Reductive carboxylation system

Figure 17-14 (A) The reductive carboxylation system used in reductive pentose phosphate pathway (Calvin-Benson cycle). The essential reactions of this system are enclosed within the dashed box. Typical subsequent reactions follow. The phosphatase action completes the phosphorylation-dephosphorylation cycle. (B) The reductive pentose phosphate cycle arranged to show the combining of three C02 molecules to form one molecule of triose phosphate. Abbreviations are RCS, reductive carboxylation system (from above) A, aldolase, Pase, specific phosphatase and TK, transketolase.

The first inhaled glucocorticoid, beclomethasone dipropionate, revolutionized asthma therapy, when it was found that topical delivery to the lung resulted in reduced systemic side-effects (adrenal suppression, oseteoporosis and growth inhibition) typically seen with oral steroid treatments. Interestingly, a further reduction in systemic exposure was achieved with the introduction of fluticasone propionate (1). The evolution of this drug stemmed from observations with the steroid 17-carboxylates that showed that these esters were active topically when esterified, while the parent acids were inactive. Thus it was realized that enzymatic hydrolysis of the ester would lead to systemic deactivation. SAR studies led to a series of carbothioates, which were very active in vivo when topically applied to rodents, but were inactive after oral administration. It was shown that fluticasone propionate (1) underwent first pass metabolism in the liver to the corresponding inactive 173-carboxylic acid (la) (Scheme 1). This observation was... 

Reduction. Carboxylic acids can be reduced satisfactorily to primary alcohols by a slight excess of TiCI and NaBH4 in the molar ratio 1 3. A molar ratio of 1 2 is the optimum for reduction of amides, lactams, and sulfoxides.1 The 1 2 system is also effective for reduction ol nitrosamines, R1 R3N—NO, to secondary amines.2... 

The electrochemical incorporation of CO2 into perfluoroalkyl derivatives has been explored in the case of (perfluoroalkyl)alkyl iodides and (perfluoroalkyl)alkenes, with an electrochemical system based on the use of consumable anodes combined with organometallic catalysis by nickel complexes. Iodide derivatives have been functionalized to the corresponding carboxylic acids by reductive carboxylation. Interesting and new results have been obtained from the fixation of CO2 into perfluoroalkyl olefins. Good yields of carboxylic acids could be reached by a carefull control of the reaction conditions and of the nature of the catalytic system. The main carboxylic acids are derived from the incorporation of carbon dioxide with a double bond migration and loss of one fluorine atom from the CF2 in a position of the double bond. 

Reduction. Carboxylic acids, esin idly by Sm and hydrochloric acid. Ytterb reduction of a-halocarbonyl compound aprotic system (MejSiCl-Nal/MeCN ai Catalytic aldol reactions. ... 

The first example has been reported of the photofixation of COg in a non-biological system this involves the formation of 9,10-dihydrophenanthrene-9-carboxylic acid from irradiation of the phenanthrene-amine-COa system in DMSO or DMF.71 Both aliphatic and aromatic amines are effective, but the polarity of the solvent is important and the reaction does not occur in THF, dioxan, or n-hexane. Yields of carboxylic acids (up to 46%) have been reported and seemingly anthracene, pyrene, naphthalene, and biphenyl also undergo this reductive carboxylation. 

The Fixation of Carbon Dioxide and Nitrogen.—As reduced carbon compounds are convenient fuels, the possibility of achieving the reductive fixation of COa in vitro is appealing, if remote. There are very few data on photochemical reactions involving carbon dioxide, for it has no low-lying excited states and has not historically been of much interest to the photochemist. However, what appears to be the first example of photofixation of COa in a non-biological system has been briefly reported.18 Photoirradiation (with a high-pressure mercury lamp) of phenanthrene in the presence of an amine and C02 in a polar solvent (MeaSO or HCONMea) yielded 9,10-dihydrophenanthrene-9-carboxylic acid, in unspecified quantum yield. The mechanism appears to involve formation of COaT by electron transfer from the photoexcited amine, followed by attack of COaT on position 9 of phenanthrene. Similar reductive carboxylation of anthracene, pyrene, naphthalene, and biphenyl was observed. 

These requirements are for the cycle as written in Fig. 6. It has been suggested that in vivo the carboxylation of ribulose-1,5-diphosphate might be a reductive carboxylation (Wilson and Calvin, 1955). Broken isolated chloroplasts and cell-free systems perform only the nonreductive carboxylation of ribulose diphosphate. It is a hypothesis, at present unproved, that in vivo enzyme systems capable of using electrons more directly from the light reactions could catalyze reductive carboxylation [Eq. (23) of Fig. 6]. Such a system might be disrupted when chloroplasts are removed from the cells. In a cycle with a reductive carboxylation, the cofactor requirements might be different. For each complete cycle (three molecules of CO2 taken up) three of the ATP molecules would not be needed if three of the NADPH molecules could be replaced by molecules of reduced ferredoxin. The total requirement would then be six ATP, three NADPH, and six reduced ferredoxin molecules per three CO2 molecules taken up. 

As for the carbon reduction cycle, probably the most important unanswered questions have to do with the mechanisms of the carboxylation reaction and other steps in the cycle. Although all of the biochemical evidence from isolated enzyme systems suggests that the carboxylation reaction is a nonreductive carboxylation of ribulose diphosphate leading to the formation of two molecules of PGA, kinetic evidence with whole cells indicates the possibility of a reductive carboxylation leading to the formation of one molecule of PGA and one molecule of triose phosphate. If this reductive carboxylation does occur, it may be that electrons are somehow conveyed directly from the light reaction to the carbon reduction cycle (Bassham, 1964). If there is such a difference between the... 

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