The carbocation continuum in terpene biosynthesis—where are the secondary cations?

Abstract

In this tutorial review, structures encountered in carbocation cascade polycyclization reactions leading to terpene natural products are surveyed. The nature of delocalization in these carbocations is discussed in detail. For select cases, the ability of functional groups in enzyme active sites to modulate this delocalization is discussed. In addition to carbocation intermediates, cationic transition state structures are also described.

Plasticity and Evolution of (+)-3-Carene Synthase and (−)-Sabinene Synthase Functions of a Sitka Spruce Monoterpene Synthase Gene Family Associated with Weevil Resistance

“…4). Similar to what has been described for other terpene synthases, these effects could help stabilize a carbocation on the C4 carbon, promoting formation of the terpinen-4-yl cation, through a cation-interaction (22,24,25) or hyperconjugation promoted through a C-H/ interaction (26,27). Phe 596 could also affect the conformation of the cyclohexene ring of the ␣-terpinyl cation by promoting an equatorial position for the C8 carbon, preventing the 5,8-cyclication needed to form (ϩ)-3-carene (23).…”

Biosynthesis of the microtubule-destabilizing diterpene pseudolaric acid B from golden larch involves an unusual diterpene synthase

“…5). The subsequent 1,2-alkyl shift and 6,10-cyclization occur in a single step (29) to form a carbocation, B, with the characteristic 5,7-fused bicyclic scaffold. Carbocations A and B are predicted to be similar in energy, and the A-to-B reaction is predicted to have an activation barrier of less than 15 kcal/mol.…”

Formation of the Unusual Semivolatile Diterpene Rhizathalene by the Arabidopsis Class I Terpene Synthase TPS08 in the Root Stele Is Involved in Defense against Belowground Herbivory

“…This step requires a rotation around the C6-C7 bond, which allows for a favorable alignment of the C6-H bond with the formally vacant p-orbital at C7 (see Supplemental Figure 12 online). Cation B was not found to be an intermediate in the conversion of A to C. Following a change in conformation (C1-to-C2), a ring-expanding 9,11 Wagner-Meerwein rearrangement leads to cation D, which is not itself an intermediate but is encountered along the reaction coordinate from C2 to E (Tantillo, 2010(Tantillo, , 2011, and subsequent 14,10 ring-closure, completing the construction of the polycyclic (A) to (D) Undamaged roots of wild-type plants. (E) to (H) Bradysia feeding damage on wild-type (WT) roots.…”

“…The isomerization step allows for a subsequent ring closure between C1 and C6 (numbered as in GGPP) to generate the cyclohexene moiety of the first carbocation intermediate (A). Cation A is then converted directly to cation C (conformer C1) via a concerted hydride shift/ spirocyclization reaction (Tantillo, 2008(Tantillo, , 2010. This step requires a rotation around the C6-C7 bond, which allows for a favorable alignment of the C6-H bond with the formally vacant p-orbital at C7 (see Supplemental Figure 12 online).…”