Geranyl pyrophosphate stereochemical

Cyclization of an allylic pyrophosphate is a key step in the biosynthesis of most monoterpenes. Early hypotheses concerning the nature of the acyclic precursor and the cyclization process are first described, and chemical models for the cyclization presented. Following a review of several representative cyclase enzymes and the reactions that they catalyze, a series of stereochemical and mechanistic experiments with partially purified cyclases are reported. The results of these studies have allowed a detailed description of events at the active site and the formulation of a unified stereochemical scheme for the multistep isomerization-cyclization reaction by which the universal precursor geranyl pyrophosphate is transformed to cyclic monoterpenes. 

Consideration of chemical models, now largely in hindsight, allows broad outlines of a cyclization scheme to be delineated. Reaction of geranyl pyrophosphate is initiated by ionization which is assisted by low pH and divalent metal ion. Conversion of the geranyl to the linalyl system precedes cyclization to the monocyclic intermediate by the established stereochemical course. The overall process occurs stepwise via a series of... 

With the preceding reviews of the enzymology of monoterpene cyclization and of model studies relevant to the cyclization process, it is possible to formulate a unified stereochemical scheme for the enzymatic cyclization of geranyl pyrophosphate (Figure 4). The proposal which follows is consistent with the implications of parallel advances in related fields, most notably the contributions of Cane (8,16,24,25,52), Arigoni (67) and Coates (68,69) on the stereochemistry of sesquiterpene and diterpene cyclizations, and of Poulter and Rilling (29,70) on the stepwise, ionic mechanism of prenyl transferase, a reaction type of which several monoterpene, sesquiterpene and diterpene cyclizations are, in a sense, the intramolecular equivalents. 

Figure 3. Unified stereochemical mechanism of monoterpene cycliza-tion from geranyl pyrophosphate.

The preceding discussion has indicated the sequence of squalene 4.8) biosynthesis as mevalonate 4.13) isopentyl pyrophosphate 4.14) dimethylallyl pyrophosphate 4.15) geranyl pyrophosphate 4.41) farnesyl pyrophosphate 4.19) squalene 4.8). Each stage involves stereochemical change at one or two carbon atoms. The presence of several prochiral centres in the molecules of this sequence meant that for stereochemical changes to be monitored they had to be chirally labelled with deuterium or tritium e.g. the condensation of isopentenyl pyrophosphate 4.14) with dimethylallyl pyrophosphate 4.15) (see Scheme 4.10) involves loss of one of the... 

Incisive model studies by Arlgonl and co-workers have, in fact, demonstrated that the anti-endo conformation of the linalyl system is preferred in the cyclization to a-terpineol, This, along with the confirmation that allylic transposition reactions occur by a net suprafaclal (syn) process,allows deduction of the helical folding of geranyl pyrophosphate and thus, by summation, all of the basic stereochemical elements of the coupled isomerlzatlon-cyclization. 

Fig. 3. Stereochemical scheme for the enzymatic cyclization of geranyl pyrophosphate (GPP) to bornyl pyrophosphate (BPP) via linalyl pyrophosphate (LPP).

An assessment of the overall stereochemistry of a given cyclization requires a determination of the stereochemical alterations at Cl and C3 of the geranyl substrate in the course of the cyclization. Since most cyclases can utilize 3RS-llnalyl pyrophosphate as an alternate substrate, the question of the configuration of the cycllzing Intermediate can be addressed directly using the optically pure linalyl antipodes. Addressing... 

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