The C−H functionalization of silyl ethers via carbene-induced C−H insertion represents an efficient synthetic disconnection strategy. In this work, site-and stereoselective C(sp 3 )−H functionalization at α, γ, δ, and even more distal positions to the siloxy group has been achieved using donor/ acceptor carbene intermediates. By exploiting the predilections of Rh 2 (R-TCPTAD) 4 and Rh 2 (S-2-Cl-5-BrTPCP) 4 catalysts to target either more electronically activated or more spatially accessible C− H sites, respectively, divergent desired products can be formed with good diastereocontrol and enantiocontrol. Notably, the reaction can also be extended to enable desymmetrization of meso silyl ethers. Leveraging the broad substrate scope examined in this study, we have trained a machine learning classification model using logistic regression to predict the major C−H functionalization site based on intrinsic substrate reactivity and catalyst propensity for overriding it. This model enables prediction of the major product when applying these C−H functionalization methods to a new substrate of interest. Applying this model broadly, we have demonstrated its utility for guiding late-stage functionalization in complex settings and developed an intuitive visualization tool to assist synthetic chemists in such endeavors.
The synthesis and evaluation of six C4-symmetric
bowl-shaped
dirhodium tetracarboxylate catalysts are described. These elaborate
high-symmetry catalysts are readily generated by means of the self-assembly
of four C1-symmetric ligands around the dirhodium core.
These catalysts are capable of highly site-selective, diastereoselective,
and enantioselective C–H functionalization reactions by means
of donor/acceptor carbene-induced C–H insertions.
Rhodium-catalyzed
C–H insertion by donor/acceptor carbenes
is a useful transformation in organic synthesis. However, the site-selectivity
of the C–H transformation on the target molecule is often a
major issue. Site-selective C–H functionalizations of challenging
substrates like N-aryl- and N-heteroaryl
piperidines could be achieved through chiral rhodium carbene intermediates,
leading to the formation of highly stereoselective C-2 products. In
addition, N-aryl morpholines and piperazines were
selectively reacted at the α position to the N-aryl group.
Regio‐ and stereoselective distal allylic/benzylic C−H functionalization of allyl and benzyl silyl ethers was achieved using rhodium(II) carbenes derived from N‐sulfonyltriazoles and aryldiazoacetates as carbene precursors. The bulky rhodium carbenes led to highly site‐selective functionalization of less activated allylic and benzylic C−H bonds even in the presence of electronically preferred C−H bonds located α to oxygen. The dirhodium catalyst Rh2(S‐NTTL)4 is the most effective chiral catalyst for triazole‐derived carbene transformations, whereas Rh2(S‐TPPTTL)4 works best for carbenes derived from aryldiazoacetates. The reactions afford a variety of δ‐functionalized allyl silyl ethers with high diastereo‐ and enantioselectivity. The utility of the present method was demonstrated by its application to the synthesis of a 3,4‐disubstituted l‐proline scaffold.
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