25 research outputs found
Cyclocondensation reactions of 2-acyl-3-indoleacetic acid derivatives with phenylglycinol. Enantioselective synthesis of 1-substituted tetrahydro-b-carboline alkaloids
Cyclocondensation reactions between a variety of 2âacylâ3âindoleacetic acid derivatives and (R )âphenylglycinol were studied. Successful results were obtained from N âalkyl keto acid derivatives. The resulting tetracyclic lactams provide straightforward access to enantiopure 1âsubstituted tetrahydroâÎČâcarboline alkaloids
Stereoselective synthesis of cis-1,3-dimethyltetrahydroisoquinolines: formal synthesis of naphthylisoquinoline alkaloids
Starting from tricyclic lactam 2, which is easily accessible by cyclocondensation of -oxoester 1 with (R)-phenylglycinol, a three-step synthetic route to enantiopure 1-substituted tetrahydroisoquinolines, including 1-alkyl-, 1-aryl-, and 1-benzyl- tetrahydroisoquinoline alkaloids as well as the tricyclic alkaloid (-)-crispine A, has been developed. The key step is a stereoselective -amidoalkylation reaction using the appropriate Grignard reagent
A general methodology for the enantioselective synthesis of 1-substituted tetrahydroisoquinoline alkaloids
Starting from tricyclic lactam 2 , which is easily accessible by cyclocondensation of ÎŽâoxoester 1 with (R )âphenylglycinol, a threeâstep synthetic route to enantiopure 1âsubstituted tetrahydroisoquinolines, including 1âalkylâ, 1âarylâ, and 1âbenzyltetrahydroisoquinoline alkaloids, as well as the tricyclic alkaloid (-)âcrispine A, has been developed. The key step is a stereoselective αâamidoalkylation reaction using the appropriate Grignard reagent
Enzymatic synthesis of benzylisoquinoline alkaloids using a parallel cascade strategy and tyrosinase variants
Benzylisoquinoline alkaloid derived pharmaceuticals are widely applied in modern medicines. Recent studies on the microbial production of benzylisoquinolines have highlighted key biological syntheses towards these natural products. Routes to non-natural benzylisoquinolines have been less explored, particularly halogenated compounds which are more challenging. Here, we show the use of a tyrosinase, tyrosine decarboxylase, transaminase, and norcoclaurine synthase which are combined in a parallel cascade design, in order to generate halogenated benzylisoquinoline alkaloids in high enantiomeric excess. Notably, mutagenesis studies are applied to generate tyrosinase mutants, which enhance the acceptance of halogenated tyrosines for use in the biocatalytic cascades developed
Studies on the Regioselectivity of the Cyclization of Tryptophanol-Derived Oxazolopiperidone Lactams
Cyclization of the lactam carbonyl on the indole ring in tryptophanol-derived oxazolopiperidone lactams 2 and 6, under the classical POCl3-promoted Bischler-Napieralski conditions and under neutral conditions via the corresponding thiolactam, has been studied. Whereas tricyclic lactam 2 only leads to products coming from an α-amidoalkylation process, bicyclic lactam 6 undergoes cyclization on the lactam carbonyl, leading to the expected indolo[2,3-a]quinolizidine derivatives
Synthesis of a tetrahydroimidazo-[2',1':2,3]thiazolo[5,4-c]pyridine derivative with Met inhibitory activity
A straightforward synthesis of the Met antagonist JLK1360 involving an alkylationcyclocondensation process using aminothiazole 1 and nitrophenacyl bromide 2, reduction of the nitro group, and coupling of the resulting tetracyclic aniline 5 with an appropriate N-acyl alanine derivative, is reported
Characterisation of a hyperthermophilic transketolase from Thermotoga maritima DSM3109 as a biocatalyst for 7-keto-octuronic acid synthesis
Transketolase (TK) is a fundamentally important enzyme in industrial biocatalysis which carries out a stereospecific carbonâcarbon bond formation, and is widely used in the synthesis of prochiral ketones. This study describes the biochemical and molecular characterisation of a novel and unusual hyperthermophilic TK from Thermotoga maritima DSM3109 (TKtmar). TKtmar has a low protein sequence homology compared to the already described TKs, with key amino acid residues in the active site highly conserved. TKtmar has a very high optimum temperature (>90 °C) and shows pronounced stability at high temperature (e.g. t1/2 99 and 9.3 h at 50 and 80 °C, respectively) and in presence of organic solvents commonly used in industry (DMSO, acetonitrile and methanol). Substrate screening showed activity towards several monosaccharides and aliphatic aldehydes. In addition, for the first time, TK specificity towards uronic acids was achieved with TKtmar catalysing the efficient conversion of D-galacturonic acid and lithium hydroxypyruvate into 7-keto-octuronic acid, a very rare C8 uronic acid, in high yields (98%, 49 mM)
Expanding the Substrate Scope of N- and O-Methyltransferases from Plants for Chemoselective Alkylation
Methylation reactions are of significant interest when generating pharmaceutically active molecules and building blocks for other applications. Synthetic methylating reagents are often toxic and unselective due to their high reactivity. SâAdenosylâlâmethionine (SAM)âdependent methyltransferases (MTs) present a chemoselective and environmentally friendly alternative. The anthranilate NâMT from Ruta graveolens (RgANMT) is involved in acridone alkaloid biosynthesis, methylating anthranilate. Although it is known to methylate substrates only at the Nâposition, the closest relatives with respect to amino acid sequence similarities of over 60â% are OâMTs catalysing the methylation reaction of caffeate and derivatives containing only hydroxyl groups (CaOMTs). In this study, we investigated the substrate range of RgANMT and a CaOMT from Prunus persica (PpCaOMT) using compounds with both, an aminoâ and hydroxyl group (aminophenols) as possible methyl group acceptors. For both enzymes, the reaction was highly chemoselective. Furthermore, generating cofactor derivatives inâ
situ enabled the transfer of other alkyl chains onto the aminophenols, leading to an enlarged pool of products. Selected MT reactions were performed at a preparative biocatalytic scale in inâ
vitro and inâ
vivo experiments resulting in yields of up to 62â%
Multienzyme one-pot cascades incorporating methyltransferases for the strategic diversification of tetrahydroisoquinoline alkaloids
The tetrahydroisoquinoline (THIQ) ring system is present in a large variety of structurally diverse natural products exhibiting a wide range of biological activities. Routes to mimic the biosynthetic pathways to such alkaloids, by building cascade reactions in vitro, represents a successful strategy and can offer better stereoselectivities than traditional synthetic methods. S-Adenosylmethionine (SAM)-dependent methyltransferases are crucial in the biosynthesis and diversification of THIQs; however, their application is often limited in vitro by the high cost of SAM and low substrate scope. In this study, we describe the use of methyltransferases in vitro in multi-enzyme cascades, including for the generation of SAM in situ. Up to seven enzymes were used for the regioselective diversification of natural and non-natural THIQs on an enzymatic preparative scale. Regioselectivites of the methyltransferases were dependent on the group at C-1 and presence of fluorine in the THIQs. An interesting dual activity was also discovered for the catechol methyltransferases used, which were found to be able to regioselectively methylate two different catechols in a single molecule
Single step syntheses of (1 S)-aryltetrahydroisoquinolines by norcoclaurine synthases
The 1-aryl-tetrahydroisoquinoline (1-aryl-THIQ) moiety is found in many biologically active
molecules. Single enantiomer chemical syntheses are challenging and although some biocatalytic
routes have been reported, the substrate scope is limited to certain structural motifs.
The enzyme norcoclaurine synthase (NCS), involved in plant alkaloid biosynthesis, has been
shown to perform stereoselective PictetâSpengler reactions between dopamine and several
carbonyl substrates. Here, benzaldehydes are explored as substrates and found to be
accepted by both wild-type and mutant constructs of NCS. In particular, the variant M97V
gives a range of (1 S)-aryl-THIQs in high yields (48â99%) and e.e.s (79â95%). A cocrystallised
structure of the M97V variant with an active site reaction intermediate analogue
is also obtained with the ligand in a pre-cyclisation conformation, consistent with (1 S)-THIQs
formation. Selected THIQs are then used with catechol O-methyltransferases with exceptional
regioselectivity. This work demonstrates valuable biocatalytic approaches to a range of
(1 S)-THIQ