Esters formed from valine

Chiral diester diamide macrocycles such as ll-180 have been synthesized (181) from esters of L-valine by, first of all, forming acyclic bisamides and then hydrolyzing the ester functions prior to template-promoted cyclization with cesium carbonate (182) and the appropriate dibromide. L-Tartaric acid has also been incorporated into a macrocycle, i.e., lll-181, of this type. 

Figure 3 describes the preparation of A-co-undecenoyl-L-valine CSP bonded to silica gel. The carboxylic acid group of L-valine was protected by the reaction with isobutylene using the method of Roeske [47]. The formed tert-butyl ester of L-valine was precipitated from diethyl ether as the oxalate by the dropwise addition of a solution of 10% oxalic acid in absolute ethanol. The precipitate is dried and the oxalate group is removed by the reaction of sodium hydroxide. The tert-butyl ester of L-valine was treated with undecenoic acid in tetrahydrofuran (THF), which resulted in A-co-undecenoyl-L-valine methyl ester. In another step, lOmM of monochlorosilane was dissolved in 20 mL of dry pyridine and was allowed to react with /V -to - u ndccenoyl-L-valine methyl ester. 

A-Phthaloyl-protected (S)-phenylalanine has been used as a ligand for rhodium in the formation of metallocarbenes from diazo compounds for C-H insertion reactions (Section D.1.2.2.3.2.). Ar-Sulfonyl-protected (S)-alanine and (S)-valine are efficient ligands for chiral Lewis acids used in the Diels-Alder reaction (Section D.1.6.1.1.1.3.). A -Sulfonyl-pro-tected (S)-phenylalanine methyl ester has been used for the enantioselective protonation of lactone enolates (Section D.2.I.). The terf-butyl ester of (S)-valine readily forms imines with carbonyl compounds which are used for the highly efficient alkylations of their azaenolates (Sections D.1.1.1.4.1D.1.5.2.4.). All these derivatives can be obtained by the standard methods described in Houben-Weyl3. 

The synthesis. X-ray structure, and electronic spectra of trnfi5-[Co(en)2Ci(Boc-L-val)]BF4 (Boc = t-butyloxycarbonyl) has been described/ The complex was prepared by reaction of tran5-[Co(en)2(OH)Cl] and an active ester form of Boc-L-valine. Cobalt(III) is coordinated in a distorted octahedral fashion by four N atoms, a Cl atom, and a carboxylate oxygen from the Boc-L-valine ligand. The... 

Pentafluorophenyl esters, obtained from pentafluorophenol and amino-acids protected with t-butoxycarbonyl groups, are formed without racemization of the amino-acid residue and are useful in peptide synthesis. Similarly useful is the fact that the pentafluorophenyl esters of JV-benzoxycarbonyl-y-methyl-L-glutamic acid and iV-benzoxycarbonyl-jS-methyl-L-aspartic acid show a particularly high ratio of the rate constants for coupling with L-valine methyl ester v. racemization in the presence of triethylamine. The reaction of S-(2,4-difluorophenyl)saIi( lic acid with alkyl chloroformates gives the esters (93 R = Et or Bu), which are claimed to... 

Studies on banana tissue slices have shown that valine and leucine concentrations increase about threefold following the climacteric rise in respiration [10]. Radioactive labeling studies have shown that valine and leucine are transformed into branched chain flavor compounds that are essential to banana flavor (2-methyl propyl esters and 3-methyl butyl esters, respectively). As can be seen in Figure 4.6, the initial step is deamination of the amino acid followed by decarboxylation. Various reductions and esterifications then lead to a number of volatiles that are significant to fruit flavor (acids, alcohols, and esters). Recent work has shown that amino acids play a role in apple flavor as well. For example, isoleucine is the precursor of 2-methyl butyl and 2-methyl butenyl esters in apples [24,25]. An unusual flavor compound, 2-isobutylthiazole, has been found to be important to the flavor of tomato. It is hypothesized that this compound is formed from the reaction of 3-methyl-l-butanal (from leucine) with cysteamine. 

Benzylidene derivatives are easily formed from esters of a-amino acids, but those of the free acids are unstable. When an ortho hydroxyl group is present in the aldehyde the derivative is stabilized by hydrogen bond formation as in (33) and Sheehan and Grenda have reported that the Schiff bases of L -valine with 5-chlorosalicylaldehyde (33) and 2-hydroxy-l-naphthaldehyde may be coupled with ethyl glycinate and methyl L-phenyl-alaninate using dicyclohexylcarbodi-imide [207]. The arylidene... 

Reactions of Sulphenic Acids.—In continuation of previous work, penicillin sulphenic acids have been trapped with vinyl ethers and keten acetals, " " with thiols, alkenes, and alkynes. A variety of products from thermolysis of N-benzyloxycarbonyl-L-(S-t-butyl)cysteinyl-L-valine methyl ester S-oxide must derive from an intermediate sulphenic acid, and isothiazolones and thiazinones formed from penicillin sulphoxides are also satisfactorily accounted for on the same basis. "... 

The action of the valine derivatives 87 on the diene 86 under EtAlCU catalysis resulted in a mixture of cycloadducts 88, which on hydrolysis with aqueous methanolic sodium carbonate furnished a mixture of the dihydro-2-pyridones 89 and 90 and the esters 91 and 92. In the case of imines derived from aliphatic aldehydes, e.g. 87 (R = Pr), all four types of product were isolated, whereas imines from aromatic aldehydes, 87 (R = Ph, 3-CIC6H4 etc.), gave only the esters 91 and 92 (equation 55). All products were formed in yields of 64-84% and in high de49. 

The iminium salt 132, generated from benzylamine hydrochloride and aqueous formaldehyde, reacts with cyclopentadiene during 3 h at room temperature to give, after basification, the cycloadduct 133 in nearly quantitative yield (equation 70). Other examples of this reaction are shown in equations 71-75. The separable diastereomers 134 and 135 are formed in the ratio 4 1 from cyclopentadiene, (—)-a-methylbenzylamine hydrochloride and aqueous formaldehyde in a combined yield of 86% (equation 75)62. Hydrochlorides 136 of methyl esters of natural amino acids [(S )-valine, (S )-isoleucine] react with cyclopentadiene and formaldehyde in aqueous THF to produce mixtures of the diastereomers 137 and 138, in which the former predominate (equation 76)63. 

Valine.—This amino acid is contained mixed with leucine in the fractions of the esters which boil between 6o° and 90° C. Its isolation and separation from leucine is of extreme difficulty, since these compounds, as well as their copper salts into which they are converted by boiling with freshly precipitated cupric oxide, tend to form mixed crystals. Its isolation was only effected by these means in certain cases, and its amount is really much more than the figures represent from its yield. It is best characterised by conversion into its phenylhy-dantoine derivative by treatment with phenyl isocyanate in alkaline solution. The phenylureido acid is first formed, and this loses a molecule of water, as shown by Mouneyrat, and is changed into its anhydride or phenylhydantoine by treatment with hydrochloric acid. The following reactions occur —... 

Leucine.—The greater part of the leucine is contained in the ester fractions, which boil between 70° and 90° C. It generally occurs in considerable amounts in the protein, and is obtained by crystallisation from water, in which it is less soluble than the other amino acids which may be present. It is seldom present in its pure, optically active form, as this is easily racemised, and the various crops of crystals most probably also contain isoleucine. It is more easily isolated by completely racemis-ing the mixture of amino acids contained in this fraction by heating in an autoclave with baryta to 160-180° C., and then, after removal of the baryta, separating it by crystallisation. The difficulty of separating it from the other amino acids, especially valine and isoleucine, makes an exact quantitative estimation almost impossible. The values which have been found are therefore minimal ones, and they will also include in many cases the yield of isoleucine. 

When the second amino acid (valine) is added to the protected, activated alanine, the nucleophilic amino group of valine attacks the activated carbonyl of alanine, displacing the anhydride and forming a peptide bond. (Some procedures use an ester of the new amino acid to avoid competing reactions from its carboxylate group.)... 

The poly(dimethylacrylamide) resin was functionalized with an internal reference norleucine residue and with the acid-labile 4-alkoxybenzyl alcohol linkage agent. Esterification of the C-terminal Fmoc-Gly residue was performed using the pentafluorophenyl ester (5 equiv) with DMAP as catalyst (1 equiv) and was complete in 1-2 hours. All peptide bond-forming reactions used Fmoc amino acid ODhbt ester (4 equiv) in DMF but a later synthesis using only 2 equiv except for the final valine (4 equiv) also gave satisfactory results. The completed decapeptide was cleaved from the resin with 95% TFA and purified by HPLC. 

Now see what happens if we replace the achiral benzyl ester group with an amide derived from the natural amino acid valine (Chapter 49). The diastereoselectivity remains the same but the chiral environment created by the single enantiomer covalently bonded to the dienophile has a remarkable effect only one enantiomer of the product is formed. 

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