The combination of photoredox catalysis and enamine catalysis has enabled the development of an enantioselective α-cyanoalkylation of aldehydes. This synergistic catalysis protocol allows for the coupling of two highly versatile yet orthogonal functionalities, allowing rapid diversification of the oxonitrile products to a wide array of medicinally relevant derivatives and heterocycles. This methodology has also been applied to the total synthesis of the lignan natural product (−)-bursehernin.Keywords photoredox catalysis; organocatalysis; enantioselective; alkylation; aldehyde; nitrile; total synthesisThe enantioselective α-alkylation of carbonyl compounds with sp 3 -hybridized halidebearing electrophiles has long been considered an elusive goal for practitioners of asymmetric catalysis. [1] Indeed, the most commonly employed strategy to achieve the stereoselective construction of α-alkyl carbonyls involves the coupling of auxiliary-based metal enolates with halo or tosyloxy alkanes. [2], [3] A critical issue for the development of catalytic variants of this venerable reaction has been the insufficient electrophilicity of alkyl halides towards silyl or alkyl enol ether π-nucleophiles (enolate equivalents that are broadly employed in asymmetric catalysis). This limitation has man-dated the use of lithium-, sodium-, or cesium-derived enolates for auxiliary controlled carbonyl α-functionalization at higher carbonyl oxidation states. Recently, however, the application of secondary amine organocatalysts has overcome several of these constraints via the direct use of aldehydes or ketones in a variety of chiral enamine α-functionalization reactions. [4] As one example, our laboratory disclosed the synergistic merger of enamine catalysis with visible-light
The first enantioselective organocatalytic α-allylation of cyclic ketones has been accomplished via singly occupied molecular orbital catalysis. Geometrically constrained radical cations, forged from the one-electron oxidation of transiently generated enamines, readily undergo allylic alkylation with a variety of commercially available allyl silanes. A reasonable latitude in both the ketone and allyl silane components is readily accommodated in this new transformation. Moreover, three new oxidatively stable imidazolidinone catalysts have been developed that allow cyclic ketones to successfully participate in this transformation. The new catalyst platform has also been exploited in the first catalytic enantioselective α-enolation and α-carbooxidation of ketones.asymmetric synthesis | organocatalysis T he enantioselective catalytic α-alkylation of simple ketones remains a fundamental goal in chemical synthesis (1-4). Seminal work from Doyle and Jacobsen (5), Trost and co-workers (6-8), Stoltz and co-workers (9, 10), Braun and co-workers (11,12), and Hartwig and co-workers (13, 14) has introduced valuable previously undescribed technologies for (i) the enantioselective alkylation of preformed or in situ generated metal enolates (5,6,(11)(12)(13)(14)(15)(16)(17) and (ii) the asymmetric and decarboxylative conversion of allyl keto carbonates to α-allylated ketones (7-10). With these key advances in place, a goal now for asymmetric catalysis has become the direct α-allylation of simple ketone substrates (18,19), an elusive yet potentially powerful bond construction (Scheme 1).Recently, we questioned whether the catalytic principles of singly occupied molecular orbital (SOMO) activation (20) might be translated to ketonic systems, thereby providing an unreported mechanism for direct and enantioselective α-carbonyl alkylation. Despite the superficial similarities between aldehydes and ketones, these carbonyl families exhibit largely different steric and electronic properties with respect to catalyst interactions. As a consequence, the translation of enantioselective activation modes between these carbonyl subclasses is often difficult (if not unattainable in many cases) (21,22). Herein, we describe the invention of a previously undisclosed family of organocatalysts that enable cyclic ketones to successfully function within the SOMO-activation platform while being chemically robust to oxidative reagents. Moreover, we document the introduction of a previously undescribed catalytic α-ketone alkylation reaction that is immediately amenable to asymmetric induction. Enantioselective SOMO CatalysisOver the last decade, the field of enantioselective synthesis has witnessed tremendous progress in the successful implementation of small organic molecules as asymmetric catalysts. In particular, two modes of carbonyl activation by chiral secondary amines have led to the discovery of a large number of previously undescribed reactions (Scheme 2): (i) Iminium catalysis (23), wherein lowest unoccupied molecular orbital (LUMO) lowering a...
Activating mutations in FLT3 confer poor prognosis for individuals with acute myeloid leukemia (AML). Clinically active investigational FLT3 inhibitors can achieve complete remissions but their utility has been hampered by acquired resistance and myelosuppression attributed to a ‘synthetic lethal toxicity’ arising from simultaneous inhibition of FLT3 and KIT. We report a novel chemical strategy for selective FLT3 inhibition while avoiding KIT inhibition with the staurosporine analog, Star 27. Star 27 maintains potency against FLT3 in proliferation assays of FLT3-transformed cells compared with KIT-transformed cells, shows no toxicity towards normal human hematopoiesis at concentrations that inhibit primary FLT3-mutant AML blast growth, and is active against mutations that confer resistance to clinical inhibitors. As a more complete understanding of kinase networks emerges, it may be possible to define anti-targets such as KIT in the case of AML to allow improved kinase inhibitor design of clinical agents with enhanced efficacy and reduced toxicity.DOI: http://dx.doi.org/10.7554/eLife.03445.001
The combination of photoredoxc atalysis and enamine catalysis has enabled the development of an enantioselective a-cyanoalkylation of aldehydes.T his synergistic catalysis protocol allows for the coupling of two highly versatile yet orthogonal functionalities,allowing rapid diversification of the oxonitrile products to aw ide arrayo f medicinally relevant derivatives and heterocycles.T his methodology has also been applied to the total synthesis of the lignan natural product (À)-bursehernin.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.