Organocatalytic DYKAT of Si-Stereogenic Silanes

Abstract

Chiral organosilanes do not exist in nature and are therefore absent from the “chiral pool”. As a consequence, synthetic approaches toward enantiopure silanes, stereogenic at silicon, are rather limited. While catalytic asymmetric desymmetrization reactions of symmetric organosilicon compounds have been developed, the utilization of racemic silanes in a dynamic kinetic asymmetric transformation (DYKAT) or dynamic kinetic resolution (DKR) would significantly expand the breadth of accessible Si-stereogenic compounds. We now report a DYKAT of racemic allyl silanes enabled by strong and confined imidodiphosphorimidate (IDPi) catalysts, providing access to Si-stereogenic silyl ethers. The products of this reaction are easily converted into useful enantiopure monohydrosilanes. We propose a spectroscopically and experimentally supported mechanism involving the epimerization of a catalyst-bound intermediate.

In light of their importance in chemical synthesis and technical materials, enantiopure silicon-containing compounds bearing a Si-stereogenic center have recently gained considerable attention.¹⁻¹⁰ However, while C-stereogenic congeners are readily accessible via a plethora of asymmetric transformations of C=X π-bonds (X = C, O, N), the synthesis of silicon-stereogenic silanes has been notoriously difficult due to the instability and therefore unavailability of the corresponding Si=X-based molecules.^11,12 Documented enantioselective approaches to Si-stereogenic organosilanes can be divided into four main categories: chromatographic resolution,¹³ chemical resolution with a stoichiometric chiral reagent,¹⁴ catalytic desymmetrization of symmetric silicon compounds,^{3−5,7,15−17} and catalytic kinetic resolutions (eq 1).¹⁸⁻²¹ We became interested in contributing potentially more general and higher-yielding synthetic strategies toward enantiopure organosilanes. Specifically, we anticipated to expand the synthetic toolbox by efficiently utilizing racemic silanes, either in a dynamic kinetic resolution (DKR) or a dynamic kinetic asymmetric transformation (DYKAT), which both have the inherent advantage of offering yields >50%. A rhodium-catalyzed dynamic kinetic asymmetric hydrosilylation has recently been described by Xu and co-workers, but organocatalysis has not previously been used in a DYKAT toward stereogenic silanes.²²

1

However, since preservation of stereochemical integrity is frequently observed in organosilicon chemistry, a challenge to overcome in such strategies is the required racemization of the Si-stereogenic center during the reaction conditions.²³⁻²⁶ Inspiration came from previous work on the desymmetrization of symmetrical silanes via a silicon hydrogen exchange reaction and general studies on silylium-based asymmetric counteranion-directed catalysis (Si-ACDC).^17,27−50 Accordingly, we focused our attention on the design of a strong and confined imidodiphosphorimidate (IDPi)-catalyzed asymmetric synthesis of Si-stereogenic silyl ethers from racemic allyl silanes (eq 2). We anticipated that this approach could benefit from the configurational lability of the silylated IDPi intermediate, enabling high enantioselectivity and full conversion of the racemic starting material. Here we report the fruition of these considerations with an IDPi-catalyzed DYKAT of racemic allyl silanes with phenols, providing Si-stereogenic silyl ethers in excellent yield and enantioselectivity.

After identifying methallyl silane 1a and propofol (2) as suitable reactants in an initial screening (see Tables S1–S3 in the Supporting Information), we began optimizing this model reaction as depicted in Table 1.⁵¹ First, different solvents were examined with IDPi catalyst 3a (entries 1–4), and toluene was identified as a preferred solvent, for example, compared to methylcyclohexane, in which scarce solubility of the IDPi catalyst was observed. We also explored variations of the aryl group on the catalyst. Indeed, IDPi catalyst 3b, bearing p-tert-butyl phenyl groups at the 3,3′-positions of the binaphthyl backbone and triflyl groups at the inner core, enabled the formation of the desired product in 94:6 e.r. (entry 5). Excitingly, the e.r. of product 4a could be further improved to 99:1 by evolving the inner core (entries 6 and 7). It is noteworthy that increasing the reaction concentration suppressed the formation of side products, leading to satisfactory yields with no significant effect on the enantioselectivity (entries 8 and 9).

Table 1. Reaction Development.

^aUnless stated otherwise, reactions were performed with rac-1a (0.025 mmol), propofol 2 (1.5 equiv), and IDPi catalysts 3a–d (2.5 mol %) in solvent (0.25 mL, 0.1 M).

^bEstimated by ¹H NMR or TLC analysis.

^cDetermined by ¹H NMR using CH₂Br₂ as internal standard.

^dEnantiomeric ratios (e.r.) determined by HPLC.

^e0.2 M.

^f0.4 M.

Under the optimized conditions, the scope and generality of the IDPi-catalyzed DYKAT of silanes was evaluated and the results are outlined in Table 2. Chiral silyl ether 4a was obtained in 70% yield with 99:1 e.r. when the reaction of rac-1a and phenol 2 was conducted on a 0.2 mmol scale. Similarly, racemic silanes bearing different linear alkyl chains could all be accommodated to provide the corresponding products 4b–f with good to excellent results (67–84% yields and 85:15 to 99:1 e.r.). Additionally, a branched-alkyl-substituted silane was also efficiently converted, furnishing the corresponding product 4g in 95% yield and 98:2 e.r.. We found that high levels of enantioinduction were maintained when silane starting materials bearing substituents with diverse electronic properties in para and meta positions on the phenyl group were subjected to the reaction conditions. Organosilanes 4h–l were readily obtained with excellent results (77–87% yields and 96.5:3.5 to 99:1 e.r.). In contrast, a moderate e.r. was obtained from the reaction of silane 1m, which bears an ortho substituent. 2-Naphthyl and thienyl moieties were compatible with the DYKAT process, affording products 4n,o in good yields and excellent enantioselectivities. In addition to being competent at the synthesis of organosilanes bearing saturated alkyl chains, a range of racemic silanes featuring alkenyl groups were tolerated equally well, enabling access to products 4p–r in 61–76% yield and 86:14 to 97:3 e.r. However, the enantiodifferentiation was less effective in the presence of a benzyl-substituted racemic silane, and product 4s was obtained in 70% yield and 75:25 e.r. It is noteworthy that the reactivity of the starting silanes is highly dependent on the nature of the allyl leaving groups; in fact, the lack of reactivity of internal alkenyl and simple allyl moieties correlates to their nucleophilicity.⁵² Moreover, we were curious to investigate substrates with an existing carbon stereocenter in the deracemization reaction with propofol. The transformation of a 1:1 diastereomeric mixture of the enantiopure starting material 1v proved to be exquisitely catalyst controlled, and the two enantiomers of IDPi 3d gave products 4t,u with 18:1 and >20:1 d.r., respectively. Furthermore, our reaction is readily scalable and a preparative synthesis of Si-stereogenic silyl ether 4a (1.8 g) was accomplished in 82% isolated yield without erosion of enantioselectivity and the catalyst was recovered in 88% yield. More importantly, monohydrosilane 5 could easily be obtained without significant loss of enantiopurity by the reductive removal of the phenolic unit with retention of Si-stereochemistry.⁵³ The described two-step approach here may facilitate the wide utilization of such hydrosilanes as chiral auxiliaries, protecting groups, reagents, and synthetic precursors.⁵⁴

Table 2. Substrate Scope^a.

^aUnless specified otherwise, reactions were performed with rac-1 (0.2 mmol, 1.0 equiv), 2,6-diisopropylphenol 2 (0.3 mmol, 1.5 equiv), and IDPi 3d (2.5 mol %) in toluene (0.1 M) at −20 °C for 4–7 days. Isolated yields are given, and enantiomeric ratios (e.r.) were determined by HPLC. Conditions of reactions starting from a silicon compound bearing a C-stereocenter: 1v (0.1 mmol, 1.0 equiv), 2 (0.15 mmol, 1.5 equiv), and IDPi 3d (2.5 mol %) in toluene (0.1 M) at −20 °C for 7 days. Conditions for gram-scale synthesis and product elaboration: rac-1 (5.8 mmol, 1.0 equiv), 2 (8.7 mmol, 1.5 equiv), and IDPi 3d (2.5 mol %) in toluene (0.1 M) at −20 °C for 3 days; 4a (0.3 mmol) and DIBAL-H (3 equiv) in hexanes (0.15 M) at rt for 3 days.

^b–40 °C.

^c0.4 M.

^d0.2 M.

^ert.

^fWith IDPi 3b as catalyst.

^gWith 5 mol % catalyst.

To shed light on the underlying reaction mechanism of the discovered DYKAT, we conducted a time-course study for the reaction of allyl silane 1a with propofol 2 catalyzed by IDPi 3d in toluene at −20 °C for 3 days. The enantiopurity of the remaining silane 1a and product 4a was continuously monitored during the course of the reaction (Figure 1A). Interestingly, the IDPi catalyst enables nearly complete control of the enantioselectivity of product 4a from the starting point of the reaction, while the remaining silane 1a undergoes a slow enantioenrichment throughout the course of the reaction, suggesting a kinetic resolution process. Meanwhile, racemization studies under IDPi catalysis were performed with enantiopure starting materials (S)-1a and (R)-1a, respectively, and no racemization was observed in both cases, excluding a DKR pathway (Figure 1B). Further, we investigated the activation of catalyst 3d with rac-1a by ³¹P NMR analysis. Upon addition of racemic silane 1a (40 equiv), the sharp singlet of IDPi 3d (1.0 equiv) present at −4.5 ppm (Figure 1C, (i)) broadened due to the averaging of the acquired spectra during the drying of trace amounts of adventitious water (Figure 1C, (ii)). This signal sharpened again and shifted significantly to −6.3 ppm after complete drying (Figure 1C, (iii)). Finally, the catalyst was fully silylated, presumably mainly into diastereomers Cat-Si1 and Cat-Si2 and two additional minor species. The two main diastereomers feature two major doublets (J_pp = 97.4 Hz) at −2.0 and −7.0 ppm and two minor doublets (J_pp = 95.1 Hz) at −3.6 and −6.9 ppm, reflecting covalent bonding between the silicon atom and presumably an oxygen atom of the catalyst (Figure 1C, (iv)).⁴⁹ It is interesting to note that there is interconversion between the epimers, which was confirmed by comparing the ³¹P NMR spectrum of the catalyst with those of (R)-1a, (S)-1a ,and rac-1a (see Figures S5–S10 in the Supporting Information). We also separately investigated the reaction of the three starting materials (R)-1a, (S)-1a, and rac-1a under the standard conditions. The same product enantiomer (S)-4a was obtained in all three cases, with similar results, showing that the IDPi catalyst largely controls the stereoselectivity, irrespective of enantiopurity and absolute configuration of the starting silane (see Figure S1 in the Supporting Information). This indicates the existence of similar intermediates, which likely are positively charged, as validated by a Hammett plot analysis (see Figure S12 in the Supporting Information). Furthermore, we monitored the reversion of the silylated catalyst into the protonated form and found the Si-(R) enantiomer to react much faster than its Si-(S) counterpart (Figure 1E,F).

Figure 1.

Mechanistic studies. (A) Time-course study with rac-1a (0.1 mmol, 1.0 equiv), 2 (0.15 mmol, 1.5 equiv), and IDPi 3d (2.5 mol %) in toluene (0.1 M) at −20 °C under Ar for 3 days. Conversions were determined by GC, and enantiomeric ratios (e.r.) were determined by HPLC. (B) Racemization studies of either (R)-1a or (S)-1a (0.1 mmol) and IDPi 3d (2.5 mol %) in toluene (0.2 M) at −20 °C for 3 days. (C) ³¹P NMR of the activation of catalyst with rac-1a (0.1 mmol, 1.0 equiv) and IDPi 3d (2.5 mol %) in toluene-d₈ (0.1 M) at −20 °C under Ar. (D) Silylation process performed under the same conditions as in (C), monitored by ³¹P NMR. (E) Reaction of (S)-1a, performed with (S)-1a (0.1 mmol, 1.0 equiv), 2 (0.15 mmol, 1.5 equiv), and IDPi 3d (2.5 mol %) in toluene-d₈ (0.1 M) at −20 °C under Ar. The variations of Cat-Si1 and Cat-H were monitored by ³¹P NMR. (F) Reaction of (R)-1a under the same conditions as in (E).

Computational studies at the PBE-D3/def2-TZVP+CPCM (toluene) level of theory (see the Supporting Information for details) indicate that the diastereomers feature similar structures and a negligible energy difference (0.4 kcal/mol), which is within the expected computational error. Indeed, Cat-Si1 and Cat-Si2 show Si–O bond lengths of 1.81 and 1.82 Å, respectively. Nonetheless, they interconvert readily under the experimental conditions, with a reaction barrier of 19.2 kcal/mol, which is consistent with the experimental findings (Figure 2A, left). In order to explain the mode of interconversion, we located the transition state; this structure suggests the existence of a pentacoordinated silicon species, in which the Si atom simultaneously establishes two Si–O bonds with comparable lengths (2.22 and 2.16 Å). As a result, the silicon fragment and the two oxygen atoms of the IDPi’s sulfonyl groups arrange in space with a distorted-bipyramidal-trigonal geometry (Figure 2A, right).

Figure 2.

(A) Computational studies and (B) proposed mechanism.

Based on the accumulated experimental and computational results, a mechanism of IDPi-catalyzed DYKAT of racemic silane can be proposed (Figure 2B). First, the reaction sequence of protonation/C–Si bond cleavage of the silane enantiomers takes place, furnishing active silyl-catalyst species Cat-Si1 and Cat-Si2, which interconvert as a result of the silyl group migration between the two diastereotopic oxygen atoms in the active site of the catalyst. The S enantiomer of the product is then generated through nucleophilic attack on Cat-Si2 that is more favorable over the reaction of Cat-Si1.

In summary, we have developed an organocatalytic DYKAT of racemic allyl silanes using propofol as a nucleophile. A variety of functionalized silicon-stereogenic silyl ethers were constructed and readily derivatized to monohydrosilanes, potentially serving as general building blocks for chemical synthesis. Moreover, we elucidated a possible epimerization route triggered by the IDPi catalyst and supported a proposed mechanism by experimental and theoretical studies. By providing a general and direct transformation of racemic silanes into optically active Si-stereogenic compounds with high efficiency, this study paves a new avenue for organosilicon chemistry, which we believe will stimulate numerous applications in polymer and materials science, as well as in medicinal chemistry.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.3c00858.

• Experimental details and analytical data for all new compounds (PDF)

Author Contributions

H.Z. and R.P. contributed equally.

Open access funded by Max Planck Society.

The authors declare the following competing financial interest(s): a patent on the general catalyst class has been filed.