Total synthesis of δ-(L-α-aminoadipyl)-L-cysteinyl-D-valine (ACV), a biosynthetic precursor of penicillins and cephalosporins

Abstract

. 57, 1388 (1979.The title compound has been synthesized as its disulfide by a classical route from the fully protected precursor N-BOC-S-trity~-6-(~-a-aminoadipyl)-~-cysteiny-~-vaine bisbenzhydryl ester. Deprotection has been achieved by oxidative removal of the trityl group with iodine, followed by removal of BOC and benzhydryl using trifluoroacetic acid. The final product is obtained in 23% overall yield from D-valine.SAUL WOLFE et MARK GORDON JOKINEN. Can. J. Chem. 57,1388Chem. 57, (1979.On a synthetise le compose mentionnt dans le titre sous forrne de disulfure par une voie classique a partir du precurseur complktement protege qui est I'ester bisbenzhydrylique de la C2-S bonds (3) of penicillin are formed with reten-In this synthesis, the final product and most of the tion of configuration, to proven chemical mech-intermediates have been obtained in crystalline form anisms. The principal reason for the lack of progress and have been characterized fully. on this aspect of the problem is that studies of the Four syntheses of ACV and (or) its stereoisomers fate of ACV and (or) the role of post-ACV inter-have been reported previously in the literature (6-9). mediates require that protoplasts or protoplast Two of these (6, 7) were directed specifically towards lysates (4) derived from P. chrysogenum or C. the LLL isomer; however, the experimental details of acremonium be employed in the biosynthetic experi-Rudinger's synthesis (6) have not yet been presented, ments. The required techniques have only become and spectroscopic and analytical data were not given available in recent years, as a result of the important for the peptide intermediates and the final product work of Abraham and his co-workers (5).of Bauer's synthesis (7). Only the synthesis of Fawcett There are, therefore, two prerequisites for any et al. (9) has been accompanied by full experimental planned investigation of the oxidative stages of details and microanalytical data for the various penicillin biosynthesis. The first is a protoplast or intermediates. In this latter work, three separate protoplast lysate system that will convert ACV deprotecting steps were needed, and the final product efficiently into penicillin; the second is a supply of was obtained in 8.5% yield from the fully protected labelled ACV. We wish to disclose a new total tripeptide. synthesis of ACV (as its disulfide), which makes thisThe syntheses of Adriaens et al. (8) and Fawcett et compound readily available for biosynthetic studies. al. (9) include an alkaline hydrolysis of a protected

Penicillin formation by cell-free extracts of Streptomycesclavuligerus. Behaviour of aminoadipyl-modified analogs of the natural peptide precursor δ-(L-α-aminoadipyl)-L-cysteinyl-D-valine (ACV)

“…This compound was synthesized from 15 and N-BOC-L-aspartic acid-a-benzhydryl ester as described for ACV (23), except that the final deprotection was accomplished with formic acid (16 h …”

“…In an earlier synthesis of ACV (23) , 15 was prepared by N-detritylation of a N,S-ditritylated found that a 15-min treatment with a 98-100% formic acid leads to selective removal of the tert-butoxycarbonyl protecting group of 16 (23), and provides the intermediate 15 as a crystalline compound in over 80% yield. This is an improvement over the earlier sequence, because of the higher yield in the introduction of the nitrogen protecting group, and the greater ease of coupling of the cysteinyl and valinyl moieties when N-tert-butoxycarbonyl is employed in place of N-trityl.…”

High performance liquid chromatography (HPLC) of natural products. V. The use of HPLC in the cell-free biosynthetic conversion of .ALPHA.-aminoadipyl-cysteinyl-valine (LLD) into isopenicillin N.

“…XXXV NO. 5 THE JOURNAL OF ANTIBIOTICS product VIa. When the latter was injected into the HPLC system (Microbondapak C-18, methanolacetonitrile -acetic acid -water, 36: 7: 2: 55), it had an identical retention time as an authentic sample of isopenicillin N reacted with GITC (Fig.…”

Synthesis and conformations of α-aminoadipyl- and glycyl-α-aminoadipylthiazepine sulfoxides

“…The organic layer was dried and evaporated to give a pale golden syrup, which, upon removal of the last traces of solvent under high vacuum, gave a white foam, 611.9 mg (100% yield); [aIDzs6 +9. ~-Carbobenzoxyamino-4~carbomethoxy-3,3-dimethyl-6-oxoperhydro-l,2,5-dithiazocine (17) (39) A solution of iodine (317 mg, 1.25 mmol) in methanol (14 mL) was stirred at room temperature and a solution ofthedipeptide 19 (306 mg, 0.5 mmol) in methanol (8.0 mL) was added dropwise during 1 h. The reaction mixture was stirred for an additional 15 min, and the solution was then cooled to OOC and the excess iodine destroyed by addition of 5% sodium thiosulfate solution (5.2 mL). The mixture was neutralized with saturated sodium bicarbonate (1.3 mL) and then evaporated to dryness.…”

“…The Boc-protected aminoadipylthiazepine 30 could also be converted to 31, in an overall 50% yield, by selective removal of Boc (p-TsOH, Et20, CH2C12, reflux, 12 h (27)), followed by neutralization and condensation with 15. Complete deprotection of 30 and 31 was achieved initially using a mixture of trifluoroacetic acid and anisole, as described previously (17). Subsequently, overnight treatment with formic acid was found to be equally effective.…”