Automated peptide and oligonucleotide synthesizers enabled a revolution in molecular biology and helped pave the way to modern synthetic biology. Similarly, fully automated synthetic chemistry could herald a new wave of innovation in biology and materials sciences by greatly facilitating access to known and novel molecules. Here, we report on an automated multistep chemical synthesizer, AutoSyn, that makes milligram-to-gram-scale amounts of virtually any drug-like small molecule in a matter of hours and demonstrate its versatility with the synthesis of ten known drugs. Of the FDA-approved small-molecule drugs for which we were able to compute a synthetic route, 87% are predicted to be synthesizable on AutoSyn. Moreover, AutoSyn enables digital synthesis protocols that ensure the reproducibility and transferability of synthesis protocols from one lab to another.

General base-catalyzed double-Michael reactions of allenes with various dinucleophiles are described. The reactions are facilitated most efficiently by a catalytic amount of trimethylphosphine, affording six types of C2-functionalized benzannulated five-membered heterocycles: benzimidazolines, benzoxazolines, benzothiazolines, 1,3-benzodioxoles, 1,3-benzoxathioles, and 1,3-benzodithioles. This atom-economical reaction is operationally simple and provides the product heterocycles in good to excellent yields. Careful mechanistic studies unveiled the phosphine-triggered general base catalysis pathway. Furthermore, the double-Michael reaction can serve as an alternative method for the selective mono-ketalization of β-diketones.

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[ N]-Cholamine is an isotope tag for metabolomics research, because it possesses 2 important properties: an NMR active isotope and a permanent charge for MS sensitivity. Here, we present a scalable synthesis of [ N]-cholamine.

Phosphine-Initiated General Base Catalysis: Facile Access to Benzannulated 1,3-Diheteroatom Five-Membered Rings via Double-Michael Reactions of Allenes.-The reaction succeeds also with DMAP as basic catalyst, but mostly with lower yields. The synthesis of acetal (VII) proceeds selectively in contrast to the nonselective ketalization of asymmetric β-diketones. In the case of substrates (X), the temperature must be raised for complete double Michael addition. In contrast, a chlorine-substituted phenyl moiety [cf.(XV)] is tolerated at 90°C. -(SZETO, J.; SRIRAMURTHY, V.; KWON*, O.; Org. Lett. 13 (2011) 20, 5420-5423, http://dx.