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This review article explores the pivotal role of conformational drivers in the discovery of drug-like molecules and illustrates their significance through real-life examples. Understanding molecular conformation is paramount to drug hunting as it can impact on- and off-target potency, metabolism, permeability, and solubility. Each conformational driver or effector is described and exemplified in a separate section. The final section is dedicated to NMR spectroscopy and illustrates its utility as an essential tool for conformational design., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

The preparation of 3-substituted tetrahydropyrazinoisoquinolines using the tributyltin hydride mediated intramolecular radical cyclization of suitably protected 2-substituted 3,4-dihydropyrazines is reported. The compounds are obtained as single enantiomers, as the relative configuration of the new generated stereogenic center is driven by the stereochemistry of the 2-substituted carbon in the starting materials, which is in turn derived from naturally occurring amino acids.

Asymmetric organocatalytic annulation of E/Z isomeric mixtures of bis(alkyl carboxylate)buta-1,3-dienes and aldehydes has been realized via enamine catalysis. In the presence of α,α-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether, excellent stereo- and enantioselectivities were achieved for a broad spectrum of substrates.

An efficient synthesis of various protected syn-β-sulfenyl amides is described. These are prepared from the corresponding enantiopure amino allylsilanes which are in turn obtained from naturally occurring amino acids. The key step for introduction of the sulfur substituent is a diastereoselective electrophilic sulfodesilylation which is carried out with phthalimidesulfenyl chloride. The resulting homochiral β-phthalimidesulfenyl amines with an allylic sulforated stereogenic center are useful building blocks, as they represent a starting point for subsequent functional manipulations., (© 2011 American Chemical Society)