- A novel approach to Bz-substituted tryptophans via Pd-catalysed coupling/annulation
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The Pd-catalysed preparation of bz-substituted tryptophans and their derivatives, starting from 2-iodoanilines and γ,δ-acetylenic amino acid derivatives, is reported.
- Jeschke,Wensbo,Annby,Gronowitz,Cohen
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- Biosynthesis of violacein, structure and function of L-tryptophan oxidase VioA from chromobacterium violaceum
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Violacein is a natural purple pigment of Chromobacterium violaceum with potential medical applications as antimicrobial, antiviral, and anticancer drugs. The initial step of violacein biosynthesis is the oxidative conversion of L-tryptophan into the corresponding α-imine catalyzed by the flavoenzyme L-tryptophan oxidase (VioA). A substrate-related (3-(1H-indol-3-yl)-2-methylpropanoic acid) and a product-related (2-(1H-indol-3-ylmethyl)prop-2-enoic acid) competitive VioA inhibitor was synthesized for subsequent kinetic and x-ray crystallographic investigations. Structures of the binary VioA?FADH2 and of the ternary VioA?FADH2 ?2-(1H-indol-3-ylmethyl)prop-2-enoic acid complex were resolved. VioA forms a "loosely associated" homodimer as indicated by small-angle x-ray scattering experiments. VioA belongs to the glutathione reductase family 2 of FAD-dependent oxidoreductases according to the structurally conserved cofactor binding domain. The substrate-binding domain of VioA is mainly responsible for the specific recognition of L-tryptophan. Other canonical amino acids were efficiently discriminated with a minor conversion of L-phenylalanine. Furthermore, 7-aza-tryptophan, 1-methyl-tryptophan, 5-methyl-tryptophan, and 5-fluoro-tryptophan were efficient substrates of VioA. The ternary product-related VioA structure indicated involvement of protein domain movement during enzyme catalysis. Extensive structure-based mutagenesis in combination with enzyme kinetics (using L-tryptophan and substrate analogs) identified Arg64 , Lys269 , and Tyr309 as key catalytic residues of VioA. An increased enzyme activity of protein variant H163A in the presence of L-phenylalanine indicated a functional role of His163 in substrate binding. The combined structural and mutational analyses lead to the detailed understanding of VioA substrate recognition. Related strategies for the in vivo synthesis of novel violacein derivatives are discussed.
- Füller, Janis J.,R?pke, René,Krausze, Joern,Rennhack, Kim E.,Daniel, Nils P.,Blankenfeldt, Wulf,Schulz, Stefan,Jahn, Dieter,Moser, Jürgen
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p. 20068 - 20084
(2016/11/05)
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- Efficient asymmetric synthesis of biologically important tryptophan analogues via a palladium-mediated heteroannulation reaction
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A novel and concise synthesis of optically active tryptophan derivatives was developed via a palladium-catalyzed heteroannulation reaction of substituted o-iodoanilines with an internal alkyne. The required internal alkyne 14a or 25 was prepared in greater than 96% de via alkylation of the Schoellkopf chiral auxiliary 19 employing diphenyl phosphate as the leaving group. The Schoellkopf chiral auxiliary was chosen here for the preparation of L-tryptophans would be available from D-valine while the D-isomers required for natural product total synthesis would originate from the inexpensive L-valine (300-g scale). Applications of the palladium-catalyzed heteroannulation reaction were extended to the first asymmetric synthesis of L-isotryptophan 38 and L-benz[f]tryptophan 39. More importantly, the optically pure 6-methoxy-D-tryptophan 62 was prepared by this protocol on a large scale (>300 g). This should permit entry into many ring-A oxygenated indole alkaloids when coupled with the asymmetric Pictet-Spengler reaction. In addition, an improved total synthesis of tryprostatin A (9a) was accomplished in 43% overall yield employing this palladium-mediated process.
- Ma,Liu,Li,Flippen-Anderson,Yu,Cook
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p. 4525 - 4542
(2007/10/03)
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- Concise synthesis of optically active ring-A substituted tryptophans
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A concise synthesis of optically active tryptophan derivatives was developed via diastereoselective alkylation of the Schollkopf chiral auxiliary 4 to provide alkyne 2 which underwent palladium-catalyzed heteroannulation with iodoanilines 1 to furnish protected tryptophans 3. Hydrolysis and subsequent saponification of 3 provided the desired tryptophans 12 in good yields.
- Ma, Chunrong,Liu, Xiaoxiang,Yu, Shu,Zhao, Shuo,Cook, James M.
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p. 657 - 660
(2007/10/03)
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