SmI₂-Mediated Cross-Coupling of Nitrones with β-Silyl Acrylates: Synthesis of (+)-Australine

The SmI₂-mediated cross-coupling of nitrones with β-silyl-α,β-unsaturated esters, followed by zinc reduction, allows an efficient and highly diastereoselective preparation of β-silyl lactams, which are precursors of β-hydroxy lactams through Tamao–Fleming oxidation. By applying the method to a cyclic, carbohydrate-derived nitrone, a new synthesis of (+)-australine has been realized in only 11 steps and in 21% overall yield from l-xylose

SmI₂-Mediated Coupling of Nitrones and <i>tert</i>-Butanesulfinyl Imines with Allenoates: Synthesis of β-Methylenyl-γ-lactams and Tetramic Acids

Nitrones and <i>tert</i>-butanesulfinyl imines undergo conjugate addition to alkyl allenoates under SmI₂-mediated reductive coupling conditions to produce novel β-methylenyl-substituted γ-amino esters. The latter were readily transformed into the corresponding β-methylenyl-γ-lactams by simple zinc reduction (<i>N</i>-hydroxy amines) or by acid hydrolysis (sulfinamides). The diastereoselective preparation of various β-methylenyl-γ-lactams offers a route to tetramic acids, the key structural features of an important class of bioactive natural products

Transition-Metal-Catalyzed Ring Expansion of Diazocarbonylated Cyclic <i>N</i>‑Hydroxylamines: A New Approach to Cyclic Ketonitrones

Novel <i>C</i>-ethoxycarbonyl cyclic ketonitrones are synthesized from the Ag- or Cu-catalyzed ring expansion of β-diazo cyclic hydroxylamines. The latter are themselves easily obtained by the addition of lithiated ethyl diazoacetate onto cyclic nitrones. The regioselective metal-catalyzed rearrangement of β-diazo cyclic hydroxylamines proved highly efficient and resulted in a synthetically useful ring expansion to produce 6- or 7-membered ring functionalized nitrones. The outcome of the two steps, i.e. nucleophilic addition of α-diazoesters to nitrones and ring expansion, is a formal nitrone homologation

Aziridination of Cyclic Nitrones Targeting Constrained Iminosugars

Rare C-7-substituted aziridinyl iminosugars can be synthesized through a short reaction sequence involving 1,3-cycloaddition of cyclic nitrones with alkynes and a Baldwin rearrangement of isoxazolines into bicyclic 2-acylaziridines. The method is efficient and completely diastereoselective, producing stable aziridinyl iminosugars in high yields

Enantioselective Ruthenium-Catalyzed 1,3-Dipolar Cycloadditions between <i>C</i>‑Carboalkoxy Ketonitrones and Methacrolein: Solvent Effect on Reaction Selectivity and Its Rational

A catalytic 1,3-dipolar cycloaddition between carboalkoxy ketonitrones and methacrolein under the effect of chiral ruthenium Lewis acid (<i>R</i>,<i>R</i>-<b>1</b>) was developed with high regio-, diastereo-, and enantiocontrol. The diastereochemical outcome of the cycloaddition reaction is marked by a significant solvent effect, and a divergent <i>endo</i> or <i>exo</i> control can be tuned by an appropriate choice of both the solvent and the <i>N</i>- and <i>O</i>-substituents of the ketonitrone. A rationale of the solvent effect, based on the computational study of the interactions between the methacrolein–Ru complex and its counteranion (SbF₆^–), is proposed to explain the selectivities obtained

Asymmetric Synthesis of α,α-Disubstituted Amino Acids by Cycloaddition of (<i>E</i>)‑Ketonitrones with Vinyl Ethers

Original acyclic (<i>E</i>)-α,α-dialkylketonitrones bearing a chiral auxiliary on their nitrogen atom were synthesized and successfully employed for the asymmetric synthesis of α,α-disubstituted amino acids using regio- and stereocontrolled 1,3-dipolar cycloaddition reactions with vinyl ethers. <i>N</i>-Glycosyl chiral auxiliaries were found to provide excellent <i>exo</i>- and π-facial stereocontrol. The obtained enantiopure cycloadducts were selectively transformed into functional α,α-disubstituted amino acids and related β-peptides through the highly regioselective opening of an intermediate quaternary anhydride

Hydroxymethyl-Branched Polyhydroxylated Indolizidines: Novel Selective α‑Glucosidase Inhibitors

α,α-Disubstituted piperidines and conformationally constrained polyhydroxylated indolizidines bearing a hydroxymethyl substituent in position 8a were synthesized from a readily available l-sorbose-derived ketonitrone. Diastereoselective vinylation under two sets of complementary conditions allowed access to both configurations of the newly formed quaternary stereocenter. Subsequent <i>N</i>-allylation and ring-closing metathesis afforded 8a-branched indolizidines in high yield. The newly prepared iminosugars demonstrated highly potent inhibition of α-glucosidases. Most interestingly, compound <b>9b</b> exhibits very high selectivity toward this class of enzymes, with an unusual mode of binding

Asymmetric Synthesis of α,α-Disubstituted Amino Acids by Cycloaddition of (<i>E</i>)‑Ketonitrones with Vinyl Ethers

Original acyclic (<i>E</i>)-α,α-dialkylketonitrones bearing a chiral auxiliary on their nitrogen atom were synthesized and successfully employed for the asymmetric synthesis of α,α-disubstituted amino acids using regio- and stereocontrolled 1,3-dipolar cycloaddition reactions with vinyl ethers. <i>N</i>-Glycosyl chiral auxiliaries were found to provide excellent <i>exo</i>- and π-facial stereocontrol. The obtained enantiopure cycloadducts were selectively transformed into functional α,α-disubstituted amino acids and related β-peptides through the highly regioselective opening of an intermediate quaternary anhydride