α- vs Ortho-Lithiation of <i>N</i>-Alkylarylaziridines: Probing the Role of the Nitrogen Inversion Process

The lithiation reaction of monophenyl- and diphenylaziridines has been investigated in detail in an effort to understand why the former undergo exclusively or mainly ortho-lithiation while the latter are lithiated exclusively at the α-position. Evidence is reported that ruled out the possibility that the α-lithiation, observed for the diphenylaziridines, is the result of an ortho- to α-translocation phenomenon, thus substantiating a direct α-deprotonation process. The role of the aziridine nitrogen lone-pair has been considered: dynamics at the aziridine nitrogen as well as complex-induced proximity effects seem to be responsible for the observed regioselectivity in both monophenyl and diphenylaziridines. It turns out that, by tuning the reaction conditions for the lithiation of trans-1-alkyl-2-methyl-3-phenylaziridines, it is possible to generate with high regioselectivity α- and/or ortho-lithiated aziridines, which can be stereoselectively functionalized by electrophilic trapping. A regioselective ortho-functionalization of diphenylaziridines is made possible by halogen− or tin−lithium exchange and by deprotonation of bis-deuterated aziridines

Regio- and Stereoselective Lithiation and Electrophilic Substitution Reactions of <i>N</i>-Alkyl-2,3-diphenylaziridines: Solvent Effect^†

The lithiation reaction of cis- and trans-N-alkyl-2,3-diphenylaziridines has been investigated. While cis-diphenylaziridines do not undergo any lithiation upon treatment with organolithiums, the lithiation reaction of the trans counterparts is completely α-regioselective and the stereochemical course of the lithiation-trapping sequence is solvent dependent:  inversion of configuration in coordinating solvents (THF or toluene/crown ether) and retention in hexane, ether, or toluene. The preparation of stereodefined functionalized N-alkyl-2,3-diphenylaziridines is described

Computer-aided retrosynthesis for greener and optimal total synthesis of a helicase-primase inhibitor active pharmaceutical ingredient

This study leverages and upgrades the capabilities of computer-aided retrosynthesis (CAR) in the systematic development of greener and more efficient total synthetic routes for the active pharmaceutical ingredient (API) IM-204, a helicase-primase inhibitor that demonstrated enhanced efficacy against Herpes simplex virus (HSV) infections. Using various CAR tools, several total synthetic routes were uncovered, evaluated, and experimentally validated, with the goal to maximize selectivity and yield and minimize the environmental impact. The CAR tools revealed several synthetic options under different constraints, which can overperform the patented synthetic route used as a reference. The selected CAR-based route demonstrated a significant improvement of the total yield from 8% (patented route) to 26%, along with a moderate improvement in the overall green performance. It was also shown that a human-in-the-loop approach can be synergistically combined with CAR to drive further improvements and deliver greener synthetic alternatives. This strategy further enhanced the green metrics by substituting solvents and merging two steps into one. These changes led to a significant improvement in the overall yield of IM-204 synthesis from 8 to 35%. Additionally, the green performance score, based on the GreenMotion metrics, was improved from 0 to 18, and the total cost of the building blocks was reduced by 550-fold. This work demonstrates the potential of CAR in drug development, highlighting its capacity to streamline synthesis processes, reduce environmental footprint, and lower production costs, thereby advancing the field toward more efficient and sustainable practices.</p

New Synthesis of Optically Active 5-Isoxazolidinones and β-Amino Acids

A new simple and stereoselective synthesis of 5-isoxazolidinones based on the reaction of lithiated 2-isopropyl-2-oxazolines with nitrones is described. A chiral version of such a methodology allows the preparation of highly enantioenriched 5-isoxazolidinones which are useful precursors for the synthesis of β-amino acid

Oxiranyl Anion-Mediated Synthesis of Highly Enantiomerically Enriched Styrene Oxide Derivatives

The stereospecific α-lithiation of optically active styrene oxides and the trapping reaction of the corresponding highly reactive intermediates with electrophiles to produce optically active styrene oxide derivatives are described. This methodology has been applied to the synthesis of an optically active oral antifungal agent of industrial interest

Michael Addition of Ortho-Lithiated Aryloxiranes to α,β-Unsaturated Malonates: Synthesis of Tetrahydroindenofuranones

A short and efficient synthesis of tetrahydroindenofuranones based on the Michael addition of ortho-lithiated aryloxiranes to alkylidene malonates followed by the nucleophilic oxirane ring-opening and subsequent lactonization is described. The methodology has been applied to the synthesis of a structural analogue of epipodophyllotoxins

Synthesis of Enantiomerically Enriched Oxazolinyl[1,2]Oxazetidines

The first stereoselective synthesis of oxazolinyl[1,2]oxazetidines based on the reaction of lithiated 2-(1-chloroethyl)-2-oxazolines with nitrones is described. Highly enantioenriched oxazolinyl[1,2]oxazetidines have also been prepared starting from a 1:1 diastereomeric mixture of optically active 2-(1-chloroethyl)-2-oxazolines

Stereospecific Synthesis of Optically Active Phenylpropylene Oxides

The stereospecific lithiation of diastereomeric phenylpropylene oxides has been studied as well as the trapping reaction with electrophiles. The reduction of the cis-α-benzoylpropylene oxide to give prevalently the anti-epoxy alcohol has been investigated as well

New Synthesis of Optically Active 5-Isoxazolidinones and β-Amino Acids

A new simple and stereoselective synthesis of 5-isoxazolidinones based on the reaction of lithiated 2-isopropyl-2-oxazolines with nitrones is described. A chiral version of such a methodology allows the preparation of highly enantioenriched 5-isoxazolidinones which are useful precursors for the synthesis of β-amino acid

Directed Ortho Lithiation of <i>N</i>-Alkylphenylaziridines

The ortho lithiation−trapping sequence of phenylaziridines is described. This methodology, which counts on the ability of the aziridino group to act as a directed metalation group (DMG), provides an easy access to functionalized arylaziridines as well as to phthalans and phthalides. The importance of the aziridine N-substituent in this DoM reaction is stressed as well