A Nuclear Magnetic Resonance Study of the Reversible Hydration of Aliphatic Aldehydes and Ketones. I. Oxygen-17 and Proton Spectra and Equilibrium Constants

Greenzaid, P.; Luz, Z.; Samuel, David

doi:10.1021/ja00980a004

Cited by 159 publications

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“…The yellow extract was washed with 5% aqueous sodium bicarbonate and water, then dried and evaporated to give a residue (1.2 g), which was used directly in the preparation of 3. As noted by others (7,8) …”

Section: Reduction Of 2a With 21-hydroxysteroid Nad Oxidoreductasesupporting

confidence: 62%

“…In an earlier paper (3) we examined the conversion of the 2 1 -hydroxycorticosteroid 5P-pregnane-3a, 2 1-diol-20-one (tetrahydrodeoxycorticosterone, THDOC, 6 ) to 5P-pregnan3a-01-20-one (7) by E. lentum, and determined that the enzymic removal of the C-2 1 hydroxy group proceeds with retention of hydrogen at C-17, but with loss of one of the two hydrogen atoms originally present at C-2 1. A consideration of the cofactor (2,4) and substrate (1) requirements for the 2 1 -dehydroxylase enzyme, together with the primary kinetic hydrogen/deuterium isotope effect at C-2 1 (3), led us to propose the mechanism for the action of this enzyme shown in Scheme 1.…”

mentioning

confidence: 99%

“…and 4a, respectively. In view of the high cost of THDOC as a starting material for synthetic procedures, the stereoselective introduction of deuterium label at C-21 was carried out by reduction of the readily available 21-aldehydes 2 and 2a, the 4-ene-3-keto functionality of ring A being subsequently reduced by Clostridium paraputr$cum (5) to the 3a-01-5P stereochemistry required by E. lentum (3 In two parallel synthetic routes, pregn-4-ene-3,20-dion-21-01 (deoxycorticosterone, DOC, I), and its analogue labelled at C-17 and -21 ( l a ) , were first converted by copper catalysed air oxidation (6)(7)(8) to the corresponding 21-aldehydes 2 and 2a (Scheme 2). To facilitate the analysis of the stereochemistry of reduction of 2 and 2a, the labelled aldehyde 2a was reduced at C-21 by the enzyme 21-hydroxysteroid NAD oxidoreductase, isolated from beef liver (9).…”

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Stereochemistry of hydrogen loss during C-21 dehydroxylation of tetrahydrodeoxycorticosterone by Eubacteriumlentum

Holland¹,

Ninniss²,

Brown³

1989

Can. J. Chem.

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. Can. J. Chem. 67, 1590 (1989). The loss of hydrogen from the C-21 position of SP-pregnane-3a,21-diol-20-one (tetrahydrodeoxycorticosterone, THDOC) during reductive removal of the 21-hydroxy group by the anaerobic bacterium Eubacterium lentum has been shown to be selective for the pro-S position by the use of THDOC labelled with deuterium at the C-21 pro-S and C-21 pro-R positions. The labelled substrates were obtained by using the bacterium Clostridium paraputrificum to reduce chemically prepared C-21 labelled samples of pregn-4-en-21-01-3,2O-dione (deoxycorticosterone, DOC) at C-3 and C-4 (5). The stereochemistry of deuterium label introduced by chemical means at C-21 of DOC was determined by comparison with a sample of 2 1 -(R)-DOC-2 1 -d produced by reduction of the corresponding aldehyde pregn-4-en-2 1-al-3,20-dione, 2 1 -d by the enzyme 21-hydroxysteroid NAD oxidoreductase from beef liver.Key words: Eubacterium, Clostridium, steroids, tetrahydrodeoxycorticosteroids. Those 2 1 -hydroxycorticosteroids that are reabsorbed into the liver after passage through the intestines can be excreted as derivatives in which the hydroxyl group at C-21 has been replaced by hydrogen ( I ) . This process is performed by the anaerobic bacterium, Eubacterium lentum, present in the intestines (2).In an earlier paper (3) we examined the conversion of the 2 1 -hydroxycorticosteroid 5P-pregnane-3a, 2 1-diol-20-one (tetrahydrodeoxycorticosterone, THDOC, 6 ) to 5P-pregnan3a-01-20-one (7) by E. lentum, and determined that the enzymic removal of the C-2 1 hydroxy group proceeds with retention of hydrogen at C-17, but with loss of one of the two hydrogen atoms originally present at C-2 1. A consideration of the cofactor (2, 4) and substrate (1) requirements for the 2 1 -dehydroxylase enzyme, together with the primary kinetic hydrogen/deuterium isotope effect at C-2 1 (3), led us to propose the mechanism for the action of this enzyme shown in Scheme 1.We have now extended our study of this enzyme by the use of substrates with asymmetric deuterium labelling at C-2 1, and report that the loss of hydrogen from C-21 in the first step of Scheme 1 is specific for the pro-S position.The substrates required for our study were the 21-(S) and 2 1 -( R ) deuterium labelled tetrahydrodeoxycorticosteroids, 4 SCHEME 1. Proposed route for C-21 dehydroxylation by E. lentum. and 4a, respectively. In view of the high cost of THDOC as a starting material for synthetic procedures, the stereoselective introduction of deuterium label at C-21 was carried out by reduction of the readily available 21-aldehydes 2 and 2a, the 4-ene-3-keto functionality of ring A being subsequently reduced by Clostridium paraputr$cum (5) to the 3a-01-5P stereochemistry required by E. lentum (3).Can. J. Chem. Downloaded from www.nrcresearchpress.com by 34.212.246.108 on 05/11/18For personal use only.

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Section: Reduction Of 2a With 21-hydroxysteroid Nad Oxidoreductasesupporting

confidence: 62%

mentioning

confidence: 99%

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confidence: 99%

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Stereochemistry of hydrogen loss during C-21 dehydroxylation of tetrahydrodeoxycorticosterone by Eubacteriumlentum

Holland¹,

Ninniss²,

Brown³

1989

Can. J. Chem.

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“…The equilibrium constant can be estimated as 1.7 M -I . The equilibrium constants for hydration of mono-and dichloroacetone have been reported (23); the pKa's for the hydrates can be calculated using Hine's equation (pKa = 14.19 -1.32C.u*) (24); the equilibrium constants for addition of hydroxide then come from a simple cycle; see Table 10.…”

Section: Hydrolysis Of Chloroacetonementioning

confidence: 99%

The chlorination of acetone: a complete kinetic analysis

Guthrie¹,

Cossar²

1986

Can. J. Chem.

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. Rate constants are reported for all of the major steps followed in the chlorination of acetone, including the chlorination of mono-and 1 , 1-dichloroacetone, the chlorination of hydroxyacetone, the chlorination and hydroxide-catalyzed rearrangement of 1,l-dihydroxyacetone, and the haloform cleavage of trichloroacetone. pK, values are reported for hydroxyacetone and monochloroacetone. Rate constants for the hydrolyses of chloroacetone and 1,l-dichloroacetone are reported; these reactions are probably not SN2 displacements but proceed by addition of hydroxide and intramolecular displacement.

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“…11B), avoiding the need for the slow hydration of CH 3 CHO (Fig. 7) (57,58). (A third option could be 1e…”

Section: Discussionmentioning

confidence: 99%

Oxidation of N-Nitrosoalkylamines by Human Cytochrome P450 2A6

Chowdhury¹,

Calcutt²,

Guengerich

2010

Journal of Biological Chemistry

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Cytochrome P450 (P450) 2A6 activates nitrosamines, including N,N-dimethylnitrosamine (DMN) and N,N-diethylnitrosamine (DEN), to alkyl diazohydroxides (which are DNA-alkylating agents) and also aldehydes (HCHO from DMN and CH 3 CHO from DEN). The N-dealkylation of DMN had a high intrinsic kinetic deuterium isotope effect ( D k app ϳ 10), which was highly expressed in a variety of competitive and non-competitive experiments. The D k app for DEN was ϳ3 and not expressed in non-competitive experiments. DMN and DEN were also oxidized to HCO 2 H and CH 3 CO 2 H, respectively. In neither case was a lag observed, which was unexpected considering the k cat and K m parameters measured for oxidation of DMN and DEN to the aldehydes and for oxidation of the aldehydes to the carboxylic acids. Spectral analysis did not indicate strong affinity of the aldehydes for P450 2A6, but pulse-chase experiments showed only limited exchange with added (unlabeled) aldehydes in the oxidations of DMN and DEN to carboxylic acids. Substoichiometric kinetic bursts were observed in the pre-steady-state oxidations of DMN and DEN to aldehydes. A minimal kinetic model was developed that was consistent with all of the observed phenomena and involves a conformational change of P450 2A6 following substrate binding, equilibrium of the P450-substrate complex with a non-productive form, and oxidation of the aldehydes to carboxylic acids in a process that avoids relaxation of the conformation following the first oxidation (i.e. of DMN or DEN to an aldehyde). P4503 enzymes are found throughout nature and catalyze many reactions, most of which are mixed function oxidations (4). The mammalian P450s are of considerable interest because of their roles in the metabolism of steroids, eicosanoids, drugs, chemical carcinogens, and other important molecules (5). The general mechanistic features of P450 reactions include substrate binding, reduction to the ferrous state, binding of O 2 , the addition of a second electron, protonation, and rearrangement to generate a reactive iron-oxygen complex poised near the substrate (6, 7). The active complex can be described as a formal FeO 3ϩ entity, with similarity to Compound I of peroxidases, which can be used to rationalize most reactions (7-9), although some alternate possibilities can also be considered. A generally accepted mechanism for many P450 oxidations involves the abstraction of a hydrogen atom by the FeO 3ϩ entity, followed by "oxygen rebound" to yield a hydroxylated product (10).Among the chemical carcinogens activated by mammalian P450s are N,N-dialkylnitrosamines (also called N-nitrosodialkylamines) (11), including those found in tobacco products and also the simple nitrosamines N,N-dimethylnitrosamine (DMN) and N,N-diethylnitrosamine (DEN) (12). The mechanism of activation is agreed to involve ␣-hydroxylation of the nitrosamine in most cases (Fig. 1). The process is generally accepted to involve hydrogen atom transfer instead of the alternate 1e Ϫ oxidation implicated for some amines (7, 8,13,14) because ...

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A Nuclear Magnetic Resonance Study of the Reversible Hydration of Aliphatic Aldehydes and Ketones. I. Oxygen-17 and Proton Spectra and Equilibrium Constants

Cited by 159 publications

References 0 publications

Stereochemistry of hydrogen loss during C-21 dehydroxylation of tetrahydrodeoxycorticosterone by Eubacteriumlentum

Stereochemistry of hydrogen loss during C-21 dehydroxylation of tetrahydrodeoxycorticosterone by Eubacteriumlentum

The chlorination of acetone: a complete kinetic analysis

Oxidation of N-Nitrosoalkylamines by Human Cytochrome P450 2A6

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