Total Synthesis of Indole Alkaloids of the Ervatamine Group. A Biomimetic Approach

Bennasar, M.‐Lluïsa; Vidal, and Bernat; Bosch, Joan

doi:10.1021/jo9600058

Cited by 21 publications

(5 citation statements)

References 16 publications

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Section: Nucleophilic Addition To N-alkyl Pyridinium Salts and Their ...mentioning

confidence: 99%

“…The dramatic changes made to the nature of the electrophile unraveled the poor regiocontrol of the addition of stabilized nucleophiles to pyridinium salts and revealed that the ratio of products obtained from the reaction was dependent upon the method used to trap the intermediate as addition of acid supported the reversibility of the addition of the enolates. Nevertheless, this TCAA-modified procedure was used for numerous syntheses of various ring systems of natural silicine and methuenine alkaloids 339 such as (±)-6-oxo-16-episilicine 340 and (±)-6-oxosilicine 341 as well as (±)-ervatamine 342 and other alkaloids from the ervatamine series. 336 The introduction of an (S)-prolinol auxiliary to the C-3 position of the pyridinium salt permitted rapid and stereoselective synthesis of (−)-N-methylervitsine by quenching the 1,4-dihydropyridine intermediate with various electrophiles, 343 yielding tetracycles in modest efficiency and diastereocontrol (Table 25).…”

Section: Regioselective Additions Of Enolates To N-alkyl Pyridinium S...mentioning

confidence: 99%

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Synthesis of Pyridine and Dihydropyridine Derivatives by Regio- and Stereoselective Addition toN-Activated Pyridines

et al. 2012

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Introduction 2643 2. Nucleophilic Addition of Organometallic Reagents to N-Acyl Pyridinium Salts 2644 2.1. Regioselective Additions to N-Acyl Pyridinium Species and Their Derivatives 2644 2.1.1. Influence of Pyridine Ring Substituents on Regioselectivity of Addition 2646 2.1.2. Control of Regio-and Diastereoselectivity by the Introduction of Removable Blocking Groups 2648 2.2. Synthesis of 4-Pyridones: 1,2-Addition to 4-Methoxypyridines 2649 2.2.1. Diastereoselective Addition to 3-Trialkylsilyl-4-methoxypyridines 2651 2.2.2. Application in the Synthesis of Natural Products Containing Chiral Piperidine Units 2652 2.3. Diastereoselective 1,2-Addition to N-Imidoyl Pyridinium Salts 2652 2.4. Enantioselective 1,2-Addition Controlled by a Chiral Catalyst 2657 2.5. Diastereoselective 1,4-Addition Controlled by Pyridine 3-Substituents 2657 3. Nucleophilic Addition to N-Alkyl Pyridinium Salts and Their Derivatives 2659 3.1. Regioselective Additions to N-Alkyl Pyridinium SaltsNature of the Nucleophile 2659 3.1.1. Organometallic Reagents as Nucleophiles 2659 3.1.2. Cyanide as Nucleophile 2663 3.2. Diastereoselective Additions of Organometallic Reagents to N-Alkyl Pyridinium Salts 2663 3.3. Regioselective Additions of Enolates to N-Alkyl Pyridinium Salts 2666 3.3.1. Wenkert Procedure: Seminal Work 2667 3.3.2. Wenkert Procedure: Addition of Nucleophiles Positioned at the Nitrogen of Indole Derivatives 2670 3.3.3. Wenkert Procedure: Addition of Enolates Located at the C-2/C-3 Position of Indoles 2671 3.3.4. Addition of Miscellaneous Nucleophiles to N-Alkyl Pyridinium Species 2674 4. Nucleophilic Additions to N-Heteroatom Pyridinium Species 2676 4.1. Nucleophilic Additions to Pyridine N-Oxides and N−O Salts 4.1.1. Properties, Synthesis, and Deprotection of Pyridine N-Oxides 4.1.2. Addition of Grignard Reagents to Pyridine N-Oxides 4.1.3. Addition of Cyanide Nucleophiles via Reissert-Type Reactions 4.1.4. Addition of Hetero Nucleophiles to Pyridine N-Oxides and N−O Salts 4.

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Section: Nucleophilic Addition To N-alkyl Pyridinium Salts and Their ...mentioning

confidence: 99%

Section: Regioselective Additions Of Enolates To N-alkyl Pyridinium S...mentioning

confidence: 99%

Synthesis of Pyridine and Dihydropyridine Derivatives by Regio- and Stereoselective Addition toN-Activated Pyridines

et al. 2012

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“…Reaction of WFA ( 1 ) with piperidine and imidazole gave its Michael adducts 22 and 23 , respectively. Oxidation (MnO 2 /CHCl 3 ) , of 1 followed by acetylation (Ac 2 O/pyridine) gave 27- O -acetyl-4-dehydrowithaferin A ( 15 ) . Treatment of 15 with Ph 3 P:I 2 in CH 2 Cl 2 at 25 °C for 1 h followed by usual workup and purification by RP-HPLC resulted in the isolation of 24 .…”

Section: Results and Discussionmentioning

confidence: 99%

“…Epoxidation ( m -CPBA/CH 2 Cl 2 ) of 45 provided the anticipated α-epoxide ( 46 ) as the major product, which on acetylation (Ac 2 O/pyridine) gave 47 . Allylic oxidation (MnO 2 /CHCl 3 ) , of 46 afforded 48 as the only product.…”

Section: Results and Discussionmentioning

confidence: 99%

Structure–Activity Relationships of Withanolides as Antiproliferative Agents for Multiple Myeloma: Comparison of Activity in 2D Models and a 3D Coculture Model

et al. 2021

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Multiple myeloma (MM) is a hematological cancer in which relapse and resistance are highly frequent. Therefore, alternatives to conventional treatments are necessary. Withaferin A, a withanolide isolated from Withania somnifera, has previously shown promising activity against various MM models. In the present study, structure–activity relationships (SARs) were evaluated using 56 withanolides. The antiproliferative activity was assessed in three MM cell lines and in a 3D MM coculture model to understand the in vitro activity of compounds in models of various complexity. While the results obtained in 2D allowed a quick and simple evaluation of cytotoxicity used for a first selection, the use of the 3D MM coculture model allowed filtering compounds that perform better in a more complex setup. This study shows the importance of the last model as a bridge between 2D and in vivo studies to select the most active compounds and ultimately lead to a reduction of animal use for more sustained in vivo studies. NF-κB inhibition was determined to evaluate if this could be one of the targeted pathways. The most active compounds, withanolide D (2) and 38, should be further evaluated in vivo.

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“…This result clearly indicated that the benzyl group had to be removed prior to the key cyclization step. Taking into account the sensitivity of alcohols 34 to acids, we turned our attention to ketone 33g . Deprotection of the indole ring of 33g with AlCl 3 33 gave (75%) the N a -unsubstituted indole 33b , which was then stereoselectively reduced with LiBEt 3 H to give (72%) diol 37b .…”

Section: Resultsmentioning

confidence: 99%

Biomimetic Total Synthesis of Ervitsine and Indole Alkaloids of the Ervatamine Group via 1,4-Dihydropyridines

1997

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Addition of the enolate derived from 2-acetylindole 1a to pyridinium salt 2 followed by in situ trapping of the initially formed 1,4-dihydropyridine 3a with Eschenmoser's salt gives tetracycle 5a. Subsequent elaboration of the exocyclic methylene and E-ethylidene substituents leads to N a-methylervitsine (17a). A similar sequence from the N a-protected 2-acetylindole 1c establishes the first total synthesis of the 2-acylindole alkaloid ervitsine. Alternatively, dihydropyridine 3a is trapped with BrSePh to give the tetracyclic selenide 7a, which is then converted to N a-methylervitsine by way of selenoxide 20. The synthesis of the alkaloids of the ervatamine group starts with the addition of the enolate derived from 2-acetyl-1-benzylindole (1g) to pyridinium salt 24 and the conversion of the resulting 1,4-dihydropyridine to 3,5-diacylated dihydropyridine 26g. Chemoselective reduction of the vinylogous amide moiety of 26g, followed by deprotection of the indole ring and LiEt3BH reduction leads to diol 37b. On sequential treatment with Eschenmoser's salt, methyl iodide, NaCNBH3, and MnO2, 37b is converted to the tetracyclic 2-acylindole 39, from which the first total synthesis of 19,20-didehydroervatamine and 20-epiervatamine is accomplished by manipulation of the 1-hydroxyethyl chain. The above syntheses can be considered as biomimetic, as cyclization of the key intermediates I and II mimics the key steps of the biosynthesis of the title alkaloids.

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Total Synthesis of Indole Alkaloids of the Ervatamine Group. A Biomimetic Approach

Cited by 21 publications

References 16 publications

Synthesis of Pyridine and Dihydropyridine Derivatives by Regio- and Stereoselective Addition toN-Activated Pyridines

Synthesis of Pyridine and Dihydropyridine Derivatives by Regio- and Stereoselective Addition toN-Activated Pyridines

Structure–Activity Relationships of Withanolides as Antiproliferative Agents for Multiple Myeloma: Comparison of Activity in 2D Models and a 3D Coculture Model

Biomimetic Total Synthesis of Ervitsine and Indole Alkaloids of the Ervatamine Group via 1,4-Dihydropyridines

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