Abstract
ABSTRACT
Thiazoles are ubiquitous motifs in bioactive molecules, making strategies for the stereospecific installation of chiral C(sp
3
)‐rich substituents on this scaffold particularly valuable for drug discovery. However, achieving such transformations remains nontrivial, as conventional C(sp
2
)–C(sp
3
) cross‐coupling approaches are often compromised by catalyst deactivation and deleterious side reactions, such as
β
‐hydride elimination. Although electrophile‐mediated coupling of alkyl boronic esters with lithiated aromatic compounds offers a potential route to C(sp
2
)–C(sp
3
) bond formation, it is ineffective for thiazoles because the heteroaromatic core lacks sufficient nucleophilicity to engage electrophiles and promote productive 1,2‐migration. Herein, we report a lithiation–borylation–aromatic Pummerer (LiBAP) strategy that enables stereospecific C5 cross‐coupling of thiazoles with boronic esters. A pendant sulfinyl group enables exocyclic electrophilic activation, triggering a Pummerer‐type 1,2‐migration while avoiding unproductive C─B bond fragmentation. The reaction proceeds with complete stereospecificity and broad functional‐group tolerance, furnishing a C2 sulfide handle on thiazole that serves as a versatile linchpin for downstream C–S diversification. A formal asymmetric synthesis of a bioactive thiazole
γ
‐secretase inhibitor was demonstrated to further highlight the synthetic utility of our LiBAP protocol.