Synthesis of hexahydropyrrolo[2,1-a]isoquinoline compound libraries through a Pictet–Spengler cyclization/metal-catalyzed cross coupling/amidation sequence

Petersen, Rico; Cohrt, A. Emil; Petersen, Michael; Wu, Peng; Clausen, Mads Hartvig; Nielsen, Thomas E.

doi:10.1016/j.bmc.2015.01.039

Cited by 16 publications

(10 citation statements)

References 47 publications

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“…Indeed, a significant number of unprecedented spiro, bridged, and fused polycycles with different degrees of saturation, conjugation, and substitution have been synthesized and expanded to a library format. This has been recently exemplified by several publications from the ELF chemistry groups detailing the associated design and validation aspects [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]. Given that most theoretical ring systems remains unexplored [39], the synthesis of novel rings represents one of the strategies embraced by the ELF chemistry consortium to expand the available chemical space.…”

Section: Page 5 Of 11mentioning

confidence: 99%

Expansion of chemical space for collaborative lead generation and drug discovery: the European Lead Factory Perspective

Karawajczyk¹,

Giordanetto²,

Benningshof³

et al. 2015

Drug Discovery Today

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High-throughput screening (HTS) represents a major cornerstone of drug discovery. The availability of an innovative, relevant and high-quality compound collection to be screened often dictates the final fate of a drug discovery campaign. Given that the chemical space to be sampled in research programs is practically infinite and sparsely populated, significant efforts and resources need to be invested in the generation and maintenance of a competitive compound collection. The European Lead Factory (ELF) project is addressing this challenge by leveraging the diverse experience and know-how of academic groups and small and medium enterprises (SMEs) engaged in synthetic and/or medicinal chemistry. Here, we describe the novelty, diversity, structural complexity, physicochemical characteristics and overall attractiveness of this first batch of ELF compounds for HTS purposes.

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Section: Page 5 Of 11mentioning

confidence: 99%

Expansion of chemical space for collaborative lead generation and drug discovery: the European Lead Factory Perspective

Karawajczyk¹,

Giordanetto²,

Benningshof³

et al. 2015

Drug Discovery Today

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“…Phenanthroindolizidines (50 [71,72]), phenanthroquinolizidines (51 [72]), tetrahydroprotoberberines (53 [67,68]), pyrroloisoquinolines (55 [69,70]), and diketopiperazine-fused THIQs (65 [73], vide infra) embody the tetrahydroisoquinoline skeleton, while indolizinoindoles (57 [74,75]), THBC-imidazolinediones (59 [76]), THBC-piperazinedione (61 [77,78]), the tetracyclic indole alkaloids (S)-harmicine (pyrrole-fused THBC, [66,79]), and (S)-eleagnine (1-methyl THBC, [66,80] represent the THBC-containing polyheterocycles. The additional ring can be already present in the imine substrate before the P-S reaction (type A) or can be built on the THIQ/THBC skeleton exploiting the functionality of some substituents (type B).…”

Section: Polyheterocyclesmentioning

confidence: 99%

“…Conversely, 13a-methylphenanthroindolizidine (n=1) 50c (R 1 = OMe, R 2 = R = H; Scheme 13) was obtained by an enantioselective approach, including inter alia, an efficient stereoselective Seebach's alkylation and P-S cyclization [72]. The additional ring can be an aromatic ring as in protoberberines 53 [67,68], a pyrrole nucleus as in pyrroloisoquinolines (55 [69,70]) and phenanthroindolizidines (50 [71,72]), a piperazine or a diketopiperazine fused ring, as in phenathroquinolizidines 51 [72] and THIQ analogs 65 [73].…”

Section: Polyheterocyclesmentioning

confidence: 99%

The Pictet-Spengler Reaction Updates Its Habits

et al. 2020

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The Pictet-Spengler reaction (P-S) is one of the most direct, efficient, and variable synthetic method for the construction of privileged pharmacophores such as tetrahydro-isoquinolines (THIQs), tetrahydro-β-carbolines (THBCs), and polyheterocyclic frameworks. In the lustro (five-year period) following its centenary birthday, the P-S reaction did not exit the stage but it came up again on limelight with new features. This review focuses on the interesting results achieved in this period (2011–2015), analyzing the versatility of this reaction. Classic P-S was reported in the total synthesis of complex alkaloids, in combination with chiral catalysts as well as for the generation of libraries of compounds in medicinal chemistry. The P-S has been used also in tandem reactions, with the sequences including ring closing metathesis, isomerization, Michael addition, and Gold- or Brønsted acid-catalyzed N-acyliminium cyclization. Moreover, the combination of P-S reaction with Ugi multicomponent reaction has been exploited for the construction of highly complex polycyclic architectures in few steps and high yields. The P-S reaction has also been successfully employed in solid-phase synthesis, affording products with different structures, including peptidomimetics, synthetic heterocycles, and natural compounds. Finally, the enzymatic version of P-S has been reported for biosynthesis, biotransformations, and bioconjugations.

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“…These challenges notwithstanding, the scientists of ELF Chemistry Consortium have developed key approaches that can facilitate novel bioactive molecule discovery, including diversity-oriented synthesis, biology-oriented synthesis, multicomponent chemistry and activity-directed synthesis, as recently described for selected examples [23][24][25][26][27][28][29][30][31][32][33][34] . The innovative chemical approaches taken by the ELF Chemistry Consortium are yielding novel, diverse and distinctive compounds that will complement existing large compound collections used for high throughput screening drug discovery applications, thus serving as a blueprint for future compound collection enhancement campaigns.…”

Section: Challengesmentioning

confidence: 99%

The European lead factory—an experiment in collaborative drug discovery

Laverty

Orrling

Giordanetto³

et al. 2016

J Med Dev Sci

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The European lead factory-an experiment in collaborative drug discovery. © 2015 Hugh Laverty, et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 20 REVIEW ARTICLEThe European lead factory-an experiment in collaborative drug discovery Abstract: The European Lead Factory (ELF) is a unique collaborative public-private partnership aiming to deliver innovative drug discovery starting points and improving the value generated by ultra-High Throughput Screening (uHTS) approaches. Composed of a unique compound collection derived from private pharmaceutical company collections and complemented with new chemistries from a unique public collection, it offers a unique uHTS platform accessible to both private companies and publicly funded researchers. One of the key challenges in setting up ELF has been to balance access to screening results with protecting the value of compounds in the collection. Through an 'honest data broker' data management platform and a royalty reward scheme based on achieved milestones, ELF has been able to overcome these challenges. Set up in 2013, it has already accepted 42 targets for screening, submitted by publicly funded researchers, and generated 12 Qualified Hit Lists. In addition, 55,000 new library compounds have been generated by the public partners and added to the 320,000 compounds made available by the companies. Although it faced many challenges in becoming operational, this unique experiment in collaboration is already generating exciting results that will hopefully, eventually lead to better medicines and tools to advance our biological knowledge, and should act as a template for future approaches in the area.

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Synthesis of hexahydropyrrolo[2,1-a]isoquinoline compound libraries through a Pictet–Spengler cyclization/metal-catalyzed cross coupling/amidation sequence

Cited by 16 publications

References 47 publications

Expansion of chemical space for collaborative lead generation and drug discovery: the European Lead Factory Perspective

Expansion of chemical space for collaborative lead generation and drug discovery: the European Lead Factory Perspective

The Pictet-Spengler Reaction Updates Its Habits

The European lead factory—an experiment in collaborative drug discovery

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