Diastereo- and Enantioselective Synthesis of Homoallylic Amines Bearing Quaternary Carbon Centers.

A Cu-catalyzed method for the efficient enantio- and diastereoselective synthesis of chiral homoallylic amines bearing a quaternary carbon and an alkenylboron is disclosed. Transformations are promoted by a readily prepared (phosphoramidite)-Cu complex and involve bench-stable γ,γ-disubstituted allyldiborons and benzyl imines; products are obtained in up to 82% yield, >20:1 dr, and >99:1 er. Reactions proceed via stereodefined boron-stabilized allylic Cu species formed by an enantioselective transmetalation. Utility of the 1-amino-3-alkenylboronate products is highlighted by a variety of synthetic transformations.

The transcriptome of the endometrium and placenta is associated with pregnancy development but not lactation status in dairy cows.

Infertility in lactating dairy cows is explained partially by the metabolic state associated with high milk production. The hypothesis was that lactating and nonlactating cows would differ in endometrial and placental transcriptomes during early pregnancy (day 28 to 42) and this difference would explain the predisposition for lactating cows to have embryonic loss at that time. Cows were either milked or not milked after calving. Reproductive [endometrium (caruncular and intercaruncular) and placenta] and liver tissues were collected on day 28, 35, and 42 of pregnancy. The hypothesis was rejected because no effect of lactation on mRNA abundance within reproductive tissues was found. Large differences within liver demonstrated the utility of the model to test an effect of lactation on tissue gene expression. Major changes in gene expression in reproductive tissues across time were found. Greater activation of the transcriptome for the recruitment and activation of macrophages was found in the endometrium and placenta. Changes in glucose metabolism between day 28 and 42 included greater mRNA abundance of rate-limiting genes for gluconeogenesis in intercaruncular endometrium and evidence for the establishment of aerobic glycolysis (Warburg effect) in the placenta. Temporal changes were predicted to be controlled by CSF1, PDGFB, TGFB1, and JUN. Production of nitric oxide and reactive oxygen species by macrophages was identified as a mechanism to promote angiogenesis in the endometrium. Reported differences in pregnancy development for lactating vs. nonlactating cows could be explained by systemic glucose availability to the conceptus and appeared to be independent of the endometrial and placental transcriptomes.

Enantio- and Diastereoselective 1,2-Additions to α-Ketoesters with Diborylmethane and Substituted 1,1-Diborylalkanes.

The catalytic enantioselective synthesis of boronate-substituted tertiary alcohols through additions of diborylmethane and substituted 1,1-diborylalkanes to α-ketoesters is reported. The reactions are catalyzed by readily available chiral phosphine/copper(I) complexes and produce ß-hydroxyboronates containing up to two contiguous stereogenic centers in up to 99:1 e.r. and greater than 20:1 d.r. The utility of the organoboron products is demonstrated through several chemoselective functionalizations. Evidence indicates the reactions occur via an enantioenriched α-boryl-copper-alkyl intermediate.

Steric and electronic effects influencing ß-aryl elimination in the Pd-catalyzed carbon-carbon single bond activation of triarylmethanols.

An analysis of the palladium-catalyzed activation of carbon-carbon single bonds within triarylmethanols has led to a greater understanding of factors influencing the ß-aryl elimination process responsible for C-C bond cleavage. A series of competition reactions were utilized to determine that ß-aryl elimination of aryl substituents containing ortho-substitution proceeds with significant preference to unsubstituted phenyl rings. Further experiments indicate that substrates containing either strongly donating or withdrawing substituents are cleaved from triarylmethanols more readily than relatively neutral species.

Pregnancy development from day 28 to 42 of gestation in postpartum Holstein cows that were either milked (lactating) or not milked (not lactating) after calving.

The objective was to determine if lactation affects fetal and placental development from day 28 to 42 of gestation. Bos taurus Holstein cows were assigned to one of the two treatments immediately after parturition (lactating (n=23) or nonlactating (dried off immediately after calving; n=20)). Cows were inseminated at ~60 days postpartum with semen from a single ejaculate. Pregnant cows were slaughtered at 1 of 3 days of gestation (day 28, 35, or 42) and tissues were collected. The interval to first insemination, services per conception, and days to pregnancy were similar for lactating and nonlactating cows. Lactating cows had greater plasma GH and nonesterified fatty acids. Nonlactating cows had greater plasma glucose, insulin, and IGF1. There was no effect of lactation on plasma progesterone or estradiol concentrations. Lactation had a negative effect on the weight of the fetus and placenta (weights were less in lactating cows). Fetuses collected from cows that became pregnant after first insemination were heavier than fetuses collected from cows that became pregnant after second or third insemination. Pregnancy after first insemination was associated with greater blood glucose and IGF1 during the first 30 days postpartum. The conclusions were that lactation negatively affects the growth of fetal and placental tissues perhaps through a mechanism that involves hormones and metabolites that are affected by lactation. Fetal growth within cows conceiving at first insemination compared to second or third insemination was more rapid and was associated with greater blood glucose and IGF1 early postpartum (before day 30).

Uterine progesterone receptor expression, conceptus development, and ovarian function in pigs treated with RU 486 during early pregnancy.

Establishment of pregnancy in the pig depends on down-regulation of progesterone receptor (PGR) in the uterine luminal and glandular epithelium during the first week after breeding. The present study evaluated the regulation of endometrial PGR by progesterone and the possible role of endometrial tumor necrosis factor (ligand) superfamily member 11 (TNFSF11) and nuclear factor-kappa B (NFKB) activation in PGR expression. Mature, cycling gilts were inseminated (Day 0) and assigned to either untreated control (n = 9) or one of two treatments that employed RU 486 to block progesterone action either before (treatment 1 [T1]) or after (treatment 2 [T2]) the initiation of PGR down-regulation. The T1 gilts were treated with RU 486 (400 mg/day) on Days 3-5 of pregnancy (n = 9), and T2 gilts were treated with RU 486 on Days 6 and 7 of pregnancy (n = 9). Uteri and ovaries were collected on Day 8 or 12 of gestation. The diameter of the conceptuses in T1 gilts was approximately half that in controls by Day 8, and normal conceptuses were not collected from any T1 gilts on Day 12. Endometrial PGR mRNA was more abundant in T1 and T2 gilts compared with control gilts. The PGR-B protein decreased from Day 8 to Day 12 in the luminal epithelium and, to some extent, in superficial glandular epithelium in control and T2 gilts. In T1 gilts, the PGR-B protein remained elevated (i.e., failed to undergo down-regulation) on Day 12. Blocking PGR action early in the cycle (i.e., on or before Day 5), therefore, prevented normal conceptus development, caused elevated PGR mRNA, and prevented the decrease in PGR protein that typically occurs in pigs. We could not confirm a role for NFKB activation in PGR down-regulation, because pigs with extreme differences in PGR and TNFSF11 expression (T1 and controls) had similar NFKB activation on Day 8. Activated NFKB within the luminal epithelium and glandular epithelium (both superficial and deep) was observed in T2 and control pigs on Day 12 when elongating conceptuses (presumably releasing interleukin 1 beta to activate NFKB) were recovered. Gilts treated with RU 486 had greater ovarian follicular growth and greater plasma estradiol concentrations. We conclude that the mechanisms controlling PGR down-regulation are progesterone-dependent and occur between Day 3 and Day 6 of pregnancy. NFKB activation did not appear to have a role in PGR down-regulation within the period that we studied. Blocking progesterone action after Day 6 did not reverse the process of PGR down-regulation, nor did it appear to affect the development of conceptuses collected on Day 12.

Enantio- and Diastereoselective Synthesis of Hydroxy Bis(boronates) via Cu-Catalyzed Tandem Borylation/1,2-Addition.

Catalytic enantioselective synthesis of 1-hydroxy-2,3-bisboronate esters through multicomponent borylation/1,2-addition is reported. Catalyst and substrates are readily available, form both a C-B and C-C bond, and generate up to three contiguous stereocenters. The reaction is tolerant of aryl, vinyl, and alkyl aldehydes and ketones in up to 95% yield, >20:1 dr, and 99:1 er. Intramolecular additions to aldehydes and ketones result in stereodivergent processes. The hydroxy bis(boronate) ester products are amenable to site-selective chemical elaboration.