The Diels–Alderase Never Ending Story

Abstract

The biosynthesis of the cholesterol-lowering drug lovastatin isolated from Aspergillus terreus has been investigated extensively by Vederas and coworkers [10]. Incorporation experiments with multiple labeled acetate and 18 O-oxygen suggested that it is biosynthesized via the polyketide pathway. Based on feeding studies and co-occurrence of 4a,5-dihydromonacolin L (3), this compound was speculated as an intermediate. This was confirmed by the successful conversion of 3 into lovastatin, using a blocked mutant of A. terreus (Scheme 21.2) [11]. Because lovastatin does not have an electron-withdrawing group in the dienophile moiety, it was proposed that the requisite Diels-Alder reaction occurred at the hexaketide stage. However, all efforts to convert 13 C-labeled hexaketide precursor 1b into lovastatin were unsuccessful due to non-enzymatic cycloadditions affording a 1 : 1 mixture of undesired diastereomers 4b (endo) and 4c (exo) in aqueous media (half life of 1b: two days) (Scheme 21.2). This clearly showed significant rate acceleration for the cycloaddition of 1b in aqueous media [12].

Mechanistic insights into Diels-Alder reactions in natural product biosynthesis

“…Considering the large number of natural products containing a cyclohexene structure, the vast majority of Diels-Alderases still remain to be isolated and characterized [5,[47][48][49][50][51][52][53]. Studies of the newly identified enzymes and structural characterization of these Diels-Alderases are expected to provide more insights into the essential features of these enzymes.…”

“…More than 400 compounds with this transannular ring structure have been identified among primary and secondary metabolites [3], leading to decades of speculation on the existence of enzymes capable of catalyzing Diels-Alder reactions in the biosynthesis of these compounds [4]. However, only a few such enzymes have been identified, which are often called "Diels-Alderases" [3][4][5][6].…”

Biogenesis of Triterpene Dimers from Orthoquinones Related to Quinonemethides: Theoretical Study on the Reaction Mechanism

“…These dimers are composed of quinonemethide and aromatic forms of nor-triterpenes, joined by two ether linkages formed between the A rings of the two celastroloids (A-A dimers), or between the A and the B rings (B-A dimers). It is noteworthy to stress that the intermediacy of orthoquinones related to quinonemethides has been implicated in the biogenesis of triterpene dimers [10,14,15,16] and recently, triterpenes with an orthoquinone system have been isolated from Celastrus orbiculatus [17]. The proposed biosynthetic mechanism includes a hetero Diels-Alder (HDA) type cycloaddition reaction between an orthoquinone and a quinonemethide triterpenoid to form A-A dimers, or a phenolic triterpenoid to form B-A dimers (Scheme 1).…”