Toshio Kumagai

Novel efficient synthesis of 1-azabicyclo[1.1.0]butane and its application to the synthesis of 1-(1,3-thiazolin-2-yl)azetidine-3-thiol useful for the pendant moiety of an oral 1β-methylcarbapenem antibiotic L-084

1-Azabicyclo[1.1.0]butane 2 was successfully synthesized by treatment of 2,3-dibromopropylamine hydrobromide 4 with organolithium compounds and was readily converted to 1-(1,3-thiazolin-2-yl)azetidine-3-thiol hydrochloride 1 and versatile azetidine derivatives 9 and 10.

Current Status of Oral Carbapenem Development

Since the discovery of thienamycin (1) in 1976, many studies on the synthesis and structure-activity relationships of parenteral-use drugs have been done and several carbapenems, imipenem (2), panipenem (3), and meropenem (7), have been marketed. The development of oral carbapenems, however, is a fairly slow process because carbapenems are considered unstable in the stomach and intestine. Recently, several orally active carbapenems without stability problems have been developed as prodrug esters or prodrug peptides, including GV-118819 (12), CS-834 (13), L-084 (14), DZ-2640 (15), and peptidic derivatives of CL 191,121 (16). The active forms (35), (41), (44), (45), (16) of these prodrugs exhibited potent and well balanced antibacterial activities as well as resistance to renal dehydropeptidase-I. The pharmacokinetic parameters of compounds (12), (13), (14), and ( 15) after oral administration to healthy volunteers were reported. The half-life (t1/2) of GV-118819 (12) was longer than that of the other compounds, while the Cmax, AUC and urinary excretion rate of L-084 (14) were higher than those of the others. In this review, the synthesis, chemical and biological properties, and pharmacokinetics of these oral carbapenems are described.

Syntheses and Pharmacokinetic Studies of Prodrug Esters for the Development of Oral Carbapenem, L-084

We discovered an orally active carbapenem, L-084, through pharmacokinetic studies on various prodrug esters of (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[1-(1,3-thiazolin-2-yl)azetidin-3-yl]thio-1-carbapen-2-em-3-carboxylic acid (LJC11,036). L-084 showed a strong antimicrobial activity against Gram-positive and Gram-negative bacteria and exhibited the highest intestinal absorption among synthesized prodrugs of LJC11,036.

Mild and chemoselective cleavage of p-nitrobenzyl esters and p-nitrobenzyloxycarbonyl amines with zinc dust

p-Nitrobenzyl esters and p-nitrobenzyloxycarbonyl amines have been efficiently deprotected by treatment with zinc dust in THF - 0.35 M phosphate buffer solution (pH 6) to obtain the parent carboxylic acids and amines. Olefinic bond, S-N bond, and diphenylmethyl- and benzyloxycarbonylamino groups are intact under the deprotection conditions

Asymmetric total synthesis of a new non-natural 1β-methoxycarbapenem

The asymmetric total synthesis of the new non-natural 1β-methoxycarbapenem (1) has been achieved via highly diastereoselective alkylation at the C-4 position of 4-acetoxyazetidin-2-one (4) with the tin enolate of thiazolidinethione (3); the stereochemistry has been confirmed by an X-ray crystal structure determination of the derivative (13).

On the Absolute Configuration in 1,4-Dihydrothiazepine Covalent Complexes Derived from Inhibition of Class A and C β-Lactamases with 6-Methylidene Penems

Serine and metallo b-lactamases catalyze the hydrolysis of blactam rings in all classes of blactam antibiotics which is a major cause of bacterial resistance to b-lactam antibiotics. Bacterial resistance is addressed clinically by combining a b-lactamase inhibitor, such as clavulanic acid, sulbactam, or tazobactam, with a b-lactam antibiotic (amoxicillin or piperacilin). Whereas this strategy is effective with the class A b-lactamase inhibitors, there is an urgent need to extend the spectrum of activity to the other classes of serine b-lactamases including the class C enzymes. Recently, new promising inhibitors of class C b-lactamases such as NXL104, AVE1330A, and diaroylphosphates have been disclosed. Reports from our laboratories on 6-methylidene penems as mechanism-based inhibitors of serine-reactive class A and C b-lactamases disclosed extensive structure–activity relationships with penems containing monocyclic, [6,5]-bicyclic,and [5,5,5]-tricyclic heterocycles that adopt the Z configuration at the C6 position. The mode of action of penem inhibitors involves acylation by the catalytic serine residues followed by b-lactam ring opening and a sequence of transformations amounting to a remarkable 7-endo trig rearrangement reaction. Penems 1–3 have been studied by a plethora of methods to establish the formation of the 1,4-dihydrothiazepine acyl–enzyme complex (Figure 1). The complex is stable to hydrolysis because of the displacement of water molecules. However, an issue concerns the absolute stereochemistry of the C7 moiety bearing the heterocyles. In dihydrothiazepine 4 bearing the methyltriazolyl heterocyle, the S-stereochemistry is evidenced by kinetic, computational, and X-ray crystallographic studies in class A and C enzymes. The dihydroimidazo ACHTUNGTRENNUNG[2,1-c]oxazine thiazepine 5 exists as the R-isomer in the crystal structure of both SHV-1 and GC1 enzymes. A novel hydrophobic p-p stacking interaction between the C7 heterocycle with Tyr105 in SHV-1 and Tyr224 in GC1 was revealed. Furthermore, calculated interaction energy differences between C7R and C7S isomers of eight 6-methylidene penems bearing [6,5]-fused bicyclic heterocycles favor the formation of the C7R over the C7S enantio-

The first asymmetric total synthesis of thienamycin-like γ-lactam and its analogue

The asymmetric total synthesis of thienamycin-like γ-lactam 1 and its analogue 2 has been accomplished by utilising highly diastereoselective alkylation of tin(II) enolate 5 on acyl imine obtained in situ from chiral 3-substituted 5-acetoxypyrrolidin-2-one 3.

Asymmetric Synthesis of New Non-natural 1b-Methylcarbapenems Bearing Methylthio Group at the C6-Position

The asymmetric total synthesis of new non-natural 1β-methylcarbapenems (1 and 2) has been accomplished starting from optically active C4-substituted azetidin-2-one (4)

Use of chiral 1,3-oxazolidine-2-thiones in the diastereoselective synthesis of aldols

A useful diastereoselective synthesis of aldols using chiral 3-acyl-1,3-oxazlidine-2-thiones, (1), (4), (7), and (9), is reported and its application to the synthesis of a chiral azetidinone (11) is described.

A general synthesis of chiral C-4-alkylated azetidin-2-ones which are of potential use as intermediates for 1β-heteroatom-substituted carbapenems

A highly diastereocontrolled alkylation at the C-4 position of 4-acetoxyazetidin-2-one (5) employing chiral tin(II) enolates of heteroatom-substituted acetyl derivatives (3a–e) furnishes new synthetic intermediates (6a–e) for 1β-heteroatom-substituted carbapenems (2).