Asymmetric Total Synthesis of (−)‐Pironetin Employing the SAMP/RAMP Hydrazone Methodology

Abstract

A convergent asymmetric total synthesis of pironetin (1), a polyketide with immunosuppressive, antitumor, and plant‐growth regulating activities is described. The synthesis was realized by coupling between the C₈–C₁₄ 2 and C₇–C₂ 15 fragments, respectively, by using a Mukaiyama‐aldol reaction. The stereogenic centers of each fragment were generated by employing the SAMP/RAMP hydrazone (SAMP=(S)‐1‐amino‐2‐methoxymethylpyrrolidine, RAMP=(R)‐1‐amino‐2‐methoxymethylpyrrolidine) methodology as a key step. An asymmetric α‐alkylation of diethyl ketone permitted the introduction of the C₁₀ stereogenic center of 2, whereas the stereocenters C₄ and C₅ of 15 were installed by an asymmetric aldol reaction. Finally, the formation of the α,β‐unsaturated δ‐lactone was achieved by ring‐closing metathesis in the presence of catalytic amounts of titanium tetraisopropoxide.