Preparation of Unnatural Amino Acids

L-hydantoin W-carbamoyl-D-amino acid D-amino acid 

However, the method has not generally been adopted for the preparation of 3-branched-a-amino acids that require simultaneous chirality control of the adjacent asymmetric centers, because the preparation of j3,j3-disubstituted a-enamide 

---

The provision of intermediates to the pharmaceutical, agrochemical, and other industries requires a number of robust synthetic methods to be available for the preparation of a single class of compounds. The choice of which method to use is determined by the scale of the reaction, economics for a specific run or campaign, ease of operation, time frame, and availability of equipment. There are a large number of methodologies available in the literature for the preparation of unnatural amino acids.3 5 6... 

V-Acyloxazolidinoncs are, therefore, readily available. The use of this class of compounds for the preparation of unnatural amino acids has been well documented.7 Di-tm-butyl azodicarboxylate (DBAD) reacts readily with the lithium enolates of V-acyloxazolidinones to provide hydrazides 6 in excellent yield and high diastereomeric ratio (Scheme 2.5) these adducts 6 can be converted to amino acids.1314... 

The chapter on amino acid derivatives is the result of a considerable amount of research on the new methods for the preparation of unnatural amino acids and derivatives at scale. Their findings cany over into other classes of compounds, but the principles are highlighted exclusively within this field. 

Alkylation of the a-carbon of benzophenone imines allows the on-resin preparation of unnatural amino acids for further transformation into unusual peptides and other classes of compounds. BEMP provides mild and selective alkylation conditions thus avoiding racemiza-tion. The use of TB AF as base avoids O-alkylation. [146] [147] [148a] [150] [151] [160] [187] [188] [212] [237] [241] [277-283]... 

There are literally thousands of hydrogenation catalysts and ligand systems available for the preparation of unnatural amino acids that can be used at scale. In many cases, the ligands were developed to circumvent legal and patent issues and to allow a company freedom to operate. Despite the plethora of ligands in the literature, few are available in bulk quantities, and thus, most of these have arisen from companies applying their own technology. 

Fotheringham, I., Archer, I., Carr, R. et al. (2006) Preparative deracemization of unnatural amino acids. Biochemical Society Transactions, 34 (2), 287-290. 

Evidently, an increase in steric hindrance around the reduced fragment requires the presence of ammonium fluoride in the reaction mixture. It should be noted that potassium fluoride has no effect. It is highly probable that ammonium fluoride is required for slow elimination of HF, which gradually desilylates the nitroso acetal fragment thus facilitating its reduction. As can be seen from Scheme 3.284, many reduction products are derivatives of unnatural amino acids. Since the initial nitroso acetals can be prepared by silylation of simple acyclic AN, possibilities have been opened for the synthesis of unnatural amino acids from available AN. 

The substrate requirements have been rationalized for Rh(dipamp) reductions. Thus, for an enamine they can be divided into four specific regions (Figure 2.1)47 This has allowed the system to be used with confidence to prepare a wide variety of unnatural amino acids.39... 

FIGURE 19.2 Examples of unnatural amino acid residues that can be biologically introduced and used to prepare triazole-linked proteins. 

Leucine dH is the enzyme used as the biocatalyst in the process commercialized by Degussa AG (Hanau, Germany) to produce v-tert-leucine (L-Tle) [24]. This unnatural amino acid has found widespread use in peptidomimetic drugs in development, and the demand for this unique amino acid continues to increase [44]. This process, which has been the subject of much study, requires a cofactor recycling system (Scheme 3. R = (CHj)jC) [45.46]. Similar to phenylalanine dH, leucine dH has been used to prepare numerous unnatural amino acids because of its broad substrate specificity [33.47.48]. 

A variety of methods have been described in this book for the preparation of amino acids. They range from the use of chiral auxiliaries (see Chapter 14), to the use of enzymes (see Chapters 13 and 16) and asymmetric hydrogenation (see Chapter 9). to total fermentation (see Chapter 4). The aim of this chapter is to put into perspective the choice of the appropriate method. We have chosen the synthesis of unnatural amino acids for illustration, but the philosophy could be applied to any class of compound. 

Asymmetric hydrogenation with Knowles catalyst, [Rh-DIPAMP-COD]BF4 has been used on a large scale to prepare L-dopa. The general method has been taken and applied to a wide variety of unnatural amino acids that are required by the pharmaceutical industry as starting materials for complex drug candidates. The scope and limitations of the catalytic method are well understood which means that the approach can be applied with confidence to a wide variety of substrates. 

Although it has some limitations, the Rh-DIPAMP system developed by Knowles has been well studied and this allows for a fair degree of certainty that it can be used with untried substrates. For this reason, it has been used to prepare a range of unnatural amino acid derivatives at scale [7, 11]. A model has been reported that allows others to predict whether Knowles catalyst can be used in a productive manner with their desired enamide. The prediction of the model is based on dividing the enamide substrate into four quadrants (Fig. 2) [7]. 

A production method for the manufacture of cysteine by fermentation has been developed by Wacker Chemie. Building on this technology, an engineered E. coli strain overexpressing the enzyme O-acetylserine sulfhydrylase, which accepts a broad range of substrates, was used to produce a number of unnatural amino acids. This included triazole-1-yl-alanine, (S)-hydroxyethyl cysteine and phenylselenocysteine, which were prepared by feeding fermentations with unnatural precursor molecules (Figure 11.44) [287].These novel unnatural amino acids may prove useful for the synthesis of combinatorial (peptide) libraries. 

Amino acid separations represent another specific application of the technology. Amino acids are important synthesis precursors - in particular for pharmaceuticals -such as, for example, D-phenylglycine or D-parahydroxyphenylglycine in the preparation of semisynthetic penicillins. They are also used for other chiral fine chemicals and for incorporation into modified biologically active peptides. Since the unnatural amino acids cannot be obtained by fermentation or from natural sources, they must be prepared by conventional synthesis followed by racemate resolution, by asymmetric synthesis, or by biotransformation of chiral or prochiral precursors. Thus, amino acids represent an important class of compounds that can benefit from more efficient separations technology. 

---