Synthesis of Pantothenic Acid

Decarboxylation of aspartic acid presumably does not occur in certain yeasts which require 8-alanine for growth in media containing aspartic acid (101) nor in strains of Corynebacterium diphtheriae which require added /3-alanine for growth in the presence of a casein hydrolyzate (84). Of the latter organisms, some were able to utilize f-carnosine (but not the d-isom-eride) in place of 8-alanine, but this resulted in a delay in their growth which did not occur when /3-alanine was used. The quantities required of /3-alanine were small and its production from carnosine is also presumably of the order of some m/iM per mg. organisms per hour (83). 

Synthesis of Pantothenate. Inhibition of the growth of yeasts from 8-alanine by aspartic acid (89,90) and by asparagine (101,120) has been ascribed to inhibition of the synthe.sis of pantothenic acid from /3-alanine. In the latter instance inhibition with several strains could be prevented by higher concentrations of /3-alanine or by replacing 8-alanine by pantothenic acid (101). Inhibition of growth of yeasts from /3-alanine was cau.sed also by 8-aminobutyric acid, and a similar explanation has been given (38,88). Systems concerned in the synthesis have been studied (124). 

In the case of two bacterial species, the rates of synthesis of pantothenate by growing and nongrowing organisms have been compared (70). 

Rates or Stnthesis and Inactivation of Pantothenate by Growing AND Nongrowing Bacteria (70) 

Escherichia coli Inorganic salts Inorganic salts with glucose +0.26 +2.8 Inorganic salts with glucose First 240 min. of logarithmic growth, MGT 61 min. +7.0 

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BaddUey J. Thain, E.M. (1951) The Synthesis of Pantothenic Acid-2 and -4 Phosphates as Possible Degradation Products of Coenzyme A. Journal of the Chemical Society, 246-251. 

The hydrogenation of ketones with O or N functions in the a- or / -position is accomplished by several rhodium compounds [46 a, b, e, g, i, j, m, 56], Many of these examples have been applied in the synthesis of biologically active chiral products [59]. One of the first examples was the asymmetric synthesis of pantothenic acid, a member of the B complex vitamins and an important constituent of coenzyme A. Ojima et al. first described this synthesis in 1978, the most significant step being the enantioselective reduction of a cyclic a-keto ester, dihydro-4,4-dimethyl-2,3-furandione, to D-(-)-pantoyl lactone. A rhodium complex derived from [RhCl(COD)]2 and the chiral pyrrolidino diphosphine, (2S,4S)-N-tert-butoxy-carbonyl-4-diphenylphosphino-2-diphenylphosphinomethyl-pyrrolidine ((S, S) -... 

Two aliphatic acids possess, for grasses, many of the growth-distortion and toxicity effects associated with the synthetic auxins on dicotyledonous plants. Trichloroacetic acid and 2,2-dichloropropionic acid (dalapon), as the sodium salts, have been called grass "hormones or auxins, although Wilkinson184 could find no growth stimulation at low concentrations, and described dalapon as an antiauxin from its interference with indole-3-acetic acid effects. The herbicidal properties of trichloroacetate do not depend on its protein-denaturing ability, and those of 2,2-dichloropropionic acid involve, at least indirectly, the synthesis of pantothenic acid. 

Pantolactone, dihydro-3-hydroxy-4//-dimethyl-2(3//)-furanone (103) which is an important starting material of the synthesis of pantothenic acid, was also easily resolved by complexation with 10a. When a solution of 10a (5.5 g, 9.93 mmol) and rac-103 (2.6 g, 20 mmol) in 1 1 benzene-hexane (20 ml) was kept at room temperature for 1 h, a 1 1 complex of 10a and (.S)-(-)- 03 was obtained, after two recrystallizations from 1 1 benzene-hexane, as colorless needles (2.05 g), which upon heating in vacuo gave (S)-(-)-103 of 99% ee (0.39 g, 30%).40 In order to clarify the mechanism of the precise chiral recognition between 10a and (S)-(-)-103, their inclusion complex crystal was studied by X-ray analysis40 and by AFM technique.41... 

D-(-)-Pantoyl lactone 1s a key intermediate for the synthesis of pantothenic acid which is a member of the vitamin B-complex and is an important constituent of Coenzyme A. Although D-(-)-pantoyl lactone has been obtained by classical optical resolution using quinine, ephedrine, and other chiral amines, catalytic asymmetric synthesis appears to be more effective... 

Other pyruvate-containing enzymes include aspartate -decarboxylase from Escherichia coli, the enzyme that catalyzes the formation of -alanine for the synthesis of pantothenic acid (Section 12.2.4) proline reductase from Clostridium sticklandiv, phosphatidylserine decarboxylase from E. coli and phenylalanine aminotransferase from Pseudomonas fluorescens. Phospho-pantetheinoyl cysteine decarboxylase, involved in the synthesis of coenzyme A (Section 12.2.1), and S-adenosylmethionine decarboxylase seem to be the only mammalian pyruvoyl enzymes (Snell, 1990). 

The hydrogenation of an a-ketolactone depicted in Scheme 12.12 is the key step for an enantioselective synthesis of pantothenic acid, which is produced by Roche... 

In contrast to these chemicals, the newer organic compounds that have come into use within the past two decades are higher cost materials, but they are also much more toxic. Examples are dalapon, which competes with panto-ate and inhibits enzymatic synthesis of pantothenic acid (D,L-N-[2,4—dihydroxy-3,3—dimethylbutyryl]-P-alanine), and the substituted ureas, s-triazines... 

USE In the synthesis of pantothenic acid, valine, leucine, cellulose esters, perfumes, flavors, plasticizers, resins, gasoline additives. 

Pantolactone, an important intermediate for the synthesis of pantothenic acid (a constituent of Coenzyme A), is commercially available in only one optically active form. The (/ )-(— )-enantiomer currently sells for slightly less than 1.00 per gram. ( S)-( + )-Pantolactone (257) must be synthesized, and it is readily accessible from L-malic acid via the 3,3-dimethyl analog 231a [80]. Selective hydrolysis of the 1-ester furnishes the monoacid 256. Reduction of the 4-ester with L-Selectride followed by lactonization then gives 257 in 40% overall yield starting from dimethyl (5)-malate (2 231a 256 —> 257). 

Enzymatic Synthesis of Pantothenic Acid by Escherichia coli Cells... 

Wagner, R. P. The in vitro synthesis of pantothenic acid by pantothenic-... 

One application of this hydrogenation with the structurally related 4,4-dimethyl-2, 3-furandione is shown in Equation 15.53. This a-ketoester undergoes hydrogenation with a neutral rhodium catalyst containing the bpm ligand shown in this equation with spectacularly high turnover numbers and good enantioselectivity. This product is used by Roche in the synthesis of pantothenic acid, a B-vitamin used for the synthesis of coenzyme... 

Scheme 12.108. A synthesis of pantothenic acid (after Stiller, E.T. Stanton, A. H. Rnkelsetin, I Keresztesy, J. C Folkers, K. /. Am. Chem. Soc.y 1940,62,1785).

Show how you might synthesize jS-aminopropionic acid from succinic anhydride. (j8-Aminopropionic acid is used in the synthesis of pantothenic acid, a precursor of coenzyme A.)... 

Wagner, R. P. (1949) The in vitro synthesis of pantothenic acid by pantothenicless and wild type Neurospora. Proc. Nat. Acad. Sci. 35, 185-190. 

Some nonstandard amino acids are not found in proteins. Examples include lanthionine, 2-aminoisobutyric acid, dehydroalanine and the neurotransmitter gamma-aminobutyric acid. Nonstandard amino acids often occur as intermediates in the metabolic pathways for standard amino acids — for example ornithine and citrulline occur in the urea cycle, part of amino acid catabolism (see below). A rare exception to the dominance of a-amino acids in biology is the P-amino acid beta alanine (3-aminopropanoic acid), which is used in plants and microorganisms in the synthesis of pantothenic acid (vitamin B5), a component of coenzyme A. 

VIII. The Bacterial Synthesis of Pantothenic Acid in Animals.29... 

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