Electrophilic aminations involve
an umpolung of a nitrogen atom,
providing an alternate, distinctive synthetic strategy. The recent
advent of various designed O-substituted hydroxylamines
has significantly advanced this research field. An underappreciated
issue is atom economy of the transformations: The necessary activating
group on the oxygen atom is left in coproduced waste. Herein, we describe
Rh-catalyzed electrophilic amination of substituted isoxazolidin-5-ones
for the synthesis of unprotected, cyclic β-amino acids featuring
either benzo-fused or spirocyclic scaffolds. Using the cyclic hydroxylamines
allows for retaining both nitrogen and oxygen functionalities in the
product. The traceless, redox neutral process proceeds on a gram scale
with as little as 0.1 mol % catalyst loading. In contrast to related
electrophilic aminations in the literature, a series of mechanistic
experiments suggests a unique pathway involving spirocyclization,
followed by the skeletal rearrangement. The insights provided herein
shed light on a nuanced reactivity of the active species, Rh-nitrenoid
generated from the activated hydroxylamine, and extend the knowledge
on electrophilic aromatic substitutions.
A series of unprotected spirocyclic β-prolines and βhomoprolines are prepared by Rh-catalyzed C−H insertion. The key intermediate, a Rh nitrenoid, is generated by the N−O bond cleavage of a substituted isoxazolidin-5-one. The reaction proceeds on a gram scale with a catalyst loading of as little as 0.1 mol %, affording spirocyclic β-amino acids that are otherwise difficult to obtain. The building blocks prepared in this work will likely find applications in medicinal chemistry.
The authors have found that an erroneous transcription of the optical rotation of the reference product 4 led to the wrong assignment of the absolute stereochemis-try of all new compounds in the paper. The structures of the compounds with the correct stereochemistry and stereochemical notations are provided below. The stereochemical model in Figure 1 should be withdrawn. The authors apologize for these errors and for any inconvenience caused.
Unlike their isocyano and isothiocyanato analogues, isocyanato esters remain almost unexplored as formal 1,3-dipoles in asymmetric catalytic reactions. The first asymmetric formal [3+2] cycloaddition involving isocyanato esters and electrophilic alkenes is reported. Diisopropyl 2-isocyanatomalonate reacts with α,β-unsaturated N-(o-anisidyl) imines in the presence of a Mg(OTf) -BOX complex to give highly substituted chiral pyrrolidinones featuring a conjugate exocyclic double bond with excellent yields and enantiomeric excesses up to 99 %. Several transformations of the resulting heterocycles, including the synthesis of a pyroglutamic acid derivative, have been carried out.
Copper triflate-BOX complexes catalyse the enantioselective conjugate addition of methyl malonate to β-trifluoromethyl-α,β-unsaturated imines to give the corresponding enamines bearing a trifluoromethylated stereogenic centre with good yields, and diastereo- and enantioselectivities. The usefulness of the method has been shown with the synthesis of optically active β-trifluoromethyl δ-amino esters and optically active trifluoromethyl piperidones.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.