Streamlined Asymmetric Reaction Development: A Case Study with Isatins

Abstract

Asymmetric reaction development within ad ay or two has been ad ream of syntheticc hemists fors everal decades. We now show that such at ask is feasible with a highly efficients treamlined screening strategyu sing the asymmetric allylation of isatinsw ith ac hiral boronc omplex as ac ase study.O ur high-throughput screening (HTS) methodi sb ased on fast optical UV/CDa nalysis of minute amounts of crude reactionm ixtures ( % 3mgs cale) and it obviates product isolation and the general need for reference compounds which greatlyr educes preliminary work and analysis time. The setup, reactions creening, analysis and data processing for5 4asymmetric allylations of nine different isatinsi ns ix differents olvents was handled by a single operatori nl ess than 20 work hours.O ne could easily extend this HTS strategy to hundreds of reactions in roughly the same time frame and further reduce the labor with commerciallya vailable automated high-throughput experimentation equipment. The effectiveness of this asymmetric reaction development strategy is confirmed with the upscales ynthesis of two representative 3-allyl-3-hydroxyisatinsin9 8-99 %y ield and with 91-94% ee under optimized conditions. Asymmetric reaction developmenti sacentral task in the chemicala nd pharmaceutical sciences. Despite impressive advancesw ith high-throughput equipment, the optimization of the yield and the enantiomeric excess of ac hiral producto ften remains am ajor bottleneck that limits the overall progress and the workflow,e specially in highly collaborative settings where on-timed elivery of drug candidates for preclinical studies is critical. Such as cenariom ay arise, for example, at the early drug discovery stage where it is necessary to quickly select and establish as ynthetic methodt hat affords fast and reliable access to an urgently neededc ompoundand analoguest hereof for initial testing purposes.E xpectations of short response times to urgentc ompound requests generate operational constraintst hat can make this ad aunting challenge. As the major focus typically lies on time-efficiency and expeditious produc-tion of the target compound(s), the use of catalysts or reagents that are not commercially available and have to be prepared separately may not be acceptable. At the same time, analytical tools that allow determination of the conversion or yield when al arge number of miniaturized reactions are performed in parallel to identify optimal conditionsm ust be in place andr eady for use. Witht he help of high-throughput screening techniquesa nd automated equipment that have become routine in many laboratories, the development of a satisfactory synthetic route can often be accomplished fairly quickly when the goal is to prepare achiral compounds. [1] This may not be the case, however, when ac hiral product in high yield and enantiomeric excess (ee)i sn eeded. The determinationo fe ither conversiono ry ield and ee valueso ften involvest wo separatem ethods and elaborate purification steps prior to the analysis. The common use of chiralc ...

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Accelerated Asymmetric Reaction Screening with Optical Assays

“…To demonstrate the value of this often overlooked scenario, we used the asymmetric allylation of isatin 93 with the chiral allylborane 94 to show how high-throughput UV/CD screening can accelerate asymmetric reaction development without introduction of an optical chemosensor or auxiliary (Scheme 20 ). 32 Fifty-four combinations of nine different isatin compounds and six different solvents were conducted in parallel and the resulting mixtures containing product 95 were quenched with NaOH/H 2 O 2 followed by HCl addition. The CD and UV spectra were then collected without further work-up and used to quantify the extent of asymmetric induction and conversion, respectively.…”

Advancement in Organic Synthesis Through High Throughput Experimentation

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