Cyanosilylation of Ketones

Figure 6.23 Proposed transition states of the asymmetric 72-catalyzed cyanosilylation of ketones describe two alternative mechanistic pathways for cooperative catalysis Addition via thiourea-bound ketone (TS 1, preferred) and addition via thiourea-bound cyanide (TS 2).

Scheme 6.85 Product range of the 73- and 74-catalyzed asymmetric cyanosilylation of ketones.

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]. 

We began our synthesis by finding the optimum reaction conditions for the catalytic asymmetric cyanosilylation of ketone 28 (Table 1). Based on previous studies,30 the titanium complex of a D-glucose derived ligand (catalyst 32 or 33) generally gives (/ )-ketone cyanohydrins, which is required for a synthesis of natural fostriecin. 

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. 

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. 

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]. 

More recently, Shibasaki et al. have extended this methodology to the enan-tioselective cyanosilylation of ketones by designing a novel bifunctional catalyst 56 containing titanium and phosphine oxide (Table 9). Thus, enantiomeric excesses up to 95% in numerous cases have been obtained [62]. 

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

Trost and coworkers developed a chiral zinc phenoxide for the asymmetric aldol reaction of acetophenone or hydroxyacetophenone with aldehydes (equations 62 and 63) . This method does not involve the prior activation of the carbonyls to silyl enol ethers as in the Mukaiyama aldol reactions. Shibasaki and coworkers employed titanium phenoxide derived from a phenoxy sugar for the asymmetric cyanosilylation of ketones (equation 64). 2-Hydroxy-2 -amino-l,l -binaphthyl was employed in the asymmetric carbonyl addition of diethylzinc , and a 2 -mercapto derivative in the asymmetric reduction of ketones and carbonyl allylation using allyltin ° . ... 

Cyanosilylation of ketones (4,542-543 5,720). In a total synthesis of natural camptothecin (9), Corey et al used this f-butyldimethylsilyl derivative rather than trimethylsilyl cyanide (5, 720-722) to effect cyanosilylation of a ketone (1). Hydrolysis of the resulting cyano silyl ether to the required amide was not accompanied by desilylation with reversal of cyanohydrin formation. By use of carefully controlled conditions and with dicyclohexyl-18-crown-6-potassium cyanide as catalyst, they were able to convert (1) into the a-hydroxy... 

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

Based on acid-base combination chemistry, Ishihara developed a catalytic enantioselective cyanosilylation of ketones by using chiral (J )-Ph2-BINOL-derived lithium phosphate, which was prepared in situ from phosphoric acid... 

Scheme 2.11 Enantioselective cyanosilylation of ketones with the use of chiral lithium(i) phosphate.

Feng developed a highly enantioselective cyanosilylation of ketones catalysed by L-phenylglycine sodium salt 54 to give the corresponding cyanohydrins (Scheme 2.34). H, and Si NMR analyses suggested the possible formation of hypervalent silicate species from the carboxylate ion of 54 and trimethylsilylcyanide. Introduction of i-PrOH greatly enhanced the reactivity without a loss of enantioselectivity. 

Scheme 7 Shibasaki s catalyst in enantioselective cyanosilylation of ketones...

Scheme 124 Asymmetric cyanosilylation of ketones early in the syntheses of different members of the bisorbicillinoid family...

Tian SK, Hong R, Deng L (2003) Catalytic Asymmetric Cyanosilylation of Ketones with Chiral Lewis Base. J Am Chem Soc 125 9900... 

The asymmetric cyanosilylation of ketones is a challenge in terms of the catalyst efficiency and substrate generality, due to the decreased steric discrimination and the lower reactivity of ketones compared with aldehydes. 

In 2002, Snapper and Hoveyda reported a chiral peptide 15-Al(OiPr)3 complex for the cyanosilylation of ketones (Scheme 19.9). This catalyst system exhibited excellent results (67->98% peld and 80-95% enantiomeric excess) for aromatic (cyclic and acyclic) and aliphatic ketones (saturated and unsaturated). Notably, the first example of catalytic enantioselective cyanide addition to an alkynyl ketone was developed. Meanwhile, the chiral ligand 15 was recyclable, readily modifiable and easily synthesised in six steps with 75% overall yield. 

Subsequently, the Feng group developed an enantioselective cyanosilylation of ketones by a catalytic double-activation catalyst system composed of chiral (J ,J )-salen 16-triethylaluminium complex and N-oxide 17 (Scheme 19.10). High catalytic turnovers (200 for aromatic ketones, 1000 for aliphatic ones) with high enantioselectivity (up to 94% enantiomeric excess for aromatic ketones, up to 90% enantiomeric excess for aliphatic ones) were achieved under mild reaction conditions. Based on the control experiments, a double-activation model was suggested (Scheme 19.10). The chiral aluminium complex performed as a Lewis acid to activate the ketone, whereas the N-oxide acted as a Lewis base to activate trimethylsilyl cyanide and form an isocyanide species. The activated nucleophile and ketone attracted and approached each other, and so the transition state was formed. The intramolecular transfer of cyanide to the carbonyl group gives the product cyanohydrin O-TMS ether. 

Scheme 19.9 Asymmetric cyanosilylation of ketones catalysed by an Al-peptide complex.

Table 13.24 Catalytic Enantioselective Cyanosilylation of Ketones Using Gd/Ligand 7a Complex...

Table 13.25 Catalytic Enantioselective Cyanosilylation of Ketones for the Synthesis of Triazole Antifungals...

Shibasaki and coworkers developed a bifunctional catalyst containing titanium and phosphine oxide for highly enantioselective cyanosilylation of ketones [225]. By steric and electronic tuning of the bifunctional catalyst, chiral quaternary a-hydroxynitrile derivatives were obtained with excellent enantiomeric excess (up... 

Asymmetric cyanosilylation of ketones and aldehydes is highly important, since the cyanohydrin product can easily be converted into optically active aminoalcohols... 

Thus, the asymmetric catalysis of cyanoethoxycarbonylation, cyanophosphoryla-tion, epoxidation of electron-deficient olefins, Michael reactions of malonates and (3-keto-esters, Strecker reaction of keto-imines, conjugate addition of cyanide to a, (3-unsaturated pyrrole amides, ring opening of meso aziridines with TMSCN and cyanosilylation of ketones (example shown below) have been successfully carried out using these complexes as asymmetric catalysts. 

S-selective, catalytic cyanosilylation of ketones (top), and application to the synthesis of a key intermediate for camptothecin (bottom)... 

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