Synthesis and Optimization of Nitroxide-Based Inhibitors of Ferroptotic Cell Death in Cancer Cells and Macrophages.

JP4-039 is an alkene peptide isostere that acts as a low-micromolar inhibitor of erastin- and RSL-3-induced ferroptotic cell death in the HT-1080 cell line. In this work, we have developed new synthetic strategies that allow access to analogues of this lead structure. Enantioselective vinylogous Mannich or cross-metathesis reactions were key to the preparation of a series of analogues that culminated in the preparation of the ca. 30-fold more potent analogue (S)-6c. Structure-activity relationship analyses used both HT-1080 cells and a luminescence-based ferroptosis assay in RAW 264.7 macrophages. In particular, α,α-disubstituted alkene peptide isosteres (Rα ≠ H) were found to exceed the potency of the corresponding glycine (Rα = H) derivatives.

An Interrupted Schmidt Reaction: C-C Bond Formation Arising from Nitrilium Ion Capture.

The rerouting of the nitrilium ion formed in the Schmidt reaction of ketones and TMSN3 to encompass C-C bond formation with an electron-rich aromatic group is reported. Thus, when the reaction is carried out in HFIP using AlCl3 or AlBr3 as the promoter, imines, iminium ions, or enamide derivatives are obtained through one-pot procedures. The scope and possible mechanisms of these new transformations are considered.

Reagent-controlled regiodivergent ring expansions of steroids.

Ring expansion provides a powerful way of introducing a heteroatom substituent into a carbocyclic framework. However, such reactions are often limited by the tendency of a given substrate to afford only one of the two rearrangement products or fail to achieve high selectivity at all. These limitations are particularly acute when seeking to carry out late-stage functionalization of natural products as starting points in drug discovery. In this work, we present a stereoelectronically controlled ring expansion sequence towards selective and flexible access to complementary ring systems derived from common steroidal substrates. Chemical diversification of the reaction intermediate affords over 100 isomerically pure analogs with spatial and functional diversity. This regiodivergent rearrangement, and the concept of using chiral reagents to affect regiocontrol in chiral natural products, should be broadly applicable to late-stage natural product diversification programs.

Synthesis of Fused Pyrimidinone and Quinolone Derivatives in an Automated High-Temperature and High-Pressure Flow Reactor.

Fused pyrimidinone and quinolone derivatives that are of potential interest to pharmaceutical research were synthesized within minutes in up to 96% yield in an automated Phoenix high-temperature and high-pressure continuous flow reactor. Heterocyclic scaffolds that are either hard to synthesize or require multisteps are readily accessible using a common set of reaction conditions. The use of low-boiling solvents along with the high conversions of these reactions allowed for facile workup and isolation. The methods reported herein are highly amenable for fast and efficient heterocycle synthesis as well as compound scale-ups.

High-Temperature Boc Deprotection in Flow and Its Application in Multistep Reaction Sequences.

A simplified Boc deprotection using a high-temperature flow reactor is described. The system afforded the qualitative yield of a wide variety of deprotected substrates within minutes using acetonitrile as the solvent and without the use of acidic conditions or additional workups. Highly efficient, multistep reaction sequences in flow are also demonstrated wherein no extraction or isolation was required between steps.

Remodeling and Enhancing Schmidt Reaction Pathways in Hexafluoroisopropanol.

The effect of carrying out two variations of the Schmidt reaction with ketone electrophiles in hexafluoroisopropanol (HFIP) solvent has been studied. When TMSN3 is reacted with ketones in the presence of triflic acid (TfOH) promoter, tetrazoles are obtained as the major products. This observation is in contrast to established methods, which usually lead to amides or lactams arising from formal NH insertion as the major products. The full product profiles of several examples of this reaction are also reported and found to include mechanistically interesting products (e.g., double ring expansion). Application of TfOH promoter in HFIP was also found to promote the reaction of a hydroxyalkyl azide with a ketone, which affords lactams following nucleophilic opening of initially formed iminium ether more efficiently than previously reported methods.