Plate-based diversity subset screening generation 2: An improved paradigm for high throughput screening of large compound files

High throughput screening (HTS) is an effective method for lead and probe discovery that is widely used in industry and academia to identify novel chemical matter and to initiate the drug discovery process. However, HTS can be time-consuming and costly and the use of subsets as an efficient alternative to screening these large collections has been investigated. Subsets may be selected on the basis of chemical diversity, molecular properties, biological activity diversity, or biological target focus. Previously we described a novel form of subset screening: plate-based diversity subset (PBDS) screening, in which the screening subset is constructed by plate selection (rather than individual compound cherry-picking), using algorithms that select for compound quality and chemical diversity on a plate basis. In this paper, we describe a second generation approach to the construction of an updated subset: PBDS2, using both plate and individual compound selection, that has an improved coverage of the chemical space of the screening file, whilst only selecting the same number of plates for screening. We describe the validation of PBDS2 and its successful use in hit and lead discovery. PBDS2 screening became the default mode of singleton (one compound per well) HTS for lead discovery in Pfizer

Metallaphotoredox-catalysed <i>sp</i>³–<i>sp</i>³ cross-coupling of carboxylic acids with alkyl halides

In the past 50 years, cross-coupling reactions mediated by transition metals have changed the way in which complex organic molecules are synthesized. The predictable and chemoselective nature of these transformations has led to their widespread adoption across many areas of chemical research1. However, the construction of a bond between two sp3-hybridized carbon atoms, a fundamental unit of organic chemistry, remains an important yet elusive objective for engineering cross-coupling reactions2. In comparison to related procedures with sp2-hybridized species, the development of methods for sp3–sp3 bond formation via transition metal catalysis has been hampered historically by deleterious side-reactions, such as β-hydride elimination with palladium catalysis or the reluctance of alkyl halides to undergo oxidative addition3,4. To address this issue, nickel-catalysed cross-coupling processes can be used to form sp3–sp3 bonds that utilize organometallic nucleophiles and alkyl electrophiles5,6,7. In particular, the coupling of alkyl halides with pre-generated organozinc8,9, Grignard10 and organoborane11 species has been used to furnish diverse molecular structures. However, the manipulations required to produce these activated structures is inefficient, leading to poor step- and atom-economies. Moreover, the operational difficulties associated with making and using these reactive coupling partners, and preserving them through a synthetic sequence, has hindered their widespread adoption. A generically useful sp3–sp3 coupling technology that uses bench-stable, native organic functional groups, without the need for pre-functionalization or substrate derivatization, would therefore be valuable. Here we demonstrate that the synergistic merger of photoredox and nickel catalysis enables the direct formation of sp3–sp3 bonds using only simple carboxylic acids and alkyl halides as the nucleophilic and electrophilic coupling partners, respectively. This metallaphotoredox protocol is suitable for many primary and secondary carboxylic acids. The merit of this coupling strategy is illustrated by the synthesis of the pharmaceutical tirofiban in four steps from commercially available starting materials