1,2‐ or 1,3‐Hydride Shifts: What Controls Guaiane Biosynthesis?

Abstract

A systematic computational study addressing the entire chemical space of guaianes in conjunction with an analysis of all known compounds shows that 1,3‐hydride shifts are rare events in guaiane biosynthesis. As demonstrated here, 1,3‐hydride shifts towards guaianes can only be realized for two stereochemically well defined out of numerous possible stereoisomeric skeletons. One example is given by the mechanism of guaia‐4(15)‐en‐11‐ol synthase from California poplar, an enzyme that yields guaianes with unusual stereochemical properties. The general results from DFT calculations were experimentally verified through isotopic‐labeling experiments with guaia‐4(15)‐en‐11‐ol synthase.

The enzyme mechanism of patchoulol synthase

“…For the formation of the bicyclic cation E according to Akhila et al ( Scheme 2 ) [ 10 ] DFT calculations have been performed previously by us as part of a general study on guaiane sesquiterpenes from germacrene A ( 8 ) [ 29 ]. After reprotonation of the neutral intermediate 6 to F the next cyclisation to G and Wagner–Meerwein rearrangement to D can be realised with low TS barriers.…”

“…cation (A) to B could not be realised. The further reaction of B to C is barrierless, but the proposed 1,4-hydride shift to D is geometrically impossible and also cannot be realised by computations.For the formation of the bicyclic cation E according to Akhila et al (Scheme 2)[10] DFT calculations have been performed previously by us as part of a general study on guaiane sesquiterpenes from germacrene A (8)[29]. After reprotonation of the neutral intermediate 6 to F the next cyclisation to G and Wagner-Meerwein rearrangement to D can be realised with low TS barriers.…”

Functional Switch and Ethyl Group Formation in the Bacterial Polytrichastrene Synthase from Chryseobacterium polytrichastri

“…An alternative two‐step process with 1,3‐ and 1,2‐hydride transfer is geometrically not possible, similar to 1,3‐hydride transfers in guaiane biosynthesis that are rare and only allowed for the few stereoisomers with suitable geometry. [31] Compound 8 may be the only case for which the red path is entered from B , because the step from F2 to E2 has an even higher TS than the C2 to D2 conversion. The high TS barriers to reach E2 from any side may explain the observation of 8 only as a minor compound in the I66F variant.…”

Hedycaryol – Central Intermediates in Sesquiterpene Biosynthesis, Part II

“…Furthermore, L2 and L3 can react in 1,3‐hydride migrations to T5 and T6 , respectively. Analogous steps are sterically not possible for L1 and L4 , as was also shown by DFT calculations [18] …”

“…The accumulated knowledge about this class of sesquiterpenes was recently summarised by us in a review article in this journal [17] . We have also performed a computational study to explore the chemical space through downstream hydride shifts for the different stereoisomers of the guaianes, showing that (suprafacial) 1,2‐hydride shifts are always possible, while 1,3‐hydride migrations can only be realised for certain geometries of the guaiane skeletons [18] . As an alternative to the deprotonation to germacrene A, cation B can also be captured by water to yield the sesquiterpene alcohol hedycaryol, which is a likewise important intermediate toward many sesquiterpene alcohols.…”