Non-natural a-amino acids

The procedure in Section C is representative of the synthesis of non-natural a-amino acids featuring the palladium cross coupling reaction of a (1-alaninc organozinc derivative with aromatic electrophiles. This methodology has been successfully extended with modifications to both the electrophile and the catalyst as shown in the Table. 

The first MCR involving isocyanides (IMCR) was reported in 1921 with the Passerini reaction (P-3CR) [8], and over the years these reactions have become increasingly important and have been highlighted in several publications (for discussions, see below). Another older MCR which leads to (non-natural) a-amino acids is the Bucherer-Bergs reaction (BB-4CR), which was first reported in 1929 [9]. This type of transformation is closely related to the Strecker reaction, with C02 employed as a fourth component. 

This strategy also gives access to a variety of non-natural a-amino acids. Furthermore, rhodium-DuPHOS complexes catalyse the asymmetric reduction of enol esters of the type PhCH = CH — C(OCOCH3) = CH2 to give (R)-2-acetoxy-4-phenylbut-3-ene (94% ee)[64]. 

Jorgensen and coworkers probed the use of [RuLJ[SbF,5] with chiral binap ligands for the synthesis of optically active non-natural a-amino acids of the piperidine type. 

These two recent communications of a high-yielding catalytic asymmetric alkylation of a-imino esters provide access to a variety of non-natural a-amino acids as well as to precursors for natural products, and therefore should prove to be extremely useful. In addition they serve to set expand the palette of metal complex types and catalysis modes for future investigations in this young field. 

More recently, non-natural a-amino acids have been resolved by a new powerful hpase AS Amano that is able to cleave the C(0)-N bond of amino acid amides. Through this method, the corresponding amino acids can be obtained with high ee (up to 99%) and high enantioselectivity ( >600) (Scheme 4.11) [21]. 

Scheme 4.11 Lipase-catalysed kinetic resolution of non-natural a-amino acids.

Presently, the zwitterionic aza-Claisen rearrangement has been developed as a reliable method to synthesize suitably protected non-natural a-amino acid derivatives, e.g., C-ahyl glycines of type 312 and 3-arylprohnes of type 313. 

We have used a series of biocatalysts produced by site-directed mutations at the active site of L-phenylalanine dehydrogenase (PheDH) of Bacillus sphaericus, which expand the substrate specificity range beyond that of the wild-type enzyme, to catalyse oxidoreduc-tions involving various non-natural L-amino acids. These may be produced by enantiose-lective enzyme-catalysed reductive amination of the corresponding 2-oxoacid. Since the reaction is reversible, these biocatalysts may also be used to effect a kinetic resolution of a D,L racemic mixture. ... 

As for Boc amino acids, all proteinogenic and several non-natural Fmoc amino acids esterified with Wang or similar resins are commercially available. Deprotection with 20% piperidine in DMF is usually complete within a few minutes, and the release of the fluorene derivative is easily monitored spectrophotometrically at 300-320 nm (see, e.g., [33]). The peak area can be used to determine the amount of chromophore released, which is proportional to the efficiency of the preceding coupling reaction. At the end of an automated peptide synthesis, inspection of the chromatogram of all Fmoc releases enables rapid assessment of the quality of the resin-bound peptide and quick location of positions in the peptide where coupling was unsuccessful or difficult. 

O. May, S. Verseck, A. S. Bommarius, and K. Drauz, Development of dynamic kinetic resolution processes for biocatalytic production of natural and non-natural L-amino acids, Org. Proc. Res. Dev. 2002, 6, 452-457. 

Figure 6 shows the complete separation of five amino acids (lysine, alanine, phenylalanine, tyrosine and tryptophan) on a column packed with cyclodextrin polymers (58). The best separation of these amino acids was obtained on the column packed with 0-cyclo-dextrin polymer. On the other hand, tryptophan could be separated on a-cyclodextrin polymer column with the best selectivity. Also, fifteen additional non-aromatic natural a-amino acids were chromatographed on p-cyclodextrin polymer, but their peaks appeared either between, or together with, those of alanine and lysine. 

In 1994 chemists at Texas A M University reported the synthesis of a non-naturally occurring amino acid (C E News, April 18, 1994, pp. 26-27) ... 

In particular, the non-naturally occurring amino acid L-tert-leucine has received significant attention due to several pharmaceutically active compounds into which it is incorporated[1). HIV-protease inhibitors developed by Novartis and Abbott are based on L-tert-leudne 2, 3. Roche has developed the anti-arthritic compound Ro 31-9790 based on its potent inhibition of collagenase 41 and a key component in the synthesis of Ro 31-9790 is the methylamide of L-tert-leucine. Boehringer Ingelheim developed a series of compounds that inhibit the ribonucleotide redudase of Herpes... 

Enhancement of proteolytic stability of peptides can be achieved by well-established procedures such as synthesis of retropeptides, isosteric replacements of the peptidic bond, A-methylation and the use of non-natural D-amino acids. Prodrugs of peptides can also be helpful, see Chapter 30. 

Another applieation of photogenerated metal coordinated ketenes is based on the addition of protie nucleophiles and has been exploited in the synthesis of amino aeids and peptides. [66] As usual, the reactive intermediate is generated by photolysis of an aminoearbene complex 46, which may be a-alkylated in a previous step. The oxazolidine auxiliary applied successfully inducing asymmetry in the P-laetam formation, allowed an enantioselective synthesis of amino aeids. Sinee both enantiomers of the auxiliary may be obtained from the corresponding phenyl glycine enantiomer, natural (5) and non-natural R) amino acid esters 47 are accessible via this route (Scheme 25). A recent review on synthetical applications of chromium carbene photochemistry has been published, [li]... 

Rotational studies extended to non-coded a-amino acids are also of biochemical relevance [154]. The effects on the conformatimial behavior of enlarging the amino acid backbone chain have been analyzed on p-alanine [155, 156] and y-amino butyric acid (GABA) [157], Both are neurotransmitters which bind to the same sites as glycine [158—160], These are also the simplest p-amino and y-amino acids and so are the natural starting point to analyze the cmiformational panorama of this type of amino acids. Other studies include a-aminobutyric acid [161], the A(-alkylated species sarcosine [162], Af,Af-dimethylglycine [163], and taurine [164]. Brief results on p-alanine and GABA are presented. 

The substrate molecule must fit exactly into the mosaic pattern of the enzyme surface. The combination is only possible if enzyme and substrate can approximate in such a way that the two hypothetical binding-planes are not more than a few Angstrdm units apart (Bergmann, 1937). Thus, pancreatic peptidase will not attack synthetic peptides made from the non-natural D-amino acids. 

The dimethyl substituted Binaphos ligand 7 was found to improve significantly the efficiency of Rh-catalyzed hydroformylation of Af-(Boc)-3-pyrroline (Scheme 14.17), where the ee was increased from 47% with Binaphos to 73% when using dimethylated ligand 7. In the related reaction of N-acetyl-3-pyrroline, the carbohydrate-based diphosphites achieved a better ee than Binaphos (71% and 66%, respectively). The aldehyde is a precursor to 3-proline non-natural ietfl-amino-acids such as this are key building blocks in biologically active compounds. 

In 1959 a new non-protein L-a-amino acid was isolated from the seeds of Acacia willardiana and later from other species of Acacia-, it proved to be l-/3-amino-/3-carboxyethyluracil (977) (59ZPC(316)164). The structure was confirmed by at least four syntheses in the next few years. The most important involves a Shaw synthesis (Section 2.13.3.1.2e) of the acetal (975) and hydrolysis to the aldyhyde (976) followed by a Strecker reaction (potassium cyanide, ammonia and ammonium chloride) to give DL-willardiine (977) after resolution, the L-isomer was identical with natural material (62JCS583). Although not unambiguous, a Principal Synthesis from the ureido acid (978) and ethyl formylacetate is the most direct route (64ZOB407). 

However, most natural peptides are composed of L-form a-amino acids and because of the ubiquitous prevalence of peptidases they have limited biostability, and consequently low bioavailability. Thus, a novel field of peptidomimetics has emerged in drug discovery, in attempts to design non-peptide compounds mimicking the pharmacophore and thus the activity of the original peptide. 

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