Adam Daïch

New and Expeditious Tandem Sequence Aza-Michael/Intramolecular Nucleophilic Substitution Route to Substituted γ-Lactams: Synthesis of the Tricyclic Core of (±)-Martinellines

A new and highly diastereoselective tandem reaction aza-Michael/intramolecular nucleophilic substitution is presented. This unprecedented tandem reaction between N-substituted alpha-bromoacetamides and Michael acceptors proceeds with good yields and excellent diastereoselectivity to provide the corresponding trisubstituted gamma-lactam systems. An application to the concise synthesis of the tricyclic core of (+/-)-martinelline alkaloids is also described.

Expedient and Practical Synthesis of CERT-Dependent Ceramide Trafficking Inhibitor HPA-12 and Its Analogues

The practical stereodivergent route to both syn- and anti-diastereomers of 1-substituted 3-aminobutane-1,4-diols based on the crystallization-induced asymmetric transformation (CIAT) approach was completed. This led to the revision of the reported stereochemistry of the first inhibitor of CERT-dependent ceramide trafficking HPA-12 from (R,R)-anti- to the (R,S)-syn-enantiomer. Due to the expeditiousness of production and inexpensive conditions developed, a series of alkyl- and aryl-substituted analogues of HPA-12 is also reported.

A Domino N-Amidoacylation/Aldol-Type Condensation Approach to the Synthesis of the Topo-I Inhibitor Rosettacin and Derivatives†

The pot, atom, and step-economic synthesis of Rosettacin topo-I poison and its derivatives has been achieved using a novel domino N-amidoacylation/aldol-type condensation, followed by decarboxylation of the ester function. The key domino procedure simply involves mixing HOBt ester as new reagent with lactam and NaH together in THF or THF/ DMF. The reaction seems to be general and led to suitable N-heterocyclic products in moderate to good yields.

Synthesis of benzo(or furo)[5,6]azepino[2,1-a]isoindolone derivatives: π-cyclisations of N-acyliminium ions

Benzo(or furo)[5,6]azepino[2,1-a]isoindolone and derivatives were obtained easily in one-pot via N-acyliminium ions by treatment of 2-(2-methoxycarbonylbenzyl(or fur-3-yl))phthalimide with alkylmagnesium iodide followed by an acidic hydrolysis.

Synthesis of highly functionalized pyrrolidines as tunable templates for the direct access to (±)-coerulescine and the tricyclic core of martinellines

An aza-Michael induced ring closure (aza-MIRC) tandem reaction of benzyl (2-bromoethyl)carbamate with various Michael acceptors is described. The N-Cbz-β-gem-disubstituted pyrrolidines thus obtained were proved to be versatile intermediates for the rapid access to both martinelline and spirooxindole backbones. An application of this strategy towards an expedient 4 step total synthesis of (±)-coerulescine is also presented.

An easy access to the exocyclic lactams analogous of the central nervous system active tricyclic nitroxapine, mianserine and chlothiapine agents using N-acyliminium chemistry

- The conformationally restrained dibenzothia(oxa)zepines and dibenzazepines 4-6 analogous to the antidepressant Sintamil® were prepared easily by π-cationic cyclization of the N-acyliminium ions 9A-C precursors with neat trifluoroacetic acid in three step-sequence starting from available amines and anhydrides. The regioselectivity in the reduction of imides especially in the maleimide derivatives as well as in the cyclization step was also discussed.

Pyrrolo[1,4]diazepines, via thermolyse of carbonylazides, and [3,2,2]cyclazines, via Diels-Alder reaction of [f]indolizines, annelated to [1]benzothiophene

Abstract Easy access to fused tricyclic pyrrolo[1,2-a][1]benzothieno[2,3-e][1,4]diazepines from the corresponding carbonyl azides by thermolysis in acetic acid is described. Moreover, new [1]benzothieno[2,3(3,2)-f]indolizines were synthesized in one-pot from 2(3)-(2-formylpyrrol-1-ylmethyl)-[1]benzothiophene and with diethyl acetylenedicarboxylate (DEAD) they led regiospecifically to [3,2,2] cyclazines fused to a [1]benzothiophene ring by 1,3-dipolar cycloaddition reaction rather than Diels-Alder adducts.

CIAT with simultaneous epimerization at two stereocenters. Synthesis of substituted β-methyl-α-homophenylalanines

Diastereoselective aza-Michael additions of phenylethylamine to 3-aroylbutenoic acids are reported. During these processes, efficient control over two new stereogenic centers on the Michael acceptor has been possible via crystallization-induced asymmetric transformation (CIAT). As an application, a convenient two-step synthesis of anti-β-methylhomophenylalanines is also described.

Domino process optimized via ab initio study for an alternative access to bicyclic lactams.

A totally new acid-free domino process to access highly functionalized bicyclic γ- and δ-lactams starting from commercially available and inexpensive ethoxymethylene derivatives is reported. Mechanisms elucidated by computational calculations led to new reaction conditions that boosted the yields up to 3.5 times higher.

Identification of Novel CERT Ligands as Potential Ceramide Trafficking Inhibitors

A highly compartmentalized enzymatic network regulates the pro‐apoptotic and proliferative effects of sphingolipids. Over‐conversion of ceramide (Cer) correlates with insensitivity to apoptosis signaling (in response to chemotherapy) and to drug resistance of cancer cells. De novo sphingomyelin biosynthesis relies on non‐vesicular ceramide trafficking by the CERT (CERamide Transfer) protein. Therefore, blocking CERT transfer, thus leading to increased intracellular ceramide availability, represents a potential anticancer strategy. Our study is based on the implementation of an in vitro binding assay, supported by in silico molecular docking. It constitutes the first attempt to explore at the molecular level for the identification of novel CERT ligands. This approach is the first step toward in silico design and optimization of CERT inhibitor candidates, potentially relevant as innovative ceramide‐transfer‐targeting therapeutic agents.