Abstract
Exploration of novel, three‐dimensional chemical space is of growing interest in the drug discovery community and with this comes the challenge for synthetic chemists to devise new stereoselective methods to introduce chirality in a rapid and efficient manner. This Minireview provides a timely summary of the development of palladium‐catalyzed asymmetric redox‐relay Heck‐type processes. These reactions represent an important class of transformation for the selective introduction of remote stereocenters, and have risen to prominence over the past decade. Within this Minireview, the vast scope of these transformations will be showcased, alongside applications to pharmaceutically relevant chiral building blocks and drug substances. To complement this overview, a mechanistic summary and discussion of the current limitations of the transformation are presented, followed by an outlook on future areas of investigation.
Highlights
Over the past two decades, the over-reliance on a limited set of reactions in drug discovery has led to chemical libraries that are densely populated with molecules rich in sp2 character.[1]
Few, if any, drug molecules currently on the market have quaternary stereocenters installed via chemical synthesis.[2a, 8] the development of broad, practical methodologies which can provide access to novel chiral motifs that are useful for drug design, with the added potential to streamline the synthesis of active pharmaceutical ingredients (APIs), are of high value to industry and the synthetic community in general.[9]
The abovementioned diazonium-centered methodology was showcased in a 6-step stereoselective synthesis of (R)-verapamil, a calcium channel blocker currently commercialized as a racemate,[37] in 29% overall yield.[35b]. The redox-relay Heck reaction was used as the key step and proceeded in excellent yield and enantioselectivity (Scheme 8)
Summary
Over the past two decades, the over-reliance on a limited set of reactions in drug discovery has led to chemical libraries that are densely populated with molecules rich in sp character.[1]. There has been an increased interest in developing robust, cost-efficient stereoselective processes for the large scale synthesis of active pharmaceutical ingredients (APIs) containing one or more stereogenic centers.[7] Few, if any, drug molecules currently on the market have quaternary stereocenters installed via chemical synthesis.[2a, 8] the development of broad, practical methodologies which can provide access to novel chiral motifs that are useful for drug design, with the added potential to streamline the synthesis of APIs, are of high value to industry and the synthetic community in general.[9]. The stereoselective α- and β-functionalization of carbonyls has been extensively studied,[11] but significantly less attention has been directed at the stereoselective synthesis of remote tertiary and quaternary stereocenters.[12] This minireview describes the development of palladium-catalyzed asymmetric Heck-type transformations. Scope of redox-relay Heck-type transformations covered in this review
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