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Reoptimization of the Organocatalyzed Double Aldol Domino Process to a Key Enal Intermediate and Its Application to the Total Synthesis of ?¹² -Prostaglandin J₃.

ABSTRACT: Re-investigation of the l-proline catalyzed double aldol cascade dimerization of succinaldehyde for the synthesis of a key bicyclic enal intermediate, pertinent in the field of stereoselective prostaglandin synthesis, is reported. The yield of this process has been more than doubled, from 14?% to a 29?% isolated yield on a multi-gram scale (32?% NMR yield), through conducting a detailed study of the reaction solvent, temperature, and concentration, as well as a catalyst screen. The synthetic utility of this enal intermediate has been further demonstrated through the total synthesis of ?¹² -prostaglandin J₃ , a compound with known anti-leukemic properties.

SUBMITTER: Pelss A

PROVIDER: S-EPMC6055629 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Reoptimization of the Organocatalyzed Double Aldol Domino Process to a Key Enal Intermediate and Its Application to the Total Synthesis of Δ<sup>12</sup> -Prostaglandin J<sub>3</sub>.

Pelšs Andrejs A Gandhamsetty Narasimhulu N Smith James R JR Mailhol Damien D Silvi Mattia M Watson Andrew J A AJA Perez-Powell Isabel I Prévost Sébastien S Schützenmeister Nina N Moore Peter R PR Aggarwal Varinder K VK

Chemistry (Weinheim an der Bergstrasse, Germany) 20180606 38

Re-investigation of the l-proline catalyzed double aldol cascade dimerization of succinaldehyde for the synthesis of a key bicyclic enal intermediate, pertinent in the field of stereoselective prostaglandin synthesis, is reported. The yield of this process has been more than doubled, from 14 % to a 29 % isolated yield on a multi-gram scale (32 % NMR yield), through conducting a detailed study of the reaction solvent, temperature, and concentration, as well as a catalyst screen. The synthetic uti ...[more]

PMID: 29774967

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Project description:Background15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), one of the major metabolites from prostaglandin D2 in arachidonic acid metabolic pathway, has potential anti-inflammatory properties. The objective of this study was to explore the effects of 15d-PGJ2-loaded poly(D,L-lactide-co-glycolide) nanocapsules (15d-PGJ2-NC) on inflammatory responses and bone regeneration in local bone defect.MethodsThe study was conducted on 96 Wistar rats from June 2014 to March 2016. Saline, unloaded nanoparticles, free 15d-PGJ2or 15d-PGJ2-NC, were delivered through a collagen vehicle inside surgically created transcortical defects in rat femurs. Interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) levels in the surrounding soft tissue were analyzed by Western blot and in the defect by quantitative real-time polymerase chain reaction over 14 days. Simultaneously, bone morphogenetic protein-6 (BMP-6) and platelet-derived growth factor-B (PDGF-B) messenger RNA (mRNA) in the defect were examined. New bone formation and EphrinB2 and osteoprotegerin (OPG) protein expression in the cortical defect were observed by Masson's Trichrome staining and immunohistochemistry over 28 days. Data were analyzed by one-way analysis of variance. Least-significant difference and Dunnett's T3 methods were used with a bilateral P< 0.05.ResultsApplication of l5d-PGJ2-NC (100 μg/ml) in the local bone defect significantly decreased IL-6, IL-1β, and TNF-α mRNA and protein, compared with saline-treated controls (P < 0.05). l5d-PGJ2-NC upregulated BMP-6 and PDGF-B mRNA (P < 0.05). New bone formation was observed in the cortical defect in l5d-PGJ2-NC-treated animals from 7th day onward (P < 0.001). Expression of EphrinB2 and OPG presented early on day 3 and persisted through day 28 in 15d-PGJ2-NC group (P < 0.05).ConclusionStable l5d-PGJ2-NC complexes were prepared that could attenuate IL-6, IL-1β, and TNF-α expression, while increasing new bone formation and growth factors related to bone regeneration.

Dataset Information

Reoptimization of the Organocatalyzed Double Aldol Domino Process to a Key Enal Intermediate and Its Application to the Total Synthesis of ?¹² -Prostaglandin J₃.

Publications

Reoptimization of the Organocatalyzed Double Aldol Domino Process to a Key Enal Intermediate and Its Application to the Total Synthesis of Δ<sup>12</sup> -Prostaglandin J<sub>3</sub>.

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Reoptimization of the Organocatalyzed Double Aldol Domino Process to a Key Enal Intermediate and Its Application to the Total Synthesis of ?12 -Prostaglandin J3.

Publications

Reoptimization of the Organocatalyzed Double Aldol Domino Process to a Key Enal Intermediate and Its Application to the Total Synthesis of Δ<sup>12</sup> -Prostaglandin J<sub>3</sub>.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Reoptimization of the Organocatalyzed Double Aldol Domino Process to a Key Enal Intermediate and Its Application to the Total Synthesis of ?¹² -Prostaglandin J₃.