New Catalytic Asymmetric Strategies for N-Heterocycle Synthesis

Informations projet

CatHet

N° de convention de subvention: 639594

DOI

10.3030/639594

Projet clôturé

Date de signature de la CE 23 Mars 2015

Date de début 1 Avril 2015

Date de fin 31 Mars 2020

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 1 548 738,00

Contribution de l’UE

€ 1 548 738,00

Coordonné par

UNIVERSITY OF BRISTOL
United Kingdom

Periodic Reporting for period 4 - CatHet (New Catalytic Asymmetric Strategies for N-Heterocycle Synthesis)

Période du rapport: 2019-10-01 au 2020-03-31

Résumé du contexte et des objectifs généraux du projet

Medicinal chemistry requires more efficient and diverse methods for the asymmetric synthesis of chiral scaffolds. Over 60% of the world’s top selling small molecule drug compounds are chiral and, of these, approximately 80% are marketed as single enantiomers. There is a compelling correlation between drug candidate “chiral complexity” and the likelihood of progression to the marketplace. Surprisingly, and despite the tremendous advances made in catalysis over the past several decades, the “chiral complexity” of drug discovery libraries has actually decreased, while, at the same time, for the reasons mentioned above, the “chiral complexity” of marketed drugs has increased. Since the mid-1990s, there has been a notable acceleration of this “complexity divergence”. Consequently, there is now an urgent need to provide efficient processes that directly access privileged chiral scaffolds. It is our philosophy that catalysis holds the key here and new processes should be based upon platforms that can exert control over both absolute and relative stereochemistry. In this proposal we outline the development of a range of N-heteroannulation processes based upon the catalytic generation and trapping of unique or unusual classes of organometallic intermediate derived from transition metal insertion into C-C and C-N sigma-bonds. We will provide a variety of enabling methodologies and demonstrate applicability in flexible total syntheses of important natural product scaffolds. The processes proposed are synthetically flexible, operationally simple and amenable to asymmetric catalysis. Likely starting points, based upon preliminary results, will set the stage for the realisation of aspirational and transformative goals. Through the study of the organometallic intermediates involved here, there is potential to generalise these new catalysis manifolds, such that this research will transcend N-heterocyclic chemistry to provide enabling methods for organic chemistry as a whole.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

Medicinal chemistry requires more efficient and diverse methods for the asymmetric synthesis of chiral scaffolds. There is a compelling correlation between drug candidate “chiral complexity” and the likelihood of progression to the marketplace. Consequently, there is now an urgent need to provide efficient processes that directly access privileged chiral scaffolds. It is our philosophy that catalysis holds the key here and new processes should be based upon platforms that can exert control over both absolute and relative stereochemistry.

Based upon the catalytic generation and trapping of unique or unusual classes of organometallic intermediate, we have developed several new synthetic methodologies. Key highlights are:

(1) A new route to 7-membered heterocyclic ring systems has been defined (J. Am. Chem. Soc. 2015, 137, 8054-8057).
(2) A versatile entry to substituted diazepanes has been developed (J. Am. Chem. Soc. 2016, 138, 11465-11468).
(3) Bifunctional amine reagents have been developed in the context of new aza-Heck reactions (Angew. Chem. Int. Ed. 2016, 55, 11198-11202).
(4) New classes of cyclopropane have been identified for C-C activation based cycloaddition (J. Am. Chem. Soc. 2016, 138, 13501-13504).
(5) The first examples of highly enantioselective aza-Heck cyclizations have been developed (Chem. Sci. 2017, 8, 1981-1985).
(6) We have developed TFA promoted C-N bond forming dearomatization reactions (J. Am. Chem. Soc. 2017, 139, 14005-14008).
(7) We have developed base promoted C-N bond forming dearomatization reactions (Angew. Chem. Int. Ed. 2017, 56, 14531-14535).
(8) We have developed a direct synthesis of lactones and lactams (Angew. Chem. Int. Ed. 2017, 56, 13824-13828).
(9) We have reported the first aza-variant of the Prilezhaev epoxidation (J. Am. Chem. Soc. 2018, 140, 17846-17850).
(10) We have reported aza-Heck reactions of carbamate protected systems (Angew. Chem. Int. Ed. 2018, 57, 5124-5128).
(11) We have developed a modular route to azepines (J. Am. Chem. Soc. 2018, 140, 2743).
(12) A method for the ortho- and enantioselective alkylation of anilides with styrenes or α-olefins has been developed (J. Am. Chem. Soc. 2018, 140, 9351-9356).
(13) An broad scope enantioselective aza-Heck reaction has been developed (J. Am. Chem. Soc. 2019, 141, 3356-3360).
(14) Multicomponent cycloaddations of electron poor cyclopropanes have been developed (Angew. Chem. Int. Ed. 2019, 58, 221-225).
(15) A method for the preparation of 8-membered heterocycles has been reported (Angew. Chem. Int. Ed. 2019, 58, 18844-18848).
(16) A strategy for the preparation of complex polyheterocycles has been developed (J. Am. Chem. Soc. 2020, 142, 1740-1745).

The work has been disseminated in top journals (as outlined above) and via >40 seminars to academia, international conferences and industry (throughout Europe, North America and Asia).

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

The work outlined above has provided new synthetic methodologies that address the broad goals of the project (see "Summary of the context and overall objectives of the project"). These methods are likely to be of use to medicinal chemists as they search for new lead compounds in the development of small molecule drug compounds. In each area, the new methodologies are enabled by the identification and development of novel reactivity modes. These reactivity modes are likely to be of interest to other academic researchers and may provide inspiration for the development of further synthetic methodologies. The results achieved build towards long term goals of providing general new cycloaddition and cyclisation reactions for the provision of medicinally important N-heterocyclic ring systems.

J. Am. Chem. Soc. 2019, 141, 3356-3360

J. Am. Chem. Soc. 2020, 142, 1740-1745

J. Am. Chem. Soc. 2018, 140, 9351-9356