Direct Precursors

Immunodiffusion and immunoprecipitation, developed ia the 1940s as a means to identify and semiquantitate specific proteias, were the direct precursors to the development ia 1953 of Immunoelectrophoresis, a method used ia many clinical laboratories (5). Single- and double-gel immunodiffusion and immunoelectrophoresis were, ia effect, the first standardized and routinely used immunoassay methods (see Electroseparations, electrophoresis). 

Amino-2 -deoxypurines. 2 -AmiQo-2 -deoxyadenosine (15) is a naturally occurring A[-nucleoside isolated from A.ctinomadura that shows antknycoplasmal activity (1,4). Adenosine is the direct precursor for its biosynthesis (30). 2 -Arnino-2 -deoxyguanosine (16), isolated from a strain of Enterobacter cloacae (1,4), shows the growth of HeLa S3 cells and Sarcoma 180 in vivo and has been tested for antibacterial activity. 

This interesting conversion of a five- into a six-membered heterocyclic ring was proven by the isolation of the enzyme GTP-cyclohydrolase from E. coli (71MI21600) and a similar one from Lactobacillus platarum (B-71MI21601) which catalyzes the reaction (300)(303). Dephosphorylation leads to 7,8-dihydro-D-neopterin (304), which is then cleaved in the side-chain to 6-hydroxymethyl-7,8-dihydropterin (305), the direct precursor of 7,8-dihy-dropteroic acid and 7,8-dihydrofolic acid (224). The alcohol (305) requires ATP and Mg " for the condensation with p-aminobenzoic and p-aminobenzoylglutamic acid, indicating pyrophosphate formation to (306) prior to the substitution step. 

The evidence accumulated to date unfortunately is not conclusive. The most accurate statement which probably can be made is that aminals are produced when aldehydes and secondary amines react, but the aminals are not necessarily the direct precursor of the enamine. 

Penicillins and cephalosporins are products of biosynthetic pathways that have many identical enzymatic steps. It is generally accepted that the tripeptide, 8-(L-a-aminoadipyl)-L-cysteinyl-D-valine (LLD-ACV), is the direct precursor to both penicillin and cephalosporin C. 

Glucuronate is reduced to L-gulonate in an NADPH-dependent reaction L-gulonate is the direct precursor of ascorbate in those animals capable of synthesizing this vitamin. In humans and other primates as well as guinea pigs, ascorbic acid cannot be synthesized because of the absence of L-g ulonolactone oxidase. L-Gulonate is metabolized ultimately to D-xylulose 5-phosphate, a constituent of the pentose phosphate pathway. 

Despite our earlier failure in formate feeding experiments, [3- C]serine, [1,2- CJglycine, and [Me- C]methionine were found to enrich C-13 in neosaxitoxin effectively (7). The best incorporation was observed with methionine, indicating it is the direct precursor via S-adenosylmethionine. Glycine C-2 and serine C-3 must have been incorporated through tetrahydrofolate system as methyl donors in methionine biosynthesis. 

While caffeine biosynthesis in coffee and tea has been reasonably well investigated, little information is available about the biosynthetic pathways of methylxanthines in cacao. Published studies34 35 have established the presence of 7-methylxanthine and adenine in cocoa. Since both coffee and tea exhibit similar pathways where theobromine is a direct precursor for caffeine, it is reasonable to assume that a similar mechanism is possible in cacao. 

Under similar conditions, reactions between pyrrolidine derivatives 632 and MTAD proceed much more slowly and less cleanly with formation of a polymeric material. When the reaction is stopped before 50% conversion is reached, starting compound 632 is isolated as the main component (c. 40%) and compound 637 as a minor product (10-14%). Mechanistically, the most difficult problem lies in the fact that a reduction step has to be involved and no particular reduction agent is present. A proposed mechanism is shown in Scheme 103. The pathway includes a Cannizzaro-type hydride transfer between dipole 633 and product 634 (keto tautomer), resulting in the formation of the iminium derivative 635, which might be responsible for the polymeric material, and hydroxy derivative 636, the direct precursor of the final products 637. The low experimental yield of 637 could be explained by this mechanism <2003EJ01438>. 

Substituted furan formation by an indirect cyclization of 1,4-dicarbonyl derivatives has also been adopted as a key step in the synthesis of 3-oxa-guaianolides. Although 1,4-dicarbonyl compounds have been traditionally considered as the direct precursors for furans, treatment of 1,4-dicarbonyl compounds having a tertiary acetoxy group with p-toluenesulfonic acid leads to only 11% yield of an alkenylfurans as derived from a cyclization/acetoxy-elimination route. The following scheme shows an alternative multi-step conversion of the 1,4-dicarbonyl that leads to a more acceptable yield of the acetoxyfuran . 

There are other synthetic routes to halides similar to compounds (39), which are direct precursors of six-membered cyclic nitronates (35) (Scheme 3.36). 

There are several advantages of this method over other approaches to the synthesis of nitronates (35). First, direct precursors (42) and (43) are readily available. Second, this process is simple and versatile. Finally, in many cases high selectivity of the method allows the synthesis of diastereometrically and enantiometrically pure nitronates (35). 

As mentioned above (66, 393), (see Scheme 3.150) silylation followed by intramolecular enantioselective cycloaddition with five-membered cyclic nitronates, containing the hydroxyl group at C-4, can produce chiral polycyclic structures (293), which are direct precursors of chiral hydroxyamino acids (294) and aminopolyols (295) (Scheme 3.179). 

Functionalized 5,6-dihydro-4// -oxazines are direct precursors of a series of useful products, for example, of proline derivatives (539), unnatural amino acids (540), and some alkaloids (541). 

Highly effective warfare agents (e.g. soman, sarin, tabun) and certain of their direct precursors. 

The reductive cleavage of the N-O bond in the isoxazolidine 162 unmasks the 1,3-amino alcohol moiety. Thus, isoxazolidines can be viewed as direct precursors of 7-amino alcohols. The reductive cleavage of the cycloadduct proved difficult. W2 Raney-Ni and nickel boride were both ineffective. In contrast, nickel-aliminium alloy in an alkaline medium efficiently reduced the N-O bond at room temperature in the presence of a base (Equation 27) <1997TA109>. 

In the inset of Fig. 5.1.3 it can be seen that the SPC formation begins in earnest around day 8 or 9 resulting in a build-up of C-even-SPC. The concentrations of the two long-chain SPC, C12 and C10, reach a maximum on day 12, and it seems that they are then rapidly converted into the shorter-chain homologues. In all cases, C6-SPC is the most abundant homologue while its direct precursor, C8-SPC, and its successor, C4-SPC, are detected at substantially lower levels. The increase in C6-SPC is almost linear from the onset of formation until about day 19 when its formation slows down finally reaching a steady level at approximately 80 pmol L-1. 

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