Dehydrophenylalanine derivatives

Frejd and co-workers utilized a different tactic for aniline cyclization by first employing a Heck-Jeffery protocol under solvent-free conditions to prepare o-amino dehydrophenylalanine derivatives from o-aminoaryl iodides with the former undergoing a spontaneous la cyclization-elimination sequence to afford 2-methoxycarbonyl indoles <06S1183>. Dimethyl(methylthio)sulfonium trifluoromethanesulfonate (DMTST) was used by the Okuma group to promote the cyclization of o-vinyl-A-p-toluenesulfonylanilide to N-tosylindole <06CL1122>. 

Table 4 Rh-catalyzed hydrogenation of the N-acetyl dehydrophenylalanine derivative 146 with the DIOP and boraDIOP ligands...

Whereas bidentate phosphites and phosphonites are excellent ligands for rhodium-catalyzed asymmetric hydrogenation, bidentate phosphoramidites (not shown) gave very poor results with low reaction rates and enantioselectivities. Results of a number of other monodentate phosphoramidites in the asymmetric hydrogenation of. V-acetyl dehydrophenylalanine derivatives are shown in Table 14.7.31-35-36-39-40... 

Aspects of the stereoselectivity of nitrile oxide cycloaddition reactions have been reviewed (89G253). The most obvious stereochemical consequence of the cycloaddition is that the configuration of the alkene is retained in the product isoxazoline and this feature continues to be exploited in asymmetric synthesis. For example, the dehydrophenylalanine derivatives (42) gave the corresponding isoxazolines (43), stereospecifi-cally (Scheme 23) (91JHC1945). 

Porter, J.R., Archibald, S.C., and Brown, J.A. 2003. Dehydrophenylalanine derivatives as VLA-4 integrin antagonists. Bioorg. Med. Chem. Lett. 

It should be noted that the NMR spectroscopy criteria detailed above are not the only available methods applicable for the determination of configuration. U. SchOllkopf and coworkers (360) have correlated the configuration of isomeric p-substituted formylaminoacrylic acid esters with the chemical shifts of the alkoxy groups. UV data have been used to assign configurations to the isomeric dehydrophenylalanine derivatives (325), an approach based on the -values for cinnamic acid, which are higher for /ra 5-cinnamic acid than for the cw-isomer. 

Conformationally Constrained Analogs. Local restriction of conformation in the linear enkephalins has included incorporation of dehydroamino acids [e.g., dehydrophenylalanine (APhe, Fig. 7.43)] and cyclopropyl-methylphenylalanine (VPhe) into the peptides (see Ref 704 for a review). In the case of the dehydrophenylalanine (APhe ) derivatives of [D-Ala, Leu ]enkephalin, the Z isomer exhib-... 

The photoisomerisation kinetics and other properties of the 1 1 inclusion complexes formed between aromatic derivatives of norbomadiene and P-cyclo-dextrin have been measured." (S)- or (R)-2-Chloropropiophenone affords partially racemised (S)- or (R)-2-phenylpropionic acid respectively by a photo-induced rearrangement via what is probably an ion or radieal intermediate," and (Z)-N-substituted benzoyl-a-dehydrophenylalanines such as (7) are photo-isomerised to 1-azetidine derivatives (8) by a 1,3-acyl migration. Irradiation of 9,9 -bifluorene-9,9 -diol (9) gives a mixture of fluoren-9-one and spiro[9H-fluorene-9,9 (10 -H)-phenanthren]-10 -one (10) whose composition is solvent dependent with the more polar solvents favouring (10). Laser flash photolysis shows the presence of two transients, one of which can be identified with the 9-fluorenyl cation (11), and which originates from photoheterolysis of the diol (9). There is also evidence to support the view that unimolecular rearrange-... 

In summary, bis(diphenylphosphino)ethane derivatives form chelates of rigid structure and defined geometry. Their complexes are efficient catalysts (Table I) for reduction of dehydroamino acids, although other prochiral olefins are reduced with low optical efficiency. For comparison purposes, the hydrogenation of dehydrophenylalanines is emphasized in tabulated data. 

The carbon-carbon double bond in dehydrophenylalanine methyl ester, its hydrochloride salt, and its A -acetyl derivative has been hydrogenated enantioselectively over cinchonine-modified Pd giving a low excess of the S -enantiomer. In each case, a H-bonding interaction of the type -N- -H -N- is proposed between the amine function of the reactant and the quinuclidine-N of the modifier. On this basis, the mechanism is suggested to be analogous to that published for the hydrogenation of ap-unsaturated acids. 

Ca. 2.1 moles aniline in ether added slowly to a soln. of the startg. m. in anhydrous ether, and allowed to stand 12 hrs. at room temp. N-trifluoroacetyl-dehydrophenylalanine anilide. Y 83%. F. e., also peptide derivs., s. E. G. Breit-holle and C. H. Stammer, J. Org. Chem. 47, 1344 (1976). 

Thermolysis of 3-alkylsulflnyl-a-amino acid derivatives is an alternative reaction which has been applied to the synthesis of dehydroamino acid compounds 325, 326). Esters and peptides with dehydroalanine, dehydroaminobutyric acid, dehydrovaline and dehydrophenylalanine units have in many cases been obtained in excellent yields. The method is especially suitable for peptides with base sensitive groups. The elimination appears to take place with particular facility in compounds in which the amino acid unit bearing the sulfoxide group is present as a tertiary amide 326). Dehydrophenylalanine and dehydroaminobutyric acid derivatives are formed as mixtures of Z- and E-isomers on sulfoxide elimination. 

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