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Development of efficient methodology to produce an optically pure enantiomer is of fundamental importance, particularly for the synthesis of biologically active natural products. Optically active compounds can be obtained by three different approaches, that is, resolution of racemates, use of a chiral pool or “chiron” (which are enantiomerically pure synthons), or asymmetric synthesis. Of these, one of the more challenging tasks involves asymmetric synthesis, which may be carried out either enzymatically or nonenzymatically. Whereas the nonenzymatic method enables us to introduce a chiral center with either a stoichiometric or catalytic amount of a chiral compound, the enzymatic method uses biological systems, such as microorganisms or isolated enzymes, to create the center of asymmetry. The purpose of this chapter is to survey asymmetric synthesis via the production of enantiomerically pure or enriched organic molecules by the enzymatic method focusing on the use of a hydrolytic enzyme, pig liver esterase (PLE; Enzyme Commission classification number, E.C. 3.1.1.1). Enzymes are classified into the following six groups based on the reactions they catalyze: Oxidoreductase (oxidation–reduction reactions); Transferase (transfer of functional groups); Hydrolase (hydrolysis reactions); Lyase (addition to double bonds or the reverse); Isomerase (isomerization reaction); and Ligase (formation of bonds coupled with pyrophosphate bond cleavage of ATP). Virtually all biochemical transformations are catalyzed in vivo by these six groups, and the biochemical aspects of these enzymes have been studied in detail. However, the practical utility of these enzymes in organic synthesis remains to be further exploited and refined. The ability of a substrate to associate with an enzyme is also one of the most significant problems. In some cases, these problems have been overcome and several enzyme reactions have been successfully used on a large scale. An enzyme reaction generally takes place when an intimate interaction between the reactant and the chiral catalyst (enzyme protein) is realized. This enzyme–substrate complex is designated as the Michaelis complex. Certain amino acid residues of the enzyme form a three‐dimensional structure as the active site. This site often contains reactive groups of the amino acids such as amino, mercapto, hydroxyl, carbonyl, carboxyl, guanidino, or imidazolyl. When the substrate is bound to the active site in a specific orientation, enantiotopic groups or faces of the substrate molecule are discriminated by the chiral enzyme. This discrimination is sufficiently sensitive to differentiate between the two hydrogen atoms in a methylene group. Thus the reaction proceeds stereospecifically. The enzyme can also distinguish among several substrates competing for an active site. Such substrate specificity is sometimes strict and sometimes broad. Synthetically useful enzymes should accept a wide range of substrates and exhibit high stereospecificity. Many enzymes meet these criteria, and PLE is one of them.
Development of efficient methodology to produce an optically pure enantiomer is of fundamental importance, particularly for the synthesis of biologically active natural products. Optically active compounds can be obtained by three different approaches, that is, resolution of racemates, use of a chiral pool or “chiron” (which are enantiomerically pure synthons), or asymmetric synthesis. Of these, one of the more challenging tasks involves asymmetric synthesis, which may be carried out either enzymatically or nonenzymatically. Whereas the nonenzymatic method enables us to introduce a chiral center with either a stoichiometric or catalytic amount of a chiral compound, the enzymatic method uses biological systems, such as microorganisms or isolated enzymes, to create the center of asymmetry. The purpose of this chapter is to survey asymmetric synthesis via the production of enantiomerically pure or enriched organic molecules by the enzymatic method focusing on the use of a hydrolytic enzyme, pig liver esterase (PLE; Enzyme Commission classification number, E.C. 3.1.1.1). Enzymes are classified into the following six groups based on the reactions they catalyze: Oxidoreductase (oxidation–reduction reactions); Transferase (transfer of functional groups); Hydrolase (hydrolysis reactions); Lyase (addition to double bonds or the reverse); Isomerase (isomerization reaction); and Ligase (formation of bonds coupled with pyrophosphate bond cleavage of ATP). Virtually all biochemical transformations are catalyzed in vivo by these six groups, and the biochemical aspects of these enzymes have been studied in detail. However, the practical utility of these enzymes in organic synthesis remains to be further exploited and refined. The ability of a substrate to associate with an enzyme is also one of the most significant problems. In some cases, these problems have been overcome and several enzyme reactions have been successfully used on a large scale. An enzyme reaction generally takes place when an intimate interaction between the reactant and the chiral catalyst (enzyme protein) is realized. This enzyme–substrate complex is designated as the Michaelis complex. Certain amino acid residues of the enzyme form a three‐dimensional structure as the active site. This site often contains reactive groups of the amino acids such as amino, mercapto, hydroxyl, carbonyl, carboxyl, guanidino, or imidazolyl. When the substrate is bound to the active site in a specific orientation, enantiotopic groups or faces of the substrate molecule are discriminated by the chiral enzyme. This discrimination is sufficiently sensitive to differentiate between the two hydrogen atoms in a methylene group. Thus the reaction proceeds stereospecifically. The enzyme can also distinguish among several substrates competing for an active site. Such substrate specificity is sometimes strict and sometimes broad. Synthetically useful enzymes should accept a wide range of substrates and exhibit high stereospecificity. Many enzymes meet these criteria, and PLE is one of them.
The syntheses of [19,3,4,4,]-( 17R)-17.20-dimethyl-7-thiaprostaglandin E l methyl esters (3 a n d 5) are described.The di-tritiated compound 3 was prepared from its protected (Z)-A19-precursor (21 ) v i a catalytic reduction with tritium gas having a specific activity of 49 Ci / mmol. The octa-deuterated compound 5 was prepared from tetrahydrofuran-dg.KEYWORDS: tritium-labeled 7-thiaprostaglandin E l , catalytic hydrogenation, deuterated 7-thiaprostaglandin El INTRODUCTIONProstaglandin E l and its analogues are now clinically used for treatment of peripheral vascular disease and so on.2 (17R)-17.20-Dimethyl-7-thiaprostaglandin E l methyl estcr3 ( 1 ) is one of orally active prostaglandin E l analogues. We report here the syntheses of (17R)-17,20-dimethyl-7-thia ( 19,20-3H2]prostaglandin E l methyl ester (3) and (17R ) -1 7.20-dimethyl -7-t hi a [ 3,3,4,4,5.5,6, 6-2H 8 ]prostaglandin E l methyl ester ( 5 ) as pharmaceutical tools. OH OH1; R = Me, R ' = H 2; R = H , R = H 3; R = M e , R = T 4; R = H , R = T The tritiated 3 was synthesized from the (Z)-A19 olefinic precursor 21 by catalytic hydrogenation with tritium gas (Scheme I). and was used for the pharmacokinetics and metabolism studies of the substance 1.Selective oxidation of the starting diol 7 with pyridinium chlorochromate (PCC) resulted in the cyclic hemiacetal formation of 8 as an oxidized product (57%). Reaction of the product 8 with ethylidenetriphenylphosphorane gave the (Z)-olefinic alcohol 9 in 67% yield, which was accompanied by c a . 15% (E)-isomer of 9 . Because the (E)-olefin is known to be less active toward catalytic hydrogenation. than the (Z)-olefin. the following reactions are carried out using a mixture of the (Z)-olefinic substance concomitant with a small amount of the (E)-olefin. Oxidation of the resulting alcohol 9with PCC yielded(52%) the aldehyde 1 0 . which was allowed to react with lithium acetylide-ethylenediamine complex to provide the acetylenic alcohol 1 1 (58%). After protection (87%) of 1 1 with trimethylsilyl group, the resulting product 12 was converted into the vinyl iodide 13 (37%) accompanied by its desilylated vinyl iodide I4 hydrogenation of the ( Z ) -A I 9 substrate 2 1 with 10% palladium on activated carbon under hydrogen atmosphere gave the ( Z ) -A 9-reduced product 2 2 . which was desilylated with tetrabutylammonium fluoride to furnish t h e product 2 after preparative HPLC purification. A similar catalytic reduction of the same precursor 2 1 under tritium gas afforded the di-tritiated product 2 3 . which was converted into the desired substance 3 after a similar preparative HPLC purification. The specific activity of the obtained 3 was found to be 4 9 Ci / mmol. Hydrolysis of the methyl ester 3 with porcine liver esterase6 gave the tritiated carboxylic acid 4 .T h e deuterium-labeled compound is the [3,3,4,4,5,5,6,6-2H 8 1 derivative 5 , where eight hydrogen atoms on the a -s i d e chain of prostaglandin El analogue 1 are substituted by deuterium atoms.T h e deuterated 5 w a s synthesized from t e t r a h y d r...
The syntheses of [7-2H]-, [7-3H]-, and (2,2.3.3.4.4-2H6]-( 1 6 s ) -1 5 -d e o x y -16-hydroxy-16-methyl-5-thiaprostaglandin E l methyl ester (2, 3, a n d 4) are described.Both 7-labeled compounds, 2 and 3 . were prepared from the A ' -precursor (1 1 ) by treatment with i n -s i t u generated tributyltin deuteride and [3H]hydride, respectively.The hexa-deuterated compound 4 was prepared starting from tetrahydrofuran-dg
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