The use of pseudoephedrine as a practical chiral auxiliary for asymmetric synthesis is described in full. Both enantiomers of pseudoephedrine are inexpensive commodity chemicals and can be N-acylated in high yields to form tertiary amides. In the presence of lithium chloride, the enolates of the corresponding pseudoephedrine amides undergo highly diastereoselective alkylations with a wide range of alkyl halides to afford α-substituted products in high yields. These products can then be transformed in a single operation into highly enantiomerically enriched carboxylic acids, alcohols, aldehydes, and ketones.

Peptidoglycan-derived muramyl dipeptide (MDP) activates innate immunity via the host sensor NOD2. Although MDP is N-acetylated in most bacteria, mycobacteria and related Actinomycetes convert their MDP to an N-glycolylated form through the action of N-acetyl muramic acid hydroxylase (NamH). We used a combination of bacterial genetics and synthetic chemistry to investigate whether N-glycolylation of MDP alters NOD2-mediated immunity. Upon infecting macrophages with 12 bacteria, tumor necrosis factor (TNF) α secretion was NOD2 dependent only with mycobacteria and other Actinomycetes (Nocardia and Rhodococcus). Disruption of namH in Mycobacterium smegmatis obrogated NOD2-mediated TNF secretion, which could be restored upon gene complementation. In mouse macrophages, N-glycolyl MDP was more potent than N-acetyl MDP at activating RIP2, nuclear factor κB, c-Jun N-terminal kinase, and proinflammatory cytokine secretion. In mice challenged intraperitoneally with live or killed mycobacteria, NOD2-dependent immune responses depended on the presence of bacterial namH. Finally, N-glycolyl MDP was more efficacious than N-acetyl MDP at inducing ovalbumin-specific T cell immunity in a model of adjuvancy. Our findings indicate that N-glycolyl MDP has a greater NOD2-stimulating activity than N-acetyl MDP, consistent with the historical observation attributing exceptional immunogenic activity to the mycobacterial cell wall.

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Advances in metal catalysis have revolutionized organic synthesis, with the scope of metal-catalyzed reactions now covering nearly all areas of carbon-carbon, carbon-hydrogen, and carbon-heteroatom bond formation. For years, the goal was to develop catalysts that were highly selective for a single transformation. However, a promising current area of research is the use of a single catalyst to mediate more than one transformation in a selective manner. Whereas much early work was focused on using a catalyst for several similar transformations, recent investigations have shown that it is also possible to employ a single catalyst for several very different transformations in a single reaction sequence. This Minireview focuses on methods in which the mechanisms of the transformations are fundamentally very different.

The selective estrogen receptor downregulator (SERD) fulvestrant can be used as second-line treatment for patients relapsing after treatment with tamoxifen, a selective estrogen receptor modulator (SERM). Unlike tamoxifen, SERDs are devoid of partial agonist activity. While the full antiestrogenicity of SERDs may result in part from their capacity to downregulate levels of estrogen receptor alpha (ER␣) through proteasome-mediated degradation, SERDs are also fully antiestrogenic in the absence of increased receptor turnover in HepG2 cells. Here we report that SERDs induce the rapid and strong SUMOylation of ER␣ in ER␣-positive and -negative cell lines, including HepG2 cells. Four sites of SUMOylation were identified by mass spectrometry analysis. In derivatives of the SERD ICI164,384, SUMOylation was dependent on the length of the side chain and correlated with full antiestrogenicity. Preventing SUMOylation by the overexpression of a SUMO-specific protease (SENP) deSUMOylase partially derepressed transcription in the presence of full antiestrogens in HepG2 cells without a corresponding increase in activity in the presence of agonists or of the SERM tamoxifen. Mutations increasing transcriptional activity in the presence of full antiestrogens reduced SUMOylation levels and suppressed stimulation by SENP1. Our results indicate that ER␣ SUMOylation contributes to full antiestrogenicity in the absence of accelerated receptor turnover. E strogens, mainly 17␤-estradiol (E2), play a crucial role in normal breast development but also contribute to mammary tumorigenesis. Antiestrogens (AEs) used for breast cancer treatment and prevention, such as tamoxifen (Tam), raloxifene (Ral), or fulvestrant (9, 17, 52, 63), block the proliferative effects of estrogens on breast epithelial and carcinoma cells by competing for estrogen receptors (ERs) (ER␣ and ER␤). Similar to other nuclear receptors, ERs activate gene transcription by binding to specific DNA sites and recruiting transcriptional coactivators in a liganddependent manner (13,40,41,70,85).AEs prevent ER activation through the induction of an altered conformation of the receptor ligand binding domain (LBD) that suppresses the recruitment of coactivators (8,66,79) and/or increases the recruitment of corepressors (23,34,45,61,77,83,94). However, selective ER modulators (SERMs) (which include Tam and Ral) have partial agonist activity in a tissue-and gene-specific manner. For example, both have estrogenic effects on bone mass (6), and Tam has estrogenic effects on the uterus (2,5,21,88,90), while Ral does not cause uterine hypertrophy (6). Tam and, to a lesser extent, Ral also have partial agonist activity in breast cancer cells in a gene-specific manner (22). The tissue-specific recruitment of coactivators and corepressors is thought to underlie selective partial agonist activity, and alterations in the expression patterns or activity of ER cofactors in breast cancer cells could contribute to the development of resistance to AE-based therapy (23,37,38,45,77,81,82).Other AEs,...