DFT Study on the Biosynthesis of Verrucosane Diterpenoids and Mangicol Sesterterpenoids: Involvement of Secondary-Carbocation-Free Reaction Cascades

[Image: see text] Some experimental observations indicate that a sequential formation of secondary (2°) carbocations might be involved in some biosynthetic pathways, including those of verrucosane-type diterpenoids and mangicol-type sesterterpenoids, but it remains controversial whether or not such 2° cations are viable intermediates. Here, we performed comprehensive density functional theory calculations of these biosynthetic pathways. The results do not support previously proposed pathways/mechanisms: in particular, we find that none of the putative 2° carbocation intermediates is involved in either of the biosynthetic pathways. In verrucosane biosynthesis, the proposed 2° carbocations (II and IV) in the early stage are bypassed by the formation of the adjacent 3° carbocations and by unusual skeletal rearrangement reactions, and in the later stage, the putative 2° carbocation intermediates (VI, VII, and VIII) are not present as the proposed forms but as nonclassical structures between homoallyl and cyclopropylcarbinyl cations. In the mangicol biosynthesis, one of the two proposed 2° carbocations (X) is bypassed by a C–C bond-breaking reaction to generate a 3° carbocation with a C=C bond, while the other (XI) is bypassed by a strong hyperconjugative interaction leading to a nonclassical carbocation. We propose new biosynthetic pathways/mechanisms for the verrucosane-type diterpenoids and mangicol-type sesterterpenoids. These pathways are in good agreement with the findings of previous biosynthetic studies, including isotope-labeling experiments and byproducts analysis, and moreover can account for the biosynthesis of related terpenes.