Silvia Vera

Organocatalytic C–H Bond Arylation of Aldehydes to Bis-heteroaryl Ketones

An organocatalytic aldehyde C-H bond arylation process for the synthesis of complex heteroaryl ketones has been developed. By exploiting the inherent electrophilicity of diaryliodonium salts, we have found that a commercial N-heterocyclic carbene catalyst promotes the union of heteroaryl aldehydes and these heteroaromatic electrophile equivalents in good yields. This straightforward catalytic protocol offers access to ketones bearing a diverse array of arene and heteroarene substituents that can subsequently be converted into molecules displaying structural motifs commonly found in medicinal agents.

Highly Enantioselective Conjugate Additions of Aldehydes to Vinyl Sulfones

Joined together, organocatalysts aldehydes and sulfones: A diaryl prolinol silyl ether was found to catalyse efficiently and enantioselectively the conjugate addition of aldehydes to vinyl sulfones (see scheme). The ample synthetic utility of the resulting adducts is illustrated.

Catalytic Conjugate Additions of Geminal Bis(sulfone)s: Expanding the Chemistry of Sulfones as Simple Alkyl Anion Equivalents

The value of cyclic gem-bis(sulfone) 4 as a simple alkyl nucleophile equivalent in catalytic C-C bond-forming reactions is demonstrated. The 1,4-type nucleophilic additions of bis(sulfone) 4 to alpha,beta-unsaturated ketones take place by assistance of catalytic guanidine base. On the other hand, pyrrolidines are able to catalyze the conjugate addition of 4 to both enones and enals, likely by means of iminium ion activation. Upon exploration of the best chiral pyrrolidine catalyst, it has been found that the addition of 4 to enals catalyzed by diphenylprolinol silyl ether 10 proceeds with very high enantioselectivity (beta-aryl-substituted enals >95% ee; beta-alkyl substituted enals up to 94% ee; ee = enantiomeric excess). Further reductive desulfonation of adducts gives rise to the corresponding beta-methyl aldehydes, as well as the derived alcohols, acetals, and methyl esters after simple (Mg, MeOH) well-established protocols. Application of the procedure to the synthesis of biologically relevant phenethyl building blocks is shown. Most interestingly, alpha-alkylation of initially obtained bis(sulfone) adducts can be done even with less reactive alkylating reagents, such as long linear-chain or branched-chain alkyl halides. Accordingly, upon the desulfonation process, a general, experimentally simple and highly enantioselective access to beta-branched aldehydes, alcohols, or esters is possible. Further exploration of the method includes the use of chiral alpha,beta-unsaturated aldehydes derived from citronellal as the Michael acceptor partners. In these instances, the sense of the conjugate addition of 4 is controlled by the chirality of the pyrrolidine catalyst, thus allowing for a stereochemically predictable access to 1,3-dimethyl arrays, such as those present in deoxygenated polyketide-type natural products. The intramolecular variation of this technology by using doubly unsaturated aldehyde-ester 22 illustrated the site selectivity of the procedure and its potential for tandem processes leading to highly substituted polycyclic systems, such as 24.

Combined α,α-dialkylprolinol ether/Brønsted acid promotes Mannich reactions of aldehydes with unactivated imines. An entry to anti-configured propargylic amino alcohols

The first enamine mediated anti-selective and highly enantioselective Mannich reaction of aldehydes and unactivated imines is reported. The key for success is the combined use of a Bronsted acid with an α,α-dialkylprolinol ether catalyst that leads to adducts with good yields (typically 70–75%), anti : syn ratios greater than 90 : 10, and ee values usually above 95%. The method works particularly well with propargylic imines and, unlike previous catalytic routes to optically active propargylamines, provides adducts featuring two contiguous stereocenters and a functionalized side chain amenable for ulterior synthetic applications.

Asymmetric synthesis of propargylic alcohols via aldol reaction of aldehydes with ynals promoted by prolinol ether–transition metal–Brønsted acid cooperative catalysis

A catalytic and highly stereoselective entry to propargylic alcohols and products derived thereof is reported based on an unprecedented cross-aldol coupling between unmodified aldehydes and ynals. The method requires an amine–metal salt–Bronsted acid ternary catalyst system and implies synergistic activation of the donor aldehyde via enamine and of the acceptor carbonyl via unique and reversible metal–alkyne complexation. Specifically, by using a combined a,a-dialkylprolinol silyl ether–CuI–PhCO2H catalyst system, remarkably high levels of diastereo- and enantioselectivity (anti/syn up to >20 : 1, ee up to >99%) are achieved.

Frontispiece: β2, 2-Amino Acid N-Carboxyanhydrides Relying on Sequential Enantioselective C(4)-Functionalization of Pyrrolidin-2,3-diones and Regioselective Baeyer–Villiger Oxidation

A catalytic enantioselective entry to β2, 2 -amino acids enabling their direct coupling with nucleophiles is described. The approach is based upon an effective bifunctional Brønsted base catalyzed construction of a quaternary carbon stereocenter at C4 position of pyrrolidin-2,3-diones. Subsequent regioselective Baeyer-Villiger oxidation of the resultant adducts gives β2, 2 -amino acid N-carboxyanhydrides as the reactive species, which can further react with nucleophiles. Following this strategy both, β2, 2 -amino acid derivatives with different functionalities at the newly created stereocenter, and spirocyclic structures can be efficiently prepared.

Asymmetric Assembly of All-Carbon Tertiary/Quaternary Nonadjacent Stereocenters through Organocatalytic Conjugate Addition of α-Cyanoacetates to a Methacrylate Equivalent

An efficient, highly diastereo- and enantioselective assembly of acyclic carbonyl fragments possessing nonadjacent all-carbon tertiary/quaternary stereoarrays is reported based on a Brønsted base catalyzed Michael addition/α-protonation sequence involving α-cyanoacetates and 2,4-dimethyl-4-hydroxypenten-3-one as novel methacrylate equivalent.

Controlling the α/γ-Reactivity of Vinylogous Ketone Enolates in Organocatalytic Enantioselective Michael Reactions

The first regio-, diastereo-, and enantioselective direct Michael reaction of β,γ-unsaturated ketones with nitroolefins is enabled by Brønsted base/hydrogen-bonding bifunctional catalysis. A squaramide-substituted tertiary amine catalyzes the reaction of a broad range of β,γ-unsaturated ketones to proceed at the α-site exclusively, giving rise to adducts with two consecutive tertiary carbon stereocenters in diastereomeric ratios of up to >20:1 and enantioselectivities generally in the 90-98 % ee range.

Development of a syn-Selective Mannich Reaction of Aldehydes with Propargylic Imines by Dual Catalysis: Asymmetric Synthesis of Functionalized Propargylic Amines.

Direct coupling of enolizable aldehydes with C-alkynyl imines is realized affording the corresponding propargylic Mannich adducts of syn configuration, thus complementing previous methods that gave access to the anti-isomers. The combination of proline and a urea Brønsted base cocatalyst is key for the reactions to proceed under very mild conditions (3-10 mol % catalyst loading, dichloromethane as solvent, -20 °C, 1.2 molar equivalents of aldehyde) and with virtually total stereocontrol (syn/anti ratio up to 99:1; ee up to 99 %). Some possibilities of further chemical elaboration of adducts are also briefly illustrated.

Catalytic Asymmetric Synthesis of Quaternary Barbituric Acids

The catalytic asymmetric α-functionalization of prochiral barbituric acids, a subtype of pseudosymmetric 1,3-diamides, to yield the corresponding 5,5-disubstituted (quaternary) derivatives remains essentially unsolved. In this study 2-alkylthio-4,6-dioxopirimidines are designed as key 1,3-diamide surrogates that perform exceedingly in amine-squaramide catalyzed C-C bond forming reactions with vinyl ketones or Morita-Baylis-Hillmann-type allyl bromides as electrophiles. Mild acid hydrolysis of adducts affords barbituric acid derivatives with an in-ring quaternary carbon in unprecedented enantioselectivity, offering valuable materials for biological evaluations.