From Heteroaromatic Acids and Imines to Azaspirocycles: Stereoselective Synthesis and 3D Shape Analysis

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Abstract

Heteroaromatic carboxylic acids have been directly coupled with imines using propylphosphonic anhydride (T3P) and NEt( iPr) ₂ to form azaspirocycles via intermediate N‐acyliminium ions. Spirocyclic indolenines (3 H‐indoles), azaindolenines, 2 H‐pyrroles and 3 H‐pyrroles were all accessed using this metal‐free approach. The reactions typically proceed with high diastereoselectivity and 3D shape analysis confirms that the products formed occupy areas of chemical space that are under‐represented in existing drugs and high throughput screening libraries.

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Transition-metal-catalyzed asymmetric allylic dearomatization reactions.

Chun-Xiang Zhuo, Chao Zheng, Shu-Li You (2014)

Dearomatization reactions serve as powerful methods for the synthesis of highly functionalized, three-dimensional structures starting with simple planar aromatic compounds. Among processes of this type, catalytic asymmetric dearomatization (CADA) reactions are attractive owing to the large number of aromatic compounds that are readily available and the fact that they enable direct access to enantiopure polycycles and spirocycles, which frequently are key structural motifs in biologically active natural products and pharmaceuticals. However, as a consequence of their high stabilities, arenes only difficultly participate in dearomatization reactions that take place with high levels of enantioselectivity. Transition-metal-catalyzed asymmetric allylic substitution reactions have been demonstrated to be powerful methods for enantioselective formation of C-C and C-X (X = O, N, S, etc.) bonds. However, the scope of these processes has been explored mainly using soft carbon nucleophiles, some hard carbon nucleophiles such as enolates and preformed organometallic reagents, and heteroatom nucleophiles. Readily accessible aromatic compounds have been only rarely used directly as nucleophiles in these reactions. In this Account, we present the results of studies we have conducted aimed at the development of transition-metal-catalyzed asymmetric allylic dearomatization reactions. By utilizing this general process, we have devised methods for direct dearomatization of indoles, pyrroles, phenols, naphthols, pyridines, and pyrazines, which produce various highly functionalized structural motifs bearing all-carbon quaternary stereogenic centers in a straightforward manner. In mechanistic investigations of the dearomatization process, we found that the five-membered spiroindolenines serve as intermediates, which readily undergo stereospecific allylic migration to form corresponding tetrahydro-1H-carbazoles upon treatment with a catalytic amount of TsOH. It is worth noting that no notable loss of the enantiomeric excess of the spiroindolenine derivatives takes place during the rearrangement process as a consequence of the intervention of a "three-center-two-electron"-type transition state, a proposal that has gained support from the results of DFT calculations. Equally intriguing, upon tuning of the electronic nature of the tethers, pyrroles or indoles undergo unprecedented Ir or Ru catalyzed intramolecular allylic alkylation promoted dearomatization/migration reactions. The operation of this novel reaction pathway provides additional information leading to a greater mechanistic understanding of the transition-metal-catalyzed enantioselective intramolecular functionalizations of pyrroles and indoles. The combined results of this effort provide not only methods for the efficient synthesis of highly enantioenriched fused and spiro polycycles but also novel strategies in the field of asymmetric catalysis.

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Molecular shape diversity of combinatorial libraries: a prerequisite for broad bioactivity.

Wolfgang H B Sauer, Matthias K. Schwarz (2003)

A computational method to rapidly assess and visualize the diversity in molecular shape associated with a given compound set has been developed. Normalized ratios of principal moments of inertia are plotted into two-dimensional triangular graphs and then used to compare the shape space covered by different compound sets, such as combinatorial libraries of varying size and composition. We have further developed a computational method to analyze interset similarity in terms of shape space coverage, which allows the shape redundancy between the different subsets of a given compound collection to be analyzed in a quantitative way. The shape space coverage has been found to originate mainly from the nature and the 3D-geometry (but not the size) of the central scaffold, while the number and nature of the peripheral substituents and conformational aspects were shown to be of minor importance. Substantial shape space coverage has been correlated with broad biological activity by applying the same shape analysis to collections of known bioactive compounds, such as MDDR and the GOLD-set. The aggregate of our results corroborates the intuitive notion that molecular shape is intimately linked to biological activity and that a high degree of shape (hence scaffold) diversity in screening collections will increase the odds of addressing a broad range of biological targets.

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Four-membered ring-containing spirocycles: synthetic strategies and opportunities.

Erick M. Carreira, Thomas Fessard (2014)

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Author and article information

Contributors

Prof. Richard J. K. Taylor: richard.taylor@york.ac.uk

Journal

Journal ID (nlm-ta): Chemistry

Journal ID (iso-abbrev): Chemistry

Journal ID (doi): 10.1002/(ISSN)1521-3765

Journal ID (publisher-id): CHEM

Title: Chemistry (Weinheim an Der Bergstrasse, Germany)

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 0947-6539

ISSN (Electronic): 1521-3765

Publication date (Electronic): 23 March 2016

Publication date (Print): 04 May 2016

Volume: 22

Issue: 19 ( doiID: 10.1002/chem.v22.19 )

Pages: 6496-6500

Affiliations

[ ¹ ] Department of ChemistryUniversity of York YorkUK

Author information

Dr. William P. Unsworth http://orcid.org/0000-0002-9169-5156

Article

Publisher ID: CHEM201600823

DOI: 10.1002/chem.201600823

PMC ID: 5071705

PubMed ID: 26918778

SO-VID: b6b0ead5-63c1-4b30-81e7-ccd108712a5d

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This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date received : 22 February 2016

Page count

Figures: 11, Tables: 0, References: 88, Pages: 5

Funding

Funded by: EPSRC

Award ID: EP/J016128/1

Funded by: University of York

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source-schema-version-number 2.0

component-id chem201600823

cover-date May 4, 2016

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.5 mode:remove_FC converted:20.10.2016

ScienceOpen disciplines: Chemistry

Keywords: 3d space,dearomatisation,lead identification,n-acyliminium ions,spirocycles

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ScienceOpen disciplines: Chemistry

Keywords: 3d space, dearomatisation, lead identification, n-acyliminium ions, spirocycles

From Heteroaromatic Acids and Imines to Azaspirocycles: Stereoselective Synthesis and 3D Shape Analysis

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Abstract

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Synthesis of 2-trifluoromethylated piperidines and azepanes

Most cited references 30

Transition-metal-catalyzed asymmetric allylic dearomatization reactions.

Molecular shape diversity of combinatorial libraries: a prerequisite for broad bioactivity.

Four-membered ring-containing spirocycles: synthetic strategies and opportunities.

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