Tabtoxinine

Tabtoxin J is a dipeptide exotoxin produced by Pseudomonas tabaci, the organism responsible for the wildfire disease of tobacco plants [141]. When hydrolyzed by peptidase, in vivo, this exotoxin releases tabtoxinine-p-lactam K, which inhibits Glutamine synthetase of the photorespiratory nitrogen cycle, causing chlorosis and death of tobacco plants [142]. 

As the dipeptide J itself does not inhibit purified Glutamine synthetase in vitro [143], the amino acid K is considered to be the active form of J and hence, the actual toxin of wildfire disease. Since, the detailed mechanism of Glutamine synthetase inhibition by tabtoxinine-(3-lactam attracts chemical interest, a synthetic approach to the toxin K and its analogs, is of increasing importance. Spiro-(3-lactam L (Fig. 11) has been found to be an efficient precursor of toxin K. 

Baldwin and co-workers have used a nitroso Diels-Alder reaction as a key step in total synthesis of tabtoxin (17), a metabolite causing leafspot disease in tobacco.41 This group has also prepared tabtoxinine /3-lactam (18), the active principle generated by in vivo enzymatic hydrolysis of 17. 

The synthesis of tabtoxinine /3-lactam is briefly outlined in Scheme 3-XII. The initial nitroso formate cycloaddition was totally regioselective and provided the basic functionality needed to ultimately prepare 18. 

A Wittig reaction of 689 with Ph3P=CHCH2CH20Li initiates the synthetic sequence leading to (— )-tabtoxinine j -lactam (806), a potent irreversible inhibitor of glutamine synthetase [224] (Scheme 107). The resultant homoallylic alcohol 793 is formed as a 20 1... 

Ozonolysis of 802 followed by PCC oxidation of the resultant mixture of lactols furnishes a 1 1 mixture of spiro lactams. The desired diastereomer 803 is readily separated by fractional crystallization. Careful hydrolysis of the lactone with In NaOH in THF—H2O (3 1) gives the Cbz-protected tabtoxinine j -lactam 805 in good yield. 

Historically thought to be the active toxin itself, tabtoxin is a precursor that must undergo hydrolysis by a peptidase to yield the biologically active form of a mono-cyclic p-lactam antibiotic (BLA) that is produced by several pathovars and isolates of Pseudomonas syringae, namely tabtoxinin-p-lactam, whose structure is 28 and was isolated in 1978 (Figure 4.12) [43]. 

Figure 4.12 Structure of tabtoxin 27, tabtoxinin-p-lactam 28, and the tabtoxin C-labeling pattern from the incorporation of L-[mef/tyZ- C]methionine, L-[l,2- C2]aspartate, L-[3,4- C2]aspartate, rac-[l,2- C2]glycerol, and [l,2- C2]acetate.

Tabtoxinine-/3-lactam (T/3L), a Tobacco Wildfire Disease Toxin. 204... 

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