Hydrocyanation of aldehydes

A rationale for the stereoinduction was provided, whereby the role of histidine is to direct the attack of cyanide to the Si-face of benzaldehyde while the Re-face 

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Table 8. Asymmetric Hydrocyanation of Aldehydes with Cyanotrimethylsilane...

It was mentioned at the beginning of this chapter that alkaloids were among the first catalysts to be used for asymmetric hydrocyanation of aldehydes. More recent work by Tian and Deng has shown that the pseudo-enantiomeric alkaloid derivatives 5/6 and 7/8 catalyze the asymmetric addition of ethyl cyanoformate to aliphatic ketones (Scheme 6.6) [50]. It is believed that the catalytic cycle is initiated by the alkaloid tertiary amine reacting with ethyl cyanoformate to form a chiral cyanide/acylammonium ion pair, followed by addition of cyanide to the ketone and acylation of the resulting cyanoalkoxide. Potentially, the latter reaction step occurs with dynamic kinetic resolution of the cyano alkoxide intermediate... 

Table 6.13 Synthetic peptide-promoted hydrocyanations of aldehydes.

The Strecker reaction is defined as the addition of HCN to the condensation product of a carbonyl and amine component to give a-amino nitriles. Lipton and coworkers reported the first highly effective catalytic asymmetric Strecker reaction, using synthetic peptide 43, a modification of Inoue s catalyst (38), which was determined to be inactive for the Strecker reactions of aldimines (see Scheme 6.5) [62], Catalyst 43 provided chiral a-amino nitrile products for a number of N-benzhydryl imines (42) derived from substituted aromatic (71-97% yield 64->99% ee) and aliphatic (80-81% yield <10-17% ee) aldehydes, presumably through a similar mode of activation to that for hydrocyanations of aldehydes (Table 6.14). Electron-deficient aromatic imines were not suitable substrates for this catalyst, giving products in low optical purities (<10-32% ee). The a-amino nitrile product of benzaldehyde was converted to the corresponding a-amino acid in high yield (92%) and ee (>99%) via a one-step acid hydrolysis. 

Asymmetric hydrocyanation of aldehydes.3 This reaction can be effected by reaction of aliphatic or aromatic aldehydes with cyanotrimethylsilane and an optically active reagent (1) derived from (2R,3R)-tartaric acid, and dichlorodiisopro-poxytitanium(IV). The actual chiral reagent may be 2, shown by H NMR to be... 

The hydrocyanation of aldehydes provides access to synthetically important a-hydroxy carboxylic acids. This reaction can be catalyzed by acids and bases, but acid catalysis is more suitable because the presence of a base leads to racemization of cyanohydrins. 

Reetz et al. found that chiral 1-boracyclopentyl chloride or methoxide can be used as a catalyst in the reaction of 3-methylbutanal and trimethylsilyl cyanide (Eq. 72) [42]. Although the asymmetric induction and yield are not good, this is the first example of chiral induction by an organoborane in the hydrocyanation of aldehydes. 

Hydrocyanation of aldehydes opens access to the synthetically valuable cyanohydrins, precursors for hydroxycarboxylic acids, a-hydroxyketones and /S-ami-noalcohols. Applying the principles of homogeneous catalysis to this reaction it is possible to obtain cyanohydrins in the optically active form, depending on how well the catalyst-ligand system is adapted to the substrate. 

A further important asymmetric biocatalytic synthesis represents the hydrocyanation of aldehydes [116] for the production of cyanohydrins which are intermediates for a broad variety of life science molecules. For example, (/ )-mandelonitrile is a versatile intermediate for the synthesis of ( )-mandelic acid, and (S)-m-phenoxybenzaldehyde cyanohydrin is a building block for the preparation of pyrethroids. 

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... 

Table 1. Asymmetric hydrocyanation of aldehydes catalyzed by chiral base...

Impressive results have been obtained by Hajos, Wiechert and coworkers [261] in enantiosdective Robinson simulations of triketones catalyzed by ( -pro-line 1.64 (R = COOH). This type of asymmetric intramolecular aldol reaction is quite general under aminoacid catalysis [261, 775]. Asymmetric hydrocyanation of aldehydes is catalyzed by dipeptides, among which 3.4 is the most efficient. Asymmetric epoxidation of chalcone by alkaline H2O2 >s catalyzed by polyami-noacids [578, 776], but this reaction is not veiy general [777]. 

Other titanium complexes derived from tartaric acid have been used as chiral catalysts. The complexes generated from diol 2.50 and TiCl2(0/-Pr)2 are used as catalysts in asymmetric ene-reactions [778, 816], and in Diels-Alder [778, 780] or [2+2] cycloadditions of ketene thioacetals and unsaturated sulfides [778, 817], The best enantiomeric excesses are observed with 2.50 (R = Me, R = Ph) [778, 817] or 2.50 (R = R = Et, Ar = 3,5-Me2CgH3) [45], These catalysts are also efficient in hydrophosphonylation [818] and in asymmetric hydrocyanation of aldehydes with Me3SiCN [778], These titanium complexes may be used in catalytic amounts provided that the reactions are run in the presence of molecular sieves [559,816],... 

Asymmetric hydrocyanation of aldehydes with MegSiCN is catalyzed by Sn(OT02 in the presence of cinchonidine 3.1 (R = H). 

Table 4.6. Catalytic asymmetric hydrocyanation of aldehydes. Numbers in the catalyst column refer to Figure 4.18 (p. 142).

Figure 4.18. Corey s dual catalyst system for asymmetric hydrocyanation of aldehydes [95].

The following subsections discuss the use of oligopeptides in aldol, Michael, Morita-BayUs-HiUman, and the hydrocyanation of aldehydes. 

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