Development of Multiple Local Computational Models in Retrosynthetic Analysis: Total Synthesis of (−)-Deoxylimonin

This work describes the development of a <i>de novo</i> strategy to access the A,D-<i>seco</i> limonoids utilizing robust synthetic operations allowing for the synthesis of a characteristic member, deoxylimonin. The retrosynthetic strategy uses resilient chemistry for the assemblage of a key carbocyclic tricycle in only 8 synthetic maneuvers. This intermediate is then amalgamated through a modern variation on the classic combination of ring cleavage and formation using an <i>oxy</i>-Michael reaction as a key synthetic operation. Two discrete local computational models were developed and rapidly integrated into the design stages of retrosynthetic analysis, illustrating how multiple local models augment the intersection of transform-based and structure-goal-based approaches.