Eric Hunt

Studies on the hydrolysis of clavulanic acid

1-Amino-4-hydroxybutan-2-one (14) has been identified as one of the major products from the hydrolysis of clavulanic acid in acidic, alkaline, or neutral solution. In alkaline or neutral solution, the amino ketone (14) is converted into other products, including two pyrazines, 2,5-bis(2-hydroxyethyl)pyrazine and 3-ethyl-2,5-bis(2-hydroxyethyl)pyrazine. A rationale for the formation of these products is discussed.

Synthesis of ethyl 3-methyl-7-oxo-4-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate and the reaction of 4-acetoxyazetidin-2-one with ethyl α-diazoacetoacetate

Ethyl 3-methyl-7-oxo-4-oxa-1-azobicylco[3.2.0]-hept-2-ene-2-carboxylate (4) has been obtained by a four-step synthesis from 4-methylthioazetidin-2-one and has been compared with the products obtained from the rhodium(II) acetate-catalysed reaction of 4-acetoxy-azetidin-2-one with ethyl α-diazoacetoacetate; this latter reaction did not give compound (4), as was previously claimed, but yielded ethyl 2-(4-acetoxy-2-oxoazetidinyl)-3-oxobutyrate as the major β-lactam product.

A new total synthesis of (±)-clavulanic acid

Abstract Regioselective reactions at the terminal double bond of the racemic azetidinone dienylether (4), provides a source of clavulanic acid and several analogues.

Biosynthesis of porphyrins and related macrocycles. Part II. Synthesis of δ-amino[5-13C]laevulinic acid and [11-13C] porphobilinogen: incorporation of the latter into protoporphyrin-IX

A short synthesis of δ-aminolaevulinic acid is described in which C-5 and the nitrogen atom are introduced as cyanide ion. The sequence is especially well suited to the preparation of material labelled at C-5 and it is used to afford δ-amino[5-13C]laevulinic acid; 13C chemical shifts are reported for the various products. [11-13C]Porphobilinogen is also synthesised from [13C]formaldehyde and this material is incorporated by extracts of Euglena gracilisinto protoporphyrin-IX. The 13C n.m.r. spectrum of the labelled porphyrin proves that the four signals near δ 97 arise from the meso-carbon atoms and that these positions are essentially equally labelled.

Total synthesis of (±)-clavulanic acid

A formal total synthesis of racemic clavulanic acid has been achieved commencing with (±)-4-methylthioazetidin-2-one (3).

Nuclear modification of clavulanic acid. The preparation of two 4,7-fused β-lactam systems

The 4,7-fused β-lactam compounds benzyl 3-methoxy-9-oxo-6-oxa-1-azabicyclo[5.2.0]non-2-ene-2-carboxylate and benzyl 3-methoxy-9-oxo-6-oxa-1-azabicyclo[5.2.0]nona-2,4-diene-2-carboxylate have been prepared by routes which utilise the total carbon–oxygen skeleton of benzyl clavulanate (2). The corresponding 4-nitrobenzyl esters were similarly prepared from 4-nitrobenzyl clavulanate and these were converted into the lithium carboxylates via hydrogenolysis. In an unsuccessful attempt to prepare one of these 4,7-fused ring systems, compound (2) was found to react with triethylamine to give two 14-membered ring compounds, dibenzyl (7RS, 16RS)-3,12-dihydroxy-9,18-dioxo-6,15-dioxa-1,10-diazatricyclo[14.2.0.07,10]octadeca-2,11-diene-2,11-dicarboxylate and its (7RS, 16SR)-isomer.

Total synthesis of β-lactamase inhibitors related to clavulanic acid

(E)-3-Methoxycarbonylmethylene-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane (6), its geometric isomer (7), and a related vinyl chloride (8) have been obtained by a three-step synthesis from 4-methylthioazetidin-2-one.

Total synthesis of β-lactamase inhibitors based on the 4-oxa-1-azabicyclo[3.2.0]heptan-7-one ring system

4-(2-Bromoethoxy)azetidin-2-one (4), 4-(1,3-dibromoisopropoxy)azetidin-2-one (5), 4-(1-benzyloxy-3-chloroisopropoxy)azetidin-2-one (6), 4-[(1-bromomethyl)prop-2-enoxy]azetidin-2-one (7), and 4-[3-bromo-1(bromomethyl)propoxy]azetidin-2-one (8) have been synthesised and their use for the preparation of bicyclic β-lactam compounds has been investigated. On treatment with base, (4) gave 4-oxa-1-azabicyclo[3.2.0]heptan-7-one, (5) gave (3RS, 5SR)-3-(bromomethyl)-4-oxa-1-azabicyclo[3.2.0]heptan-7-one (9) and its (3RS, 5RS)isomer (21), and (6) gave (3RS, 5SR)-3-(benzyloxymethyl)-4-oxa-1-azabicyclo[3.2.0]heptan-7-one (10) and its (3RS, 5RS)-isomer (22). Compound (7) did not undergo cyclisation; instead elimination occurred to give a conjugated diene, 4-(1-methylene-prop-2-enoxy)azetidin-2-one. Cyclisation of (8) gave not only the fivemebered-ring compound but also the six-membered-ring compound, 4-(bromomethyl)-5-oxa-1-azabicyclo[4.2.0]octan-8-one.Compounds (9) and (21) reacted with a variety of nucleophilic reagents to give products derived by displacement of bromide. Catalytic hydrogenation of (10) removed the benzyl group to give the hydroxymethyl compound. Removal of the benzyl group from (22) under these conditions gave a hydroxymethyl compound which rearranged on silica gel to give 3,9-dioxa-7-azabicyclo[4.2.1]nonan-4-one.Differences in the 1H n.m.r, spectra of pairs of stereoisomers such as (9) and (21), and (10) and (22), are discussed. Relative stereochemistries have been deduced for two natural products previously isolated from Streptomyces clavuligerus. Compound (9) and some of its relatives have been found to be β-lactamase inhibitors.

Biosynthesis of porphyrins and related macrocycles. Part VI. Nature of the rearrangement process leading to the natural type III porphyrins

Logical analysis of the problem posed by the constant formation in nature of type III porphyrins, e.g. protoporphyrin-IX (6), focuses attention on C–C bond making and bond breaking around the carbon atoms from which the interpyrrolic bridges are built (at C-5, C-10, C-15, and C-20). An approach to the study of such processes is outlined, based on double [13C] labelling combined with n.m.r. spectroscopy.[2,11-13C2]Porphobilinogen (17) has been prepared and applied (a) to determine the size of 13C–13C coupling for directly bonded carbon atoms in the porphyrin macrocycle and (b) to indicate that a biosynthetically significant 13C–13C coupling occurs between carbon atoms separated by three bonds. A coupled enzyme system has been developed from chicken blood cells and beef liver mitochondria which produces sufficient protoporphyrin-IX for spectroscopic and chemical work (20–30 mg); a similar system from Euglena gracilis is also described.[2,11-13C2] Porphobilinogen diluted with unlabelled porphobilinogen has been converted enzymically into protoporphyrin-IX; the 13C spectra of the dimethyl ester (i) as such, (ii) with a praseodymium shift reagent, and (iii) after chemical modification establish that the formation of type III porphyrins by both enzyme systems (avian and algal) is characterised by the same three precise features which are described.

Biosynthesis of type-III porphyrins: nature of the rearrangement process

During the biosynthesis of the macrocycle of natural porphyrins (type-III isomer), the porphobilinogen (PBG) unit forming ring D, and no other PBG unit, is found to undergo intramolecular rearrangement; 13C-n.m.r. measurements using double labelled [2,11-13C2] PBG were used.