Constructing Tertiary Alcohols with Vicinal Stereocenters: Highly Diastereo- and Enantioselective Cyanosilylation of α-Branched Acyclic Ketones and Their Kinetic Resolution

Open AccessCCS ChemistryRESEARCH ARTICLE6 Jun 2022Constructing Tertiary Alcohols with Vicinal Stereocenters: Highly Diastereo- and Enantioselective Cyanosilylation of α-Branched Acyclic Ketones and Their Kinetic Resolution Wen-Biao Wu, Xin Yu, Jin-Sheng Yu, Xin Wang, Wen-Guang Wang and Jian Zhou Wen-Biao Wu Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, East China Normal University, Shanghai 200062 Google Scholar More articles by this author , Xin Yu School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100 Google Scholar More articles by this author , Jin-Sheng Yu Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, East China Normal University, Shanghai 200062 Google Scholar More articles by this author , Xin Wang *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] College of Chemistry, Sichuan University, Chengdu 610064 Google Scholar More articles by this author , Wen-Guang Wang *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100 Google Scholar More articles by this author and Jian Zhou *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, East China Normal University, Shanghai 200062 State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.021.202101030 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail We report the first highly diastereo- and enantioselective C–C bond-forming reaction of racemic α-branched ketones to construct tertiary alcohols with adjacent stereocenters. Accordingly, a highly stereoselective cyanosilylation of racemic ketones is developed using our bifunctional cyanating reagent, Me2(CH2Cl)SiCN, giving Cα-tetrasubstituted silyl cyanohydrins with two vicinal stereocenters in up to >20:1 diastereomeric ratio (dr) and 90–98% enantiomeric excess (ee) values, which can undergo various diversification reactions by manipulating the chloromethyl group. A highly selective kinetic resolution of acyclic α-branched ketones is also developed that allows facile access to acyclic α-alkyl, allyl, and propargyl ketones with good recovery and excellent ee values. The synthetic value of this protocol is further demonstrated by the formal synthesis of the anti-obesity agent, taranabant (MK-0364). The activation of Jacobsen’s privileged catalyst (salen)AlCl by a suitable phosphorane plays a crucial role in the reaction. X-ray crystallographic analysis of single crystals of phosphorane–(salen)AlCl complexes and theoretical calculations help provide a working model. The present transformation opens a new path for the catalytic stereoselective synthesis of stereochemically complex tertiary alcohols featuring two stereocenters (adjacent or not) from racemic ketones. Download figure Download PowerPoint Introduction Enantiopure tertiary alcohols with adjacent stereocenters are privileged structures in natural products, drugs, and pharmaceutically active compounds (Scheme 1a),1–4 and highly diastereo- and enantioselective assembly of such alcohols is key to future advances in many fields of medicinal research.5,6 However, despite significant progress in the catalytic enantioselective synthesis of tertiary alcohols, facile access to stereochemically complex tertiary alcohols with high structural diversity remains a long-standing goal. This is because the unfavorable steric hindrance and diminished steric dissimilarity of carbon substituents on prochiral carbons makes control of both diastereo- and enantioselectivity in the key catalytic C–C bond-forming step challenging. To date, the only general strategy to forge tertiary alcohols with vicinal stereocenters is the coupling of prochiral substrates with prochiral ketones (Scheme 1b, eq 1). By using this methodology, notable advances have been made in stereoselective reactions of prochiral substrates with ketones, including borylative coupling using allenes7 or alkenes,8 allylboration of γ,γ-disubstituted allylboronic acids9 or allyldiboronates,10 reductive coupling processes involving olefins,11,12 and aldol-type reactions of silyl ketene imines.13 However, this strategy cannot be used with nonprochiral nucleophiles to prepare tertiary alcohols with vicinal stereocenters. Therefore, we wanted to explore an alternative strategy of catalytic diastereo- and enantioselective addition of nucleophiles to racemic α-branched ketones because such ketones are often readily accessed as racemic mixtures (Scheme 1b, eq 2). Scheme 1 | (a–c) Synthesis of chiral tertiary alcohols featuring vicinal stereocenters. Download figure Download PowerPoint Two attractive features can be anticipated for this strategy. First, it allows the use of nonprochiral nucleophilic functionalities such as cyanide and acetylide to produce functional tertiary alcohols with vicinal stereocenters, which provides facile access to chiral tertiary alcohols bearing a synthetic handle for complexity-generating synthesis. Second, it offers the promise of accessing optically active α-branched ketones via kinetic resolution. Notably, catalytic enantioselective synthesis of acyclic α-branched aliphatic ketones is still undeveloped, although they are versatile building blocks in organic synthesis.14 The possibility of using a kinetic resolution strategy to recover highly enantioenriched ketones that are difficult to access by known methods is attractive.15–23,a However, despite these intriguing features, catalytic stereoselective synthesis of chiral tertiary alcohols with vicinal stereocenters from racemic α-branched ketones remains a challenge (Scheme 1b).24–26 This is possibly because the α-substituent on the ketone substrate can interfere with the recognition of the ketones by the catalyst, which hinders the reaction development. As supporting evidence, in contrast to the success of the synthesis of tertiary alcohols from achiral ketones,24–26 no successful catalytic asymmetric C–C bond-forming reactions of racemic α-branched ketones to construct vicinal stereocenters are available to date, apart from dynamic kinetic reductive amination27 and hydrogenation reactions.28–30 To accomplish the desired process, we speculated that the chiral catalyst should be flexible to overcome the influence of the α-substituent of the racemic ketones and recognize one enantiomer selectively to form a “matched” catalyst–ketone complex.31 This complex could then undergo the C–C bond-forming reaction substantially faster than the “mismatched” complex, thereby providing control of both diastereo- and enantioselectivity. Here, we demonstrate the feasibility of this strategy in a highly diastereo- and enantioselective ketone cyanosilylation to forge tertiary cyanohydrins with two vicinal stereocenters (Scheme 1c), enabled by a three-component catalyst system consisting of chiral (salen)AlCl, phosphorane, and hexamethylphosphoramide (HMPA). Enantioselective ketone cyanation is a very important C–C bond-forming process because it can be used to convert simple substrates into chiral tertiary cyanohydrins, valuable precursors to many chiral synthons such as tertiary α-hydroxy carbonyl compounds, diols, and β-amino alcohols.32–36 Although highly enantioselective protocols have been developed by the groups of Shibasaki,37–40 Hoveyda,41 Deng,42,43 Corey,44 Feng,45–48 Jacobsen49,50 and Ishihara,51,52 independently, reported protocols can be used to construct only one stereocenter from achiral ketones. While tertiary cyanohydrins with vicinal stereocenters are particularly useful synthons for complexity-generating syntheses, highly stereoselective cyanation of racemic ketones remains unexplored. This is because the small shielding effect of the cyanide source renders control of both diastereo- and enantioselectivity challenging. With our interest in the cyanation reactions, we have developed the first highly enantioselective cyanosilylation of aliphatic ketones53 by using a phosphorane to activate Jacobsen’s privileged (salen)AlCl complex.54–58 This method was later extended to the sequential synthesis of chiral tertiary alcohols with an α-chloromethyl acetyl group through cyanosilylation using the bifunctional reagent Me2(CH2Cl)SiCN ( 2) developed by us,59 which gave higher reactivity and enantioselectivity than that achieved with the widely used trimethylsilyl cyanide (TMSCN). Based on these results, we envisioned that by varying the substituents on the readily available phosphorane ligand, the chiral pocket of the phosphorane–(salen)AlCl complexes could be flexibly tuned, thereby facilitating the selective recognition of one enantiomer of racemic α-branched ketones to form the matched complex. Meanwhile, the use of a suitable Lewis basic co-catalyst that can interact with 2 would enhance the steric hindrance of the cyanating species and increase the diastereo- and enantioselectivity.60,61 With this hypothesis in mind, we selected acyclic α-allylated aliphatic ketone 1a to optimize the conditions for the cyanosilylation. This substrate not only allows the synthesis of allylated cyanohydrins but also offers the promise of accessing chiral α-allylated aliphatic ketone derivatives that are not attainable by using reported methods.62,b Experimental Methods General procedure for kinetic resolution of α-branched ketones and their catalytic asymmetric cyanosilylation To a 5 mL vial was added α-branched ketone (±)- 1 (0.5 mmol, 1.0 equiv), (R,R)- 3 (30.4 mg, 0.05 mmol, 10 mol %), and ylide 4b (15.9 mg, 0.05 mmol, 10 mol %), followed by the addition of anhydrous ClCH2CH2Cl (1.0 mL) and HMPA (45 μL, 0.25 mmol, 0.5 equiv), successively. The resulting mixture was cooled to −30 °C for 0.5 h, and Me2(CH2Cl)SiCN (41 μL, 0.30 mmol, or 38 μL, 0.28 mmol) was added. After being stirred at −30 °C for 4 days, the reaction mixture was rapidly passed through a short pad of silica gel and washed with ether. The obtained organic solution was concentrated in vacuo to give the crude product. To determine the conversion of the reaction, the crude residue was first dissolved in CDCl3 and analyzed by 1H NMR spectroscopy. Then the analysis sample and the remaining crude residue were recombined and purified by silica gel column chromatography using petroleum ether (PE)/Et2O (10∶1, v/v) as the eluent to afford the desired products. More experimental details and characterization are available in the Supporting Information. Results and Discussion Optimization of the reaction conditions We began by evaluating the performance of various phosphoranes 4 in (salen)AlCl (R,R)- 3-mediated cyanosilylation of (±)- 1a with Me2(CH2Cl)SiCN ( 2) in Et2O at −30 °C.59 As expected, in the absence of phosphorane co-catalyst, (salen)AlCl failed to mediate the reaction (Table 1, entry 1). Inclusion of a range of phosphoranes in the reaction revealed that their structure affected the reaction outcome significantly (entries 2–7). Phosphorane 4a, with the smallest shielding group, activated (salen)AlCl effectively to promote the reaction but afforded the major diastereomer of cyanohydrin 5a [diastereomeric ratio (dr) = 8.6:1] in only 50% enantiomeric excess (ee) (entry 2). When the hydrogen of 4a was replaced with an methyl group, the use of phosphorane 4b led to a clear improvement in the ee value of the major diastereomer (2S,3R)- 5a to 85% ee, albeit with a lower dr (entry 3 vs 2). Further changes to the substituent on the phosphorane to isopropyl, phenyl, or alkoxyl groups did not improve the result further. Nevertheless, studies of solvent effects revealed that when CH2Cl2 was used, (salen)AlCl/ 4b achieve a selectivity s-factor of up to 15, affording cyanohydrin (2S,3R)- 5a with 94% ee and 18:1 dr, with (S)- 1a being recovered with only 61% ee (entry 8). Table 1 | Optimization of Conditionsa Entry 4 Additive (0.5 mmol) Solvent Conv. (%)b 5a (S)- 1a s-Factorg Yield (%)c ee (%)d,e (syn/anti) drb Recovery (%)f ee (%)d 1 — — Et2O 0 — — — — 0 — 2 4a — Et2O 50 43 50/62 8.6∶1 41 24 2 3 4b — Et2O 52 43 85/89 6.3∶1 41 67 8 4 4c — Et2O 47 39 87/97 3.8∶1 42 24 2 5 4d — Et2O 26 20 74/75 5.1∶1 62 15 3 6 4e — Et2O 45 38 89/97 2.5∶1 43 33 3 7 4f — Et2O 45 39 94/>99 5.7∶1 43 47 6 8 4b — CH2Cl2 44 39 94/>99 18∶1 45 61 15 9 4b Ph3PO CH2Cl2 56 39 92/>99 10∶1 39 89 16 10 4b Et3N CH2Cl2 52 44 80/>99 15∶1 40 66 8 11 4b DMAP CH2Cl2 55 47 91/>99 12∶1 44 79 11 12 4b n-Bu3PO CH2Cl2 42 37 91/>99 15∶1 53 47 7 13 4b HMPA CH2Cl2 52 42 98/85 17∶1 42 87 26 14 4b HMPA DCE 50 40 98/>99 19∶1 43 83 28 15h 4b HMPA DCE 50 45 98/>99 18∶1 40 85 33 16h,i 4b HMPA DCE 52 43 97/>99 18∶1 42 90 33 Note: DMAP, 4-dimethylaminopyridine. aConditions: (±)- 1a (0.5 mmol), 2 (0.28 mmol), (R,R)- 3 (0.05 mmol), 4 (0.05 mmol), −30°C, 4 days. bDetermined by 1H NMR analysis of the crude reaction mixture. cIsolated yield based on (±)- 1a. dDetermined by chiral HPLC analysis. eThe syn/anti ratio refers to the ratio of (2S,3R)- 5a and (2R,3R)- 5a. fThe recovery of 1a. gs = ln[(1 − C)(1 − ee)]/ln[(1 − C)(1 + ee)], C refers to the conversion of (±)- 1a, and the ee refers to the ee values of recycled 1a. hHMPA (0.25 mmol). i 2 (0.30 mmol). To further improve the ee of the cyanohydrin (2S,3R)- 5a and the remaining ketone (S)- 1a, we next tried optimizing a Lewis base to interact with Me2(CH2Cl)SiCN ( 2) to form a bulkier nucleophilic species with enhanced steric hindrance,60,61 making it harder for the “mismatched” catalyst–ketone species to participate in the reaction. To our delight, the inclusion of 1.0 equiv of Lewis basic additives indeed increased the stereoselectivities of the cyanosilylation as well as the ee values of the recovered (S)- 1a (entries 9–13). Of the five typical Lewis bases evaluated, HMPA was the best. Its use improved the s-factor to 26, giving (2S,3R)- 5a in 98% ee and 17:1 dr, with 42% recovery and 87% ee of (S)- 1a (entry 13). Based on this result, further screening of a series of halogenated solvents revealed that the use of 1,2-dichloroethane (DCE) improved the s-factor to 28 (entry 14). Reducing the amount of HMPA to 50 mol % slightly improved the s-factor to 33, affording (2S,3R)- 5a in 98% ee and 18:1 dr (entry 15). To access α-allyl ketone 1a in excellent ee value, we adjusted the amount of cyanating reagent 2 and found that the use of 0.6 equiv of 2 relative to (±)- 1a furnished (S)- 1a in 42% recovery and 90% ee, and 5a in 43% yield, 97% ee, and 18:1 dr (entry 16). Evaluation of substrate scope The scope of diastereo- and enantioselective cyanosilylation was then evaluated under the optimal reaction conditions: DCE at −30 °C, 0.56 equiv 2 relative to the racemic ketone, the combination of (R,R)- 3 and phosphorane 4b (10 mol %, each) catalysts, and 50 mol % HMPA (Scheme 2). The reported yield was based on the amount of ketone 1. As shown in Scheme 2, α-allylated ketones 1a– 1o, bearing a range of substituted phenyls, naphthyls, or heteroaryls at the α-position, all worked well to give the desired cyanohydrins 5a– 5o in good to high isolated yield and dr value, as well as 91–98% ee. α-Prenyl, cinnamyl, propargyl, methyl, ethyl, benzyl, isopropyl, and CH2CO2Et-substituted ketones 1p– 1w also afforded the corresponding adducts 5p– 5w in 8∶1 to >20∶1 dr and 90–98% ee. The ethyl ketone 1x furnished the corresponding adduct 5x in 15∶1 dr and 80% ee. To our delight, α,α-diaryl and dialkyl ketones were also viable substrates for the cyanosilylation, giving the desired adducts 5y and 5z in 90% ee and 95% ee, respectively, albeit with moderate dr values. The α-quaternary allylated ketone 1zb also worked under the standard condition, giving silyl cyanohydrin 5zb with adjacent quaternary-tetrasubstituted stereogenic centers in 85% ee, but with poor dr value. These results clearly show the potential of α-branched ketones for the facile synthesis of chiral tertiary alcohols with vicinal tertiary (quaternary)-tetrasubstituted stereocenters, which has been a largely unexplored field of research.7–13 Scheme 2 | Scope of the asymmetric cyanosilylation and kinetic resolution. Reaction conditions: (±)-1 (0.5 mmol), 2 (0.28 or 0.30 mmol), (R,R)-3 (0.05 mmol), 4b (0.05 mmol), HMPA (0.25 mmol), DCE (1.0 mL), stirred at −30°C for 4 days. For the asymmetric cyanosilylation 0.28 mmol of 2 was used, and 0.30 mmol was used in kinetic resolution. aThe ee values were determined by chiral HPLC analysis. bThe isolated yield of cyanohydrins was calculated based on (±)-1. cs = ln[(1 − C)(1 − ee)]/ln[(1 − C)(1 + ee)], C refers to the conversion of (±)-1, determined by 1H NMR analysis of the crude reaction mixture, and the ee refers to the ee values of recycled 1. dAt −10 °C. eAt −50 °C, using CH2Cl2 as solvent. Download figure Download PowerPoint The substrate scope of the kinetic resolution of racemic α-branched ketones was also investigated under similar conditions, with an increased amount of 2 from 0.56 to 0.60 equiv, to improve the enantioselectivity of the recovered ketone. Considering there are no effective methods to access chiral acyclic α-allylated aliphatic ketones, α-allylated methyl ketones (±)- 1a– 1o with a range of substituted α-phenyl groups were tested. The corresponding (S)- 1a– 1o could be isolated with 38–45% recovery, and 82–96% ee. The nature and position of the substituents on the α-phenyl group had no clear influence on the outcome of the reaction. Electron-donating methyl or methoxy groups or electron-withdrawing halogen atoms or trifluoromethyl groups were all tolerated. With a 1- or 2-naphthyl, 2-thienyl, or 2-furyl group, the corresponding ketones (S)- 1l– 1o were obtained in 90–96% ee. α-Prenyl, cinnamyl, or propargyl substituted ketones (S)- 1p– 1r were also afforded with excellent ee values. Moreover, α-aryl ketones (S)- 1s– 1u, bearing an α-methyl, ethyl, or benzyl group, were readily recovered with 90–92% ee. Unfortunately, α-isopropyl or CH2CO2Et-substituted ketones (S)- 1v and (S)- 1w were obtained in only 20% and 55% ee, respectively. Ethyl ketone 1x could be recovered with high ee values. Thus, this method can be applied to access a broad range of α-aryl α-alkyl methyl ketones with excellent ee values; however, many challenging cases were identified. The method is inefficient for accessing α,α-diaryl or α,α-dialkyl ketones, as evidenced by the kinetic resolution of 1y and 1z with poor selectivity. Attempts to resolve α-quaternary ketone 1zb were also unsuccessful. The failure to resolve ketones 1v, 1y, 1z, and 1zb may be due to the similar steric hindrance of the substituents on the α position, making it difficult for the chiral catalyst to selectively recognize one enantiomer of the corresponding racemic ketones. The formation of a “matched” catalyst-substrate complex that can undergo the cyanosilylation much faster than the “mismatched” complex is crucial for the enantioenrichment of the remaining enantiomer of the substrates.c To investigate the possibility of extending the methodology further, the cyanosilylation of β-allylated ketone 6 was also attempted, affording cyanohydrin 7 in 39% yield, 11∶1 dr and 90% ee, with (S)- 6 being recovered in 70% ee (Scheme 3a). This result demonstrated that it is possible to use racemic β-substituted ketones for the highly diastereo- and enantioselective synthesis of tertiary alcohols with nonadjacent stereocenters. Scheme 3 | (a and b) Kinetic resolution of β-allylated ketone and comparison of Me2(CH2Cl)SiCN with TMSCN. Download figure Download PowerPoint It should be noted that the nature of our bifunctional cyanating reagent, Me2(CH2Cl)SiCN, had a significant impact on the outcome of the reaction. As shown in Scheme 3b, under the same reaction conditions, the utilization of Me2(CH2Cl)SiCN allowed (S)- 1a to be obtained with 40% recovery and 85% ee, with the simultaneous synthesis of cyanohydrin 5a in 45% yield, 18:1 dr and 98% ee. In sharp contrast, when TMSCN was used as the cyanating reagent, (S)- 1a was recovered in only 46% ee, and 8 was synthesized with a diminished 5.6:1 dr and 93% ee. This result is consistent with our previous observations59 and suggests wide range of potential applications of Me2(CH2Cl)SiCN for the development of catalytic enantioselective cyanation reactions. Gram-scale synthesis and synthetic utility To demonstrate the practical application of our method, the kinetic resolution of 13 mmol of (±)- 1a was conducted, using 5.0 mol % of the catalyst combination under standard conditions, giving 1.02 g of (S)- 1a in 45% recovery and 92% ee and 1.77 g of cyanohydrin 5a in 44% yield, 17∶1 dr, and 97% ee (Scheme 4a). This result confirms that the method can be readily scaled up for preparative use. Scheme 4 | (a–d) Gram-scale synthesis and synthetic utility. Download figure Download PowerPoint The resulting chloromethylsilyl cyanohydrins are valuable synthons for complexity-generating synthesis (Scheme 4b). For example, reacting 5a with lithium diisopropylamide (LDA) resulted in a 1,5-transfer of the chloromethyl group and, following hydrolysis, tertiary alcohol 9, bearing a chloromethyl acetyl group, was obtained. Notably, two new reactions centered on the chloromethylsilyl group were observed. Reduction of 5a by diisobutylaluminum hydride (DIBAL-H) gave aldehyde 10, the chloromethyl group of which could react with the formyl group to afford tertiary alcohol 11, bearing an α-acetyl group. Alternatively, the chloromethylsilyl group could serve as an electrophile. The one-pot reduction of the cyano group of 5a with LiAlH4 followed by sulfonamide formation led to the generation of cyclic silane 12, possibly through a 1,6-intramolecular nucleophilic substitution step. Subsequent desiliconization afforded N-methyl sulfonamide 13 without erosion of ee. The relative and absolute configuration of 13 was confirmed by X-ray crystallography, and that of 5a was then assigned to be 2S,3R. The α-allylated ketones obtained are multifunctional chiral building blocks of high synthetic value (Scheme 4c). For example, the diastereoselective reduction of (S)- 1a with L-selectride gave the desired alcohol 14 in 80% yield, >20∶1 dr, and 95% ee, which could undergo cyclization upon treatment with N-bromosuccinimide (NBS) to furnish cis-2,3,5-trisubstituted tetrahydrofuran 15, with a 5-bromomethyl group, in 72% yield. A further substitution with NaN3, followed by reduction and protection, afforded compound 16 in 68% yield over three steps. The relative and absolute configuration of 16 was assigned by X-ray analysis, while those of 14 and 15 were determined by analogy. Accordingly, the absolute configuration of recovered α-branched ketone 1a was assigned to be S. The value of this kinetic resolution was further demonstrated in the formal synthesis of taranabant (MK-0364), an anti-obesity agent developed by Merck63,64 (Scheme 4d). A convenient synthesis for routine laboratory use was developed by Lee et al.65 involving a chiral auxiliary-based synthesis of (S)- 17. Our method avoided extra steps for introducing and removing the chiral auxiliary while suppressing racemization of the chiral ketone, as shown by a 2.0 mmol scale resolution to afford (S)- 17 in 90% ee and 48% recovery, with a high s-factor of 58. Mechanistic studies The activation of chiral (salen)AlCl complex by a phosphorane plays a key role in determining the outcome of the reaction. As shown in entries 1–7 of Table 1, without the assistance of the phosphorane co-catalyst, no reaction took place, and the size of the substituent on the phosphoranes had a clear influence on both the diastereo- and enantioselectivity. Our understanding of the asymmetric induction of this cyanosilylation advanced considerably when tetraphenylborate counter anion was used to stabilize the complex; this allowed single crystals of the [phosphorane–(salen)Al] complex 18 to be obtained, which were suitable for X-ray diffraction analysis. Based on this crystal structure analysis, complex 18 is derived from equal molecular amounts of (R,R)- 3 and phosphorane 4b, exhibiting an octahedral geometry with a six-coordinate Al atom, in which a tetrahydrofuran molecule is bound to the metal center below the equatorial plane (Scheme 5a). The phosphorane bound to the aluminum center in an O-coordination fashion, which shows the O atom of phosphorane oriented cis to the P atom. This orientation permits more conformational communication between the substituents of the salen ligand and those of the axial phosphorane ligand. This supported our hypothesis that the coordination of phosphorane 4 to (salen)AlCl (R,R)- 3 could adjust the chiral pocket of the catalyst, probably due to steric repulsion between the substituents of the phosphorane and that of the chiral skeleton. Notably, although previous studies from this lab had found that the binding of a phosphorane to Jacobsen’s catalysts, (salen)MX, could lead to complexes with enhanced catalytic properties,66,67 the structures of such phosphorane–salen metal complexes, which were based solely on information obtained by NMR and high-resolution mass spectrometry (HRMS) analysis, remained unclear. Considering the intriguing catalytic properties of chiral (salen)AlCl and (salen)TiCl2 complexes activated by a suitable phosphorane ligand in asymmetric cyanation reactions, we hope the understanding of the structure of such phosphorane–salen metal complexes will be helpful for developing chiral or achiral phosphorous ylide ligand-derived chiral metal complexes for asymmetric catalysis, which is a field in its infancy.68 Scheme 5 | (a–c) X-ray crystal structures of the [phosphorane–(salen)Al] complex and DFT calculations. Download figure Download PowerPoint Additionally, the Lewis basic additive HMPA was also used to improve the stereoselectivity. NMR analysis revealed that the interaction of HMPA and Me2(CH2Cl)SiCN ( 2) might produce a bulky nucleophilic species, HMPA(SiMe2CH2Cl)(N=C:), similar to Corey’s proposal that binding of TMSCN by Ph3PO led a more reactive isocyanide species Ph3P(OTMS)(N=C:).61 For details of NMR analysis, see Section 5 of Supporting Information. Finally, density functional theory (DFT) calculations cast some light on the diastereo- and enantioselective cyanosilylation of α-branched ketones. The optimized structures of “matched” and “mismatched” transition-state (TS) models are shown in Schemes 5b and 5c. The R-enantiomer of ketone 1u bound to chiral catalyst 4b/(R,R)- 3 forms the “matched” TS, TS-(2 S ,3 R ), in which the catalyst backbone and two α-substituents shield the Si face of the ketone carbonyl group well, and thus the attack of HMPA(SiMe2CH2Cl)(N=C:) takes place preferentially from the Re-face to form adduct (2S,3R)- 5u. In the orientation of “mismatched” TS-(2 S ,3 S ) resulting from the binding of the S-enantiomer of 1u to catalyst 4b/(R,R)- 3, the α-benzyl and phenyl substituents of the ketone are placed on the Si and Re face of the plane, respectively, which retards attack of the nucleophilic species from the Re-face. The calculated Gibbs free energy gap between TS-(2 S ,3 S ) and TS-(2 S ,3 R ) is 2.0 kcal·mol–1. This result is consistent with the observation that the R-enantiomer of ketone 1u was consumed first in the cyanosilylation, allowing (S)- 1u to be enantioenriched and recovered in the kinetic resolution. Conclusion We have developed the first highly diastereo- and enantioselective cyanosilylation of α-branched ketones, which opens a new route to the synthesis of chiral tertiary alcohols of adjacent or nonadjacent stereocenters: namely, the catalytic enantioselective addition of nucleophiles to racemic ketones. Concurrently, the unprecedented highly enantioselective kinetic resolution of α-branched acyclic ketones has also been developed, thereby providing facile access to α-aryl α-aliphatic ketones that are difficult to access by other methods. Our bifunctional cyanating reagent Me2(CH2Cl)SiCN has been shown to be superior to