D/-VALiNE

ANTIBIOTICS - BETA-LACTAMS - PENICILLINS AND OTHEPE] (Vol 3) d-(L-a-Aminoadipyl)-L-cysteinyl-D-valine (LLD-ACV) [32467-88-2]... 

Almost all actinomycins have the same chromophore, a planar phenoxa2inone dicarboxyUc acid called actinocin. In dactinomycin, the stmcture of which is shown in Figure 12, the two pendent pentapeptide lactones are identical, but in other actinomycins these lactones may be different. In other actinomycins the first amino acid, amide linked with actinocin, is usually L-threonine, as in dactinomycin the second position is sometimes D-aHo-isoleucine instead of D-valine the third position may be sarcosine or oxoproline the fourth position is sarcosine and the fifth position is sometimes /V-methyl isoleucine instead of /V-methylvaline. The lactone ring is always present. 

Amino-4,6-dimethyl-3-oxo-3//-phenoxazine-l,9-dicarboxylic acid also named actinocin is the chromophor of the red antineoplastic chromopeptide aetinomyein D (formula A). Two cyclopenta-peptide lactone rings (amino acids L-threonine, D-valine, L-proline, sarcosine, and 7V-methyl-L-valine) are attached to the carboxy carbons of actinocin by two amide bonds involving the amino groups of threonine. 

Therapeutic Function Used in treatment of rheumatoid arthritis Chemical Name 3-Mercapto-D-valine Common Name Dimethylcysteine... 

The first biosynthetic steps are two reactions that generate ACV from its constituent amino acids L-a-aminoadipic add, L-cysteine and L-valine. L-a-aminoadipic acid and L-cysteine are condensed by the enzyme AC synthetase and, in the next step, the resultant 8-(L-a-aminoadipyl)-L-cysteine is coupled with L-valine. In this step the configuration of L-valine is inverted to D-valine. 

Figure 6.9 Formation of isopenicillin N from its constituent amino acids. After condensation of L-a-aminoadipic acid with L-cysteine, L-valine is coupled. During this transformation, the configuration of the latter amino acid inverts to give D-valine.

Originally, 1 was prepared by medicinal chemists from three key components, namely, a cyclopentanone moiety 2, a pyrazole moiety 3, and commercially available D-valine, as depicted in Scheme 2.1 [1], These synthetic disconnections provided an applicable and convergent route to 1, and consequently, were utilized in our strategy to develop an efficient and scalable synthesis of 1. 

Since preparation of pyrazole 3 was deemed straightforward (vide infra.) and D-valine tert-butyl ester was commercially available, our efforts focused on developing a synthesis of tbe more challenging cyclopentanone 2 [3], The original synthetic method for 2 by medicinal chemists is depicted in Scheme 2.2. 

The (5-lactam antibiotics are now so extensively described that we cannot attempt to summarize the literature. Since our emphasis is on sulfur, we note that the sulfur atoms of the thiazolidine or dihydrothiazine rings derive from a common tripeptide, 8-(L-a-aminoadipyl)-L-cysteinyl-D-valine 1, ACV or Arnstein tripeptide . ACV is converted to a (5-lactam structure, isopenicillin N 2 and thereafter, the two pathways diverge, i.e. to benzylpenicillin 3 or to cephalosporin C 4 (Scheme 1). There have been extensive studies of the genes and enzymes involved in (5-lactam biosynthesis.18,19... 

Christensen16 isolated the dipeptide valylvaline from completely hydrolyzed gramicidin. This worker later showed that he had isolated a racemic mixture of D(-)-valyl-D(-)-valine and L(+)-valyl-L(4)-valine rather than dipeptides containing one d and one L-residue.17... 

Still using heterogeneous gramicidin, Synge24 isolated the D-leucylglycine, L-alanyl-D-valine and L-alanyl-D-leucine from partial hydrolysates of gramicidin. He also had less conclusive evidence for the tripeptides alanyl-valylleucine or alanylleucylvaline. 

Hinman, Caron and Christensen26 corrected the earlier report by Christensen16. They reported that the dipeptides found on the hydrolysis of gramicidin were D-valyl-L-valine and L-valyl- D-valine. 

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