ABSTRACT
Two new fates of imine intermediates formed on radical cyclizations of ene-sulfonamides have been identified, reduction and hydration/fragmentation. Tin hydride-mediated cyclizations of 2-halo-N-(3-methyl-N-sulfonylindole)anilines provide spiro[indoline-3,3'-indolones] or spiro-3,3'-biindolines (derived from imine reduction), depending on the indole C2 substituent. Cyclizations of 2-haloanilide derivatives of 3-carboxy-N-sulfonyl-2,3-dihydropyrroles also presumably form spiro-imines as primary products. However, the lactam carbonyl group facilitates the ring-opening of these cyclic imines by a new pathway of hydration and retro-Claisen-type reaction, providing rearranged 2-(2'-formamidoethyl)oxindoles.
ABSTRACT
1,1-Divinyl-2-phenylcyclopropanes are entry points to a rich area of rearrangement chemistry. With N,N-diallyl amide substrates, tandem radical cyclizations can be initiated at room temperature. Warming provides products of pure thermal rearrangements with acids, ester, and amides. These isomerizations give vinylcyclopentenes resulting from divinylcyclopropane rearrangements and more deeply rearranged tricyclic spirolactams resulting from aromatic Cope rearrangements followed by ene reactions. Conversion of the carbonyl group to an alcohol or ether opens retro-ene pathways followed by either tautomerization or Claisen rearrangement.
Subject(s)
Acids/chemistry , Amides/chemistry , Cyclopropanes/chemistry , Esters/chemistry , Vinyl Compounds/chemistry , Cyclization , Free Radicals/chemical synthesis , Free Radicals/chemistry , Molecular Structure , TemperatureABSTRACT
A radical [3 + 2]-divinylcyclopropane annulation cascade has been extended to encompass five D-ring variants of the meloscine/epimeloscine core structure. Representative ABCD tetracyclic intermediates were further elaborated with novel substituted E-rings through subsequent transformations of advanced intermediates that provided opportunities for late-stage variation of the B-ring (lactam) N-substituents which were also developed.
Subject(s)
Cyclopropanes/chemical synthesis , Polycyclic Compounds/chemical synthesis , Quinolines/chemical synthesis , Cyclization , Cyclopropanes/chemistry , Models, Molecular , Molecular Structure , Polycyclic Compounds/chemistry , Quinolines/chemistryABSTRACT
Radical cyclizations of cyclic ene sulfonamides provide stable bicyclic and tricyclic aldimines and ketimines in good yields. Depending on the structure of the precursor, the cyclizations occur to provide fused and spirocyclic imines with five-, six-, and seven-membered rings. The initial radical cyclization produces an α-sulfonamidoyl radical that undergoes elimination to form the imine and a phenylsulfonyl radical. In a related method, 3,4-dihydroquinolines can also be produced by radical translocation reactions of N-(2-iodophenylsulfonyl)tetrahydroiso-quinolines. In either case, very stable sulfonamides are cleaved to form imines (rather than amines) under mild reductive conditions.
Subject(s)
Imines/chemical synthesis , Polycyclic Compounds/chemical synthesis , Sulfonamides/chemical synthesis , Sulfones/chemistry , Crystallography, X-Ray , Cyclization , Free Radicals/chemistry , Imines/chemistry , Models, Molecular , Molecular Structure , Polycyclic Compounds/chemistry , Sulfonamides/chemistryABSTRACT
The rotational preferences of N-(2-bromo-4,6-dimethylphenyl)-N-methyl 2-phenylpropanamide were studied as a model of precursors for Hartwig asymmetric oxindole cyclizations. The atropisomers of this compound were separated by flash chromatography, and then the enantiomers were resolved and the interconversions of the stereocenter and the N-Ar axis were studied. Under thermal conditions, the axis is very stable. Under the basic conditions of the Hartwig cyclization, both the stereocenter and the chiral axis equilibrate via enolate formation. The N-Ar rotation barrier of a 2-phenylacetamide analogue was reduced from 31 kcal mol(-1) in the precursor to 17 kcal mol(-1) in the enolate. Reasons for this dramatic barrier reduction and implications of both N-Ar and amide C-N rotations for Hartwig cyclizations are discussed.
Subject(s)
Benzeneacetamides/chemistry , Indoles/chemistry , Phenylpropionates/chemistry , Cyclization , Oxindoles , StereoisomerismABSTRACT
The highly conserved human and mouse SLC39A14 and SLC39A8 genes encode the ZIP14 and ZIP8 transporters, respectively-functioning as divalent cation/bicarbonate symporters and expressed in dozens of tissues. Due to alternative splicing of exons 4, human and mouse SLC39A14 genes each encode two distinct gene products, whereas SLC39A8 produces a single product. This lab previously noted that ZIP14A and ZIP14B show highly variable expression in different cell types, suggesting differences in metal uptake function. We ligated mouse ZIP14A, ZIP14B and ZIP8 cDNA coding regions into the Xenopus-specific vector pXFRM, transcribed these in vitro, and microinjected the capped RNAs into Xenopus oocytes. K(m) and V(max) values for Cd, Zn and Fe uptake were determined. Electrogenicity studies using a potassium gradient confirmed that (just as we found previously for ZIP8) ZIP14A- and ZIP14B-mediated divalent Cd- or Zn-bicarbonate complexes are electroneutral. Competitive inhibition of Cd and Zn uptake with ten additional divalent cations showed a unique gradient of patterns for each of ZIP14A, ZIP14B and ZIP8. ZIP14 proteins are prominent in the gastrointestinal tract and ZIP8 protein is located on the surface of renal proximal tubular epithelial cells. It is known that renal Fanconi syndrome can be caused by five nonessential heavy metals: Cd(2+), Hg(2+), Pb(2+), Pt(2+) and U(2+). In the present study we show that these five divalent cations are usually competitors of ZIP14- and/or ZIP8-mediated Zn uptake; our data thus support the possible involvement of intestinal ZIP14 for uptake of these five metals into the body and ZIP8 for efficient uptake into the kidney.
