A Family of Related Fungal and Bacterial Di‐ and Sesterterpenes: Studies on Fusaterpenol and Variediene

Abstract

The absolute configuration of fusaterpenol (GJ1012E) has been revised by an enantioselective deuteration strategy. A bifunctional enzyme with a terpene synthase and a prenyltransferase domain from Aspergillus brasiliensis was characterised as variediene synthase, and the absolute configuration of its product was elucidated. The uniform absolute configurations of these and structurally related di‐ and sesterterpenes together with a common stereochemical course for the geminal methyl groups of GGPP unravel a similar conformational fold of the substrate in the active sites of the terpene synthases. For variediene, a thermal reaction observed during GC/MS analysis was studied in detail for which a surprising mechanism was uncovered.

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

“…This suggests a nonclassical structure , between the monocyclic 3° cation and bicyclic humulyl 2° cations, leading to the following multiple annulations ( vide infra ). A similar reaction is also found in variediene biosynthesis. , …”

“…Then a C–C bond rearrangement takes place to yield the 5,6,5,5-tetraspirocyclic mangicol core skeleton ( IM14b ), which is subjected to a deprotonation to form PD . Notably, this new route is not only kinetically and thermodynamically the most favorable pathway but also appears to provide a versatile biosynthetic pathway leading to the formation of related terpenes/terpenoids, including tsukubadiene, variediene, , deoxyconidiogenol/conidiogenone, , and phomopsene/methyl phomopsenonate , (Figure B,C). A careful structural comparison of the terpene cyclases responsible for the formation of mangicol, tsukubadiene, variediene, deoxyconidiogenol, and phomopsene could be helpful to clarify how the structural diversification is controlled.…”

“…A similar reaction is also found in variediene biosynthesis. 54,55 We next located the later stage of mangicol biosynthesis, that is, the formation of the spirotricyclic structure (Figure 5). Route A is very similar to the previously proposed pathway, in which the annulation of IM11 takes place to give 5,9,5-tricyclic intermediate IM12 having B-and D-rings with a slight endothermicity, followed by 1,2-H shift via TS_12−13 with a large stabilization energy to give the bridgehead 3°carbocation IM13.…”

Enzymatic Synthesis of Variediene Analogs

“…AbVS is a bifunctional enzyme with a prenyltransferase (PT) and a terpene cyclase (TC) domain that naturally converts DMAPP and IPP through geranylgeranyl diphosphate (GGPP) into variediene ( 1 , Scheme 1 ). Based on the results from labelling experiments[ 26 , 27 ] and computational studies,[ 28 , 29 ] the reactions from GGPP proceed through 1,11‐10,14 cyclisation to A , followed by Wagner‐Meerwein rearrangement and ring opening to B with a specific stereochemical course that places Me16 in the pro ‐ S and Me17 in the pro ‐ R position. A reverse 14,11 ring closure with simultaneous 2,10 cyclisation leads to C that is the precursor of 1 by deprotonation.…”

“…Among class I diterpene synthases only taxadiene synthase from Taxus brevifolia [12] and catenul‐14‐en‐6‐ol synthase from Catenulispora acidiphila [25] have been investigated for their tolerance towards non‐natural substrate analogs. In order to expand this knowledge, we have now investigated the potential of the fungal variediene synthase from Aspergillus brasiliensis (AbVS), [26] a homolog of the earlier characterised variediene synthase from Emericella variecolor (EvVS), [27] to convert analogs of DMAPP through in vitro reactions with IPP.…”