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.

Figure 1. Suzuki-Miyaura cross-coupling.

(a) Examples of drugs and late-stage drug candidates where Suzuki-Miyaura coupling is used to form key carbon–carbon bonds (shown in blue) with heterocyclic coupling partners. (b) The Suzuki-Miyaura reaction is strategically powerful in drug synthesis and design due to its robustness and tolerance of heterocycles. (c) This work: asymmetric Suzuki-Miyaura coupling to form Csp³–Csp² bonds using heterocycles where X, Y or Z≠CH.

Figure 2. Asymmetric Suzuki-Miyaura coupling using vinyl- and heteroaryl boronic acids.

(a) Cross-coupling vinylboronic acids to cyclic allyl chlorides. Conditions: 0.4 mmol of allyl chloride, 0.8 mmol of vinylboronic acid, [Rh(cod)(OH)]₂ (2.5 mol%), ligand (6 mol%), Cs₂CO₃ (1.0 eq) in THF at 60 °C. (b) Testing various heteroaromatic boronic acids in asymmetric cross-coupling. (c) Hetereoaryl boronic acids used in combination with different allyl chlorides. Conditions: 0.4 mmol of allyl chloride, 1.2 mmol of heteroaryl boronic acid, [Rh(cod)(OH)]₂ (2.5 mol%), ligand (6 mol%), Cs₂CO₃ (1.00 eq) in THF at reflux. *In these experiments Xyl-P-PHOS was used instead of BINAP. ^†It is difficult to determine the ee of product 10 and the ee values here have an estimated error of ±10%. ^‡Allyl bromide was used instead of allyl chloride. ^§The reaction was performed at r.t. for 16 h. ^‖In these experiments 5 mol% [Rh(cod)(OH)]₂ and 12 mol% ligand was used and the reaction stirred for four hours at reflux while protected from light. All yields are isolated yields. Enantiomeric excesses determined by HPLC, GC or SFC using a chiral non-racemic stationary phase. **Reaction using (S)-BINAP and stirred at room temperature 48 h.

Figure 3. Asymmetric Suzuki-Miyaura coupling with pyridine-derived boronic acids.

(a) Examination of pyridine boronic acid derivatives and core-modified pyridyl boronic acids. (b) Cross-coupling of various chloropyridineboronic acids. (c) Pyridine inhibits an asymmetric coupling reaction while 2-Cl-pyridine does not, suggesting that the role of the 2-Cl-unit is to make the pyridine-based partner less Lewis basic and bind less effectively to Rh-species. (d) Addition of water to the 2-Cl-pyridinyl boronic acid simplifies its NMR spectra in DMSO suggesting it breaks aggregates into monomers. (e) Tentative reaction mechanism for the Rh-catalyzed cross-coupling. All yields are isolated yields.

Figure 4. Coupling piperidenyl derivatives.

(a) Addition of arylboronic acids to N-Boc-3-chloro-4-piperidene. Conditions: piperidinyl chloride (1.0 equiv.), boronic acid (2.0 equiv.), [Rh(cod)(OH)]₂ (2.5 mol%), A (6 mol%), Cs₂CO₃ (1.0 equiv.) in THF at 80 °C with stirring for 16 h. Enantiomeric excess determined by HPLC using a chiral non-racemic stationary phase. (b) Addition of heteroaromatic- and vinylboronic acids to N-Boc-3-chloro-4-piperidene. *(S)-BINAP was used instead of (R)-A. ^†(R)-BINAP was used instead of (R)-A. All yields are isolated yields. **Reaction using (S)-A run and stirred at room temperature 72 h.

Figure 5. Further transformation of asymmetric Suzuki-Miyaura products and applications in drug and natural product synthesis.

(a) Representative transformations of different asymmetric coupling products: cross-coupling and S_NAr reactions with 2-pyridine derivatives, nucleophile addition to an aldehyde, dehalogenation/hydrogenation, chemoselective ring opening with BBr₃ and nitro-group reduction/hydrogentation. (b) Application of the method to the synthesis of the drug (−)-preclamol and the natural product (+)-isoanabasine. (c) Syntheses of the anticancer agent niraparib by Merck. Merck’s first process route involved resolution of racemic starting material by HPLC. Their second-generation route used an enzymatic lactamization approach to provide enantiomerically pure material. (d) To highlight the robustness and flexibility of asymmetric Suzuki-Miyaura coupling we used it as the key step in three different approaches to niraparib. All three syntheses intercept an intermediate reported by Merck and show high overall yields and levels of enantioselectivity. All yields are isolated yields.