Conjugate addition of cyanide

Formal oxidation of pyrrolidine to the succinimide stage affords a series of compounds used as anticonvulsant agents for treatment of seizures in petit mal epilepsy. Knoevnagel condensation of benzaldehyde with ethyl cyanoacetate affords the unsaturated ester, 9. Conjugate addition of cyanide ion leads to the di-nitrile ester (10). Hydrolysis in mineral acid affords the succinic acid (11), presumably by decarboxylation of the intermediate tricarboxyllie acid. Lactamization with methylamine gives phensuximide (12). ... 

Diethylaluminum cyanide mediates conjugate addition of cyanide to a, (3-unsaturated oxazolines. With a chiral oxazoline, 30-50% diastereomeric excess can be achieved. Hydrolysis gives partially resolved a-substituted succinic acids. The rather low enantioselectivity presumably reflects the small size of the cyanide ion. 

The medicinal chemists subsequently discovered an improved route to racemic acid 9 that started with 2-bromo-2-cyclopente-l-one 11 (Scheme 7.2) [5]. Suzuki-Miyaura cross-coupling of 11 with 4-fluorophenyl boronic acid 12 provided 13 in 67% yield. Conjugate addition of cyanide furnished ketone 14 in 71% yield. Reduction of 14 with NaB H4 gave a 2.8 1 mixture of desired 15 and undesired 16 which were separated by silica gel chromatography. The observed diastereoselec-tivity with the cyano group was similar to ester 6. Hydrolysis of 15 with 5 M NaOH in MeOH gave racemic acid 9 in 91% yield, which was resolved as outlined in Scheme 7.1. 

Such dideoxynucleosides as CNT (306) and the potent anti-HIV drug ddC (307) have been obtained (280), respectively, from the butenolide 248 and from its saturated analogue. Thus, conjugate addition of cyanide to 248, followed by reduction of the lactone group, acetylation of HO-1, and coupling with silylated thymine, afforded, after deprotection, compound 306. 

Triethylaluminum-hydrogen cyanide and diethylaluminum cyanide are also useful reagents for conjugate addition of cyanide. The latter is the more reactive of the two reagents. These reactions presumably involve the coordination of the aluminum reagent as a Lewis acid at the carbonyl oxygen. 

Phosphorous oxychloride (POCI3) can also be used without further activation. For the synthesis of the antidepressant (/ )-(—)-rolipram 24, cyclization of the (3-hydroxy amide 21 with POCI3 gave the oxazoline intermediate 22. Diastereo-selective conjugate addition of cyanide gave the cyano derivative 23, which was further transformed to (/ )-( )-rolipram (Scheme 8.11). 

In recent years, Ireland and his colleagues have made a major contribution to the total synthesis of tetra- and penta-cyclic triterpenoids. The details of some of this work have been published in a series of papers.55-58 The tetracyclic ketone (75) was conceived as a key intermediate in the synthesis of shionone (76). Three routes to (75) were undertaken.55 The most efficient involved a triethylaluminium-catalysed conjugate addition of cyanide to the enone (77) (see Vol. 5, p. 135). The second... 

What is the controlling factor in the stereochemical outcome of the conjugate addition of cyanide to enone 1 ... 

Hydrocyanation of the unsaturated aldehyde (287) under mild conditions afforded the cyanohydrin (288), the product of kinetic control. More forcing conditions led to the 16a-cyano-aldehyde (289). " A cyanohydrin is unstable only in a relatively hindered site such as C(20) attempted conjugate addition of cyanide to the unsaturated B-nor-aldehyde (290) was Unsuccessful. 

A sugar-based ligand such as 172 served as a promising chiral ligand for the catalytic enantioselective conjugate addition of cyanide to a, 8-unsaturated A-acylpyrroles as shown in... 

The formation of the a-bond has been carried out by conjugate addition of cyanide ion, used as a carboxy anion equivalent, to 2-phenylsulfonyl 1,3-dienes followed by functional group transformation and final... 

Two distinct chiral metal complexes operate cooperatively to catalyze a highly enantioselective conjugate addition of cyanide to unsaturated imides (Scheme 5). Under optimized conditions, the dual-catalyst system afforded distinctly superior results relative to the (salen)AlCl complex. 

The conjugate addition of cyanide to a,p-unsaturated carboxylic acid derivatives provides versatile chiral building blocks. The resulting -cyano adducts can be converted into y-aminobutyric acids (GABA analogues) under reducing conditions, 1,2-dicarboxylic acids via hydrolysis, and -amino acids via Curtius rearrangement. 

Lanthanide Bimetallic and Polymetallic Asymmetric Catalysts 687 Table 13.32 Catalytic asymmetric conjugate addition of cyanide to a,p-unsaturated imides (S,S)-[(salen)AI]20 (2 mol%)... 

Scheme 13.34 Catalytic asymmetric conjugate addition of cyanide to p-aryl, alkyl, and alkenyl ap-unsaturated /V-acyl pyrroles.

Thus, the asymmetric catalysis of cyanoethoxycarbonylation, cyanophosphoryla-tion, epoxidation of electron-deficient olefins, Michael reactions of malonates and (3-keto-esters, Strecker reaction of keto-imines, conjugate addition of cyanide to a, (3-unsaturated pyrrole amides, ring opening of meso aziridines with TMSCN and cyanosilylation of ketones (example shown below) have been successfully carried out using these complexes as asymmetric catalysts. 

This chemistry was extended to a catalytic conjugate addition of cyanide to cx-substituted cx,p-unsaturated fV-acylpyrroles 15 followed by enantioselective protonation (Scheme 13) [53]. In this reaction, gadolinium enolate was generated in situ via conjugate addition of a gadolinium isonitrile to 15. Products 16 containing cx-secondary alkyl- and a-aryl-substimted tertiary stereocenters, which are usually difficult to access via enantioselective alkylation or arylation, were successfully produced, in addition to a-methyl and ethyl-substituted A -acylpyrroles. 

Catalytic Enantioselective Conjugate Addition of Cyanide to P,P-Disubstituted afi-Unsaturated Carbonyl Compounds... 

Scheme 16 Catalytic enantioselective conjugate addition of cyanide to P,P-disubstituted a,P-unsaturated carbonyl compounds...

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