A pilot-plant scale desymmetrization of the cyclic meso-epoxide 4b, using a chiral lithium amide prepared from symmetrical diamine 17, was designed and implemented to provide allylic alcohol 3b in ...high yield and greater than 99% ee. This chiral alcohol was converted to ketone 2b, a key intermediate in a new asymmetric synthesis of LY459477. Chiral diamine 17 was prepared from a readily available chiral precursor, (R)-α-methylbenzylamine, and could be recovered from the reaction mixture and reused. Studies performed to probe the mechanism of the rearrangement reaction of epoxide 4b showed that diamine 17 provided an optimal combination of selectivity and scaleability for this process.
This article describes the development and optimization of chemical reactions and subsequent preparation of the API LY503430 under cGMPs to fund first human dose (FHD) clinical evaluation as a ...potential therapeutic agent for Parkinson's disease. Reasons and rationale are presented for changes in solvents and reagents. One of the major developments presented here is the replacement of a chiral chromatography with a diastereomeric salt resolution. This article also discusses a preferred orientation issue with LY503430 which complicated the XRPD analysis.
4-Methoxyphenylbutyric acid (2) is smoothly demethylated in 3 h at 180 °C when melted with pyridinium hydrochloride (Pyr·HCl), affording 4-hydroxyphenylbutyric acid (3), a key starting material for ...the preclinical candidate LY518674 (1). The adaptation of this chemistry to 22-L and pilot-plant scale is described, including findings to facilitate product isolation, selection of a compatible extraction solvent, and observation of an unusual relationship between the number of solvent extractions and the Pyr·HCl stoichiometry. To the best of our knowledge, this represents the first literature report of the use of this classic demethylation chemistry on multikilogram scale.
Cryptophycin fragment A (
1) was prepared in high enantiomeric purity in 10 steps from (
R)-carvone. A stereoselective bioreduction of (
R)-carvone to neodihydrocarveol and a regioselective ...Baeyer-Villiger oxidation of cyclohexanone
8 with pertrifluoroacetic acid were employed in this synthesis.
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Recent advances in methyltransferase biocatalysis Bennett, Matthew R; Shepherd, Sarah A; Cronin, Victoria A ...
Current opinion in chemical biology,
April 2017, 2017-Apr, 2017-04-00, Letnik:
37
Journal Article
Recenzirano
Odprti dostop
•S-adenosyl methionine-dependent methyltransferases are ubiquitous in nature.•Analogs of S-adenosyl methionine can be produced enzymatically.•Crystallography has improved understanding of ...methyltransferase selectivity.•Tandem assays utilizing methyltransferases lead to industrially relevant compounds
S-adenosyl-L-methionine-dependent methyltransferses are ubiquitous in nature, methylating a vast range of small molecule metabolites, as well as biopolymers. This review covers the recent advances in the development of methyltransferase enzymes for synthetic applications, focusing on the methyltransferase catalyzed transformations with S-adenosyl methionine analogs, as well as non-native substrates. We discuss how metabolic engineering approaches have been used to enhance S-adenosyl methionine production in vivo. Enzymatic approaches that enable the more efficient generation of S-adenosyl methionine analogs, including more stable analogs, will also be described; this has expanded the biocatalytic repertoire of methyltransferases from methylation to a broader range of alkylation reactions. The review also examines how the selectivity of the methyltransferase enzymes can be improved through structure guided mutagenesis approaches. Finally, we will discuss how methyltransferases can be deployed in multi-enzyme cascade reactions and suggest future challenges and avenues for further investigation.
S‐adenosyl‐l‐methionine (SAM)‐dependent methyltransferases (MTs) catalyse the methylation of a vast array of small metabolites and biomacromolecules. Recently, rare carboxymethylation pathways have ...been discovered, including carboxymethyltransferase enzymes that utilise a carboxy‐SAM (cxSAM) cofactor generated from SAM by a cxSAM synthase (CmoA). We show how MT enzymes can utilise cxSAM to catalyse carboxymethylation of tetrahydroisoquinoline (THIQ) and catechol substrates. Site‐directed mutagenesis was used to create orthogonal MTs possessing improved catalytic activity and selectivity for cxSAM, with subsequent coupling to CmoA resulting in more efficient and selective carboxymethylation. An enzymatic approach was also developed to generate a previously undescribed co‐factor, carboxy‐S‐adenosyl‐l‐ethionine (cxSAE), thereby enabling the stereoselective transfer of a chiral 1‐carboxyethyl group to the substrate.
Methyltransferase enzymes (MTs) selectively deliver methyl substituents to an array of molecules, thereby controlling gene expression or modulating the bioactivity of therapeutically important natural products. A MT was engineered for selective carboxy(m)ethylation to give an orthogonal MT that was combined with the SAM‐derivatising enzyme CmoA to create new carboxymethylation pathways.
An animal's welfare state is directly influenced by the mental state, which is shaped by experiences within the environment throughout the animal's life. For zoo‐housed animals, visitors to the zoo ...are a large part of that environment and a fluctuating influence within it. This study examines the impact of zoo visitors on the space use of five species of zoo‐housed primates (Eastern black‐and‐white colobus monkeys, Colobus guereza, n = 5, Allen's swamp monkeys, Allenopithecus nigroviridis, n = 2, DeBrazza's monkeys, Cercopithecus neglectus, n = 3, Bolivian gray titi monkeys, Callicebus donacophilus, n = 3, and crowned lemurs, Eulemur coronatus, n = 3). Specifically, we considered whether primates' distance from visitor areas changed as crowd sizes increased. Data were collected using the ZooMonitor app. Observers recorded spatial coordinates for each animal over periods ranging from 12 to 32 months. Data were analyzed using two types of regression models (linear and logistic) to examine the influence of visitors on the location of the primates. Both analyses revealed a statistically significant but small decrease in primate distance from visitor viewing glass as the number of visitors increased. Behavioral indicators of welfare were also unaffected by the presence of visitors. These results suggest that, with additional validation, distance from visitors may be one promising, simple way to evaluate the influence of visitors on primate welfare.
Five species were studied in their zoo habitats. None showed an increase in distance from viewing windows as crowds increased.*
Research Highlights
The relationship between zoo crowd size and distance from visitors was examined for five primate species.
Primates did not retreat as crowd sizes increased.
Primates showed a small but significant decrease in distance from increasing crowd sizes.
Proximity to visitors may be valuable as a simple tool for inferring animal welfare.
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