Complementary Ways to Diastereomers of Bridged Aminopiperidine Derivatives - A Stereochemical Challenge

Vilsmaier, Elmar

doi:10.1002/(sici)1521-3897(200003)342:3<218::aid-prac218>3.0.co;2-o

J. prakt. Chem.

2000

DOI: 10.1002/(sici)1521-3897(200003)342:3<218::aid-prac218>3.0.co;2-o

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Complementary Ways to Diastereomers of Bridged Aminopiperidine Derivatives - A Stereochemical Challenge

Elmar Vilsmaier¹

Abstract: Abstract. Routes to diastereomers of constrained 4-aminopiperidines -a common pharmaceutically used diaminic building block -are realized mainly on the basis of CN-double bond species or their radicalic or anionic analogues. Kinetically controlled reactions on the one hand and thermodynamic control of reactions, reversible introduction of a repulsive group, direction of a reactant by intramolecular complexation, or involvement of radicalic or anionic intermediates with strong isomerization tendency on the othe… Show more

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Cited by 5 publications

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Cyclopropylamines from N,N‐Dialkylcarboxamides and Grignard Reagents in the Presence of Titanium Tetraisopropoxide or Methyltitanium Triisopropoxide

Meijere

Chaplinski

Winsel

et al. 2010

Chemistry A European J

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Thirty-three different N,N-dialkyl- and N-alkyl-N-phosphorylalkyl-substituted carboxamides 9-17 were treated with unsubstituted as well as with 2-alkyl-, 2,2-dialkyl-, and 3-alkenyl-substituted ethylmagnesium bromides 6 in the presence of stoichiometric amounts of titanium tetraisopropoxide or methyltitanium triisopropoxide to furnish substituted cyclopropylamines 20-25 in 20-98% yield, depending on the substituents with no (1:1) to excellent (>25:1) diastereoselectivities. Generally higher yields (up to 98%) of the cyclopropylamines 20-28 without loss of the diastereoselectivity were obtained with methyltitanium triisopropoxide as the titanium mediator. Under these conditions, even dioxolane-protected ketones and halogen-substituted and chiral as well as achiral alkyloxyalkyl-substituted carboxamides could be converted to the correspondingly substituted cyclopropylamines with unsubstituted as well as phenyl- and a variety of alkyl-substituted ethylmagnesium bromides in addition to numerous heteroatom-containing (e.g., halogen-, trityloxy-, tetrahydropyranyloxy-substituted) Grignard reagents (62 examples altogether). The transformation of N,N-diformylalkylamines 54 with ethylmagnesium bromide in the presence of methyltitanium triisopropoxide to N,N-dicyclopropyl-N-alkylamines 55 can be brought about in up to 82% yield (6 examples). An asymmetric variant of the titanium-mediated cyclopropanation of N,N-dialkylcarboxamides has been developed by applying chiral titanium mediators generated from stoichiometric amounts of titanium tetraisopropoxide and chiral diamino or diol ligands, respectively. The most efficient chiral mediators turned out to be titanium bistaddolates that provided the corresponding cyclopropylamines with enantiomeric excesses (ee) of up to 84%. Evaluation of several silyl-based additives revealed that the reaction can also efficiently be carried out with substoichiometric amounts (down to 25 mol%) of the titanium reagent, as long as 2-aryl- or 2-ethenyl-substituted ethylmagnesium halides are used and a concomitant slight decrease in yields is accepted. The newly developed methodology was successfully applied for the preparation of analogues with cyclopropylamine moieties of known drugs and natural products such as the nicotine metabolite (S)-Cotinine as well as the insecticides Dinotefuran and Imidacloprid.

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Cyclopropylamines from N,N‐Dialkylcarboxamides and Grignard Reagents in the Presence of Titanium Tetraisopropoxide or Methyltitanium Triisopropoxide

Meijere

Chaplinski

Winsel

et al. 2010

Chemistry A European J

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Investigation into the Chemistry of Highly Substituted [(Aminocyclopropyl)methyl]alkoxyamines (3‐Azabicyclo[3.1.0]hexanes)

2015

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Enamines prepared from N‐alkoxy‐4‐oxo‐2,2′,6,6′‐tetramethylpiperidines were selectively chlorinated in the allyl position and subsequently transformed into bicyclic [(aminocyclopropyl)methyl]alkoxyamines by reaction with various nucleophiles. The products were formed, supposedly via iminium intermediates, in reasonable to high yields, possessing varying degrees of hydrolytic stability. Structural elucidation by NMR spectroscopy strongly suggested an endo position of the amine substituent. The obtained, highly functionalized alkoxyamines could be of interest as polymer additives or biologically active intermediates.

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Synthesis of Monosaccharide‐Derived Spirocyclic Cyclopropylamines and Their Evaluation as Glycosidase Inhibitors

Blüchel¹,

Ramana²,

Vasella³

2003

Helvetica Chimica Acta

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The glucose‐, mannose‐, and galactose‐derived spirocyclic cyclopropylammonium chlorides 1a–1d, 2a–2d and 3a–3d were prepared as potential glycosidase inhibitors. Cyclopropanation of the diazirine 5 with ethyl acrylate led in 71% yield to a 4 : 5 : 1 : 20 mixture of the ethyl cyclopropanecarboxylates 7a–7d, while the Cu‐catalysed cycloaddition of ethyl diazoacetate to the exo‐glycal 6 afforded 7a–7d (6 : 2 : 5 : 3) in 93–98% yield (Scheme 1). Saponification, Curtius degradation, and subsequent addition of BnOH or t‐BuOH led in 60–80% overall yield to the Z‐ or Boc‐carbamates 11a–11d and 12a–12d, respectively. Hydrogenolysis of 11a–11d afforded 1a–1d, while 12a–12d was debenzylated to 13a–13d prior to acidic cleavage of the N‐Boc group. The manno‐ and galacto‐isomers 2a–2d and 3a–3d, respectively, were similarly obtained in comparable yields (Schemes 2 and 4). Also prepared were the differentially protected manno‐configured esters 24a–24d; they are intermediates for the synthesis of analogous N‐acetylglucosamine‐derived cyclopropanes (Scheme 3). The cyclopropylammonium chlorides 1a–1d, 2a–2d and 3a–3d are very weak inhibitors of several glycosidases (Tables 1 and 2). Traces of Pd compounds, however, generated upon catalytic debenzylation, proved to be strong inhibitors. PdCl$\rm{_{4}^{2-}}$ is, indeed, a reversible, micromolar inhibitor for the β‐glucosidases from C. saccharolyticum and sweet almonds (non‐competitive), the β‐galactosidases from bovine liver and from E. coli (both non‐competitive), the α‐galactosidase from Aspergillus niger (competitive), and an irreversible inhibitor of the α‐glucosidase from yeast and the α‐galactosidase from coffee beans. The cyclopropylamines derived from 1a–1d or 3a–3d significantly enhance the inhibition of the β‐glucosidase from C. saccharolyticum by PdCl$\rm{_{4}^{2-}}$, lowering the Ki value from 40 μM (PdCl$\rm{_{4}^{2-}}$) to 0.5 μM for a 1 : 1 mixture of PdCl$\rm{_{4}^{2-}}$ and 1d. A similar effect is shown by cyclopropylamine, but not by several other amines.

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Complementary Ways to Diastereomers of Bridged Aminopiperidine Derivatives - A Stereochemical Challenge

Cited by 5 publications

References 50 publications

Cyclopropylamines from N,N‐Dialkylcarboxamides and Grignard Reagents in the Presence of Titanium Tetraisopropoxide or Methyltitanium Triisopropoxide

Cyclopropylamines from N,N‐Dialkylcarboxamides and Grignard Reagents in the Presence of Titanium Tetraisopropoxide or Methyltitanium Triisopropoxide

Investigation into the Chemistry of Highly Substituted [(Aminocyclopropyl)methyl]alkoxyamines (3‐Azabicyclo[3.1.0]hexanes)

Synthesis of Monosaccharide‐Derived Spirocyclic Cyclopropylamines and Their Evaluation as Glycosidase Inhibitors

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Complementary Ways to Diastereomers of Bridged Aminopiperidine Derivatives - A Stereochemical Challenge

Cited by 5 publications

References 50 publications

Cyclopropylamines from N,N‐Dialkylcarboxamides and Grignard Reagents in the Presence of Titanium Tetraisopropoxide or Methyltitanium Triisopropoxide

Cyclopropylamines from N,N‐Dialkylcarboxamides and Grignard Reagents in the Presence of Titanium Tetraisopropoxide or Methyltitanium Triisopropoxide

Investigation into the Chemistry of Highly Substituted [(Aminocyclopropyl)methyl]alk­oxyamines (3‐Azabicyclo[3.1.0]hexanes)

Synthesis of Monosaccharide‐Derived Spirocyclic Cyclopropylamines and Their Evaluation as Glycosidase Inhibitors

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Investigation into the Chemistry of Highly Substituted [(Aminocyclopropyl)methyl]alkoxyamines (3‐Azabicyclo[3.1.0]hexanes)