Stereospecific synthesis of silicon-stereogenic optically active silylboranes and general synthesis of chiral silyl Anions

Silicon-stereogenic optically active silylboranes could potentially allow the formation of chiral silyl nucleophiles as well as the synthesis of various chiral silicon compounds. However, the synthesis of such silicon-stereogenic silylboranes has not been achieved so far. Here, we report the synthesis of silicon-stereogenic optically active silylboranes via a stereospecific Pt(PPh3)4-catalyzed Si–H borylation of chiral hydrosilanes, which are synthesized by stoichiometric and catalytic asymmetric synthesis, in high yield and very high or perfect enantiospecificity (99% es in one case, and >99% es in the others) with retention of the configuration. Furthermore, we report a practical approach to generate silicon-stereogenic silyl nucleophiles with high enantiopurity and configurational stability using MeLi activation. This protocol is suitable for the stereospecific and general synthesis of silicon-stereogenic trialkyl-, dialkylbenzyl-, dialkylaryl-, diarylalkyl-, and alkylary benzyloxy-substituted silylboranes and their corresponding silyl nucleophiles with excellent enantiospecificity (>99% es except one case of 99% es). Transition-metal-catalyzed C–Si bond-forming cross-coupling reactions and conjugate-addition reactions are also demonstrated. The mechanisms underlying the stability and reactivity of such chiral silyl anion were investigated by combining NMR spectroscopy and DFT calculations.


Previous work
Here, we report the synthesis of silicon-stereogenic optically active silylboranes and the generation of a wide range of chiral silyl nucleophiles.We found that the Pt(PPh 3 ) 4 -catalyzed borylation of chiral hydrosilanes, which are synthesized by stoichiometric and catalytic asymmetric synthesis, in high yield and perfect stereoselectivity with retention of their configuration (Fig. 1B).The single-crystal X-ray diffraction analyses of these chiral silylboranes are presented.The synthesized silicon-stereogenic silylboranes are easy to handle and can be used as silicon-stereogenic silyl-group transfer reagents with high enantiomeric purity, exhibiting complete enantiospecificity in the generation of chiral silyllithiums, silicon-silicon bond-forming reactions.In addition, we demonstrate that palladium(0)-catalyzed C-Si bond-forming cross-coupling reactions and copper(I)-catalyzed silylconjugate-addition reactions can also be conducted with perfect stereospecificity.

Results and discussion
We started the investigation of the synthesis of silicon-stereogenic optically active silylboranes based on our previous research 116 .The most important aspect of this study is to unambiguously determine the absolute configuration of the hydrosilane, the silylborane, and the silyl anion.For that purpose, we first searched for a chiral crystalline hydrosilane that can be analyzed by single-crystal X-ray diffraction analysis.Ideally, the silylborane produced by the hydrosilane should be crystalline as well.Moreover, to determine the stereochemistry of the silyllithium, crystalline products should be obtained by trapping the silyllithium without loss of the stereochemistry.Although this was a very difficult task, we finally settled on the chiral crystalline hydrosilane (-)-(R)-[(1,1'-biphenyl)−4-yl](cyclohexyl)methylsilane [(-)-(R) −1a], which was prepared with >99% ee by resolution of the corresponding racemic hydrosilane using preparative HPLC equipped with a chiral column (Fig. 2A; for details, see the Supplementary Information) 118 .The absolute configuration of (-)-(R)-1a was unequivocally determined via single-crystal X-ray diffraction analysis (for details, see the Supplementary Information).After screening potential catalysts for the borylation of (-)-(R)-1a (for details, see the Supplementary Information), we found that Pt(PPh 3 ) 4 is suitable for the borylation of (-)-(R)-1a and bis(pinacolato)diboron, which affords ] in 73% yield with perfect enantiospecificity (>99% ee; >99% es).A single-crystal X-ray diffraction analysis of the product unambiguously confirmed the reaction proceeded with retention of the configuration of the silicon-stereogenic center (Fig. 2A; for details, see the Supplementary Information).
We then investigated the reaction of the chiral silylborane (-)-(R)-2a with chlorotriphenylsilane in the presence of methyl lithium as a nucleophilic activator of the silylboranes in order to observe whether the synthesized chiral silylborane could act as a silicon-stereogenic silyl-group transfer reagent (Fig. 2B).When (-)-(R)-2a (>99% ee) was treated with methyl lithium in THF at -78 °C for 10 min, it subsequently reacted with chlorotriphenylsilane to furnish (+)- yield with perfect enantiospecificity (>99% ee; >99% es).A single-crystal X-ray diffraction analysis confirmed the absolute configuration to be (+)-(S)-3a; the nucleophilic reaction, therefore proceeds with retention of the configuration (Fig. 2B; for details, see the Supplementary Information).
We then decided to investigate the stereospecificity and configurational stability of the silicon-stereogenic optically active silyl nucleophiles generated from the chiral silylboranes.As shown in Fig. 2C, the chiral silyl nucleophile can be expected to be formed first in the equilibrium between ate complex A and silyllithium intermediate B from (-)-(R)-2a (>99% ee) via treatment with methyl lithium in THF at -78 °C.The nucleophile was then quenched with 1.0 M aqueous HCl to give the corresponding chiral hydrosilanes (-)-(R)-1a in 83% yield with >99% ee (entry 1) 79 .The absolute configuration of (-)-(R)-1a remains unchanged, demonstrating that all processes proceed with retention of the configuration and perfect enantiospecificity (>99% es) 79,81,90 .Even when the reaction temperature was increased to -40 °C, (-)-(R)-1a was obtained with >99% ee, albeit that the yield decreased to 68% (entry 2), and 26% of (-)-(R)-2a was recovered (for details, see the Supplementary Information).Further increasing the reaction temperature to room temperature resulted in a decreased yield of 21%, while the enantiomeric purity remained high (entry 3, >99% ee).Only 17% of (-)-(R)-2a was recovered, and other unidentified side products were observed (for details, see the Supplementary Information).Next, we examined the nucleophilic activators for the silylboranes.When we used n-butyl lithium instead of methyl lithium, a yield of 54% was obtained with >99% ee (entry 4).With the more reactive and basic sec-butyl lithium, the yield was further reduced to only 20%, albeit the stereospecificity of the protonation remained unchanged (>99% ee) (entry 5).Interestingly, when lithium tert-butoxide was used as the nucleophile, the reaction did not proceed, even though lithium tert-butoxide has been reported to be a good activator for other silylboranes such as Me 2 PhSi-B(pin) (entry 6) 122 .With potassium tert-butoxide, only an 8% yield was obtained, while the erosion of the enantiomeric purity (>99% ee) was not observed (entry 7).When the reaction was carried out with methylmagnesium bromide, the enantiomeric excess of (-)-(R)-1a was reduced to 95% and the yield was very low (6%; entry 8).When toluene was used as the solvent, the yield of (-)-(R)-1a was 32% with >99% ee (entry 9), whereas the use of n-hexane as the solvent resulted in 43% yield with >99% ee, suggesting that a less polar solvent affects the yield but not the stereoselectivity (entry 10).In addition, when (-)-(R)-2a was treated with methyl lithium in THF at -78 °C for a longer reaction time of 2 h, (-)-(R)-1a was obtained in 87% yield with >99% ee after quenching with 1.0 M aqueous HCl (entry 11).These results demonstrate the high stability of the chiral ate complex and the silyllithium with regard to stereochemistry.
In order to investigate the reaction mechanism for the reaction of silylborane and MeLi, we conducted DFT calculations at the B3LYP-D3/Def2-SVP level (Fig. 2D).The reaction between model silylborane 2 and MeLi first forms complex INT-1 (-7.6 kcal/mol), which spontaneously transforms to a thermodynamically stable boronate complex INT-2 (-20.4 kcal/mol) through TS-1 (-1.1 kcal/mol) with a low activation barrier (G ‡ = 6.5 kcal/mol).Boronate INT-2 proceeds via transition state TS-2 (-12.3 kcal/mol) to form silyl lithium INT-3 (-22.5 kcal/mol) while retaining its stereochemistry.The low activation barriers (G ‡ = 8.1 and 10.2 kcal/mol) and an energy change of only -2.1 kcal/mol suggest an equilibrium between INT-2 and INT-3, which is consistent with the results of the NMR experiments described above (vide supra).The reaction of INT-3 with HCl forms INT-4, which is rapidly converted into protonation product 1 via TS-3 with a very low activation barrier (G ‡ = 1.1 kcal/mol) with retention of the configuration.We hypothesize that the high stereospecificity observed during the generation of silyl anions can be attributed to the avoidance of generating silyl radicals and chloride ions, which can lead to racemization of the silicon center 90,123 .

Methods
Representative procedure for the platinum-catalyzed borylation of chiral hydrosilane Chiral hydrosilane 1 (0.30 mmol, 1.0 equiv), bis(pinacolato)diboron (0.75 mmol, 2.5 equiv) were placed in a vial with a screw cap containing a Teflon®-coated rubber septum under air.The vial was placed in a glove box, and then Pt(PPh 3 ) 4 (0.006 mmol, 2.0 mol %) was added to the vial in the glove box under an argon atmosphere.After closing the vial, the reaction vial was removed from the glove box, and then dry cyclohexane (0.3 mL) was added to the vial via a syringe.After being stirred at 80 °C for 24 h, the reaction mixture was analyzed by GC to check the completeness of the reaction.The mixture was directly filtered through celite with Et 2 O as an eluent, and then the resultant solution was concentrated under reduced pressure.The crude product was purified by flash column chromatography (SiO 2 , hexane/Et 2 O, 100:0 to 99:1) to give the corresponding product 2.
Representative procedure for activation of chiral silylborane with methyl lithium followed by reaction with chlorosilane Chiral silylborane 2 (0.10 mmol, 1.0 equiv) was placed in a vial with a screw cap containing a Teflon®-coated rubber septum.After the vial was connected to manifold with nitrogen and a vacuum line through a needle, it was evacuated and backfilled with nitrogen.This cycle was repeated three times.Dry THF (0.5 mL) was added to the vial through the rubber septum using a syringe, and the mixture was cooled to -78 °C.Then, MeLi (0.15 mmol, 1.5 equiv) was added to the vial.After the mixture was stirred at -78 °C for 10 min, chlorosilane (0.20 mmol, 2.0 equiv) was added dropwise to the vial at -78 °C.The mixture was allowed to warm to room temperature and stirred for 1 h.After that, the mixture was quenched by the addition of EtOH and filtered through a short silica-gel column with Et 2 O as an eluent, then the resultant solution was concentrated under reduced pressure.The crude product was purified by flash column chromatography (SiO 2 , hexane/Et 2 O, 100:0 to 99:1) and then further purified by GPC to give the corresponding product 3.

Reported synthetic routes to silicon-stereogenic optically active silyllithiums
Li• chloride-induced racemization * B Synthesis

of chiral silylboranes and the generation of the corresponding chiral silyl nucleophiles
2