Iridium‐Catalyzed Asymmetric Allylic Amination with Polar Amines: Access to Building Blocks with Lead‐Like Molecular Properties

Tosatti, Paolo; Horn, Joachim; Campbell, Amanda; House, David; Nelson, Adam; Marsden, Stephen P.

doi:10.1002/adsc.201000721

Cited by 37 publications

(20 citation statements)

References 56 publications

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“…The Pd‐catalyzed asymmetric allylic substitution, that is, Tsuji–Trost reaction proceeding via pseudo‐symmetric ( meso ‐type) π‐allyl‐Pd intermediates carrying chiral ligands, has been intensively studied . However, while a number of useful protocols exist for Pd‐catalyzed (and Ir‐catalyzed) enantioselective allylic aminations, we were surprised to learn that only few (and little convincing) examples have been reported for the asymmetric N‐allylation of amino acid esters, despite them representing a well‐accessible and highly relevant class of N‐nucleophiles . Therefore, we were challenged to develop an efficient methodology for such reactions, which we disclose herein.…”

Section: Figurementioning

confidence: 98%

Pd‐Catalyzed Asymmetric N‐Allylation of Amino Acid Esters with Exceptional Levels of Catalyst Control: Stereo‐Divergent Synthesis of ProM‐15 and Related Bicyclic Dipeptide Mimetics

Dohmen

Reiher

Albat

et al. 2020

Chemistry A European J

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A general and powerful method for the stereo‐controlled Pd‐catalyzed N‐allylation of amino acid esters is reported, as a previously largely unsolved synthetic challenge. Employing a new class of tartaric acid‐derived C2‐symmetric chiral diphosphane ligands the developed asymmetric amination protocol allows the conversion of various amino acid esters to the N‐allylated products with highest levels of enantio‐ or diastereoselectivity in a fully catalyst‐controlled fashion and predictable configuration. Remarkably, the in situ generated catalysts also exhibit outstanding levels of activity (ligand acceleration). The usefulness of the method was demonstrated in the stereo‐divergent synthesis of a set of new conformationally defined dipeptide mimetics, which represent new modular building blocks for the development of peptide‐inspired bioactive compounds.

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Section: Figurementioning

confidence: 98%

Pd‐Catalyzed Asymmetric N‐Allylation of Amino Acid Esters with Exceptional Levels of Catalyst Control: Stereo‐Divergent Synthesis of ProM‐15 and Related Bicyclic Dipeptide Mimetics

Dohmen

Reiher

Albat

et al. 2020

Chemistry A European J

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“…Despite this significant challenge some groups are now tackling this actively. [59] Unprotected polar functionality is often (though not always) [60] poorly compatible with many reagents owing to reasons of reactivity, insolubility in nonpolar solvents, or coordination to a catalyst.…”

Section: Lead-oriented Synthesismentioning

confidence: 99%

Lead‐Oriented Synthesis: A New Opportunity for Synthetic Chemistry

2012

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The pharmaceutical industry remains solely reliant on synthetic chemistry methodology to prepare compounds for small-molecule drug discovery programmes. The importance of the physicochemical properties of these molecules in determining their success in drug development is now well understood but we present here data suggesting that much synthetic methodology is unintentionally predisposed to producing molecules with poorer drug-like properties. This bias may have ramifications to the early hit- and lead-finding phases of the drug discovery process when larger numbers of compounds from array techniques are prepared. To address this issue we describe for the first time the concept of lead-oriented synthesis and the opportunity for its adoption to increase the range and quality of molecules used to develop new medicines.

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“…Regioselectivity is practically independent of the solvent, whereas enantioselectivity is eroded in DMF and, notably, in DMSO, but not in MeCN. Low selectivity with DMSO was also observed by us for a hydroxylation reaction,9c whereas a beneficial effect of this solvent has been reported for allylic amination reactions run under aerobic conditions 9b…”

Section: Resultsmentioning

confidence: 64%

Iridium‐Catalyzed Allylic Substitutions with Cyclometalated Phosphoramidite Complexes Bearing a Dibenzocyclooctatetraene Ligand: Preparation of (π‐Allyl)Ir Complexes and Computational and NMR Spectroscopic Studies

Raskatov

Jäkel

Straub

et al. 2012

Chemistry A European J

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(π-Allyl)Ir complexes derived from dibenzocyclooctatetraene and phosphoramidites by cyclometalation are effective catalysts for allylic substitution reactions of linear monosubstituted allylic carbonates. These catalysts provide exceptionally high degrees of regioselectivity and allow the reactions to be run under aerobic conditions. A series of (π-allyl)Ir complexes were prepared and characterized by X-ray crystal structure analyses. An allylic amination with aniline displayed different resting states depending on the presence of a strong base. DFT calculations were carried out on the mechanistic aspects of these reactions. The results suggest that for the (π-allyl)Ir complexes, the formation and reactions with nucleophiles proceed with comparable rates.

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Iridium‐Catalyzed Asymmetric Allylic Amination with Polar Amines: Access to Building Blocks with Lead‐Like Molecular Properties

Cited by 37 publications

References 56 publications

Pd‐Catalyzed Asymmetric N‐Allylation of Amino Acid Esters with Exceptional Levels of Catalyst Control: Stereo‐Divergent Synthesis of ProM‐15 and Related Bicyclic Dipeptide Mimetics

Pd‐Catalyzed Asymmetric N‐Allylation of Amino Acid Esters with Exceptional Levels of Catalyst Control: Stereo‐Divergent Synthesis of ProM‐15 and Related Bicyclic Dipeptide Mimetics

Lead‐Oriented Synthesis: A New Opportunity for Synthetic Chemistry

Iridium‐Catalyzed Allylic Substitutions with Cyclometalated Phosphoramidite Complexes Bearing a Dibenzocyclooctatetraene Ligand: Preparation of (π‐Allyl)Ir Complexes and Computational and NMR Spectroscopic Studies

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