Insecticide resistance in the malaria vector, Anopheles gambiae is a serious problem, epitomized by the multi-resistant Akron strain, originally isolated in the country of Benin. Here we report resistance in this strain to pyrethroids and DDT (13-fold to 35-fold compared to the susceptible G3 strain), but surprisingly little resistance to etofenprox, a compound sometimes described as a “pseudo-pyrethroid.” There was also strong resistance to topically-applied commercial carbamates (45-fold to 81-fold), except for the oximes aldicarb and methomyl. Biochemical assays showed enhanced cytochrome P450 monooxygenase and carboxylesterase activity, but not that of glutathione-S-transferase. A series of substituted α,α,α,-trifluoroacetophenone oxime methylcarbamates were evaluated for enzyme inhibition potency and toxicity against G3 and Akron mosquitoes. The compound bearing an unsubstituted phenyl ring showed the greatest toxicity to mosquitoes of both strains. Low cross resistance in Akron was retained by all analogs in the series. Kinetic analysis of acetylcholinesterase activity and its inhibition by insecticides in the G3 strain showed inactivation rate constants greater than that of propoxur, and against Akron enzyme inactivation rate constants similar to that of aldicarb. However, inactivation rate constants against recombinant human AChE were essentially identical to that of the G3 strain. Thus, the acetophenone oxime carbamates described here, though potent insecticides that control resistant Akron mosquitoes, require further structural modification to attain acceptable selectivity and human safety.

Macrocyclic propargyl acetates containing a furan ring were prepared using the CrCl2-promoted reaction. In the presence of either a Au(I) or a Au(III) catalyst, a tandem 3,3-rearrangement-transannular [4+3] cycloaddition reaction occurred to provide multiple fused ring systems. The transannular [4+3] cycloaddition reactions of the macrocyclic propargyl acetates are regio- and diastereospecific. The regiochemistry of the product is controlled by the position of the acetoxy group in the starting material and the stereochemistry of the reaction depends on the ring size.

Gold catalysts with N-heterocyclic carbene ligands have become an attractive tool for organic synthesis. Two new gold complexes (9, 11) are prepared and their structures are determined by X-ray structural analysis. Their catalytic activities have been studied with a new intramolecular cyclopropanation reaction starting from the propargyl esters tethered to a terminal alkene. Although no or low enantioselectivity was observed with 9 or 11, the insight gained from this study is the importance of the steric effects of the NHC ligand.

A 14-membered macrocycle with an allene and a furan strategically located at across the ring from each other is synthesized using an allene ring closing metathesis reaction. Upon treatment of the macrocycle with a catalytic amount of Pd(OAc) 2 and other additives, the first transannular [4+3] cycloaddition occurred to yield 37% of a tetracyclic compound containing the ABC ring structure of the natural products cortistatins.Carbocyclic seven-membered rings appear in a variety of natural products and have provided a strong impetus for the development of new synthetic methodology. The potent cytostatic natural product cortistatin A, which contains a center oxabicyclo[3.2.1] octene ring system (Scheme 1), further underscores the significance of the development of synthetic methodologies in this area. The intermolecular version of the [4+3] cycloaddition reaction has been widely investigated for over three decades. [1][2][3] The intramolecular versions of [4+3] cycloadditions have also been investigated although not as widely as its intermolecular counterpart. [4][5][6] To the best of our knowledge, unlike the Diels-Alder reaction, 7-9 the transannular [4+3] cycloaddition variant has not been reported. In this communication, we report our successful implementation of the first transannular [4+3] cycloaddition reaction to the synthesis of the ABCD ring carbon frame of the cortistatins.The cortistatins contain a central oxabicyclo[3.2.1]-octene ring system. The first synthesis of cortistatin A was recently reported starting from a steroid precursor, prednisone. 10 Our retrosynthetic analysis in Scheme 1 indicates that a transannular [4+3] cycloaddition should provide an efficient synthetic route to the polycyclic structure frame of cortistatins by forming four rings in one transformation.In order to verify the feasibility of the transannular approach, our plan is to first synthesize a simple macrocycle containing both a furan moiety and an oxy-allyl cation precursor function. Common functional groups for generating oxyallyl cations are α-halogenated ketones. 1,2,4 However, at least one example was reported in which an allene oxide functional group was implicated in a [4+3] cycloaddition reaction. 11 In addition, nitrogen-stabilized oxyallyl cations can be generated in situ via epoxidations of allenamides, which can undergo inter-and intramolecular [4+3] cycloadditions with dienes. [12][13][14] Considering the advances in the chemistry of ring closing metathesis (RCM), 15,16 and a report from Janssen and Krause on © 2008 Elsevier Ltd. All rights reserved. *Corresponding author. Tel.: +0-513-529-2825; fax: +0-513-529-5715; e-mail: gungbw@muohio.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the produc...

No abstract