Enantiodivergent Kinetic Resolution of 1,1′‐Biaryl‐2,2′‐Diols and Amino Alcohols by Dipeptide‐Phosphonium Salt Catalysis Inspired by the Atherton–Todd Reaction

Abstract

A highly enantiodivergent organocatalytic method is disclosed for the synthesis of atropisomeric biaryls via kinetic resolution inspired by a dipeptide‐phosphonium salt‐catalyzed Atherton–Todd (A‐T) reaction. This flexible approach led to both R‐ and S‐enantiomers by fine‐tuning of bifunctional phosphonium with excellent selectivity factors (s) of up to 1057 and 525, respectively. The potential of newly synthesized O‐phosphorylated biaryl diols was illustrated by the synthesis of axially chiral organophosphorus compounds. Mechanistic investigations suggest that the bifunctional phosphonium halide catalyst differentiates between the in‐situ‐generated P‐species in the A‐T process, mainly involving phosphoryl chloride and phosphoric anhydride, thus leading to highly enantiodivergent O‐phosphorylation reactions. Furthermore hydrogen bonding interactions between the catalysts and phosphorus molecules were crucial in asymmetric induction.

Asymmetric synthesis of N-bridged [3.3.1] ring systems by phosphonium salt/Lewis acid relay catalysis

“…Encouraged by the initial results, we next explored the asymmetric version of this cascade reaction. For the development of effective catalysts, given our recent progress in developing phosphonium-involved bifunctional catalytic systems [38][39][40][41] , we chose amide-, dipeptide-and thiourea-derived phosphonium salts as candidate catalysts because of their representative hydrogen-bonding and ion-pairing features. Pleasingly, all tested phosphonium salt catalysts were effective in promoting this reaction, furnishing the desired N-bridged azabicyclo[3.3.1] nonane product in high yields and excellent diastereoselectivities (all > 20:1 d.r.)…”

“…The groups of Maruoka, Ooi, and Zhao have pioneered to make significant contributions in this field [33][34][35][36][37] . Recently, our group has developed a series of multi-/bifunctional phosphonium salt catalysts and demonstrated their applications in a variety of asymmetric synthetic reactions [38][39][40][41] . In connection to the above synthetic challenge and our disclosure of phosphonium salts and their successful applications in asymmetric synthesis, we envisioned that the employment of highly tunable bifunctional phosphonium salts together with metal-free Lewis acid catalysts may result in a practical cascade transformation towards constructing these synthetically challenging azabicyclo[3.3.1]nonane scaffolds.…”

Organocatalytic atroposelective construction of axially chiral nonsymmetric biaryltriols and their applications in asymmetric synthesis and heavy metal ion detection

“…As a consequence, considerable attention has been paid to developing practical methods for the construction of such scaffolds. 4 In contrast, nonsymmetric axially chiral biaryldiols or biaryltriols, another important branch of biaryldiols, have been seldomly investigated. This situation probably arises from the lack of delicate methodologies towards these skeletons, although their potential as efficient chiral ligands or catalysts has already been disclosed.…”

Enantiodivergent Kinetic Resolution of 1,1′‐Biaryl‐2,2′‐Diols and Amino Alcohols by Dipeptide‐Phosphonium Salt Catalysis Inspired by the Atherton–Todd Reaction

“…Thew idely used VA NOL molecule (1s)was recovered via this KR mode with S-configuration in 95 % ee;a nd further the NOBIN (1t)w as also subjected to the kinetic resolution system, albeit with moderate enantioselectivity.U nfortunately,w hen the spirocyclic diol 1u was used, low selectivity (s = 2) was observed under the current catalytic system, probably due to the extremely rigid structure.The absolute stereochemistry of the product 3aa obtained in Table 2w as determined by X-ray crystallographic analysis. [17] Subsequently,w ef urther evaluated the scope of the KR process via the A-T reaction by phosphonium salt P8 (Table 3). Generally,v arious biaryl diols 1 and phosphine oxides 2 with different substitution patterns were effectively resolved with similarly high selectivity;a ll substrates tested were recovered in good to excellent ee (up to 99 % ee)w ith 44-61 %isolated yield.…”

“…Thea bsolute stereochemistry of the product 3aa obtained in Table 3w as assigned to be R by X-ray crystallographic analysis. [17] Synthetic applications.A st he obtained atropisomeric biaryls are very useful intermediates to synthesize valuable molecules,the appealing synthetic scalability and practicality of this chemistry were demonstrated (Figure 2). Scaled-up resolutions of the biaryl diols 1a and 1q by catalyst P8 and P12 were performed, leading to the corresponding compounds with very high selectivities of 458 and 174, respectively.Additionally,the derivatizations of the chiral products were also investigated to prove the applicability of these reactions;a nd exemplarily the O-phosphorylated product (R)-3aa was readily transformed into different classes of important axially chiral ligands/catalysts [18] via simple-steps of organic operation (Figure 2b).…”