A series of strained bi- and tricyclic amides has been shown to be unusually sensitive to cleavage of the C-N bond adjacent to the amide moiety. This bond undergoes facile breaking when subjected to treatment with H2/Pd(OH)2, MeI, and DDQ. In each case, the reaction is highly regioselective and mainly results in breaking the C-N bond that deviates the farthest from its natural planar state. Preliminary experiments that bear on the mechanisms of these reactions are described.

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“Twisted” amides containing non-standard dihedral angles are typically hypersensitive to hydrolysis, a feature that has stringently limited their utility in water. We have synthesized a series of bridged lactams that contain a twisted amide linkage but which exhibit enhanced stability in aqueous environments. Many of these compounds were extracted unchanged from aqueous mixtures ranging from the strongly basic to the strongly acidic. NMR experiments showed that tricyclic lactams undergo reversible hydrolysis at extreme pH ranges, but that a number of compounds in this structure class are indefinitely stable under physiologically relevant pH conditions; one bicyclic example was additionally water-soluble. We examined the effect of structure on the reversibility of amide bond hydrolysis, which we attributed to the transannular nature of the amino acid analogs. These data suggest that medium-bridged lactams of these types should provide useful platforms for studying the behavior of twisted amides in aqueous systems.

A tandem Diels-Alder/azido Schmidt reaction sequence provides rapid access to the core skeleton shared by several Stemona alkaloids including stenine, neostenine, tuberstemonine, and neotubererostemonine. The discovery and evolution of inter-and intramolecular variations of this process and their applications to total syntheses of (±)-stenine and (±)-neostenine is described. The stereochemical outcome of the reaction depends on both substrate type and reaction condition, enabling the preparation of both (±)-stenine and (±)-neostenine from the same diene/dienophile combination. KeywordsTotal synthesis; Stemona alkaloids; Diels-Alder; azides; Schmidt reaction Chinese and Japanese traditional medicines have for centuries utilized extracts of stemonaceous plants as remedies for the treatment of respiratory ailments. These extracts and the isolated Stemona alkaloids have been associated with insecticidal, anthelmintic, antitussive and various neurochemical effects, although mechanisms have rarely been identified. 1 Recently, interest in these alkaloids was further piqued by the demonstration of effective in vivo activity of two skeletally-related Stemona alkaloids, neostenine 3 and neotuberostemonine 4, against citric acid-induced cough in guinea pig animal models. 2 In addition, the Stemona alkaloid tuberstemonine 2 has demonstrated inhibitory activity on excitatory transmission at the crayfish neuromuscular junction. 3 The Stemona alkaloids have attracted substantial interest from synthetic chemists partly because of these links to biological activity and partly from their challenging structural complexity. Stenine has been the focus of several successful synthetic efforts 4 and has inspired a number of synthetic approaches. 5 In addition, tuberostemonine 2 was synthesized by Wipf. 6 However the stenine isomer, neostenine 3, had not yet been prepared via total synthesis at the outset of this project. 7A noteworthy challenge in any stenine synthesis is the construction of the B ring, which is fused to three additional rings. In addition, each of its carbon atoms is a stereogenic center. This issue was addressed using an intramolecular Diels-Alder cyclization in three out of the four first-published syntheses of this target (Scheme 1; the stenine numbering system used E-mail: jaube@ku.edu. Supporting Information Available. Experimental details and characterization data for all new compounds, including X-ray structures (CIF files) of 3 and 28. This material is available free of charge via the internet at http://pubs.acs.org. throughout is that presented in a recent review 1f ). The first synthesis of stenine by Hart in 1990 not only set the precedent for utilizing a Diels-Alder approach to this target, but also established an iodolactonization/Keck allylation sequence as a solution to the problem of stereoselective ethyl group installation. 4a,b Morimoto utilized a chiral oxazoline-based intramolecular DielsAlder cyclization of 5 to synthesize the naturally occurring enantiomer of stenine. 4c-e Padwa applied a...

Sirtuins are a family of NAD+-dependent deacetylases (class III histone deacetylases). Seven mammalian sirtuins, SIRT1-7, are identified, as the functions and locations differ greatly. SIRT1 and SIRT2 locate in nucleus and cytoplasm, while SIRT3-5 in mitochondria. Sirtuins are not only involved in many important biological processes such as apoptosis, cellular senescence, endocrine signaling, glucose homeostasis, aging, and longevity, it can also control circadian clocks and mitochondrial biogenesis. Small molecules that can modulate the sirtuins activity have been shown to have potentials for treating many human diseases such as type II diabetes, cancer, rheumatoid arthritis, cardiovascular and other age-relating diseases. Some polyphenolic natural products such as Resveratrol, Fisetin, and Quercetin have demonstrated health benefits due to their SIRT1 activation effects. Some structurally diverse synthetic compounds, such as SRT1720, SRT1460, Selisistat (EX 527), and AGK2 were used as small molecular SIRT modulators (IC50 = 0.04-100 μM) to treat ischemic stroke, myocardial infarction, neurodegenerative diseases, cancer, aging, and obesity. In order to get better understanding of how the small molecules interact with the sirtuin, the small molecules that having SIRT inhibitory or activation effect, found by HTS or other modern medicinal chemistry techniques, are reviewed in this article.