Lity. Exactly the same trend was observed for pivaloyl ester 21. Though each
Lity. The identical trend was observed for pivaloyl ester 21. While each are viable alternatives to 18, the presence of the thioether ligand is vital for obtaining optimal yields of extremely enantioenriched product. Scope of reactionNIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptWith the optimal leaving group in hand, we prepared a array of enantioenriched substrates for cross-coupling by the basic methods outlined in Scheme two. Synthesis with the chiral alcohol intermediates was accomplished by CBS reduction with the corresponding ketone25 or enantioselective arylation from the requisite aldehyde.26,27 Absolute configuration with the intermediate alcohols was assigned using the accepted models for selectivity for every reaction.28 The absolute configuration was then confirmed by the Competing Enantioselective Coccidia Purity & Documentation Conversion (CEC) Method.29 DCC coupling appended the necessary leaving group with no loss of ee, giving the starting materials for the transformation.23 A range of functional groups are nicely tolerated below our optimized reaction situations (Tables 1 and two). One example is, products containing internal alkenes, 24 and 25, are formed in high yield and within the case of 25, with higher ee (Table 1, entries two and 3). On top of that, the elevated steric bulk of 24 will not considerably slow down the reaction. The presence of a TMS-protected alkyne can also be compatible together with the reaction conditions and 26 is formed inJ Am Chem Soc. Author manuscript; out there in PMC 2014 June 19.Wisniewska et al.Page81 yield and 99 es (entry 4). TMS-alkynes are very easily deprotected towards the totally free terminal alkyne, which gives a convenient functional handle for further elaboration. Oxygenation can also be well tolerated beneath reaction conditions. Substrates containing a silyl ether or perhaps a free of charge alcohol form 27 and 28 in fantastic yield and with high es (entries five and six). Moreover, the use of zinc reagents permits for cross-coupling of substrates containing sensitive functionality including acetals (entry 7) also as electrophilic fragments for example esters (entry eight). We did not observe decomposition in the acetal or addition to the ester beneath our reaction circumstances. With these promising benefits we moved to nitrogenated substrate classes. N-Heterocycles, amines, and imides are common functional groups in biologically active molecules (Figure 1, compounds 1 and 3). Since nitrogen-based ligands are usually employed in nickel-catalyzed cross-coupling reactions, we anticipated that this class of substrates could be problematic. Initially, we synthesized a morpholine-containing substrate. Morpholine is a widespread motif in several pharmaceuticals, such as the antibiotic linezolid, anticancer agent gefitinib, and analgesic dextromoramide.30 We were pleased to find out that the morpholino ring was effectively tolerated in our cross-coupling and 31 was formed in 68 yield. Amides are also properly tolerated within the reaction; 32 was formed in 84 yield with fantastic es (entry 10). Phthalimides are exciting because they are HSP drug readily deprotected to reveal major amines. Encouraged by these benefits, we subsequent designed an indole substrate. This class of substrates is particularly challenging because the indole moiety stabilizes carbocation intermediates, which, if formed, would afford racemic product and elevated levels of byproducts resulting from elimination (Scheme 3a). In prior research, we obsereved that cross-coupling of indole substrates under our original Kumada coupling conditi.