Toward Asymmetric Synthesis of Pentaorganosilicates

Introducing chiral silicon centers was explored for the asymmetric Rh-catalyzed cyclization of dihydrosilanes to enantiomerically enriched spirosilanes as targets to enable access to enantiostable pentacoordinate silicates. The steric rigidity required in such systems demands the presence of two naphthyl or benzo[b]thiophene groups. The synthetic approach to the expanded spirosilanes extends Takai’s method (Kuninobu et al. in Angew Chem Int Ed 52(5):1520–1522, 2013) for the synthesis of spirosilabifluorenes in which both a Si–H and a C–H bond of a dihydrosilane are activated by a rhodium catalyst. The expanded dihydrosilanes were obtained from halogenated aromatic precursors. Their asymmetric cyclization to the spirosilanes were conducted with [Rh(cod)Cl]2 in the presence of the chiral bidentate phosphane ligands (R)-BINAP, (R)-MeO-BIPHEP, and (R)-SEGPHOS, including derivatives with P-(3,5-t-Bu-4-MeO)-phenyl (DTBM) groups. The highest enantiomeric excess of 84% was obtained for 11,11′-spirobi[benzo[b]-naphtho[2,1-d]silole] with the DTBM-SEGPHOS ligand.


Introduction
Chirality is a cornerstone in chemistry, crucial to live, and increasingly important to materials science. The synthesis of chiral organic molecules has become commonplace [1]. Simple examples of the numerous ones available are Knowles's synthesis of l-DOPA and Sharpless' asymmetric epoxidation resulting in compounds of high enantiomeric excess (ee) [2,3]. Common approaches to introduce chirality are nucleophilic substitution of pro-chiral systems and asymmetric catalysis [4]. Once a chiral carbon center is formed, it retains its chirality in the absence of competing associative/ dissociative reactions.
In strong contrast to compounds having chiral carbon centers, those with a chiral silicon center are not found in nature. Kipping reported the first optically active silicon compounds early in the previous century [5], and the first examples of chiral resolution on a practical scale were presented much later [6]. Extensive pioneering work on stereospecific reactions towards chiral silicon compounds was done by the group of Sommer [7]. During the same period, Corriu and coworkers laid the foundation of much that we know today about stereoselectivity in substitution reactions on silicon [8]. It is evident that chiral silicon compounds can only be acquired synthetically, some of the more recent methods towards these compounds are excellently reviewed elsewhere [9][10][11].
Chirality in tetracoordinate silicon derivatives has become a topic of recent interest and is driven by asymmetric catalysis using rhodium complexes carrying chiral diphosphane or diene ligands [12]. Examples include chiral silicon-ferrocenes by enantioselective activation of C-H bonds, enantioselective 1,4-silicon shifts from aryl to alkyl groups, and the chiral silylation using iridium complexes [13][14][15]. Here, we describe our synthetic approach toward chiral silanes for which we have a need in our program on chiral pentacoordinate silicon compounds.
Dedicated to the memory of George A. Olah.
It is important to recognize that the synthesis of enantiostable tetracoordinate silicon compounds is inherently more challenging than their carbon counterparts due to the tendency to form pentacoordinate intermediates or products, which readily undergo racemization [16]. The bigger atomic radius of silicon stabilizes such species, termed silicates, whereas the pentacoordinate carbon ones are instead transition structures [17]. Before proceeding with our synthesis on tetracoordinate silicon compounds, it is relevant to highlight the potential involvement and characteristics of silicates.
Pentacoordinate Si-intermediates are well documented for S N 2 reactions. Racemization at the Si-center occurs readily via Berry pseudorotations (BPR), [18][19][20] causing isomerization between different trigonal bipyramid conformations via a low energy square pyramidal transition state. This change of geometry underlies the racemization process and can only be inhibited by increasing the barriers for isomerization. Recently, Strohman's group provided such an example of selective inhibition for an S N 2-type substitution at a prochiral silicon center [21]. They were able to obtain a chiral compound by selectively hampering one of the BPRs of the five coordinate Si-intermediate.
Earlier, we have shown computationally how to impede Berry pseudorotations to obtain chiral, enantiostable pentaorganosilicate salts and presented a synthetic method to accomplish this [22]. Silicate anions with five carbon substituents are usually short-lived species, observable only by mass spectrometry or low temperature NMR, but their stabilization increases substantially when four of the five Si-C bonds are formed by two bidentate ligands, such as biphenyls [23][24][25]. Such stable pentaorganosilicates, but with larger aromatic ligands, prevent formation of a square pyramidal conformation, thus hampering the BPR and preventing racemization. NMR spectroscopy revealed for ethyl,bis([2] naphthylpyrrol)silicate ( Fig. 1) a BPR barrier of over 21 kcal mol − 1 and showed two diastereotopic ethylene hydrogens [22]. However, demonstrating unequivocally the inhibition of BPRs also demands an enantiomerically pure silicate to be isolable. It is in this context that we pursue the synthesis of chiral silanes, because these are the starting point to generate silicates. Therefore, we seek an enantioselective synthetic approach to symmetrical spirosilanes with large aromatic groups.
Conventionally, spirosilanes are obtained from the reaction of SiCl 4 with a dilithiated biaryl system generated from its dihalide (Scheme 1) [22]. Obtaining the chiral products than requires separation into the enantiomers by, e.g., chiral HPLC [23]. We envisioned that it might be advantageous to explore an enantioselective synthesis. Our approach is based on recent work by Takai and coworkers, who (a) reported on the synthesis of 9H-9sila-fluorenes using a rhodium catalyst for Si-H and C-H bond activation [26] and (b) showed that spirosilanes could be obtained in high enantiomeric excess from dihydrosilanes on using a Rh-catalyst with a chiral (R)-BINAP diphosphane ligand (Scheme 2) [27]. The mechanism proposed for the reaction involves sequential oxidative additions of the Rh-catalyst at an aromatic C-H bond and a Si-H bond, followed by H 2 -elimination and reductive elimination to a monohydrosilane, which undergoes the same catalytic cycle to give the spirosilane [28].
We sought to expand the scope of the chiral synthesis by using sterically more demanding substituents than  . Such systems would ideally confirm the ability to control the chirality of silicates and potentially reduce racemization of chiral silanes by the contaminating presences of silicates. At the same time, we realized that the increased steric bulk might affect the cyclization reaction unfavorably. Derivatives of the larger aromatic substituents 2-phenylnaphthalene and 2-phenylbenzo[b]thiophene that were examined in this study are shown in Scheme 4. The selection of the two aromatic cores (naphthalene and benzo[b] thiophene) was derived from silicates that have been shown to be configurationally rigid. Double ring closure of dihydrosilanes 3a with two 2-phenylnaphthyl groups and 3c with two 2-phenylbenzothio[b]thiophenyl groups will result into the two targeted spirosilanes. Additional t-butyl groups increase the sterics of 3d. Dihydrosilanes 3b and 3e were selected to resemble more the noted examples where the silicon atom is substituted on the phenyl ring. The methoxy-group on 3b would also hinder unwanted reactions of the rhodium catalyst with the 3-CH bond of the naphthalene ring.

Results and Discussion
To explore the increased size of the substituents on the synthesis of dihydrosilanes and the subsequent enantioselective cyclization to spirosilanes by using the procedure of Takai and coworkers [23], we felt it important to be able to reproduce their result as benchmark.
The synthesis of the dihydrosilanes with larger aromatic groups proved to be more difficult than those with the biphenyl groups and could only be accomplished by introducing a silyl group on the larger rings, i.e., the naphthalene and benzo[b]thiophene groups. The most productive synthetic approach was to lithiate the bromo precursors with either t-BuLi or iPr-MgCl·LiCl, followed by treatment with SiCl 4 to obtain the dichlorosilane and treatment with LiAlH 4 to form the dihydrosilanes, which could only be obtained in poor yields. Illustrative is the synthesis of silane 3a from 1-bromo-2-phenylnapthalene with a yield of only 4% with trihydrosilane 6 as major isolated product in 33% yield (Scheme 5). Evidently, steric congestion plays a significant role and hampers the second nucleophilic addition at SiCl 4 . The naphthyl crowding effect is even more pronounced on introducing a silyl group at the phenyl group, as in 3b, which we were unable to obtain.
For 2-phenylbenzo[b]thiophene the synthetic access proved to be more favorable than for 2-phenylnaphthalene. (Scheme 6). Thus, 3c could be prepared in 53% yield by reacting the Grignard reagent of bromide 7c with subsequently HSiCl 3 and LiAlH 4 . The product showed the expected Si-H interaction using 1 H-NMR spectroscopy. Steric factors do have an influence on the accessibility of the benzo-[b]thiophene group, which became evident  In contrast to 2-phenylnaphthalene access silylation of the phenyl substituent ring of 2-phenylbenzo[b]thiophene (8) proved feasible, giving 3e, be it in only 8% of impure material, besides trihydrosilane 9 as major product (Scheme 7). This again illustrates that steric congestion hampers the second nucleophilic addition at silicon.

Asymmetric Catalysis
To assess the rhodium catalyzed asymmetric synthesis of dihydrosilanes, we re-examined the intramolecular cyclization of dihydrosilane 1a using (R)-BINAP and [Rh(cod)Cl] 2 to obtain the 2,2′-dimethoxy-9,9′-spiro-9-silabifluorene 2a in 84% yield and 79% ee (Table 1), which is in excellent agreement with the reported 81% ee. We note that lower ee's were obtained if the reaction was not executed under inert conditions and degassed solvents.
The intramolecular double cyclization of the bulkier dihydrosilanes 3a and 3c using (R)-BINAP and [Rh(cod) Cl] 2 yielded the corresponding spirosilanes 4a (< 10%) and 4c (8.1%) in 52 and 54% ee, respectively. Whereas we had expected higher ee's, anticipating that steric congesting would positively influence the distinction between the formation of both enantiomers [29], the ee's were, in fact,  lower than that obtained for 2a. This effect must be due to the larger ring substituents, which apparently reduces the enantioselectivity. Also the fact that minor impurities were obtained, which could be removed by washing with n-pentane to significantly reduce the yields (e.g., to 8.1% for 4c), is also indicative for the steric sensitivity for cyclization. In searching to improve the enantioselectivity, we explored other chiral ligands for the Rh-catalyzed bicyclization of 3c (Table 1). Formation of spirosilane 4c from 3c using the chiral methoxy-phenyl ligand MeO-BIPHEP and the bulkier 3,5-t-Bu-4-MeO-MeO-BIPHEP gave still lower ee's of 45% and even 13%, respectively. Apparently, the bulkier phenyl rings around the coordinating phosphorus ligand reduce the enantioselectivity of the reaction. It is than most intriguing that we found a much higher ee of 84% on using the quite large DTBM-SEGPHOS ligand, albeit with an expected lower yield of 31%. Clearly, with this bulky chiral ligand the transfer of chirality is effectively transferred in the Rh-catalyzed cyclization reaction. On removing the tBu and OMe substituents of the ligand's two P-phenyl groups, i.e., SEGPHOS, the steric bulk of the ligand reduces and so does the ee to 27%, while also reducing the yield (to 24%) Evidently, the bidentate ligand systems BIPHEP and SEG-PHOS have significant effects on the enantioselective cyclization, whereas they merely differ in carrying OMe versus 1,3-dioxole groups.

Conclusion
This research has expanded the scope of the asymmetric Rh-catalyzed cyclization of dihydrosilanes to spirosilanes with more bulky ring systems. The successful synthesis of the naphthalene and benzo[b]thiophene dihydrosilanes 3a and 3c and their conversion to the corresponding spirosilanes 4a and 4c showed that the Rh-catalyzed cyclization can introduce modest to high enantioselectivity. The P-ligand systems that were used in the investigation range from (R)-BINAP to (R)-MeO-BIPHEP to (R)-SEGPHOS and include P-phenyl and P-(3,5-t-Bu-4-MeO)-phenyl groups. The highest ee of 84% was obtained for the formation of 4c on using the Rh-ligand DTBM-SEGPHOS, with a modest yield of 31%. This finding shows that congested spirosilanes can be synthesized with modest to high enantioselectivity, which bodes well for the direct synthesis of enantiostable silicates. Our survey also reveals limitations such as the synthetic access of the required dihydrosilane precursors where the increased steric congestion has a debilitating effect, inhibiting the second nucleophilic substitution at silicon, thereby rendering trihydrosilanes; formation of byproducts also hampers product purification.

Experimental Section
General All reagents were bought from Sigma-Aldrich and used as received unless specified otherwise. Pyridine was dried using activated molecular sieves (3 Å). Tetrahydrofuran (THF) was distilled subsequently from LiAlH 4 and sodium/potassium alloy and diethyl ether from sodium/potassium alloy. n-Butyllithium was purchased as 1.6 M solutions in hexanes. Tetrachlorosilane was distilled and refluxed before use to remove HCl. Syntheses were performed using standard Schlenk techniques. NMR spectra were recorded on a Bruker Avance 400 ( 1 H, 13 C, 29 Si, 2D spectra). NMR chemical shifts are internally referenced to the solvent for 1 H (CHCl 3 : 7.26, THF: 3.58, CH 2 Cl 2 : 5.32) and 13 C (CHCl 3 : 77.16, THF: 67.58, CH 2 Cl 2 : 53.84), and externally for 29 Si to TMS. Melting points were measured on samples in sealed capillaries and are uncorrected. HR-ESI-MS measurements of silicates were measured on a Varian IonSpec FT-ICR mass spectrometer, for LR-MS a Bruker micrOTF system was used. Separation of enantiomers was performed on a Chiralpak IA column.