Efficient and highly diastereoselective preparation of a myrtenal derived bis-sulfoxide and its preliminary evaluation as chiral acyl donor

Treatment of disulfide 7 with NaIO₄ in EtOH at rt gave monosulfoxide 8 (95%), while at 50 °C it gave trans-bis-sulfoxide 6a (84%, >99% de). In contrast, treatment of 7 with MCPBA gave bis-sulfone 9 (95%). The anion of 6a reacted with benzaldehyde affording carbinol 10 (76%, >99% de). The absolute configuration of 8, 6a, and 10 was established by single crystal X-ray diffraction analyses.     

A simple metal free highly diastereoselective synthesis of heteroaryl substituted (±) cyclohexanols by a branched domino reaction

A self diastereoselective, simple metal free and efficient branch domino reaction gave multiple heteroaryl substituted (±) cyclohexanols with five chiral centres in >95% yields. The reactions that occur are Claisen Schmidt condensation followed by Michael addition and Aldol reactions of heteroaryl carbaldehydes and acetyl pyridine derivatives. Mechanistic study of the reactions shows excellent self diastereoselectivity (dr > 99%) in the intermediate steps which results selectively in the formation of one set of enantiomers out of sixteen possible enantiomeric pairs. The self diastereoselectivity of reaction in all the steps dominates due to the steric hindrance induced by the bulky heteroaryl groups. The stereochemistry of the synthesized compounds is established using single crystal XRD.     

A concise and efficient route to the Alzheimer's therapeutic agent (R)-arundic acid

A short and efficient procedure for the preparation of (R)-arundic acid, a therapeutic agent for the treatment of Alzheimer's disease, has been developed. Based on cheap and commercially available (1R)-(+)-camphor as the source of chiral information, (R)-arundic acid is synthesized in a four-step cyclic sequence with 55% overall yield and high optical purity, ≥98% ee. Alkyl halide and acetylene constitute the only consumable carbon sources of this method, which allows obtaining of both enantiomers and recycling of chiral auxiliary.     

Enantioselective silicon-boron additions to cyclic 1,3-dienes catalyzed by the platinum group metal complexes

Silaborations of 1,3-cyclohexadiene and 1,3-cycloheptadiene were achieved using catalysts prepared from different combinations of phosphorus ligands and group 10 metal compounds. For the six-membered compound, 1,4-adducts with up to 82% ee were obtained employing Pt(0) and phosphoramidite ligands. For the seven-membered diene optimal conditions were found using catalysts based on Ni(0), but the highest selectivity observed was merely 22% ee. No improvement of the chiral induction was obtained using chiral silylboranes in combination with chiral phosphoramidite ligands in the additions to 1,3-cyclohexadiene. The adduct obtained from cyclohexadiene was used in allylborations of aldehydes under microwave irradiation to produce homoallylic alcohols with moderate to good diastereoselectivity.     

Cyclopalladation of enantiopure oxazolines having the prochiral CMe2 moiety at position 2 of the heterocycle

(R)-4-Ethyl-2-(1,1-dimethylpropyl)-2-oxazoline (1) and (S)-4-tert-butyl-2-(1,1-dimethylbutyl)-2-oxazoline (2) were synthesized in two steps from the corresponding enantiopure amino alcohols and acid chlorides in a total yield of 95% and 72%, respectively. (S)-2-(1-Adamantyl-1-methylethyl)-4-isobutyl-2-oxazoline (3) was obtained from adamantyl bromide and l-leucinol in five steps in a total yield of 82%. Reactions of oxazolines 1–3 with Pd(OAc)₂ in AcOH or CH₂Cl₂ followed by treatment with LiCl afforded the corresponding μ-Cl dimeric cyclopalladated complexes 15, 17, and 20 in good yield. Compounds 15, 17, and 20 reacted with PPh₃ to furnish the corresponding mononuclear complexes 16, 19, and 21. The ³¹P NMR spectra of trans(N,P) adducts 16, 19, and 21 contained signals of two diastereomers in a ratio of ca. 1.3:1.     

Application of the addition of triorganozincates to N-(tert-butanesulfinyl)imines to the enantioselective synthesis of α-amino acids

Highly enantiomerically enriched N-protected α-amino acids can be easily prepared from optically pure N-(tert-butanesulfinyl)imines by a four-step sequence involving: diastereoselective addition of a triorganozincate to the imine, removal of the sulfinyl group, benzoylation of the nitrogen atom of the obtained primary amine and oxidation of one of the substituents on the carbon atom α to the nitrogen. Using the same configuration in the sulfinyl chiral auxiliary, amino acids with the (R) or the (S) configuration can be prepared by choosing the proper combination of imine and organozincate. α,α-Disubstituted α-amino esters with high optical purity can also be prepared by the diastereoselective addition of trialkylzincates to α-imino esters.     

Diastereocontrolled addition of organometallic reagents to S-chiral N-(tert-butanesulfinyl)-α-fluoroenimines

Grignard and organolithium reagents efficiently react with (S)-N-(tert-butanesulfinyl)-α-fluoroenimines to provide chiral allylamines in excellent yields and with diastereomeric ratios of up to 96:4. Acidic removal of the sulfinyl group and simple functional group transformations allow to get enantiopure fluoroolefin dipeptide mimics.     

C(3)-alkylation and cyclization of pyrazino[1,2-b]isoquinolin-4-ones

To avoid the epimerization of the C(11a)-stereocenter previously observed in 6,11a-cis-pyrazino[1,2-b]isoquinolin-1,4-diones, we present in this paper the C(3)-alkylation of 1-methoxy-pyrazino[1,2-b]isoquinolin-4-ones to obtain all-cis derivatives through a very reliable protocol. The success of the acid-promoted cyclization to get pentacyclic (R₃=arylmethyl) or tetracyclic (R₃=2-bromo-2-propenyl) compounds is dependent on the nature of the C(3)-unsaturated chain and of the N-substituent, but these limitations have been overcome by using trifluoromethanesulfonic as a superacid catalyst. The C-(3)-alkylation of pyrazino[1,2-b]isoquinolin-4-one is also studied.     

Practical method for the synthesis of (R)-homopipecolinic acid and (R)-homoproline esters from ω-chloroalkanoic acids and available chiral amines

A practical synthesis of (R)-homopipecolinic acid methyl ester 1 and (R)-homoproline methyl ester 2 was performed utilizing (i) a direct intramolecular cyclization of ω-chloro-β-enamino esters 11 and 12, which were prepared from available (S)-1-phenylethylamine or (S)-1-(1-naphthyl)ethylamine and ω-chloro-β-keto esters 5 and 10, respectively and (ii) a highly diastereoselective NaBH₄ reduction followed by hydrogenolysis. The present method is a short-step process using inexpensive and readily available substrates and reagents with fewer wasted materials.     

Base-catalyzed three-component direct Mannich reaction of enolizable ketones with high syn-selectivities

The three-component direct Mannich reaction between aldehydes, p-toluenesulfonamide, and enolizable ketones was achieved for the first time with organic bases as the catalysts. The corresponding N-tosylated β-aminoketones were obtained in high yields and good to excellent diastereoselectivities using TMG as the catalyst. Through reduction of the ketone group, the reaction product may be converted into β-aminol with excellent diastereoselectivity.