Here we report that
chiral Mn(I) complexes are capable of H–P
bond activation. This activation mode enables a general method for
the hydrophosphination of internal and terminal α,β-unsaturated
nitriles. Metal−ligand cooperation, a strategy previously not
considered for catalytic H–P bond activation, is at the base
of the mechanistic action of the Mn(I)-based catalyst. Our computational
studies support a stepwise mechanism for the hydrophosphination and
provide insight into the origin of the enantioselectivity.
In contrast to the well-studied asymmetric catalyzed synthesis of tetrahydroquinolines, the asymmetric methodologies toward 3,4-dihydroquinolin-2-ones are quite rare. Herein, the first asymmetric cascade reaction is reported between ethynyl benzoxazinanones and mixed-anhydrides generated from aryl acetic acids and pivaloyl chloride, based on synergistic catalysis. This allowed the formation of attractive 3,4-dihydroquinolin-2-ones bearing two vicinal chiral centers at C3 and C4 in high yields with excellent diastereo- and enantioselectivities. A plausible chiral induction model for this reaction was proposed. The utility of this methodology was exemplified by further elaboration of the cyclization products by removal of the N-protecting groups.
Asymmetric 1,6-addition of malonates to para-quinone methides has been developed by using amide-phosphonium salts derived from easily available chiral α-amino acids as bifunctional phase transfer catalysts. Stabilized para-quinone methides with various substituents on the phenyl ring were reacted with diphenyl malonates to give functionalized diaryl methines in excellent yields and high to excellent ee's. Furthermore, to show the utility of this methodology, a gram scale synthesis of an 1,6-addition adduct and its further elaboration into the key intermediate for synthesis of GPR40 agonists were also described.
Dearomative functionalization of
heteroaromatics, a readily available
chemical feedstock, is one of the most straightforward approaches
for the synthesis of three-dimensional, chiral heterocyclic systems,
important synthetic building blocks for both synthetic chemistry and
drug discovery. Despite significant efforts, direct nucleophilic additions
to heteroaromatics have remained challenging because of the low reactivity
of aromatic substrates associated with the loss of aromaticity, as
well the regio- and stereoselectivities of the reaction. Here we present
a catalytic system that leads to unprecedented, high-yielding dearomative
C-4 functionalization of quinolines with organometallics with nearly
absolute regio- and stereoselectivities and with a catalyst turnover
number (TON) as high as 1000. The synergistic action of the chiral
copper catalyst, Lewis acid, and Grignard reagents allows us to overcome
the energetic barrier of the dearomatization process and leads to
chiral products with selectivities reaching 99% in most cases. Molecular
modeling provides important insights into the speciation and the origin
of the regio- and enantioselectivity of the catalytic process. The
results reveal that the role of the Lewis acid is not only to activate
the substrate toward a potential nucleophilic addition but also to
subtly control the regiochemistry by preventing the C-2 addition from
happening.
Chiral bisphosphine ligands are of key importance in transition-metal-catalyzed asymmetric synthesis of optically active products. However, the transition metals typically used are scarce and expensive noble metals, while the synthetic routes...
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