Conformationally constrained

CM Topham, A McLeod, E Eisenmenger, JP Overmgton, MS Johnson, TL Blundell. Erag-ment ranking in modelling of protein structure. Conformationally constrained environmental ammo acid substitution tables. J Mol Biol 229 194-220, 1993. 

Conformationally constrained peptides with Phe, Tyr, Trp, and His units an-nelated with heterocycles 99T585. 

The most direct evidence that stereoelectronic effects are also important in these reactions follows from the specificity observed in hydrogen atom abstraction from conformationally constrained compounds,18 60 C-H bonds adjacent to oxygen113"118 or nitrogen110 and which subtend a small dihedral angle with a lone pair orbital (<30°) are considerably activated in relation to those where the dihedral angle is or approaches 90°. Thus, the equatorial H in 20 is reported to be 12 times more reactive towards /-butoxy radicals than the axial 11 in 21.115... 

However, steric factors are also important.74 Ruchardt and coworkers showed, for a series of acyclic alkyl derivatives, that a good correlation exists between kd and ground state strain.75,76 Additional factors are important for bicyclic and other conformationally constrained azo-compounds.49 51 77 Wolf78 has described a scheme for calculating kd based on radical stability (HOMO Jt-deloealization energies) and ground state strain (stcric parameters). 

Ikegashira et al. reported another recent example of the successful exploitation of conformational locks. They describe the discovery of a novel class of hepatitis C virus NS5B RNA polymerase inhibitors [42]. By designing and synthesizing conformationally constrained analogs of 40 (see Fig. 8.9), they obtained a series of novel compounds with significantly improved potency. Compound 41 was, for example, shown to be 7-fold more potent, see Fig. 8.9. 

Noji, S., Yamanaka, H., Hara, Y., Adachi, T., Tsuruha, J. I., Doi, S., Hase, Y., Noguchi, T., Ando, I., Ogura, N., Ikeda, S., Hashimoto, H. Discovery of conformationally constrained tetracyclic compounds as potent hepatitis G virus NS5B RNApolymerase inhibitors./. Med. Chem. 2006, 49, 6950-6953. 

The previously raised possibility of hyperconjugation for alkylboranes (12a<- 12b) becomes of greater concern for the conformationally constrained rings of boracycloalkanes. The search for unambiguous physical evidence for hyperconjugation even in Me3B (12a 12b) has been inconclu-... 

Winkler, M., Knall, A.C., Kulterer, M.R. and Klempier, N. (2007) Nitrilases catalyze key step to conformationally constrained GABA analogous y-amino acids in high optical purity. The Journal of Organic Chemistry, 72, 7423-7426. 

Sequential pyrrolidine and hydantoin ring-forming reactions via intramolecular [2+3] cycloaddition have been applied to the stereoselective solid-phase synthesis of conformationally constrained tricyclic triazacyclopenta [C]pentalene scaffold 43 < 1999JOC8342>. These novel compounds 43 share the structural complexity characteristic of certain alkaloid natural products, angular triquinanes. The retrosynthetic analysis is shown in Scheme 87. 

An application of these rather unusual high-temperature Mitsunobu conditions in the preparation of conformationally constrained peptidomimetics based on the l,4-diazepan-2,5-dione core has recently been disclosed by the group of Taddei (Scheme 6.102b) [208]. Cydization of a hydroxy hydroxamate dipeptide using the DIAD/Ph3P microwave conditions (210 °C, 10 min) provided the desired 1,4-diaze-... 

The hemispherands, spherands, calixarenes, and related derivatives. A number of hosts for which the pre-organization criterion is half met (the hemispherands) (Cram et al., 1982) or fully met (the spherands) (Cram, Kaneda, Helgeson Lein, 1979) have been synthesized. An example of each of these is given by (251) and (252), respectively. In (251), the three methoxyl groups are conformationally constrained whereas the remaining ether donors are not fixed but can either point in or out of the ring. This system binds well to alkali metal ions such as sodium and potassium as well as to alkylammonium ions. The crystal structure of the 1 1 adduct with the f-butyl ammonium cation indicates that two linear +N-H - 0... 

Conformationally constrained 2-cyclohexenones which cannot undergo the lumiketone rearrangement (cf. chapter 3.1.5) are efficiently reduced to cyclohexanones (4.18) 420). 

Yokomatsu, Y., Yoshida, Y., Nakabayashi, N., and Shibuya, S., Simple and efficient method for preparation of conformationally constrained aminome-thylene gem-diphosphonate derivatives via Beckmann rearrangement,. Org. Chem., 59, 7562, 1994. 

The conjugate addition of activated nitrogen nucleophiles, such as hydroxylamine and hydrazine derivatives, to a,/3-unsaturated bicyclic lactam 284 gave the corresponding /3-amino product 285 in good yield and excellent diastereoselectivity. These products can be manipulated to afford enantiopure /3-aminopyrrolidinones of potential application as conformationally constrained, substituted glutamate templates (Equation 45) <2001J(P1)2997>. 

The most common bicyclic 5-6 system with one bridgehead N-O and one extra heteroatom described in the period covered in this chapter has been the diketopiperazine derived from proline as it is present in natural products, in biologically active synthetic molecules, and has been used as starting material for the preparation of conformationally constrained peptidomimetics. The classical approach to this class of molecule is the ring closing of the dipeptide derived from proline and another amino acid via nucleophilic attack of the NH2 to the activated carboxylic group. This method has been applied several times to prepare different diketopiperazines for different uses. 

Conformationally constrained tertiary amides analog 2000TL4533... 

Huscroft et al. [15] reported a new series of conformationally constrained hNKl antagonists containing an 8-azabicyclo[3.2.1]octane core. The N-2 methyl tetrazole analogue 11 had an attractive profile with high hNKl affinity (1 nM) and long lasting... 

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