Bernard Delpech

Antiplasmodial benzophenone derivatives from the root barks of Symphonia globulifera (Clusiaceae).

In an effort to find antimalarial drugs, a systematic in vitro evaluation on a chloroquine-resistant strain of Plasmodium falciparum (FcB1) was undertaken on sixty plant extracts collected in French Guiana. The ethyl acetate extract obtained from the root barks of Symphonia globulifera exhibited a strong antiplasmodial activity (97% at 10 microg/ml). The phytochemical investigation of this extract led to the isolation of nine polycyclic polyprenylated acylphloroglucinol (PPAPs) compounds and two oxidized derivatives. All compounds showed antiplasmodial activity with IC(50)s ranged from 2.1 to 10.1 microM. A LC/ESI-MS(n) study performed on polyprenylated benzophenones previously isolated from Moronobea coccinea provided a reliable method for their detection in the extract and structural elucidation.

Highly Stereoselective Synthesis of Primary, Secondary, and Tertiary α-S-Sialosides under Lewis Acidic Conditions

N-acetyl 4-O,5-N-oxazolidinone protected sialyl phosphates of either anomeric configuration are excellent donors for the formation of α-S-sialosides at -78 °C in dichloromethane with primary, secondary, and tertiary thiols including galactose 3-, 4-, and 6-thiols. The reactions, which proceed under typical Lewis acid promoted glycosylation conditions, are highly α-selective and do not suffer from competing elimination of the phosphate.

One-pot formation of piperidine- and pyrrolidine-substituted pyridinium salts via addition of 5-alkylaminopenta-2,4-dienals to N-acyliminium ions: application to the synthesis of (±)-nicotine and analogs.

Addition of 5-alkylaminopenta-2,4-dienals onto N-acyliminium ions, generated in situ from α-hydroxycarbamates derived from pyrrolidine or piperidine, in the presence of zinc triflate, followed by dehydrative cyclization, allowed the formation of pyridinium salts substituted at their 3-position by a five- or six-membered nitrogen heterocycle. Subsequent N-dealkylation of the pyridinium moiety and deprotection of the secondary amine or reduction of the carbamate function led to (±)-nicotine and analogs.

Enhancement of 5-aminopenta-2,4-dienals electrophilicity via activation by O,N-bistrifluoroacetylation. application to an N-acyl Pictet-Spengler reaction.

Aminopentadienals resulting from the condensation of tryptamine or homoveratrylamine with glutaconaldehydes were treated with trifluoroacetic anhydride, allowing the formation of tetrahydro-beta-carbolines and tetrahydroisoquinolines bearing an enal function. In this N-acyl Pictet-Spengler reaction the electrophilicity of the aminopentadienals was dramatically increased by O,N-bistrifluoroacetylation. Recovery of the nitrogen nucleophilicity was achieved using a reductive process, and the heterocyclic amines were converted into aminonitriles by a Strecker reaction in the presence of butanal. Cyclization, by intramolecular Michael addition of the in situ generated enamines onto the enal moiety, was achieved in the presence of zinc triflate and involved cyanide ion trapping. In this manner, compounds related to protoemetine and dihydrocorynantheal were obtained, and a reduction step led to a short synthesis of (+/-)-protoemetinol.

Stereoselective, Electrophilic α-C-Sialidation

5-N-Acetyl-5-N,4-O-oxazolidinone protected α- and β-sialyl phosphates react with allyltributylstannane and a variety of trimethylsilyl enol ethers to give α-sialyl C-glycosides in high yield and excellent selectivity. Elimination to give the 2,3-glycal is minimized by the presence of the oxazolidinone ring. The oxazolidinone ring can be subsequently cleaved under mild conditions at room temperature leaving in place the native acetamide group.

Exploration of an imide capture/N,N-acyl shift sequence for asparagine native peptide bond formation.

Imide capture of a C-terminal peptidylazide with a side-chain thioacid derivative of an N-terminally protected aspartyl peptide leads to the formation of an imide bond bringing the two peptide ends into close proximity. Unmasking of the N(α) protecting group and intramolecular acyl migration results in the formation of a native peptide bond to asparagine.

Synthesis of N-acyl-5-aminopenta-2,4-dienals via base-induced ring-opening of N-acylated furfurylamines: scope and limitations.

N-Acylation of furfurylamines provided 1, which on double deprotonation with LDA led to the formation of N-acyl-5-aminopenta-2,4-dienals 2 via an isomerization involving opening of the furan ring. The scope and limitations of the procedure were examined by considering the influence of substituents on the carbonyl group and also on the heterocycle moiety. The efficacy of the reaction was shown to be very dependent on the nature of these groups.

Concise construction of sarain A core according to a biosynthetic proposal: cyclization through an intramolecular Mannich-type reaction involving an endocyclic N-acyliminium ion.

Since its isolation from the Mediterranean marine sponge Reniera sarai by Cimino and co-workers, sarain A (1) has been the target of synthetic approaches by the Weinreb, Heathcock, Overman, Cha, Porter, and Huang groups and by our laboratory. These efforts culminated in the total synthesis of the natural product by Overman and co-workers. The interest in this compound by the organic chemistry community is due to its unique structure, in which a diazatricyclic core bears two very different macrocycles. The most intriguing feature of the molecular architecture of this compound is an unusual interaction between a tertiary amine and an aldehyde that gives it a zwitterionic character. A biosynthetic pathway for sarain A, based on Baldwin and Whitehead s hypothesis for the manzamine alkaloids, was initially proposed by two laboratories. Later, it was postulated that the formation of the C3–C2’ bond (natural product numbering) could result from a Mannich reaction. Therefore, a modified scheme, involving the condensation of malonaldialdehyde with long chain aminoaldehydes, was put forward for the possible construction of the skeleton of this alkaloid. Accordingly, sarain A might arise from a fully saturated C12 aminoaldehyde, a sphingolipid-derived dialdehyde and two molecules of malondialdehyde (Scheme 1). Based on these biogenetic considerations, the formation of the diazatricyclo[5.4.0.0]undecane skeleton corresponding to the core of sarain A was investigated previously in our laboratory. However, moving away from our biogenetic proposal, an intramolecular Hosomi–Sakuraitype reaction, similar to that described by Weinreb, was used to form the C3–C2’ bond in that study. Herein, we report our work concerning the concise formation of a model compound possessing this tricyclic core that follows more faithfully the biosynthetic proposal of Scheme 1. A plan was elaborated employing lithium (Z)-3-bromoacrylate and the sodium enolate of malondialdehyde as synthons for the unstable dialdehyde (Scheme 2).

Synthesis and evaluation of 3-deoxy and 3-deoxy-3-fluoro derivatives of gluco- and manno-configured tetrahydropyridoimidazole glycosidase inhibitors.

Three tetrahydropyridoimidazole-type glycosidase inhibitors have been synthesized with the 3-deoxy ribo- and arabino-, and 3-deoxy-3-fluoro gluco-configurations and two of them screened for activity against α- and β-gluco- and mannosidase enzymes. Only one substance, the 3-deoxy-3-fluoro-derivative of the gluco-configured tetrahydropyridoimidazole was found to have any activity against a single enzyme, sweet almond β-glucosidase, and even then at a level 100-fold lower than that of the corresponding simple gluco-configured tetrahydropyridoimidazole thereby underlining the importance of the 3-hydroxy group in the key substrate-enzyme interactions.

Se-(9-Fluorenylmethyl) Selenoesters; Preparation, Reactivity, and Use as Convenient Synthons for Selenoacids

Se-(9-Fluorenylmethyl) selenoesters are readily prepared, stable precursors to selenocarboxylates, which they liberate on treatment with DBU. Fm selenoesters are compatible with the use of TFA for the removal of Boc groups and with simple peptide bond forming reactions. Amino acid derived selenocarboxylates condense directly with amines to give amides, react smoothly with isocyanates and isothiocyanates to give amides, and couple with electron-deficient azides also to give amides.