DFT Study on the Biosynthesis of Asperterpenol and Preasperterpenoid Sesterterpenoids: Exclusion of Secondary Carbocation Intermediates and Origin of Structural Diversification

Abstract

The biosynthetic pathway to asperterpenol, a sesterterpenoid featuring a 6/6/8/5 tetracyclic ring system, was proposed to involve three secondary (2°) carbocation intermediates (B, D, and I), but it remains controversial whether or not these are viable. Further, the proposed 11/6/5 tricyclic intermediate C has the same “ChemDraw” structure as an intermediate in the biosynthesis of preasperterpenoid, which has a very different 5/7/(3)­6/5 pentacyclic skeleton. Here, we present a detailed scrutiny of the asperterpenol/preasperterpenoid biosynthetic pathways based on comprehensive DFT calculations.

Enantioselective Total Synthesis of Dysiherbols A, C, and D

“…While this bioinspired synthetic tactic appears to be attractive, its realization in practice could be problematic. Indeed, the assumed [1,2]-H migration from the carbocation species IV – V is difficult to occur under nonenzymatic conditions due to the unfavorable thermodynamic factor . Keeping this concern in mind, we decided to adopt an alternative way to assemble the tetracyclic skeletons I and II , hinging on the so-called “inverted bioinspired bond-formation tactics”.…”

Cyclopropylcarbinyl-to-Homoallyl Carbocation Equilibria Influence the Stereospecificity in the Nucleophilic Substitution of Cyclopropylcarbinols

“…Hydroxy-substituted CPC cations adopt geometries with significant homoallylic character (with long C–C bonds) . The opening of the CPC structures to homoallylic cations was also proposed to explain their rearrangement to allylic cations in the absence of nucleophiles. ,, Finally, homoallylic cations in equilibrium with cyclopropylcarbinyl cations have been described in biosynthetic pathways, where the homoallylic structure is between 2 and 10 kcal/mol higher in energy than the CPC structure. ,,,, …”

“…4,38,39 Finally, homoallylic cations in equilibrium with cyclopropylcarbinyl cations have been described in biosynthetic pathways, where the homoallylic structure is between 2 and 10 kcal/mol higher in energy than the CPC structure. 14,16,19,21,23 In investigating this homoallylic cation, we discovered that the C2−C4 bond opening is not the only rearrangement available to CPC cations such as 2a/b. Indeed, a whole number of other rearrangements, which to the best of our knowledge have not been systematically considered before, are actually crucial to the reactivity of these highly substituted CPC cations (Figure 4).…”

“…The base cyclopropylcarbinyl/bicyclobutonium cation (C 4 H 7 + ) system has been heavily studied since Roberts’ 1951 report that cyclobutyl and cyclopropylcarbinyl electrophiles solvolyze readily to form the same mixture of cyclobutyl, cyclopropylcarbinyl, and homoallyl products, hinting at a common intermediate . CPC/BCB cations have since been proposed as intermediates in a variety of organic reactions/rearrangements − and terpene biosynthetic pathways. − An array of spectroscopic, NMR, and computational techniques have been used to probe the C 4 H 7 + system, − which is now understood as an equilibrating mixture of triply degenerate σπ-bisected cyclopropylcarbinyl I and non-classical bicyclobutonium II cations (Figure B). These are similar in energy and interconvert stereospecifically through low-energy transition structures (TSs) on a flat potential energy surface (PES).…”

Revision of the Peniroquesine Biosynthetic Pathway by Retro-Biosynthetic Theoretical Analysis: Ring Strain Controls the Unique Carbocation Rearrangement Cascade

“…However, cis-trans isomerization of IM8 would not occur due to the high strain caused by the trans -fused 7/4-bicyclic skeleton (Figure B). In general, TCs tightly pre-regulate the conformation of the starting materials, controlling the conformations of all reactive intermediates and the reactivity of the cationic intermediates in the active site pocket. − Hence, it seems implausible for such a large conformational change to occur in the late stage of biosynthesis. Thus, we continued the retro-biosynthetic analysis using IM8′(chair, cis ) and finally located a new energetically favorable and step-economical pathway (Scheme and Figure ).…”