Synthesis of Functionalized Organosilicon Compounds/Distal Ketones via Ring-Opening Giese Addition of Cycloalkanols under Organophotocatalytic Conditions.

Visible-light-induced organophotocatalyzed ring-opening followed by remote Giese addition of tertiary cycloalkanols with ß-silylmethylene malonates has been developed under mild reaction conditions for the synthesis of organosilicon compounds, bearing a ketone group distally substituted with a silyl group with an additional dialkyl malonate functional handle in moderate to good yields (34-72%). The protocol also worked well with diverse Michael acceptors, such as alkylidene/benzylidene malonates, trifluoro methylidene malonate, benzylidene malononitrile, α-cyano-enone, and α-cyano vinyl sulfone, and delivered desired valuable distally functionalized ketones. To showcase the potential of the method, various synthetic transformations of the obtained product were also demonstrated.

Eosin-Y/Cu(OAc)2-catalyzed aerobic oxidative coupling reactions of glycine esters in the dark.

Catalytic aerobic oxidative coupling reactions of glycine esters with ß-keto acids, indoles, naphthols, and pyrrole have been realized at ambient temperature via the manipulation of the ground state reactivity of eosin-Y in the presence of Cu(OAc)2 in the dark. This method delivers structurally diverse unnatural amino acid derivatives under mild reaction conditions. UV-vis absorption spectroscopy, cyclic voltammetry, X-ray photoelectron spectroscopy, high-resolution mass spectrometry, and control experiments were performed to formulate a plausible mechanistic pathway. The step economy, broad substrate scope, use of air as a green oxidant, and operationally simple set-up make this protocol highly appealing for both academic and industrial applications.

Solvent-free synthesis of enantioenriched ß-silyl nitroalkanes under organocatalytic conditions.

An enantioselective 1,4-conjugate addition of nitromethane to ß-silyl α,ß-unsaturated carbonyl compounds catalyzed by bifunctional squaramide catalysts has been developed. This methodology offers both enantiomers of ß-silyl nitroalkanes in good to excellent yields (up to 92%) and enantioselectivities (up to 97.5% ee) under solvent-free conditions at room temperature. Control experiments reveal that the presence of a ß-silyl group in the enones is crucial for high reactivity under the optimized reaction conditions.

Ag(I)-Fesulphos-Catalyzed Enantioselective Synthesis of 3-Silylproline Derivatives.

An efficient catalytic asymmetric 1,3-dipolar cycloaddition of N-benzylidineiminoglycinate-derived azomethine ylides to ß-silylmethylene malonates catalyzed by a Ag(I)-Fesulphos complex has been developed, affording fully substituted 3-silylproline derivatives with an all carbon quaternary center. The silylproline derivatives were obtained in moderate-to-good yields (up to 81%) in high diastereoselectivities and enantioselectivities (dr up to 95:5; er up to 96:4). Tamao-Fleming oxidation of selected 3-silylproline derivatives provided not only an efficient route but also the shortest route to 3-hydroxyproline derivatives, which are not accessible by direct 1,3-dipolar cycloadditions of azomethine ylide with frequently used arylidene/alkylidene malonates.

Organocatalytic decarboxylative aldol reaction of ß-ketoacids with α-ketophosphonates en route to the enantioselective synthesis of tertiary α-hydroxyphosphonates.

The first example of an asymmetric organocatalyzed decarboxylative aldol reaction of ß-ketoacids (aroylacetic acids) with α-ketophosphonates that produces a quaternary chiral centre has been developed. A quinidine based bifunctional urea derivative was identified as the preferred catalyst affording γ-aroyl tertiary α-hydroxyphosphonates in good yield and enantioselectivity. The 31P NMR spectroscopic study was performed to shed light on the reaction mechanism.

Organocatalyzed enantioselective Michael addition/cyclization cascade reaction of 3-isothiocyanato oxindoles with arylidene malonates.

An organocatalyzed Michael addition-cyclization reaction between 3-isothiocyanatooxindoles and arylidene malonates has been developed for the synthesis of highly functionalized 3,2'-pyrrolidinyl spirooxindole derivatives. The reaction was catalyzed by a quinine derived tertiary amino-thiourea based bifunctional catalyst or its pseudo-enantiomeric quinidine derived catalyst providing both the enantiomers of the desired product. The products were obtained in high yields and with excellent diastereo- (up to 99 : 1 dr) and enantioselectivities (up to >99% ee).

"On Water" Organocatalyzed [4 + 2] Cycloaddition of Enones and Nitro Dienes for the Enantioselective Synthesis of Densely Substituted Cyclohexanones.

An "on water" hydroquinine-based primary amine-benzoic acid organocatalyst system was found to be best suited to produce 3,4,5-trisubstituted cyclohexanones with a nitro group in the 4-position from enones and nitro dienes under ambient conditions in good yield, with good diastereoselectivity, and with excellent enantioselectivity. An appreciable rate enhancement by water was observed compared to organic solvents. Mechanistic analysis of the reaction suggests that it followed an endo [4 + 2] cycloaddition with enamine of enone as diene and nitro diene as dienophile.

Towards an asymmetric organocatalytic α-cyanation of ß-ketoesters.

This communication describes the first proof of concept for an asymmetric α-cyanation of ß-ketoesters using a hypervalent iodine-based electrophilic cyanide-transfer reagent. A series of different organocatalysts has been investigated and it was found that the use of naturally occurring Cinchona alkaloids allows obtaining the target products in good yields and with moderate enantioselectivities up to er = 76:24 under operationally simple conditions.

A facile synthesis of 5,5-dideutero-4-dimethyl(phenyl)silyl-6-undecyl-tetrahydropyran-2-one as a deuterium labeled synthon for (-)-tetrahydrolipstatin and (+)-δ-hexadecanolide.

Deuterium-labeled biologically active compounds are gaining importance because they can be utilized as tracers or surrogate compounds to understand the mechanism of action, absorption, distribution, metabolism, and excretion. Deuterated drug molecules (heavy drugs) become novel as well as popular because of better stability and bioavailability compared with their hydrogen analogs. Labeling of organic molecules with deuterium at specific positions is thus gaining popularity. In this work, we have exploited a highly regioselective and enantioselective direct Michael addition of methyl-d3 alkyl ketones to dimethyl(phenyl)silylmethylene malonate that was catalyzed by (S)-N-(2-pyrrolidinylmethyl)pyrrolidine/trifluoroacetic acid/ D2 O combination with high yield and isotopic purity. The 5,5-dideutero-4-dimethyl(phenyl)silyl-6-undecyl-tetrahydropyran-2-one was obtained from the adduct of methyl-d3 undecanyl ketone and dimethyl(phenyl)silylmethylene malonate by a silicon controlled diastereoselective ketone reduction, lactonization, and deethoxycarbonylation. The dideuterated silylated tetrahydropyran-2-one is the precursor for geminal (2) H2 -labeled (+)-4-hydroxy-6-undecyl-tetrahydropyran-2-one, an advanced intermediate for gem-dideutero (-)-tetrahydrolipstatin and (+)-δ-hexadecanolide syntheses.

Highly regio- and enantioselective organocatalytic conjugate addition of alkyl methyl ketones to a beta-silylmethylene malonate.

(S)-N-(2-pyrrolidinylmethyl)pyrrolidine/trifluoroacetic acid (3:1) combination catalyzed the direct addition of alkyl methyl ketones to beta-dimethyl(phenyl)silylmethylene malonate at the methyl terminal with high yield and excellent regio- and enantioselectivity. The silyl group played crucial roles in regioselection and substrate reactivity.