Sigmatropic reaction | EPFL Graph Search

A sigmatropic reaction in organic chemistry is a pericyclic reaction wherein the net result is one σ-bond is changed to another σ-bond in an uncatalyzed intramolecular reaction. The name sigmatropic is the result of a compounding of the long-established sigma designation from single carbon–carbon bonds and the Greek word tropos, meaning turn. In this type of rearrangement reaction, a substituent moves from one part of a π-bonded system to another part in an intramolecular reaction with simultaneous rearrangement of the π system. True sigmatropic reactions are usually uncatalyzed, although Lewis acid catalysis is possible. Sigmatropic reactions often have transition-metal catalysts that form intermediates in analogous reactions. The most well-known of the sigmatropic rearrangements are the [3,3] Cope rearrangement, Claisen rearrangement, Carroll rearrangement, and the Fischer indole synthesis. Overview of sigmatropic shifts Woodward–Hoffman sigmatropic shift nomenclature

Asymmetric Total Synthesis of Indole Alkaloids (+)-Condyfoline, (-)-Tubifoline, (+)-Dasycarpidone and (+)-Uleine

Bastien Delayre

The development of a titanium(III)-mediated cascade electrocyclisation/rearrangement for theenantioselective total synthesis of indole alkaloids (+)-condyfoline and (-)-tubifoline serve as the basisof the first chapter of this thesis. An introduction will focus on the use of domino sequencesincorporating a 1,2-shift in the context of complex natural product synthesis. The design of such adomino process is then presented, along with preliminary results originating from our research groupconcerning the titanium(III)-mediated Cadogan cyclisation. This novel domino sequence enabled thefirst enantioselective total synthesis of (+)-condyfoline. These results provided insights into themechanistic nature of the formal 1,2-shift, indicating that the formal 1,2-migration most likelyproceeds via 1,5-sigmatropic rearrangement rather than retro-Mannich/Mannich sequence. Theisolation of (+)-condyfoline enabled a re-investigation of its isomerisation process to Strychnos isomer(-)-tubifoline. The chapter concludes with synthetic studies towards (+)-tronoharine and (+)-tubotaiwine.The second chapter of this thesis deals with the development of an integratedOxidation/Reduction/Cyclisation (iORC) sequence for the enantioselective total synthesis of the Uleinefamily of monoterpene indole alkaloids. A brief introduction will review our group's previous effortsto implement iORC sequences for the total synthesis of alkaloids. The step-by-step development of theiORC sequence is described, along with the endgame strategy for the synthesis of (+)-nordasycarpidone, (+)-dasycarpidone, (-)-dasycarpidol and (+)-uleine. The chapter ends with theattempted titanium(III)-mediated cyclisation/rearrangement sequence towards (+)-uleine, andattempted iORC sequence towards (+)-condyfoline.The third chapter of this thesis reports a novel synthesis of benzofuro[3,2-b]indolines from onitrostylbene precursors using a titanium(III)-mediated interrupted Cadogan reaction. A rapidinvestigation of the substrate scope is presented. The remaining of the chapter reports our efforts toapply this newly developed transformation for the total synthesis of bis-indole alkaloid phalarine.The last chapter is dedicated to our synthetic studies towards (+)-pestalustaine A, a recently isolatedsesquiterpene possessing a unique 5/6/7-fused tricyclic system. A designed formal [3+2] reaction wasenvisioned to provide access to this novel sesquiterpene, but resulted in the isolation of a Wilson-Clokerearrangement product.

EPFL2022

Developing the Catalytic Applications of 1,3,2-Diazaphospholenes

John Henry Reed

The development of new catalytic methods for organic synthesis is a critical endeavour in order to obviate the economic and ecological drawbacks of stoichiometric organic synthesis. While catalysis can offer significant advantages in terms of atom-economy, step-economy and energy input, the catalysts themselves may suffer from pitfalls such as toxicity or scarcity. Consequently, there is a growing need to develop catalysts based on more sustainable materials such as phosphorus. This thesis is an account of the work done in developing the catalytic applications of 1,3,2-diazaphospholenes. The first chapter provides an introduction to the canonical reactivity of phosphorus-based catalysts, fol-lowed by a review of the known reactivity of 1,3,2-diazaphospholenes, in order to provide context for experimental work presented in this thesis. Chapter 2 describes the development of a new methodology to effect enantioselective 1,4-reductions of Î±,Î²-unsaturated carbonyl compounds. In order to overcome issues of reactivity and selectivity, a new class of chiral 1,3,2-diazaphospholenes, based around a rigid backbone, were designed. Various Î±,Î²-unsaturated acyl pyrroles, ketones and amides were reduced with moderate to excellent levels of enan-tioselectivity. Chapter 3 presents the development of a cascade reaction triggered by a 1,3,2-diazaphospholene-catalysed 1,4-reduction of allylic acrylate esters. The intermediary enolate that is thus formed undergoes a [3,3]-sigmatropic rearrangement, thereby generating a new carbon-carbon bond. We demonstrate that the diastereoselectivity of this process can be modulated through different catalysts and solvent choices, while a proof-of-principle for an enantioselective variant is given. Chapter 4 demonstrates the viability of Î±,Î²-unsaturated carboxylic acids as substrates for 1,3,2-diazaphospholene catalysed reductions. It is shown that the presence of the acidic proton on the carbox-ylate group does not inhibit the reactivity. An example demonstrating the possibility for enantioselectivity at the Î±-position is also provided. Finally, a view on the opportunities that still exist in the field of diazaphospholene catalysis is offered.

EPFL2021

Path integral evaluation of equilibrium isotope effects

Jiri Vanicek, Tomas Zimmermann

A general and rigorous methodology to compute the quantum equilibrium isotope effect is described. Unlike standard approaches, ours does not assume separability of rotational and vibrational motions and does not make the harmonic approximation for vibrations or rigid rotor approximation for the rotations. In particular, zero point energy and anharmonicity effects are described correctly quantum mechanically. The approach is based on the thermodynamic integration with respect to the mass of isotopes and on the Feynman path integral representation of the partition function. An efficient estimator for the derivative of free energy is used whose statistical error is independent of the number of imaginary time slices in the path integral, speeding up calculations by a factor of ~60 at 500 K and more at room temperature. We describe the implementation of the methodology in the molecular dynamics package AMBER 10. The method is tested on three [1,5] sigmatropic hydrogen shift reactions. Because of the computational expense, we use ab initio potentials to evaluate the equilibrium isotope effects within the harmonic approximation and then the path integral method together with semiempirical potentials to evaluate the anharmonicity corrections. Our calculations show that the anharmonicity effects amount up to 30% of the symmetry reduced reaction free energy. The numerical results are compared with recent experiments of Doering et al., [J. Am. Chem. Soc. 128, 9080 (2006); J. Am. Chem. Soc.129, 2488 (2007)] confirming the accuracy of the most recent measurement on 2,4,6,7,9-pentamethyl-5-(5,5-2H2) methylene- 11,11a-dihydro- 12H-naphthacene as well as concerns about compromised accuracy, due to side reactions, of another measurement on 2-methyl-10-(10,10-2H2) methylenebicyclo [4.4.0]dec-1- ene.