Organocatalytic Asymmetric Synthesis of Si-Stereogenic Siloxanols

We report the organocatalytic synthesis of Si-stereogenic compounds via desymmetrization of a prochiral silanediol with a chiral imidazole-containing catalyst. This metal-free silylation method affords high yields with enantioselectivity up to 98:2 for various silanediol and silyl chloride substrate combinations (including secondary alkyl, vinyl, and H groups), accessing products with potential for further elaboration. NMR and X-ray studies reveal insight into the H-bonding interactions between the imidazole organocatalyst and the silanediol and the dual activating role of the Lewis basic imidazole to account for the high enantioselectivity.

−15 The catalytic asymmetric synthesis of enantioenriched Si-stereogenic silanes remains rare, particularly methods that produce organosilanes with handles for further synthetic transformation. 16,17While several examples for desymmetrization of prochiral disilanes have been reported, 18−28 there are only two recent reports of asymmetric methods for desymmetrization of prochiral silanediols to access enantioenriched silanols: 29−31 He and co-workers reported a Cucatalyzed sigma-bond metathesis approach for SiO-H insertion (Figure 1a), 29 and Zhu and Oestreich reported an imidodiphosphorimidate (IDPi)-catalyzed silylation with allylsilanes (Figure 1b). 30Both the Cu-and IDPi-catalyzed methods require a tert-butyl group for high levels of enantioenrichment.While several options exist for the enantioselective organocatalytic silylation of alcohols (Figure 1c), 32−36 organocatalytic transformations of silanols remain rare, with only four recent related examples giving access to Sistereogenic silyl ethers. 27,30,37,38ere, we report a novel organocatalytic asymmetric synthesis of Si-stereogenic siloxanols upon the desymmetrization of prochiral silanediols (Figure 1d).Based on our expertise with silanediols, 39−41 we posited that enantioenriched Si-stereogenic compounds could be accessed upon selective silylation of one enantiotopic hydroxy group.−35 From our initial evaluation of a series of nonenzymatic organocatalysts (Figure 2), chiral imidazole 4a was one of the only leads identified for the enantioselective desymmetrization of prochiral silanediols with readily available chlorosilanes. 32ur initial investigations considered the silylation of silanediols 1a and 1b with unoptimized conditions, e.g., stoichiometric quantities of 4a (see SI, Table S1).Initial investigations with hydrido-chlorosilane 2a led to challenges with product isolation under unoptimized conditions, so chlorosilane 2b and silanediol 1b were employed for optimization studies.Preliminary results produced siloxanol 3bb in 65% yield with 80:20 er (Table 1, entry 1).Notably, no bis-silylation product (via infrared) was observed under these conditions.Imidazole catalyst 4a also has the ability to be quantitatively recycled using a simple acid−base extraction sequence without loss of catalytic efficiency. 32e proceeded to optimize conditions for the organocatalytic desymmetrization using silanediol 1b with chlorosilane 2b, where the choice of solvent and control of exogenous acid proved to be key factors in achieving high yield and enantioselectivity (Table 1).Switching from THF to toluene improved yields of 3bb to 93% and enantioselectivity to 95:5 (entry 1 vs 2).Catalyst loading at 20 mol % maintains high yield and enantioselectivity, albeit with a longer reaction time (16 h vs 3h, entry 3).Using Et 3 N in place of DIPEA also affords an excellent yield, albeit with reduced enantioselectivity (entry 4).Using DBU afforded 3bb with low enantioselectivity (entry 5) and low yield due to the formation of trisiloxane 5 (isolated), which we had not observed under other silylation conditions.Using an inorganic base such as Cs 2 CO 3 was ineffective for the transformation due to poor solubility, and significant unreacted starting material was observed (entry 6).When α-pinene was investigated as a scavenger to manage endogenous acid (entries 7−9), 42−46 the best overall combination of yield and enantioselectivity was observed using a 1:1 of DIPEA/pinene (entry 9).Reducing the reaction time to 4 h led to a corresponding decreased yield, confirming that 8−16 h is generally required (entry 10).Comparing DCM and chlorobenzene solvents retains similar product yields but reduces the enantioselectivity (entries 12−13).The yield and enantioselectivity remain high using a 5 mol % catalyst loading of 4a (entry 13), and these conditions were used as the optimized conditions.It is notable that the organocatalyst can be quantitively recycled after each reaction, a practice employed for reaction optimization and substrate scope experiments.
Due to the thermodynamic favorability of Si−O bond formation, 47−49 we were aware that bis-silylation may also proceed to afford achiral trisiloxane 5 during the desymmetrization process.Since the formation of the achiral trisiloxane would reduce yields of the desired enantioenriched product, care was taken to identify any byproducts during the desymmetrization.Under optimized conditions, only a single silylation of the silanediol was observed, and siloxanol 3 appears inert to further siloxane formation (Scheme 1).
Exploring the scope of silanediols with diphenylmethylchlorosilane (2b) demonstrated that silanediols bearing mixed aryl-alkyl substituents generally offer the best combination of reactivity and stability (Table 2).Siloxanol 3bb was synthesized on a gram scale in 98% yield with 98:2 er (Table 2).4-Fluoro-1-naphthyl 1c was silylated to afford 3cb in 56% yield and 92:8 er, with the reduced yield attributed to product instability on silica gel.Using a 2-naphthyl (2-Np), otolyl, or phenyl instead of 1-naphthyl (1-Np) shows that the enantioselectivity is sensitive to the steric interactions of the  aryl group while maintaining a generally consistent 86:14 er.With diarylsilanediol 1a, the two aryl substituents reduce the ability of the catalyst to effectively discriminate between the two OH of the prochiral silanediol, affording 3ab with only moderate enantioselectivity (83%, 70:30 er).Replacement of the branched i-butyl with linear n-butyl still proceeds with good enantioselectivity (83:17 er).Inclusion of electrondonating 4-MeOPh with the n-butyl group (1i) degrades the enantioenrichment to 77:23.Notably, the use of a tert-butylsubstituted silanediol, which has been previously reported, 29,30 is not tolerated and does not proceed with selectivity: the silylation of 1j is either not selective or unreactive, depending on chlorosilane pairing, which is attributed to steric bulk disrupting silanediol H-bonding to the organocatalyst (vide infra).
Next, the scope of the chlorosilane was investigated to include vinyl and hydrido functional handles on silicon (Table 2).Silylation of 1b using dimethylphenylchlorosilane 2c maintains a high enantioselectivity (97:3 er) for the formation of siloxanol 3bc.Pairing vinylchlorosilane 2d with 1b maintains high enantioselectivity (97:3 er) for the synthesis of vinylsiloxanol 3bd.Now using optimized conditions, we also demonstrated the utility of hydridochlorsilane 2a to isolate hydridosiloxanols under these conditions.Silyation of mixed aryl-alkyl silanediols again afforded the highest selectivity when using 2a, where selective silylation with similar diaryl substituents is more challenging.Notably, when using 2a, the desymmetrization of the isopropyl substrate 1g produced 3ga in excellent 98:2 enantioselectivity with the SiH functional handle.Desymmetrization of the tert-butyl silanediol 1j proceeds with low yield and selectivity, which further highlights the opportunities for isobutyl and isopropyl in this methodology.When 2a was used in conjunction with either 1a or 1b, selectivity was reduced (70:30 and 85:15, respectively).In the case of n-butyl, product 3ia, a low selectivity and low yield are observed, with an equimolar quantity of the trisiloxane byproduct also isolated.Trialkylsilyl chlorides without the aryl group proved unreactive for the transformation while using Ph 3 SiCl gave poor yield and selectivity (see SI Figure S4).
Imidazole rings are known to be potent Lewis base catalysts for silylation of alcohols, 50−52 and 4a was designed to function as a chiral Lewis base activator of chlorosilanes during the desymmetrization of meso-diols. 32Therefore, it is reasonable to expect Lewis base activation of 2 by 4a for the silylation of silanediol 1. 29 Si NMR spectra of the equimolar mixture of 2b  29 Si resonance appearing at −9.6 ppm accompanied by the disappearance of the 2b resonance at 10.2 ppm (Figure 3).−53 The role of the organocatalyst as a Lewis base during silylation was further evaluated by synthesizing and testing analogues that lacked the imidazole component (Figure 4a).When (R)-2-(benzylamino)-N-((R)-3,3-dimethylbutan-2-yl)-3,3-dimethylbutanamide (4b) was evaluated for the desymmetrization of 1b with 2b, no reaction was observed, resulting in quantitative recovery of starting material.We next turned to evaluate (R)-2-(pyridyl)-N-((R)-3,3-dimethylbutan-2-yl)-3,3dimethylbutanamide (4c) since heterocycles containing a pyridine have been shown to be active catalysts in silylation. 51,54Pyridine analogue 4c also did not catalyze silylation of the silanediol, affording only recovered starting material.According to prior reports of 4a for the silylation of meso-diols, including an achiral Lewis base cocatalyst was also observed to improve reaction times without negative impacts on enantioselectivity. 35When achiral Lewis bases such as Nmethyl imidazole (NMI) and 5-(ethylthio)-1H-tetrazole ( 6) were investigated as cocatalysts, no rate acceleration was observed.The addition of NMI reduced yield and enantioselectivity, suggesting that NMI can act as a competitor to 4a rather than as a cocatalyst (Figure 4b).The addition of 6 afforded a reduced yield, but no change in enantioselectivity was observed. 35oth 1 H NMR and X-ray cocrystallization experiments highlight the H-bonding interactions between the silanediol and organocatalyst.In an enantiopure cocrystal of silanediol 1a and organocatalyst 4a (Figure 5a), 4a adopts a dual binding mode with a single hydroxy group of 1a, generating a chiral environment to promote enantioselective desymmetrization.This structure the imidazole function as an H-bond acceptor for SiOH (O-NH 1.74 Å), while demonstrating the amide operating as an H-bond donor to the oxygen of the silanol (NH-O 2.14 Å). 1 H NMR binding studies with 4a also confirm the hydrogen-bonding interactions with the silanediol in solution, showing shifts for both the amide and imidazole signals (Figure 5b).Upon mixing 4a and 1b in deuterated benzene, the amide proton signal exhibits a downfield shift (Δδ NH = 0.37 ppm), and both protons of the imidazole shift upfield (ΔδH a = 0.55 ppm and ΔδH b = 0.42), consistent with a H-bonding interaction at both positions.The binding affinity (K a ) was calculated according to the shift of imidazole peak H b to be K a Hb = 191 ± 25. 55−60 An NMR binding study of 4a with 1a confirmed a lower binding affinity (K a = 90 ± 3; see SI, Figure S3), which was expected since this substrate (1a) afforded reduced enantioselectivity in the desymmetrization reaction.
To elucidate the interplay between catalyst and silanediol binding, additional binding studies were conducted with 1b, 1e, and 1j, where it was determined that high K a values correlate with high levels of enantioenrichment (Table 3).Comparing the binding of silanediol 1a revealed that modest binding can produce moderate enantioenrichment, while silanediol 1b forms the strongest association to 4a and produces high enantioenrichment.Silanediols 1e and 1j produce signal shifts of the same magnitude, yet due to the rate of shifting, 1e has a greater K a .To visualize this trend, product ee was graphed as a function of the silanediol binding affinity (K a ) with 4a (Figure 6).The graph shows a strong correlation between high K a and enantioenrichment (R 2 = Table 2. Substrate Scope a,b a Isolated yields are after column chromatography; catalyst quantitatively recycled after synthesis of each substrate.Enantiomeric ratio determined using HPLC with a Diacel CHIRALPAK AD-H, AS-H, or OD-H column.3bb Performed on a gram scale; all other reactions conducted on a 0.15 mmol scale.b High conversion observed; lower isolated yield attributed to the instability of 3cb on silica gel.0.997).From this relationship, we conclude that the main factor dictating the enantioenrichment of siloxanol products is the ability of the parent silanediol to form a strong H-bonding complex with 4a.Additional binding experiments between silanediol 1b and benzyl analogue 4b (see SI, Figure S8) also support that the imidazole is necessary for a strong H-bonding complex for desymmetrization.The performance of the varying substrates, alongside the results of the X-ray and NMR binding studies, overall supports that the selectivity of the process is dependent on the binding and steric interactions between the silanediol and 4a, as well as the chlorosilane.
Our experimental evidence suggests that a single molecule of 4a fulfills the dual catalytic role for H-bonding molecular recognition of the prochiral silanediol and Lewis base activator of the chlorosilane.In this case, the 1 H NMR and X-ray study findings provide evidence for the formation of the 4a•1 complex, while 29 Si NMR reveals an interaction between 4a and 2 that is similar to previous reports of the formation of pentacoordinate halosilane-Lewis base adducts. 52,61,62However, experiments with several Lewis base additives did not demonstrate cocatalysis and afforded decreased yield and/or selectivity, which supports that only one molecule of the organocatalyst is serving a dual catalytic role.This is in contrast to previous reports for meso-diols, where Lewis basic additives and computational studies support that two molecules of 4a are engaged desymmetrization. 35Our substrate scope provides insight into the asymmetric induction, where enantioselectivity is attributed to the orientation of the bulky groups of organocatalyst 4a and the alkyl group of silanediol 1 to leave only one angle of approach for silyl chloride 2. At least one aryl group on 2 is necessary for silylation of unbound OH to proceed.A full mechanistic study is underway to establish a more detailed mechanism for the Lewis base-catalyzed enantioselective silylation of prochiral silandiols in comparison to meso-diols.In conclusion, this work reports the development of a metalfree synthesis of Si-stereogenic siloxanol compounds from prochiral silanediols with high yields and enantioselectivity while incorporating silane and vinyl functional handles.X-ray and NMR binding studies, and a comparison of catalyst analogues, support that this transformation is catalyzed via a two-point H-bonding interaction of the bifunctional imidazole catalyst with the silanediol.This H-bonding activation method shows scope effective with secondary alkyl groups (i.e., isobutyl and isopropyl), which indicates future potential for diaster-eoselective applications with chiral carbon and stereogenic silicon.New methods for efficient access to Si-stereogenic compounds containing various functional handles are expected to have important applications for materials, medicinal chemistry, and catalysis.Δδ (ppm) for silanediols 1a, 1b, 1e, and 1j calculated for shift of imidazole H b .b Error was calculated as 95% confidence intervals based on the fit of the NMR titration data to the model.

Figure 2 .
Figure 2. Preliminary screening of nonenzymatic catalysts for silylative desymmetrization (See the SI for full details).

Figure 4 .
Figure 4. (a) Replacing the imidazole ring of organocatalyst 4a with a phenyl or pyridyl group results in loss of catalyst activity.(b) Adding NMI as a cocatalyst; adding 6 as a cocatalyst.

Figure 6 .
Figure 6.Preliminary correlation of ee% of siloxanol product to silanediol-catalyst binding affinity (K a ).

Table 1 .
Optimization of Silanediol Desymmetrization Using 4a aCatalyst quantitatively recycled after each optimization trial.b Isolated yield after column chromatography.c Determined using HPLC with Diacel CHIRALPAK AD-H column.d Formation of double silylated (trisiloxane) product is observed under these conditions, which accounts for the lower yield.e Low yield due to poor solubility of Cs 2 CO 3 in PhMe; remaining mass recovered is 1b.f Pinene = ±α-Pinene, used in 1:1 ratio with base, if indicated.g Remaining mass recovered is 1b.The absolute configuration of 3bb was determined to be (S) based on analogy to 3aa and 3ga, based on comparison to known compounds (See the SI) Scheme 1. Bis-Silylation Not Observed during Desymmetrization with either 4a or NMI at room temperature in C 6 D 6 showed a strong

Table 3 .
Binding Data (K a ) of Silanediols with 4a