Natural Diels-Alderases: Elusive and Irresistable

Abstract

Eight examples of biosynthetic pathways wherein a natural enzyme has been identified and claimed to function as a catalyst for the [4 + 2] cycloaddition reaction, namely, Diels-Alderases, are briefly reviewed. These are discussed in the context of the mechanistic challenges associated with the technical difficulty of proving that the net formal [4 + 2] cycloaddition under study indeed proceeds through a synchronous mechanism and that the putative biosynthetic enzyme deploys the pericyclic transition state required for a Diels-Alder cycloaddition reaction.

Figure 1

Possible Transition Structures in the Diels-Alder reaction

Figure 2

Parent Diels-Alder Reaction. Bond lengths in Angstroms. a) CASSCF/STO-3G calculated transition structures from Bernardi et al. 1985. CAS2 and CAS1 are in parentheses and lower-level 4-31G basis set calculations are in brackets. b) CASSCF/STO-3G calculated transition structures by Houk et al. 1993.

Figure 3

Orbital calculations for the asymmetric endo transition structure in the reaction of acrolein with butadiene.

Figure 4

Becke3LYP/6-31G* calculations for the asynchronous endo and exo transition structures for the reaction of acetylene dicarboxylic acid with isoprene by Singleton et al. 2001.

Figure 5

Becke3LYP/6-31G* calculated asynchronous and forced Cs symmetry saddle point synchronous transition structures for the reaction of TAD with 1,3-butadiene by Singleton et al. 2001. Asynchronous TS is 1.1 kcal/mol lower in energy than synchronous TS.

Figure 6

Becke3LYP/6-31G* calculated asynchronous endo- and exo- transition structures for the reaction of PTAD with tert-butyl-butadiene

Figure 7

Biosynthesis of Solanapyrone A (4) and B (3) with Solanapyrone synthase as putative cyclase.

Figure 8

Biosynthesis of Lovatastatin (10) with LNKS as cyclase.

Figure 9

Model reaction with LNKS as cyclase in the enzymatic reaction of 11.

Figure 10

Proposed biosynthesis of macrophomate where macrophomate synthase functions as cyclase.

Figure 11

Model active site of MPS with binding of 15 and 17 utilizing crystal structure information and proposed transition structure.

Figure 12

Proposed biosynthesis of Riboflavin via a key [4+2] cycloaddition to provide the isolated and structurally characterized intermediate 24.

Figure 13

Biosynthesis of Spinosyn A (24) where SpnF has been proposed as the putative cyclase.

Figure 14

Proposed biosynthesis of Pyrroindomycins with PyrE3 and PyrI4 as cyclases.

Figure 15

Biosynthesis of Thiocillin 34 via TclM as cyclase.

Figure 16

Proposed mechanism for the transformation of 25 to 26 in presence of TclM.

Figure 17

Proposed enantiodivergent biogenesis of the Stephacidins and Notoamides through a formal [4+2] cycloaddition.

Figure 18

Unified biosynthesis of the monooxopiperazine and dioxopiperazine families of alkaloids containing a bicyclo[2.2.2]diazaoctane ring system.

Figure 19

Biosynthesis of Versipelostatin (43) with VstJ as cyclase.