Total synthesis of the endogenous inflammation resolving lipid resolvin D2 using a common lynchpin

Li, John; Leong, May May; Stewart, Alastair G.; Rizzacasa, Mark A.

doi:10.3762/bjoc.9.310

Cited by 13 publications

(12 citation statements)

References 34 publications

(50 reference statements)

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“…To date, RvD2 has been produced only by total synthesis methods, with no reports of the efficient production of RvD2 by an in vitro enzymatic reaction. However, total synthesis methods have some limitations, including low yield, toxicity of chemicals, and the time-consuming 20-step process required 12 . The combinatorial approach using both enzymatic and chemical reactions described here could be a very attractive option for overcoming difficulties in the production of RvD2.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of two new lipid mediators from docosahexaenoic acid by combinatorial catalysis involving enzymatic and chemical reaction

Heo

et al. 2020

Sci Rep

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Omega-3 polyunsaturated fatty acids (PUFAs) have been known to have beneficial effects in the prevention of various diseases. Recently, it was identified that the bioactivities of omega-3 are related to lipid mediators, called pro-resolving lipid mediators (SPMs), converted from PUFAs, so they have attracted much attention as potential pharmaceutical targets. Here, we aimed to build an efficient production system composed of enzymatic and chemical catalysis that converts docosahexaenoic acid (DHA) into lipid mediators. The cyanobacterial lipoxygenase, named Osc-LOX, was identified and characterized, and the binding poses of enzyme and substrates were predicted by ligand docking simulation. DHA was converted into three lipid mediators, a 17S-hydroxy-DHA, a 7S,17S-dihydroxy-DHA (RvD5), and a 7S,15R-dihydroxy-16S,17S-epoxy-DPA (new type), by an enzymatic reaction and deoxygenation. Also, two lipid mediators, 7S,15R,16S,17S-tetrahydroxy-DPA (new type) and 7S,16R,17S-trihydroxy-DHA (RvD2), were generated from 7S,15R-dihydroxy-16S,17S-epoxy-DPA by a chemical reaction. Our study suggests that discovering new enzymes that have not been functionally characterized would be a powerful strategy for producing various lipid mediators. Also, this combination catalysis approach including biological and chemical reactions could be an effective production system for the manufacturing lipid mediators.

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Section: Resultsmentioning

confidence: 99%

Synthesis of two new lipid mediators from docosahexaenoic acid by combinatorial catalysis involving enzymatic and chemical reaction

Heo

et al. 2020

Sci Rep

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“…In 2013, Rizzacasa et al [ 86 ] disclosed the total synthesis of RvD2 by a convenient and high yield approach, also based on a Sonogashira coupling. By coupling the hydroxyester 41 embodying the triple bond with the iodide 42 , catalysed by (Ph3P)2PdCl2/CuI, intermediate 43 was formed in high yield ( Scheme 8 ).…”

Section: Resolvins From Dhamentioning

confidence: 99%

“…Maresins protect the human body, limiting neutrophil infiltration, enhancing macrophage phagocytosis, reducing the production of pro-inflammatory factors, stimulating tissue regeneration, and controlling pain. MaRs derived from DHA show action in metabolic diseases, nervous system diseases, and kidney and inflammatory bowel diseases, as well as in tissue regeneration and pain control [ 77 , 86 ]. MaR-1 appears to be a molecule with potential for the treatment of motor neuron diseases such as amyotrophic lateral sclerosis (ALS) or spinal muscular atrophy (SMA), which are fatal neurodegenerative diseases that cause loss of motor function and progressive degeneration [ 55 ].…”

Section: Maresins From Dhamentioning

confidence: 99%

“…MaR-1 and Mar-2 are produced by enzymatic hydrolysis with epoxide hydrolase and with soluble epoxide hydrolase (sHE), respectively, as depicted in Scheme 31 . [ 25 , 40 , 77 , 85 , 86 , 89 , 90 ].…”

Section: Maresins From Dhamentioning

confidence: 99%

“… Synthesis of resolvin D2, as reported by Rizzacasa et al [ 86 ]. Reagents and conditions: i. Ph 3 PdCl 2 , CuI, Et 3 N, 0 °C to rt, 83%; ii.…”

Section: Figures Schemes and Tablesmentioning

confidence: 99%

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Resolvins, Protectins, and Maresins: DHA-Derived Specialized Pro-Resolving Mediators, Biosynthetic Pathways, Synthetic Approaches, and Their Role in Inflammation

et al. 2022

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Marine organisms are an important source of natural products with unique and diverse chemical structures that may hold the key for the development of novel drugs. Docosahexaenoic acid (DHA) is an omega-3 fatty acid marine natural product playing a crucial regulatory role in the resolution of inflammation and acting as a precursor for the biosynthesis of the anti-inflammatory specialized pro-resolving mediators (SPMs) resolvins, protectins, and maresins. These metabolites exert many beneficial actions including neuroprotection, anti-hypertension, or anti-tumorigenesis. As dysregulation of SPMs is associated with diseases of prolonged inflammation, the disclosure of their bioactivities may be correlated with anti-inflammatory and pro-resolving capabilities, offering new targets for drug design. The availability of these SPMs from natural resources is very low, but the evaluation of their pharmacological properties requires their access in larger amounts, as achieved by synthetic routes. In this report, the first review of the total organic syntheses carried out for resolvins, protectins, and maresins is presented. Recently, it was proposed that DHA-derived pro-resolving mediators play a key role in the treatment of COVID-19. In this work we also review the current evidence on the structures, biosynthesis, and functional and new-found roles of these novel lipid mediators of disease resolution.

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Hydrozirconation of Alkynes

Milligan,

Hammill,

Crocker

et al. 2023

Organic Reactions

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Since the first preparation of organozirconocenes from alkenes and alkynes in 1972, hydrozirconation has become one of the most commonly used stoichiometric methods to convert readily available starting materials into reactive but stable organometallic intermediates. A broad range of subsequent transformations may be employed to convert organozirconocenes in situ into high‐value functionalized products, often with the strategic formation of one (or several) new carbon–carbon bonds. This chapter focuses on the hydrozirconation of terminal and internal alkynes, and the subsequent synthetic transformations of the resulting alkenylzirconocenes. Zirconocene hydrochloride, Cp 2 Zr(H)Cl, is most frequently employed for the hydrozirconation step and can be used as a reagent or prepared in situ. Subsequent reactions of alkenylzirconocenes include additions to inorganic electrophiles such as halogens, as well as in situ ligand transfers to other metals, such as palladium and zinc, that further expand the range of accessible bond formations. The initial discussion focuses on the mechanism and stereochemical considerations, and on the steric and electronic factors that determine the regiochemistry of the either kinetically or thermodynamically controlled hydrozirconation. The “Scope and Limitations” section presents information on functional group compatibilities and is organized by the type of synthetic transformation of alkenylzirconocenes. Representative applications of the hydrozirconation of alkynes are showcased in syntheses of natural products, comparisons to alternative methods for the hydrometallation of alkynes. The goal of this chapter is to demonstrate the significance of hydrozirconation in organic synthesis, including the utility of the stoichiometric zirconium organometallics obtained from alkyne substrates, and to provide inspiration for the future development of new synthetic methods and strategies.

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Total synthesis of the endogenous inflammation resolving lipid resolvin D2 using a common lynchpin

Cited by 13 publications

References 34 publications

Synthesis of two new lipid mediators from docosahexaenoic acid by combinatorial catalysis involving enzymatic and chemical reaction

Synthesis of two new lipid mediators from docosahexaenoic acid by combinatorial catalysis involving enzymatic and chemical reaction

Resolvins, Protectins, and Maresins: DHA-Derived Specialized Pro-Resolving Mediators, Biosynthetic Pathways, Synthetic Approaches, and Their Role in Inflammation

Hydrozirconation of Alkynes

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