In this report, we disclose our findings regarding the remarkable effect of a low-level impurity found in the solvent used for a ruthenium-catalyzed direct arylation reaction. This discovery allowed for the development of a robust and high-yield arylation protocol that was demonstrated on a multikilogram scale using carboxylate as the cocatalyst. Finally, a practical, scalable, and chromatography-free synthesis of the biaryl core of Anacetrapib is described.
While nonracemic catalysts can generate nonracemic products with or without the nonlinear relationship in enantiomeric excesses between catalysts and products, racemic catalysts inherently give only a racemic mixture of chiral products. Asymmetric catalysts, either in nonracemic or racemic form, can be further evolved into highly activated catalysts with association of chiral activators. This asymmetric activation process is particularly useful in racemic catalysis through selective activation of one enantiomer of the racemic catalyst. Recently, a strategy whereby a racemic catalyst is selectively deactivated by a chiral additive has been reported to yield nonracemic products. However, reported herein is an alternative and conceptually opposite strategy in which a chiral activator selectively activates, rather than deactivates, one enantiomer of a racemic chiral catalyst. The advantage of this activation strategy over the deactivation counterpart is that the activated catalyst can produce a greater enantiomeric excess in the products—even with the use of a catalytic amount of activator relative to chiral catalyst—than that attained by the enantiomerically pure catalyst on its own. Therefore, asymmetric activation could provide a general and powerful strategy for not only the use of atropisomeric, racemic ligands but also chirally flexible and proatropisomeric ligands without enantiomeric resolution!
We report herein a simple, scalable, transition-metal-free approach to the synthesis of alpha-aryl methyl ketones from diazonium tetrafluoroborate salts under mild conditions. This methodology uses easily accessible and nontoxic starting material and was applied to the multi-kilogram-scale preparation of 1-(3-bromo-4-methylphenyl)propan-2-one.
Desymmetrization of cyclohexadienylsilanes available from Birch reduction of the corresponding
arylsilanes is efficiently carried out using Sharpless asymmetric dihydroxylation and aminohydroxylation. Complete diastereocontrol and reasonable enantiocontrol have been attained during
the preparation of the desired diols. An excellent regiocontrol has also been observed during
aminohydroxylation of dienylsilanol 6b. The resulting diol 8 and hydroxycarbamate 27 have then
been elaborated further, offering a straightforward access to various types of cyclitols, aminocyclitols,
carbasugars, as well as the antibiotic palitantine 4. The complete functionalization of the original
arylsilanes 5 is thus typically achieved in fewer than eight steps with high stereoselectivities and
excellent overall yield.
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