuclear magnetic resonance (Rao and Foster, 1963 Glass,... 

Simon, S.R., and Konigsberg, W.H. (1966) Chemical modification of hemoglobins A study of conformation restraint by internal bridging. Proc. Natl. Acad. Sci. USA 56, 749. 

In this form of catalysis, inclusion of the substrate in the CD cavity provides an environment for the reaction that is different from that of the bulk, normally aqueous, medium. In the traditional view, the catalytic effect arises from the less polar nature of the cavity (a microdielectric effect) and/or from the conformational restraints imposed on the substrate by the geometry of inclusion (Bender and Komiyama, 1978). However, catalysis may also arise as a result of differential solvation effects at the interface of the CD cavity with the exterior aqueous environment (Tee and Bennett, 1988a,b Tee, 1989). 

As another example, the three-dimensional structure of Cytochrome c has been determined on the basis of structural information from pseudocontact paramagnetic chemical shifts, Curie-Dipolar cross-correlation, secondary structure constraints, dipolar couplings and 15N relaxation data [103]. This protein has a paramagnetic center, and therefore the above-mentioned conformational restraints can be derived from this feature. Dipolar couplings do not average to zero because of the susceptibility tensor anisotropy of the protein. The structure determination of this protein without NOE data gives an RMSD (root... 

The variable enantioselectivities seen in these results likely stem from conformational restraints imposed by the cyclic structures, which prevent the allylic alcohols from attaining an ideal conformation for the epoxidation process (see Fig. 6A.9, below, for the proposed ideal conformation). 

One remaining puzzle is the decreasing ApA), per D from methylamine to dimethylamine to trimethylamine in solution. Such behavior was ascribed to an inductive effect,51,53 but inductive effects ought to be linear in the number of deuteriums. It may be that conformational restraints due to additional methyls increase the negative hyperconjugation. Computations might be informative. 

A remarkable case of RCM assisted by conformational restraint is that shown in equation 39. This involves a substrate in which the two double bonds are separated by 13 single bonds only one of which forms part of a ring, but in which an additional constraint is imposed by the hydrogen bond. When a mixture of the four stereoisomers denoted by 57 is treated with catalyst 19 under the conditions indicated, only one of the isomers undergoes RCM to give (S,S,S)-5H, showing that in this case the configuration... 

Steric or conformational restraints imposed by substituents on the ligand can impose stereoselectivity or can enforce some stereospecificity. Thus (J )-epe stereospedfically forms (317) with the methyl group equatorial rather than axial,1087 and (5,5)-pep also prefers (65%) the A configuration (318) with the methyl groups adjacent to X.1088 In both systems the configuration about Co and S... 

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