Mechanism and Stereochemistry

The monoterpene cyclization reaction (Scheme 4) consists of the stereoselective binding of GPP at the active site in either a right-handed or left-handed helical conformer followed by metal ion-dependent ionization of the diphosphate ester and syn migration of the diphosphate group to C3 to generate enzyme-bound (3R)- or (3S)-linalyl diphosphate (LPP),respectively,thereby allowing the requisite rotation about the newly generated C2-C3 single bond. Subsequent C6-C1 cyclization of the anti,endo conformer of LPP is initiated by a second ionization of this bound intermediate to form the universal monocyclic intermediate, the a-terpinyl cation. Whether the (4R)- or (4S)- antipode is formed depends on the configuration at C3 of the linalyl intermediate which, in turn, depends on the initial folding of GPP at the active site. Termination of the reaction via deprotonation or nucleophile capture may be preceded by myriad intervening cyclizations to the remaining double bond, hydride shifts, and other rearrangements shown in Table 2.

Apparent from Scheme 4 is the necessity of the ionization-isomerization step to the cisoid linalyl intermediate for cyclization to the a-terpinyl cation, a reaction not directly possible from the geranyl substrate because of the trans-C2,C3 bond. A notable feature of all monoterpene cyclases is the ability to utilize LPP

Table 2. Summation of mechanisms involved in the biosynthesis of selected monoterpenes derived from the a-terpinyl cation. Numbering is based on the a-terpinyl cation shown in

Scheme 3

Product Mechanism Reference limonene deprotonation 25

terpinolene deprotonation 32

a-terpineol capture of C8 cation by water 15

1,8-cineole capture of C8 cation by water, C8-C1 ether linkage 41,42

bornyl diphosphate C1-C8 ring closure,C2 cation capture by diphosphate 43

camphene C1-C8 ring closure, WM rearrangement, deprotonation 32,44

a-pinene C2-C8 ring closure, deprotonation 31

^-pinene C2-C8 ring closure, deprotonation 31

endo-fenchol C2-C8 ring closure, WM rearrangement,

C2 cation capture by water 29

b-phellandrene 1,3 hydride shift, deprotonation 32,45

a-terpinene 1,2 hydride shift, deprotonation 45

y-terpinene 1,2 hydride shift, deprotonation 45

a-thujene 1,2 hydride shift, C2-C4 ring closure, deprotonation 46

sabinene 1,2 hydride shift, C2-C4 ring closure, deprotonation 47

sabinene hydrate 1,2 hydride shift, C2-C4 ring closure, C1 capture by water 30

3-carene deprotonation-mediated C5-C8 ring closure 48

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