Access to P-chiral phosphine oxides by enantioselective allylic alkylation of bisphenols

A biscinchona alkaloid-catalyzed AAA reaction for the construction of P-stereogenic center compounds was developed.


General information
Commercially available materials purchased was used as received. 1 H NMR were recorded on a Bruker Avance (400 MHz) spectrometer, and reported as δ in units of parts per million (ppm) relative to tetramethylsilane (δ 0.00), and splitting patterns are designated as singlet (s), doublet (d), triplet (t), quartet (q), dd (doublet of doublets), m (multiplets). 13 C NMR were reported on a Bruker Avance (101 MHz) spectrometer, and reported as δ in units of parts per million (ppm) relative to the signal of chloroform-d (δ 77.16 triplet). 31 P NMR were reported on a Bruker Avance (162 MHz) spectrometer. 19 F NMR were reported on a Bruker Avance (376 MHz) spectrometer. Mass spectra were obtained using electrospray ionization (ESI) mass spectrometer. And the novel substrates and products were characterized in this ESI.

Experimental Section
1. General procedure for the synthesis of substrates 1

.1 General procedure for the synthesis of substrates 1
To a dry round bottomed flask equipped with a magnetic stir bar, added Phenols 1 (1 equiv) in THF, then 2 NaH (1.2 equiv) was added with nitrogen. The reaction was stirring at 0 °C for 30 minutes. When the reaction completed, 3 (0.5 equiv) was added to the mixture at 0 °C for 1h with nitrogen, and then 24h at room temperature. Extracted with CHCl3 and the organic phase was dried over MgSO4.The resulting crude residue was purified via column chromatography on silica gel to afford the desired products 4.
To a dry round bottomed flask equipped with a magnetic stir bar, added LDA (4 equiv) at -78 °C , 4 (1 equiv) dissolved in pure and dry THF was added in 60 min at -78 °C . The resulting reaction mixture was stirred at -78 °C for another 60 min, then it was allowed to warm up to rt and it was stirred at rt for 12 h. After the reaction was completed, quenched with saturated aqueous NH4Cl solution, then extracted with CHCl3. The organic phase was separated and the combined organic phase was dried over MgSO4, filtered and the solvent was removed. The crude product was first purified by linear correlation between the log (e.r.) values and the Charton constants with R 2

Correlation studies related to the computation
All substrates mono negative ion studied here were geometrically optimized at M06-2X/6-311g(d,p) level (SDD for I atom) with Gaussian 09 software. 1-3 SMD solvating model was used for describe the solvating effect of chloroform. 4 IR vibration values were obtained by performing frequency analysis at the same level. Sterimol parameters were calculated for the geometry optimized structures using Molecular Modeling Pro software. 5 NPA charges were obtained using NBO package build-in Gaussian 09. 6 Charton values were taken from literature. 7 The stepwise regression was performed using Matlab (R2018a) software. 8 All parameters examined in this study were listed in Table S1-S2.

POEt
Standard orientation:

Et
Standard orientation: Standard orientation:

Cl
Standard orientation:

Br
Standard orientation: Standard orientation:

Computation studies
Unless noted, all energetics are reported in kcal/mol, and the bond lengths are reported in angstroms (Å).
Structures were generated using CYLview. 9 Due to the large catalysis system, to reduce the computation time, transition states towards product 3k were explored and benzyl-substituted MBH carbonates were simplified to methyl-substituted ones. All transition states were optimized using the ONIOM method implemented in Gaussian09 1 at gas phase. M06-2X functional 2 with 6-31G(d) basis set was used for the high-layer and PM6 method for the low-layer. Quinuclidine ring moiety of the catalyst, which is far from reaction center, was treated as the low layer. The rest of the system was treated as the high layer. The frequency calculations were conducted at the same level of theory to confirm the nature of stationary points and obtain the thermal corrections. The high-level solution-phase energies of the transition states were calculated with SMD method 3 in chloroform. M06-2X functional 2 with 6-311+(d,p) basis set was used for the high-layer and PM6 method for the low-layer. Intermolecular non-covalent interactions (NCI) in transition states were analyzed by Multiwfn 10 using Independent Gradient Model (IGM). 11 The corresponding NCI pictures were generated using VMD. 12 NCI analysis indicated that the interaction between tert-butyl and catalyst is favored. However, if the tert-butyl group linked to phosphorous atom is replaced by adamantyl group, the steric effect between catalyst and substrate will be more remarkable. The steric effect destabilizes TS2, which is crucial for excellent enantioselectivity.      (2)).

Calculated Cartesian coordinates and energies
And next we added Boc protected substrate 2a to racemic 3d under room temperature as (3) showed, and finally we got 3d with 54.5:45.5 e.r. value with the contrary configuration. When the 2a was changed to 2b, the racemic 3d also produced a 53.0:47.0 e.r. value.
It indicated there is a decompose process accompanied by the generating process of the products with the existence of (DHQ)2PHAL, and this phenomenon facilitated the kinetic resolution process. But when the reaction were happened under low temperature, these processes of decompose and kinetic resolution are absolutely not main controlling factors of the e.r. values.  CHCl3). HPLC separation (Chiralpak AD, 4.6 x 250mm; i-PrOH / hexane = 1 / 4, 1.0 mL/min, 210 nm; tr (minor) = 6.0 min, tr (major) = 6.8 min, 97 :