Cyclic conformation

C12-C13 would facilitate the ring closure, monocyclic diene 170 was chosen as the metathesis substrate. Indeed, exposure of 170 to catalyst A provided cycliza-tion product 171 in 94% yield within 6 h, without the aid of a cyclic conformational constraint. 

In this case, severe dipolar repulsion can destabilize the cyclic conformation relative to the noncyclic geometry. 

Kinetic template effects have been involved in the formation of crown ethers, with respect to the cyclization step involving a nucleophilic displacement of halide or tosylate by alkoxide ions. It has been proposed that cyclization of the linear bifunctional precursor is enhanced by a cyclic conformation in which the alkoxide cation brings the two ends of the molecule into close proximity... 

Presumably, the growing chain would have a cyclic conformation or in some other way would avoid excessive charge separation. 

An A -methyl-amino-oxy amino acid has also been incorporated into peptides using standard SPPS procedures. Reaction of these peptides with native reducing sugars yields neoglycopeptides via a chemoselective reaction with the amino-oxy side chains, maintaining the linked sugars in their cyclic conformations and... 

In Section II.C we will present novel tricyclic xanthene derived amino acid templates, which allow the construction of libraries of cyclic conformationally constrained peptide loop mimetics using the split-and-mix method without having to use tagging and deconvolution strategies. In Section III we will focus on parallel and combinatorial approaches devoted to the synthesis of small molecule, non-peptidic compound collections, which in addition offer the possibility to incorporate structural features derived from protein epitope mapping into conformationally constrained peptide mimetics. 

Lactams or related cyclic, conformationally fixed amides are more readily N-alkylated than acyclic amides [96], As illustrated by the examples in Scheme 6.23, structurally elaborate alkylating agents can be used to alkylate lactams. During the workup of such reactions it should be kept in mind that four- and six-membered lactams are readily hydrolyzed by aqueous base (Scheme 3.8), and most lactams are also readily hydrolyzed by aqueous acids. Prolonged treatment of lactams with alkali metal hydroxides or acids during the work-up should therefore be avoided. 

The activity of these particular groupings probably arises in part from the distance between the nitrogen atom and the hydrocarbon branch (at the silicon atom). A similar structure-activity relationship has also been noted in carbon systems (60). However, the silicon-nitrogen system may assume a cyclic conformation in which the unshared electrons of the nitrogen are coordinated with the d orbitals of the silicon atom (14). The potential for such a structural feature does not exist in most carbon systems. Silicon-to-nitrogen coordination is an important feature of the silatranes (61, 62), although physical evidence for such coordination in open-chain silylalkylamines is lacking (52). 

Hruby, V. J., and Bonner, G. G. (1994) Design of novel synthetic peptides including cyclic conformationally and topographically constrained analogs. Methods. Mol. Biol. 35, 201-240. 

The approximate equilibrium geometry of the open-chain structure of (HF is shown in Fig. 14. The energy of interaction relative to three HF molecules is —9.4 kcal/mol. The open-chain trimer structure is thus less stable than the cyclic trimer by approximately 2.2 kcal/mol. For the former structure we calculate an energy per hydrogen bond of —4.7 kcal/mol whereas for the latter we find only a value of —3.9 kcal/mol. Thus, the ring strain in the cyclic structure reduces the energy of interaction. The cyclic conformer, however, contains one more bond which ultimately leads to the higher stability. 

A series of cyclic conformationally constrained peptides related to somatostatin were designed, synthesized and tested for opioid receptor interaction by Hruby and his collaborators. Compounds (17)-(22) were found to be pure opioid antagonists (GPI) with high affinity (IC50 = 1.2 to 4.3 nM) and exceptional selectivity for p over S opioid receptors (Table 3.1) and with minimal or no somatostatin-like activity (ligand binding assays)[63-65]. 

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