Asymmetric Total Synthesis of C2-OH Lycopodium Alkaloids (−)-Palhinine B, (−)-Palhinine C, and (+)-Palhinine B Enabled by Stereocontrolled Diels–Alder Strategy

High Resolution Image Download MS PowerPoint Slide The first asymmetric total synthesis of Lycopodium alkaloids bearing a 1,2-amino alcohol motif, including (−)-palhinine B, (−)-palhinine C, and (+)-palhinine B, has been achieved. The synthesis features early stage installation of a chiral C2-OH group from a tyrosine-derived 1,2-amino alcohol, which governs the overall stereochemical outcome at C7, C13, C15, and a quaternary stereogenic center at C12 of the tetracyclic palhinine skeleton. A highly diastereoselective Diels–Alder reaction of a masked ortho -benzoquinone, followed by a thiol-mediated acyl radical cyclization, enables rapid construction of the isotwistane core. DFT-guided analysis revealed the challenge of late-stage C2-OH inversion and led to a successful chemo- and diastereoselective reduction of a caged hemiaminal ketone, providing access to the C2 epimer. This work establishes a unified asymmetric strategy for complex Lycopodium alkaloids and highlights the integration of computation with synthetic design.