Enantioselective cyanosilylation

For other catalytic asymmetric cyanosilylation of aldehydes, see C.-D. Hwang, D.-R, Hwang, B.-J. Uang, Enantioselective Addition of Trimethylsilyl Cyanide to Aldehydes Induced by a New Chiral TiflV) Complex, J. Org Chem 1998,63,6762-6763, and references tited therein. 

Corey reported a catalytic enantioselective cyanosilylation of methyl ketones using combination of a chiral oxazaborolidinium and an achiral phosphine oxide, [Eq. (13.23)]. An intermolecular dual activation of a substrate by boron and TMSCN by the achiral phosphine oxide (MePh2PO) is proposed as a transition-state model (54). The same catalyst was also used for cyanosilylation of aldehydes ... 

The cross-linked dendritic BINOLate p-71 (20mol%) was also used as a supported catalyst in the asymmetric cyanosilylation of pivalaldehyde in CH2CI2. The catalyst was reused several times after separation from the reaction mixture by filtration. In 20 consecutive reactions, the cyanohydrine product was formed in >90% yield. Initially, an increase in enantioselectivity was observed from 72%... 

The computations suggested that the enantioselectivity of the cyanosilylation arose from direct interactions between the ketone substrate and the amino-acid derived unit of the catalyst type represented by thiourea 72. On the basis of this insight, the Jacobsen group designed thiourea catalysts 73 and dipepetide thiourea catalyst 74 [67]. These optimized catalysts gave access to a broader spectrum of silylated cyanohydrins (e.g., 1-6) and proved to be more active (88-97% yield) and more enantioselective (98-98% ee) than 72 (Scheme 6.85) [242]. 

Systematic investigations of the catalyst structure-enantioselectivity profile in the Mannich reaction [72] led to significantly simplified thiourea catalyst 76 lacking both the Schiff base unit and the chiral diaminocyclohexane backbone (figure 6.14 Scheme 6.88). Yet, catalyst 76 displayed comparable catalytic activity (99% conv.) and enantioselectivity (94% ee) to the Schiff base catalyst 48 in the asymmetric Mannich reaction of N-Boc-protected aldimines (Schemes 6.49 and 6.88) [245]. This confirmed the enantioinductive function of the amino acid-thiourea side chain unit, which also appeared responsible for high enantioselectivities obtained with catalysts 72, 73, and 74, respectively, in the cyanosilylation of ketones (Schemes 6.84 and 6.85) [240, 242]. 

Our proposed transition state model for this catalytic enantioselective cyanosilylation of ketone is shown as 35.30a The titanium acts as a Lewis acid to activate the substrate ketone, while the phosphine oxide acts as a Lewis base to activate TMSCN. The intramolecular transfer of the activated cyanide to the activated ketone should give the ( )-cyanohydrin in high selectivity. The successful results described above clearly demonstrate the practicality of our asymmetric catalyst for cyanosilylation of ketones. 

Deng et al. later found that dimeric cinchona alkaloids such as (DHQ AQN (8, Scheme 6.6) and (DHQD PHAL (9, Scheme 6.7) - both well known as ligands in the Sharpless asymmetric dihydroxylation and commercially available - also catalyze the highly enantioselective cyanosilylation of acetal ketones with TMSCN... 

Cyanosilylation of methyl ketones has been carried out using diphenylmethylphos-phine oxide and trimethylsilyl cyanide, generating a phosphorus isonitrile-type species, Ph2MeP(OTMS)(N=C ), as the reactive intermediate.271 A chiral oxazaborolidinium ion catalyst renders the reaction enantioselective. 

Stereoselective formation of carbon carbon and carbon heteroatom bonds remains an important goal in synthetic chemistry. Very recently lanthanide alkoxides were successfully utilized in enantioselective C-C bond forming reactions. Catalysis of aldol, cyanosilylation, nitroaldol and Michael reactions has been ascribed to the basic character of lanthanide alkoxides [158, 250, 251]. Ln3(OfBu)9 was successfully employed in test runs and subsequently optically active bidentate ligands were used (Fig. 35) [250a]. 

Activation of Me3SiCN by coordination of the Si to lithium BINOL-ate as catalyst has been shown to result in the enantioselective formation of cyanohydrins 73 from aromatic and heteroaromatic aldehydes with 82-98% ee (Scheme 7.15) [71]. (For experimental details see Chapter 14.5.4). Several other groups have used dual activation with a chiral Lewis acid and a non-chiral Lewis base [72]. Asymmetric cyanosilylation of PhCOMe and its congeners has also been reported to occur in the presence of sodium phenyl glycinate as catalyst, with up to 94% ee [73],... 

Asymmetric cyanosilylation of ketones and aldehydes is important because the cyanohydrin product can be easily converted into optically active aminoalcohols by reduction. Moberg, Haswell and coworkers reported on a microflow version of the catalytic cyanosilylation of aldehydes using Pybox [5]/lanthanoid triflates as the catalyst for chiral induction. A T-shaped borosilicate microreactor with channel dimensions of 100 pm X 50 pm was used in this study [6]. Electroosmotic flow (EOF) was employed to pump an acetonitrile solution of phenyl-Pybox, LnCl3 and benzal-dehyde (reservoir A) and an acetonitrile solution of TMSCN (reservoir B). LuC13-catalyzed microflow reactions gave similar enantioselectivity to that observed in analogous batch reactions. However, lower enantioselectivity was observed for the YbCl3-catalyzed microflow reactions than that observed for the batch reaction (Scheme 4.5). It is possible that the oxophilic Yb binds to the silicon oxide surface of the channels. 

Lanthanide Lewis acids catalyze many of the reactions catalyzed by other Lewis acids, for example, the Mukaiyama-aldol reaction [14], Diels-Alder reactions [15], epoxide opening by TMSCN and thiols [14,10], and the cyanosilylation of aldehydes and ketones [17]. For most of these reactions, however, lanthanide Lewis acids have no advantages over other Lewis acids. The enantioselective hetero Diels-Alder reactions reported by Danishefsky et al. exploited one of the characteristic properties of lanthanides—mild Lewis acidity. This mildness enables the use of substrates unstable to common Lewis acids, for example Danishefsky s diene. It was recently reported by Shull and Koreeda that Eu(fod)3 catalyzed the allylic 1,3-transposition of methoxyace-tates (Table 7) [18]. This rearrangement did not proceed with acetates or benzoates, and seemed selective to a-alkoxyacetates. This suggested that the methoxy group could act as an additional coordination site for the Eu catalyst, and that this stabilized the complex of the Eu catalyst and the ester. The reaction proceeded even when the substrate contained an alkynyl group (entry 7), or when proximal alkenyl carbons of the allylic acetate were fully substituted (entries 10, 11 and 13). In these cases, the Pd(II) catalyzed allylic 1,3-transposition of allylic acetates was not efficient. 

Finally, carbohydrate ligands of enantioselective catalysts have been described for a limited number of reactions. Bis-phosphites of carbohydrates have been reported as ligands of efficient catalysts in enantioselective hydrogenations [182] and hydrocyanations [183], and a bifunctional dihydroglucal-based catalyst was recently found to effect asymmetric cyanosilylations of ketones [184]. Carbohydrate-derived titanocenes have been used in the enantioselective catalysis of reactions of diethyl zinc with carbonyl compounds [113]. Oxazolinones of amino sugars have been shown to be efficient catalysts in enantioselective palladium(0)-catalyzed allylation reactions of C-nucleophiles [185]. 

Table 9. Enantioselective cyanosilylation of ketones using bifunctional catalyst 56...

Soon after, the same research group found that dimeric cinchona alkaloids such as (DHQ)2AQN (125) and (DHQD)2PHAL (33) can also be used as highly enantioselective organic Lewis base catalysts for the cyanosilylation of acetal ketones (131,... 

Inoue et al. reported that a complex prepared from AlMes and peptide Schiff base 166 is available for asymmetric cyanosilylation of aldehydes (Scheme 10.239) [630]. The enantioselectivity observed is not as high, even with a stoichiometric amount of the complex (up to 71% ee). A more recent study by Snapper and Hoveyda has, however, revealed that a similar catalyst system using Al(()t-Pr) ), and peptide Schiff base 167 is quite effective in catalytic asymmetric cyanosilylation of both aromatic and aliphatic ketones (66->98%, 80-95% ee wifh 10-20 mol% of fhe catalyst) [631]. 

In the presence of 168 a (9mol%) and a phosphine oxide (Bu),P(O) and Ph2P(O)Me for aromatic and ahphatic aldehydes, respectively, 36 mol%), slow addition of TMSCN achieves excellent enantioselectivity with a wide range of aldehydes (86-100%, 83-98% ee). The Al complex has been proposed to work as a bifunctional catalyst for dual activation of the two reactants - the Lewis acidic Al center enhances the electrophilicity of aldehydes and the Lewis basic phosphine oxide induces cyanide addition by nucleophihc activation (Scheme 10.240). This catalytic asymmetric cyanosilylation has been used for the total synthesis of epothilones [652]. 

The Lewis acid-Lewis base bifunctional catalyst 178a, prepared from Ti(Oi-Pr)4 and diol 174 (1 1), realizes highly enantioselective cyanosilylation of a variety of ketones to (R)-cyanohydrin TMS ethers (Scheme 10.241) [645]. The proposed mechanism involves Ti monocyanide complex 178b as the active catalyst this induces reaction of aldehydes with TMSCN by dual activation. Interestingly, the catalyst prepared from Gd(Oi-Pr)3 and 174 (1 2) serves for exclusive formation of (S)-cyanohy-drin TMS ethers [651]. The catalytic activity of the Gd complex is much higher than that of 178a. The results of NMR and ESI-MS analyses indicate that Gd cyanide complex 179 is the active catalyst. It has been proposed that the two Gd cyanide moieties of 179 play different roles - one activates an aldehyde as a Lewis acid and the other reacts with the aldehyde as a cyanide nucleophile. 

Fuerst, D.E. and Jacobsen, E.N. (2005) Thiourea-catalyzed enantioselective cyanosilylation of ketones. Journal of the American Chemical Society, 127, 8964-8965. 

A sugar-based catalyst for catalytic asymmetric cyanosilylation has been developed. This catalyst, 248, is derived from tri-O-acetyl-D-glucal via the intermediates shown in Scheme 39. It incorporates a Lewis acidic and a Lewis basic site within the molecule, and it was found that the conformational constraint induced by the phenyl group was necessary for good enantioselectivity. Treatment of benzaldehyde and TmsCN with catalytic quantities of 248 gave after acid hydrolysis the cyanohydrin 249 in 80% ee, and several other aldehydes behaved similarly. 

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