Leucine alkylation

Proteinaceous Surfactants Prepared by Covalent Attachment of L-Leucine / -Alkyl Esters to Food Proteins by Modification with Papain... 

Table VI. Functionality of Products Prepared from Succinylated Proteins by Papain-Catalyzed Attachment of L-Leucine -Alkyl Esters...

New N-vinyloxycarbonyl leucine alkyl esters have been synthesized from vinyl chloroformate and polymerized to yield polymers and copolymers optically and physiologically active with liquid crystals properties (Ref. 146). 

The nonpolar amino acids (Figure 4.3a) include all those with alkyl chain R groups (alanine, valine, leucine, and isoleucine), as well as proline (with its unusual cyclic structure), methionine (one of the two sulfur-containing amino acids), and two aromatic amino acids, phenylalanine and tryptophan. Tryptophan is sometimes considered a borderline member of this group because it can interact favorably with water via the N-H moiety of the indole ring. Proline, strictly speaking, is not an amino acid but rather an a-imino acid. 

Meyers has demonstrated that chiral oxazolines derived from valine or rert-leucine are also effective auxiliaries for asymmetric additions to naphthalene. These chiral oxazolines (39 and 40) are more readily available than the methoxymethyl substituted compounds (3) described above but provide comparable yields and stereoselectivities in the tandem alkylation reactions. For example, addition of -butyllithium to naphthyl oxazoline 39 followed by treatment of the resulting anion with iodomethane afforded 41 in 99% yield as a 99 1 mixture of diastereomers. The identical transformation of valine derived substrate 40 led to a 97% yield of 42 with 94% de. As described above, sequential treatment of the oxazoline products 41 and 42 with MeOTf, NaBKi and aqueous oxalic acid afforded aldehydes 43 in > 98% ee and 90% ee, respectively. These experiments demonstrate that a chelating (methoxymethyl) group is not necessary for reactions to proceed with high asymmetric induction. 

S,N-Ditrityl-L-cysteine diethylamine selt L-Tyrosine lower alkyl ester L-lsoleucine lower alkyl ester Benzyl-L-proline hydrochloride L-Leucine lower alkyl ester Ammonia Hydrogen chloride Glycine lower alkyl ester... 

Alanine, valine, and leucine, (amino-acids with alkyl substituents only) react in a manner very like that of glycine (49—53). All the reactions are rather slow and boiling solutions are normally employed in the preparative reactions. With the cis- and /raws-isomers of Pt(NHs)2Cl2 substitution of the chloride only occurs. Since the tfraws-labilising influence of the incoming groups of the amino-acids is very small, the —NH2 groups remain stable. Consequently chelated complexes are only formed by the amino-acids in the case of the cts-isomer. 

Rapid monoalkylations are achieved in good yield compared with classical methods. Of particular interest is the synthesis of ot-amino acids by alkylation of aldimines with microwave activation. Subsequent acidic hydrolysis of the alkylated imine provides leucine, serine, or phenylalanine in preparatively useful yields within 1-5 min [50], Alkylation of phenylacetonitrile was performed by solid-liquid PTC in 1-3 min under microwave irradiation (Eq. 36 and Tab. 5.14). The nitriles obtained can subsequently be quickly hydrolyzed in a microwave oven to yield the corresponding amides or acids [56]. 

The biomimetic protocol was invented by Julia and Colonna, and involves the use of polyamino acids (such as poly-(L)-leucine) as the catalysts for peroxide oxidation of chalcones, styryl alkyl ketones and conjugated alkenones. The substrate range is broad, especially when using immobilized catalysts and an organic solvent containing the substrate, urea-hydrogen peroxide and an organic base (Scheme 22)[101]. 

The nonpolar or hydrophobic amino acids—glycine, alanine, valine, leucine, and isoleucine-have alkyl side chains (or simply a hydrogen atom in the case of glycine). 

The numerous preparations of mono-, di-, tri-, and hexafluoro derivatives of valine, norvaline, leucine, norleucine, and isoleucine, using classical methods of amino acid chemistry (e.g., amination of an a-bromoacid, " azalactone, Strecker reaction, amidocarbonylation of a trifluoromethyl aldehyde, alkylation of a glycinate anion are not considered here. Pure enantiomers are generally obtained by enzymatic resolution of the racemate, chemical resolution, or asymmetric Strecker reaction. ... 

Figure 2.1 Schematic diagram of the hydrophobic interaction between two leucine side chains of a protein. By displacing part of the hydrate envelope, the two alkyl side chains occupy the same water cavity while many of the water molecules (represented by circles) become randomized. Thus the entropy of the system increases, resulting in a favorable stabilization.

Alkylation of the 4-substituted lactone (35), derived from the (1 / )-leucine methyl ester, is an example of a very efficient 1,3-induction25. 

In addition, the /erf-butyl esters of valine and tert-leucine are excellent chiral auxiliaries in asymmetric alkylation of their imines. These chiral auxiliaries are preferentially used in the alkylation of cyclic ketones (73 to >99% ee)17 and /i-oxo esters (44 to >99% ee)18,, 9 and the absolute configuration of the products can be safely predicted. 

Instead of alanine and valine, several other chiral auxiliaries have been used, such as tert-leucine13, leucine14 and isoleucine15. In some cases diastereomeric excesses may be higher with the dihydropyrazines 5 and 6, derived from 0,0-dimethyl-alkylation with 3-bromo-propyne gives a de of 60% with (2S)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazine (3), in contrast to 85% de with 516 and >95% de with 613. 

From the different substituted 3,6-dialkoxy-2,5-dihydropyrazines tested, the /erf-leucine/ glycinc-derived derivative (1 R1 = t-Bu R2 = H) gives the highest diastereomeric excess in alkylations of the lithiated derivatc (typically >95% de)13. However, the relative cost and availability of tot-leucine limits the broad utilization of this derivative. The commercially available valinc/glycine-based dialkoxydihydropyrazine (see Section 1.1.1.4.6.1.) represents the best alternative in terms of de (90 to >95%), alkylation yield, and yield of hydrolysis. 

Alkylation of this derivative and subsequent hydrolysis provides optically pure or almost pure 2-alkylated 2-amino-4-methylpentanoates 3 (a-alkylated leucine derivatives)14. However, hydrolysis of the alkylated dihydrodimethoxypyrazines 2 to the amino acid methyl esters proceeds rather slowly compared to the mono-substituted systems, and even fails in some cases. 

Musty or potato-like flavor and aroma have been observed as a defect in milk (Hammer and Babel 1957) and Gruyere de Comte cheese (Dumont et al. 1975). This off-flavor results from the production of nitrogenous cyclic compounds by Pseudomonas taetrolens and P. perolens (Morgan 1976). Musty-flavored compounds produced by these organisms include 2,5-dimethylpyrazine and 2-methoxy-3-isopropyl-pyrazine. The Gruyere de Comte with potato off-flavor contained 3-methoxy-2-propyl pyridine, as well as alkyl pyrazine compounds (Dumont et al. 1975). Murray and Whitfield (1975) postulated that alkyl pyrazines are formed in vegetables by condensation of amino acids such as valine, isoleucine, and leucine with a 2-carbon compound. Details of the synthetic mechanism in pseudomonads are unknown. 

Reaction type 6C (Table 10-1) occurs during the biosynthesis of leucine and valine (Fig. 24-17). The rearrangement is often compared with the nonenzy-matic acid-catalyzed pinacol-pinacolone rearrangement in which a similar shift of an alkyl group takes place (Eq. 13-57). The enzyme-catalyzed rearrangement... 

The asymmetric addition of organomagnesium and organolithium reagents to a,P-unsaturated carbonyl compounds and especially imines can be achieved in situations where rigid chelation controls the geometry of the transition state. Stereospecific alkyl addition occurs in the case of a chiral leucine-derived imine to provide overall asymmetric alkyl addition to an a,P-unsaturated aldehyde (Scheme 107).380 381... 

The best preventive measure against racemization in critical synthetic steps (e.g. fragment condensation, see p. 239) is to use glycine (which is achiral) or proline (no azlactone) as the activated carboxylic acid component. The next best choice is an aliphatic monoamino monocarboxylic acid, especially with large alkyl substituents (valine, leucine). Aromatic amino acids (phenylalanine, tyrosine, tryptophan) and those having electronegative substituents in the /7-position (serine, threonine, cysteine) are, on the other hand, most prone to racemization. Reaction conditions that inhibit azlactone formation and racemization are non-polar solvents, a minimum amount of base, and low temperature. If all precautions are taken, one still has to reckon with an average inversion of 1 % per condensation reaction. This means, for example, that a synthetic hectapeptide contains only 0.99100 x 100% = 37% of the fully correct diastereomer (see p. 233 f.). 

---