Dimethylzinc. A leaving group bearing a pendant ligand could serve two functions (Scheme 1c). Coordination to a zinc reagent could activate the substrate for oxidative addition and facilitate the subsequent transmetallation step. We anticipated that tuning the properties on the X and L groups would supply a synergistic enhancement of reactivity.Benefits AND DISCUSSIONIdentification of traceless directing group for Negishi coupling To test our hypothesis we examined a variety of activating groups to promote the crosscoupling of benzylic electrophiles with dimethylzinc (Figure 2). As anticipated, easy benzylic ether four was unreactive. Subsequent, we employed a thioether together with the thought that formation from the zinc-sulfur bond would deliver a strong thermodynamic driving force forJ Am Chem Soc. Author manuscript; readily available in PMC 2014 June 19.Wisniewska et al.Pagethe reaction.21 Though substrate five was extra reactive, elimination to supply styrene 23 was the major pathway. We reasoned that if thioether five underwent oxidative addition, sluggish transmetallation could have resulted in -hydride elimination to offer alkene 23 as the important product. To promote transmetallation over -hydride elimination, we examined ethers and thioethers bearing a second ligand (Group 2). Though acetal 6 and 2-methoxyethyl ether eight remained unreactive, hydroxyethyl thioether 7 afforded the preferred cross-coupled item 22 because the main species, albeit with low enantiospecificity (es).22 To raise the yield and enantiospecificity with the transformation, we improved the cooridinating potential of the directing group by switching to a pendant pyridyl ligand. Pyridyl ether ten was the initial from the oxygen series to afford an appreciable yield of preferred product with excellent es. In contrast, pyridyl thioether 11, afforded reduced yields than 7, with important erosion of enantiomeric excess. Carboxylic acids 12 and 13 afforded the desired solution in moderate yield, but with significantly less than satisfactory es. We reasoned that as a way to accomplish greater reactivity and higher es we could invert the carboxylic acid to an isomeric ester. These compounds would be less probably to undergo radical racemization, which is additional probably for thioethers than ethers, enhancing the es. Moreover, preserving the thiol functionality would permit for strong coordination of zinc for the leaving group. Certainly, a series of isomeric ester leaving groups offered the preferred item in both synthetically beneficial yields and high es (Group 3). While the ester leaving groups addressed the concern of chirality transfer, their synthesis necessitated employing protecting groups to mask the cost-free thiol, which added a step to the synthetic sequence (see SI for information).LM10 Moreover, totally free thiols are not optimal substrates since they may be susceptible to oxidative decomposition.Pepinemab We postulated that using 2(methylthio)ester 18 instead would simplify substrate synthesis and avert oxidative decomposition with the starting material.PMID:24211511 This directing group is particularly hassle-free since (methylthio)acetic acid is commercially obtainable and can be quickly appended onto the benzylic alcohol through a DCC coupling.23 Functionalized together with the thioether directing group, (R)-18 cross-coupled to afford (S)-22 in 81 and exceptional es with overall inversion of configuration (Figure two and Table 1, entry 1).24 Uncomplicated esters had been also evaluated to figure out the value of a pendant ligand in these transformations (Figure two, Group four). Each acetyl.