We herein describe the first diastereoselective synthesis of the Solanum alkaloid tomatidine 1. The synthesis has been accomplished in 11 steps and 24.9 % overall yield (longest linear sequence). This methodology, which involves a convergent synthon insertion followed by a sequence of ring opening/nitrogen substitution/ring closing, allowed the generation of 1 on > 2 g scale. The synthetic challenge with the diastereoselective generation of the unusual spiroaminoketal moiety was solved through a combined azide reduction/addition sequence. The first diastereoselective synthesis of the phytosteroid yamogenin is also reported. Tomatidine has shown promising antibiotic properties against persistent forms of Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA). In particular, it possesses the unique ability to kill persistent forms of S. aureus and MRSA while simultaneously potentiating the antibiotic efficacy of aminoglycoside antibiotics against wild type strains of the bacteria.