A variety of novel syn-2-alkoxy-3-amino-3-arylpropan-1-ols was prepared through LiAlH(4)-promoted reductive ring-opening of cis-3-alkoxy-4-aryl-beta-lactams in Et(2)O. The latter gamma-aminoalcohols were easily converted into cis-5-alkoxy-4-aryl-1,3-oxazinanes using formaldehyde in THF. Both series of compounds were evaluated against a chloroquine sensitive strain of Plasmodium falciparum (D10), revealing micromolar potency for almost all representatives. Eleven compounds exhibited antimalarial activity with IC(50) values of
A new and efficient one‐pot approach towards chiral azetidin‐2‐ones has been developed starting from (2S)‐chloro‐1‐propanol, affording novel β‐lactams in high diastereomeric (80–89 %) and enantiomeric excess (90 %).
Stereoselective Synthesis of Chiral 4-(1-Chloroalkyl)-β-Lactams Starting fromAmino Acids and Their Transformation into Functionalized Chiral Azetidines and Pyrrolidines. -Treatment of amino acids with NaNO2 and HCl followed by reduction and selective oxidation provides a new, convenient approach to α-chloroaldehydes. These compounds are converted into β-lactams of type (V) with good stereoselectivity. Reduction of the latter gives chiral azetidines which upon heating allow stereoselective access to highly substituted pyrrolidines. -(DEKEUKELEIRE, S.; D'HOOGHE, M.; TOERNROOS, K. W.; DE KIMPE*, N.; J.
cis-4-(1-Chloro-1-methylethyl)-1-(omega-hydroxyalkyl)azetidin-2-ones were diastereoselectively transformed into novel trans-1-aza-4-oxabicyclo[3.3.0]octan-8-ones and trans-1-aza-5-oxabicyclo[4.3.0]nonan-9-ones upon treatment with 1 equiv of AgBF4 and pyridine in toluene via intramolecular nucleophilic trapping of N-acyliminium intermediates by the hydroxyl moiety. Additionally, the corresponding aza-analogues of the aforementioned bicyclic gamma-lactams (i.e., trans-1,4-diazabicyclo[3.3.0]octan-8-ones and trans-1,5-diazabicyclo[4.3.0]nonan-9-ones) were prepared in a convenient way starting from cis-4-(1-chloro-1-methylethyl)-1-{omega-[(tert-butoxycarbonyl)amino]alkyl}azetidin-2-ones applying the same reaction conditions. The intermediate N-acyliminium ions were formed by ring expansion of the starting beta-lactams through generation of a transient silver(I)-induced carbenium ion.
trans- and cis-1-Alkyl-4-aryl-3-chloroazetidin-2-ones, prepared through cyclocondensation of chloroketene and the appropriate imines in a diastereoselective way, were transformed into the corresponding non-activated trans- and cis-2-aryl-3-(hydroxymethyl)aziridines via reductive ring contraction using LiAlH(4) in Et(2)O. Furthermore, trans-2-aryl-3-(hydroxymethyl)aziridines were transformed into 2-amino-3-arylpropan-1-ols and anti-2-amino-3-aryl-3-methoxypropan-1-ols by means of an unprecedented ring opening by LiAlH(4) and by MeOH, respectively. cis-2-Aryl-3-(hydroxymethyl)aziridines were shown to be highly reluctant to undergo ring opening by LiAlH(4) and MeOH under similar reaction conditions.
β-Lactams represent flexible building blocks suitable for the preparation of a large variety of nitrogen-containing target compounds. In the present study, the formerly neglected synthetic potential of 4-haloalkyl-β-lactams has been elaborated in detail with a focus on the preparation of different mono-and bicyclic heterocycles. A first approach involved ring transformations of these halogenated building blocks toward stereodefined aziridines, azetidines, pyrrolidines, and piperidines via intermediate aziridinium or azetidinium ions. In a second part, novel and stereoselective entries into 1,4-and 3,4-fused bicyclic β-lactams were developed through either a radical or an ionic cyclization protocol. Furthermore, the ring enlarge ment of halogenated β-lactams into functionalized mono-and bicyclic pyrrolidin-2-ones was established as the aza-analog of the cyclobutylmethylcarbenium ion to cyclopentylcarbenium ion rearrangement. Finally, chiral versions toward azetidin-2-ones and ring transformation products were elaborated, involving the synthesis of 3(S)-alkoxy-4(S)-[1(S)-chloroethyl]azetidin-2-ones and the preparation of bicyclic β-lactams annelated to piperazines, morpholines, and diazepanes.
SummaryA variety of 2-amino-3-arylpropan-1-ols, anti-2-amino-3-aryl-3-methoxypropan-1-ols and anti-2-amino-1-arylpropan-1,3-diols were prepared selectively through elaboration of trans-4-aryl-3-chloro-β-lactams. In addition, a number of 2-(azidomethyl)aziridines was converted into novel 2-[(1,2,3-triazol-1-yl)methyl]aziridines by Cu(I)-catalyzed azide-alkyne cycloaddition, followed by microwave-assisted, regioselective ring opening by dialkylamine towards 1-(2,3-diaminopropyl)-1,2,3-triazoles. Although most of these compounds exhibited weak antiplasmodial activity, six representatives showed moderate antiplasmodial activity against both a chloroquine-sensitive and a chloroquine-resistant strain of Plasmodium falciparum with IC50-values of ≤25 μM.
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