ZuschriftenScheme 2. Substrate scope.[a] The reactions were conducted using 0.5 mmol of the amides 1.Y ields of the isolated alcohols 2 and amines 3 are given.[b] The reaction was conducted using 5equiv of NaH, 2equiv of ZnI 2 and 2equiv of NaI.[c] The reaction was conducted using 7equiv of NaH and 3.5 equiv of ZnCl 2 .[d] 1aj > 98 %ee; 2aj > 97 %ee; 3aj > 98 % ee as measured by the Mosher method (see the Supporting Information).[e] Amine 3ak was formed in 35 %yield. [f]Amine 3al was formed in 31 %yield. Bn = benzyl, Ph = phenyl, TIPS = triisopropylsilyl.Scheme 5. DFT calculations for model reactions of benzamide with (ZnH 2 ) 2 or (ZnHCl) 2 species. Energy changes and bond lengths at the wB97XD/SDD&6-31 + G* (scrf = smd, THF) level of theory are shown in kcal mol À1 and ,respectively.

Screening of fragment libraries is a valuable approach to the drug discovery process. The quality of the library is one of the keys to success, and more particularly the design...

The fragment approach has emerged as a method of choice for drug design, as it allows difficult therapeutic targets to be addressed. Success lies in the choice of the screened chemical library and the biophysical screening method, and also in the quality of the selected fragment and structural information used to develop a drug-like ligand. It has recently been proposed that promiscuous compounds, i.e., those that bind to several proteins, present an advantage for the fragment approach because they are likely to give frequent hits in screening. In this study, we searched the Protein Data Bank for fragments with multiple binding modes and targeting different sites. We identified 203 fragments represented by 90 scaffolds, some of which are not or hardly present in commercial fragment libraries. By contrast to other available fragment libraries, the studied set is enriched in fragments with a marked three-dimensional character (download at 10.5281/zenodo.7554649).