Hydroxyproline methylation

The submitters obtained N-Boc-4-hydroxyproline methyl ester from Synthetech, Inc. [Albany, OR, (503) 967-6575] or Bachem California [Torrance, CA, (310) 530-1571] and dried THF over 4A molecular sieves for two days prior to use (Karl-Fischer titration gave 145 pg/mL water). The checkers purchased N-Boc hydroxyproline methyl ester (97%) and fert-butyl acetate (99+%) from Aldrich Chemical Co. and obtained THF (HPLC grade) from Fisher Scientific. 

Difluoroproline (22) was first reported in 1977, synthesized as apotential inhibitor of collagen biosynthesis. The chiral tricyclic diketopiperazine was prepared from (25,4/ )-4-hydroxyproline methyl ester and oxidized to the chketone. Fluorination with sulfur tetrafluoride and hydrolysis produced 22 (Fig. 3.10). 

The broth of Streptomyces refuineus has afforded the antibiotic anthramycin (XXVIIIa) with antitumour activity. The constitution of the compound was established by spectroscopic methods [I32J. It has been synthesised [133] from V-benzoyloxy-4-methyl-2-nitrobenzoyl-L-hydroxyproline methyl ester... 

Hydroxylated amino acids (eg, 4-hydroxyproline, 5-hydroxylysine) and A/-methylated amino acids (eg, /V-methylhistidine) are obtained by the acid hydrolysis of proteins. y-Carboxyglutamic acid occurs as a component of some sections of protein molecules it decarboxylates spontaneously to L-glutamate at low pH. These examples are formed upon the nontranslational modification of protein and are often called secondary protein amino acids... 

The interaction with both synthetic and naturally occurring amino acids has been studied extensively glycine (138, 173, 219-221), a-(173, 219) and /3-alanine (138, 220), sarcosine (219), serine (222), aspartic acid (138, 173, 222-226), asparagine (222), threonine (222), proline (219), hydroxyproline (219), glutamic acid (138, 222-225), glutamine (222), valine (219, 227), norvaline (219), methionine (222, 226), histidine (228, 229), isoleucine (219), leucine (219, 230), norleu-cine (219), lysine (222), arginine (222), histidine methyl ester (228), phenylalanine (138, 222), tyrosine (222), 2-amino-3-(3,4-dihydroxy-phenyl jpropanoic acid (DOPA) (222), tryptophan (222), aminoiso-butyric acid (219), 2-aminobutyric acid (219,231), citrulline (222), and ornithine (222). 

Isolation of individual amino acids started about 1820 by 1904 all of the naturally occurring amino acids in proteins had been isolated except methionine (Mueller, 1922) and threonine (Rose, 1937). One of the earliest methods for the separation of amino acids was through the differential volatility of their methyl or ethyl esters (Emil Fischer, 1901). This approach led to the discovery of valine, proline, and hydroxyproline. [In the 1970s Fischer s method was modified for microanalysis of proteins, separating the amino acid esters by gas phase chromatography. Separation is now usually performed by hplc (high pressure liquid chromatography).]... 

Derivatives of the 2,5-diazabicyclo[2.2.1]heptaine ring system (bridged piperazines) have been prepared from 4-hydroxyprolines. In a multistep transformation from tra j-4-hydroxy-L-proline (the last step was cyclization with benzylamine) a mixture of diastereoisomers 71 was obtained and separated [92H(34)241]. In a similar manner, the methyl and oxo analogs were obtained [67AJC1493 92H(34)679]. The commercially available N-... 

The red pigment isolated in crystalline form from the reaction products of 1-methyl-3,4-benzoquinone and 4-hydroxyproline ethyl ester was identified as 4-(4 -hydroxy-2 -carbethoxy-l -pyrrolidyl)-5-methyl-l,2-benzoquinone (115).283 This highly colored compound should probably be formulated as a zwitterion (116). Similar pigments can be obtained by the interaction of o-benzoquinone with proline, hydroxyproline, pyrrolidine, and glycine. Suzuki has shown... 

N-Protected ds-4-hydroxyproline lactones react with nucleophiles to generate the corresponding c/.s-4-hydroxy pro line derivatives, e.g. the methyl ester with methanol, 141 the amide with ammonia, 141 or peptides with sterically unhindered amino acid esters. 143 ... 

In a similar manner, l-cyclopentene-3-carboxylic acid (67a) and lV-t-Boc-(S)-3,4-didehydroproline (67b) can be transformed to methyl c/s-2-hydroxycyclopentane-l-carboxylate (70a) and methyl (3R, 2S )-7V-t-Boc-3-hydroxyprolinate (70b) in 67% and 76% overall yields (4 steps), respectively (equation 28)91. 

Many pyrroles have been identified in roasted coffee. Regarding their formation in coffee pyridine, pyrrole and N-methyl-2-formylpyrrole are trigonellin derivatives 3 and 4 typical pyrroles from primary amino acids and 6 to 8 hydroxyproline derived Maillard products ( 26 ). ... 

Other Oxazolidine as well as Thiazolidine Derivatives for Branching Amino Acids. The cyclic derivative of alanine and other amino acids employed most frequently for a-allq lation is not (1) but rather the benzaldehyde acetal (5), either with a benzoyl or with a Cbz group on nitrogen. These compounds were used for the preparation of 2-methyl-2-aminobutanoic acid, a-methylphenylalanine, a-methyllysine, 2-methylaspartic acid, and 2-methylglutamic acid. Bicyclic compounds containing oxazolidinone rings such as (6) (from alanine, leucine, and phenylalanine) and (7) (from azetidinecaiboxylic acid, proline, " hydroxyproline, and cysteine ) have also been applied to the synthesis of branched amino acids. 

Flavourings that are useful for aromatising bakery and chocolate food products can be made from sulphur-free amino acids by the reaction with cyclic ketones (Fig. 3.36) such as 4-hydroxy-2,5-dimethyl-3(2//)-furanone (26), maltol (63) or 2-hydroxy-3-methyl-2-cyclopenten-l-one (64, cyclotene) [109]. Amino acids of special interest are leucine, valine, proline and hydroxyproline. The reaction is carried out favourably in fat or propylene glycol. 

Many a.a. residues undergo posttranslational enzymatic amidation, hydroxyla-tion, oxidation, esterification, glycosylation, methylation, or cross-linking. Some segments of the polypeptide chains may be removed (Figure 7.1). Modified residues in a given protein can be used for analytical purposes, e.g., hydroxyproline (ProOH), which is characteristic for collagens. 

Following strategy C, Miao and Chan used 3-hydroxyproline 4 as starting material for the reparation of catalyst 5, containing a methyl imidazolium tag on the side chain and tetrafluoroborate as the counter ion (Figure 3) ... 

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