Part I: Application of Pd-Peppsi Complexes in Regioselective Cross-Coupling and Natural Product Total Synthesis; Part II: Room Temperature, Additive-Free Carbon-Sulfur Coupling Using Novel NHC-Pd Complexes

The first part of this research is focused on the development of an efficient method for the regioselective Suzuki-Miyaura cross-coupling of allylboronic acid pinacol ester derivatives with aryl and heteroaryl halides using Pd-PEPPSI-IPent (Pyridine Enhanced Pre-catalyst Preparation Stabilization and Initiation) that would be selective for the linear product. Pd-PEPPSI-IPent showed high selectivity (>97%) at the carbon of the allylboron reagent to generate the desired linear isomer under mild reaction conditions (i.e., THF, 70 C, 5M KOH). In the case of trisubstituted allylboronates with different substituents on the olefin, minor olefin geometry isomerization was observed (E/Z 80/20). Using this method, isoprenylated natural products methylated cathafuran A and lakoochin A were synthesized. Although the prenyl and geranyl side chains could be installed onto advanced 2-arylbenzofuran building blocks with high selectivity, significant amounts of an unwanted side product were observed. A dramatic solvent effect on the selectivity for the Directed ortho Metalation (DoM) of 1,5-dichloro-2,4-dimethoxybenzene, a key building block in our synthetic strategy to cathafuran A and lakoochin A, was observed. A series of time-course and labelling studies has revealed that deprotonation occurs exclusively at C3 followed by isomerization of the anion to C6 in THF. In contrast, when DoM was performed in Et2O, deprotonation again occurred selectively at C3, but now no isomerization occurs. Labeling studies also revealed that deuterium has an enormous kinetic isotope effect (KIE) that suppresses not only the original DoM reaction at C3 when deuterium is present there, but also suppresses isomerization to C6 when the label is at that site. The second part of this research focused on the development and application of new, easily activated NHCPdII pre-catalysts featuring a trans-oriented morpholine ligand in carbon-sulfur cross-coupling chemistry. [(IPent)PdCl2(morpholine)] was identified as the most active pre-catalyst, effectively coupling a variety of deactivated aryl halides with aryl, alkyl, and silyl thiols at ambient temperature. Mechanistic studies revealed that, in contrast to other common NHCPdII pre-catalysts, these complexes are rapidly reduced to the active NHCPd0 species in the presence of KOtBu, thus avoiding the need for additives, external activators, or cumbersome pre-activation steps.