Robust Organocatalysts for the Cleavage of Vegetable Oil Derivatives to Aldehydes through Retrobenzoin Condensation.

A series of thiazolium salts was prepared and tested for the cleavage of the α-hydroxyketone derived from methyl oleate. The robustness of these precatalysts was determined by dynamic thermogravimetric analyses (TGA). It has been shown that the stability of these species is mainly governed by the nature of the counter-anion and some of them were found to be stable until 350-400 °C. The α-hydroxyketone derived from methyl oleate was cleaved under reactive distillation conditions using optimized, thermally robust N-butylthiazolium triflate to give the cleavage product, namely, nonanal and methyl azelaaldehydate, with 85 and 70 % yields. A range of α-hydroxyketones derived from several fatty acids was cleaved to give the corresponding bio-based aldehydes with up to 98 % isolated yields. Finally, this protocol was successfully applied to a high-oleic sunflower oil derivative.

Dodecyl sorbitan ethers as antimicrobials against Gram-positive bacteria.

A range of amphiphilic sorbitan ethers has been synthesized in two steps from sorbitan following an acetalization/hydrogenolysis sequence. These sorbitan ethers and the acetal intermediates have been evaluated as antimicrobials against Gram-negative and Gram-positive bacteria. No antimicrobial activity was observed for Gram-negative bacteria. However, the compounds bearing a linear dodecyl chain exhibit antimicrobial activity (MIC as low as 8µg/mL) against Gram-positive bacteria such as Listeria monocytogenes, Enterococcus faecalis and Staphylococcus aureus. Encouraged by these preliminary results, dodecyl sorbitan was tested against a range of resistant strains and was found to be active against vancomycin-, methicillin- and daptomycin-resistant strains (MIC=32-64µg/mL).

An asymmetric pericyclic cascade approach to 3-alkyl-3-aryloxindoles: generality, applications and mechanistic investigations.

The reaction of L-serine derived N-arylnitrones with alkylarylketenes generates asymmetric 3-alkyl-3-aryloxindoles in good to excellent yields (up to 93%) and excellent enantioselectivity (up to 98% ee) via a pericyclic cascade process. The optimization, scope and applications of this transformation are reported, alongside further synthetic and computational investigations. The preparation of the enantiomer of a Roche anti-cancer agent (RO4999200) 1 (96% ee) in three steps demonstrates the potential utility of this methodology.

Structure-enantioselectivity effects in 3,4-dihydropyrimido[2,1-b]benzothiazole-based isothioureas as enantioselective acylation catalysts.

The catalytic activity and enantioselectivity in the kinetic resolution of (±)-1-naphthylethanol with a range of structurally related 3,4-dihydropyrimido[2,1-b]benzothiazole-based catalysts is examined. Of the isothiourea catalysts screened, (2S,3R)-2-phenyl-3-isopropyl substitution proved optimal, giving good levels of selectivity in the kinetic resolution of a number of secondary alcohols (S values up to >100 at ~50% conversion). Low catalyst loadings (0.10-0.25 mol%) of the optimal isothiourea can be used to generate enantiopure alcohols (>99% ee) in good yields.

Biobased Aldehydes from Fatty Epoxides through Thermal Cleavage of ß-Hydroxy Hydroperoxides*.

The ring-opening of epoxidized methyl oleate by aqueous H2 O2 has been studied using tungsten and molybdenum catalysts to form the corresponding fatty ß-hydroxy hydroperoxides. It was found that tungstic acid and phosphotungstic acid gave the highest selectivities (92-93 %) towards the formation of the desired products, thus limiting the formation of the corresponding fatty 1,2-diols. The optimized conditions were applied to a range of fatty epoxides to give the corresponding fatty ß-hydroxy hydroperoxides with 30-80 % isolated yields (8 examples). These species were fully characterized by 1 H and 13 C NMR spectroscopy and HPLC-HRMS, and their stability was studied by differential scanning calorimetry. The thermal cleavage of the ß-hydroxy hydroperoxide derived from methyl oleate was studied both in batch and flow conditions. It was found that the thermal cleavage in flow conditions gave the highest selectivity towards the formation of aldehydes with limited amounts of byproducts. The aldehydes were both formed with 68 % GC yield, and nonanal and methyl 9-oxononanoate were isolated with 57 and 55 % yield, respectively. Advantageously, the overall process does not require large excess of H2 O2 and only generates water as a byproduct.

Tandem multi-step synthesis of C-carboxyazlactones promoted by N-heterocyclic carbenes.

Cascade reaction sequences incorporating N-heterocyclic carbene-based organocatalysis have been developed that allow the direct preparation of a range of (+/-)-4-phenoxycarbonylazlactones in good isolated yields (66-84%) from the corresponding N-p-anisoyl amino acids.

Heterocyclic lithium amides as chiral ligands for an enantioselective hydroxyalkylation with n-BuLi.

Chiral heterocyclic structures based on 3-aminopyrrolidines (3APs), 3-aminotetrahydrothiophens (3ATTs), and 3-aminotetrahydrofurans (3ATFs) have been synthesized. The corresponding lithium amides have been evaluated as chiral ligands in the condensation of n-BuLi on o-tolualdehyde. The returned levels of induction were in the 46-80% ee range. The cheap and easily prepared 3ATFLi's turned out to be also the best ligands, giving access to the expected R or S alcohols in a same 80% level of induction at -78 degrees C in THF. In all cases, the sense of induction depends on the absolute configuration of C(8) on the 3-amino appendage. A general concept is proposed to rationalize the process of induction in the presence of organolithium species.

Synthesis, surfactant properties and antimicrobial activities of methyl glycopyranoside ethers.

A series of amphiphilic methyl glucopyranoside ethers incorporating various alkyl chain lengths has been synthesized from commercially available methyl glucopyranosides following an acetalisation/hydrogenolysis sequence. The amphiphilic properties of ethers and acetal intermediates were evaluated. Both families exhibit excellent surfactant properties with a maximum efficiency obtained for compounds bearing a linear dodecyl chain (CMC = 0.012 mM, γsat. = 30 mN m-1). Antimicrobial activity studies revealed an efficient activity (0.03 < MIC < 0.12 mM) against Gram-positive bacteria such as Listeria monocytogenes, Enterococcus faecalis, Enterococcus faecium and Staphylococcus aureus. More importantly, these compounds were found to be active against multi-resistant strains such as vancomycin-, methicillin- and daptomycin-resistant strains. Finally, it was found that antimicrobial activities are closely related to physicochemical properties and are also influenced by the nature of the carbohydrate moiety.

Enantioselective conjugate addition of a lithium ester enolate catalyzed by chiral lithium amides.

Mixed aggregates of chiral lithium amide and lithium ester enolate have been employed in the enantioselective conjugate addition on alpha,beta-unsaturated esters. Michael adducts were obtained in ee's up to 76% combining a lithium enolate and a chiral 3-aminopyrrolidine lithium amide. The sense of the induction was found to be determined by both the relative configuration of the stereogenic centers borne by the amide and the solvent in which the reaction was conducted. [reaction: see text]

Thiazolylidene-catalyzed cleavage of methyl oleate-derived α-hydroxy ketone to the corresponding free aldehydes.

The thiazolylidene-catalyzed cleavage of the α-hydroxy ketone derived from methyl oleate gave the corresponding aldehydes under nonoxidative conditions through a retro-benzoin process. The aldehydes produced are in equilibrium with their corresponding acyloins. To illustrate the synthetic utility of this protocol, the aldehydes were recovered by distillation.

Identification of New Nonsteroidal RORα Ligands; Related Structure-Activity Relationships and Docking Studies.

A high throughput screen was developed to identify novel, nonsteroidal RORα agonists. Among the validated hit compounds, the 4-(4-(benzyloxy)phenyl)-5-carbonyl-2-oxo-1,2,3,4-tetrahydropyrimidine scaffold was the most prominent. Among the numerous analogues tested, compounds 8 and 9 showed the highest activity. Key structure-activity relationships (SAR) were established, where benzyl and urea moieties were both identified as very important elements to maintain the activity. Most notably, the SAR were consistent with the binding mode of the compound 8 (S-isomer) in the RORα docking model that was developed in this program. As predicted by the model, the urea moiety is engaged in the formation of key hydrogen bonds with the backbone of Tyr380 and Asp382. The benzyl group is located in a wide hydrophobic pocket. The structural relationships reported in this letter will help in further optimization of this compound series and will provide novel synthetic probes helpful for elucidation of complex RORα physiopathology.

Asymmetric pericyclic cascade approach to spirocyclic oxindoles.

The reaction of chiral N-arylnitrones with carbocyclic alkylarylketenes generates spirocyclic oxindoles in good yields and with excellent levels of enantioselectivity (90-99% ee) via a pericyclic cascade process.

An asymmetric hetero-claisen approach to 3-alkyl-3-aryloxindoles.

The reaction of a chiral N-phenylnitrone derived from Garner's aldehyde with alkylarylketenes generates 3-alkyl-3-aryloxindoles directly in excellent yields and with good to excellent levels of enantioselectivity (up to 90% ee).

Enantioselective conjugate addition of a lithium ester enolate catalyzed by chiral lithium amides: a possible intermediate characterized.

Two 1:1 noncovalent mixed aggregates between a lithium enolate and two diastereomeric lithium amides have been identified spectroscopically in THF. The NMR data, as well as DFT theoretical calculations, shine some light on a puzzling reversal of induction, observed when switching from one diastereomer of the amide to the other in the enantioselective Michael addition of the lithium enolate to an unsaturated ester.

N-Heterocyclic carbene catalysed beta-lactam synthesis.

N-Heterocyclic carbenes promote the formal [2+2] cycloaddition of ketenes with N-tosyl imines to give the corresponding beta-lactams in good to excellent isolated yields; chiral NHCs give beta-lactams in high e.e. after crystallisation.

Probing the efficiency of N-heterocyclic carbene promoted O- to C-carboxyl transfer of oxazolyl carbonates.

Screening of a range of azolium salts, bases and solvents for reactivity indicates that triazolinylidenes, generated in situ with KHMDS in THF, promote the Steglich rearrangement of oxazolyl carbonates with high catalytic efficiency (typical reaction time 5 min at <1.5 mol % NHC). This protocol shows wide substrate applicability, even allowing the efficient generation of vicinal quaternary centers. An improved experimental procedure is also described that allows a simplified one-pot reaction protocol to be employed with similarly high catalytic efficiency.

Origin of the detrimental effect of lithium halides on an enantioselective nucleophilic alkylation of aldehydes.

The effect of lithium halides on the enantioselectivity of the addition of methyllithium on o-tolualdehyde, in the presence of chiral lithium amides derived from chiral 3-aminopyrrolidines (3APLi), has been investigated. The enantiomeric excess of the resulting 1-o-tolylethanol was found to drop upon addition of significant amounts of LiCl, introduced before the aldehyde. The competitive affinity between the lithium amide, the methyllithium, and the lithium halides in THF was examined by multinuclear NMR spectroscopy and DFT calculations. The results showed that the original mixed aggregate of the chiral lithium amide and methyllithium is rapidly, totally, and irreversibly replaced by a similar 1:1 complex involving one lithium chloride or bromide and one lithium amide. While the MeLi/LiX substitution occurs with some degree of epimerization at the nitrogen for the endo-MeLi:3APLi complex, it is mostly stereospecific for the exo-type arrangements of the aggregate. The thermodynamic preference for mixed aggregates between 3APLi and LiX was confirmed by static DFT calculations: the data show that the LiCl and LiBr aggregates are more stable than their MeLi counterparts by more than 10 kcal.mol(-1) provided THF is explicitly taken into account. These results suggest that a sequestration of the source of chirality by the lithium halides is at the origin of the detrimental effect of these additives on the ee of the model reaction.