Synthesis of novel fused β-lactams by intramolecular 1,3-dipolar cyclo-additions. Part 7. (9RS,9aRS)-9,9a-dihydro-5-methyl-8-oxo-9-phenoxyacetamido-8H-azeto[1,2-a]-v-triazolo[5,1-c]pyrazine-6-carboxylic acids and (3bRS,4RS,7SR)-4,5-dihydro-5-oxo-4-phenoxyacetamido-3bH-azeto[1′,2′:3,4]-imidazo[1,5-c]-v-triazole-7-carboxylic acid
“…Structure−activity relationship studies of a series of O -2-isocephems have revealed promise for this class as orally absorbed antibiotics that exhibit comparable or better activity against some common pathogenic bacteria relative to the analogous cephalosporins. Additionally, the development of methodology for the preparation of multicyclic β-lactams has attracted considerable interest as the syntheses of a number of novel multicyclic β-lactams have been reported recently 2 and some of these compounds have potent biological activity. , …”
The reaction of Ox-glycyl chloride with a chiral imine derived
from the combination of d-(R)-glyceraldehyde acetonide and protected d-threonine afforded
optically active, highly functionalized
cis-substituted β-lactams 11 and 12.
These β-lactams provide versatile intermediates for
the
syntheses of biologically important carbacephalosporins, isooxacephems,
and other multicyclic
β-lactams. Desilylation and oxidation of 12 with
Dess−Martin periodinane followed by intramolecular cyclization produced a novel tricyclic β-lactam 17
and a 1-(hydroxymethyl)-O-2-isocephem
18 with [6R,7R] absolute
configuration. Removal of the Ox protecting group and acylation of
17 in
a one-pot reaction followed by saponification furnished the target salt
24. Alternatively, reaction
of phthaloylglycyl chloride with the chiral imine derived from the
combination of l-(S)-glyceraldehyde
acetonide and protected d-threonine gave only one
enantiomeric azetidinone 27 in high yield.
Further manipulation of 27 provided a new tricyclic
β-lactam 39 with [6S,7S] absolute
configuration
which satisfies the stereochemistry typically required for
antibacterial activity. This synthetic
procedure provides a short, versatile and enantioselective method of
preparing polycyclic β-lactams.
Biological testing of these tricyclic β-lactams indicated that
salt 39 has potential inhibitory activity
against four typical strains of bacteria.
“…Structure−activity relationship studies of a series of O -2-isocephems have revealed promise for this class as orally absorbed antibiotics that exhibit comparable or better activity against some common pathogenic bacteria relative to the analogous cephalosporins. Additionally, the development of methodology for the preparation of multicyclic β-lactams has attracted considerable interest as the syntheses of a number of novel multicyclic β-lactams have been reported recently 2 and some of these compounds have potent biological activity. , …”
The reaction of Ox-glycyl chloride with a chiral imine derived
from the combination of d-(R)-glyceraldehyde acetonide and protected d-threonine afforded
optically active, highly functionalized
cis-substituted β-lactams 11 and 12.
These β-lactams provide versatile intermediates for
the
syntheses of biologically important carbacephalosporins, isooxacephems,
and other multicyclic
β-lactams. Desilylation and oxidation of 12 with
Dess−Martin periodinane followed by intramolecular cyclization produced a novel tricyclic β-lactam 17
and a 1-(hydroxymethyl)-O-2-isocephem
18 with [6R,7R] absolute
configuration. Removal of the Ox protecting group and acylation of
17 in
a one-pot reaction followed by saponification furnished the target salt
24. Alternatively, reaction
of phthaloylglycyl chloride with the chiral imine derived from the
combination of l-(S)-glyceraldehyde
acetonide and protected d-threonine gave only one
enantiomeric azetidinone 27 in high yield.
Further manipulation of 27 provided a new tricyclic
β-lactam 39 with [6S,7S] absolute
configuration
which satisfies the stereochemistry typically required for
antibacterial activity. This synthetic
procedure provides a short, versatile and enantioselective method of
preparing polycyclic β-lactams.
Biological testing of these tricyclic β-lactams indicated that
salt 39 has potential inhibitory activity
against four typical strains of bacteria.
Additionsreaktion des Mischanhydrids (IV) mit der aus den Komponenten (I) und (II) erhältlichen Schiffbase (III) gibt die isomeren Lactame (Va) (3 z2‐Isomerengemisch) und (Vb) + (Vc); (Vb) wird dann wie angegeben in die Titelverbindung (IXa) übergeführt.
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