Asymmetric Suzuki-Miyaura coupling of heterocycles via Rhodium-catalysed allylic arylation of racemates

Abstract

Using asymmetric catalysis to simultaneously form carbon–carbon bonds and generate single isomer products is strategically important. Suzuki-Miyaura cross-coupling is widely used in the academic and industrial sectors to synthesize drugs, agrochemicals and biologically active and advanced materials. However, widely applicable enantioselective Suzuki-Miyaura variations to provide 3D molecules remain elusive. Here we report a rhodium-catalysed asymmetric Suzuki-Miyaura reaction with important partners including aryls, vinyls, heteroaromatics and heterocycles. The method can be used to couple two heterocyclic species so the highly enantioenriched products have a wide array of cores. We show that pyridine boronic acids are unsuitable, but they can be halogen-modified at the 2-position to undergo reaction, and this halogen can then be removed or used to facilitate further reactions. The method is used to synthesize isoanabasine, preclamol, and niraparib—an anticancer agent in several clinical trials. We anticipate this method will be a useful tool in drug synthesis and discovery.

Catalytic asymmetric synthesis of geminal-dicarboxylates

“…Nicotinic acid did not give product 3e , but addition of a chloro group in the 2-position of the pyridyl ring allowed moderate yields and enantioselectivities to be achieved in formation of 3f and 3g . This observation is consistent with previous Rh-catalysed asymmetric processes, 59 and overall these experiments suggest that many other carboxylic acid bearing heterocycles and heteroatoms would be compatible with this method if appropriate protecting group strategies are used.…”

Impact of Cross-Coupling Reactions in Drug Discovery and Development

“…The development of synthetic methodology has evolved [21] to meet the need for preparing 3Dtype molecules, including rhodium-catalyzed asymmetric Suzuki-Miyaura reaction with aryls, vinyls, heteroaryls, and heterocycles. Application of the asymmetric sp 2 -sp 3 Suzuki-Miyaura methodology [22] enabled the synthesis of clinical candidates preclamol (15, a dopamine D2 receptor partial agonist studied for the treatment of schizophrenia), niraparib (16, MK−4827, a 2017 approved poly-(ADP ribose) polymerase (PARP) inhibitor indicated for ovarian cancer), and natural product isoanabasine (17), which are all presented in Figure 3 with their corresponding Fsp 3 values calculated using SwissADME [23] online tool. An example of the trend to increase Fsp 3 during the Lead Optimization phase, leveraging crosscoupling reactions in drug design, comes from the evolution of the SAR approach for novel Eprostanoid receptor 4 (EP4) antagonists ( Figure 4) [24,25] that eventually led to the discovery of LY3127760 [26].…”

“…The crucial synthetic steps for the preparation of compounds 18 and 19 are Pd-mediated cross-coupling reactions (Scheme 2). Suzuki-Miyaura coupling of quinoline or naphthalene (21) with 3-chloro-phenyl-boronic acid using PdCl 2 (dppf)•CH 2 Cl 2 and potassium carbonate led to the corresponding ester derivatives (22) as penultimate compounds in the synthesis. This approach led to a route that enabled a rapid exploration of analogs for SAR optimization.…”

Rational Design of an Iron‐Based Catalyst for Suzuki–Miyaura Cross‐Couplings Involving Heteroaromatic Boronic Esters and Tertiary Alkyl Electrophiles

“…However, the propensity for elimination reactions has resulted in a smaller number of Suzuki–Miyaura reactions that involve at least one sp 3 ‐hybridized substrate. Fewer still are examples involving heteroaromatic coupling partners, which can inhibit catalysis (Figure a) . The dearth of these substrates is notable considering that nearly 70 % of all pharmaceutical molecules contain at least one heterocycle .…”