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An asymmetric synthesis of HCV NS5B nucleoside polymerase inhibitor (1) is described. This novel route features several remarkably diastereoselective and high-yielding transformations, including construction of the all-carbon quaternary stereogenic center at C-2 via a thermodynamic aldol reaction. A subsequent glycosylation reaction with activated uracil via C-1 phosphate and installation of the cyclic phosphate group using an achiral phosphorus(III) reagent followed by oxidation provides 1.

Amides are among the most prevalent organic functional groups, especially as components of natural products and pharmaceuticals and as the backbone of peptides.[1,2] The most common means of preparing amides is the dehydrative coupling of amines with carboxylic acids, but the need to fully protect other functional groups and to employ excess amounts of coupling reagents renders it increasingly unattractive in comparison to a new generation of bond-forming reactions. Carbon–carbon bonds, for example, are now routinely prepared from prefunctionalized reagents, such as boronic acids, using operationally simple and catalytic conditions, which tolerate unprotected functional groups. Amide-forming reactions that meet these strict criteria have the potential to facilitate small-molecule drug discovery and enable chemo-selective bioconjugation reactions. Our group and others have therefore sought to identify mechanistically unique amide-forming reactions from precursors other than amines and carboxylic acids.[3–7]

Acylboranes are among the most elusive boron-containing organic functional groups, a fact that has impeded development of new reactions employing them as substrates. A new synthesis of acyltrifluoroborates from benzotriazole (Bt)-based N,O-acetals has been developed. Two other routes provide acyltrifluoroborates containing alcohols, aldehydes, and carbamates. The ketone-like reactivity of the acyltrifluoroborate functional group is demonstrated, and the first X-ray structure of an acyltrifluoroborate is reported.

Alkylidene Meldrum's acids are allylated in a conjugate fashion by allyltin nucleophiles under mild Sc(OTf)(3)-catalyzed conditions. The addition is functional group tolerant and reactions with nonracemic alkylidenes are highly diastereoselective. Allylation of alkylidenes derived from alpha-ketoesters yield all-carbon quaternary stereocenters.

The one-pot synthesis of tetrahydrofluorenones, the core 6-5-6 tricyclic structural motif found in norditerpenoid natural products, from alkylidene Meldrum's acids via thermal Diels-Alder/BF3.OEt2-catalyzed Friedel-Crafts acylation reactions is described. A series of tetrahydrofluorenones was assembled in good yields, and the Diels-Alder/Friedel-Crafts acylation protocol allowed modification of the substitution within the rings.

[reaction: see text] The Yb(OTf)3-catalyzed annulation reactions of phenols with 5-alkylidene Meldrum's acids enabled the synthesis of structurally diverse heterocycles in high isolated yields. A series of 4-substituted 3,4-dihydrocoumarins, 2,2-disubstituted 4-chromanones, coumarins, and 2-substituted chromones were readily and efficiently assembled, including the naturally occurring coumarins citropten, scoparone, and ayapin. Addition of phenols to biselectrophilic 5-alkylidene Meldrum's acids proceeded through two distinct multibond-forming modes: Friedel-Crafts C-alkylation/O-acylation and Friedel-Crafts C-acylation/O-alkylation. The regioselectivity of the catalytic annulation reaction was controlled by the degree of substitution on the alkylidene moiety.

Although many methods have been reported for the Knoevenagel condensation of aldehydes and Meldrum’s acid, most are not general or use unconventional reagents and conditions. We have found that alkylidene Meldrum’s acids form readily in benzene solution under mild pyrrolidinium acetate catalysis, and that this reaction is general, highly functional group compatible, and can be scaled-up easily.

Acyltrifluoroborates (I), (IV) are extremely reactive acyl donors in the amidation reaction with O-benzoyl hydroxylamines (II), (VI) and isoxazolidines, e.g. (VIII).

Alkylidene Meldrum’s acids are allylated in a conjugate fashion by allyltin nucleophiles under mild Sc(OTf)3-catalyzed conditions. The addition is functional group tolerant and reactions with nonracemic alkylidenes are highly diastereoselective. Allylation of alkylidenes derived from α-ketoesters yield all-carbon quaternary stereocenters.

Although many methods have been reported for the Knoevenagel condensation of aldehydes and Meldrum’s acid, most are not general or use unconventional reagents and conditions. We have found that alkylidene Meldrum’s acids form readily in benzene solution under mild pyrrolidinium acetate catalysis, and that this reaction is general, highly functional group compatible, and can be scaled-up easily.

The Yb(OTf)3-catalyzed annulation reactions of phenols with 5-alkylidene Meldrum's acids enabled the synthesis of structurally diverse heterocycles in high isolated yields. A series of 4-substituted 3,4-dihydrocoumarins, 2,2-disubstituted 4-chromanones, coumarins, and 2-substituted chromones were readily and efficiently assembled, including the naturally occurring coumarins citropten, scoparone, and ayapin. Addition of phenols to biselectrophilic 5-alkylidene Meldrum's acids proceeded through two distinct multibond-forming modes: Friedel−Crafts C-alkylation/O-acylation and Friedel−Crafts C-acylation/O-alkylation. The regioselectivity of the catalytic annulation reaction was controlled by the degree of substitution on the alkylidene moiety.