Abstract
The rapid generation of molecular complexity from simple reactants is a key challenge in organic synthesis. Spiro compounds, underrepresented 3D motifs in chemical libraries, represent a challenge due to the creation of spiro quaternary carbon and the need to control the 3D shape in one step. Herein, we report the first ring contraction/formal [6 + 2] cycloaddition using synergistic Pd(0)/secondary amine catalysis, obtaining [5,5]-spiropyrazolone derivatives in excellent yields and stereoselectivities. We demonstrate that this reaction has a broad scope of early and late stage derivatization that will benefit the creation of highly valuable chemical libraries using spiropyrazolone motifs. We detected the key palladium activated intermediate in its protonated form by mass spectrometry and characterized its structure by infrared spectroscopy and DFT calculations, allowing us to propose a conceivable mechanistic pathway for this reaction.
Highlights
The enantioselective synthesis of carbon stereocenters with four different carbon substituents is a challenging aim
We report the first ring contraction/formal [6 + 2] cycloaddition using synergistic Pd(0)/secondary amine catalysis, obtaining [5,5]-spiropyrazolone derivatives in excellent yields and stereoselectivities. We demonstrate that this reaction has a broad scope of early and late stage derivatization that will benefit the creation of highly valuable chemical libraries using spiropyrazolone motifs
We envisioned that 7-membered ring 1a is activated by a transition metal that would favour the opening of the ring, while the enal is activated by a secondary amine catalyst to furnish a [5,5]spiropyrazolone
Summary
The enantioselective synthesis of carbon stereocenters with four different carbon substituents (called quaternary stereocenters) is a challenging aim. Synergistic catalysis[3,4] has recently become one of the most promising strategies for the development of new reactions due to its versatility and the possibility to activate both starting materials at the same time, allowing for a wider scope and diminishing the necessity to use highly active starting materials. The advantage of synergistic catalysis is that both starting materials are activated at the same time by different catalysts. The activation energy of the reaction is smaller and, despite kinetic issues due to the need for two catalytic cycles, Pyrazole moieties can be found in natural products like withasomnine and formycin and can be found in a plethora of biologically active compounds such as HIV-1 integrase inhibitors, antibacterial agents, neuroprotective agents (edavarone X), pain killers and anti-
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