Stereoselective cyanation

Photo-oxidation of l,l-dialkyl-2-arylhydrazines by single-electron transfer with trimethylsilyl cyanide (TMSCN) as cyanide ion source leads to regio- and stereoselective a-hydrazino nitriles. This stereoselective cyanation of hydrazines takes place on the more substituted carbon atom compared with the results obtained with tertiary amines (Scheme 5). 

The stereoselective cyanation of [1,1 ]-binaphthalenyl-2,2 -diiodide was developed by M. Putala and co-workers using zinc cyanide and catalytic amounts of Pd(dppf)2. The resulting dinitrile was converted to the corresponding [1,1 ]-binaphthaienyi-2,2 -dicarbaldehyde in high yield using the Stephen reduction. 

Z)-Alk-2-enenitriles are also available from the hydrocyanation of acetylenes, which occurs with cis stereospecificity when catalysed by a nickel(O) complex, and from the stereoselective cyanation of vinyl halides, catalysed by tetracyano-cobaltate(i). The latter procedure is equally applicable to the stereoselective synthesis of the corresponding ( )-isomers. Also, the ( )- and (Z)-isomers (17) and (18) react with piperidine with retention of configuration to provide (19) and (20) respectively (Scheme 30). In contrast, the corresponding reaction with sodium methoxide gives rise to the (Z)-isomer only. 

For this class of reactions, only a few examples which proceed with reasonable diastereoselectivity are known. Allylation of a-methoxycarbamate 1, easily obtained as a 1 1 mixture of isomers by anodic oxidation of protected threonine, produces an 83 17 mixture of enantiomers on treatment with trimethyl(2-propcnyl)silanel03. Cyanation with trimcthylsilyl cyanide proceeds less stereoselectively (67 33 93 % yield). 

Addition of Ketene Acetals and Enoles In recent years, much attention has been given to the synthesis of optically active nitrogen-containing compounds, with the key step being the highly stereoselective nucleophilic addition of ketene silyl acetals to nitrones (Scheme 2.174). Similar to nitrone cyanations, in ketene silyl acetal reactions one observes an accelerating effect with thiourea derivatives (633). 

In addition, stereoselective synthesis of solenopsin A has been reported by four research groups. An approach utilizing the stereoselective reductive de-cyanation (596) starts with aminonitrile 229, prepared from 2-picoline. It was selectively hydrogenated in the presence of Pd-C, followed by alkylation with undecyl bromide, affording 231. Reductive decyanation of 231 with NaBH4 in MeOH led to predominant (8 2) formation of the trans isomer (232) which was then debenzylated to ( )-solenopsin A (Id). The cis product (Ic) was in turn prepared by treatment of 231 with sodium in liquid ammonia followed by de-benzylation (Scheme 10). 

Aldehydes, ketones, and acetals react with allyltrimethylsilane in the presence of a catalytic amount of BiX3 (X = C1, Br, OTf) to give homoallyl alcohols or homoallyl alkyl ethers (Equation (52)).91-93 The BiX3-catalyzed allylation of aldehydes and sequential intramolecular etherification of the resulting homoallylic silyl ethers are involved in the stereoselective synthesis of polysubstituted tetrahydropyrans (Equation (53)).94,95 Similarly, these Lewis acids catalyze the cyanation of aldehydes and ketones with cyanotrimethylsilane. When a chiral bismuth(m) catalyst is used in the cyanation, cyanohydrines are obtained in up to 72% ee (Equation (54)). a-Aminonitriles are prepared directly from aldehydes, amines, and cyanotrimethysilane by the BiCl3-catalyzed Strecker-type reaction. 

Carbonylation of [CoH(CN)5]3- in strongly alkaline media results in the formation of [Co(CN)2-(CO)2]2- and the intermediacy of the short-lived tetracyanocobaltate(I) ion [Co(CN)4]3" in this process has been inferred from mechanistic studies (Scheme 9).15 Under very similar conditions [CoH(CN)s]3- catalyzes the cyanation of vinyl halides to form a,j3-unsaturated nitriles with retention of configuration (equation 6). Oxidative addition of vinyl halide to the intermediate [Co(CN)4]3- ion is stereoselective and in the a complex so produced reductive coupling of the vinyl and cyano ligands gives the stereoretentive organic product and regenerates [Co(CN)4]3-.78... 

The allylation and cyanation of aldehydes and ketones are mediated by BiCl3 and BiBr3 [174, 175]. When a chiral bismuth(lll) catalyst is used for cyanation, cyanohydrins are obtained in up to 72% ee (Scheme 14.85) [175]. The Bi(OTf)3-promoted intramolecular Sakurai cyclization of homoallylic alcohols is involved as a key step in the stereoselective synthesis of polysubstituted tetrahydropyrans (Scheme 14.86) [176]. In the presence of the BiCl3-xMl binary catalyst, allyltrimethylsilane [177] and silyl enolates [178] are acylated to give aUyl ketones and /l-dikelories, respectively. 

The 2,6-czs-dihydropyran 340 was synthesized by the Panek-modified Prins reaction between the chiral aldehyde 338 and the chiral syn-allylsilane 339 mediated by triflic acid. The key point of the stereoselectivity is the sterically hindered electron-withdrawing mesylsulfonate, which induced the chair-like transition state 341. Cyanation, regioselective oxymercuration, and... 

Due to their synthetic utility and pharmaceutical applications, a number of synthetic routes to a,P-unsatuiated nitriles have been developed. Classical methods include dehydration of amides [15] or aldoximes [16], Wittig- [17] and Peterson-type [18, 19] olefination processes, ammoxidation of alkenes [20], and carbocyanation of alkynes [21], These approaches suffer variously from high waste generation, low yields and poor stereoselectivity. As such the transition metal-catalysed cyanation of vinyl halides is an attractive route for the synthesis of alkaiyl nitriles. Whilst several instances of such transformations have been reported in the literature, the area remains underdeveloped, particularly in comparison to analagous cyanations of aryl halides. 

This multi-step scheme illustrates the synthetic efforts that have been invested in the construction of homochiral biaryl 15 without loss of enantiomeric purity. It covers many significant modem synthetic reactions diastereoselective cyanation, of the carbonyl group in (-i-)-9 in step i, promoted by a fi-orientation of the carbonyl oxygen to the orffio-substituent as the result of a stereoelectronic effect [52] oxidative removal of the Cr(CO)3 group in 13 (step vi) and stereoselective azidation with inversion of the configuration (step vii). For more details, the interested reader should consult the cited literature. 

Naked cyanide-acetone cyanohydrin a simple, efficient and stereoselective hydro-cyanating reagent. C. L. Liotta, A. M. Dabdoub and L. H. Zalkow, Tetrahedron Let., 1117(1977)... 

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