Ronald W. Ratcliffe

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.

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 .

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.

Synthesis and activity of 2-(sulfonamido)methyl-carbapenems: Discovery of a novel, anti-MRSA 1,8-naphthosultam pharmacophore

A series of 1beta-methyl carbapenems substituted at the 2-position with lipophilic, acyclic and cyclic (sulfonamido)methyl groups was prepared and evaluated for activity against resistant gram-positive bacteria. From these studies, the 1,8-naphthosultamyl group emerged as a novel, PBP2a-binding, anti-MRSA pharmacophore worthy of further exploration.

The synthesis of novel 8a-aza-8a-homoerythromycin derivatives via the beckmann rearrangement of (9z)-erythromycin a oxime

The (9E)-oxime of erythromycin A (1) was isomerized to the (9Z)-isomer 2 in the presence of strong base. Stereospecific Beckmann rearrangement of the (9Z)-oxime led to a series of novel 8a-aza-8a- homoerythromycin A derivatives. In vitro data is provided that shows the 8a-methyl derivative 10 to be equally active with its positional isomer azithromycin.

Synthesis and properties of 2-(naphthosultamyl)methyl-carbapenems with potent anti-MRSA activity: discovery of L-786,392.

A series of 1beta-methyl-2-(naphthosultamyl)methyl-carbapenems bearing dicationic groups on the naphthosultamyl moiety was prepared and evaluated for activity against resistant gram-positive bacteria. Based on a combination of excellent in vitro antibacterial activity, acceptable mouse acute toxicity, and a desirable fragmentation pattern on beta-lactam ring opening, the analog 2g (L-786,392) was selected for extended evaluation.

Benzothiazolylthio carbapenems: potent anti-MRSA agents

Abstract A series of sulfur-linked benzothiazolyl carbapenems has been prepared and evaluated against a battery of microorganisms. Many of the compounds displayed good activity against methicillin-resistant Staphylococcus aureus (MRSA). Data is presented which delimits the pharmacophore and provides a preliminary SAR.

Preparation and activities of 4″-epi and 4″-deoxy-4″-amino analogs derived from 9-deoxo-8a-aza-8a-homoerythromycin A☆

Abstract The preparation and biological activity of the novel aza macrolides 6, 8, 11–13 and 15–20 are reported. These analogs display in vitro antibacterial properties that are superior to erythromycin A.

The preparation and reactions of 2-azidocarbapenems

Abstract The preparation of 2-azasubstituted carbapenems is reported, wherein reactions of intermediate 2-azides provide the amine, 1,2,3-triazolines, 1,2,3- triazoles, and aziridines.

Novel transannular rearrangements of azalide iminoethers

Abstract The transannular reactions between the aglycone hydroxyl groups and the iminoether and lactone groups of the 9a- and 8a-azalide iminoethers 4 and 5 were investigated under a variety of conditions. Translactonization by the 11-hydroxyl groups of 4 and 5 were found to give the corresponding 13-membered iminoethers 21 and 9. The thermal rearrangement of 4 produced an epimeric mixture of the 9,11-iminoethers 15 and 16. Further elaboration of isomer 16 produced 8-epi azithromycin 20. Finally, we have proposed an alternative structure, the amino γ-lactone 25, for one of the reported products (14) from the Beckmann rearrangement of erythromycin A (9E)-oxime 13. An authentic sample of 9a-aza-9a-homoerythromycin A 14 was prepared in three steps from iminoether 4.