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Herein we report our observations from the study of the classical Robinson annulation reaction under solvent‐free mechanochemical activation by means of high‐speed ball milling. In particular, the enantioselective synthesis of the Wieland‐Miescher ketone was used as model reaction. (S)‐Proline was employed as chiral organocatalyst, either alone or in the presence of additives in order to determine their influence on the reaction's speed and stereoselectivity. Most interesting, among the additives that were examined, four solvate ionic liquids (SIL) afforded the desired product with significantly improved enantioselectivity relative to the mechanochemically‐activated reaction catalyzed by (S)‐proline alone. Furthermore, the required reaction time was reduced from 3 days to 90 min. The potential of other proline‐type organocatalysts was explored in this ball‐milling process. Initial attempts to increase the scope of the reaction to afford related annulation products were unsuccessful. HPLC‐MS experiments were carried out in order to detect some of the species that intervene in the mechanism of the (S)‐proline‐catalyzed Robinson cyclization reaction involving 2‐methyl‐1,3‐cyclohexanedione and methyl vinyl ketone. [ABSTRACT FROM AUTHOR]

Achiral, inexpensive beta-alanine was converted into the title chiral amide 1 in 53% overall yield. C-Alkylation of (R,R)-1 required formation of its dianion derivative, (R,R)-1-Li2, which was best achieved by direct metallation with two equivalents of n-BuLi in THF solution and at -78°C. Treatment of (R,R)-1-Li2 with various alkyl halides afforded the monoalkylated products 3-6 in 24-85% yield and 65-86% diastereoselectivity. The effect of LiCl additive or HMPA co-solvent on the diastereoselectivity of the alkylation reaction was essentially negligible, although reaction yields generally improved. Chemical correlation of the major diastereomer from the methylation reaction with (S)-alpha-methyl-beta-alanine shows that addition of the electrophile takes place preferentially on the enolate's Si face. This conclusion is also supported by molecular modelling studies (ab initio HF/3-21G), which indicate that the conformation of lowest energy for (R,R)-1-Li2 presents a more sterically hindered Re face of the enolate. The theoretical studies also provided useful insight into the importance of hydrogen bonding and attractive p-p interactions in (R,R)-1. Furthermore, the calculations predict a determining role for N-Li-O chelation in (R,R)-1-Li, as well as an interesting ion triplet configuration for dilithium dianion (R,R)-1-Li2.

A few years ago, the synthesis of chiral phosphoric acids supported on chiral BINOL frameworks was accomplished by T. Akiyama and M. Terada. Subsequent relevant applications demonstrated the importance of chiral phosphoric acids as privileged chiral inducers in asymmetric organocatalysis. In the present report, we discuss the development of novel chiral phosphorodiamidic acids derived from C 2-symmetric trans -1,2-diaminocyclohexane aliphatic frameworks. The preparation of the new chiral Brønsted acids, based on the intermediacy of a 1,3,2-diheterophospholan-2-oxide moiety, turned out to be challenging since several plausible synthetic methodologies proved to be ineffective. Furthermore, the five-membered heterocyclic moiety turned out to be easily hydrolyzed when exposed to nucleophilic alcohols or water. Complementary to the successful multistep synthesis reported here, it was possible to obtain crystals of the key precursor of the desired phosphorodiamidic acid, which proved suitable for X-ray diffraction analysis and hence to establish important conformational characteristics of the novel heterocycle. [ABSTRACT FROM AUTHOR]

Simple organoatalysts are used as substituents for natural products in the enantioselective amination of [alpha]-substituted [alpha]-cyanoacetates with azodicarboxylates. The enantioselectivity obtained with properly designed chiral amines is found to be satisfactory and the amination reaction has proceeded smoothly even when the catalyst loading is reduced to 1 mol %.

A theoretical study is carried out on the conformational interconversions in 1,3-dithiane 1,1-dioxide (1,3-dithiane sulfone), where four minima and five transition states are identified. Individual Gauge for Localized Orbitals (IGLO) calculations of the [.sup.1.J.sub.C-H] one-bond coupling constants in 1,3-dithiane sulfone are carried out and the constants are compared with those obtained for 1,3-dithiane, thiane, and thiane sulfone to explain their magnitude in terms of stereoelectronic interactions.