Rhodium-Catalyzed Asymmetric Suzuki and Related Cross-Coupling Reactions

Stephen Webster,^† Laura Cunningham,^† and Stephen P. Fletcher^†,* Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, United Kingdom

stephen.fletcher@chem.ox.ac.uk

Abstract

We describe in this account our progress towards the development of new catalytic asymmetric cross-coupling reactions. We focus on the application of boronic acids in the synthesis of enantioenriched C(sp²)–C(sp³) coupled products from prochiral and racemic starting materials. Specifically, we describe the rhodium-catalyzed Suzuki–Miyaura-type arylations of allylic halides and cyclobutenes, their key mechanistic features, and their applications to complex-molecule synthesis and scale-up.

Introduction

C(sp²)–C(sp²) cross-coupling reactions are well established. In particular, the Suzuki–Miyaura cross-coupling (SMC) has emerged as a popular synthetic tool, owing to its experimental convenience and the robustness of the arylboronic acid reagents employed.¹ Its ubiquitous application has biased the structures of drug candidate libraries towards unsaturated arene-rich scaffolds, despite low saturation and the absence of stereogenic centers reducing the chances of success in drug discovery programs.^2,3 Therefore, developing synthetic reaction systems that combine the generality and practicality of the SMC but yield enantiomerically enriched products with C(sp³) centers has been an area of active research.³

Transition-metal-catalyzed asymmetric allylic addition and hydrofunctionalization of alkenes have become effective tools for enantioselectively forming C–C bonds.^4–6 However, despite sporadic reports of aryl nucleophiles being utilized in these reactions, there are not yet generally useful and selective methods for employing (hetero)aryl species as nucleophiles.^7–10

Our group has developed several enantioselective crosscouplings between (hetero)aromatic boronic acids and a variety of coupling partners. In the rest of this article, we will review our studies on the development and applications of these asymmetric arylations (Figure 1).

Summary and Outlook

In the field of asymmetric catalysis, developing reaction systems that can exploit the generality and practical simplicity of the Suzuki–Miyaura cross-coupling but yield enantiomerically enriched three-dimensional products with sp³ centers has been a longstanding challenge. We have developed a number of asymmetric Rh-catalyzed cross-couplings of sp²-hybridized boronic acid derivatives with allylic (pseudo)halides and mildly activated olefins. We have also demonstrated the applicability of these new methodologies on scales that are relevant to “real-world” process settings by scaling up an asymmetric cross-coupling reaction to give over 100 g of product.⁶⁸ In that work, a racemic bicyclic substrate was coupled with furan-2- boronic acid pinacol ester using standard equipment available in an academic laboratory. The simplicity and typical efficiency of the reactions described above—both in terms of practical efficiency and atom economy—make these reactions an important step forward in developing useful asymmetric sp³–sp² coupling reactions. There are, however, many major challenges that remain in developing such reactions before they can be widely used in a variety of transformations, in particular, the challenge of developing regio- and enantioselective reactions of acyclic and non-symmetrical acyclic racemic allyl halides. Developing and applying such methods that do not involve simple pseudo-symmetrical substrates offer many exciting opportunities in the future.

References

(†) Stephen Webster − orcid.org/0000-0002-2445-8417; Laura Cunningham − orcid.org/0000-0002-3206-8435; Stephen P. Fletcher − orcid.org/0000-0001-7629-0997.

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