Nerolidyl pyrophosphate

Further biosynthetic studies by Cane et have shown that the conversion of farnesyl pyrophosphate (15) into nerolidyl pyrophosphate (16) proceeds by a net syn (suprafacial) process and that the subsequent cyclization to cyclonerodiol (17) occurs in a trans manner (Scheme 4). This careful piece of work was achieved by incorporation studies with doubly labelled nerolidol and mevalonate precursors and then by ascertaining the chirality of the acetate derived by Kuhn-Roth oxidation through enzymatic conversion (malate synthase/fumarase incubation) into labelled malate. In a subsequent series of experiments with labelled precursors, Cane et have confirmed that (i) only the C-7 hydroxy-group in cyclonerodiol is derived from water whereas the C-3 hydroxy-group is derived... 

A very complete account has been published58 of the excellent labelling studies which have been carried out to elucidate cyclonerodiol (94) biosynthesis and the enzymatic conversion of farnesyl pyrophosphate into nerolidyl pyrophosphate (Vol. 10, pp. 5—7). 

The mechanism whereby farnesyl pyrophosphate (6 = 2) is converted into squalene (7) has aroused much chemical and biochemical interest. An intermediate isolated from yeast is the C30 pyrophosphate (9). Rilling et suggested the cyclopropanoid structure (9a) while the cyclic pyrophosphate diester (9b) was suggested by Popjak et The universal involvement of this intermediate is supported by the incorporation of radioactivity from the diester (9), prepared from yeast, into squalene (7) by a rat liver system. However, the suggested mechanism for the formation of the diester is difficult to reconcile with the observation that nerolidyl pyrophosphate is not incorporated. 

A combination of the in vitro results and co-occurrence patterns suggests a biogenetic map such as that outlined in Scheme 13. It should be noted, however, that alternative routes are available, e.g. Andersen and SyrdaP have suggested a pathway leading from (— )-nerolidyl pyrophosphate through to (— )-a-cedrene via (— )-y-curcumene. 

Cane DE, Ha H-J (1988) Trichodiene Biosynthesis and the Role of Nerolidyl Pyrophosphate in the Enzymatic Cyclization of Famesyl Pyrophosphate. J Amer Chem Soc 110 6865... 

Nerolidyl pyrophosphate does not serve as a precursor for squalene (Poulter and Rilling, 1981). The condensation requires NADPH in yeasts and, if this reductant is not present, famesyl pyrophosphate (8) accumulates. During the course of the reaction, two pyrophosphate groups are released, one hydrogen lost and one hydrogen replaced by a hydrogen from NADPH. One (15 )-hydrogen atom is removed from famesyl pyrophosphate. 

Tri5 (encoding trichodiene synthase). TRI5 catalyzes cyclization of all-tran -FPP via nerolidyl pyrophosphate to TDN [36,45]. 

Cane D E, Iyengar R, Shiao M-S 1981 Cyclonderodiol biosynthesis and the enzymatic conversion of farnesyl to nerolidyl pyrophosphate. J Am Chem Soc 103 914-931... 

The mechanism of the tail-to-tail coupling is shown in Fig. 8.4. In this example, a molecule of farnesyl pyrophosphate (6) reacts with one of nerolidyl pyrophosphate (7) forming the tail-to-tail link between the two chains. Reductive elimination of the pyrophosphate residue by enzyme bound TPNH gives squalene (2), which is the precursor for, inter alia, the steroids. 

The fact that farnesyl pyrophosphate is converted into triterpenes by tail-to-tail addition (Fig. 79) is of crucial importance. Tail refers to the pyrophosphate end. Correctly speaking, it is not two molecules of farnesyl pyrophosphate that react together but one molecule of farnesyl pyrophosphate with one molecule of nerolidyl pyrophosphate, an isomer of farnesyl pyrophosphate. The addition takes place reductively. The product is a symmetrical 30 C entity, sequalene. It is widely distributed in the plant and animal kingdoms, even though steady state concentrations may often be very small. This is what one would expect, since squalene is the... 

The enzymatic conversion of famesyl pyrophosjAiate to nerolidyl pyrophosphate and the cyclization of the latter to cyclonerodiol (15) has been studied. labelling experiments have established that the conversion... 

If the initial cyclization of trans trans- or cis, /raw -farnesyl pyrophosphates (52-OPP and 51-OPP) occurs upon the terminal (10, 11) double in an anti-Markovnikov orientation, eleven-membered cyclic dienyl carbonium ions are produced. Deprotonation of the trans, trans-intermediate affords humulene (97) while bis-homoallyl- cyclobutyl carbinyl cyclization furnishes, after elimination, caryophyllene (99). Although the all traw -configuration of the three double bonds in humulene would appear to require trans, rra -farnesyl pyrophosphate as precursor, the possibility exists that the immediate predecessor of caryophyllene is cis, /rtz 5-farnesyl (or cisoid nerolidyl) pyrophosphate. 

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