Kelvin L. Billingsley

A General and Efficient Method for the Suzuki–Miyaura Coupling of 2‐Pyridyl Nucleophiles

The Suzuki-Miyaura reaction has become one of the most valuable synthetic processes for the construction of carbon-carbon bonds,[1] and our laboratories has developed many highly active catalyst systems that efficiently process challenging combinations of aryl halides and boronic acids.[2] Recently, we have been able to extend our methodology to the cross-coupling of heteroaryl boronic acids and esters, which serve as important building blocks for the assembly of biologically active molecules.[3]-[4] However, 2-substituted nitrogen-containing heteroaryl organoboranes, which are of importance for the construction of numerous natural products and pharmaceutically interesting compounds,[5] were not effectively coupled using our standard conditions. Further examination of the literature indicated that only a few methods have been developed that allow for the Suzuki-Miyaura reaction of 2-pyridyl nucleophiles with aryl halides, and in these examples, only aryl iodides have been demonstrated as suitable coupling partners.[3],[6]-[10] The difficulty can be attributed to several factors: (1) electron-deficient heteroaryl boron derivatives undergo transmetallation at a relatively slow rate (2) these reagents rapidly decompose via a protodeboronation pathway. The lack of an efficient method to process this class of nucleophiles led us to develop a technique specifically designed to accomplish this transformation. We found that catalysts based upon phosphite or phosphine oxide ligands (1-4) were highly active for the Suzuki-Miyaura reaction of 2-pyridyl boron derivatives with 1-bromo-4-butylbenzene (Scheme 1).[6] The use of these has been pioneered by the work of Li, and elegant applications by Ackermann and Wolf have appeared more recently. However, the reaction remained sensitive to the nature of the nucleophile and base. For example, the reaction of commercially-available reagents, such as 2-pyridyl boronic acid,[7] pinacol boronate ester[8] or N-phenyl diethanolamine boronate ester,[9] with 4-n-butylbromobenzene produced low yields of the desired biaryl product (Table 1, Entries 1-3). Similarly, attempts to use organotrifluoroborates resulted in a low conversion of the aryl bromide (Table 1, Entry 4).[10] Although 2-pyridylboronates have been employed in Suzuki-Miyaura reactions, the cross-coupling processes result in only poor to modest yields of the desired biaryl product.[11] However, when lithium triisopropyl 2-pyridyl boronate (A) was employed as the nucleophile, the desired product could be obtained in an 85% yield with 100% conversion of the aryl halide (Table 1, Entry 5). Although A is not yet commercially available, it is stable under an argon atmosphere for up to a month, and it can be prepared in near quantitative yield from 2-bromopyridine via lithium halogen exchange and immediate in situ quenching of the resulting anion with triisopropylborate. In addition, this reaction could be performed in multigram quantities to provide A in an excellent yield. Lithium triisopropyl 2-(6-methoxypyridyl)boronate (B) and lithium triisopropyl 2-(5-fluoropyridyl)boronate (C) were also prepared employing this protocol in 90% and 96% yield, respectively. Similarly, under these conditions, 2-bromopyridines possessing a protected aldehyde (D) or a nitrile (E) could be efficiently transformed to the corresponding boronates.[12] Scheme 1 Effective Phosphite and Phosphine Oxide Ligands Table 1 The Effects of the Base and Nucleophile[a] A catalyst based upon Pd2dba3 and 1 proved to be highly effective for the Suzuki-Miyaura reactions of A with aryl and heteroaryl bromides. For example, this system efficiently combined 3,5-(bis-trifluoromethyl)bromobenzene (Table 2, Entry 2) and 4-bromoanisole (Table 2, Entry 3) with A to furnish the desired biaryl in 82% and 74% yield, respectively. In addition, ortho-substituted aryl bromides were coupled in good to excellent yields (Table 2, Entries 4-5). Heteroaryl bromides were also suitable coupling partners as seen in the reactions of A with 5-bromopyrimidine (Table 2, Entry 6) and 4-bromoisoquinoline (Table 2, Entry 7) which smoothly resulted in a 91% and 82% yield, respectively, of the desired heterobiaryl compound. Utilizing a Pd2dba3/2 catalyst, a range of lithium triisopropyl 2-pyridylboronates possessing functional groups were successfully cross-coupled with aryl bromides. Indeed, this catalyst system allowed for the reaction of B and C with a variety of electron-poor, -neutral, -rich and ortho-substituted aryl bromides (Table 2, Entries 9-12). In addition, the reaction of 4-bromobenzonitrile and D furnished the desired biaryl in a 63% yield (Table 2, Entry 13). However, the cross-coupling reactions utilizing E resulted in incomplete conversion in its reaction with a variety of aryl bromides. We attributed this difficulty to the relatively slow rate of transmetallation of the highly electron deficient 2-pyridylboronate. Overall, however, this protocol still represents the most general method for the Suzuki-Miyaura reaction of 2-pyridyl nucleophiles with aryl or heteroaryl bromides. Table 2 The Reaction of A-D with Aryl Bromides[a] Despite the efficacy of the Pd2dba3/1 catalyst system for the reactions of lithium triisopropyl 2-pyridylboronates with aryl bromides, more modest yields of the desired biaryls were obtained in the reactions of the corresponding aryl or heteroaryl chlorides. Employing 2 as the supporting ligand, however, provided a more active catalyst for this transformation. For example, the reaction of A with 4-chlorobenzonitrile furnished the desired product in 73% yield (Table 3, Entry 1). In addition, unactivated aryl chlorides were efficiently coupled as the reactions of 4-n-butylchlorobenzene (Table 3, Entry 2) and 4-chloroanisole (Table 3, Entry 4) with A resulted in a 76% and 78% yield, respectively, of the desired product. Similarly, under these conditions, ortho-substituted aryl chlorides were suitable substrates as the reaction of 2-chloro-p-xylene and A proceeded in a 70% yield (Table 3, Entry 3). In addition, a heteroaryl chloride, 3-chloropyridine, was coupled with A in an excellent yield to give o,m-bipyridine (Table 3, Entry 6). Table 3 The Reaction of A and B with Aryl Chlorides[a] In summary, we have developed an efficient method for the Suzuki-Miyaura reaction of lithium triisopropyl 2-pyridylboronates. The boronates can be readily prepared in one step from the corresponding 2-bromo or 2-iodopyridine. This represents the first relatively general Suzuki-Miyaura cross-coupling reaction of these substrates with aryl and heteroaryl bromides and chlorides.

An improved system for the palladium-catalyzed borylation of aryl halides with pinacol borane.

A highly efficient method for the palladium-catalyzed borylation of aryl halides with an inexpensive and atom-economical boron source, pinacol borane, has been developed. This system allows for the conversion of aryl and heteroaryl iodides, bromides, and several chlorides, containing a variety of functional groups, to the corresponding pinacol boronate esters. In addition to the increase in substrate scope, this is the first general method where relatively low quantities of catalyst and short reaction times can be employed.

Toward a Biorelevant Structure of Protein Kinase C Bound Modulators: Design, Synthesis, and Evaluation of Labeled Bryostatin Analogues for Analysis with Rotational Echo Double Resonance NMR Spectroscopy

Protein kinase C (PKC) modulators are currently of great importance in preclinical and clinical studies directed at cancer, immunotherapy, HIV eradication, and Alzheimers disease. However, the bound conformation of PKC modulators in a membrane environment is not known. Rotational echo double resonance (REDOR) NMR spectroscopy could uniquely address this challenge. However, REDOR NMR requires strategically labeled, high affinity ligands to determine interlabel distances from which the conformation of the bound ligand in the PKC-ligand complex could be identified. Here we report the first computer-guided design and syntheses of three bryostatin analogues strategically labeled for REDOR NMR analysis. Extensive computer analyses of energetically accessible analogue conformations suggested preferred labeling sites for the identification of the PKC-bound conformers. Significantly, three labeled analogues were synthesized, and, as required for REDOR analysis, all proved highly potent with PKC affinities (∼1 nM) on par with bryostatin. These potent and strategically labeled bryostatin analogues are new structural leads and provide the necessary starting point for projected efforts to determine the PKC-bound conformation of such analogues in a membrane environment, as needed to design new PKC modulators and understand PKC-ligand-membrane structure and dynamics.

Modular Total Synthesis of Protein Kinase C Activator (−)-Indolactam V

A concise, eight-step total synthesis of (-)-indolactam V, a nanomolar agonist of protein kinase C, is reported. The synthesis relies upon an efficient copper-catalyzed amino acid arylation to establish the indole C4-nitrogen bond. This cross-coupling method is applicable to a range of hydrophobic amino acids, providing a platform for further diversification of indolactam alkaloid scaffolds and studies on their potent biological activity.

Hyperpolarized Sodium [1-13C]-Glycerate as a Probe for Assessing Glycolysis In Vivo

Hyperpolarized 13C magnetic resonance spectroscopy (MRS) provides unprecedented opportunities to obtain clinical diagnostic information through in vivo monitoring of metabolic pathways. The continuing advancement of this field relies on the identification of molecular probes that can effectively interrogate pathways critical to disease. In this report, we describe the synthesis, development, and in vivo application of sodium [1-13C]-glycerate ([13C]-Glyc) as a novel probe for evaluating glycolysis using hyperpolarized 13C MRS. This agent was prepared by a concise synthetic route and formulated for dynamic nuclear polarization. [13C]-Glyc displayed a high level of polarization and long spin-lattice relaxation time-both of which are necessary for future clinical investigations. In vivo spectroscopic studies with hyperpolarized [13C]-Glyc in rat liver furnished metabolic products, [13C]-labeled pyruvate and lactate, originating from glycolysis. The levels of production and relative intensities of these metabolites were directly correlated with the induced glycolytic state (fasted versus fed groups). This work establishes hyperpolarized [13C]-Glyc as a novel agent for clinically relevant 13C MRS studies of energy metabolism and further provides opportunities for evaluating intracellular redox states in biochemical investigations.