Aspirin, or acetylsalicylic acid is widely used to control pain, inflammation and fever. Important to this function is its ability to irreversibly acetylate cyclooxygenases at active site serines. Aspirin has the potential to acetylate other amino acid side-chains, leading to the possibility that aspirin-mediated lysine acetylation could explain some of its as-yet unexplained drug actions or side-effects. Using isotopically labeled aspirin-d3, in combination with acetylated lysine purification and LC-MS/MS, we identified over 12000 sites of lysine acetylation from cultured human cells. Although aspirin amplifies endogenous acetylation signals at the majority of detectable endogenous sites, cells tolerate aspirin mediated acetylation very well unless cellular deacetylases are inhibited. Although most endogenous acetylations are amplified by orders of magnitude, lysine acetylation site occupancies remain very low even after high doses of aspirin. This work shows that while aspirin has enormous potential to alter protein function, in the majority of cases aspirin-mediated acetylations do not accumulate to levels likely to elicit biological effects. These findings are consistent with an emerging model for cellular acetylation whereby stoichiometry correlates with biological relevance, and deacetylases act to minimize the biological consequences of nonspecific chemical acetylations.

The synthesis of dehaloperophoramidine, a non-halogenated derivative of the marine natural product perophoramidine, and its biological activity towards HCT116, HT29 and LoVo colorectal carcinoma cells is reported. A [3,3]-Claisen rearrangement and an epoxide opening/allylsilylation reaction installed the contiguous all-carbon quaternary stereocentres with the required relative stereochemistry.

The bioactive alkaloid natural product perophoramidine and the related family of compounds known as the communesins have inspired the synthesis community for more than a decade. Many of the elegant approaches have required the synthesis of complex intermediates that have not always reacted in the expected manner. In this study we describe a series of cyclic ethercontaining precursors that were prepared during our synthetic studies towards these natural products. Attempts to open the cyclic ether ring and trap the resulting stabilised carbocation with a carbon nucleophile ultimately led to the preparation of a diallyl-substituted all carbon quaternary centre. Subsequent attempts to differentiate between the two allyl groups resulted in a relatively clean transformation to an unexpected compound. Extensive structural characterisation, including small molecule X-ray crystallography, showed that a dearomatisation reaction had occurred.

A simple and efficient asymmetric synthesis of novel sp3-rich pyrrolidine chemical scaffolds over five steps starting from simple ketones is described. Key steps involve the use of tert-butanesulfinamide as a chiral auxiliary to perform an asymmetric Tsuji-Trost allylation, with subsequent cross-metathesis with an acrylate ester and reduction of the sulfinimine/cyclisation of the resulting amine giving the pyrrolidine scaffolds in high yields and diastereoselectivites. By removing the chiral auxiliary and functionalising the ester group, the resulting scaffold core can be further derivatised. Introduction Compounds containing a pyrrolidine ring usually possess a wide range of biological activities such as, anticancer, antitumor and anti-biotic activity.[1] Specifically, chiral pyrrolidines constitute a large group of heterocyclic organic compounds which are useful building blocks of pharmaceuticals, [2,3] vitamins, dyes, drug candidates, hormones, agrochemicals [4] and alkaloid natural products. [5,6] Furthermore, these compounds have been used as ligands for transition metals, organocatalysts, [7][8][9] and effective chiral controllers in asymmetric synthesis. [10][11][12] It has been observed that there is a significant interest in the stereoselective synthesis of chiral pyrrolidines, using N-tert-butanesulfinyl imines as a chiral auxiliary. In particular, by the addition of Grignard reagents [13] or hydride[14] to γ-chlorinated N-tert-butanesulfinyl imines followed by cyclisation, or via Wacker-type oxidation cyclisation of alkenes with tertbutanesulfinamide nucleophiles [15] or iodocyclisation of homoallylic sulfonamides. [16] Recently, the diastereoselective α-allylation of a variety chiral α-N-tert-butanesulfinyl imines using Tsuji-Trost reaction has been reported by Stockman and co-workers.[17] In particular, under mild reaction conditions, compounds bearing an allyl group at the α-position of chiral N-tert-butanesulfinyl imines were obtained in high yields, with good diastereoselectivity and substrate tolerance. In a following report, the α-allylation of chiral N-tert-butanesulfinyl imines derived from symmetric cyclic ketones was reported.[18] Hence, we envisioned taking advantage of the Tsuji-Trost allylation of N-tert-butanesulfinyl imines to access, in five steps, pyrrolidine-based chemical scaffolds as outlined in Scheme 1. We aimed to achieve this through cross metathesis of the allylated N-tert-butanesulfinyl imines, followed by reduction and finally ring cyclisation, using an intramolecular Michael addition. Scheme 1. Outline of the asymmetric synthesis of pyrrolidine chemical scaffolds 5. Results and Discussion

Intramolecular oxidative amination of readily accessible aminocyclooct‐4‐enes provides rapid and regioselective access to the 9‐azabicyclo[4.2.1]nonane framework characteristic of the natural product anatoxin‐a (1). This has enabled the synthesis of sp3‐rich chemical scaffolds suitable for diversification. A library of 881 lead‐like compounds is reported alongside a formal synthesis of anatoxin‐a (1).