Ketimine intermediate

Two unique type Had syntheses of pyrroles that were reported both involved cyclopropane fragmentations. The first allowed for a synthesis of 2-arylpyrroles <06SL2339>. In the event, treatment of stannylcyclopropane 25 with -BuLi followed by benzonitrile produced 2-phenylpyrrole 26 via tin-lithium exchange, addition to the nitrile, ring fragmentation of ketimine intermediate, intramolecular condensation, and loss of dibenzylamine. 

PLP-dependent enzymes catalyze the following types of reactions (1) loss of the ce-hydrogen as a proton, resulting in racemization (example alanine racemase), cyclization (example aminocyclopropane carboxylate synthase), or j8-elimation/replacement (example serine dehydratase) (2) loss of the a-carboxylate as carbon dioxide (example glutamate decarboxylase) (3) removal/replacement of a group by aldol cleavage (example threonine aldolase and (4) action via ketimine intermediates (example selenocysteine lyase). 

Group d). The fourth group of PLP-dependent reactions are thought to depend upon formation of the ketimine intermediate of Eq. 14-28. In this form the original a-hydrogen of the amino acid has been removed and the C = NH+ bond of the ketimine is polarized in a direction that favors electron withdrawal from the amino acid into the imine group. 

Figure 14-10 Models of catalytic intermediates for aspartate aminotransferase in a half-transamination reaction from aspartate to oxalocetate. For clarity, only a selection of the active site groups are shown. (A) Michaelis complex of PLP enzyme with aspartate. (B) Geminal diamine. (C) Ketimine intermediate. The circle indicates a bound water molecule. See Jansonius and Vincent in Jurnak and McPherson.163 Courtesy of J.N. Jansonius.

Thus, two major differences between the reductive alkylation of primary and secondary amines are the increased steric hindrance in the latter case, and the fact that tertiary amine formation cannot proceed through a ketimine intermediate. 

Wu and co-workers developed a synthesis of benzannulated nitrogen heterocycles 120 and 121 based on the addition of sodium methoxide to 2-alkynylbenzo-nitriles 118 in methanol, followed by the Pd(PPh3)4-catalyzed heteroannulation of ketimine intermediate 119 with aryl iodides [104]. The 5-exo versus 6-endo mode of cyclization leading to isoindoles 120 or isoquinolines 121, respectively, proved to be dependent on the nature of the substituent on the terminal alkyne carbon. 2-(2-Phenylethynyl) benzonitrile 118a underwent exclusive 5-exo cyclization whereas 2-(l-hexynyl)benzonitrile 118b led to mixtures of isomers with a marked preference for the 6-endo mode of cyclization. This endo/exo balance was attributed to steric interactions between the entering group and the substituent on the terminal alkyne carbon (Scheme 8.49). 

Early findings by Suzuki and co-workers [109] showed that the palladium-catalyzed iminocarbonylative cross-coupling reaction between 9-alkyl-9-BBN derivatives, t-butylisocyanide, and arylhalides gives access to alkyl aryl ketones 132 after hydrolysis of the corresponding ketimine intermediates 131. Presumably, the concentration of free isocyanide is kept to a minimum by its coordination with the borane. Formation of an iminoacylpalladium(II) halide 130 by insertion of isocyanide to the newly formed arylpalladium complex followed by a transmetallation step afford the ketimine intermediates 131 (Scheme 8.52). 

Investigations show that the active amino group of acetoacetate decarboxylase—the one that is concerned with the formation of the ketimine intermediate—has an especially low pK (26, 27). Model experiments revealed that amines of low pK are the best nonenzymic catalysts in particular, cyanomethylamine led to a rate of decarboxylation that is only a few orders of magnitude less than that for the enzymic system (28, 29, 30). 

Figure 19-10. The pyruvate formation with the N-terminal cysteine. The C-2 carbonyl in pyruvic acid initially forms a ketimine intermediate (A). The sulfhydryl (SH) group of Cys-1 generated from the reduced cysteine 1-98 disulfide bond in Iso tends to favor the formation of the more thermodynamically stable cyclic thiazoUdiae pyruvate intermediate (B).

Protonation at Cq, of the quinonoid intermediate (mechanism A) leads to the formation of the external aldimine of the product and eventually to the release of the amine that usually represents the rate-limiting step of the reaction/ Protonation at C4 (mechanism B) constitutes the main side reaction and leads to the formation of a ketimine intermediate. Actually, the rate of the abortive transamination is very low (about... 

A PLP cofactor attached to the lysine in an His-Lys-X-X-X-Pro-X-Gly-X-Gly motif is a crucial feature of these proteins. Additionally crucial is a conserved cysteinyl residue, which serves as the persulfide site. These proteins belong to fold-type 1 of PLP-dependent enzymes and are homodimers. Each monomer is subdivided into a large domain with one molecule of PLP in aldimine linkage with a Lys residue and a small domain, where the critical cysteinyl residue is located in the middle of a loop. An extended lohe in CDS contains the conserved Cys and constitutes one side of the entrance to the active site. This lohe in CSD may he responsible for the ability of the enzyme to discriminate between selenocysteine and cysteine. NifS binds and transforms the cysteine substrate in a manner usual for PLP-containing enzymes up to the stage of the central quinonoid intermediate. Cysteine desulfuration is initiated by the formation of a Schifif base between cysteine and PLP, followed by the abstraction of sulfur from the substrate and formation of an enzyme-bound cysteine persulfide and alanine via a ketimine intermediate. The cysteine residue acts as a nucleophile and attacks the sulfhydryl... 

Cys desulfurases were also reported to catalyze the decomposition of selenocysteine to L-alanine and elemental selenium with varying efficiency. The catalytic mechanism of both cysteine desulfuration and selenocysteine deselenation is similar. The PLP-binding Lys is the base that accepts the Ca proton of the substrate and reprotonates the intermediate to form a ketimine species. The selenohydryl group of L-seleno-cysteine is probably deprotonated and present in an anionic form. The deprotonation of the selenohydryl group may be facilitated by a His residue, located in the active site. The Cys residue is not essential for deselenation process. Selenium is, then, released spontaneously from the ketimine intermediate. ... 

This class usually include inhibitors able to form stable aromatic products through enzyme-catalyzed aromatization, or stable ketimine intermediates." The generated adducts involve the formation of a covalent interaction between the substrate and the cofactor, but not with the protein, differently from the two previous... 

The higher eukaryotes contain aldolases with mechanisms of action involving the formation of a ketimine intermediate between substrate and an essential ac-... 

Fig. 13, Hypothetical stereochemical mechanism for the pyruvyl-containing amino acid decarboxylases consistent with retention of configuration at the a-carbon of the amino acid. The a-carboxyl function is arbitrarily positioned above the si face of the initial ketimine intermediate.

Ketone synthesis." A method for ketone synthesis is based on A-allylation of 3-methyl-2-aminopyridine and exploiting the coordination ability of the pyridine moiety to stabilize cyclic rhodia-ketimine intermediates that are active in insertion to 1-alkenes. In situ hydrolysis of the demetalated ketimine products affords ketones. 

The oxadiazine ring has been elaborated onto the pyridine ring in both routes reported so far. Cyclocondensation of (231) with phenacyl bromides afforded bicyclic products (232) directly (Scheme 19) <78PJS1, 83JHC381>. When using phenylmethylketones, the ketimine intermediates formed were metallated and then treated with bromine <83JHC38l>. In both approaches excellent yields can be achieved. 

The preparation of aryl ketones can be achieved starting from benzoic acids and nitriles (as the reaction medium) under Pd catalysis via the ketimine intermediates (Scheme 22.11) [20a]. A similar protocol has been developed for the synthesis of aryl amidines replacing the nitrile with a cyan-amide [20b]. 

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