Reformatsky Reaction to Alkynyl N- tert-Butanesulfinyl Imines: Lewis Acid Controlled Stereodivergent Synthesis of β-Alkynyl-β-Amino Acids.

A highly diastereoselective Refortmatsky reaction to N- tert-butanesulfinyl propargylaldimines and ketimines is presented. The reaction proceeded with excellent yields and diastereoselectivities provided by the sulfinyl group in the presence of MeAl. The use of TBSOTf as a Lewis acid promoter switched the sense of the stereoinduction.

"Anti-Michael addition" of Grignard reagents to sulfonylacetylenes: synthesis of alkynes.

In this work, the addition of Grignard reagents to arylsulfonylacetylenes, which undergoes an "anti-Michael addition", resulting in their alkynylation under very mild conditions is described. The simplicity of the experimental procedure and the functional group tolerance are the main features of this methodology. This is an important advantage over the use of organolithium at -78 °C that we previously reported.

Expanding the Potential of Heteroaryl Vinyl Sulfones.

The easily available vinyl sulfone 3 showed great potential for new applications in several fields such as organic synthesis and bioconjugate formation. This was demonstrated by performing a systematic assessment of its reactivity in Michael, radical, and cycloaddition reactions. Heteroaryl vinyl sulfone 3 presented excellent output in terms of reactivity and selectivity, proving superior to phenyl vinyl sulfone 1 and with clear advantages over bis-sulfone 2.

Mono- and Bimetallic Alkynyl Metallocenes and Half-Sandwich Complexes: A Simple and Versatile Synthetic Approach.

A general process for the synthesis of alkynyl mono and dimetallic metallocenes and half-sandwich complexes has been developed. This approach uses the addition of lithium derivatives of sandwich or half-sandwich complexes to arylsulfonylacetylenes. The reaction occurs in two steps (lithiation and anti-Michael addition to alkynylsulfone followed by elimination of the ArSO moiety) to form the corresponding mono- or bimetallic alkynes in clearly higher yields, simpler experimental procedures, and more environmentally benign conditions than those of the so far reported for the synthesis of this type of products.

Sustainable Synthesis of Oximes, Hydrazones, and Thiosemicarbazones under Mild Organocatalyzed Reaction Conditions.

Pyrrolidine catalyzes very efficiently, presumably via iminium activation, the formation of acyloximes, acylhydrazones, and thiosemicarbazones derived from aromatic and aliphatic aldehydes using equimolar amounts of reagents and green solvents. Experimental simplicity and excellent yields after a simple filtration are the main advantages of the method, being an alternative to those currently available especially for the acyl derivatives, which do not work under uncatalyzed conditions. Its application to the synthesis of acyloximes by direct condensation between aldehydes and acylhydroxylamines is unprecedented.

A straightforward alkynylation of Li and Mg metalated heterocycles with sulfonylacetylenes.

Coupling of alkynyl moieties to heterocyclic rings, without using transition metals, can be easily performed by the reaction of aryl or heteroaryl sulfonylacetylenes with heteroaryl-Li compounds or their corresponding less reactive magnesium derivatives.

Copper-catalyzed diastereo- and enantioselective desymmetrization of cyclopropenes: synthesis of cyclopropylboronates.

A novel Cu-catalyzed diastereo- and enantioselective desymmetrization of cyclopropenes to afford nonracemic cyclopropylboronates is described. Trapping the cyclopropylcopper intermediate with electrophilic amines allows for the synthesis of cyclopropylaminoboronic esters and demonstrates the potential of the approach for the synthesis of functionalized cyclopropanes.

Asymmetric nucleophilic monofluorobenzylation of allyl and propargyl halides mediated by a remote sulfinyl group: synthesis of homoallylic and homopropargylic fluorides.

Fluorinated 2-(p-tolylsulfinyl)benzyl carbanions react with allyl and propargyl halides in a highly stereoselective way, providing homoallylic and homopropargylic fluorides, respectively, with high optical purity. Theoretical calculations found transition states for these transformations whose relative stabilities are consistent with the experimentally observed stereoselectivity.

Stereochemical aspects and the synthetic scope of the S(H)i at the sulfur atom. Preparation of enantiopure 3-substituted 2,3-dihydro-1,2-benzoisothiazole 1-oxides and 1,1-dioxides.

Intramolecular homolytic substitution (SHi) on the sulfur atom at acyclic N-(o-bromobenzyl)sulfinamides takes place with a complete inversion of the configuration and provides an excellent tool to connect N-tert-butanesulfinylimines with enantiopure 3-substituted benzo-fused sulfinamides (1,2-benzoisothiazoline 1-oxides) and the related pharmacologically relevant sulfonamides.

A general aminocatalytic method for the synthesis of aldimines.

A general and efficient biomimetic method for the synthesis of aldimines from aldehydes and compounds bearing the NH2 group in the presence of pyrrolidine as a catalyst has been developed. These organocatalytic reactions, based on the application of the concept of nucleophilic catalysis, proceed with outstanding yields in the absence of acids and metals under simple conditions and minimum experimental manipulation. The method has been mainly applied to the synthesis of N-sulfinyl and N-sulfonyl imines, but its general validity has been proven with the preparation of representative N-phosphinoyl, N-alkyl, and N-aryl imines.

Organocatalytic Michael addition/intramolecular Julia-Kocienski olefination for the preparation of nitrocyclohexenes.

An asymmetric organocatalytic [3 + 3] annulation strategy based on a Michael addition/intramolecular Julia-Kocienski olefination sequence has been developed for the synthesis of 4-substituted-5-nitrocyclohex-1-ene compounds. The strategy is an alternative to the direct reluctant enantioselective Diels-Alder approach. The potential of the methodology has been demonstrated with a concise enantioselective formal synthesis of trandolapril.

Intermolecular alkyl radical additions to enantiopure N-tert-butanesulfinyl aldimines.

The sulfinyl group in (R)-N-tert-butanesulfinyl aldimines provides efficient control of the stereoselectivity in the intermolecular reactions with alkyl radicals. The methodology is applicable to aryl, heteroaryl, benzyl, and alkynyl imines, even those containing CN, CO2Me, COR, and OH groups. The best results are attained with hindered radicals (tertiary and secondary ones) without C═N bond reduction.

Use of lithiated chiral o-sulfinylbenzyl carbanions for the one-pot building of linear fragments containing up to four connected stereocenters.

The reaction of o-sulfinylbenzyl carbanions with prochiral Michael acceptors, such as differently sized cycloalkenones, proceeded with high levels of stereoselectivity, generating molecules containing up to three asymmetric carbon centers in just one synthetic step. All these reactions involved the use of either a proton or an acylating reagent as the final electrophile. Furthermore, the trapping of the enolate resulting from Michael addition with prochiral electrophiles, such as aldehydes or N-sulfonylimines, allowed the highly stereoselective synthesis of densely functionalized compounds containing four chiral centers in just a one-pot sequence, the stereochemical outcome of the sequence being controlled by the sulfinyl auxiliary.

Copper(I)-catalyzed formal carboboration of alkynes: synthesis of tri- and tetrasubstituted vinylboronates.

The first copper-catalyzed formal carboboration of alkynes, in which a C-B bond and a C-C bond are created in a single catalytic cycle, is presented. The reaction proceeds with high regioselectivity and syn-stereoselectivity to form tri- and tetrasubstituted vinylboronic esters from commercially available bis(pinacolato)diboron. A subsequent cross-coupling reaction gives access to highly substituted alkenes.

Enantioselective aza-Henry reactions of cyclic α-carbonyl ketimines under bifunctional catalysis.

The aza-Henry reaction of nitroalkanes with the C=N group of 2-aryl-3H-indol-3-ones catalyzed by thiourea-chincona derivatives takes place with good yield and high ee's.

Asymmetric intramolecular Pauson-Khand reaction mediated by a remote sulfenyl or sulfinyl group.

In this work, we report the use of the asymmetric intramolecular Pauson-Khand reactions of 4-aryl-4-cyano-1,6-enynes for obtaining enantiomerically enriched bicyclo[3.3.0]octenones, and the influence of both the quaternary stereocenter and the sulfur functions located at ortho-position of the aryl group, on their stereoselectivity and reactivity.

Expanding the scope of arylsulfonylacetylenes as alkynylating reagents and mechanistic insights in the formation of Csp2-Csp and Csp3-Csp bonds from organolithiums.

We describe the unexpected behavior of the arylsulfonylacetylenes, which suffer an "anti-Michael" addition of organolithiums producing their alkynylation under very mild conditions. The broad scope, excellent yields, and simplicity of the experimental procedure are the main features of this methodology. A rational explanation of all these results can be achieved by theoretical calculations, which suggest that the association of the organolithiums to the electrophile is a previous step of their intramolecular attack and is responsible for the unexpected "anti-Michael" reactions observed for substituted sulfonylacetylenes.

Role of quaternary ammonium salts as new additives in the enantioselective organocatalytic β-benzylation of enals.

We report herein the efficiency of quaternary ammonium salts as co-catalysts in organocatalytic Michael reactions involving iminium activation of α,β-unsaturated aldehydes. The enantioselective formal benzylation of these substrates has been optimized and used to rationalize the role of the ammonium salts in these processes.

Asymmetric nucleophilic monofluorobenzylation of carbonyl compounds: synthesis of enantiopure vic-fluorohydrins and α-fluorobenzylketones.

Asymmetric nucleophilic monofluoroalkylation of a broad range of aldehydes with an α-fluoro-γ-sulfinylbenzyl carbanion takes place with complete control of the facial selectivity at the carbanion and good to high anti-diastereoselectivity to give easily separable mixtures of two optically pure 1,2-fluorohydrin derivatives (up to 24:1 anti/syn). Separation and removal of the p-tolylsulfinyl group with tBuLi provides enantiomerically pure anti-1,2-disubstituted-1,2-fluorohydrins, whereas α-fluorobenzylketones can be obtained by desulfinylation of the mixture followed by pyridinium chlorochromate oxidation (one-pot process).

Stereocontrolled fluorobenzylation of vinyl sulfones and α,β-unsaturated esters mediated by a remote sulfinyl group. Synthesis of functionalized enantiomerically pure benzylic fluorides.

A sulfinyl group in an ortho position confers enough chemical and configurational stability to monofluorobenzylcarbanions to evolve in a completely stereoselective way in their reactions with β-substituted vinyl sulfones and α,β-unsaturated esters. Reactions afford easily separable mixtures of two epimers differing in the configuration of the center derived from the Michael acceptor (up to 98% de). They can be easily converted into enantiomerically pure γ-fluorinated γ-phenylsulfones and γ-phenylesters bearing two chiral centers.

Synthesis of enantiomerically pure anti-1,2-diaryl and syn-1,2-alkylaryl vic-selenoamines.

Phenylselenyl benzylcarbanion stabilized by an (S)-2-p-tolylsulfinyl group evolves in a highly stereoselective way in the reactions with (S)-N-(p-tolylsulfinyl)imines at -98 °C affording diastereomerically pure 1,2-selenoamino derivatives in good yields. The syn or anti relationship of the obtained compounds depends on the alkyl or aryl character of the imine. They are easily transformed into enantiomerically pure (1R,2S)-1-aryl[or (1S,2S)-1-alkyl]-2-(phenylseleno)-2-phenylethylamines by reaction with t-BuLi and subsequent methanolysis of the generated sulfinamide derivatives with TFA.

An organocatalytic approach to enantiomerically enriched α-arylcyclohexenones and cyclohexanones.

The presence of a p-nitrophenyl group converts acetone into an excellent and versatile nucleophile in organocatalytic processes, able to react with α,β-unsaturated aldehydes affording β-substituted α-arylcyclohexenones via a Michael reaction/aldol reaction/dehydration sequence, which occurs in good yields, ee up to 96% and complete diastereoselectivity. The resulting compounds are excellent synthons for the diastereoselective preparation of a variety of synthetically useful polysubstituted cyclohexanones and derivatives.

Synthesis of optically pure vic-sulfanyl amines mediated by a remote sulfinyl group.

Enantiomerically pure syn-1,2-diaryl-1,2-sulfanylamine derivatives can be obtained in a completely stereoselective manner by reaction of the benzylcarbanion Li-(S)-1 with N-phenyl (or PMP)-arylidene aldimines and further desulfinylation with t-BuLi. Theoretical studies at the DFT (mPW1PW91) level with the CPCM model, by using the Gaussian09 program, provide a good explanation for the stereochemical results.

Asymmetric synthesis of α-alkyl α-selenocarbonyl compounds catalyzed by bifunctional organocatalysts.

A new organocatalytic approach for the synthesis of a variety of α-alkyl, α-phenylselenyl ketones as well as their corresponding esters and amides, by the addition of α-selenocarbonyl derivatives to nitroalkenes catalyzed by thiourea or squaramide cinchona catalysts, is presented. This catalytic system allows the preparation in high yields of enantiomerically enriched selenocarbonyl derivatives bearing two chiral centers with excellent ee's and dr's by using catalytic loadings of 3 mol%.