A General Strategy for the Synthesis of Monohydroxy-eicosatetraenoic Acids: Total Synthesis of 5(S)-Hydroxy-6(E),8,11,14(Z)-eicosatetraenoic Acid (5-HETE) and 12(S)-Hydroxy-5,8,14(Z), 10(E)-eicosatetraenoic Acid (12-HETE)

Nicolaou, K. C.; Ladduwahetty, T.; Taffer, Ira M.; Zipkin, Robert E.

doi:10.1055/s-1986-31612

Cited by 49 publications

(10 citation statements)

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“…All attempts to improve the yield of 7 while retaining a high stereoselectivity were unsuccessful. Moreover, other methods explored did not give a stereoselective and concurrent high-yielding reduction of alkyne 21 . , The spectroscopic data (UV, IR, NMR, and MS) for the methyl ester 7 of 22-OH-PD1 ( 6 ) were in accord with the structure (Supporting Information). …”

Section: Resultsmentioning

confidence: 90%

“…The crude product was purified by column chromatography on silica (hexanes/EtOAc, 4:6) to afford the title compound 19 as a yellow oil. Yield: 81 mg (94%); [α] D 20 −9 (c 0.2, MeOH); 1 H NMR (400 MHz, CDCl 3 ) δ 5.72−5.58 (m, 2H), 4.46− 4.41 (m, 1H), 3.67 (t, J = 5.9 Hz, 2H), 3 (20). To a solution of vinyl bromide 15 (253 mg, 0.57 mmol, 1.0 equiv) in Et 2 NH (1.2 mL) and benzene (0.4 mL) was added Pd(PPh 3 ) 4 (20 mg, 0.02 mmol, 3 mol %), and the reaction was stirred for 45 min in the dark.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

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Synthesis and Anti-inflammatory and Pro-resolving Activities of 22-OH-PD1, a Monohydroxylated Metabolite of Protectin D1

et al. 2014

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Protectin D1 (PD1 (3)), a C22-dihydroxylated polyunsaturated fatty acid biosynthesized from all-Z-docosahexaenoic acid, belongs to the new family of endogenous mediators referred to as specialized pro-resolving lipid mediators. PD1 (3) is a natural product that displays potent anti-inflammatory properties together with pro-resolving actions including inhibition of polymorphonuclear leukocyte (PMN) infiltration and promotion of macrophage phagocytosis and efferocytosis. Given its potent endogenous actions, this compound has entered several clinical development programs. Little has been reported on the metabolism of PD1 (3). The synthesis and biological evaluations of the ω-22 monohydroxylated metabolite of PD1 (3), named herein 22-OH-PD1 (6), are presented. LC-MS/MS data of the free acid 6, obtained from hydrolysis of the synthetic methyl ester 7, matched data for the endogenously produced 22-OH-PD1 (6). Compound 6 exhibited potent pro-resolving actions by inhibiting PMN chemotaxis in vivo and in vitro comparable to its precursor PD1 (3) and decreased pro-inflammatory mediator levels in inflammatory exudates. The results reported herein provide new knowledge of the metabolism of the protectin class of specialized pro-resolving mediators.

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Section: Resultsmentioning

confidence: 90%

Section: ■ Experimental Sectionmentioning

confidence: 99%

Synthesis and Anti-inflammatory and Pro-resolving Activities of 22-OH-PD1, a Monohydroxylated Metabolite of Protectin D1

et al. 2014

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“…Deprotection of the two TBS groups in 18 with five equivalents of TBAF in THF at 0 °C gave an 85% yield of the diol 19 . 27 The internal alkyne in 19 was reduced to the Z , E , E , Z ,Z-pentaene ester 6 in 50% yield using a modified Lindlar hydrogenation reaction 28 with high stereoselectivity, as only one diastereomer was detected by HPLC and 1 H NMR analyses. Finally, hydrolysis of the methyl ester 6 at 0 °C with dilute aqueous LiOH in MeOH followed by mild acidic workup with aqueous NaH 2 PO 4 29 resulted in a 71% yield of PD1 n-3 DPA ( 5 ) after purification by column chromatography (Scheme 2 ).…”

Section: Resultsmentioning

confidence: 99%

Total Synthesis of the Lipid Mediator PD1_n-3 DPA: Configurational Assignments and Anti-inflammatory and Pro-resolving Actions

et al. 2014

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The polyunsaturated lipid mediator PD1n-3 DPA (5) was recently isolated from self-resolving inflammatory exudates of 5 and human macrophages. Herein, the first total synthesis of PD1n-3 DPA (5) is reported in 10 steps and 9% overall yield. These efforts, together with NMR data of its methyl ester 6, confirmed the structure of 5 to be (7Z,10R,11E,13E,15Z,17S,19Z)-10,17-dihydroxydocosa-7,11,13,15,19-pentaenoic acid. The proposed biosynthetic pathway, with the involvement of an epoxide intermediate, was supported by results from trapping experiments. In addition, LC-MS/MS data of the free acid 5, obtained from hydrolysis of the synthetic methyl ester 6, matched data for the endogenously produced biological material. The natural product PD1n-3 DPA (5) demonstrated potent anti-inflammatory properties together with pro-resolving actions stimulating human macrophage phagocytosis and efferocytosis. These results contribute new knowledge on the n-3 DPA structure-function of the growing numbers of specialized pro-resolving lipid mediators and pathways.

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“…At first, we planned to build the E,E ‐diene unit through Stille coupling reactions. Based on the literature precedent47–49 on protected α‐hydroxyalkynes, several radical hydrostannylation reactions have been carried out to obtain E ‐vinylstannanes or E ‐vinylhalides. However, in our test, with the chosen protecting groups, moderate stereoselectivity was observed (for instance, see Scheme ).…”

Section: Resultsmentioning

confidence: 99%

A Versatile and Stereocontrolled Total Synthesis of Dihydroxylated Docosatrienes Containing a Conjugated E,E,Z‐Triene

Dayaker¹,

Balas²

2014

Chemistry A European J

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A versatile strategy featuring a Colvin rearrangement, hydrozirconation, a Sonogashira cross-coupling reaction and a Z-selective Wittig olefination, was successfully developed for the construction of a conjugated E,E,Z-triene subunit, flanked on both sides by two Z-allylic hydroxyl groups. This chemical pattern is found in many endogenous lipid metabolites such as maresin 1 (MaR1), neuroprotectin D1 (NPD1), and its aspirin triggered-isomer AT-NPD1, which not only counter-regulate inflammation but also actively orchestrate (at nanomolar doses) the resolution and termination program of acute inflammation while promoting wound healing, return to homeostasis and neuroprotection. Unlike previous approaches, the advantages of the present strategy are obvious, as it allows us to modify the nonpolar tail, the carboxylated head or both ends of the molecule without repeating the whole synthetic sequence (about 26-34 steps according to the literature). Thus, the first total syntheses of NPD1 methyl ester epimer (which can also be considered as an enantiomer of AT-NPD1) and its n-3 docosapentaenoic acid derived analogue were achieved from a highly functionalized and late advanced pivotal intermediate. This innovative route may be easily adapted to gain access to other dihydroxylated metabolites and analogues of polyunsaturated fatty acids containing a conjugated E,E,Z-triene subunit. Different epimers/diastereoisomers may be obtained by purchasing the suitable optically pure (S)- and/or (R)-1,2,4-butanetriol(s) as a chiral pool for both stereogenic centers.

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A General Strategy for the Synthesis of Monohydroxy-eicosatetraenoic Acids: Total Synthesis of 5(S)-Hydroxy-6(E),8,11,14(Z)-eicosatetraenoic Acid (5-HETE) and 12(S)-Hydroxy-5,8,14(Z), 10(E)-eicosatetraenoic Acid (12-HETE)

Cited by 49 publications

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Synthesis and Anti-inflammatory and Pro-resolving Activities of 22-OH-PD1, a Monohydroxylated Metabolite of Protectin D1

Synthesis and Anti-inflammatory and Pro-resolving Activities of 22-OH-PD1, a Monohydroxylated Metabolite of Protectin D1

Total Synthesis of the Lipid Mediator PD1_n-3 DPA: Configurational Assignments and Anti-inflammatory and Pro-resolving Actions

A Versatile and Stereocontrolled Total Synthesis of Dihydroxylated Docosatrienes Containing a Conjugated E,E,Z‐Triene

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A General Strategy for the Synthesis of Monohydroxy-eicosatetraenoic Acids: Total Synthesis of 5(S)-Hydroxy-6(E),8,11,14(Z)-eicosatetraenoic Acid (5-HETE) and 12(S)-Hydroxy-5,8,14(Z), 10(E)-eicosatetraenoic Acid (12-HETE)

Cited by 49 publications

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Synthesis and Anti-inflammatory and Pro-resolving Activities of 22-OH-PD1, a Monohydroxylated Metabolite of Protectin D1

Synthesis and Anti-inflammatory and Pro-resolving Activities of 22-OH-PD1, a Monohydroxylated Metabolite of Protectin D1

Total Synthesis of the Lipid Mediator PD1n-3 DPA: Configurational Assignments and Anti-inflammatory and Pro-resolving Actions

A Versatile and Stereocontrolled Total Synthesis of Dihydroxylated Docosatrienes Containing a Conjugated E,E,Z‐Triene

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Total Synthesis of the Lipid Mediator PD1_n-3 DPA: Configurational Assignments and Anti-inflammatory and Pro-resolving Actions