Semicorrins are a class of chiral, C2-symmetric, bidentate nitrogen-donor ligands derived from pyroglutamic acid. Structurally inspired by natural corrinoid and porphinoid metal complexes, semicorrins are characterized by a rigid framework containing a vinylogous amidine system embedded in a bicyclic structure. Semicorrins have been designed specifically for use in asymmetric catalysis and have shown high enantioselectivity in several transition metal-catalyzed transformations, particularly with copper and cobalt complexes. The conformational rigidity and C2-symmetry of semicorrins restrict the number of possible catalyst–substrate arrangements and thereby the number of competing diastereomeric transition states.
Semicorrins readily form chelate complexes with a range of transition metals, including Co(II), Cu(II), Ni(II), Pd(II), and Rh(I). Depending on the metal ion, ligand structure, and reaction conditions, both mono- and bis(semicorrinato) complexes can be synthesized. For example, a stable, hydroxyisopropyl-substituted mono(semicorrinato)copper(II) complex was prepared with copper(II) acetate under neutral conditions; this complex could be converted to the corresponding bis(semicorrinato)copper(II) complex by the addition of base.
History Inspired by earlier work from Eschenmoser's group, as well as foundational studies by Noyori and Aratani on chiral salicylaldimine ligands for asymmetric carbenoid cyclopropanation, semicorrin ligands were first developed in the 1980s by Pfaltz and coworkers at ETH Zürich. Semicorrins had originally been synthesized as intermediates in the total synthesis of corrinoid and hydroporphinoid compounds like vitamin B12 (cobalamin) or coenzyme F430, a hydroporphinoid nickel complex involved in bacterial methanogenesis. With a background in corrin chemistry from his graduate work in Eschenmoser's laboratory, Pfaltz recognized that the vinylogous amidine motif found in corrinoid and porphinoid ligands could serve as a starting point for designing C2-symmetric ligands for metal-catalyzed reactions. He hypothesized that such ligands could exert strong stereocontrol in asymmetric reactions if chirality elements were placed near the coordination sites.
Synthesis Semicorrins feature a bicyclic structure connected via a central vinylogous amidine system. Each pyrrole-derived ring features a stereogenic center adjacent to the metal coordination site, enabling effective asymmetric induction due to the close proximity of chirality to the metal center. The classical synthetic route to semicorrins involves condensation of an imino ester (2) with an enamine (5), both derived from commercially available (+)- or (−)-pyroglutamic acid (1). This strategy was first devised by Eschenmoser during his synthetic studies towards the corrin system and later adapted for chiral ligand synthesis by Pfaltz. Pfaltz's route proceeds via methanolysis of 1 to afford methyl pyroglutamate, treatment with Meerwein's salt to give imino ester 2, condensation with 3 to yield enamine 4, and decarboxylation under acidic conditions to afford enamine 5. Condensation of fragments 2 and 5 under acidic conditions (e.g. trifluoroacetic acid) then yields semicorrin ligand 6, which can be obtained on a multigram scale in overall yields of 30–40%.
The resulting ligands can be further modified at the ester substituents to tune steric and electronic properties. Common derivatives include the sterically demanding hydroxyisopropyl (10, from methyl Grignard addition to 6) and (trialkylsilyloxy)methyl semicorrins (11, from reduction of 6 followed by silylation of the resulting alcohol 7), which have proven useful in asymmetric catalysis. Alternatively, the substituents at the stereogenic centers can be diversified early in the synthesis by modifying the carboxyl group of pyroglutamic acid.
Applications in asymmetric catalysis
Copper-catalyzed cyclopropanations The first successful application of semicorrin complexes was Pfaltz's copper-catalyzed, enantioselective cyclopropanation of alkenes with α-diazo esters, affording enantioenriched cyclopropanecarboxylates. This work was inspired by Noyori's and Aratani's pioneering studies with (salicylaldiminato)copper(II) catalysts. In Pfaltz's protocol, a stable bis(semicorrinato)copper(II) complex (1) serves as a catalyst precursor. The active catalyst, which is presumed to be a mono(semicorrinato)copper(I) complex (2), is formed in situ either by heating in the presence of the diazo compound or by reduction with phenylhydrazine at room temperature. Alternatively, the active copper(I) catalyst can be generated in situ from the free ligand and copper(I) tert-butoxide.
High enantioselectivities were obtained with terminal alkenes, dienes, and some 1,2-disubstituted alkenes. While Pfaltz's (semicorrinato)copper catalysts provide excellent enantioselectivities with monosubstituted alkenes, their performance with 1,2-di- and trisubstituted alkenes is surpassed by Aratani's (salicylaldiminato)copper catalysts. Moderate trans/cis-selectivity is a common limitation of both systems (vide infra). Besides Pfaltz's and Aratani's catalysts, chiral copper(I) bis(oxazoline) (BOX), dinuclear rhodium(II) carboxylate, amidate, or phosphate, and ruthenium(II) diphosphine complexes have also exhibited strong enantiocontrol in diazo-mediated cyclopropanations.
(Semicorrinato)copper complexes have also been employed in the intramolecular, enantioselective cyclopropanation of alkenyl diazo ketones, affording moderate to high enantioselectivities. With the same substrates, low to moderate enantioselectivities were observed using Aratani's (salicylaldiminato)copper(II) catalysts. On the other hand, allyl diazoacetates showed significantly lower enantioselectivities under Pfaltz's conditions. This selectivity trend is reversed for chiral rhodium(II) complexes, which provide high enantioselectivities with allyl diazoacetates and low enantioselectivities with alkenyl diazo ketones.
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