Biomedical subjects

H J Reich

Publications and source records attributed to H J Reich.

5 recordsLinked to original sources

PubMed2001

Amine-chelated aryllithium reagents--structure and dynamics.

Multinuclear NMR studies of five-membered-ring amine chelated aryllithium reagents 2-lithio-N,N-dimethylbenzylamine (1), the diethylamine and diisopropylamino analogues (2, 3), and the o-methoxy analogue (4), isotopically enriched in (6)Li and (15)N, have provided a detailed picture of the solution structures in ethereal solvents (usually in mixtures of THF and dimethyl ether, ether, and 2,5-dimethyltetrahydrofuran). The effect of cosolvents such as TMEDA, PMDTA, and HMPA has also been determined. All compounds are strongly chelated, and the chelation is not disrupted by these cosolvents. Reagents 1, 2, and 3 are dimeric in solvents containing a large fraction of THF. Below -120 degrees C, three chelation isomers of the dimers are detectable by NMR spectroscopy: one (A) with both nitrogens coordinated to one lithium of the dimer, and two (B and C) in which each lithium bears one chelating group. Dynamic NMR studies have provided rates and activation energies for the interconversion of the 1-A, 1-B, and 1-C isomers. They interconvert either by simple ring rotation, which interconverts B and C, or by amine decoordination (probably associative, DeltaG(++)(-93) = 8.5 kcal/mol), which can interconvert all of the isomers. The dimers of 1 are thermodynamically more stable than those of model systems such as phenyllithium, o-tolyllithium, or 2-isoamylphenyllithium (5, DeltaDeltaG > or = 3.3 kcal/mol). They are not detectably deaggregated by TMEDA or PMDTA, although HMPA causes partial deaggregation. The dimers are also more robust kinetically with rates of interaggregate exchange, measured by DNMR line shape analysis of the C-Li signal, orders of magnitude smaller than those of models (DeltaDeltaG(++) > or = 4.4 kcal/mol). Similarly, the mixed dimer of 1 and phenyllithium, 13, is kinetically more stable than the phenyllithium dimer by >2.2 kcal/mol. X-ray crystal structures of the TMEDA solvate of 1-A and the THF solvate of 3-B showed them to be dimeric and chelated in the solid state as well. Compound 4, which has a methoxy group ortho to the C-Li group, differs from the others in being only partially dimeric in THF, presumably for steric reasons. This compound is fully deaggregated by 1 equiv of HMPA. Excess HMPA leads to the formation of ca. 15% of a triple ion (4-T) in which both nitrogens appear to be chelated to the central lithium.

Journal Article↗

PubMed2001

The regioselectivity of addition of organolithium reagents to enones and enals: the role of HMPA.

The role of polar solvents (particularly HMPA) in controlling the ratio of 1,2 to 1,4 addition of sulfur-substituted organolithium reagents to cyclohexenones and hexenal was studied. Low-temperature, multinuclear NMR studies provided quantitative information about the ratio of contact (CIP) and solvent-separated (SIP) ion pairs in solutions of dithianyllithiums and phenylthiobenzyllithiums in THF-HMPA solutions. The ratio of contact and separated ion pairs was manipulated by changes in the strength of solvation (generally through the addition of HMPA). Although the results are consistent with the CIP/SIP distribution being an important factor in determining the regioselectivity of these additions (Curtin-Hammett limitations prevent a direct correlation), it cannot be the only one. Changes in diastereomeric product ratios upon addition of HMPA suggest that complexation of HMPA to lithium has two effects. First, it causes ion pair separation, which enhances 1,4 addition. Second, it lowers the Lewis acidity and catalytic effectiveness of the lithium cation, which also favors 1,4 addition. For most sulfur-stabilized lithium reagents, 2 equiv of HMPA suffice to achieve >95% 1,4 addition, whereas 4 equiv of DMPU are required to achieve identical regiochemical and stereochemical results.

Journal Article↗

PubMed2001

Chelated aryllithium reagents: ring size and chelating group effects.

[figure: see text] Chelation and aggregation in phenyllithium reagents with potential 5-, 6-, and 7-ring chelating ether and amine ortho substituents have been examined utilizing variable-temperature 6Li and 13C NMR spectroscopy, 6Li and 15N isotope labeling, and the effects of solvent additives. Both ether and amine form strong 5-ring chelates; 6-ring ether chelates compete well with THF, but 6-ring amine chelates barely do, and 7-ring amine chelates do not. o-Methoxymethylphenyllithium (4) forms an open dimer (9) and a pentacoordinate monomer with PMDTA (10).

Journal Article↗

PubMed1998

Ergosteroids III. Syntheses and biological activity of seco-steroids related to dehydroepiandrosterone.

The unusual activity of some D-ring-seco estrogens led us to prepare several seco steroids related to dehydroepiandrosterone (DHEA) and to test for their ability to mimic thyroid hormone and 7-oxo-DHEA (1) as inducers of thermogenic enzymes in rats' livers. Only one, 3 beta-acetoxy-17a-oxa-androst-5-ene-7,17-dione (17), was capable of inducing both mitochondrial glycerophosphate dehydrogenase and malic enzyme. The closely related 3 beta-hydroxy-17a-oxa-androsta-5,15-diene-7,17-diones (both 14 alpha and 14 beta, 14 and 15) induce the formation of malic enzyme but not of glycerophosphate dehydrogenase. The 3 beta-propionyl ester of the above 14 alpha steroid was not active, presumably because it was not deacylated in vivo. The 16,17 dicarboxylic acid (9) produced by opening the D-ring also induced the formation of malic enzyme but not of glycerophosphate dehydrogenase. 3 beta-Acetoxyandrost-5-ene-7,16,17-trione, an intermediate in the synthesis of D-ring seco compounds enhanced the formation of both enzymes. Twelve other D-ring seco compounds were not active. Seco androstanes oxygenated at position 7 and with expanded A or B rings were not active.

Animals↗

PubMed1991

In vitro metabolism of [14C]4-chlorobiphenyl and [14C]2,2',5,5'-tetrachlorobiphenyl by hepatic microsomes from rats and pigeons. Evidence against an obligatory arene oxide in aromatic hydroxylation reactions.

1. The catalytic activities of cytochromes P-450IA1 and P-450IIB1 in control and Aroclor 1254 treated rats and pigeons (1 mmol/kg) were assessed using [14C]4-chloro- and [14C]2,2',5,5'-tetrachlorobiphenyl as substrates. Treatment of rats resulted in increases of the total amount of chloroform-extractable metabolites of [14C]4-chlorobiphenyl from 37.2 (control) to 199.4 and 221.6 nmol/hr per mg microsomal protein at 48 and 120 hr post treatment. The portion of [14C]4-chloro-3',4'-dihydroxybiphenyl (M4) and of a second unidentified dihydroxylated metabolite (M3) increased during these incubations from 13.7% for controls to 53.5% at 48 hr and 69.12% at 120 hr post treatment. 2. [14C]4-chloro-3'-hydroxybiphenyl (M1) and [14C]4-chloro-4'-hydroxybiphenyl (M2) were the major metabolites formed by pigeon hepatic microsomes; however, the amounts formed were 38.7- and 29.3-fold less, respectively, than in untreated rats. Treatment of pigeons with Aroclor 1254 increased the metabolite formation from 1.0 (control) to 13.6 and 22.4 nmol/hr per mg microsomal protein at 48 hr and 120 hr post treatment respectively; however, only small amounts of metabolites M3 (0.5 nmol/hr per mg protein) and M4 (2.0 nmol/hr per mg protein) were detected. 3. Treatment of rats with Aroclor 1254 resulted in an approximately two-fold increase in the rate of metabolism of [14C]2,2',5,5'-tetrachlorobiphenyl, and the ratio of 3- to 4-hydroxylation increased from 0.45 (control) to 0.6 and 0.8 at 48 hr and 120 hr post treatment respectively. The rate of metabolism of [14C]2,2',5,5'-tetrachlorobiphenyl by control and Aroclor 1254 treated pigeons was up to 23-fold lower than in rats and there was no evidence for the formation of the diol metabolite M3. However, as with rats, the ratio of meta- to para-carbon atom hydroxylation increased from 0.58 (controls) to 0.72 at 120 hr post treatment. 4. From the evidence presented, it is suggested that cytochromes P-450IA1 and P-450IIB1 may not metabolize PCB-congeneric substrates via an obligatory arene oxide intermediate.

Animals↗