Stereochemistry, conformational restriction

Cromakalim (137) is a potassium channel activator commonly used as an antihypertensive agent (107). The rationale for the design of cromakalim is based on P-blockers such as propranolol (115) and atenolol (123). Conformational restriction of the propanolamine side chain as observed in the cromakalim chroman nucleus provides compounds with desired antihypertensive activity free of the side effects commonly associated with P-blockers. Enantiomerically pure cromakalim is produced by resolution of the diastereomeric (T)-a-meth5lben2ylcarbamate derivatives. X-ray crystallographic analysis of this diastereomer provides the absolute stereochemistry of cromakalim. Biological activity resides primarily in the (—)-(33, 4R)-enantiomer [94535-50-9] (137) (108). In spontaneously hypertensive rats, the (—)-(33, 4R)-enantiomer, at dosages of 0.3 mg/kg, lowers the systoHc pressure 47%, whereas the (+)-(3R,43)-enantiomer only decreases the systoHc pressure by 14% at a dose of 3.0 mg/kg. 

With the support of quantum mechanics this proteolysis study has readily shown that fluorinated amino acid side chains are able to direct enzyme substrate interactions, which can have an influence on proteolytic stability. Depending on the absolute stereochemistry and on the position within the sequence, aTfm amino acids can considerably stabilize peptides against proteolysis. The unique electrostatic properties of carbon-bound fluorine, however, may also induce a contrary effect. The conformational restrictions of C -dialkylation seem to be partly dimin-ishable by the electrostatic consequences of fluorination. With this knowledge. 

The erythro/threo diastereomers of a larger variety of 4,5-disubstituted 1,3-dioxanes (chiral conformationally restricted arachidonic acid analogs 54-59) proved to be of enantiomerically pure stereochemistry (cf. Scheme 17) (99TA139) the epimers were clearly identified by the coupling patterns of the protons in positions 4, 5, and 6, reflecting the ax,equ (threo) and equ,equ (erythro) relationships of the two substituents. 

To solve the inactivation issues mentioned above, the concept of conformationally restricted (Z)-fluoro-olefm dipeptide isosteres that mimic the active trans conformation of the DPP IV inhibitors was applied by Welch and co-workers to the preparation of inhibitors having Ala-T fCF CHJ-Pro structure (76 and 78) and their inhibitory activities were evaluated (see Figure 10.6) [36, 37]. DPP IV inhibitory activities and the stability of the inhibitors 76 and 77, in comparison with those of the model dipeptide Ala-Pro derivative 78 are summarized in Table 10.2. These fluoro-olefin analogues, 76 and 77, showed better DPP IV inhibitory activity than that of 78. In particular, u-76 having the same relative stereochemistry as the natural dipeptide (L-Xaa-L-X aa) configurations exhibited potent... 

First, the stereochemistry at C-8 is set by the Z olefin geometry, which was obtained via a standard Wittig reaction. Conformational restrictions placed on dibenzocyclooctadiene ring systems are generally limited to the twist-boat-chair (TBC) and the twist-boat (TB) limiting conformations. The stereodefmed Z-alkene excludes the TB structure. We therefore expected carbons 6, 7, 8, and 9 to assume the chair-like transition state geometry of the TBC conformation. 

In this regard, the authors probed different substituents and stereochemistries, mainly in position 5, 6, and 9 of the pyranose core of 242-(Z), to explore the role of the stereoelectronic interactions [102-105], conformational restrictions [106-108], and formation of intramolecular hydrogen bonds in the stereocontrol of this reaction. For the anomeric effect, see [109]. For the anomeric effect of protons, see [110], and for the formation of intramolecular hydrogen bonds [111] in the stereocontrol of this reaction. 

In the first of four chapters in this volume of Topics in Stereochemistry, Michinori Oki presents a comprehensive review of atropisomerism with special reference to the literature of the past two decades. The review summarizes restricted rotation about sp2-sp2, sp2-sp, and sp3-sp3 bonds and it concludes with an analysis of reactions of isolated rotational isomers. It places particular emphasis on the magnitude of rotation barriers as a function of structure (incidentally identifying some of the largest barriers yet measured to conformer interconversion) and on the isolation of stable single-bond rotational diastereomers. 

As described above, the stereochemical course of the reaction was proven to be accompanied by inversion of configuration. The most probable explanation is that the substrate adopts a planar conformation at some stage of the reaction, and the chirality of the product is determined by the face of this intermediate that is approached by a proton. If this assumption is correct and the conformation of the substrate in the active site of the enzyme is restricted in some way, the steric bulk of the o-substituents will have some effect on the reactivity. Thus, studies of the o-substituted compounds will give us information on the stereochemistry of the intermediates. 

NMR parameters, such as chemical shifts and coupling constants, have been extensively investigated through the use of organic compounds that exhibit restricted rotation, such as oximes. NMR data are routinely used in determination of the stereochemistry of organic compounds and rigid strucmres, such as oxime conformers, can help in the interpretation of many of the physical and chemical properties that are associated with effects of lone pairs on different types of systems that contain nitrogen. 

The first approach is shown in figure 3.1. This approach uses various techniques (e.g., alanine scanning) to identify the smallest peptide segment with biological activity within the overall peptide. This minimal bioactive segment may be cyclized or have its stereochemistry altered in order to attain restriction of conformational freedom and... 

As can be seen, both routes lead to the same product. Nevertheless, in compounds where the conformational flexibility of the bicyclobutane frameworks is restricted, 1,3-addition is found to be favored via the diequatorial mode.12,13 This aspect is illustrated in a reaction in which iodine reacted with tricyclo[4.1.0.02,7]heptane in carbon tetrachloride to give 6,7-diiodobicy-clo[3.1. l]heptane (9) in 55% yield.13 In support of this stereochemistry, the majority of results obtained from the dculeration of tricyclo[4.1.0.02,7]heptane suggested that the attack is from the equatorial position.14 Theoretical studies also support the notion that the equatorial approach of an electrophile to the bridgehead of bicyclo[l.1.0Jbutane is thermodynamically favored.14,15... 

Pyridines attached to another aryl or hetaryl ring also introduce the possibility of restricted rotation about the biaryl linkage. Typically, this requires three substituents at the or/ o-positions on the biaryl as in the case of the naphthyl derivatives 48, where the stereochemistry is determined by NMR spectroscopy <2001J(P1)1785>. Other methods of determining conformations, such as the comparison of experimental and computed circular dichroism spectra, have been applied to the related Yaoundamine alkaloids such as the derivative 49 <1997T2817>. 

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