Guillaume Vincent

Stereodivergent Synthesis of Substituted N,O‐Containing Bicyclic Compounds by Sequential Addition of Nucleophiles to N‐Alkoxybicyclolactams

The functionalization of amides by the direct addition of two successive nucleophiles to the carbonyl group for the synthesis of cyclic or acyclic amines is a topic of growing interest. Usually the amide is activated as a chloro or triflyloxyiminium intermediate, a thioamide, or an imide before the successive addition of organometallic reagents, hydride, or other nucleophiles. However, the direct addition of Grignard reagents with heating, or organolithium compounds at room temperature, to bicyclic lactams followed by hydride reduction has been reported. The same sequence with amides or N-alkyl monocyclic lactams is less common but has precedent. In fact, we successfully employed this latter strategy to construct stereoselectively the 2,6-trans-disubstituted piperidine framework 5 of porantheridine (6) from isoxazolidino[2,3-a]piperidin-7-one 4, which we had obtained from our efficient and straightforward ring-rearrangement metathesis of the strained bicyclic nitroso Diels–Alder adduct 1 a (Scheme 1). Nevertheless, our synthetic scheme required the cleavage of the N O bond and the benzylation of the resulting lactam prior to the key step; the benzyl group had to be removed afterward. Therefore, it would be of great interest to realize the successive addition of two nucleophiles directly onto isoxazololactam 3 ; a high level of stereoselectivity should be induced by the shape of the bicyclic framework. The realization of this “one-pot” sequence would improve the efficiency of the overall process by eliminating extra protection/deprotection steps. The N O bond would, in fact, act as a protecting group and, more importantly, as an activating and stabilizing group. The addition of the first nucleophile would be possible under milder conditions than with the corresponding alkyl amide and would form the relatively stable chelated intermediate 7, which is related to the N-methoxy Weinreb amides that are known not to undergo twofold addition of the first nucleophile (Scheme 2). Addition of acid would then generate the transient alkoxyimmium species 8. The presence of the cyclic isoxazolidine would force the side chain at position C3a of the alkoxypiperidinium unit in a pseudoequatorial position, and the stereoelectronically preferred axial attack of a nucleophile should lead diastereoselectively to 9. Scheme 1. Ring-rearrangement metathesis of nitroso Diels–Alder cycloadducts and our previous synthesis of porantheridine (6).

FeCl3‐Mediated Friedel–Crafts Hydroarylation with Electrophilic N‐Acetyl Indoles for the Synthesis of Benzofuroindolines

IRONic electrophilic indoles! The C3-regioselective hydroarylation of N-acetyl indoles with aromatic nucleophiles mediated by FeCl(3) features a rare example of the electrophilic reactivity of the indole core in a Friedel-Crafts reaction. This indole umpolung allows us straightforward access to the tetracyclic benzofuroindoline motif found in the natural product diazonamide A, which is a potent antitumor agent.

Direct Oxidative Coupling of N-Acetyl Indoles and Phenols for the Synthesis of Benzofuroindolines Related to Phalarine†

Inspired by the biogenetic synthesis of benzofuroindoline-containing natural products, we designed an oxidative coupling between phenol and N-acetyl indoles. This straightforward and direct radical process, mediated by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and FeCl3 allowed the regioselective synthesis of benzofuro[3,2-b]indolines, whose structure is found in the natural product phalarine.

Stereodivergent Synthesis of Piperidine Alkaloids by Ring-Rearrangement Metathesis/Reductive Lactam Alkylation of Nitroso Diels–Alder Cycloadducts

A general methodology for the stereoselective synthesis of 2-(2-hydroxyalkyl)piperidine alkaloids by ring-rearrangement metathesis of nitroso Diels-Alder cycloadducts is reported. The approach is illustrated by the formal synthesis of porantheridine and the total synthesis of andrachcinidine through a diastereodivergent allylation of an N-alkoxy bicyclic lactam. The asymmetric synthesis of the latter alkaloid provides new insights into the configurational stability of cycloadducts between chloronitroso reagents and cyclopentadiene.

Bioinspired Direct Access to Benzofuroindolines by Oxidative [3 + 2] Annulation of Phenols and Indoles

The straightforward entry to benzofuroindoline containing natural product-like scaffolds has been achieved by a challenging [3 + 2] oxidative coupling between phenols and indoles. The reaction proceeds by NIS-oxidation of the indole followed by the trapping of the resulting electrophilic intermediate by phenol.

Synthetic approaches to racemic porantheridine and 8-epihalosaline via a nitroso Diels-Alder cycloaddition/ring-rearrangement metathesis sequence.

The application of a sequence involving a nitroso Diels-Alder cycloaddition and a ring-rearrangement metathesis to the total synthesis of (+/-)-8-epihalosaline and the formal synthesis of (+/-)-porantheridine is described. The formation of the 2,6-trans-disubstituted piperidine backbone of porantheridine has been accomplished by addition of a Grignard reagent onto an N-benzylpiperidone followed by a highly diastereoselective reduction of the imminium intermediate in one pot.

Regioselective hydroarylation reactions of C3 electrophilic N-acetylindoles activated by FeCl3: an entry to 3-(hetero)arylindolines.

A method for the direct and rare umpolung of the 3 position of indoles is reported. The activation of N-acetylindole with iron(III) chloride allows the C-H addition of aromatic and heteroaromatic substrates to the C2=C3 double bond of the indole nucleus to generate a quaternary center at C3 and leads regioselectively to 3-arylindolines. Optimization, scope (50 examples), practicability (gram scale, air atmosphere, room temperature), and mechanistic insights of this process are presented. Synthetic transformations of the indoline products into drug-like compounds are also described.

Iron-Mediated Domino Interrupted Iso-Nazarov/Dearomative (3 + 2)-Cycloaddition of Electrophilic Indoles

An efficient domino reaction combining different classes of pericyclic reactions leads to chiral complex polycyclic indoline-based architectures from achiral starting materials under mild conditions. This practical method is based on the ability of iron(III) chloride to promote both 4π electrocyclizations of 2,4-dienals and the C2-C3 umpolung of N-acetylindoles during the dearomative (3 + 2) cycloadditions.

Ring-Rearrangement Metathesis of Nitroso Diels–Alder Cycloadducts

Strained nitroso Diels-Alder bicyclo[2.2.1] or [2.2.2] adducts functionalized with alkene side chains of diverse length undergo a ring-rearrangement metathesis process with external alkenes and Grubbs II or Hoveyda-Grubbs II ruthenium catalysts, under microwave irradiation or classical heating, to deliver cis-fused bicycles of various ring sizes, which contain a N-O bond. These scaffolds are of synthetic relevance for the generation of molecular diversity and to the total synthesis of alkaloids. The observation of unexpected reactions, such as epimerization or one-carbon homologation of the alkene side chain, is also reported.

Synthesis of 3,3-Spiroindolines via FeCl3-Mediated Cyclization of Aryl- or Alkene-Containing 3-Substituted N–Ac Indoles

We report the cyclization of 3-substituted N-acetylindoles for the straightforward synthesis of 3,3-spiroindolines via the Friedel-Crafts reaction of an appended aryl group or the formal [2 + 2] cycloaddition of an appended alkene. Our strategy involves an Umpolung of the C2═C3 bond of the indole nucleus during FeCl3-mediated hydroarylation or annulation reactions.