Stereocontrol of intramolecular Diels-Alder reactions: synthetic studies and transition structure modeling with c5-substituted 1,3,8-nonatrienes and nonadienynes.

An investigation into the endo/exo selectivity and pi-diastereofacial selectivity of ester-tethered intramolecular Diels-Alder reactions is reported. High levels of exo selectivity are realized with terminally substituted dienophiles, and high lk pi-diastereofacial selectivities are induced by the presence of a bulky dioxolanyl substituent at the allylic position of the tether. Precursors 19S, 20S, and 21S, readily prepared from glucose, provide densely functionalized bicyclic lactones of predictable stereochemistry in high yields in enantiomerically pure form upon thermolysis at 110 degrees C. B3LYP/6-31G(d) theory provides good descriptions of transition structures for these reactions and allows an understanding of the formation of the major cycloadducts.

The developmental toxicity of inhaled methanol in the CD-1 mouse, with quantitative dose-response modeling for estimation of benchmark doses.

The developmental toxicity of the alternative motor vehicle fuel methanol was assessed in mice by the inhalation route. Pregnant CD-1 mice were exposed to 1,000, 2,000, 5,000, 7,500, 10,000, or 15,000 ppm methanol for 7 hr/day on days 6-15 of gestation. Sham-exposed controls were exposed to filtered air under similar conditions. Additional control groups were left in their home cages either unhandled or food-deprived for 7 hr/day to match the food deprivation experienced by the exposed mice. Dams were observed twice daily and weighed on alternate days during the exposure period. Blood methanol concentrations were determined in some mice on gestation days 6, 10, and 15. On day 17, the remaining mice were weighed and killed and the gravid uteri removed. Implantation sites, live and dead fetuses and resorptions were counted, fetuses were examined externally and weighed as a litter. Half of each litter was examined for skeletal morphology and the other half of each litter was examined for internal soft tissue anomalies. One dam died in each of the 7,500, 10,000, and 15,000 ppm methanol exposure groups, but no dose-response relationship was evident for maternal death. The sham-exposed and food-deprived controls as well as all methanol exposed dams gained less weight than did unexposed dams fed ad libitum, but methanol did not exacerbate this effect. Significant increases in the incidence of exencephaly and cleft palate were observed at 5,000 ppm and above, increased embryo/fetal death at 7,500 ppm and above (including an increasing incidence of full-litter resorptions), and reduced fetal weight at 10,000 ppm and above. A dose-related increase in cervical ribs or ossification sites lateral to the seventh cervical vertebra was significant at 2,000 ppm and above. Thus, the NOAEL for the developmental toxicity in this study was 1,000 ppm. A log-logistic dose response model was applied to the incidence data for exencephaly, cleft palate, resorption and cervical rib, and maximum likelihood estimates (MLEs) and benchmark dosages (BDs, the lower 95% confidence interval of the MLEs) corresponding to 1% and 5% added risk above background were calculated. The MLE for 5% added combined risk of having either exencephaly or cleft palate or being resorbed was 3667 ppm, and the corresponding BD was 3,078 ppm. For cervical rib, the 5% added risk values for the MLE and BD were 824 and 305 ppm, respectively. The BDs for 1% added risk were 1915 ppm for exencephaly, cleft palate or resorption, and 58 ppm for cervical rib.(ABSTRACT TRUNCATED AT 400 WORDS)

Significance of supernumerary ribs in rodent developmental toxicity studies: postnatal persistence in rats and mice.

Pregnant Sprague-Dawley rats and Swiss-Webster mice were gavaged with bromoxynil at 15 and 96.4 mg/kg/day, respectively, on Days 6-15 of gestation. The frequency of supernumerary ribs (SNR), which are here defined as any degree of ossification lateral to the first lumbar vertebrae, was determined in fetuses at term and offspring on Postnatal Days 6, 20, and 40. Bromoxynil induced significant increases in the incidence of SNR in fetuses of both species. In rats, SNR occurred in 62% of treated fetuses as compared to 14% in controls; in mice these values were 45% and 11%, respectively. The postnatal incidence and persistence of SNR was species dependent. In the rat, postnatal SNR incidence in treated animals did not differ significantly from controls. In contrast, in mice the bromoxynil-induced elevated incidence of SNR persisted through Day 40 (42.3% in treated vs 0% in controls). Analysis of SNR was also done on the basis of their length (greater or less than 1/2 the length of the 13th rib). In the mouse, the incidence of smaller SNR was much lower on Day 40 as compared to Day 20; in contrast the incidence of larger SNR persisted through Day 40. In the rat, the incidence of larger SNR was too small to draw conclusions as to the postnatal fate of these structures. As in the mouse, however, the incidence of smaller SNR was significantly lower by Day 40. The significance of SNR in developmental toxicity remains problematic. The impact of this anomaly on animals is difficult to assess.(ABSTRACT TRUNCATED AT 250 WORDS)