Progress in the development of asymmetric Heck couplings of arenes and acyclic olefins has been limited by a tenuous understanding of the factors that dictate selectivity in migratory insertion and β-hydride elimination. On the basis of key mechanistic insight recently garnered in the exploration of selective Heck reactions, we report here an enantioselective variant that delivers β-, γ-, or δ-aryl carbonyl products from acyclic alkenol substrates. The catalyst system imparts notable regioselectivity during migratory insertion and promotes the migration of the alkene's unsaturation toward the alcohol to ultimately form the ketone product. The reaction uses aryldiazonium salts as the arene source, yields enantiomeric products from opposite starting alkene configurations, and uses a readily accessible ligand. The racemic nature of the alkenol substrate does not bias the enantioselection.

The influence of size, surface charge and surface functionality of poly(amido amine) dendrimers and silica nanoparticles (SNPs) on their toxicity was studied in immunocompetent mice. After systematic characterization of nanoparticles, they were administered to CD-1 (caesarean derived-1) mice to evaluate acute toxicity. A distinct trend in nanotoxicity based on surface charge and functional group was observed with dendrimers regardless of their size. Amine-terminated dendrimers were fatal at doses >10 mg/kg causing haematological complications such as disseminated intravascular coagulation-like manifestations whereas carboxyl- and hydroxyl-terminated dendrimers of similar sizes were tolerated at 50-fold higher doses. In contrast, larger SNPs were less tolerated than smaller SNPs irrespective of their surface functionality. These findings have important implications in the use of these nanoparticles for various biomedical applications.

A general, highly selective asymmetric redox-relay oxidative Heck reaction using achiral or racemic acyclic alkenols and boronic acid derivatives is reported. This reaction delivers remotely functionalized arylated carbonyl products from acyclic alkenol substrates, with excellent enantioselectivity under mild conditions, bearing a range of useful functionality. A preliminary mechanistic investigation suggests that the regioselectivity of the initial migratory insertion is highly dependent on the electronic nature of the boronic acid and more subtle electronic effects of the alkenyl alcohol.

The brominated chamigrene sesquiterpenes constitute a large subclass of bromocyclohexane containing natural products, yet no general enantioselective strategy for the synthesis of these small molecules exists. Herein we report a general strategy for accessing this family of secondary metabolites including the enantioselective synthesis of (−)-α- and (−)-ent-β-bromochamigrene, (−)-dactylone, and (+)-aplydactone. Access to these molecules is enabled by a stereospecific bromopolyene cyclization initiated by the solvolysis of an enantioenriched vicinal bromochloride.

The brominated chamigrene sesquiterpenes constitute a large subclass of bromocyclohexane containing natural products, yet no general enantioselective strategy for the synthesis of these small molecules exists. Herein we report a general strategy for accessing this family of secondary metabolites including the enantioselective synthesis of (−)-α-and (−)-ent-β-bromochamigrene, (−)-dactylone, and (+)-aplydactone. Access to these molecules is enabled by a stereospecific bromopolyene cyclization initiated by the solvolysis of an enantioenriched vicinal bromochloride. Dihalides Light the WayA highly general approach to the brominated chamigrene sesquiterpenes has been realized via a stereospecific bromopolyene cyclization of an enantioenriched bromochloride. The total synthesis of (+)-aplydactone has been accomplished for the first time via an intramolecular [2+2] cycloaddition.Keywords asymmetric synthesis; halogenation; natural products; solvolysis; terpenes Of the roughly 300 natural products that have been isolated and structurally characterized containing a bromocyclohexane motif (1, Figure 1a), [1a-c] more than 50 are represented by the brominated chamigrene sesquiterpenes (2, Figure 1a). Most members of this family differ in their level of saturation, halogenation, and oxygenation (3-8, Figure 1b). The structural variety within the halogenated chamigrenes is complemented by diverse biological * nburns@stanford.edu.Supporting information for this article is given via a link at the end of the document. HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript activities, with noteworthy examples including antibacterial, [2] antifungal, [3] antiviral, [4] anthelmintic, [5] and anticancer [6] effects. To date, the total synthesis of (+)-elatol 6 by Stoltz and Grubbs [7a] constitutes the only enantioselective synthesis of a member of the halogenated chamigrene sesquiterpenes. A general enantioselective approach for the synthesis of this class of molecules has yet to be reported. [7b-e] Along these lines, we set out to develop a strategy that would enable rapid construction of the spirocyclic core and thus facilitate elaboration to structurally disparate members of this family of small molecules for further chemical and biological investigations.We were particularly intrigued by the cancer preventive agent dactylone (7) [8] and a related congener, aplydactone (8). [9] Dactylone has been shown to suppress phenotype expression at non-cytotoxic doses in human lung, colon, and skin tumor cell lines and therefore holds promise as a molecular tool for anticancer studies. [8c] Dactylone and aplydactone were originally isolated from the sea hare Aplysia dactylomela in 1987, however the structure of aplydactone was not disclosed until 2001 with the assistance of X-ray crystallography. [9] In that report, it was suggested that 8 may arise from an intramolecular [2 + 2] cycloaddition of 7. Accordingly, we selected dactylone 7 as a synthetic target with the objective of also interrog...