Chiral β-fluoroamines are increasingly prevalent in medicinal compounds, but there are few efficient methods to access them from achiral starting materials. To address this, a multicomponent organocascade reaction was developed in which chiral α-fluoro-β-amino aldehydes were generated in a single flask from achiral α,β-unsaturated aldehydes (2), using catalyst 12a. Conversions up to 85%, dr's up to 98:2, and ee's up to 99% of the corresponding alcohol (9) were achieved in this reaction.The incorporation of fluorine into medicinal compounds is increasingly prevalent with, "20-25% of drugs in the pharmaceutical pipeline contain [ing] at least one fluorine atom."1 MK-0731 (1 , Figure 1) is one example, developed by Merck for the treatment of Taxanerefractory cancer.2 More specifically, β-fluoroamines, as in 1, are increasingly common substructures in medicinal compounds, because fluorine can improve the bioavailability of amine drugs by decreasing the basicity of neighboring amine groups.1 Additionally, α-fluoro-β-amino acids are useful building blocks of therapeutic β-peptides.3 Despite the increasing use of β-fluoroamino moieties in medicinal compounds, efficient synthetic methods for their preparation are sparse. Recently, Pd-catalyzed olefin aminofluorination reactions were reported, in which achiral β-fluoroamines were generated in a single step.4 β-Fluoroamines containing a single stereocenter can be produced using a one-pot organocatalytic α-fluorination/reductive amination protocol.5 Accessing chiral β-fluoroamines with vicinal stereocenters (as in 1) usually requires the use of chiral starting materials. We are aware of only two efficient (i.e., one-pot) methods for preparing these compounds from achiral starting materials. One is an asymmetric olefin aminofluorination reaction, in which chiral β-fluoroamines are generated from achiral α,β-unsaturated esters.6 The asymmetric induction in this method is not catalytic; stoichiometric quantitites of a chiral amine nucleophile are used. In addition, an organocatalytic Mannich reaction using α-fluoro-β-dicarbonyl compounds as nucleophiles produced chiral β-fluoroamines in high yield and selectivity (dr ≥ 92:8).7 However, the dr decreased to 4:1 during subsequent decarboxylation to produce α-fluoro-β-amino acid derivatives.7b We supposed that an organocascade reaction (Scheme 1) would be a highly selective and green chemical method SBrenner@brooklyn.cuny.edu. Supporting Information Available General experimental conditions and full characterization data for compounds 2i, 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 9i and 13. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public Access Author ManuscriptOrg Lett. Author manuscript; available in PMC 2011 August 6. Iminium-catalyzed conjugate additions of amine nucleophiles to α,β-unsaturated aldehydes have been reported,8 as have enamine-catalyzed fluorinations of saturated aldehydes.9 It was anticipated that these two complementary functionalizations could be combined as an org...

We disclose a general method for selective ortho-C−H arylation of cyclic and N,N-dialkyl benzamides with boronic acids enabled by versatile ruthenium(II) complexes. This method features a general C−H arylation of ubiquitous aromatic tertiary benzamides by weak O-coordination. The transformation is characterized by its operational simplicity, the use of inexpensive, air-stable Ru(II) catalysts, scalability, and wide substrate scope. The reaction proceeds with high monoarylation selectivity to furnish valuable tertiary amide biaryls. Most crucially, the method provides the long-sought alternative to the classic directed-ortho-metalation (DoM) strategy, obviating the need for cryogenic conditions and strong lithium bases.

Products of a novel iminium-catalyzed oxa-Michael addition undergo a kinetic resolution by a subsequent enamine-catalyzed intermolecular reaction. This is a rare example of kinetic resolution by enamine catalysis, and the first organocascade kinetic resolution. This resolution produces enantioenriched 2,6-cis-tetrahydropyrans and, notably, cascade products with absolute and relative configurations normally not observed using this diphenyl prolinol silyl ether. This resolution thus provides new insight into asymmetric induction in reactions employing this catalyst.

A new cascade reaction involving an iminium-catalyzed intramolecular oxa-Michael addition followed by an enamine-catalyzed intermolecular Michael addition is reported herein. This cascade reaction generates enantiopure, highly functionalized tetrahydropyrans and tetrahydrofurans in a one-pot reaction and in up to 89 % combined yield and up to 99 % ee. This cascade reaction is catalyzed by diaryl prolinol silyl ethers, which are a privileged class of catalysts. The stereochemical outcome of these cascade reactions is unprecedented. Computational studies indicate that this stereochemical outcome arises from nonclassical hydrogen-bonding interactions between the electrophile and the substrate, and from entropic considerations of preorganization. The unprecedented configurations of the cascade products, combined with the computational models, reveal for the first time that asymmetric induction by diaryl prolinol silyl ether catalysts is not always exclusively reagent controlled. The stereochemical outcome also arises from a kinetic resolution or dynamic kinetic resolution of the β-stereocenter through an enamine-catalyzed intermolecular reaction. This unprecedented organocascade reaction mechanism may be adaptable to diaryl prolinol silyl ether-catalyzed cascade reactions, in which both the iminium- and enamine-catalyzed steps are intermolecular, an underdeveloped type of cascade reaction.