Crystallization-Based Synthetic Route to Antimalarial Agent BRD5018: Diazocene Ring Formation via a Staudinger-aza-Wittig Reaction on an Azetidine-Ribose Template

Abstract

The development of an entirely crystallization-based synthetic route to the antimalarial BRD5018 is described, which assembles a structurally complex bicyclic azetidine scaffold adorned with five stereogenic centers without the need for any chromatographic separations. A diastereoselective glycine ester Claisen rearrangement, diastereomeric salt resolution, and diastereoselective iodo-lactonization are utilized to provide an efficient access to three contiguous stereogenic centers on an acyclic template with the desired relative and absolute configurations. A tandem aziridine ring-opening/azetidine ring-closure on the derived 2-amino-1,4-diol template was developed to efficiently establish the all-cis trisubstituted azetidine scaffold with the proper ancillary functionality for end-game maneuvers. d-Ribose-2,3-acetonide provided a conveniently differentiated vicinal syn-diol suitable for the planned reductive amination/periodate cleavage/Staudinger-aza-Wittig sequence to form the eight-membered diazocene ring. An early quantitative installation of the diaryl acetylene moiety via a Sonogashira coupling on an electronically matched methyl 4-bromocinnamate circumvented a low-yielding, late-stage reaction in the first-generation synthesis. Multiple crystalline intermediates enabled the complete removal of chromatography from the synthesis resulting in a substantially reduced cost and waste generation with enhanced throughput and quality control.

Synthesis of Cycloheptatriene-Containing Azetidine Lactones

“…A particularly useful variant of the Norrish–Yang reaction would include a nitrogen atom at the β position of the photoexcitable ketone (such as 6 in Figure B) and would provide a route to azetidines in a simple manner . Azetidines have elicited recent interest as useful scaffolds for biologically active molecules. − This approach fails, however, because of an increased electron density at the β position (a lone pair of electrons on nitrogen). More facile than γ H-radical abstraction is quenching of the triplet excited state through a rapid electron transfer from nitrogen to form a ketyl radical anion, which opens a more favorable degradation pathway through the scission of the C–N bond, yielding methylketones and imine oligomers, or amines through complex reductive processes (Figure B). , While undesirable in the context of azetidinol formation, generation of ketyl radical anions by photoinduced electron transfer has found numerous synthetic applications .…”

Mechanochemical synthesis of β-cyclodextrin urea derivatives under reactive CO2 atmosphere by Staudinger aza-Wittig reaction

“…Staudinger aza-Wittig reactions are nowadays regularly employed in many fields of organic chemistry, as a step of a reaction sequence, 1 in syntheses of poly-substituted cyclic derivatives, 2–5 or for isotopic labelling. 6 This sequential reaction involves the formation of iminophosphorane from phosphane and organic azide, known as the Staudinger reaction, 7,8 and the reaction of the latter, known as the aza-Witting reaction, with aldehyde, CO 2 , CS 2 or isocyanate to give imine, isocyanate, isothiocyanate or carbodiimide, respectively.…”

Stereoselective Synthesis of 12-Tetrazolyl Substituted (E)-5H-Quinazolino[3,2-a]quinazolines via Sequential Ugi-Azide/Staudinger/aza-Wittig/Addition/Ag(I)-Catalyzed Cyclization

“…Pyrrolopiperazine-2,6-diones were synthesized by employing a simple Ugi/nucleophilic substitution/N-acylation/debenzoylation sequence with high chemical yields and good diastereoselectivities . Aza-Wittig reaction has become an effective method for preparing nitrogen-containing heterocyclic compounds. − Therefore, we envisage that some heterocyclic compounds would easily be prepared if the Ugi-azide reaction was efficiently combined with the aza-Wittig reaction. On the basis of our application of Ugi and aza-Wittig reactions in the synthesis of N-heterocycles, − we hope to report here a new efficient and stereoselective synthesis of 12-tetrazolyl substituted ( E )-5 H -quinazolino­[3,2- a ]­quinazolines through sequential Ugi-azide/Staudinger/aza-Wittig/addition/Ag­(I)-catalyzed cyclization.…”