Pavel Kočovský

C-Nucleosides: Synthetic Strategies and Biological Applications

While natural and synthetic N-nucleosides are vulnerable to enzymatic and acid-catalyzed hydrolysis of the nucleosidic bond, their C-analogues are much more stable. Several C-nucleosides are naturally occurring compounds, e.g., pseudouridine (isolated from the yeast t-RNA) and showdomycin (an antibiotic). Development of novel synthetic methodologies allowed the preparation of a large variety of synthetic analogues, which found numerous applications in medicinal chemistry and chemical biology. Most important biologically active C-nucleosides are the inhibitors of purine nucleosides phosphorylase or IMP dehydrogenase. A number of artificial aryl-C-nucleosides capable of π-stacking are being vigorously investigated as building blocks in chemical biology. In the past few years, several Artificial Expanded Genetic Information Systems (AEGIS)1 have been successfully developed as prime examples of synthetic biology, a newly emerging interdisciplinary area, with the ultimate goal to design systems where high-level behaviors of the living matter are mimicked by artificial chemical systems.2,3

Carbamates : A method of synthesis and some syntehtic applications

Abstract Alcohols are converted into unsubstituted carbamates by treatment with trichloroacetyl isocyanate followed by hydrolysis on Al 2 O 3 . This extremely mild procedure tolerates various labile functional groups. The synthetic utility of the carbamate moiety as a control element is demonstrated on epoxidation and epoxide opening.

Asymmetric reduction of imines with trichlorosilane, catalyzed by sigamide, an amino acid-derived formamide: scope and limitations

Enantioselective reduction of ketimines 6-10 with trichlorosilane can be catalyzed by the N-methyl valine-derived Lewis-basic formamide (S)-23 (Sigamide) with high enantioselectivity (< or = 97% ee) and low catalyst loading (1-5 mol %) at room temperature in toluene. The reaction is efficient with ketimines derived from aromatic amines (aniline and anisidine) and aromatic, heteroaromatic, conjugated, and even nonaromatic ketones 1-5, in which the steric difference between the alkyl groups R(1) and R(2) is sufficient. Simple nitrogen heteroaromatics (8a,b,d) exhibit low enantioselectivities due to the competing coordination of the reagent but increased steric hindrance in the vicinity of the nitrogen (8c,e) results in a considerable improvement. Cyclic imines 32d-d exhibited low to modest enantioselectivities.

Dynamic Kinetic Resolution in the Asymmetric Synthesis of β‐Amino Acids by Organocatalytic Reduction of Enamines with Trichlorosilane

A new methodology based on the organocatalytic asymmetric hydrosilylation of enamines that allows a direct access to a range of β and β -amino acid derivatives was presented. The results show a successful reduction of aromatic substrates, a sterically more hindered ortho-substituted derivatives, and the thiophenyl analogue exhibiting lower reactivity. Fast enamine-imine equilibration is crucial as imines are chiral but racemic, while α-alkyl β-amino acids can be accessed by the symmetrical Mannich reaction. The α-alkyl derivatives have relative and absolute configuration due to their reduction with LiAlH into a known amino alcohols. Predominant formation of the anti isomer in 3o is consistent with conformation of the imine intermediate in the catalytic reduction.

Enantioselective Baeyer-Villiger oxidation catalyzed by palladium(II) complexes with chiral P,N-ligands.

Asymmetric Baeyer-Villiger reaction of symmetrical cyclobutanones 1a-j with urea-hydrogen peroxide (UHP) can be catalyzed by a complex of Pd(II) and the new terpene-derived P, N-ligand 7. The resulting lactones 2a-j were obtained in high yields and with good enantioselectivity (< or =81% ee).

Asymmetric allylation of aldehydes with allyltrichlorosilane promoted by chiral sulfoxides

Allylation of aldehydes with allyltrichlorosilane in the presence of sulfoxides is reported. The use of excess of (R)-methyl-p-tolylsulfoxide resulted in the formation of the corresponding homoallylic alcohols in good yields and moderate enantiomeric excesses.

Allylic alcohols as substrates for the palladium(0)-catalyzed allylic substitution

Abstract A new method has been developed which allows palladium(0)-catalyzed allylic substitution to occur between allylic alcohols and anionic C-nucleophiles:

New pyridine-derived N-oxides as chiral organocatalysts in asymmetric allylation of aldehydes

Abstract New chiral pyridine-type N -oxides 5a – e have been synthesized from (+)-α-pinene (+)- 6 in four steps including photochemical oxidation, followed by Krohnke annulation, α-alkylation, and N -oxidation. The methoxy derivative (+)- 5d exhibited the highest enantioselectivity as a catalyst in the title reaction, producing ( S )-(–)- 3 of 68% e.e.

Stereochemistry of the palladium-catalyzed allylic substitution: the syn-anti dichotomy in the formation of (π-allyl)palladium complexes and their equilibration☆

Abstract The mechanism of palladium(0)-catalyzed allylic substitution has been investigated with the aim of finding whether or not the intermediate (π-allyl)palladium complexes can arise in a syn fashion as an alternative to the well known anti-mechanism. Using (diphenylphosphino)acetate as a leaving group and stereochemically biased substrates 30b and 35b evidence for the syn stereochemistry has been acquired (30b → 31 and 35b → 36). This reversal of stereochemistry is facilitated by severe steric congestion in the starting allylic esters (which impairs the ordinary anti-mechanism) and is boosted by the pre-coordination of the Pd(0) reagent to the leaving group. The latter effect apparently lowers the activation entropy. With cyclohexene derivatives 10b, 18b, and 19b and acyclic substrate 25b, where steric hindrance does not operate, the anti-mechanism producing η3-complexes dominates even for (diphenylphosphino)acetates. At elevated temperature, rapid equilibration of η3-complexes (13 ⇄ 14 and 20 ⇄ 21) has been observed prior to the reaction with a nucleophile. This effect has been attributed to the presence of (diphenylphosphino)acetate ion acting as a ligand for palladium.

Asymmetric molybdenum(0)-catalyzed allylic substitution

Abstract Application of new ligands ( R )-(−)- 8 , ( S )-(+)- 16 , and ( S )-(+)- 17 to the title reaction ( 1 or 2 → 3 ) led to excellent regio- and enantioselectivities (>30:1; ≤98% ee); although lacking the C 2 -symmetry, the catalysts can be viewed as quasi - C 2 -symmetrical since the single chiral center is sufficient to determine the sense of wrapping of the metal by the ligand.