Aza-Quasi-Favorskii Reaction: Construction of Highly Substituted Aziridines through a Concerted Multibond Rearrangement Process.

A new molecular rearrangement, the aza-Quasi-Favorskii rearrangement, has been developed for the construction of highly substituted aziridines. Electron-deficient O-sulfonyl oximes react readily with α,α-disubstituted acetophenone-derived enolates to furnish highly substituted aziridines via this unprecedented domino process. In-depth computational studies reveal an asynchronous yet concerted nitrenoid-type rearrangement pathway.

Synthesis of (±)-Setigerumine†I: Biosynthetic Origins of the Elusive Racemic Papaveraceae Isoxazolidine Alkaloids*.

The biosynthetic origins of the structurally related racemic isoxazolidine Papaveraceae alkaloids Setigerumine I, Dactylicapnosinine and Dactylicapnosine have remained elusive since their original isolation over two decades ago. Herein we report the first biosynthetic hypothesis for their formation and, inspired by it, the first synthesis of (±)-Setigerumine I with accompanying computational rationale. Based on the results, these isoxazolidine alkaloids arise from racemizing oxidative rearrangements of prominent isoquinoline alkaloids Noscapine and Hydrastine. The key steps featured in this synthesis are a room temperature Cope elimination and a domino oxidation/inverse-electron demand 1,3-dipolar cycloaddition of an axially chiral, yet configurationally unstable, intermediate. The work opens this previously inaccessible family of natural products for biological studies.

Intramolecular N-Me and N-H aminoetherification for the synthesis of N-unprotected 3-amino-O-heterocycles.

A mild Rh-catalyzed method for synthesis of cyclic unprotected N-Me and N-H 2,3-aminoethers using an olefin aziridination-aziridine ring-opening domino reaction has been developed. The method is readily applicable to the stereocontrolled synthesis of a variety of 2,3-disubstituted aminoether O-heterocyclic scaffolds, including tetrahydrofurans, tetrahydropyrans and chromanes.

Conformationally Locked Pyramidality Explains the Diastereoselectivity in the Methylation of trans-Fused Butyrolactones.

A stereoselectivity model inspired by the total synthesis of stemona alkaloids is developed to explain why enolate-derived 3,4-fused butyrolactones are methylated with a preference for syn alkylation. The model shows how conformational locking present in nonplanar enolate structures favors syn over anti methylation, due to less significant structural distortions in the syn pathway. The developed model was also successfully used to rationalize selectivities of previously documented methylation reactions.

Synthesis of Highly Substituted Cyclopropanes via the Quasi-Favorskii Rearrangement of α,α-Dichlorocyclobutanols.

A method for the synthesis of highly substituted cyclopropanes via a quasi-Favorskii rearrangement is described. The method includes the combination two chemical transformations starting from α,α-dichlorocyclobutanones prepared via the [2 + 2] Staudinger ketene cycloaddition between either terminal- or cis-olefins and dichloroketene. First, α,α-dichlorocyclobutanones are reacted with organocerium reagents to afford the corresponding tertiary alcohols in good to excellent yields through a nucleophilic addition reaction that provided exclusively anti-products. Second, upon irreversible deprotonation, the tertiary α,α-dichlorocyclobutanols underwent a ring-contraction reaction (i.e., quasi-Favorskii rearrangement) to form structurally diverse cyclopropanes in moderate to good yields. The syn-stereoselectivity during the quasi-Favorskii rearrangement was evaluated using DFT analysis.

Total synthesis of isatindigotindoline C.

Total synthesis of isatindigotindoline C, a 3,3'-spiropyrrolidine oxindole alkaloid, is achieved in two steps using an exo-selective decarboxylative 1,3-dipolar cycloaddition as the key step. The synthesis verifies the originally assigned relative anti-stereochemistry for the bis-oxindole core of isatindigotindoline C.

Arylboronic Acid-Catalyzed C-Allylation of Unprotected Oximes: Total Synthesis of N-Me-Euphococcine.

O-Unprotected keto- and aldoximes are readily C-allylated with allyl diisopropyl boronate in the presence of arylboronic acid catalysts to yield highly substituted N-α-secondary and tertiary homoallylic hydroxylamines. The method was used in the total synthesis of the trace alkaloid N-Me-Euphococcine.

Enantioselective Catalytic Allylation of Acyclic Ketiminoesters: Synthesis of α-Fully-Substituted Amino Esters.

We report the first direct catalytic enantioselective allylation of acyclic α-ketiminoesters to afford α-allyl-α-aryl and α-allyl-α-trifluoromethyl amino esters in excellent isolated yield (91-99%) and with high optical purity (90-99+% ee). The allylation proceeds on a gram scale with 5-10 mol % of indium(I) iodide and commercially available BOX-type ligands. The allylated products are easily converted to enantiomerically enriched α-substituted proline derivatives.

Formal Synthesis of ent-Cephalotaxine Using a One-Pot Parham-Aldol Sequence.

A short formal synthesis of ent-Cephalotaxine is achieved. The approach features a new Lewis acid-mediated [2,3]-Stevens rearrangement of N-allylated prolineamide to generate a key quaternary stereogenic center. Additionally, a one-pot Parham-aldol sequence was developed to rapidly assemble two of the four rings in the cephalotaxine core.