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Chemistry of Essential Oils
Published in K. Hüsnü Can Başer, Gerhard Buchbauer, Handbook of Essential Oils, 2020
The synthesis of l-menthol (94) provides an interesting example of different routes operating in economic balance. The three production routes in current use are shown in Figure 6.40. The oldest and simplest route is extraction from plants of the Mentha genus and M. arvensis (corn mint) in particular. This is achieved by freezing the oil to force the l-menthol to crystallize out. Diethylamine can be added to myrcene (70) in the presence of base and rearrangement of the resultant allyl amine (224) using the optically active catalyst ruthenium (S)-BINAP perchlorate gives the homochiral enamine (225). This can then be hydrolyzed to d-citronellol (209). The chiral center in this molecule ensures that, on acid-catalyzed cyclization, the two new stereocenters formed possess the correct stereochemistry for conversion, by hydrogenation, to give l-menthol as the final product. Starting from the petrochemically sourced m-cresol (226), propenylation gives thymol (97), which can be hydrogenated to give a mixture of all eight stereoisomers of menthol (227). Fractional distillation of this mixture gives racemic menthol. Resolution was originally carried out by fractional crystallization, but recent advances include methods for the enzymic resolution of the racemate to give l-menthol.
Biocatalysts: The Different Classes and Applications for Synthesis of APIs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The aldolase-catalyzed reaction proceeds via two different mechanisms, a Schiff base formation (class I aldolases) or by Zn2+ activation (class II aldolases), as depicted in the opposite scheme for DHAP-dependent enzymes. The mechanism of class I aldolases (a) is characterized by the formation of an imine between the terminal amino group of a Lys residue and the carbonyl oxygen atom of the substrate DAHP. The imine may rearrange to an enamine that attacks nucleophilicly the aldehyde carbonyl carbon. Subsequent hydrolysis gives the new aldol and the free enzyme. The first steps in the reaction mechanism of the class II aldolases such as tagatose-1,6-diphosphate aldolase or fructose-1,6-diphosphate aldolase (b) are the binding of DAHP and the abstraction of a proton from the activated C1 by a functional group of the active site. The following steps (not shown), are glyceraldehyde-3-phosphate binding with subsequent C–C bond formation, and proton transfer.
Where Cancer and Bacteria Meet
Published in Ananda M. Chakrabarty, Arsénio M. Fialho, Microbial Infections and Cancer Therapy, 2019
Alexandra Merlos, Ricardo Perez-Tomás, José López-López, Miguel Viñas
As natural anionophores tambjamines facilitate the permeabilization of cell membranes and thus upset the normal intracellular ionic balance. Spectroscopic analysis of the structure of tambjamines revealed strong hydrogen bonding between these compounds and the chloride anion [87]. The two heterocycles and the enamine moiety are essentially coplanar. A chloride anion interacts with the pyrrole and enamine N-H groups, whereas the indole moiety is rotated 180° and interacts with a second chloride anion. However, in their preferred conformation tambjamines bind with the anion through the hydrogen bond cleft involving the three N-H groups of the molecule [90].
Asymmetric organocatalysis in drug discovery and development for active pharmaceutical ingredients
Published in Expert Opinion on Drug Discovery, 2023
In 2018, Eli Lilly labs reported a practical asymmetric fluorination approach to the synthesis of new fluoroamino-thiazine BACE inhibitors using proline and imidazolidinone organocatalysts [37]. In fact, they developed a large-scale process (multigram scale) for the synthesis of the fluorinated amino alcohol tert-butyl N-[(3S,4S)-3-(5-acetamido-2-fluorophenyl)-4-fluoro-4-(hydroxymethyl)tetrahydrofuran-3-yl]carbamate 10 which is a precursor to the potent β-secretase (BACE) inhibitor LY2886721 which is currently in Phase II clinical trials, starting from the N-Boc protected amino-formyltetrahydrofuran substrate 9 (Figure 2, c). The team used Selectfluor® along with D-proline as the catalyst (although it was used at a stoichiometric level) in trifluoroethanol and it afforded the fluorinated target 10 in 70% yield and 98% ee after passing through a silica gel pad. The mechanism should follow the usual route involving the enamine intermediate formed from proline followed by electrophilic fluorination.
Synthesis and preliminary structure-activity relationship study of 3-methylquinazolinone derivatives as EGFR inhibitors with enhanced antiproliferative activities against tumour cells
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Yan Zhang, Qin Wang, Luolan Li, Yi Le, Li Liu, Jing Yang, Yongliang Li, Guochen Bao, Longjia Yan
Based on the result of EGFRwt-TK and four tumour cell assays, we found that the similar structure–activity relationship (SAR) was observed in cell lines and EGFR-TKs. The amide group (4d and 4e) instead of enamine was more potent than the ketene group (4a), vinyl group (4c), urea group (4 g) and other groups (4 b and 4f). Besides, compound A showed lower inhibitor activities against four tumour cell lines than the compounds 4a–4g. The reason may be due to the lower stability of compound A in cells. Generally, compound 4d was the best in the synthesised compounds and particularly showed much higher inhibitor activities than Gefitinib against four tumour cells. These data indicate that 4d was worth to further investigation.
Human carbonic anhydrases and post-translational modifications: a hidden world possibly affecting protein properties and functions
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Anna Di Fiore, Claudiu T. Supuran, Andrea Scaloni, Giuseppina De Simone
Non-enzymatic protein glycation is an irreversible PTM affecting K and R residues as well as N-terminal amino acids, which is generally initiated by the condensation of the carbonyl group of reducing sugars with the amino group of proteins. At first, it generates a Schiff base (aldimine) adduct that is unstable and can rearrange via an enamine intermediate to generate a 1-amino-1-deoxy-2-ketose (ketoamine) product, also known as the Amadori compound. In the case of glucose, this reaction yields to Nε-(1-deoxy-D-fructos-1-yl)-lysine. Glycated proteins can either further react to form advanced glycation endproducts (AGEs), which contain modified K and R residues, or react directly with sugar-derived dicarbonyl compounds also to form AGEs102. In human, this process generally occurs under patho-physiological conditions generally associated with a hyperglycaemic status, such as diabetes, but it has also been observed in the course of neurodegenerative and cardiovascular diseases, and aging. Extensive non-enzymatic glycation can alter the three-dimensional structure of a protein, with possible effects on its functional properties103–105.