Asymmetric synthesis of N-benzyl-5-methylhydroxy-piperidone and modular synthesis of C1-substituent tetrahydroisoquinolines (THIQ) and C2-symmetric bisisoquinolines (C2-BIQ) and their catalytic application in enantioselective Henry reaction

The core objective of this thesis is to develop effective strategies for the asymmetric synthesis of N-benzyl-5-methoxypiperidone, a common building block embedded in many biologically active compounds such as cytisine, vareniciline, paroxetine, tacamonine, and deplaincheine. Two main approaches were investigated: (1) chiral auxiliary, and (2) asymmetric catalysis. Both approaches successfully gave the enantiopure N-benzyl-5-methylhydroxy. With (S)-4-benzyloxazolidinone as the chiral auxiliary, asymmetric synthesis of (R)-N-benzyl-5-methylhydroxy-piperidone was achieved in six steps in 20% overall yield. The key step in this synthesis involved the diastereoselective aldol reaction of (S)-methyl 5-(4-benzyl-2-oxooxazolidin-3-yl)-5-oxopentanoate with 1,3,5-trioxane. The major diastereomeric aldol adduct was subjected to hydrolysis, amidation, chiral auxiliary removal and intramolecular cyclization to give the required enantiopure (R)-N-benzyl-5-methylhydroxy-piperidone.. Asymmetric catalysis through desymmetrization of 1,3-diols as precursor to N-benzyl-5-methoxy-piperidone, using chiral metal-ligand catalysts and lipases was investigated. Desymmetrization using Trost catalyst on our 1,3-diols only offered up 47% ee and 51% yield of monobenzoate product. On the hand, desymmetrization using lipase AK on our 1,3-diols provided up to 92% ee and 93% yield of (R)-monoacetate after optimization. In addition, we also found that desymmetrization of 1,3-diacetate gave the opposite enantiomer (S)-monoacetate in 95% ee and 41% yield. Therefore, in this approach, access to two enantiomers of N-benzyl-5-methoxy-piperidone was achieved in 70-80% yield in two steps after desymmetrization. The two asymmetric synthetic approaches provided a significant improvement in the overall yield of N-benzyl-5-methoxy-piperidone product. While the chiral auxiliary approach offererd enantiopure product in up to 20% yield afet six step, synthetic method using lipase provided up to 45% overall yield afeter six steps, which are higher comparing to Gallagher’s enzymatic resolution approach (approximately 15% yield after five steps). In addition, opposite enantiomeric product can also be conveniently obtained using the same type of lipase. Another objective of this work was to develop an effective modular synthesis of C1-substituent tetrahydroisoquinoline amino alcohols (THIQ) and C2-symmetric bisisoquinoline amino alcohols (C2-BIQ). The synthesis only comprised of two steps: H2SO4-catalyzed N-acyl Pictet Spengler reaction between (S)-4-benzyloxazolidinone and aldehyde substrates, followed by hydrolysis under alkali condition. The reactions proceeded smoothly under easy conditions and the products were obtained in high yields and purities. This synthetic approach provides modular, convergent methodology for the synthesis novel THIQ. To the best of our knowledge, this is the first diastereoselective approach towards the synthesis tetrahydroisoquinoline amino alcohol with tunable substituent group at C1. Application of these THIQs and C2-BIQs as chiral ligands in the Cu(II)-catalyzed asymmetric Henry reaction was also investigated. An optimal catalytic system of Cu(OAc)2.H2O-NNO THIQ (10 mol%) was found to promote the asymmetric Henry reaction between aromatic aldehydes and nitromethane to give the β-nitroalcohol products in up to 96% yield and up to 80% ee.CHEMICAL and BIOMOLECULAR ENGINEERIN

Short synthesis of phenylpropanoid glycosides calceolarioside A and syringalide B

An efficient and practical three-step synthesis of phenylpropanoid glycosides calceolarioside A and syringalide B in >62% overall yield is disclosed. The key step involves the chemoselective and regio selective direct O-4 cinnamoylation of unprotected 2-phenylethyl-β-d-glucosides with cinnamic anhydrides using a chiral 4-pyrrolidinopyridine organocatalyst. This approach serves as a model for the short synthesis of phenylpropanoid glycosides acylated at O-4 without protection/deprotection steps

Targeted Synthesis of 3,3′-, 3,4′- and 3,6′-Phenylpropanoid Sucrose Esters

In this study, we report on an orthogonal strategy for the precise synthesis of 3,3′-, 3,4′-, and 3,6′-phenylpropanoid sucrose esters (PSEs). The strategy relies on carefully selected protecting groups and deprotecting agents, taking into consideration the reactivity of the four free hydroxyl groups of the key starting material: di-isopropylidene sucrose 2. The synthetic strategy is general, and potentially applies to the preparation of many natural and unnatural PSEs, especially those substituted at 3-, 3′-, 4′- and 6′-positions of PSEs

Targeted synthesis of 3,3'-, 3,4'- and 3,6'-phenylpropanoid sucrose esters

In this study, we report on an orthogonal strategy for the precise synthesis of 3,3'-, 3,4'-, and 3,6'-phenylpropanoid sucrose esters (PSEs). The strategy relies on carefully selected protecting groups and deprotecting agents, taking into consideration the reactivity of the four free hydroxyl groups of the key starting material: di-isopropylidene sucrose 2. The synthetic strategy is general, and potentially applies to the preparation of many natural and unnatural PSEs, especially those substituted at 3-, 3'-, 4'- and 6'-positions of PSEs.Nanyang Technological UniversityPublished versionThis research was funded by the College of Engineering (Startup Grant), Nanyang Technological University, Singapore

An orthogonal approach for the precise synthesis of phenylpropanoid sucrose esters

Phenylpropanoid sucrose esters (PSEs) are plant-derived metabolites that exist widely in medicinal plants and possess important bioactivities. Their precise synthesis is challenging due to the distinct and diverse substitution patterns at the sugar framework, and it is scarcely reported. Orthogonal protection/deprotection strategies for disaccharides are more complex and less developed than those for monosaccharides. We disclose a precise synthesis of PSEs starting from 2,1′:4,6-di-O-diisopropylidene sucrose 7via an orthogonal protection/deprotection and selective cinnamoylation strategy. We demonstrate the strategy for the synthesis of several PSEs cinnamoylated at the O-3 and O-4′ positions of diisopropylidene sucrose 7. The strategy is enabled by a carefully selected and synergistic set of protecting groups and deprotecting agents under the optimized conditions. It potentially gives access to the ∼150 reported PSEs and opens the door for the custom synthesis of unnatural PSEs for industrial applications. The reported work also presents a viable strategy for the general orthogonal protection/deprotection of disaccharides for the precise synthesis of other classes of phenylpropanoid esters and related compounds.Nanyang Technological UniversityPublished versionWe thank the Interdisciplinary Graduate School and the School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore for financial support (CoE, Startup Grant)

Nanosensor detection of synthetic auxins in planta using corona phase molecular recognition

Synthetic auxins such as 1-naphthalene acetic acid (NAA) and 2,4-dichlorophenoxyacetic acid (2,4-D) have been extensively used in plant tissue cultures and as herbicides because they are chemically more stable and potent than most endogenous auxins. A tool for rapid in planta detection of these compounds will enhance our knowledge about hormone distribution and signaling and facilitate more efficient usage of synthetic auxins in agriculture. In this work, we show the development of real-time and nondestructive in planta NAA and 2,4-D nanosensors based on the concept of corona phase molecular recognition (CoPhMoRe), to replace the current state-of-the-art sensing methods that are destructive and laborious. By designing a library of cationic polymers wrapped around single-walled carbon nanotubes with general affinity for chemical moieties displayed on auxins and its derivatives, we developed selective sensors for these synthetic auxins, with a particularly large quenching response to NAA (46%) and a turn-on response to 2,4-D (51%). The NAA and 2,4-D nanosensors are demonstrated in planta across several plant species including spinach, Arabidopsis thaliana (A. thaliana), Brassica rapa subsp. chinensis (pak choi), and Oryza sativa (rice) grown in various media, including soil, hydroponic, and plant tissue culture media. After 5 h of 2,4-D supplementation to the hydroponic medium, 2,4-D is seen to accumulate in susceptible dicotyledon pak choi leaves, while no uptake is observed in tolerant monocotyledon rice leaves. As such, the 2,4-D nanosensor had demonstrated its capability for rapid testing of herbicide susceptibility and could help elucidate the mechanisms of 2,4-D transport and the basis for herbicide resistance in crops. The success of the CoPhMoRe technique for measuring these challenging plant hormones holds tremendous potential to advance the plant biology study.Agency for Science, Technology and Research (A*STAR)National Research Foundation (NRF)Singapore-MIT Alliance for Research and Technology (SMART)This research was supported by the National Research Foundation (NRF), Prime Minister's Office, Singapore, under its Campus for Research Excellence and Technological Enterprise (CREATE) program. The Disruptive & Sustainable Technology for Agricultural Precision (DiSTAP) is an interdisciplinary research group of the Singapore-MIT Alliance for Research and Technology (SMART) Center. T.T.S.L. was supported on a graduate fellowship by the Agency of Science, Research and Technology, Singapore. M.P. is grateful for the support of the Samsung scholarship. A.D. was supported on the Singapore-MIT undergraduate research fellowship

Measuring the Accessible Surface Area within the Nanoparticle Corona using Molecular Probe Adsorption

Copyright © 2019 American Chemical Society. The corona phase - the adsorbed layer of polymer, surfactant, or stabilizer molecules around a nanoparticle - is typically utilized to disperse nanoparticles into a solution or solid phase. However, this phase also controls molecular access to the nanoparticle surface, a property important for catalytic activity and sensor applications. Unfortunately, few methods can directly probe the structure of this corona phase, which is subcategorized as either a hard, immobile corona or a soft, transient corona in exchange with components in the bulk solution. In this work, we introduce a molecular probe adsorption (MPA) method for measuring the accessible nanoparticle surface area using a titration of a quenchable fluorescent molecule. For example, riboflavin is utilized to measure the surface area of gold nanoparticle standards, as well as corona phases on dispersed single-walled carbon nanotubes and graphene sheets. A material balance on the titration yields certain surface coverage parameters, including the ratio of the surface area to dissociation constant of the fluorophore, q/KD, as well as KD itself. Uncertainty, precision, and the correlation of these parameters across different experimental systems, preparations, and modalities are all discussed. Using MPA across a series of corona phases, we find that the Gibbs free energy of probe binding scales inversely with the cube root of surface area, q. In this way, MPA is the only technique to date capable of discerning critical structure-property relationships for such nanoparticle surface phases. Hence, MPA is a rapid quantitative technique that should prove useful for elucidating corona structure for nanoparticles across different systems

Decoding early stress signaling waves in living plants using nanosensor multiplexing

Abstract Increased exposure to environmental stresses due to climate change have adversely affected plant growth and productivity. Upon stress, plants activate a signaling cascade, involving multiple molecules like H2O2, and plant hormones such as salicylic acid (SA) leading to resistance or stress adaptation. However, the temporal ordering and composition of the resulting cascade remains largely unknown. In this study we developed a nanosensor for SA and multiplexed it with H2O2 nanosensor for simultaneous monitoring of stress-induced H2O2 and SA signals when Brassica rapa subsp. Chinensis (Pak choi) plants were subjected to distinct stress treatments, namely light, heat, pathogen stress and mechanical wounding. Nanosensors reported distinct dynamics and temporal wave characteristics of H2O2 and SA generation for each stress. Based on these temporal insights, we have formulated a biochemical kinetic model that suggests the early H2O2 waveform encodes information specific to each stress type. These results demonstrate that sensor multiplexing can reveal stress signaling mechanisms in plants, aiding in developing climate-resilient crops and pre-symptomatic stress diagnoses

Monitoring of Antibiotic Residues in Aquatic Products in Urban and Rural Areas of Vietnam

Antibiotic residues in aquatic products in Vietnam were investigated. A total of 511 fish and shrimp samples were collected from markets in Ho Chi Minh City (HCMC), Thai Binh (TB), and Nha Trang (NT) from July 2013 to October 2015. The samples were extracted with 2% formic acid in acetonitrile and washed with dispersive C18 sorbent. Thirty-two antibiotics were analyzed by LC-MS/MS. Of the 362 samples from HCMC, antibiotic residues were found in 53 samples. Enrofloxacin was commonly detected, at a rate of 10.8%. In contrast, samples from TB and NT were less contaminated: only 1 of 118 analyzed samples showed residues in TB and only 1 of 31 showed residues in NT. These differences were attributed to the local manufacturing/distribution systems. To understand the current status of antibiotic use and prevent adverse effects that may be caused by their overuse, continual monitoring is required