Alanine 4- pyridyl

Recently the Bohlmann-Rahtz synthesis has received greater attention. Baldwin has employed this method for the construction of heterocyclic substituted a-amino acids. Exposure of alkynyl ketone 39 to 3-aminocrotoyl ester 40 resulted in the Michael product 41. Thermolysis then gave rise to the desired pyridyl-P-alanines 42. 

With N,0 mixed donor ligands several complexes have been reported with ligands such as 4,5-dichloro-2-cyano-3,6-dione-l,4-cyclohexen-l-ol,1445 isonicotinic acid,1446 p-aminobenzoic acid,1447 alanine, histidine or histamine derivatives,1448-1450 [N(0)C(CN)2]-,1451 pyridine-carboxylate derivatives, 1452 1454 [N(pph20)2] (263),1455 bis(sulfonyl)amide derivatives,1456,1457 tris(pyridyl)-... 

Fig. 24.8) [122]. Whilst this protocol can be used to prepare 3-pyridyl-alanine derivatives [22], the corresponding 2-pyridyl-alanine cannot be made [122]. However, Adamczyk has prepared several 2-pyridyl-alanine analogues through hydrogenation of the pyridine-N-oxide substrates in 80-83% ee (see Fig. 24.8) [123]. In general, only when the 2- and 6-positions of the pyridine ring are occupied can 2-, 3- or 4-pyridyl-alanine derivatives be prepared, without nitrogen modification, via hydrogenation with [phospholane-Rh]+ catalysts [122-124].

After formation of the aldimine, numerous factors in the enzyme facilitate deprotonation of the a-carbon (Fig. 3, Step II). The lysine liberated by transimi-nation is utilized as a general base and is properly oriented for effective deprotonation [11]. Furthermore, the inductive effects of the ring system are tuned to increase the stabilization of the quinoid intermediate. For example, the aspartate group that interacts with the pyridyl nitrogen of the co enzyme promotes proto-nation to allow the ring to act as a more effective electron sink. In contrast, in alanine racemase, a less basic arginine residue in place of the aspartic acid is believed to favor racemization over transamination [12]. 

The terdentate ligand ft-(2-pyridyl)alanine forms zinc complexes with a considerable degree of enantioselectivity.524 Zinc complexes of 2-pyridyl azo compounds,525 oximes526 and sulfonamides527 have also been described. 

Fmoc-amino acids used as building blocks of testing compounds are as follows Fmoc-Asp(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Met-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Lys (Boc)-OH, Fmoc-Ile-OH, Fmoc-His(Trt)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pmc)-OH, Fmoc-Phe-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Pro-OH, Fmoc-Trp(Boc)-OH, Fmoc-D-Ala-OH, Fmoc-D-Arg(Pmc)-OH, Fmoc-D-Trp(Boc)-OH, Fmoc-D-Cys(Trt)-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-D-Glu(OtBu)-OH, Fmoc-D-His(Trt)-OH, Fmoc-D-Gln(Trt)-OH, Fmoc-D-Leu-OH, Fmoc-D-Met-OH, Fmoc-D-Pro-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-D-Lys(Boc)-OH, Fmoc-D-Tyr(tBu)-OH, Fmoc-D-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-D-Asn(Trt)-OH, Fmoc-3-(4-pyridyl)alanine, Fmoc-D-3-(3-pyridyl)alanine, Fmoc-4-tert-butoxyproline, Fmoc-3-chlorophenylalanine, Fmoc-norleucine, Fmoc-2-cyclohexylglycine, Fmoc-2-aminoisobutyric acid, Fmoc-tranexamic acid, Fmoc-(i ,S)-3-amino-3-(2-furyl)propionic acid, Fmoc-(i ,S)-(6,7-di-methoxy)-l,2,3,4-tetrahydroquinoline-3-carboxylic acid, Fmoc- (R, S)-3-amino-3-(4-hydroxyphenyl)propionic acid, Fmoc-(i ,S)-3-aminovaleric acid, Fmoc-(i ,5 )-3-amino-3-(3,4-dichlorophenyl)propionic acid, Fmoc-isonipecotic acid, Fmoc-(i ,S)-3-amino-3-(3,4-methylenedioxyphenyl)... 

The chemical viability of the L-dopa diol cleavage process involved in the generation of the acromelic acid C-4 substituents has been examined in a biomimetic sense by Baldwin s group in syntheses of stizolobic acid 16,22 3-(6-carboxy-2-oxo-4-pyridyl)alanine 17,22 and stizolobinic acid 1523 (Figure 5). 

The distal extradiol cleavage of L-dopa 12, catalyzed by an iron-dependent dioxygenase, gives an alanyl muconic semialdehyde derivative 18 which, on cyclization and lactol oxidation, yields stizolobic acid 16. The pyrone ring is then ammonolyzed24 to give 3-(6-carboxy-2-oxo-4-pyridyl)alanine 17 (Scheme 3). 

A biomimetic catechol cleavage reaction was carried out on dihydro-caffeic acid derivative 1922 using the iron(III)-catalyzed peracetic acid cleavage process of Pandell.25 This produced the cyclized muconic acid derivative 20 which could be transformed into pyrone 21 by treatment with hydrochloric acid. Bromination followed by azide displacement gave key intermediate 22 which could either be reduced directly to (i)-stizolobic acid 16 or ammonolyzed and then reduced to give ( )-3-(6-carboxy-2-oxo-4-pyridyl)alanine 17 (Scheme 4). 

A number of CSPs have been developed that are based on optically active synthetic helices formed by the asymmetric polymerization of methacrylate monomers. These polymers have been formed using either chiral monomers such as (S)-acryloylphenyl-alanine (73) and N-methylacryloyl-(S)-cyclohexylethylamine (73), or achiral monomers such as triphenyl methacrylate (74) and diphenyl-2-pyridyl-methyl methacrylate (74). In the latter case, the polymers were prepared using chiral cation catalysts including (—)-spartene-butyllithium and (+)-6-benzylsparteine-butyllithium complexes (74). The commercially available forms of these CSPs are listed in Table 3. 

A new strategy for the synthesis of heterocyclic a-amino acids utilizing the Hantzsch dihydropyridine synthesis was developed in the laboratory of A. Dondoni." ° The enantiopure oxazolidinyl keto ester was condensed with benzaldehyde and fert-butyl amino crotonate in the presence of molecular sieves in 2-methyl-2-propanol to give a 85% yield of diastereomeric 1,4-dihydropyridines. The acetonide protecting group was removed and the resulting amino alcohol was oxidized to the target 2-pyridyl a-alanine derivative. 

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