Trimethylsilyl cyanohydrin, enantioselective

Verkade and co-workers have shown the usefulness of their phosphazanes in various stoichiometric as well as catalytic reactions <1999PS(144)101>. Compound 290 was used to promote the cyanohydration of benzaldehyde with trimethylsilyl cyanide (TMSCN). The cyanohydrin was isolated in 95% yield, but no enantioselectivity was noticed <2002JOM(646)161>. Compounds 291 and 292 were attached to dendrimers and shown to be effective in the catalysis of Michael reactions, nitroaldol reactions, and aryl isocyanate trimerizations <2004ASC1093>. 

A binaphthol-modified Ti(IV) complex effects enantioselective addition of trimethylsilyl cyanide to aldehydes to form optically active cyanohydrin derivatives (Scheme 124). The highest ee value of 82% is achieved in the reaction of isovaleraldehyde with 20 mol % of the catalyst (286a). Use of a tartrate-derived modifier in combination with molecular sieves 4A is also effective for this type of addition and results in... 

Enantioselective Cyanohydrin Formation. Magnesium complexes formed with the anionic semicorrin-type ligand (5) catalyze the addition of Cyanotrimethylsilane to aldehydes, leading to optically active trimethylsilyl-protected cyanohydrins. In the presence of 20 mol % of the chloromagnesium complex (9), prepared from equimolar amounts of (5) and BuMgCl, cyclohexanecarbaldehyde is smoothly converted to the corresponding cyanohydrin derivative with 65% ee. Addition of 12 mol % of the bisoxazoline (10) results in a dramatic increase of enantioselectivity to 94% ee (eq 8). Replacement of (10) by its enantiomer reduces the selectivity to 38% ee. This remarkable... 

In 1993 Corey et al. [60] reported a new enantioselective method for synthesis of chiral cyanohydrins [61] from aldehydes and trimethylsilyl cyanide (TMSCN) by the use of a pair of synergistic chiral reagents. Reaction of cyclohexane carbaldehyde 78 and trimethylsilyl cyanide (TMSCN) 79 in the presence of 20 mol % chiral magnesium complex 80 afforded the cyanohydrin TMS ether 81 in 85 % yield with 65 % ee. This modest enantioselectivity was fiirther enhanced to 94 % ee by addition of a further 12 mol % of the bis(oxazoline) 70 (Sch. 34). 

Optically pure cyanohydrins serve as highly versatile synthetic building blocks [24], Much effort has, therefore, been devoted to the development of efficient catalytic systems for the enantioselective cyanation of aldehydes and ketones using HCN or trimethylsilyl cyanide (TMSCN) as a cyanide source [24], More recently, cyanoformic esters (ROC(O)CN), acetyl cyanide (CH3C(0)CN), and diethyl cyanophosphonate have also been successfully employed as cyanide sources to afford the corresponding functionalized cyanohydrins. It should be noted here that, as mentioned in Chapter 1, the cinchona alkaloid catalyzed asymmetric hydrocyanation of aldehydes discovered... 

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. 

Johnson s group developed a catalytic asymmetric cyanation/1,2-Brook rearrangement/C-acylation of acylsilanes with cyanoformates (Scheme 19.14). In the presence of (i ,/ )-(salen)Al 19, the corresponding cyanohydrin trimethylsilyl ethers of a-keto esters were obtained in moderate to good enantioselectivities (61-82% enantiomeric excess). Access to chiral (silyloxy)nitrile anions is facilitated by metal cyanide-promoted Brook rearrangement reaction of acylsilanes. 

Aldehydes and ketones are readily transformed into the corresponding cyanohydrin trimethylsilyl ethers when treated with cyanotrimethylsilane in the presence of Lewis acids (eq 1), triethylamine, or solid bases such as Cap2 or hydroxyapatite. The products can be readily hydrolyzed to the corresponding cyanohydrins. The cyanosilylation of aromatic aldehydes can be achieved with high enantioselectivity in the presence of catalytic amounts of a modified Sharpless catalyst consisting of titanium tetraisopropoxide and L-(+)-diisopropyl tartrate (eq 2). Catalysis with chiral titanium reagents yields aliphatic and aromatic cyanohydrins in high chemical and optical yields... 

Addition to Carbonyls, Imines (Strecker-type Reactions), and Heteroaromatic Rings (Reissert-type Reactions). Cyanohydrin trimethylsilyl ethers are of significant synthetic interest as they can be transformed into a variety of multifunctional intermediates. Aldehydes and ketones can be enantioselectively converted to cyanohydrin trimethylsilyl ethers when treated with cyanotrimethylsilane in the presence of a Lewis acid and a chiral ligand. Enantioselective and/or diastereoselective formation of cyanohydrins and their derivatives has been reported and most of these reactions involve chiral ligands and metal catalysts containing Ti (eq 24), Sm (eq 25), and A1 (eq 26). ... 

Noteworthy is that the reaction between trimethylsilyl (TMS) cyanide and triphenylphosphine oxide seems to generate a new reactive cyanide donor, isocyanophosphorane Ph3P(OTMS)(N=C ) and this species is crucial for high enantioselectivity. The novel process described herein has several other advantages such as (i) predictability of absolute configuration of cyanohydrin products from a mechanistic model as described in Scheme 1.3 (ii) easy and efficient recovery of the catalytic ligand. 

The catalyst (10c) turned out to be effective for highly enantioselective hydrocya-nation of a wide range of ketones to give cyanohydrin trimethylsilyl ether with high ees (Scheme 2.44) [97]. 

Silyl cyanides react enantioselectively with such electrophiles as aldehydes, ketones, imines, activated azines, or,/ unsaturated carbonyl compounds, epoxides, and aziridines in the presence of chiral Lewis acid catalysts to give functionalized nitriles, versatile synthetic intermediates for hydroxy carboxylic acids, amino acids, and amino alcohols (Tables 3-6, 3-7, 3-8, and 3-9, Figures 3-6, 3-7, and 3-8, and Scheme 3-154). ° Soft Lewis acid catalytst, the reaction of epoxides with trimethylsilyl cyanide often leads to isonitriles, which are derived from silylisonitrile spiecies (Schemes 3-155 and 3-156). Soft Lewis base such as phosphine oxide also catalyzes the reaction and cyanohydrin silyl ethers of high ee s are isolated. 

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