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.

Versatile Synthetic Approach for Selective Diversification of Bicyclic Aza-Diketopiperazines.

Herein, we report a convenient synthesis of unprecedented aza-diketopiperazines (aza-DKPs). The strategy is based on selective diversification of bicyclic aza-DKP scaffolds by click reaction, N-acylation, and/or N-alkylation. These scaffolds containing either azido or amino groups were obtained by a key Rh(I)-catalyzed hydroformylative cyclohydrocarbonylation reaction of allyl-substituted aza-DKP. The methodology is readily amenable to the parallel synthesis of original aza-DKPs to enlarge the chemical diversity of aza-heterocycles.

Fast & easy preparation of 3D scaffolds from methyl benzoate by a diversity oriented synthesis strategy based on Diels-Alder and ene-reactions.

Thermic dimerization of methyl 1,3-cyclohexadiene 2-carboxylate gave original 3D-shape compounds by Diels-Alder cycloaddition and original [6 + 4]-ene reaction. Further selective modifications on an endo [4 + 2] cycloadduct via a diversity oriented synthesis (DOS) strategy quickly led to the preparation of a small library of original 3D scaffolds, providing access to a larger and unexplored chemical space for drug discovery processes.

Treatment of pure red cell aplasia and autoimmune haemolytic anaemia in chronic lymphocytic leukaemia with Campath-1H.

A patient with chronic lymphocytic leukaemia (CLL) progressive on fludarabine therapy and life-threatening anaemia related to immune haemolysis and pure red cell aplasia was treated with Campath-1H. The patient had sustained complete remission of both CLL and anaemia, but died of recurrent sepsis and cachexia 10 months after completion of the treatment. Campath-1H (alemtuzumab), a humanised anti-CD52 monoclonal antibody, is a potent therapeutic agent against advanced CLL and immune cytopenias. It could be indicated in the treatment of severe immune complications of CLL unresponsive to corticosteroids. Prolonged immunosuppression is a serious side-effect leading to severe infectious complication.