Catalytic Enantioselective Synthesis of a cis-β-Boronyl Cyclobutylcarboxyester Scaffold and Its Highly Diastereoselective Nickel/Photoredox Dual-Catalyzed Csp³–Csp² Cross-Coupling to Access Elusive trans-β-Aryl/Heteroaryl Cyclobutylcarboxyesters

Abstract

Chiral cyclobutanes are components of numerous bioactive natural products, and consequently, they have also gained significant attention in medicinal chemistry. Optically enriched cyclobutylboronates can serve as valuable synthetic intermediates for the synthesis of a broad variety of chiral cyclobutanes through exploiting the versatility of the boronyl functionality. Herein, by using a high-throughput ligand screening approach, an efficient method for the asymmetric conjugate borylation of a cyclobutene 1-carboxyester was optimized, leading to a highly enantioenriched cis-β-boronyl cyclobutylcarboxyester scaffold (99% ee, >20:1 dr). Of the 118 ligands screened, the Naud family of phosphine–oxazoline ligands was found to be the most effective. Computational modeling of the possible preinsertion complexes shows a large preference for the π-bound Cu­(I)–alkene complex where the substrate’s large benzhydryl ester occupies a relatively unhindered quadrant of the chiral ligand in a spatially tight environment that is highly specific for the cyclobutenoate substrate and imparts much lower selectivity with larger ring substrates. The cis diastereoselectivity is proposed to arise from a sterically controlled, irreversible protodecupration step. A highly diastereoselective nickel/photoredox dual-catalyzed Csp3–Csp2 cross-coupling of the corresponding trifluoroborate salt with aryl/heteroaryl bromides and cycloalkenyl nonaflates was developed, providing access to a wide diversity of trans-β-aryl/heteroaryl and cycloalkenyl cyclobutylcarboxyesters with an excellent diastereoselectivity and high retention of optical purity (91–99% ee, >20:1 dr). Azaheterocyclic halides, which are notoriously challenging substrates in Pd-catalyzed cross-coupling, are successful with this Ni/photoredox manifold. A stereoconvergent model based on steric factors is proposed for the key carbon–carbon bond forming step, leading to a high diastereoselectivity. Despite the radical nature of the cross-coupling conditions, the flanking carboxyester proved to be a reliable chirality relay group to maintain the stereochemical integrity of the organoboron intermediate. Furthermore, mild oxidation of the carbon–boron bond and extension of the catalytic asymmetric conjugate borylation reaction to a three-component aldol reaction with an aldehyde afford valuable enantioenriched cyclobutane products.

Expedient Synthesis of Oxaboracyclic Compounds Based on Naphthalene and Biphenyl Backbone and Phase‐Dependent Luminescence of their Chelate Complexes

“…Subsequent reaction with CO 2 followed by standard hydrolytic workup afforded the anionic boracyclic derivative 3 which was resistant to further hydrolytic cleavage of B−F bonds. It represents the first example of arylcarboxylate chelating the BF 2 moiety although some related non‐aromatic analogues were reported [25,26] …”

“…It represents the first example of arylcarboxylate chelating the BF 2 moiety although some related non-aromatic analogues were reported. [25,26] In a similar approach, carboxylation was followed by full deprotection of a BF 3 À group with Me 3 SiCl which after final hydrolysis resulted in the formation of 4. Compound 4 was postulated already in 1965 as the product of dehydration of 8borononaphtoic acid obtained by electrophilic ipso-borylation…”

Boron, silicon, nitrogen and sulfur-based contemporary precursors for the generation of alkyl radicals by single electron transfer and their synthetic utilization

“…A sequence of asymmetric conjugate borylation – trifluoroborate formation – Ni catalyzed cross coupling in photoredox conditions from cyclobutene 1-carboxyesters 28 opens an access to the synthesis of enantioenriched trans -heteroaryl cyclobutylcarboxyesters 29 (Scheme 8). 31 The initial borylation is cis -selective. High-throughput screening was achieved to determine the best ligand for the copper catalysis.…”

Incorporation of a cyclobutyl substituent in molecules by transition metal-catalyzed cross-coupling reactions

“…The irradiation of the enantiomerically enriched cyclobutyltrifluoroborate salt 65 and (hetero)aryl bromides (Scheme 32, eqn (1)) or cycloalkenyl nonaflates 67 (Scheme 32, eqn (2)), using a nickel/iridium photoredox catalytic system, was reported to produce a diversity of optically active trans 2-(hetero)aryl- and 2-cycloalkenyl cyclobutanecarboxylates 66 and 68 respectively, by the formation of Csp 3 –Csp 2 bonds with excellent diastereoselectivity and with high retention of the optical purity (ee = 91–99%, dr = 20 : 1) 52 (Scheme 32).…”

“…To explain this trans -stereoselectivity, a radical intermediate P is postulated to react with the nickel complex O to produce Q and R . As intermediate Q is favored, (less steric interactions), the trans -cyclobutane is formed 52 (Scheme 33).…”