The total synthesis of cytotoxic polyketides myceliothermophins E (1), C (2) and D (3) through a cascade-based cyclization to form the trans-fused decalin system is described. The convergent synthesis delivered all three natural products through late-stage divergence and facilitated unambiguous C21 structural assignments for 2 and 3 through X-ray crystallographic analysis which revealed an interesting dimeric structure between its enantiomeric forms.