ChemInform Abstract: Flexible Molecules with Defined Shape. Part 11. Conformer Equilibria in 2,4‐Disubstituted Pentane Derivatives.

Abstract

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The Discodermolide Hairpin Structure Flows from Conformationally Stable Modular Motifs

“…This is rarely the case, because differential energetic requirements ordinarily lead to conformational diversity among the microenvironments. 21 In the present instance, however, the overriding conformational preference induced largely by steric factors (i.e., A 1,3 strain and syn-pentane interactions 8,12,13 ) leads to a dominant 3D form under all three circumstances. Insofar as the conformational preferences of DDM dictate the latter under very different physical conditions, the methyl-hydroxy-methyl triad and related moieties suggest themselves as modular, Lego-like elements that permit straightforward application of molecular mechanics-guided conformational principles to prediction of the bioactive conformations of related natural and synthetic products.…”

“…At the same time, we draw inspiration from the pioneering work of Hoffmann and co-workers who have investigated synpentane interactions in substituted pentane and related systems. 12,13 To suppress the influence of electrostatic effects that frequently dominate conformational preferences in force field conformational searches, 14 the carbamate side chain was excised subsequent to evaluating steric aspects of the resulting molecule. In a first calculation, we replaced the hydroxyls at positions 7, 11, and 17 with methyl groups.…”

“…To pinpoint the energetic source of the persistent torsional characteristics of the hairpin geometry, we focus on the C5−C18 region with the reasonable assumption that the conformational mobility of the more flexible carbamate and lactone side chains (Figures and ) has little influence on it. At the same time, we draw inspiration from the pioneering work of Hoffmann and co-workers who have investigated syn -pentane interactions in substituted pentane and related systems. , …”

“…8 The outcome was foreshadowed by the conformational principles laid down by Hoffmann and coworkers. 12,13 The present study reinforces as well as adds to the previous discussions in four distinct ways by (1) highlighting the dominance of steric interactions in the multiconformational DDM solution ensemble, (2) applying quantum chemical density functional (DFT) calculations and comparative conformer energetics to examine the surprising persistence of conformational integrity in solution, the solid-state and at the tubulin binding site, (3) proposal of a new binding mode for (þ)discodermolide on β-tubulin, and (4) suggesting it to be favored in terms of the drug's bioactive conformation and SAR.…”

Design and Synthesis of (+)-Discodermolide–Paclitaxel Hybrids Leading to Enhanced Biological Activity

“…11 In particular, variable temperature and co-solvent titration NMR studies provided evidence of intramolecular hydrogen bonds between the C(7)-OH and the C(1)-carbonyl, in conjunction with interactions between the carbamate nitrogen and the C(3) and C(7) hydroxyl groups. We postulated that syn- pentane interactions 21 were responsible for the proposed turn geometry of the backbone. Importantly, biological studies of epimers bearing inverted stereogenicities at the C(7), C(11), C(16) and C(17) revealed significantly lower activities, which led us to suggest that the conformation of the molecular segment between C(7)–C(17) is conserved upon binding.…”