Biological evaluation of indolizine-chalcone hybrids as new anticancer agents.

One-Pot Regiospecific Synthesis of Indolizines: A Solvent-Free, Metal-Free, Three-Component Reaction of 2-(Pyridin-2-yl)acetates, Ynals, and Alcohols or Thiols

Metal-Free Cascade Approach toward Polysubstituted Indolizines from Chromone-Based Michael Acceptors

Gold-catalyzed bicyclic annulations of 4-methoxy-1,2-dienyl-5-ynes with isoxazoles afford indolizine derivatives with a structural rearrangement. The mechanism of these new annulations does not involve α-imino gold carbenes generated from gold π-alkyne intermediates. We postulate alkyne attack on gold π-allenes, yielding vinyl gold carbenes. These newly generated carbenes react with isoxazole derivatives to yield Z-3-imino-2-en-1-als, further enabling sequential cyclizations to deliver indolizine derivatives in two distinct classes.

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Gold-catalyzed bicyclic annulations of 4-methoxy-1,2-dienyl-5-ynes with isoxazoles to form indolizine derivatives via an Au-π-allene intermediate

Herein, a simple and regioselective synthesis of (2-hydroxyphenyl)(3-(trifluoromethyl/cyano/phosphonate)-1H-pyrazol-5-yl)methanones as pyrrolomycin analogues was reported. This reaction could proceed from 3-formylchromones and the corresponding diazo compounds by a silver-mediated one-pot cascade reaction under mild conditions with a broad substrate scope. Most of all, some products displayed potent antibacterial activities.

Silver-mediated synthesis of novel 3-CF3/CN/phosphonate-substituted pyrazoles as pyrrolomycin analogues from 3-formylchromones and diazo compounds

Herein is reported an efficient, one-pot domino process through a 1,6-aza-Michael addition-triggered sequence and an original Mitsunobu-type concerted sequence for the synthesis of tetracyclic systems containing a bis-N,O-acetal junction. This methodology led to the construction of four new bonds, the cleavage of three C–O bonds, and the generation of an asymmetric center. Mitsunobu activation afforded final ring closure involving the creation of two bonds, which remains unprecedented among reported Mitsunobu-type sequences. The latter occurred in a regioselective fashion at the challenging C6-position of 2-pyridone intermediates. In the case of adequately substituted enantiopure amino alcohols, up to 95:5 of diastereoisomeric excess was achieved. Computational studies allowed the discrimination of a favored pathway for Mitsunobu sequence and supported the regioselectivity as well as the diastereoselectivity observed for this step.

Original Mitsunobu-Triggered Sequence Involved in a One-Pot Domino Process toward Tetracyclic Systems Bearing a Bis-N,O-acetal Junction

Two successive original routes leading to two novel families of polyheterocycles starting from the versatile chromone-based Michael acceptors platform are reported herein. The major aspect of this work is the selective access to these frameworks by changing the course of the domino process involved in their formation. First, enaminochromanones were selectively accessed under uncommon kinetic control. In this study, we showed that the tuning of the selectivity toward the kinetic product could be achieved by key structural modifications of the different reaction partners involved in the domino process. Once selectivity was efficiently controlled, enaminochromanones were ultimately transformed into a more complex family of polyheterocycles containing the pyrrolo-oxazinone framework. Here, the modulation of the domino sequence toward these particularly scarce structures was enabled by a pivotal switch in reactivity induced by aryl-λ3-iodanes.

Structure-Based Kinetic Control in a Domino Process: A Powerful Tool Toward Molecular Diversity in Chromone Series.

Introduction
Gossypol is an axially chiral natural polyphenol classically extracted from the Malavaceae family. Nevertheless, its extraction and isolation from a plant can be quite complicated and extremely time-consuming since gossypol is known to be sensitive to degradation under solvents, high temperature and light action. Moreover, its purification over column chromatography is a challenging problem due to its ability to oxidise and the existence of various tautomer forms.

Objective
To develop an efficient “one-step” strategy for simultaneous extraction and semi-synthesis by short-circuiting critical gossypol isolation and purification steps.

Methodology
Gossypol was first isolated from Cienfuegosia digitata roots, characterised (by 1D and 2D NMR) and quantified (by UV spectrophotometry). Thus, aniline was selected to test the “one-step” in situ trapping of freshly extracted gossypol leading to a Schiff base analogue. After screening solvents and extraction times on this model reaction, the “SECheM” (simultaneous extraction and chemical modification) concept was successfully extended to other amines, underlining the efficiency and the robustness of the strategy.

Results
After having shown that gossypol occurred as a major compound in C. digitata roots, different experimental procedures using Soxhlet extraction in the presence of aniline pointed out the best conditions for the SECheM concept (7 h of reaction and extraction time in ether as solvent). Ultimately, the concept has been generalised to 17 other amines.

Conclusion
This is a report of the first semi-synthesis that allows: (1) “in situ” preparation of more stable gossypol Schiff base derivatives directly from ground plant material and (2) circumvention of gossypol extraction and purification problems. Copyright © 2017 John Wiley & Sons, Ltd.

Thomas Lepitre

Papers

Metal-Free Cascade Approach toward Polysubstituted Indolizines from Chromone-Based Michael Acceptors

Original Mitsunobu-Triggered Sequence Involved in a One-Pot Domino Process toward Tetracyclic Systems Bearing a Bis-N,O-acetal Junction

Structure-Based Kinetic Control in a Domino Process: A Powerful Tool Toward Molecular Diversity in Chromone Series.

Development of SECheM Concept for Isolation and Chemical Modification of Gossypol Directly from Cienfuegosia digitata