Conformationally Fixed Chiral Bisphosphine Ligands by Steric Modulators on the Ligand Backbone: Selective Synthesis of Strained 1,2-Disubstituted Chiral cis-Cyclopropanes

Abstract

A new series of C 1-symmetric P-chirogenic bisphosphine ligands of the type (R)-5,8-Si-Quinox-tBu3 (Silyl = SiMe3, SiEt3, SiMe2Ph) have been developed. The bulky silyl modulators attached to the ligand backbone fix the phosphine substituents to form rigid chiral environments that can be used for substrate recognition. The ligand showed high performances for a copper­(I)-catalyzed asymmetric borylative cyclopropanation of bulky silyl-substituted allylic electrophiles to afford higher disfavored 1,2-cis-silyl-boryl-cyclopropanes than the other possible isomers, trans-cyclopropane and allylboronate (up to 97% yield; 98% ee; cis/trans = >99:1; cyclopropane/allylboronate = >99:1). Detailed computational studies suggested that the highly rigid phosphine conformation, which is virtually undisturbed by the steric interactions with the bulky silyl-substituted allyl electrophiles, is key to the high stereo- and product-selectivities. Furthermore, the detailed computational analysis provided insight into the mechanism of the stereoretention or -inversion of the chiral alkylcopper­(I) intermediate in the intramolecular cyclization.

Stereospecific Csp3 Suzuki–Miyaura Cross-Coupling That Evades β-Oxygen Elimination

“…Immediately upon the first addition of aqueous CsOH solution we observed almost complete disappearance of 27-syn and 27-anti and formation of two new compounds tentatively assigned as dihydroxy siloxaborolate salts 29-syn and 29-anti. Independent synthesis and isolation of these materials support this assignment, as 11 B NMR confirms the presence of a single tetracoordinate pyramidalized borate; 1 H NMR supports the loss of the pinacol ester fragment, and HRMS characterization of the mixture is consistent with expected molecular weights (SI, pages 73−74). While 27-syn is fully consumed to generate the corresponding 29-syn, the conversion of 27-anti to 29-anti appears to arrest at ∼80% even after addition of another 0.5 equiv of CsOH solution, suggesting that the diastereomeric pinacol boronates 27-syn and 27-anti may possess different relative stability and rates of hydrolysis.…”

“…Silanes have been utilized as masked alcohols as early as 1984 as they are easily converted to the latter via stereospecific Fleming–Tamao oxidation . Encouragingly, Yun and co-workers have reported the successful cross-coupling of a primary alkyl pinacol boronic ester with a β-phenyldimethylsilyl substituent, and recently Ito and co-workers employed a cyclopropyl variant . Using a route developed by Suginome and co-workers to vicinal silylboronic esters (Figure A), we generated a secondary alkyl pinacol boronic ester with a β-phenyldimethylsilyl substituent ( 4 ) and submitted it to cross-coupling conditions but observed none of the desired product (Figure B), potentially due to the low reactivity of this highly hindered nucleophile.…”

“…9 Encouragingly, Yun and co-workers have reported the successful crosscoupling of a primary alkyl pinacol boronic ester with a βphenyldimethylsilyl substituent, 10 and recently Ito and coworkers employed a cyclopropyl variant. 11 Using a route developed by Suginome and co-workers to vicinal silylboronic esters (Figure 2A), 9 we generated a secondary alkyl pinacol boronic ester with a β-phenyldimethylsilyl substituent (4) and submitted it to cross-coupling conditions but observed none of the desired product (Figure 2B), potentially due to the low reactivity of this highly hindered nucleophile. To overcome this, we drew inspiration from previous reports by Morken, 2m Suginome, 2a,c,f,r Molander, 2b,h Hall, 2e,k and Takacs, 2n,p demonstrating that proximal Lewis basic functional groups can promote transmetalation of secondary alkyl boronates.…”

“…Although secondary alkyl pinacol ester 25 proved to be remarkably stable under aqueous basic cross-coupling conditions, we asked whether a pinacol siloxaborolate could undergo further hydrolysis facilitated by intramolecular activation by the silanolate group (Figure 4D). Interrogating the speciation of boronates under our reaction conditions proved challenging by NMR due to minimal deviation in 11 B and 1 H chemical shifts, so we turned to reaction monitoring via direct injection HPLC to provide real-time reaction progress. 17 A diastereomeric mixture of 27 was dissolved in DMSO, and aqueous CsOH solution was dosed in while monitoring via real-time HPLC (Figure 4E).…”

Copper-Catalyzed Diastereo- and Enantioselective Borylative Cyclization

“…In particular, an enantioselective intramolecular borylative cyclization of a diverse range of hydrocarbons with various electrophiles such as carbonyl, imine, and electron-withdrawing alkene for the construction of boron-containing carbocycles and heterocycles using copper catalysis is emerging as a key theme in modern synthesis [10,15,17]. Since the first report of copper-catalyzed borylative intramolcular cyclization of allylic carbonates by Ito and Sawamura [18], the cyclization reaction has grown in popularity and been extensively studied [19]. The aim of this review is to highlight the recent development of copper-catalyzed borylative cyclization of unsaturated hydrocarbons with various electrophiles (Figure 1).…”