Asymmetric cyanohydrin synthesis

Groger, H., Copan, E., Bathuber, A. and Vorlop, K. (2001) Asymmetric synthesis of an (R)-cyanohydrin using enzymes entrapped in lens-shaped gels. Organic Letters, 13, 1969-1971. 

Duffield, J.J. and Regan, A.C. (1996) Asymmetric synthesis of tetronic acids by Blaise reaction of protected optically active cyanohydrins. Tetrahedron Asymmetry, 7, 663-666. 

The first report on the reaction of D-pseudoephedrine 66 with phosphoryl chloride appeared as early as 1962 [49], More recently it was found that this condensation gave 2-chloro-l,3,2-oxazaphospholidine 2-oxides 67 as a single diastereomer which was subsequently esterified with racemic aldehyde cyanohydrins 68 without racemization at the phosphorus atom. The prepared diastereomeric esters 69 were used as substrates for the asymmetric synthesis of optically active cyanohydrins 72, which involves the intermediate formation of the tertiary esters 70, as shown in Scheme 22 [50],... 

Scheme 22 Asymmetric synthesis of optically active cyanohydrins 72...

This example (the cyanohydrin reaction) appears to me to provide a simple solution for the natural asymmetric synthesis. The formation of the sugar, as the plant physiologists assume, occurs in the chlorophyll grain, which itself is composed of optically active substances.. . . The prepared sugar is released and later on used by the plant, as is known, for the preparation of other organic components. Their asymmetry is thus explainedfrom the nature of the building material. Of course, they also provide material for new chlorophyll... 

It is of some historical interest that Kiliani s cyanohydrin synthesis (24) enabled Emil Fischer (25) to carry out the first asymmetric synthesis. Lapworth (26) used this base-catalyzed nucleophilic 1,2-addition reaction in one of the first studies of a reaction mechanism. Bredig (27,28) appears to have been the first to use quinine (29) in this reaction as the chiral basic catalyst. More recently, others (20) have used basic polymers to catalyze the addition of cyanide to aldehydes. The structure of quinine has been known since 1908 (30). Yet it is of critical importance that Prelog s seminal work on the mechanism of this asymmetric transformation (eq. [4]) could not have begun (16) until the configuration of quinine was established in 1944 (31,32). 

Roberge, C., Eleitz, E., Pollard, D. and Devine, P., Asymmetric synthesis of cyanohydrin derived from pyridine aldehyde with cross-linked aggregates of hydroxynitrile lyases. Tetrahedron Lett., 2007, 48, 1473-1477. 

Nanda, S., Kato, Y. and Asano, Y., A new (i )-hydroxy-nitrile lyase from Prunus mume asymmetric synthesis of cyanohydrins. Tetrahedron, 2005, 61, 10908. 

A New (/ )-Hydroxynitrile Lyase from Prunus mume for Asymmetric Synthesis of Cyanohydrins... 

A new hydroxynitrile lyase (HNL) was isolated from the seed of Japanese apricot Prunus mume). It accepts benzaldehyde and a large number of unnatural substrates for the addition of HCN to produce the corresponding (7 )-cyanohydrins in excellent optical and chemical yields. A new high-performance liquid chromatography (HPLC)-based enantioselective assay technique was developed for the enzyme, which promotes the addition of KCN to benzaldehyde in a buffered solution (pH 4.0). Asymmetric synthesis of (7 )-cyanohydrins by a new HNL is described (Figure 8.4). ... 

Table 8.3 HNL-catalyzed asymmetric synthesis of cyanohydrins with aromatic aldehydes...

The chiral titanium reagent preparerd in situ from the chiral 1,4-diol and dichlorodiisopropoxytitanium is expected to be applicable to various reactions catalyzed by Lewis acids. We, therefore, investigated the asymmetric synthesis of cyanohydrins from aldehydes and cyanotrimethylsilane employing the chiral titanium reagent.(20)... 

Asymmetric synthesis of cyanohydrins is an important process in organic synthesis because cyanohydrins can be easily converted into a variety of valuable synthetic intermediates such as a-hydroxy acids, a-hydroxy ketones, and g-amino alcohols. 

L. Garcia Ruano, A. M. Martin Castro, and J. H. Rodriguez, Reactions of chiral [3-ketsul-foxides with HtyV( N Asymmetric synthesis of cyanohydrin derivatives. Tetrahedron Lett. 52 3195 (1991). 

J. D. Elliott, V. M. F. Choi, and W. S. Johnson, Asymmetric synthesis via acetal templates. 5. Reactions with cyanotrimethylsilane. Enantioselective preparation of cyanohydrins and derivatives, J. Org. Chem. 78 2294 (1983). 

In general, the method of enzymatic cyanohydrin synthesis promises to be of considerable value in asymmetric synthesis because of the synthetic potential offered by the rich chemistry of enantiomerically pure cyanohydrins, including their stereoselective conversion into other classes of compounds such as a-hydroxy carboxylic acids or respective esters, w c-diols, / -aminoalcohols, aziridins, a-azido(amino/fluoro)nitriles, and acyloins [501, 516]. 

For recent reviews/highlights on the asymmetric synthesis (by enzymatic, organocatalytic and organometallic methods) of cyanohydrins and their applications, see references 2-8. 

The reinvestigation of Breding s asymmetric cyanohydrin synthesis by Prelog during the mid-1950s [33] undoubtedly promoted the concept of asymmetric synthesis, and led the way to more efficient reactions. The advent of synthetically useful levels of enantioselectivity can be dated to the late 1950s, when Pracejus reported that methyl phenyl lcetene could be converted to (—)-a-phenyl methylpro-pionate in 74% ee by using O-acetylquinine as catalyst [34]. 

Optically active a-hydroxy carboxylic acids are useful intermediates in medicinal chemistry and asymmetric synthesis (Coppola and Schuster 1997). Enantioselective biotransformations of a-hydroxy nitriles (cyanohydrins) are important because they can lead to a dynamic kinetic resolution from readily available starting material. 

Givens58 and Pirrung59 used photolabile 3 3 -dimethoxybenzoin esters for the protection of phosphotriesters. A complication attending the use of racemic 3 5 dimethoxybenzoin is the generation of four diastereoisomers if the phosphate is chiral. An asymmetric synthesis of 3, 5 -dimethoxybenzoin 303 [Scheme 7.30] via the 0-trimethylsilyl-3,5-dimethoxybenzaldehyde cyanohydrin 303 minimises the number of diastereoisomers created in the phosphorylation of chiral alcohols. Thus reaction of 303 with 2 - cyanoethoxy)(NPNf-diisopropy amino)-chlorophosphine afforded the phosphoramidite 30.4 which then reacted with Boc-Ser-OMe to give the two diastereoisomeric phosphotriesters 303, Photode-... 

Asymmetric synthesis by means of a cyandiydrin is an imprvtant process in organic synthesis, because the cyanohydrin can be easily converted into a variety of valuable synthetic intermediates, such as a-hy-droxy ketones, a-hydroxy acids, y-diketones, p-amino alcohols, 4-oxocarboxylic esters, 4 xonitriles, a-amino acids and acyl cyanides. More specifically, the (S)-cyanohydrin of m-phenoxybenzaldehyde is a building block for the synthesis of the insecticide deltamethrin, or (IR)-cis-pyrethroids. ... 

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]. 

Although these resolution techniques can be successfully employed in some cases, they cannot compete with the direct asymmetric synthesis of optically active cyanohydrins. 

Thus, the preparation of the optically active cyanohydrins and aminonitriles has been a major topic of interest in the field of asymmetric synthesis. However, a practical method for cyanation was not reported until the early 1980 s, except for the use of an enzyme, oxynitrilase a flavoprotein isolated from seeds and blossoms of various Prunaceae species, which catalyzes the addition of hydro-... 

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