Enantioselectivity cyanosilylation

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 ... 

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... 

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

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. 

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 2.53 Enantioselective cyanosilylation of aldehyde with the use of chiral potassium(i) cobaltate(iii) complexes.

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

An unsymmetrical salen ligand bearing a Lewis base catalyses Ti(OPr-i)4-promoted addition of TMSCN to benzaldehyde with as little as 0.05 mol% loading, quantitative conversion is achieved in 10 min at ambient temperature. Another salen catalyst - a bifunctional salen-phosphine oxide-Ti(IV) combination - promotes enantioselective cyanosilylation of aldehydes. Fine tweaking of the structure of another series of bifunctional chiral salen-Ti(IV) complexes allows the enantioselectivity to be reversed. Biaryl-bridged salen-titanium complexes are also highly efficient catalysts, one example giving 87% ee at room temperature. ... 

Subsequently, Kim and Song reported the enantioselective cyanosilylation of aldehydes catalysed by (/ ,/ )-(salen)Al 3/triphenylphosphine oxide (Scheme 19.2). The (salen)Al 3 alone induced no enantioselectivity and reactivity, which indicated a double activation process occurring within the catalysis. The complex functioned as a Lewis acid to activate the aldehyde, while triphenylphosphine oxide acted as a Lewis base for the activation of trimethylsilyl cyanide. 

The bifunctional catalyst 9 was then applied in a total synthesis of Epo-thilone A and B in 2000 by the Shibasaki group (Scheme 19.6). The key step is the enantioselective cyanosilylation to a thiazole-based a,p-unsaturated aldehyde. In the presence of catalyst 9 (5 mol%) and tributylphosphine oxide (80 mol%) in dichloromethane, the corresponding cyanohydrin was obtained in 97% yield and 99% enantiomeric excess. It should be noted that slow addition of trimethylsilyl cyanide (>50 h) was essential to aehieve this result. 

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. 

Caille and coworkers finished the synthesis of AMG 221 in 2009, by the use of an enantioselective cyanosilylation of 3-methylbutan-2-one as the key step (Scheme 19.11). Using the double-activation catalytic system mentioned above, the key intermediate cyanohydrin derivative was isolated in 88% yield (47.2 g) with 85% enantiomeric excess. Six additional steps allowed to the synthesis of AMG 221, which is an inhibitor of llp-hydro g steroid dehydrogenase type 1. 

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... 

Li, Y, He, B., Qin, B., Feng, X., Zhang, G. (2005). Highly enantioselective cyanosilylation of aldehydes catalyzed by novel 3-amino alcohol—titanium complexes. Cheminform, 36. http //dx.doi.Org/10.1002/chin.200511101. 

In 2004, Feng et al. reported enantioselective cyanosilylation of ketones catalyzed by chiral organoaluminum complex 56 (Scheme 40) [72, 73]. Their strategy involves the simultaneous activation of electrophiles by chiral Lewis acid 56 and of nucleophiles (TMSCN) by achiral Lewis base 57. 

Chen F-X, Zhou H, Liu X, Qin B, Feng X, Zhang G, Jiang Y (2004) Enantioselective cyanosilylation of ketones by a catalytic double-activation method with an aluminum complex and an N-oxide. Chem Eur J 10 4790-4797... 

Alaaeddine A, Roisnel T, Thomas CM, Carpentiera J-F (2008) Discrete versus in situ-generated aluminum-salen catalysts in enantioselective cyanosilylation of ketones role of achiral ligands. Adv Synth Catal 350 731-740... 

In 2004, Corey reported highly enantioselective cyanosilylation of aldehydes catalyzed by chiral BLA (3b) (Scheme 1.3) [5]. Under the standard conditions (10mol% of (3b) and 20mol% of PhsPO in toluene at 0 °C), a variety of both aromatic and aliphatic aldehydes have been transformed into cyanohydrins with >90% enantiomeric purity. 

The subsequent study revealed that the chiral BLA (2b) is a potent chiral Lewis acid for enantioselective cyanosilylation of methyl ketones promoted by TMS cyanide and diphenylmethyl phosphine oxide as coreactants (to generate Ph2MeP(OTMS)(N=C as a reactive intermediate) (Scheme 1.4) [6]. The rational for the observed face selectivity can be explained by a transition state assembly in... 

Scheme 1.4 Enantioselective cyanosilylation of methyl ketones catalyzed by (2b).

Recently, hydrocyanation and cyanosilylation reactions with other type of chiral aluminum complexes were reported. In 1999, Shibasaki and Kanai reported enantioselective cyanosilylation of aldehydes catalyzed by Lewis acid-Lewis base bifunctional catalyst (64a) [56, 57]. In this catalyst, aluminum center works as a Lewis acid to activate the carbonyl group, and the oxygen atom of the phosphine oxide works as a Lewis base to activate TMSCN. Asymmetric induction was explained by the proposed transition state model having the external phosphine oxide coordination to aluminum center, thus giving rise to pentavalent aluminum... 

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