Valine alkylation

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. 

Several alkyl aryl sulfides were electrochemically oxidized into the corresponding chiral sulfoxides using poly(amino acid)-coated electrodes448. Although the levels of enan-tioselection were quite variable, the best result involved t-butyl phenyl sulfoxide which was formed in 93% e.e. on a platinum electrode doubly coated with polypyrrole and poly(L-valine). Cyclodextrin-mediated m-chloroperbenzoic acid oxidation of sulfides proceeds with modest enantioselectivity44b. 

Subsequently, a number of reactions at poly-L-valine coated carbon electrodes 237-243) gj.g reported to yield optically active products. Reductions, e.g. of citraconic acid or l,l-dibromo-2,2-diphenylcyclopropane as well as the oxidation of aryl-alkyl sulfides proceeded with chiral induction at such electrodes... 

Enantioselective enolate alkylation can be done using chiral auxiliaries. (See Section 2.6 of Part A to review the role of chiral auxiliaries in control of reaction stereochemistry.) The most frequently used are the A-acyloxazolidinones.89 The 4-isopropyl and 4-benzyl derivatives, which can be obtained from valine and phenylalanine, respectively, and the c -4-methyl-5-phenyl derivatives are readily available. Another useful auxiliary is the 4-phenyl derivative.90... 

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. 

Michael reaction of enamines of u-alkyl- -keto esters. The chiral lithioen-amine (1), prepared from (S)-valine /-butyl ester, does not react with methyl vinyl ketone or ethyl acrylate unless these Michael acceptors are activated by ClSi(CH3)3... 

The use of chiral auxiliaries has been developed into elegant three-step sequences to achieve high ee s (Figure 2). In the general scheme a ketone is derivatized with a chiral amine. Low temperature lithiation and alkylation followed by hydrolysis produces the alkylated ketone in moderate to excellent ee s. The auxiliaries most often used are (S)-valine tert-butyl ester (Koga), l-amino-2-methoxymethylpyrrolidine (Enders) and (S)-2-amino-1-... 

The bisthieno[2,3-c 3, 2 -/]azocine 157 containing a bicyclic azocine fragment has been obtained for the first time by cyclization of A/ ,N -bis-(thienyl-2-methyl)valine ester 156 with organolithium compounds (Scheme 42). Compound 156 has been formed by the alkylation of valine ester with thienylmethylbromide in acetonitrile in the presence of potash (98SL1355). 

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. ... 

An example of an ionophore that is a cage carrier is valinomycin (9.56). This cyclic peptide lactone consists of three molecules each of L-valine, D-a-hydroxyisovaleric acid, and L-lactate. The six highly polarized lactone carbonyl oxygens line the inside of the ring, whereas the nonpolar alkyl groups point to the outside of the molecule. Thus... 

Valine-derived (5)-2-ethoxy-4,5-dihydro-4-isopropyloxazole, obtained by alkylation of 4-isopropyl-2-oxazolidinone with Meerwein s reagent, has been used to convert secondary tion and alkylation occurs smoothly to give alkylated derivatives I, which can be deprotected to give tetrahydroisoquinolines 2 with recovery of the chiral auxiliary28. 

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. 

Depending on the nature of the imine, deprotonation and alkylation occurs either at the amine residue or at the carbonyl part of the molecule. Deprotonation of the amine residue (chiral auxiliary), as observed in the reaction of valine derived imines, can be excluded by choosing optimized metalation conditions3. 

Chiral enamines prepared from /f-oxo esters and the tcrt-butyl ester of (.V)-valine are lithiated by LDA (—78 °C, toluene or THF, 1 h)18 19. Both enantiomers of the alkylation product are obtained with a high degree of diastercoselectivity starting from one auxiliary when the reaction is performed under the addition of different ligands (see Table 6). Addition of one equivalent of hexamethylphosphoric triamide (1IMPA) causes coordination of the lithium atom and alkylation from the top side18. 

Unsymmetrical 3,6-dialkoxy-2,5-dihydropyrazines (e.g., 3 and 4), derived from L-valine and either glycine11 or alanine12, respectively, have been more extensively studied. These reagents are commercially available in both enantiomeric forms6. In general, considering diastereomeric excess, alkylation yield and hydrolysis, the best results are obtained with these unsymmetrical derivatives. 

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. 

If a-H-amino acids (e.g L-valine) are employed as the chiral auxiliary, racemization may occur on hydrolytic workup. In order to avoid this racemization, the initial alkylation product has to be hydrolyzed under neutral conditions using a phosphate buffer solution11. 

Due to these limitations Evans et al. focussed on the exploration of imide-derived enolates (165). They expected these systems to react stereoselective in carbon-carbon bond formation and that the derived imides might be readily hydrolized or reduced under the mild conditions required for the construction of complex products, One of the two chiral 2-oxazolidones (175) chosen for study by Evans et al.179) is derived from (S)-valine and was readily prepared from this inexpensive commercially available a-amino acid having an optical purity exceeding 99 %. The preparation of the related imide-derived enolate (165) is shown in the next scheme. Alkylation reactions employing (175) resulted in excellent diastereoface selection, as summarized in Table 4 179). 

The disadvantage in using such symmetrical bislactim ethers is that half the chiral auxiliary ends up as part of the product molecule thus only half of the auxiliary can be recovered and reused. This drawback is avoided in the mixed bislactim ether prepared from a chiral auxiliary (L-valine) and a racemic amino acid (e.g., DL-alanine). Regiospecific deprotonation followed by diastereoselective alkylation leads to the required a-methyl amino acid ester (193) (83T2085) the de is >95%. In this method, the chiral auxiliary (L-valine) is recovered intact. (Scheme 59). 

Using the corresponding (6R) isomer (from D-valine and DL-alanine), alkylation with 2-chloro-3-methyl quinoxaline followed by further transformation has yielded an aldose reductase inhibitor in optically pure form (90T7745). 

Such a rearrangement is not observed with glycine, alanine, 2-aminobutanoic acid or 2-amino-3-cyclohexylpropanoic acid, occurs partially with valine and isoleucine, but is complete with phenylalanine, tyrosine and threonine. By analogy with previous dediazoniation studies on 2-amino acids in acidic media,309 this rearrangement has been explained by the anchimeric assistance of alkyl (Val, lie), aryl (f he, Tyr) or hydroxy (Thr) groups during the dediazoniation process 306 for example, in the case of phenylalanine (4). 

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