Cyanohydrin 1-acylation

Effenberger and coworkers have utilized the tolerance of methyl ketones by the recombinant enzyme to develop an alternative synthesis of tetronic acids and their amino derivatives, as shown in Figure 5.18. Treatment of O-acyl cyanohydrins with lithium disilazide resulted in base-induced ring closure to amino tetronic acid derivatives. Alternatively, the cyanohydrins could be converted to a-hydroxy esters prior to acylation, and the same base-induced cyclization then led to tetronic acid derivatives [89]. 

DBU catalyses cyanoacylation of ketones, R OR2, with aromatic acyl cyanides giving O-acyl cyanohydrin adducts, ArOCO-C(CN)R1R2, in fair to good yields in 2 h at ambient temperature.256... 

Thus, the O-acylated cyanohydrins 81 are cyclized in the presence of perchloric acid to 2-oxazolin-4-onium salts 82, which are then deprotonated to the corresponding 2-oxazolin-4-ones 8368,69 (equation 30). 

In particular, the use of hydroxynitrile lyase has proved to be a general and reliable method for obtaining a-hydroxy nitriles of both configurations [22]. An interesting approach is the Upase- and baseacyl-cyanohydrin for a synthetic DKR [23]. This is a combination of two reaction systems the dynamic, base-catalyzed equiUbrium between acetone cyanohydrin, acetone, HCN, aldehyde and a racemic cyanohydrin and the lipase-catalyzed enantioselective and irreversible acylation of the hydroxyl group. The combination yields the... 

Keywords cyanohydrins, trimethylsilyl cyanide, 0-acyl cyanohydrine... 

Acyl cyanides have also been used with catalytic amounts of 19 in the presence of a Lewis base, giving acylated cyanohydrins with high yields and enantiomeric excesses (entry 2). Similarly, ethyl cyanoformate led to cyanohydrin carbonates (entry 3). ° Interestingly, catal5Aic amounts of... 

The enantiomeric excess of the acylated cyanohydrins was increased by treating the product with a suitable lipase enzyme that only hydrolysed the minor enantiomer. High enantiomeric excesses of the remaining major enantiomer were obtained (up to 99% enantiomeric excess with benzaldehyde). ... 

Khan and coworkers prepared the ligand 23, which led to complex 24 bearing four titanium atoms after the addition of titanium tetraisopropoxide and water (Scheme 7.17). The cyanation of aldehydes with KCN/AC2O works similarly to complex 19, giving acylated cyanohydrins in nearly quantitative yields and 85-95% enantiomeric excesses. Importantly, complex 24 precipitated after addition of hexane to the reaction mixture, and the filtrated catalyst was reused without affecting the enantiomeric excess (the yield decreases to 88% after 4 runs). 

Dimeric titanium-salen, prepared from macrocyclic chiral salen ligand 26, was used in the preparation of acyl cyanohydrins from aldehydes and ethylcyanoformate (Scheme 7.18). A ligand/metal ratio of 1 2 was found to be optimum for the enantioselectivity, confirming the dimeric titanium-salen structure as the catal34ically active complex. This was strengthened by the observation of a linear correlation between the enantiomeric excesses of... 

Hamberg, A., Lundgren, S., Wigstrand, E., Moberg, C., and Hull, K. (2007) High-throughput synthesis and analysis of acylated cyanohydrins. 

Enantiomerically enriched O-trimethylsilyl cyanohydrins were transformed directly into O-acyl-cyanohydrins using various anhydrides or acid chlorides in the presence of a catalytic amount of Sc(OTf)3 (Scheme 12.40) [94]. 

In addition, Moberg et al. have reported a synthesis of enantioenriched O-acylated cyanohydrins cooperatively catalysed by a chiral titanium complex and an achiral base such as TEA. The reaction occurred between acyl cyanides and prochiral aldehydes in dichloromethane at —40 °C, providing the corresponding O-acylated cyanohydrins in good to high yields (64-93%) and moderate to high enantioselectivities ranging from 20 to 96% ee. As shown in Scheme 7.17, it was supposed that the Lewis acid was able to activate both the acyl cyanide and the aldehyde whieh was verified by NMR spectroseopy, and the Lewis base simultaneously served to liberate the... 

Scheme 7 Chirality transfer in unsaturated O acyl cyanohydrins.

The Reforrnatsku reaction of a-halogenated carboxylic esters with silylated cyanohydrins combined with an intramolecular acylation reaction gives fluorinated derivatives of tetronic acid [28] (equation 17) It is noteworthy to mention that this particular reaction sequence only proceeds with ultrasonic irradiation A very... 

Besides acylation and alkylation reactions, typical carbonyl reactions, such as reduction and substitution, are known. Thus, the oxo group in position 3 of 8 is attacked by sodium cyanide, resulting in the cyanohydrin in 55% yield. Subsequent dehydration with p-toluene-sulfonic acid and acetylation in position 5 gives 1-benzothiepin 12.90... 

Very few optically active cyanohydrins, derived from ketones, are described in the literature. High diastcrcosclectivity is observed for the substrate-controlled addition of hydrocyanic acid to 17-oxosteroids27 and for the addition of trimethyl(2-propenyl)silane to optically active acyl cyanides28. The enantioselective hydrolysis of racemic ketone cyanohydrin esters with yeast cells of Pichia miso occurs with only moderate chemical yields20. 

Protected cyanohydrins may be employed as acyl anion equivalents in 1,4-additions in the presence of HMPA129. For instance cyanohydrins prepared from arylaldehydes add in a 1,4-fashion under thermodynamic control (THF or THF/HMPA) to cyclohexenone, isophorone and decalone systems in the latter case c/.s-octahydro-2(l/f)-naphthalenones are exclusively obtained 130-131. 

Several reports on DKR of cyanohydrins have been developed using this methodology The unstable nature of cyanohydrins allows continuous racemization through reversible elimination/addition of HCN under basic conditions. The lipase-catalyzed KR in the presence of an acyl donor yields cyanohydrin acetates, which are not racemized under the reaction conditions. 

In 1992, Oda et al. reported a one-pot synthesis of optically active cyanohydrin acetates from aldehydes, which were converted to the corresponding racemic cyanohydrins through transhydrocyanation with acetone cyanohydrin, catalyzed by a a strongly basic anion-exchange resin [46]. The racemic cyanohydrins were acetylated by a lipase from P. cepacia (Amano) with isopropenyl acetate as the acyl donor. The reversible nature of the base-catalyzed transhydrocyanation enabled continuous racemization of the unreacted cyanohydrins, thereby effecting a total conversion (Figure 4.21). 

Stork first demonstrated the utility of protected cyanohydrins as acyl anion equivalents in 1971 [2]. The acetal-protected cyanohydrin 8 was transformed into the corresponding anion with LDA in THF/HMPA, which was then alkylated with a range of alkyl halides, including secondary bromides (Scheme 2). A mild acidic hydrolysis yielded a cyanohydrin, which provided the ketone after treatment with base. The Stork cyanohydrin alkylation and its variants have become important methods in natural product synthesis [3,4]. 

The reaction of aldehydes with MnOz in the presence of cyanide ion in an alcoholic solvent is a convenient method of converting aldehydes directly to esters.214 This reaction involves the cyanohydrin as an intermediate. The initial oxidation product is an acyl cyanide, which is solvolyzed under these reaction conditions. 

The cyclobutane ring was then cleaved by hydrolysis of the enamine and ring opening of the resulting (3-diketone. The relative configuration of the chiral centers is unaffected by subsequent transformations, so the overall sequence is stereoselective. Another key step in this synthesis is Step D, which corresponds to the transformation 10-IIa => 10-la in the retrosynthesis. A protected cyanohydrin was used as a nucleophilic acyl anion equivalent in this step. The final steps of the synthesis in Scheme 13.11 employed the C(2) carbonyl group to introduce the carboxy group and the C(l)-C(2) double bond. 

Curtius reaction org chem A laboratory method for degrading a carboxylic acid to a primary amine by converting the acid to an acyl azide to give products which can be hydrolyzed to amines. kard e as re,ak-shan cyanaicohoi See cyanohydrin.. sT an al ka.hol ... 

In conjunction with the establishment of the cyanohydrin DCL, the DCR process was subsequently addressed. Thus, selected lipases and a suitable acyl donor [isopropenyl acetate (34)] were applied to the system (Scheme 6.7). This selective enzymatic resolution of the DCL provided cyanoacetate product (35) as the major product at the reaction conditions used, thus demonstrating the efficiency of the concept. 

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