Catalytic asymmetric cyanohydrin

Catalytic Asymmetric Cyanohydrin Synthesis," North. M. Synlett, 1993, 807... 

M. North, Catalytic asymmetric cyanohydrin synthesis, Synlett 1993, 807-820. 

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. 

The addition of hydrogen cyanide to a carbonyl group results in the formation of an a-hydroxy nitrile, a so-called cyanohydrin (A, Scheme 6.1) [1]. Compounds of this type have in many instances served as intermediates in the synthesis of, e.g., a-hydroxy acids B, a-hydroxy aldehydes C, fS-amino alcohols D, or a-hydroxy ketones E (Scheme 6.1) [1], In all these secondary transformations of the cyanohydrins A, the stereocenter originally introduced by HCN addition is preserved. Consequently, the catalytic asymmetric addition of HCN to aldehydes and ketones is a synthetically very valuable transformation. Besides addition of HCN, this chapter also covers the addition of trimethylsilyl cyanide and cyanoformate to car-... 

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. 

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. 

Optically active cyanohydrins can be easily transformed to P-hydroxy amines, a-hydroxy and a-amino carboxylic acids, which represent versatile intermediates for the synthesis of biologically important compounds, including insecticides and medicines [189, 190]. Asymmetric cyanation of carbonyl compounds catalyzed by chiral metal complexes, particularly titanium compounds, has provided one of the most convenient protocols to the access of these type of compounds. The first example of catalytic asymmetric cyanation of aliphatic aldehydes was realized in Reetz s group using BINOL-Ti complex as the catalyst to give the cyanohydrins in up to 82% ee [104] (Scheme 14.85). 

To avoid the intrinsic instability of cyanohydrins and their silyl ether, Saa and coworkers reported catalytic asymmetric cyanophosphonylation reaction of aldehydes with commercially available diethyl cyanophosphonate [58]. In these works, Lewis acid-Lewis base bifunctional catalyst (65) prepared by mixing BI-NOLAM ligand with amino arms as Lewis base and Et2AlCl was found to work nicely (Scheme 6.46). Since a strong positive nonlinear effect was observed in this reaction, actual catalyst is in equilibrium with some oligomeric species of the aluminum complexes. Bifunctional catalyst (65) could also catalyze cyanosilylation of... 

Cyanation of carbonyl compounds has one of the richest histories of any transformation in the field of asymmetric catalysis, and intensive research efforts have continued unabated since the editorial deadline for the first edition of Comprehensive Asymmetric Catalysis in 1998. This chapter will summarize all efforts in this area from 1998 to date, highlighting the most important catalytic systems from a synthetic and/or mechanistic standpoint. Significant advances in both the cyanation of aldehydes (formation of secondary cyanohydrins Section 28.2.1) and the cyanation of ketones (formation of tertiary cyanohydrins Section 28.2.2) will be addressed [1,2]. 

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. 

The Inoue laboratory reported the first asymmetric hydrocyanation of an aldehyde using a synthetic peptide, cydo[(S)-Phe-(S)-His] (38), to give the cyanohydrin of benzaldehyde in high optical purity (up to 90% ee at 40% conversion). The ee-value of the product was found to diminish with increased reaction time (Scheme 6.5) [57]. The catalytic activity of 38 is presumed to arise from the bifunctional character of the catalyst, wherein aldehyde activation occurs through hydrogen-... 

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. 

When certain cyclodipeptides are used as catalysts for the enantioselective formation of cyanohydrins, an autocatalytic improvement of selectivity is observed in the presence of chiral hydrocyanation products [80]. A commercial process for the manufacture of a pyrethroid insecticide involving asymmetric addition of HCN to an aromatic aldehyde in the presence of a cyclic dipeptide has been described [80]. Besides HCN itself, acetone cyanohydrin is also used (usually in the literature referred to as the Nazarov method), which can be activated cata-lytically by certain lanthanide complexes [81]. Acetylcyanation of aldehydes is described with samarium-based catalysts in the presence of isopropenyl acetate cyclohexanone oxime acetate is hydrocyanated with acetone cyanohydrin as the HCN source in the presence of these catalytic systems [82]. 

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... 

---