Ketimines deprotonation

For methyl ketimines good regiochemical control in favor of methyl deprotonation, regardless of imine stereochemistry, is observed using LDA at -78° C. With larger A-substituents, deprotonation at 25° C occurs anti to the nitrogen substituent.115... 

However, the syn and anti isomers of imines are easily thermally equilibrated. They cannot be prepared as single stereoisomers directly from ketones and amines so this method cannot be used to control regiochemistry of deprotonation. By allowing lithiated ketimines to come to room temperature, the thermodynamic composition is established. The most stable structures are those shown below, which in each case represent the less substituted isomer. 

Aminotransferases (transaminases) catalyze the reversible interconversions of pairs of a-amino and a-keto acids or of terminal primary amines and the corresponding aldehydes by a shuttle mechanism in which the enzyme alternates between its PLP form and the corresponding PMP form. In the first half-reaction the PLP form of the enzyme binds the amino acid (or amine) and forms the coenzyme-substrate Schiff s base. Cleavage of the C-a—H bond is then followed by protonation at C-4. Hydrolysis of the resulting ketimine then gives a keto acid (or aldehyde), leaving the enzyme in the PMP form. The latter is recycled to the PLP form by condensation with an a-keto acid, deprotonation at C-4, protonation at C-a and transaldimina-tion to release the a-amino acid formed. 

Racemization of the Amino Acid Substrate Deprotonation of the a-carbon of the amino acid leads to tautomerization of the Schiff base to the quinonoid ketimine, as shown in Figure 9.2. The simplest reaction that the ketimine can undergo is reprotonation at the now symmetrical a-carbon. This is not a stereospecific process therefore, displacement of the substrate by the reactive lysine residue results in the racemic mixture of d- and L-amino acid. 

The deprotonated aldimine is reprotonated at carbon-4 by reaction with a histamine residue to form the pyridoxamine phosphate ketimine. Hydrolysis of this complex yields the free oxoacid (oxaloacetate), leaving pyridoxamine phosphate at the catalytic site (Ivanov and Karpeisky, 1969). 

The Af,0-enolato ligands 146 are usually prepared by deprotonation of the corresponding conjugated acids which, for ketimines, can be formulated as consisting of the tautomeric forms 147-149. However, some of them have been prepared (i) by reacting nitriles with the corresponding S-diketonato complexes, or with 2-oxoalkyl or enolato complexes (Section in.C, Chapter 6 ) or (ii) by oxidation of diketoamines with metal complexes in the presence of a base (Section n.B.3). Although the most abundant tautomeric form of a S-ketimine depends on the nature of the substituents, they wiU be represented as 148. 

Asymmetric Synthesis of a-Amino Acids. Chiral ketimines prepared from the title ketone and glycinates can be deprotonated and treated with electrophiles, such as alkyl halides (eq 1), or Michael acceptors, to give a-subsdtuted a-amino acids with moderate to excellent levels of diastereoselectivity. 

Compared with aldehydes and ketones, aldimines and ketimines are less reactive towards nucleophilic addition. Furthermore, imine additions are subject to steric constraints, and rapid deprotonation proceeds with imines bearing ot-hydrogen atoms. The Lewis acid promoted addition methodology has provided a solution to these problems. 

Recent research by Bergbreiter, Newcomb, Meyers and their respective coworkers has shown that a variety of factors, such as the base, the temperature of deprotonation, and the size of the substituent on nitrogen, control the structure of the metallated imine and ultimately the regiochemistry of the alkylation reaction. In contrast to metal enolates, where the more-substituted species is usually the more thermodynamically stable, less-substituted sy/i-metallated ketimines, e.g. (89), are the most thermodynamically stable of the possible isomers of unsymmetrical systems. An explanation for the greater stability of syn imine anions compared with anti imine anions has been presented by Houk, Fraser and coworkers. ... 

The first examples of alkylations at the more-substituted position of an unsymmetrical ketimine were actually reported by Hosomi et al., who carried out deprotonations with alkyllithium reagents at lower temperatures (Scheme 47). 

Fortunately, the use of lithiated hydrazones derived from (S)- or ( )-l-amino-2-methoxymethylpyiro-lidine (SAMP or RAMP) as nucleophiles for asymmetric alkylations have provided a solution to the problems described above with metallated acyclic ketimines and aldimines. Lithiated SAMP or RAMP hydrazones of cyclic ketones are also alkylated in high yields. A major advantage of these chiral hydrazones is that their derivatives of aldehydes, acyclic and cyclic ketones all yield mainly ( )cc-. (Z)cN-Iithiated species on deprotonation with LDA in ethereal solvents under kinetic control. The ( )cc-configuration obtains as a result of the minimization of steric interactions in the usual closed transition... 

Grignard reagents as bases alkyllithium reagents are not generally useful because of competing addition to the carbon-nitrogen double bond. Depending upon the experimental conditions e.g. solvent, temperature and base) and the nature of the N-substituent, deprotonation of the unsymmetrical ketimines (2 =... 

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. ... 

Deformylation of the cleavage product yields L-kynurenine, which is the substrate for hydrolytic C—C cleavage by kynureninase, a pyridoxal 5 -phosphate-dependent enzyme. The a-amino group of L-kynurenine is attached to the PLP cofactor, and deprotonation of the a-carbon forms a ketimine linkage, which provides an electron sink to assist C-C hydrolytic cleavage, as shown in Figure 27. 

The most usual reagent for the metallation of aldimines and ketimines and the corresponding hydrazines is LDA. The lithiations are generally carried out in mixtures of THF and hexane. The formation of the lithium derivatives, which proceeds rather smoothly at temperatures in the region — 30 to + 10 °C, is visible by the appearance of a yellow colour. The use of BuLi cannot be recommended, since addition of this reagent across the C=N bond may seriously compete with the deprotonation. 

To a solution of lithium diisopropylamide (LDA, 0.105-0.150 mol) at 0°C in 150 mL THF (prepared from 0.105-0.150 mol n-BuLi and 0.2 mol diisopropylamine) was added a solution of 0.1 mol a-chloro ketimine in 20 mL THF. The deprotonation was complete after 2 h at 0°C, then 0.1-0.2 mol acetone was added dropwise to the solution of 3-chloro-1-aza-allylic anion. After the addition, the reaction mixture was stirred for 10 h at room temperature. The reaction mixture was then poured into water and extracted with ether (3 X100 mL). The combined extracts were dried over MgS04, and the solvent was removed under reduced pressure. The product was purified via vacuum distillation between 50°C and 60°C at 13 mmHg. 

The possibilities for the formation of carbon—carbon bonds involving aromatic compounds have been enormously enhanced by the use of transition metal catalysts, and this area has been the subject of several reviews. Some of these concentrate on the applications of specific metals, and there have been surveys of the use of compounds of silver, copper and nickel,mthenium, and palladium in catalysis. The metalation of carbon-hydrogen bonds, preceding functionalization, may be aided by carboxylate ions, and this subject has also been reviewed. There is evidence here for concerted base-assisted deprotonation as shown in (10). In the carboxylate-assisted reaction of aryl ketimines with alkyl halides, a ruthenium-bonded intermediate (11) has been proposed, which subsequently adds the alkyl halide. " ... 

---