Enantioselective Hydrocyanation of Aldehydes

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. 

---

Interest in the synthesis of enantiopure 2-hydroxycarboxylic acids via asymmetric enzymatic transformations is still increasing and two pathways have risen into prominence recently. The first is based on enantioselective hydrocyanation of the appropriate aldehyde in the presence of an oxynitrilase (hydroxynitrile lyase, EC 4.1.2.10), which gives rise to the corresponding enantiomerically pure cyanohydrin, followed by chemical hydrolysis in the presence of strong acid (Figure 16.1, route a). This latter step generates copious quantities of salt and is not compatible with sensitive functional groups, which is a serious limitation. 

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... 

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... 

Recently, the enantioselective addition of hydrocyanic acid to aldehydes, analogous to the synthesis of (/ )-cyanohydrins, yielding (.S)-cyanohydrins in very high optical purity, with (S )-oxynitrilase as catalyst, was reported20,21. 

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... 

In 2000, Kagan and Holmes reported that the mono-lithium salt 10 of (R)- or (S)-BINOL catalyzes the addition of TMS-CN to aldehydes (Scheme 6.8) [52]. The mechanism of this reaction is believed to involve addition of the BI NO Late anion to TMS-CN to yield an activated hypervalent silicon intermediate. With aromatic aldehydes the corresponding cyanohydrin-TMS ethers were obtained with up to 59% ee at a loading of only 1 mol% of the remarkably simple and readily available catalyst. Among the aliphatic aldehydes tested cyclohexane carbaldehyde gave the best ee (30%). In a subsequent publication the same authors reported that the salen mono-lithium salt 11 catalyzes the same transformation with even higher enantioselectivity (up to 97% Scheme 6.8) [53], The only disadvantage of this remarkably simple and efficient system for asymmetric hydrocyanation of aromatic aldehydes seems to be the very pronounced (and hardly predictable) dependence of enantioselectivity on substitution pattern. Furthermore, aliphatic aldehydes seem not to be favorable substrates. 

Furthermore, we considered that the hydrocyanation of cinnamic aldehyde (2c) suffers from an unfavorable equilibrium [7, 8] and (apparent) mediocre enantioselectivity [7], which could be increased to >96% only upon careful optimization [8]. We reasoned that the equilibrium would be improved by removing the cyanohydrin Ic by in-situ hydrolysis. Moreover, such a bienzymatic procedure would also obviate the erosion of the cyanohydrin ee which tends to become apparent at the... 

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]. 

Cyclic dipeptides, especially cyclo[(S)-phenylalanyl-(S)-histidyl], are efficient and selective catalysts for the hydrocyanation of aromatic aldehydes (Fig. 5) [41]. The catalysts are not available commercially but can be synthesized by conventional methods and their structure can be varied easily (Fig. 5) [41,42,43]. The catalysts are only selective in a particular heterogeneous state, described as a clear gel [41,43]. It seems that their method of precipitation is crucial [41,44] and that reproducing literature results is not always easy [42]. A recent study confirmed the importance of the aggregate formation and reported a second order rate dependence on the concentration of the cyclic dipeptide [45]. These findings indicate that the enantioselective catalytic species is not monomeric but either a dimer or polymer. 

In the last decade, optically pure cyanohydrins (a-hydroxynitriles) have become a versatile source for the synthesis of a variety of chiral building blocks. Diverse methods for the enantioselective synthesis of cyanohydrins have been published and reviewed111. Besides enzyme catalyzed methods, hydrocyanation or silylcyanation of aldehydes or ketones controlled by chiral metal complexes or cyclic dipeptides, as well as diastereoselective hydrocyanation of chiral carbonyl compounds, have been applied with moderate success. 

Hydrocyanation is the addition of HCN across carbon-carbon or carbon-heteroatom multiple bonds to form products containing a new C-C bond. The majority of examples from organometallic chemistry involve the addition of HCN across carbon-carbon multiple bonds, as shown in Equations 16.2 and 16.3. Lewis acids and peptides have been used to catalyze the enantioselective addition of HCN to aldehydes and imines to form cyanohydrins and precursors to amino acids.The addition of HCN to unactivated olefins requires a catalyst because HCN is not sufficiently acidic to add directly to an olefin, and the C-H bond is strong enough to make additions by radical pathways challenging. However, a large number of soluble transition metal compounds catalyze the addition of HCN to alkenes and alkynes. 

By analogy with the synthesis of a-hydroxy acids one can envisage a one-pot synthesis of a-hydroxy amides from aldehydes via hydrocyanation and in situ NHase-catalyzed hydrolysis to the amide. Since enantioselective NHases are very rare, the enantioselectivity should be derived from HnL-catalyzed hydrocyanation. The second step has been described for the Rhodococcus erythropolis NHase-catalyzed hydration of (R)-mandelonitrile to give the (R)-amide with retention of enantiopurity [43]. 

The Sorghum (S)-oxynitrilase exclusively catalyzes the addition of hydrocyanic acid to aromatic aldehydes with high enantioselectivity, but not to aliphatic aldehydes or ketones [519, 526], In contrast, the Hevea (S)-oxynitrilase was also found to convert aliphatic and a,/ -unsaturated substrates with medium to high selectivity [509, 527]. The stereocomplementary almond (R)-oxynitrilase likewise has a very broad substrate tolerance and accepts both aromatic, aliphatic, and a,/ -unsaturated aldehydes [520, 521, 523, 528, 529] as well as methyl ketones [530] with high enantiomeric excess (Table 9). It is interesting to note that this enzyme will also tolerate sterically hindered substrates such as pivalaldehyde and suitable derivatives 164 which are effective precursors for (R)-pantolactone 165 [531],... 

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]. 

Generally, the use of other heterocycles besides quinoline would be considered modifications of the original Reissert protocol. This reaction has been extended to convert an acyl chloride into an aldehyde through a one-pot process by adding the acyl chloride to a solution of quinoline and hydrocyanic acid, and subsequent steam distillation of the entire mixture with sulfuric acid. In addition, the formation of the Reissert compound has been modified to occur enantioselectively using TMSCN as the nucleophilic species in the presence of a Lewis acid-Lewis base bifunctional catalyst. Moreover, tri-n-butyltin cyanide and acetone cyanohydrin are also used for the preparation of the Reissert compounds. 

---