Synthesis 1,4-addition reactions with cyanohydrins

Today, the most promising synthesis of optically active cyanohydrins, especially with respect to the enantioselectivity of the reaction, is the enzyme-catalyzed addition of hydrogen cyanide to aldehydes and ketones, respectively. 

The synthesis of the furan-imidazole derivatives, shown in Scheme 2, were also described by Wang et al. [34]. Reaction of 4-(dimethylamino)benzalde-hyde (20) with trimethylsilylcyanide (TMS)-CN in the presence of Znl2 produced the TMS cyanohydrin 21. Compound 21 was treated with LDA followed by the addition of 3,4,5-trimethoxybenzaldehyde to give the benzoin intermediate 22. Oxidation with CUSO4 in aqueous pyridine, followed by reaction with 3-furaldehyde in acetic acid, produced the substituted imidazole 23. 

Addition of a cyanohydrin acetal anion to [(benzene)Cr(CO)3] followed by reaction with allyl bromide produces the cyclohexadiene derivative (73) in 94% yield, which undergoes a Diels-Alder reaction rapidly to give a tricyclic framework (74). After quenching with methyl iodide and disassembling of the cyanohydrin group, the diketone (75) is obtained in 50% yield overall (equation 51).125 These products are obviously interesting as potential intermediates for synthesis. 

The addition of hydrogen cyanide to carbonyl compounds gives a-hydroxy cyanides (cyanohydrin synthesis). The reaction is reversible, and the extent of the cyanohydrin formation depends upon the structure of the Carbonyl compound. The equilibrium highly favors the formation of aliphatic and alicyclic cyanohydrins however, aryl alkyl ketones react to a lesser extent, and diaryl ketones, not at all. The reaction may be accomplished by mixing the carbonyl compound with liquid hydrogen cyanide in the presence of a basic catalyst. The equilibrium... 

Two common procedures in carbohydrate chemistry result in adding or removing one carbon atom from the skeleton of an aldose. The Wohl degradation shortens an aldose chain by one carbon, whereas the Kiliani-Fischer synthesis lengthens it by one. Both reactions involve cyanohydrins as intermediates. Recall from Section 21.9 that cyanohydrins are formed from aldehydes by addition of the elements of HCN. Cyanohydrins can also be re converted to carbonyl compounds by treatment with base. 

The non-equivalence of enantiomers through the spontaneous breaking of mirror-symmetry in nature is amplified by asymmetric autocatalytic reaction [34], e.g. Frank s spontaneous asymmetric synthesis [35, 36] (Fig. 7-8). Alberts and Wyn-berg have reported in enantioselective autoinduction that chiral lithium alkoxide products may be involved in the reaction to increase the enantioselectivity (Eq. (7.9)) [37]. The product % ee however does not exceed the level of catalyst % ee. In asymmetric hydrocyanation catalyzed by cyclic dipeptides, the (Si-cyanohydrin product complexes with the cyclic peptide to increase the enantioselectivity in the (S)-cyanohydrin product, the reaction going up to 95.8% ee (Eq. (7.10)) [38]. In the presence of achiral amine, (/ )-l-phenylpropan-l-ol catalyzed carbonyl-addition reaction of diethylzinc has been reported to show lower % ee than that of the catalyst employed [39]. 

The addition reaction of carbon-11 labelled cyanide ion to the bisulphite addition adduct of an aldehyde has been extended to prepare carbon-11 labelled amines. Maeda and coworkers prepared both p- and m-octopamine [2-(p-and m-hydroxyphenyl)-2-hydroxyethyl-amine] from the corresponding benzaldehyde by reducing the cyanohydrin formed in the reaction between the appropriate benzaldehyde and cyanide ion both under enzymatic conditions and by the basic modification of the Bucherer-Strecker synthesis, with borane-THF. The synthesis of / -octopamine is presented in equation 64. 

Most of the elementary reactions in the classic MCRs are equilibrium processes. Therefore, thermodynamic factors can significantly impact the reaction pathways in addition to the reaction kinetics. A classic example is the Strecker synthesis of a-amino nitrile 9 from aldehydes, amines, and cyanide (Scheme 15.5). The key step in this reaction is the nucleophilic addition of cyanide to the in situ formed iminium. However, condensation of a carbonyl compound with an amine leading to iminium is an equilibrium process, especially under aqueous conditions. Therefore, the desired addition reaction is in competition with direct addition of cyanide to the aldehyde, leading to cyanohydrin 10. However, since the formation of both 9 and 10 were reversible, only the more stable adduct 9 was produced at the expense of cyanohydrin 10 under thermodynamically controlled conditions. 

As part of a projected synthesis of corrins, a simple synthesis of y-substi-tuted y-butyrolactams via the conjugate addition of hydrogen cyanide to unsaturated ketones is described contrary to a much earlier report, the )S-cyanohydrin (101) is not produced, but a mixture of the two butyro-lactams (102) and (103) is isolated, (103) being convertible into (102) by reaction with basic cyanide solution. Reaction of one of those, (102), with potassium t-butoxide in t-butyl alcohol gave, inter alia, the semi-corrinoid (104), These transformations are outlined in Scheme 35. 

Our strategy for the synthesis of (+)-dactylolide (2.217) is outlined in Scheme 2.69. We envisioned that the 20-membered macrolactone in 2.332 could be constructed by intramolecular iV-heterocyclic carbene (NHC)-catalyzed oxidative macrolactonization of co-hydroxy aldehyde 2.333. Intramolecular NHC-catalyzed oxidative esterification reactions have been recognized as an attractive tool and rapidly growing area in the synthetic community. Indeed, several examples of these reactions have recently been reported [208-216], which clearly provide a new opportunity for the development of catalytic acyl transfer agents in macrolactonization reactions of co-hydroxy aldehydes in the presence of oxidants. The substrate for the macrolactonization reaction would be derived firom the cyanohydrin alkylation of 2,6-dr-tetrahydropyran enal 2.335 with dienyl chloride 2.334. 2,6 -di-tetrahydropyran enal would in turn be constructed by employing the 1,6-oxa conjugate addition reaction of co-hydroxy 2,4-dienal 2.336. Despite the... 

The most general methods for the syntheses of 1,2-difunctional molecules are based on the oxidation of carbon-carbon multiple bonds (p. 117) and the opening of oxiranes by hetero atoms (p. 123fl.). There exist, however, also a few useful reactions in which an a - and a d -synthon or two r -synthons are combined. The classical polar reaction is the addition of cyanide anion to carbonyl groups, which leads to a-hydroxynitriles (cyanohydrins). It is used, for example, in Strecker s synthesis of amino acids and in the homologization of monosaccharides. The ff-hydroxy group of a nitrile can be easily substituted by various nucleophiles, the nitrile can be solvolyzed or reduced. Therefore a large variety of terminal difunctional molecules with one additional carbon atom can be made. Equally versatile are a-methylsulfinyl ketones (H.G. Hauthal, 1971 T. Durst, 1979 O. DeLucchi, 1991), which are available from acid chlorides or esters and the dimsyl anion. Carbanions of these compounds can also be used for the synthesis of 1,4-dicarbonyl compounds (p. 65f.). 

Out first example is 2-hydroxy-2-methyl-3-octanone. 3-Octanone can be purchased, but it would be difficult to differentiate the two activated methylene groups in alkylation and oxidation reactions. Usual syntheses of acyloins are based upon addition of terminal alkynes to ketones (disconnection 1 see p. 52). For syntheses of unsymmetrical 1,2-difunctional compounds it is often advisable to look also for reactive starting materials, which do already contain the right substitution pattern. In the present case it turns out that 3-hydroxy-3-methyl-2-butanone is an inexpensive commercial product. This molecule dictates disconnection 3. Another practical synthesis starts with acetone cyanohydrin and pentylmagnesium bromide (disconnection 2). Many 1,2-difunctional compounds are accessible via oxidation of C—C multiple bonds. In this case the target molecule may be obtained by simple permanganate oxidation of 2-methyl-2-octene, which may be synthesized by Wittig reaction (disconnection 1). 

Miscellaneous Reactions. Sodium bisulfite adds to acetaldehyde to form a white crystalline addition compound, insoluble in ethyl alcohol and ether. This bisulfite addition compound is frequendy used to isolate and purify acetaldehyde, which may be regenerated with dilute acid. Hydrocyanic acid adds to acetaldehyde in the presence of an alkaU catalyst to form cyanohydrin the cyanohydrin may also be prepared from sodium cyanide and the bisulfite addition compound. Acrylonittile [107-13-1] (qv) can be made from acetaldehyde and hydrocyanic acid by heating the cyanohydrin that is formed to 600—700°C (77). Alanine [302-72-7] can be prepared by the reaction of an ammonium salt and an alkaU metal cyanide with acetaldehyde this is a general method for the preparation of a-amino acids called the Strecker amino acids synthesis. Grignard reagents add readily to acetaldehyde, the final product being a secondary alcohol. Thioacetaldehyde [2765-04-0] is formed by reaction of acetaldehyde with hydrogen sulfide thioacetaldehyde polymerizes readily to the trimer. 

Addition of cyanide ion to a carbonyl compound leads to a cyanohydrin, a process with many applications including the synthesis of amino adds via an aminonitrile. The dired reaction between an aldehyde, KCN and NH4CI in acetonitrile leads to a mixture... 

Kiliani-Fischer synthesis is a means of lengthening the carbon backbone of a carbohydrate. The process begins with the reaction of hydrogen cyanide (HCN) with an aldehyde to produce a cyanohydrin. Treatment of the cyanohydrin with barium hydroxide followed by acidification yields an aldose with an additional carbon atom, as shown in Figure 16-16. The formation of the cyanohydrin creates a new chiral center as a racemic mixture. 

Initial preparative work with oxynitrilases in neutral aqueous solution [517, 518] was hampered by the fact that under these reaction conditions the enzymatic addition has to compete with a spontaneous chemical reaction which limits enantioselectivity. Major improvements in optical purity of cyanohydrins were achieved by conducting the addition under acidic conditions to suppress the uncatalyzed side reaction [519], or by switching to a water immiscible organic solvent as the reaction medium [520], preferably diisopropyl ether. For the latter case, the enzymes are readily immobilized by physical adsorption onto cellulose. A continuous process has been developed for chiral cyanohydrin synthesis using an enzyme membrane reactor [61]. Acetone cyanhydrin can replace the highly toxic hydrocyanic acid as the cyanide source [521], Inexpensive defatted almond meal has been found to be a convenient substitute for the purified (R)-oxynitrilase without sacrificing enantioselectivity [522-524], Similarly, lyophilized and powered Sorghum bicolor shoots have been successfully tested as an alternative source for the purified (S)-oxynitrilase [525],... 

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