Cyclic model compounds, conformational

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... 

In order to invest ate the relationship between the structure and reactivity of model compounds for biopolymers, the structure of cyclic peptides as models for biopolymers must be made dear. The molecular conformation is determined by the bond length, bond angle, and internal rotation an e. With the bond length and bond an e the values for ordinary amides such as N-mefhylacetamide are usually adopted 16,... 

From the methodological point of view, a different F factor derived from the correlation of energies of relevant acyclic compounds should have been used. The anomeric carbon atom in II is secondary, whereas in 2-substituted tetrahydropyrans it is tertiary. The introduction of a third substituent at the anomeric carbon may result in a change of preferred conformation (58, 59), appropriate angles (60), and the magnitude of the anomeric effect (61), thus making cyclic models inadequate for the calculation presented above. 

Cyclic molecules of small numbers of ring-atoms are rigid and compact that they can serve as model-compounds for plastic crystals. As the number of ring-atoms increases they develop different conformational isomers. This series of compounds is thus suited to study the interrelation between conformational and orientational dynamic disorder. 

On that basis, conformers A and E can break down by the loss of the axial alkoxy group. Conformer can undergo a cleavage via the fission of the carbon-oxygen bond of the ring but conformer cannot break down (no primary electronic effect). Conformer must therefore be unreactive and this prediction was verified experimentally (38, 50) by studying the reactivity of the tricyclic orthoester 62 (54-66) which is a perfect rigid model for conformer , as shown by X-ray analysis (57). Indeed, compound 62 was found completely stable under the mild acid conditions that are normally used for the hydrolysis of other cyclic orthoesters. Thus, conformer is a remarkably unreactive conformer which must be eliminated. 

Interestingly, we were intrigued by the ESI mass spectrum of the compound, as the observed base peak consisted of [M-S02+Na]+. This led us to explore a thermal retro-Diels-Alder reaction that could afford the desired enone 69. It is noteworthy that the chemistry of cyclic enol-sulfites would appear to be an under-explored area with a few references reporting their isolation being found [57]. At last, we were also able to prepare epoxy ketone 70 from 69 in three steps, albeit epoxidation did not take place unless the TES group was removed. Spartan models reaffirmed our initial conformational assessment of enone 69 and epoxy ketone 70, which contain sp3-hybridized C8a and s/r-hybridized C8b (p s e u d o-. v/r - h y b r i d i zed C8b for 70) at the AB-ring junction (Fig. 8.12) and displayed the desired twisted-boat conformation in A-ring. 

Robust peptide-derived approaches aim to identify a small drug-like molecule to mimic the peptide interactions. The primary peptide molecule is considered in these approaches as a tool compound to demonstrate that small molecules can compete with a given interaction. A variety of chemical, 3D structural and molecular modeling approaches are used to validate the essential 3D pharmacophore model which in turn is the basis for the design of the mimics. The chemical approaches include in addition to N- and C-terminal truncations a variety of positional scanning methods. Using alanine scans one can identify the key pharmacophore points D-amino-acid or proline scans allow stabilization of (i-turn structures cyclic scans bias the peptide or portions of the peptide in a particular conformation (a-helix, (i-turn and so on) other scans, like N-methyl-amino-acid scans and amide-bond-replacement (depsi-peptides) scans aim to improve the ADME properties." ... 

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