Variety Of Electron-withdrawing Groups Research Articles

A Simple Zinc-Mediated Method for Selenium Addition to Michael Acceptors.

In this work, we focused our attention on seleno-Michael type reactions. These were performed using zinc-selenolates generated in situ from diphenyl diselenide 1, 1,2-bis(3-phenylpropyl)diselenide 30, and protected selenocystine 31 via an efficient biphasic Zn/HCl-based reducing system. Alkenes with a variety of electron-withdrawing groups were investigated in order to gauge the scope and limitations of the process. Results demonstrated that the addition to acyclic α,β-unsaturated ketones, aldehydes, esters amides, and acids was effectively achieved and that alkyl substituents at the reactive β-centre can be accommodated. Similarly, cyclic enones undergo efficient Se-addition and the corresponding adducts were isolated in moderate to good yield. Vinyl sulfones, α,β-unsaturated nitriles, and chalcones are not compatible with these reaction conditions. A recycling experiment demonstrated that the unreacted Zn/HCl reducing system can be effectively reused for seven reaction cycles (91% conversion yield at the 7° recycling rounds).

On the Mechanism of Cu-Catalyzed Enantioselective Extended Conjugate Additions: A Structure-Based Approach

The enantioselective 1,6-addition to unsaturated carbonyl compounds offers unique opportunities to study the range of selectivities one can obtain using Cu catalysis. Here, a substrate–reagent approach to obtain structural information on the mechanism of extended conjugate additions is reported. By studying the influence of several halides in the Grignard reagent and in the Cu source on the enantioselective 1,6-addition, it was shown that it is advantageous to use a combination of EtMgBr as Grignard reagent and CuI as Cu source. Furthermore, exploring substrates bearing several alkyl esters revealed that tBu-ester substrates enhance the enantiodiscrimination in the 1,6-addition and allow the addition of BnCH2MgBr. Substrates with a variety of electron-withdrawing groups were investigated as well, identifying that ester substrates are optimal for the 1,6-addition. Two other investigations feature Me-substituted olefin substrates and substrates with all possible olefin geometries. These studies show unprecedented high enantioselectivity in the 1,6-addition when α-Me substrates are used and give relevant insight into the 1,6-addition mechanism. Finally, substrates with three or four olefins in conjugation with the electron-withdrawing groups were studied. Here, a 1,8-addition is reported that gives the corresponding products in reasonable yield, regio- and stereoselectivity. With the combined results of these studies, elucidating key substrate and reagent parameters, an adapted mechanism for the enantioselective 1,6-addition is proposed. This mechanism features the activation of a dimeric precatalyst by an equivalent of Grignard reagent, active catalyst coordination to the internal olefin of the substrate in a CuI-π-complex, followed by coordination of the catalyst to the remote olefin forming another CuI-π-complex. From the latter CuI-complex, an oxidative addition gives a CuIII-σ-complex at the δ-carbon, followed by transfer of the alkyl moiety to the δ-position. This reductive elimination yields the product and reforms the active CuI catalyst via transmetalation with another molecule of Grignard reagent.

The synthesis of novel nonclassical reversed bridge quinazoline antifolates as inhibitors of thymidylate synthase

Abstract2‐Amino‐6‐methyl‐5‐(pyridin‐4‐ylsulfanyl)‐3H‐quinazolin‐4‐one (3, AG337) a lipophilic thymidylate synthase inhibitor, is currently in clinical trials as an antitumor agent. On the basis of the crystal structure of 3 and the classical inhibitor 10‐propargyl‐5,8‐dideazafolic acid (1, PDDF) with thymidylate synthase, we designed and synthesized a series of nonclassical 2‐amino‐6‐substituted‐3H‐quinazolin‐4‐ones 4–13, with a variety of electron withdrawing groups in the side chain (with the exception of compound 4). Molecular modeling indicates that these reversed bridge (N9–C10) 6‐substituted analogues orient their side chain C10‐substituent such that it lies between that of 1 and 3. These compounds were obtained by reduc tive amination of 6‐aminoquinazoline 16 and the appropriate aryl aldehyde 17 or aryl ketone 18. For ana logues 11–13, the yield depended on the substitutents on the aryl ketone 18 (comparison of 11 and 13). With the exception of analogue 13, all the compounds in the series were poor inhibitors of thymidylate synthase from Lactobacillus casei, Pneumocystis carinii and human sources.

Cardioselective antiischemic ATP-sensitive potassium channel (K(ATP)) openers. 6. Effect of modifications at C6 of benzopyranyl cyanoguanidines.

The effect on potency and selectivity of modifications at the C6 position of the cardioprotective K(ATP) opener BMS-180448 (2) is described. Structure-activity studies show that a variety of electron-withdrawing groups (ketone, sulfone, sulfonamide, etc.) are tolerated for cardioprotective activity as measured by EC(25) values for an increase in time to the onset of contracture in globally ischemic rat hearts. Changes made to the sulfonamido substituent indicate that compounds derived from secondary lipophilic amines are preferred for good cardioprotective potency and selectivity. The diisobutyl analogue 27 (EC(25) = 0.04 microM) is the most potent compound of this series. The cardiac selectivity of 27 results from a combination of reduced vasorelaxant potency and enhanced cardioprotective potency relative to the potent vasodilating K(ATP) openers (e.g., cromakalim). The diisobutylsulfonamide analogue 27 is over 4 orders of magnitude more cardiac selective than cromakalim (1). These results support the hypothesis that the cardioprotective and vasorelaxant properties of K(ATP) openers follow distinct structure-activity relationships. The mechanism of action of 27 appears to involve opening of the cardiac K(ATP) as its cardioprotective effects are abolished by the K(ATP) blocker glyburide.