Asymmetric Construction of Polycyclic Indoles through Olefin Cross‐Metathesis/Intramolecular Friedel–Crafts Alkylation under Sequential Catalysis

Abstract

The combination of mechanistically distinct organocatalysis and transition-metal catalysis has enabled novel transformations beyond those possible with single catalytic systems.[1] Sequential catalysis involving a binary catalytic system often reduces labor and waste and enables the use of more readily available starting materials for a given transformation.[2] Chiral Brønsted acids have been shown to be efficient catalysts for asymmetric Friedel-Crafts reactions. [3,4] In particular, intramolecular Friedel-Crafts-type reactions provide a direct route to polycyclic indoles, such as tetrahydropyrano [3,4-b]indoles (THPIs) and tetrahydro-b-carbolines (THBCs), [5,6] which are frequently encountered in biologically active natural products and pharmaceuticals.[7] Despite considerable efforts devoted to asymmetric intramolecular FriedelCrafts-type Michael addition reactions, there are few successful examples.[8] Most notably, the tedious procedure for the preparation of substrates for the intramolecular FriedelCrafts reaction limits its synthetic applications.Xiao et al. recently demonstrated an elegant rutheniumcatalyzed tandem cross-metathesis (CM)/intramolecular hydroarylation sequence for the efficient synthesis of polycyclic indoles.[9] The Lewis acidic ruthenium species generated in situ catalyzes the Friedel-Crafts alkylation reaction. As part of our research program towards the development of enantioselective Friedel-Crafts reactions, [10] we envisaged that sequential olefin cross-metathesis and asymmetric intramolecular Friedel-Crafts alkylation reactions might be used to construct enantiomerically pure polycyclic indoles (Scheme 1). Chiral phosphoric acids were chosen as catalysts for the asymmetric Friedel-Crafts reaction because of their strong activation of unsaturated carbonyl compounds. We hoped that these catalysts would suppress the racemic reaction caused by Lewis acidic ruthenium species.[9] Furthermore, the Friedel-Crafts reaction should accelerate the CM reaction by converting the metathesis product into an alkylation product. Herein, we report our preliminary results on an enantioselective intramolecular Friedel-Crafts alkylation based on sequential catalysis. When we began our study, no efficient enantioselective Friedel-Crafts alkylation of indolyl enones was known.[11] We chose the indolyl enone 1 a as the model substrate and explored the use of chiral Brønsted acid catalysts for this transformation. With chiral phosphoric acids 5 (5 mol %) in toluene at À20 8C, the desired reaction proceeded smoothly to give 2 a with 59-96 % ee (Table 1). The chiral phosphoric acid 5 h bearing 9-phenanthryl groups afforded 2 a with greater than 95 % conversion and 96 % ee and thus proved to be the optimal catalyst (Table 1, entry 8). Further examination of the reaction conditions revealed that the reaction proceeded with optimal enantioselectivity (98 % ee) at 08C in toluene (Table 1, entry 13).Various substituted indolyl enones were subjected to the intramolecular Friedel-Crafts alkylation under these optimiz...

Iridium‐Catalyzed Asymmetric Allyl­ic Substitutions with Bulky ­Amines/Oxidative Double Bond Cleavage – Entry into the Reetz Synthesis of Amino Alcohols

“…In this regard, Bandini and Eichholzer reported an elegant allylic alkylation of indoles in the presence of a gold complex, providing an efficient synthesis of 1‐vinyl‐ and 4‐vinyl‐THCs in a highly enantioselective manner 3f. Furthermore, You and co‐workers described an olefin cross metathesis (CM)/intramolecular asymmetric Friedel–Crafts alkylation sequence, which offered a powerful platform to construct enantioenriched tetrahydropyrano[3,4‐b]indoles (THPIs) and tetrahydro‐β‐carbolines (THBCs) 3g…”

Designed Macrocyclic Kinase Inhibitors

“…However, with Hoveyda-Grubbs 2nd generation catalyst and/or Zhan-1B catalyst in the presence of additives such as trifluoroacetic acid (TFA) or HCl, the RCM proceeded smoothly with high conversion furnishing the desired macrocycle in 68% yield. 100 …”

Tandem Catalysis Utilizing Olefin Metathesis Reactions

“…A tandem olefin metathesis/Brønsted acid‐catalyzed transformation strategy was also described by You and co‐workers . In a series of studies, the authors reported enantioselective CM/intramolecular Friedel‐Crafts, RCM/isomerization/Pictet–Spengler, and CM/intramolecular aza‐Michael tandem reactions that enabled straightforward syntheses of polycyclic indole derivatives with excellent yields and ee values (Scheme ).…”