Aldehydes enantioselective cyanation

In addition to this, asymmetric 1,3-dipolar cyclization reactions of nitrones with olefins,40 41 catalytic enantioselective cyanation of aldehydes,42 catalytic enantioselective animation,43 and aza-Michael reactions44 have been reported, and high enantioselectivities are observed. 

Lundgren, S. Wingstrand, E. Penhoat, M. Moberg, C. Dual Lewis acid-Lewis base activation in enantioselective cyanation of aldehydes using acetyl cyanide and cyanoformate as cyanide sources. J. Am. Chem. Soc. 2005,127, 11592-11593. 

Cyanation of aldehydes and ketones is an important chemical process for C C bond formation." " Trimethylsilyl cyanide and/or HCN are commonly used as cyanide sources. The intrinsic toxicity and instability of these reagents are problematic in their applications. Acetyl cyanide and cyanoformates were used as cyanide sources in the enantioselective cyanation of aldehydes catalyzed by a chiral Ti complex and Lewis base (Scheme 5.31)." The Lewis base was necessary for the good yields and selectivities of these reactions. The desired products were obtained in the presence of 10mol% triethyl amine and 5mol% chiral titanium catalyst (Figure 5.14). Various aliphatic and aromatic aldehydes could be used in these reactions. 

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... 

Moberg and coworkers also achieved the highly enantioselective cyanation of aldehydes by using the dual activation concept (Table 4.5) [30]. It is known that the Lewis acidic dimeric salen-Ti complex 8 catalyzes the cyanation of benzaldehyde with... 

Scheme 4.10 Enantioselective cyanation of aldehydes with cyanoformic esters catalyzed by (S)-ALB (7) and cinchonine.

Table 4.5 Dual Lewis acid-Lewis base activation in enantioselective cyanation of aldehydes using acetyl cyanide.

The bifunctional catalysts developed by Shibasaki and coworkers effective in the asymmetric cyanation of aldehydes and ketones (see Section 6.2) have been applied to good effect in the cyanation of imines. For instance, aluminium BINOL (6.65) catalyses the cyanation of aromatic and a,p-unsaturated N-fluorenylaldimines using TMSCN in good ee, while gadolinium complexes of the glucose-derived ligand (6.71) and derivatives have been used in the enantioselective cyanation of ketimines. ... 

Discovered in the middle of the 19th century, the Strecker reaction is one of the earliest atom-economic multicomponent reactions. Amino nitriles were simply obtained from ammonia, hydrogen cyanide and an aldehyde. These products are important intermediates for the synthesis of natural and unnatural a-aminoacids. Due to the ever-increased demand for enantioenri-chied a-aminoacids, the asymmetric Strecker reaction has emerged as a viable synthetic method. Since the first report published in 1996, the catalytic enantioselective cyanation of preformed imines was intensively studied and several excellent reviews were devoted to this topic. ... 

Tridentate chiral Schiff bases derived from (- -)-Q -pinene (123) catalyse enantioselective addition of diethylzinc to aryl aldehydes. Steric, aryl stacking, and electronic effects are significant in the transition state, the latter being probed by a Hammett plot of ee versus for a series of benzaldehydes. Complexes of the Schiff base (123) with titanium(IV) catalyse enantioselective cyanation. ... 

A multicomponent bifunctional catalytic system based on a titanium complex was also used for the efficient enantioselective cyanation of aldehydes with ethyl cyanoformate [221]. The catalyst was readily prepared by the reaction of Ti(O Pr)4 with (S)-6,6 -Br2BINOL in combination with cinchonine and (lR,2S)-(—)-N-methylephedrine. As shown in Scheme 14.91, the optimized catalyst combination (10 mol%) promotes the reaction smoothly to afford the desired cyanohydrins ethyl carbonates in moderate to excellent isolated yields (up to 95%) with high enantioselectivities (up to 94% ee). Although the mechanistic aspects... 

Sansano reported the enantioselective cyanation of aldehydes with benzoyl cyanide using BINOLAM-Ti(IV) complex as a catalyst without the presence of additives, good chemical yields and moderate enantioselectivities of the reaction have been achieved (Scheme 14.92) [222]. The Lewis basic side chains at 3,3 -positions of BINOL ligand are believed to play an important role and a bifunctional mechanism has been proposed. 

Figure 3-6. Chiral catalysts for enantioselective cyanation of aldehydes.

Sn(OTf)2 can function as a catalyst for aldol reactions, allylations, and cyanations asymmetric versions of these reactions have also been reported. Diastereoselective and enantioselective aldol reactions of aldehydes with silyl enol ethers using Sn(OTf)2 and a chiral amine have been reported (Scheme SO) 338 33 5 A proposed active complex is shown in the scheme. Catalytic asymmetric aldol reactions using Sn(OTf)2, a chiral diamine, and tin(II) oxide have been developed.340 Tin(II) oxide is assumed to prevent achiral reaction pathway by weakening the Lewis acidity of Me3SiOTf, which is formed during the reaction. 

Complexation of an amino acid derivative with a transition metal to provide a cyanation catalyst has been the subject of investigation for some years. It has been shown that the complex formed on reaction of titanium(IV) ethoxide with the imine (40) produces a catalyst which adds the elements of HCN to a variety of aldehydes to furnish the ( R)-cyanohydrins with high enantioselectivity[117]. Other imines of this general type provide the enantiomeric cyanohydrins from the same range of substrates11171. 

Very few methods developed recently are applicable to the cyanation of not only electron-rich but also electron-deficient aromatic, as well as aliphatic aldehydes. Titanium(IV)-derived complex 1 (Fig. 1), reported by Uang, catalyzes the hydro cyanation of aromatic, a, 3-unsaturated, and aliphatic aldehydes with high enantioselectivity (>88% ee for all substrates reported) [15]. Similarly, Ti(IV)-catalyst 2 developed by Choi has proved to be highly enantioselec-tive for the cyanation of various classes of aldehydes (>90% ee for most substrates) [16]. Belokon and co-workers reported two chiral salen-based systems (salen)VO catalyst 3a and [(salen)TiO]2 3b, both of which provided moderate levels of enantioselection when applied to the asymmetric cyanation of diverse... 

Recently, Bu and Liang reported that the level of enantioinduction provided by chiral (salen)Ti(IV) catalysts was considerably dependent on the substitution of the chiral ligand, prompting them to prepare catalyst 4. As a result, they observed excellent enantioselectivity for the cyanation of all aromatic aldehydes investigated (>92% ee for all 10 examples no example of an aliphatic aldehyde was reported) [26]. 

Shibasaki and co-workers applied (BINOL)Al(III)-derived catalyst 5a, previously developed for the cyanation of aldehydes [28], to the asymmetric Strecker reaction. This catalyst proved to be highly enantioselective for both aromatic and a,p-unsaturated acyclic aldimines (>86% ee for most substrates) (Scheme 8) [63-65]. Aliphatic aldimines underwent cyanide addition with lower levels of enantioselectivity (70-80% ee). A significant distinction of 5 relative to other catalysts is, undoubtedly, its successful application to the hydrocyanation of quinolines and isoquinolines, followed by in situ protection of the sensitive cx-amino nitrile formed (this variant of the Strecker reaction is also known as the Reissert reaction [66]). Thus, Shibasaki has shown that high enantioselectivities (>80% ee for most substrates) and good yields are generally obtainable in the Reissert reaction catalyzed by 5b [67,68]. When applied to 1-substituted... 

Extension of this reaction toward a one-pot asymmetric Mannich-hydrocyanation reaction sequence was also reported by the Barbas group [29]. In this one-pot two-step process proline-catalyzed asymmetric Mannich reaction of unmodified aldehydes with the a-imino glyoxylate was performed first, then diastereoselective in situ cyanation. The resulting /i-cyanohydroxymethyl a-amino acids were obtained with high enantioselectivity (93-99% ee) [29]. Another one-pot two-step reaction developed by Barbas et al. is the Mannich-allylation reaction in which the proline-catalyzed Mannich reaction is combined with an indium-promoted allylation [30], This one-pot synthesis was conducted in aqueous media and is the first example of a direct organocatalytic Mannich reaction in aqueous media [28, 30]. 

The reaction of benzaldehyde with hydrogen cyanide in the presence of 2 mol % of the catalyst in toluene at -20 °C for 8 h furnished the corresponding (i )-cyanohydrin in 97% yield and an enantioselectivity of 97%. The asymmetric cyanation of various aromatic and heteroaromatic aldehydes similarly proceeded to give the optically active cyanohydrins, although aromatic aldehydes with electron withdrawing groups such as NO2 and CN and aliphatic aldehydes... 

Chiral haloboranes such as diisopinocampheylchloroborane 2.16 (R = Cl) or cyclic borane 2.61 have been used as catalysts in Diels-Alder reactions or in hydro-cyanation of aldehydes, but poor enantioselectivities were observed [778], Cata-... 

Some other very important events in the historic development of asymmetric organocatalysis appeared between 1980 and the late 1990s, such as the development of the enantioselective alkylation of enolates using cinchona-alkaloid-based quaternary ammonium salts under phase-transfer conditions or the use of chiral Bronsted acids by Inoue or Jacobsen for the asymmetric hydro-cyanation of aldehydes and imines respectively. These initial reports acted as the launching point for a very rich chemistry that was extensively developed in the following years, such as the enantioselective catalysis by H-bonding activation or the asymmetric phase-transfer catalysis. The same would apply to the development of enantioselective versions of the Morita-Baylis-Hillman reaction,to the use of polyamino acids for the epoxidation of enones, also known as the Julia epoxidation or to the chemistry by Denmark in the phosphor-amide-catalyzed aldol reaction. ... 

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