Computational Exploration of Anomalous Regioselectivities in Cycloadditions of Ketenes to Oxazolines.

Thermal (2 + 2) cycloadditions of several N-carboalkoxy (R)-2-tert-butyldihydrooxazoles with ketenes have been studied experimentally by the Ghosez group. Contrary to results from Seebach and co-workers that the electrophilic addition of acylating agents occurs ß to dihydrooxazole nitrogen, Ghosez found major cycloadducts resulting from an attack of ketene carbonyl carbon ß to oxygen. We investigate the potential energy surface for the cycloaddition of diphenyl- and phenylchloroketenes to two (R)-2-tert-butyldihydrooxazoles with ωB97X-D and mPW1PW91 density functional theory and DLPNO-CCSD(T) wave function theory. These (2 + 2) cycloadditions are concerted but highly asynchronous, and the selectivity trends in ketene addition cases are in good agreement with the experiment. We propose a model based on the buildup of charge in oxazoline to reconcile the regiochemical differences between Ghosez and Seebach's observations.

Productive Syntheses of Privileged Scaffolds Inspired by the Recognition of a Diels-Alder Pattern Common to Three Classes of Natural Products.

Identification of a common Diels-Alder pattern in three classes of bioactive natural products led us to study the synthesis and cycloaddition of a new class of cyclic dienes readily available from ß,γ-unsaturated lactams. A practical and readily scalable route to the parent p-methoxybenzyl-protected 6- and 7-membered ß,γ-unsaturated lactams was developed. These were readily transformed into the corresponding O-silylated dienes, which were reacted with dimethyl and diethyl fumarate to yield stereoselectively highly functionalized bicyclic adducts. These exhibited unexpected and versatile transformations upon acid hydrolysis depending on the nature of the dienophile substituents and the acid catalyst. All reactions have been performed on multigram quantities. These transformations provide a convenient, economical, and easily scalable pathway for the rapid construction of functionally and stereochemically dense privileged scaffolds for the construction of libraries of natural products-inspired molecules of pharmacological relevance.

Mechanisms and Conformational Control of (4 + 2) and (2 + 2) Cycloadditions of Dienes to Keteniminium Cations.

Selectivities in (4 + 2) and (2 + 2) cycloadditions of keteniminium cations with 1,3-dienes studied experimentally by Ghosez et al. were explored with ωB97X-D density functional theory. Reactions of keteniminium cations with 1,3-dienes are influenced by the s-cis or s-trans nature of the diene. s-Trans dienes react to give an intermediate enamine that leads to favored formation of (2 + 2) cycloadducts across the keteniminium C-C bond. The first step of the cycloaddition is rate-determining, and reaction occurs by attack on the central carbon of the keteniminium cation and subsequent C-C bond formation. In contrast, s-cis constrained dienes lead to preferential formation of (4 + 2) products by both stepwise and concerted mechanisms involving regioselective addition to the keteniminium C-N bond. Diels-Alder reaction occurs via a concerted mechanism if the diene termini are held in close proximity, as in cyclopentadiene.

Discovery of a subnanomolar and selective spirocyclic agonist of the glucocorticoid receptor.

Pure diastereomeric spirocyclic analogs of fluorocortivazol were conveniently prepared by a short and efficient synthetic sequence recently developed in our laboratory. The structures and conformations of several key products were confirmed by single crystal X-ray diffraction analysis. Conformational assignments were also supported by DFT calculations. Biological evaluation led to the identification of a highly potent hGR agonist with excellent anti-inflammatory effects in the subnanomolar range. All tested compounds from this series were also selective versus the progesterone receptor.

Remote substituent effects and regioselective enhancement of electrophilic substitutions in helical aromatic oligoamides.

The bromination of helically folded oligoamides of 8-amino-4-isobutoxy-2-quinolinecarboxylic acid by N-bromosuccinimide has been investigated. Bromination occurs preferentially if not exclusively at one position in the sequence despite the presence of multiple, up to seven, a priori comparable, reaction sites. Reactions are up to 2 orders of magnitude faster in a folded octamer than in a short nonhelical dimer, despite the steric hindrance that is expected in a compact folded conformation. The presence of substituents remote from the reaction site have considerable influence, resulting in the loss of regioselectivity, or in the slowing down of the reaction by several orders of magnitude.

Specificity and reversibility of the transpeptidation reaction catalyzed by the Streptomyces R61 D-Ala-D-Ala peptidase.

The specificity of the Streptomyces R61 penicillin-sensitive D-Ala-D-Ala peptidase has been re-examined with the help of synthetic substrates. The products of the transpeptidation reactions obtained with Gly-L-Xaa dipeptides as acceptor substrates are themselves poor substrates of the enzyme. This is in apparent contradiction with the classically accepted specificity rules for D-Ala-D-Ala peptidases. The Gly-L-Xaa dipeptide is regenerated by both the hydrolysis and transpeptidation reactions. The latter reaction is observed when another Gly-L-Xaa peptide or D-Alanine are supplied as acceptors. Utilization of substrates in which the terminal -COO(-) group has been esterified or amidated shows that a free carboxylate is not an absolute prerequisite for activity. The results are discussed in the context of the expected reversibility of the transpeptidation reaction.

Enantioselective vicinal bis-acylation of olefins.

A two-step sequence for the asymmetric vicinal acylation of olefins by a [2+2+1] strategy is reported. The key reaction is a [2+2] cycloaddition of an olefin to a chiral keteniminium salt derived from N-tosylsarcosinamide. This is followed by a regioselective Baeyer-Villiger oxidation of the resulting cyclobutanone to yield a lactol derivative that is equivalent to the product of addition of a carboxyl and a carbonyl group to the olefin. N-Tosylsarcosinamides derived from prolinol methyl ether and 2,5-dimethylpyrrolidine gave the best yields and diastereoselectivities. Five- and six-membered cycloolefins only gave cis products as expected. With seven- and eight-membered rings and cis 1,2-disubstituted acyclic olefins, partial or complete epimerisation of the cis to the trans adducts was observed. Facial selectivities were generally good except for terminal olefins. The oxidation step proceeded in high yields to give crystalline compounds which could usually be obtained in enantiopure form by simple recrystallisation.

Selective targeting of synthetic antioxidants to mitochondria: towards a mitochondrial medicine for neurodegenerative diseases?

Mitochondria are the major source of superoxide, and are responsible for activating apoptosis and oxidative damage during acute neuronal cell death and neurodegenerative disorders like Alzheimer and Parkinson diseases. While the molecular mechanisms by which mitochondrial oxidative stress triggers apoptosis are still investigated, attempts to achieve neuroprotection using antioxidant molecules have already been successful in several models of neuronal cell death. To increase the availability of antioxidant drugs at the mitochondrial level within cells, Michael P. Murphy recently proposed to covalently couple antioxidant molecules to a membrane-permeable lipophilic cation serving as carrier. Since mitochondria maintain at rest a potential of -180 mV, the diffusible cationic moiety drives the accumulation of the complex inside the matrix towards a diffusion equilibrium: for a monovalent cationic carrier, a thousand-fold accumulation of the complex is theoretically achievable; for a divalent cation, a million-fold accumulation is expected. Such mitochondria-targeted versions of natural antioxidants have successfully been synthesized and were found to counteract the pro-apoptotic effects of exogenous oxidative insults, while having no effects in models mimicking physiological apoptosis. Based on these observations, we carried out the synthesis of targeted variants of the artificial free radical scavengers 4-hydroxy-2,2,6,6-tetramethylpiperidin-N-oxide (TEMPOL) and Salen-Mn(III) complex of o-vanillin (EUK-134). Our preliminary results indicate that these targeted compounds, while delaying apoptosis after an exogenous oxidative insult, are not more active than their untargeted variants. This questions the general efficiency of the targeting procedure used and/or suggests that the main pro-apoptotic effector targets of exogenous oxidative insults are not located within mitochondria.