An axial-to-axial chirality transfer strategy for atroposelective construction of C–N axial chirality

•Unique axial-to-axial chirality transfer for C–N axial construction•Ability to assemble two vicinal and remote stereogenic axes•Step-economic scalable synthesis of enantioenriched phenanthridinones•Broad scope, good yields, excellent enantioselectivities Axial widely exists in bioactive natural products, pharmaceuticals, chiral materials, ligands catalysts asymmetric catalysis. As such, the efficient, modular, enantioselective assembly these scaffolds from readily available starting materials represents one most challenging yet fascinating directions synthetic organic chemistry. In sharp contrast well-developed C–C chirality, atroposelective construction has been less investigated because innate higher degree rotational freedom latter. Herein, we report an efficient atropisomers via palladium/chiral norbornene cooperative The key success is unique process, which scarcely reported. This strategy expected inspire future studies find applications broad research fields. axially skeletons are ubiquitous ligands. However, their remains a formidable challenge low configurational stability compared with that atropisomers. general method accessing through based on obtained originates preformed transient high fidelity. A variety phenanthridinones (44 examples, up >99% ee). can be applied axes double C–H arylation or further transformation products diastereoinduction. Additionally, reaction mechanism process elucidated by density functional theory calculations. know, atropisomers, e.g., biaryls, prevalent privileged frameworks, well developed past decades.1Liao G. Zhou T. Yao Q.J. Shi B.F. Recent advances biaryls transition metal-catalysed functionalization.Chem. Commun. 2019; 55: 8514-8523Crossref PubMed Google Scholar, 2Wang Y.B. Tan B. Construction compounds organocatalysis.Acc. Chem. Res. 2018; 51: 534-547Crossref Scopus (334) 3Kumarasamy E. Raghunathan R. Sibi M.P. 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When methyl ester-substituted (N2?) N1?, dropped 76% 8). C2-amide substituted (N3?) proved inferior stereoselectivity 9). stronger Cs2CO3 K2CO3, 10). Besides MeCN, DMF solvent 11). Notably, loading N1? could reduced 25 mol % without obvious erosion enantioselectivity, although concentration longer time required 12). With hand, set out explore scope 3). principle, different electronic properties tolerated, providing moderate yields (42%–96%) (87%–98% ortho-substituents compatible, ethyl (3b), tert-butyldimethylsilyl (TBS)-protected hydroxymethyl (3c), ester (3d), phenyl (3e), fluoro (3f), benzyloxy (3g), methoxy (3h). Moreover, bearing additional substituents other positions examined, alkyl (3i 3k), (3l), chloro (3j), bromo (3m), (3n), (3o) 3- 4-positions amenable. bicyclic (3s–3u) polycyclic (3v) investigated, they (91%–96% densely functionalized substrates led penta-substituted aromatics (3w 3x) yields. heteroaryl 1y deliver 3y 50% 96% Remarkably, meta-substituted iodides, problematic reactions,44Catellani provided mono arylated (3p–3r) regioselectivity stereocontrol. Subsequently, bromides evaluated 4). group, ortho-substitution extended groups, (3A), nitro (3B), naphthyl (3C), corresponding (83%–97% 93%–98% Modifications para-position aniline moiety (3D), (3E), aldehyde (3F), alkenyl (3G), alkynyl (3H). serve useful handles manipulations. modifications ortho-position investigated. general, sterically bulky moieties ensuring process. Switching tert-butyl OTBS (3I), (3K–3M), TBS-protected (3J) produced enantiocontrol. almost no observed when hindered introduced (3N–3P). Nevertheless, react moiety, (3Q–3V) regioselectivities (90%–98% Particularly noteworthy showed chemoselectivity. contained reactive C(sp2)–X sites, selectively occurred electron-withdrawing (3D, 3U, 3V). absolute configuration 3h 3C unambiguously determined (R) X-ray crystallographic analysis, assigned analogy. understand aforementioned interesting substituent effect (DFT) calculations 5A). Just expected, reducing size ortho-substituent (3a versus 3aa). surprising uncover meta-substitution (blue part) significantly increased axis, same (3a? 3a, 3R 3R?, 3Q 3Q?). We related ground-state distortion ortho-substituent. DFT-optimized structures 3Q? 5A. shift substitution meta- ortho-position, steric repulsions ortho-methyl obviously distorted structure, reflected dihedral angle (12.2° 20.8°). destabilized ground state, (33.0 25.9 kcal/mol). 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DFT-computed profile S5 S6. calculations, on-cycle resting state. rate-determining step TS18, 12, 28.3 kcal/mol. computations alternative considerations supplemental information. atropisomer series stereoselectivity-controlling steps, elaborated 8. 8A presents 3a. N2?-coordinated Pd(II)iodide 10, regioisomeric favor formation selectivity intrinsic frontier orbital interaction Pd(II). alkene olefin acts electrophilic component, nucleophilic component. LUMO (lowest unoccupied orbital) ?? smaller distribution position, position S7). Through step, transfers 14 (the competing formations cyclometallated [Figure S7] detailed discussion information). intermediates. induction fragment. revealed 8B, TS18 8.5 favorable TS34, strong preference (S)-axial highlighted disfavor contrast, do not exist thus favored S8] Afterward, controls irreversible step. states TS39 8C. fragment tBu amidyl TS39, results 2.7 (R)-C–N S9] agreement level configurations analysis. modular convergent wide range features include ability axes, economy, scalability. broader implications synthesis.