Gold(I)-Catalyzed Synthesis of Furopyrans: Insight into Hetero-Diels–Alder Reactions

Romain Pertschi (1) , Patrick Wagner (1) , Nayan Ghosh (1) , Vincent Gandon (2, 3) , Gaëlle Blond (1)

1 LIT - Laboratoire d'Innovation Thérapeutique
2 ICMMO - Institut de Chimie Moléculaire et des Matériaux d'Orsay
3 LCM - Laboratoire de chimie moléculaire

We report herein the synthesis of complex molecules containing furopyran cores through a gold(I)-catalyzed hetero Diels-Alder cascade reaction. During this process, the diene and the dienophile are produced concomitantly by the action of a single catalyst from a single starting material. Moreover, six bonds, four heterocycles and four controlled stereogenic centers are formed in a one-step operation. DFT calculations provide the mechanistic basis of this unprecedented reaction. The last 30 years have witnessed an upsurge in the development of methodologies enabling the synthesis of intricate molecular scaffolds from simple precursors. In addition to these new synthetic strategies, the quest for molecular complexity has often resulted in important fundamental insight into selectivity principles. 1 A particularly promising strategy to rapidly construct complex molecules is to trigger domino reactions that convert simple starting materials into highly sophisticated targets by creating several bonds in a one-pot operation. 2 Achieving complexity with brevity is indeed a key to ideal synthesis. The use of transition metal-catalyzed transformations as part of a domino process considerably decreases the energy cost of the overall transformation and favors highly selective reactions due to the pre-organization of the reactive intermediates around the metallic center. In particular, homogeneous gold(I)-catalyzed reactions have attracted much attention because of the great diversity of original and complex molecules that can be obtained from adequately designed substrates, under mild reaction conditions. 3 Recently, few methodologies have been developed using gold(I)-catalysis in domino processes, including hetero Diels-Alder reactions. The hetero Diels-Alder reaction (HDA) is among the most efficient methods for the synthesis of functionalized heterocycles with control of regio-, diastereo-and enantioselectivity. 4 Most of the gold(I)-triggered HDA reported so far rely on the in situ generation of the diene and/or of the dienophile, starting with two different reagents. 5 However, HDA between diene and dienophile obtained from single starting substrate using gold-catalyst remains elusive. We report herein the synthesis of complex polycyclic molecules 4 containing furopyran cores of interest 6 through a gold(I)-catalyzed domino reaction involving HDA (Scheme 1). During this process, both of the dienophile 2 and the diene 3 are produced concomitantly by the action of a single catalyst from a single starting material 1. To our knowledge, this concept has never been exploited. Moreover, during this transformation , six bonds, four heterocycles and four controlled stere-ogenic centers are formed in a one-step operation with 100% atom economy. DFT calculations provide the mechanistic insight of this unprecedented reaction. Scheme 1. Gold(I)-catalyzed hetero Diels-Alder cascade reaction for the synthesis of furopyrans derivatives 4.

Domaines: Chimie

Romain Pertschi, Patrick Wagner, Nayan Ghosh, Vincent Gandon, Gaëlle Blond. Gold(I)-Catalyzed Synthesis of Furopyrans: Insight into Hetero-Diels–Alder Reactions. Organic Letters, 2019, 21 (15), pp.6084-6088. ⟨10.1021/acs.orglett.9b02228⟩. ⟨hal-02989337⟩