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. 2021 Oct 13;143(40):16580-16588.
doi: 10.1021/jacs.1c06572. Epub 2021 Oct 1.

Chemoselective Electrosynthesis Using Rapid Alternating Polarity

Yu Kawamata  1 , Kyohei Hayashi  1 , Ethan Carlson  1 , Shobin Shaji  2 , Dirk Waldmann  2   3 , Bryan J Simmons  4 , Jacob T Edwards  4 , Christoph W Zapf  4 , Masato Saito  1 , Phil S Baran  1
Affiliations

Chemoselective Electrosynthesis Using Rapid Alternating Polarity

Yu Kawamata et al. J Am Chem Soc. .

Abstract

Challenges in the selective manipulation of functional groups (chemoselectivity) in organic synthesis have historically been overcome either by using reagents/catalysts that tunably interact with a substrate or through modification to shield undesired sites of reactivity (protecting groups). Although electrochemistry offers precise redox control to achieve unique chemoselectivity, this approach often becomes challenging in the presence of multiple redox-active functionalities. Historically, electrosynthesis has been performed almost solely by using direct current (DC). In contrast, applying alternating current (AC) has been known to change reaction outcomes considerably on an analytical scale but has rarely been strategically exploited for use in complex preparative organic synthesis. Here we show how a square waveform employed to deliver electric current-rapid alternating polarity (rAP)-enables control over reaction outcomes in the chemoselective reduction of carbonyl compounds, one of the most widely used reaction manifolds. The reactivity observed cannot be recapitulated using DC electrolysis or chemical reagents. The synthetic value brought by this new method for controlling chemoselectivity is vividly demonstrated in the context of classical reactivity problems such as chiral auxiliary removal and cutting-edge medicinal chemistry topics such as the synthesis of PROTACs.

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Figures

Figure 1.
Figure 1.
Types of waveforms in electrosynthesis and proposed reaction control enabled by rapid alternating polarity (rAP). (A) Illustration of direct current (DC) and alternating current (AC). (B) rAP waveform and implementation into a commercial device. (C) Hypothesis of achieving chemoselectivity by rAP through differentiating slow and fast electrochemical processes, and demonstration of its utility in a highly complex setting.
Figure 2.
Figure 2.
Difference between rAP and DC electrolysis in general carbonyl reduction. (A) A striking difference in reaction outcome by employing rAP with various frequencies and currents. acc = constant current, cp = constant potential. bNMR yield. Isolated yields are shown in parenthesis. cConditions adopted from reference . (B) Functional group tolerance in the reduction of phthalimides benchmarked with the latest DC electrolysis conditions. Reactions were performed on 0.05–0.1 mmol scale unless otherwise noted. aConditions were adopted from reference . bMeCN/tBuOH (1:1) was used as solvent. cMeCN was used as solvent. d100 mA was applied instead of 20 mA. (C) Discovery of chemoselectivity unachievable by known synthetic methods. aConditions were adopted from reference . bConditions were adopted from reference . cConditions were adopted from reference . (D) Generality of carbonyl reduction by rAP. aSee Supporting Information for reaction conditions for each substrate. bDC conditions were adopted from reference .
Figure 3.
Figure 3.
Synthetic applications of rAP. (A) Reductive removal of Evans auxiliary with high chemoselectivity among multiple carbonyl groups. (B) Highly chemoselective reduction for diversification of PROTAC molecules. (C) Rapid deoxygenation of thalidomide analogs and modulation of cereblon binding affinity.
Figure 4.
Figure 4.
Experimental and computational rationale for unique reactivity of rAP. (A) Chemoselectivity follows reduction potential and can be predicted by FMO analysis. (B) Experimental evidence to support SET mechanism. (C) Deuterium labeling study to identify the source of proton and the fate of carboxylic acid. (D) Frequency-dependent reaction profile for carbonyl reduction, oxidative decarboxylation, and Shono oxidation. (E) Proposed mechanism based on Figure 4A–4D. (F) Demonstration of precise redox reaction based on the understanding of rAP chemoselectivity.
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