Dehydro-amino acid

The use of rhodium catalysts for the synthesis of a-amino acids by asymmetric hydrogenation of V-acyl dehydro amino acids, frequently in combination with the use of a biocatalyst to upgrade the enantioselectivity and cleave the acyl group which acts as a secondary binding site for the catalyst, has been well-documented. While DuPhos and BPE derived catalysts are suitable for a broad array of dehydroamino acid substrates, a particular challenge posed by a hydrogenation approach to 3,3-diphenylalanine is that the olefin substrate is tetra-substituted and therefore would be expected to have a much lower activity compared to substrates which have been previously examined. 

The effects of temperature on enantioselectivities have been examined using a Rh-Et-DuPhos catalyst in both MeOH [56d] and THF [144]. With /5-dehydro-amino acid derivative 73 in MeOH, an increase in temperature was found to have a slight beneficial effect for both ( ) and (Z)-isomers over a 70°C range, with maximum values being observed between 0°C and 25°C. In THF, however, the effect is much more pronounced, especially for the (Z)-isomer which varies in selectivity from 65% ee at 10 °C to 86% ee at 25 °C. Interestingly, when substrate 72 was reduced with a Rh-Et-BPE catalyst in THF, this temperature dependence on enantioselectivity for the (Z)-isomer was most apparent, the se-lectivities varying from 43% ee (10°C) to 90% ee (40°C). Examination of these results also seemed to indicate that the hydrogenation of /9-dehydroamino acid derivatives follows an unsaturated pathway (vide supra) [144]. 

Bppfoh and bppfa derivatives have been applied most successfully for the Rh-catalyzed hydrogenation of dehydro amino acid derivatives such as MAC (ee 97%) and of functionalized ketones [7]. The nature of the amino group has a significant effect on enantioselectivity and often also on activity, and is used to tailor the ligand for a particular substrate. Rh-bppfa complexes were among the first catalysts able to hydrogenate tetrasubstituted C=C bonds, albeit with relatively low activity (Table 25.2, entries 2.1-2.3). Ferrophos, one of the very few li-... 

Recently, Merck chemists reported the Rh-josiphos-catalyzed hydrogenation of unprotected dehydro / -amino acids with ee-values up to 97%, but relatively low activity [23]. It was also shown that not only simple derivatives but also the complex intermediate for MK-0431 depicted in Scheme 25.2 can be hydrogenated successfully, and this has been produced on a > 50 kg scale with ee-values up to 98%, albeit with low to medium TONs and TOFs [24]. 

L/Rh = 2 SCR=500 (aromatic enamides), 50 (/i-dehydro amino acid esters) and 1000 for the other substrates. 

In contrast to dehydro a-amino acids, the hydrogenation of acetylated /1-dehy-droamino acid derivatives has only recently been of industrial interest and, accordingly, no applications on a larger scale have yet been reported. Several ligands such as certain phospholanes or phosphoramidites might have industrial potential, but until now these have only been tested on model substrates under standard conditions [50]. Chiral Quests TangPhos and Binapine (Fig. 37.10) have been shown to hydrogenate several acetylated dehydro / -amino acid derivatives with ee-values of 98-99% and TONs of 10000 at r.t., 1 bar [3, 47]. 

With this background, the finding by Merck chemists [51] that unprotected dehydro / -amino acids are good substrates for the Rh-catalyzed hydrogenations was both very unexpected and very exciting. Interestingly, deuteration experiments indicate that it is not the enamine C=C bond which is reduced but the tautomeric imine Not only simple derivatives but also the complex intermediate for MK-0431 (see Fig. 37.10) can be hydrogenated successfully, and the latter has been pro-... 

Fig. 37.10 Hydrogenation of /i-dehydro amino acid derivatives substrate and ligand structures.

Besides Ir-diphosphines, two more catalyst systems have shown promise for industrial application. As mentioned in Section 37.5.2, the Rh-Josiphos-cata-lyzed hydrogenation of unprotected /1-dehydro amino acid derivatives by Merck actually involves the hydrogenation of a C=N and not a C=C bond (see Fig. 37.10) [3, 51]. Noyori s Ru-PP-NN catalyst system seems also suitable for C=N hydrogenation [129], and was successfully applied in a feasibility study by Dow/Chirotech for the hydrogenation of a sulfonyl amidine [130]. Avecia also showed the viability of its CATHy catalyst for the transfer hydrogenation of phosphinyl imines [115] (see Fig. 37.34). 

SYNTHESIS OF A CYLINDRICALLY CHIRAL DIPHOSPHINE AND ASYMMETRIC HYDROGENATION OF DEHYDRO AMINO ACIDS... 

Figure 4 The biosynthesis of nisin A as a representative example of the posttranslational maturation process of lantibiotics. Following ribosomal synthesis, NisB dehydrates serine and threonine residues in the structural region of the prepeptide NisA. NisC subsequently catalyzes intramolecular addition of cysteine residues onto the dehydro amino acids in a stereo- and regioselective manner. Subsequent transport of the final product across the cell membrane by NisT and proteolytic cleavage of the leader sequence by NisP produces the mature lantibiotic. For the sequence of the leader peptide, see Figure 6. Adapted with permission from J. M. Willey W. A. van der Donk, Annu. Rev. Microbiol. 2007, 61, 477-501.

U. Schmidt, x-Mercapto-u-amino-acids and Dehydro-amino acids. Syntheses, Relationships and Interconversions, Pure Appl. Chem. 49, 163 (1977). 

Cyclization of a dipeptide having a hydroxylamine unit at the N-terminus is the second general method for the synthesis of 1-hydroxypiperazine-2,5-diones. Thus, Japanese workers have reported that the N-bromoacetyl derivatives (210) obtained from the corresponding dehydro amino acid esters, on treatment with hydroxylamine, give low yields of 1-hydroxy-3-alkylidenepiperazine-2,5-diones (211) (78BCJ550). The corresponding iodo compounds lead to better yields, whereas the chloroacetyl derivative does not cyclize under these conditions. 

The efforts of synthetic organic chemists over the course of the past two decades have brought about a number of selective asymmetric catalyses (Chapters 2-5). Phosphine-Rh(I) catalyzed hydrogenation of dehydro amino acids (75) and phosphine-Ni-aided olefin codimerization (70, 16) were early milestones on the road to highly enantioselective... 

Ligand Variations in the Rh-Catalyzed Hydrogenation of Dehydro-Amino Acids and Esters... 

The linkage in madumycin II (92) of the D-alanine and oxazole residues (the latter thought to arise by cyclization of an acyldehydroserine) is considered significant insofar as the cooccurrence of d- and dehydro amino acids in microbial compounds had been previously noted (61), and a possible relationship between these systems suggested. Several microbial metabolites which display antibiotic properties incorporate a,(i-dehydro amino acids and their derivatives (62). 

DEHYDRO AMINO ACIDS Tfiphenyl-phosphine-Diethyl azodicaiboxylate. 

Catalyst (2) Dehydro amino acid (3) Substrate catalyst Temp. (°C) ee (%)... 

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