Burton G. Christensen

A novel synthesis of the carbapen-2-em ring system

Abstract A new synthesis of the carbapenem ring system, as found in thienamycin and related natural products, has been developed. The key step involves a highly efficient carbene insertion reaction which produces the bicyclic ring system by forming the N3 bond.

Synthetic carbapenem antibiotics III. 1-Methyl thienamycin

Total syntheses of 1α- and 1β-methyl thienamycin are reported. 1β-Methyl thienamycin retains the antibacterial activity of thienamycin and is highly resistant to hydrolysis by DHP-I enzyme.

An efficient synthesis of 2-substituted-thio-6-hydroxyethyl-penem-3-carboxylic acids via 2-thioxopenams

Abstract Allyl and p -nitrobenzyl (5R, 6S)-6-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-2-thioxopenam-3-carboxylates ( 19 ) were synthesized by base mediated cyclization of the corresponding 1-carboxylmethyl-4-phenoxy (thiocarbonyl)thio-2-azetidinones ( 16 ). The thioxopenams underwent alkylation and Michael reactions to produce 2-alkylthio- and 2-alkenylthio-penem derivatives 20 and 21 .

The synthesis of N-(tetrazol-5-yl)azetidin-2-ones

Abstract A series of N-(tetrazol-5-yl)azetidin-2-ones have been prepared from serine and threonine and evaluated as antibiotics against a range of bacteria.

Total synthesis of (−) homothienamycin

Abstract The total synthesis of a ring expanded analog of thienamycin has been developed. The key step utilizes a highly efficient carbene insertion reaction to form the carbacephem ring system.

Nuclear analogs of β-lactam antibiotics I. The synthesis of 6β-amidocyclonocardicins

Abstract A synthesis of a cyclic analog of the β-lactam antibiotic nocardicin A and a new synthon for N-unsubstituted azetidinones is described.

Exploring the Positional Attachment of Glycopeptide/β-lactam Heterodimers

Further investigations towards novel glycopeptide/β-lactam heterodimers are reported. Employing a multivalent approach to drug discovery, vancomycin and cephalosporin synthons, 4, 2, 5 and 10, 18, 25 respectively, were chemically linked to yield heterodimer antibiotics. These novel compounds were designed to inhibit Grampositive bacterial cell wall biosynthesis by simultaneously targeting the principal cellular targets of both glycopeptides and β-lactams. The positional attachment of both the vancomycin and the cephalosporin central cores has been explored and the SAR is reported. This novel class of bifunctional antibiotics 28∼36 all displayed remarkable potency against a wide range of Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA). A subset of compounds, 29, 31 and 35 demonstrated excellent bactericidal activity against MRSA (ATCC 33591) and 31 and 35 also exhibited superb in vivo efficacy in a mouse model of MRSA infection. As a result of this work compound 35 was selected as a clinical candidate, TD-1792.

Synthetic carbapenem antibiotics II. Stereoisomers of 7-hydroxyethyl-2,2,5-trimethyl-3-oxa-1-azabicyclo[4.2.O]octan-8-one

Abstract The titled compounds are key synthetic intermediates in the structure-activity relationship studies of novel 1-methyl carbapenem antibiotics. Preparation and structural determination of these stereoisomers by x-ray crystallography and proton NMR spectroscopy are reported.

A Multivalent Approach to Drug Discovery for Novel Antibiotics

The design, synthesis and antibacterial activity of novel glycopeptide/β-lactam heterodimers is reported. Employing a multivalent approach to drug discovery, vancomycin and cephalosporin synthons, A and B respectively, were chemically linked to yield heterodimer antibiotics. These novel compounds were designed to inhibit Gram-positive bacterial cell wall biosynthesis by simultaneously targeting the principal cellular targets of both glycopeptides and β-lactams. The antibiotics 8a˜f displayed remarkable potency against a wide range of Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA). Compound 8e demonstrated excellent bactericidal activity against MRSA (ATCC 33591) and initial evidence supports a multivalent mechanism of action for this important new class of antibiotic.

Total synthesis of thienamycin analogs. II Synthesis of 2-alkyl and 2-aryl thienamycin nuclei

Abstract A new general synthesis leading to 2-alkyl and 2-aryl-1-carba-2-penem-3-carboxylic acids involves the preparation of a key thiolester intermediate 3. This is reacted with Me2CuLi or (C6H5)2MgCuX to give the corresponding methyl or phenyl ketone which undergoes a Wittig reaction to give the desired penems, which can be deblocked photolytically or by hydrogenolysis to give acids with good antibacterial activity.