Atroposelective Synthesis of Isoriccardin C through a C−H Activated Heck Type Macrocyclization

Marx, Lisa; Lamberty, Daniel; Choppin, Sabine; Colobert, Françoise; Speicher, Andreas

doi:10.1002/ejoc.202100017

Cited by 9 publications

(6 citation statements)

References 30 publications

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“…Moreover, in collaboration with Speicher et al, we applied our method towards the first total synthesis of atropopure isoriccardin C. An atropostereose- lective macrocyclization through an oxidative Heck type C-H activation process allowed complete control of the atroposelectivity (de > 98%) and the traceless character of the sulfinyl moiety in ortho position of the biaryl enabled the introduction of an OH group (Scheme 4) [17].…”

Section: Resultsmentioning

confidence: 99%

Control of atropoisomerism: an access to valuable compounds

Choppin,

Wencel-Delord,

Colobert

2024

Comptes Rendus. Chimie

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Many natural, biologically active compounds are stereogenic with a unique tridimensional structure that is on the origin of the specific interactions with the active binding site.This concept of chirality goes beyond chiral stereocenters, englobing also atropoisomerism related to a hindered rotation around an axis with the isolation of atropostable conformers at room temperature. Atropoisomerism is well-known in biaryls, however this phenomenon is encountered in many pharmaceutically relevant compounds such as heterobiaryl, diarylamines, benzamides and anilides.Currently four FDA-approved drugs are atropostable and many others are in clinical trials. It is also important to note that almost 30% of recent FDA-approved small molecules are "proatropisomeric" and interact with a target in a specific chiral conformation.Given this vivid interest in C-C but also C-N atropisomerically stable compounds, this account will detail the new atropoisomeric strategies we developed and their applications in the synthesis of relevant molecules and ligands.

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Section: Resultsmentioning

confidence: 99%

Control of atropoisomerism: an access to valuable compounds

Choppin,

Wencel-Delord,

Colobert

2024

Comptes Rendus. Chimie

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“…The synthetic potential of this methodology was further elegantly demonstrated within the synthesis of isoriccardin C. In this case, sulfoxide-directed atroposelective intramolecular Heck reaction was used to close the macrocyclic structure and induce the chirality of the final natural product …”

Section: Synthesis Of Atropisomeric Biaryls Via C–h Functionalization...mentioning

confidence: 99%

Sulfoxide-Directed or 3d-Metal Catalyzed C–H Activation and Hypervalent Iodines as Tools for Atroposelective Synthesis

Choppin

Wencel‐Delord

2023

Acc. Chem. Res.

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Conspectus The expanding applications of atropisomeric compounds combined with the growing diversity of such chiral molecules translate into an urgent need for innovative synthetic strategies allowing their rapid, efficient, and sustainable synthesis. Recently, the C–H activation approach has provided new opportunities for synthesizing axially chiral compounds. The two complementary approaches allowing implementation of the C–H activation methodology toward the synthesis of the chiral molecules imply either ortho-functionalization of the preexisting prochiral or atropo-unstable biaryl substrates or direct C–H arylation of sterically encumbered aromatics. The first approach required the preinstallation of a directing group on a biaryl precursor, which drastically limits the diversity of thus generated products. To tackle this important synthetic limitation, we have envisioned using a chiral sulfoxide as both directing group and chiral auxiliary. Indeed, in addition to efficiently coordinating the Pd-catalyst thus allowing chiral induction, the sulfoxide moiety can be easily removed, via the sulfoxide/lithium exchange, after the C–H activation step, thus guaranteeing an almost unlimited postdiversification of the atropisomeric products. The efficiency and generality of this concept could be illustrated by developing atropo-diastereoselective oxidative Heck reaction, direct acetoxylation, and iodination, as well as direct arylation. Besides, the synthetic utility of this methodology was demonstrated by designing an expedient synthesis of a direct steganone precursor. This unique transformation also allowed us to build up unprecedented triaryl scaffolds with two perfectly controlled chiral axes, original chiral skeletons for new ligand design. While considering the atroposelective direct arylations, the clear antagonism between the harsh reaction conditions frequently required for the coupling of two sterically hindered compounds and the atropo-stability of the new product, resulted in the scarcity of such transformations. To solve this fundamental challenge, we have focused on the application of a low-valent cobalt catalyst, prompted to catalyze C–H activation of indoles at the C2 position under extremely mild reaction conditions (room temperature). Accordingly, atroposelective C2-arylation of indoles could be achieved using an original carbene ligand and delivering the uncommon atropoisomerically pure indoles in excellent yields and enantioselectivities. Detailed combined experimental and theoretical mechanistic studies shed light on the mechanism of this transformation, providing strong evidence regarding the origin of the enantioselectivity. Finally, the antagonism between steric hindrance required to guarantee the atropo-stability of a molecule and harsh reaction conditions required to couple two partners is a strong limitation not only for the development of atroposelective C–H arylation reaction but also for the development of direct synthesis of the C–N axially chiral compounds. Despite the long history and i...

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“…In 2021, Speicher and co-workers completed the total synthesis of another bis(bibenzylic) macrocycle, isoriccardin C ( 117.1 , Figure ). In contrast to the previous examples, C–H activation allowed this novel atroposelective Heck cyclization to proceed in the absence of activating groups such as the triflate or iodo groups seen in the previous strategies. Styrene precursor 117.2 was prepared containing a chiral sulfinyl directing group with excellent enantiopurity (>99% ee), crucial for the atropodiastereoselective macrocyclization step.…”

Section: Thermodynamic Resolutions Of Atropisomersmentioning

confidence: 99%

Stereodynamic Strategies to Induce and Enrich Chirality of Atropisomers at a Late Stage

Roos,

Chiang,

Murray

et al. 2023

Chem. Rev.

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Atroposelective Synthesis of Isoriccardin C through a C−H Activated Heck Type Macrocyclization

Cited by 9 publications

References 30 publications

Control of atropoisomerism: an access to valuable compounds

Control of atropoisomerism: an access to valuable compounds

Sulfoxide-Directed or 3d-Metal Catalyzed C–H Activation and Hypervalent Iodines as Tools for Atroposelective Synthesis

Stereodynamic Strategies to Induce and Enrich Chirality of Atropisomers at a Late Stage

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