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Syntheses of penicillin N, [6 alpha-3H]penicillin N and [10-14C,6 alpha-3H]penicillin N.

ABSTRACT: 1. Penicillin N was synthesized by coupling alpha-amino-alpha-p-nitrobenzyl-N-p-nitro-benzyloxycarbonyl-D-adipate with 6-aminopenicillanic acid benzyl ester, followed by removal of the protecting groups through hydrogenolysis. 2. alpha-Amino-alpha-p-nitrobenzyl-N-p-nitrobenzyloxycarbonyl-D-[5-14C]adipate was prepared by treating alpha-p-nitrobenzyl-N-p-nitrobenzyloxycarbonyl-D-glutamic acid with [14C]diazomethane followed by rearrangement with silver trifluoromethanesulphonate. 3. Coupling of alpha-amino-alpha-p-nitrobenzyl-N-p-nitrobenzyloxycarbonyl-D-[5-14C]adipate with 6-aminopenicillanic acid benzyl ester gave triprotected [10-14C]penicillin N. 4. 3H was introduced at C-6 of the Schiff's base derivative (10) by oxidation followed by reduction with NaB3H4. 5. The so-derived (6 alpha-3H)-labelled Schiff's base was hydrolysed to give 6-amino [6 alpha-3H]penicillanic acid benzyl ester p-toluenesulphonic acid salt, which after coupling as the free amine with alpha-amino-alpha-p-nitrobenzyl-N-pnitrobenzyloxycarbonyl-D-adipate and then hydrogenolysis, yielded [6alpha-3H]penicillin N. 6. Triprotected [10-14C]penicillin N and triprotected [6alpha-3H]penicillin N in admixture were hydrogenolysed to give [10-14C,6alpha-3H]penicillin N.

SUBMITTER: Baldwin JE

PROVIDER: S-EPMC1161725 | biostudies-other | 1980 Mar

REPOSITORIES: biostudies-other

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Project description:1. [2-(3)H,U-(14)C]- or [3-(3)H,U-(14)C]-Lactate was administered by infusion or bolus injection to overnight-starved rats. Tracer lactate was injected or infused through indwelling cannulas into the aorta and blood was sampled from the vena cava (A-VC mode), or it was administered into the vena cava and sampled from the aorta (V-A mode). Sampling was continued after infusion was terminated to obtain the wash-out curves for the tracer. The activities of lactate, glucose, amino acids and water were followed. 2. The kinetics of labelled lactate in the two modes differed markedly, but the kinetics of labelled glucose were much the same irrespective of mode. 3. The kinetics of (3)H-labelled lactate differed markedly from those for [U-(14)C]lactate. Isotopic steady state was attained in less than 1h of infusion of [(3)H]lactate but required over 6h for [U-(14)C]lactate. 4. (3)H from [2-(3)H]lactate labels glucose more extensive than does that from [3-(3)H]lactate. [3-(3)H]Lactate also labels plasma amino acids. The distribution of (3)H in glucose was determined. 5. Maximal radioactivity in (3)HOH in plasma is attained in less than 1min after injection. Near-maximal radioactivity in [(14)C]glucose and [(3)H]glucose is attained within 2-3min after injection. 6. The apparent replacement rates for lactate were calculated from the areas under the specific-radioactivity curves or plateau specific radioactivities after primed infusion. Results calculated from bolus injection and infusion agreed closely. The apparent replacement rate for [(3)H]lactate from the A-VC mode averaged about 16mg/min per kg body wt. and that in the V-A mode about 8.5mg/min per kg body wt. The apparent rates for [(14)C]lactate (;rate of irreversible disposal') were 8mg/min per kg body wt. for the A-VC mode and 5.5mg/min per kg body wt. for the V-A mode. Apparent recycling of lactate carbon was 55-60% according to the A-VC mode and 35% according to the V-A mode. 7. The specific radioactivities of [U-(14)C]glucose at isotopic steady state were 55% and 45% that of [U-(14)C]lactate in the A-VC and V-A modes respectively. We calculated, correcting for the dilution of (14)C in gluconeogenesis via oxaloacetate, that over 70% of newly synthesized glucose was derived from circulating lactate. 8. Recycling of (3)H between lactate and glucose was evaluated. It has no significant effect on the calculation of the replacement rate, but affects considerably the areas under the wash-out curves for both [2-(3)H]- and [3-(3)H]-lactate, and calculation of mean transit time and total lactate mass in the body. Corrected for recycling, in the A-VC mode the mean transit time is about 3min, the lactate mass about 50mg/kg body wt. and the lactate space about 65% of body space. The V-A mode yields a mass and lactate space about half those with the A-VC mode. 9. The area under the wash-out curve for [(14)C]lactate is some 20-30 times that for [(3)H]lactate, and apparent carbon mass is 400-500mg/kg body wt. and presumably includes the carbon of glucose, pyruvate and amino acids, which are exchanging rapidly with that of lactate.

Project description:Alpha-amino acids are the building blocks of proteins and are widely used as components of medicinally active molecules and chiral catalysts. Efficient chemo-enzymatic methods for the synthesis of enantioenriched alpha-amino acids have been developed, but it is still a challenge to obtain non-natural amino acids. Alkene hydrogenation is broadly useful for the enantioselective catalytic synthesis of many classes of amino acids, but it is not possible to obtain alpha-amino acids bearing aryl or quaternary alkyl alpha-substituents using this method. The Strecker synthesis-the reaction of an imine or imine equivalent with hydrogen cyanide, followed by nitrile hydrolysis-is an especially versatile chemical method for the synthesis of racemic alpha-amino acids. Asymmetric Strecker syntheses using stoichiometric amounts of a chiral reagent have been applied successfully on gram-to-kilogram scales, yielding enantiomerically enriched alpha-amino acids. In principle, Strecker syntheses employing sub-stoichiometric quantities of a chiral reagent could provide a practical alternative to these approaches, but the reported catalytic asymmetric methods have seen limited use on preparative scales (more than a gram). The limited utility of existing catalytic methods may be due to several important factors, including the relatively complex and precious nature of the catalysts and the requisite use of hazardous cyanide sources. Here we report a new catalytic asymmetric method for the syntheses of highly enantiomerically enriched non-natural amino acids using a simple chiral amido-thiourea catalyst to control the key hydrocyanation step. This catalyst is robust, without sensitive functional groups, so it is compatible with aqueous cyanide salts, which are safer and easier to handle than other cyanide sources; this makes the method adaptable to large-scale synthesis. We have used this new method to obtain enantiopure amino acids that are not readily prepared by enzymatic methods or by chemical hydrogenation.

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Syntheses of penicillin N, [6 alpha-3H]penicillin N and [10-14C,6 alpha-3H]penicillin N.

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