One-Pot Synthesis of D‑Halotryptophans by Dynamic Stereoinversion Using a Specific L‑Amino Acid Oxidase

 

 

Christian Schnepel, Isabell Kemker, and Norbert Sewald
Organic and Bioorganic Chemistry, Department of Chemistry, Bielefeld University, PO Box 100131, 33501 Bielefeld, Germany

 

 

INTRODUCTION
The synthesis of chiral building blocks like amino acids has strongly benefited from tremendous progress in biocatalysis within the last decades. Proteinogenic amino acids are being predominantly produced by fermentation processes, e.g., the production of glutamate and lysine proceeds on a million-ton scale per year. Many of them find application as bulk materials for chemistry and nutrition or serve as additives in feedstuff, respectively.1 Particularly, the synthesis of non-native amino acids has attracted interest in the past decade as such building blocks have potential in protein research, for example, to study the influence of non-natural amino acids on biocatalyst properties.2 Noncanonical amino acids can be integrated into peptides by solid-phase synthesis, while so-called xenoproteins are usually synthesized in a recombinant fashion by making use of selective pressure incorporation or the expanded genetic code.3,4 Even though tryptophan (Trp) is a low-abundance amino acid, its biological significance is extraordinary and made Trp derivatives widely applied handles.5,6 This particular amino acid acts as a biosynthetic precursor for plenty of natural products.

 

Thus, many efforts were undertaken to develop selective synthetic strategies yielding functionalized Trp by means of chemo- and biocatalysis. For example, assembly of the chiral Trp scaffold could be accomplished by enantioselective Strecker amino acid synthesis. Schöllkopf’s chiral auxiliary was frequently applied to obtain chiral amino acids (Scheme 1A).9,10 Acylated Trp derivatives can be derived by simple reaction of L-serine with substituted indoles in the presence of acetic anhydride. Kinetic resolution of racemic Trp catalyzed by an acylase affords the L-configured enantiomer.11 A straightforward enzymatic approach developed by Goss et al. utilizes Trp synthase from Salmonella enterica to obtain a range of substituted Trp derivatives.12,13 In the enzyme, a Michaeltype addition takes place where indole-C3 attacks a pyridoxal phosphate-linked amino acrylate residue initially formed upon serine dehydration. This simple one-step biotransformation made a large set of halogenated and alkylated Trp derivatives accessible. Recently, Arnold and Micklefield independently embarked on engineering Trp synthase to accept L-threonine as an electrophilic co-substrate, resulting in β-methyl Trp derivatives.14,15 A major obstacle is that these synthetic pathways require previous formation of substituted indoles, e.g., via Fischer indole synthesis or Pd-catalyzed annulation, respectively, which may render the process inefficient and laborious.16,17 In contrast, a plethora of biotransformations has been discovered to be capable of performing direct modification of the Trp scaffold with high selectivity while avoiding elaborate directing groups.18 Typical modifications of Trp encompass hydroxylation known from the initial step of serotonin biosynthesis, nitration catalyzed by a cytochrome P450 enzyme, or alkylations.19−22 Particularly, enzymatic halogenation emerged as an important methodology for selective C−H activation (Scheme 1B). The halogenated products allow for a range of subsequent derivatizations, e.g., nucleophilic substitution or Pd-catalyzed cross-couplings.

 

Thus, we and other groups sought to employ flavin-dependent Trp halogenases to selectively halogenate the indole moiety while merely consuming O2, the cofactor FADH2, and a halide salt.23,24 Its preparative utility became feasible by CLEA immobilization, providing access to bromotryptophan (Br-Trp) on a gram scale.25 The directing influence of substituents present at the indole of Trp on the RebH-catalyzed halogenation was investigated.26 Enzyme engineering by directed evolution to improve halogenase efficiency was shown to provide improved catalyst stability, high-throughput assay design, as well as an extended substrate scope.27−30 Notably, the halogen substituent serves as a reactive handle for Pd-catalyzed crosscouplings. The groups of Goss and O’Connor first embarked on sequential cascades combining enzymatic halogenation and Suzuki−Miyaura cross-coupling, also allowing for altered spectral properties of the aryl-substituted Trp derivatives.31−33

 

One-pot procedures carried out on the preparative scale were later reported by the Lewis group34 and by us.35 Inspired by a seminal study by Gröger et al.,36 Micklefield and co-workers employed compartmentalization to overcome incompatibility between the halogenase and the Pd catalyst, thus providing an important milestone in this field.37 Very recently, Goss and coworkers embarked on an intriguing chemogenetic approach that merged enzymatic halogenation with cross-coupling in vivo, albeit without mentioning conversions.38

 

The use of biocatalysts in reaction cascades, in multistep enzyme reactions, or combined with chemocatalysts attracts great attention. Especially when enzymes and metal catalysts are mutually used, compatibility issues have to be overcome. Multienzyme cascades provide novel pathways applicable in the production of valuable chemicals in vitro. Current developments on chemoenzymatic synthesis and their challenges have been reviewed by Flitsch et al.39 and Bornscheuer et al.40

 

Amino acid decarboxylation or deamination offers important transformations, providing the corresponding tryptamines or α-keto acids, respectively. Enzymatic deamination catalyzed by aminotransferases, amine dehydrogenases, or amino acid oxidases (AAOs), for example, can be employed in the latter case.41 In general, AAOs only require molecular oxygen to catalyze Cα-oxidation, yielding an α-imino acid intermediate that spontaneously hydrolyzes to give the α-keto acid. The catalytic cycle starts with hydride transfer to FAD. The resulting FADH2 subsequently reacts with O2 to form the flavin hydroperoxide, which finally releases hydrogen peroxide.42 There are L-selective AAOs as well as their D-selective counterparts known. While D-AAOs found broad application in biotechnology, handling of L-AAOs is hampered by severe obstacles. In particular, heterologous L-AAO expression proves challenging due to low protein solubility, misfolding, and potential toxicity for the expression host. Therefore, these
enzymes are less attractive for large-scale applications. An LAAO from Rhodococcus opacus is one of the few well-studied representatives where expression succeeded albeit with low yield and unsatisfying enzyme activity.43 Very recently, an elaborate survey was reported about a fungal L-AAO expressed in Pichia pastoris followed by its biochemical characterization.44,45 D-AAOs found wide application in biotechnology up to now, e.g., in kinetic resolution of chiral amines as well as for the synthesis of α-keto acids. In 2015, Turner et al. embarked on the synthesis of non-natural Phe analogues using a multistep cascade starting from substituted cinnamic acids.

 

These compounds were initially aminated by ammonia lyase and subsequently deracemized with either a deaminase or a DAAO in the presence of a nonselective reducing agent.46 As the current state of the art on L-AAOs accepting Trp derivatives is very limited, we felt inspired to study an AAO from L. aerocolonigenes (RebO) as the only described member with high specificity toward substituted Trp. RebO (EC 1.4.3.23, Uniprot ID: Q8KHS0), a 52 kDa flavoprotein, was previously characterized to elucidate its role in the biosynthesis of the indole carbazole rebeccamycin.47−49 RebH-catalyzed C7-halogenation of Trp is followed by oxidative deamination induced by RebO, resulting in 7-chloroindolyl pyruvate as a biosynthetic intermediate of the rebeccamycin pathway (Scheme 2). Prior studies indicated that RebO prefers L-7-chlorotryptophan (7-Cl-Trp), but the biotechnological use of this enzyme has not been explored yet.

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CAS No. 1020253-85-3 3-Pyridinamine, 6-bromo-5-methoxy- Catalog No.:AG0006DX MDL No.:MFCD21603641 MF:C6H7BrN2O MW:203.0366	CAS No. 1020253-86-4 2H-Pyrido[1,2-a]pyrimidine-9-carboxylic acid, 1,3,4,6-tetrahydro-6-oxo-, ethyl ester Catalog No.:AG0006DW MDL No.: MF:C11H14N2O3 MW:222.2405	CAS No. 1020276-38-3 Piperidine, 4-(4-chloro-3-methoxyphenyl)- Catalog No.:AG0006DV MDL No.: MF:C12H16ClNO MW:225.7145
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