Geranyl modification

For substituted allylic systems, both a- and y-substitution can occur. Reaction conditions can influence the a- versus "/-selectivity. For example, the reaction of geranyl acetate with several butylcopper reagents was explored. Essentially complete a- or y-selectivity could be achieved by modification of conditions.28 In ether both CuCN and Cul led to preferential "/-substitution, whereas a-substitution was favored for all anions in THF. 

Replacement of the famesyl group by lipid analogues could be performed for full length Ras proteins in vitro by means of the enzyme famesyltrans-ferase. When such partially modified Ras constructs were applied in Xenopus oocytes the cellular machinery completed modification (endoprotease activity, carboxymethylation and palmitoylation). In these cases the H-Ras famesyl group could be stripped off most of its isoprenoid features that distinguish it from a fatty add without any apparent effect on its ability to induce oocyte maturation and activation of mitogen-activated protdn kinase In contrast, replacement by the less hydrophobic isoprenoid geranyl causes severely delayed oocyte activation. 

The possibility of nucleophilic attack on different carbons in the resonance-stabilized carbocation facilitates another modification exploited by nature during terpenoid metabolism. This is a change in double-bond stereochemistry in the allylic system. The interconversions of geranyl diphosphate, linalyl diphosphate, and neryl diphosphate provide neat but satisfying examples of the chemistry of simple allylic carbocations. 

The compounds geranyl diphosphate, farnesyl diphosphate, and geranylgeranyl diphosphate are biochemical precursors of monoterpenes, sesquiterpenes, and diterpenes respectively, and virtually all subsequent modifications of these precursors involve initial formation of an allylic cation through loss of diphosphate as the leaving group. 

Proteins with an isoprenoid modification possess either a C15-famesyl residue or a C20-geranyl-geranyl residue. Both residues are bound via a thioester linkage to a cysteine residue. As with myristoylation, these are constitutive, stable modification performed by farnesyl or geranyl transferases. 

The isoprenoid modification can be found, among others, on the Ras protein and other members of the Ras superfamily (see chapter 9), as well as with the a-subunit of G-protein (see chapter 5). The Pycomplex of G-proteins is also associated with the membrane via geranylation. 

The prenyl transferases are a class of enzymes that is involved in post-translational modification of membrane-associated proteins. These enzymes catalyze the transfer of a farnesyl (FTase, EC 2.5.1.58, for structural information see References 55-65) or geranyl-geranyl group (GGTase I, EC 2.5.1.59 GGTase n, EC 2.5.1.60, for structural information... 

Battersby and Co-workers (25-28), Money et al (29) and Leete et al (30) all reported the specific incorporation of [2- C] mevalonic acid and [2- C] geraniol into representative examples of the corynanthe, aspidosperma and iboga groups of alkaloids, and in each case the distribution of radioactivity was in full agreement with the monoterpene hypothesis developed by Thomas (23) and Wenkert (2U), and according to the biogenetic isoprene rule that monoterpene are formed in nature by suitable modification of geranyl pyrophosphate (31). 

The possible legioselecdvity and the preference for ( )>aUylic alcohol Hxxluction using the reoxida tive modification are demonstrated in a projected synthesis of cembranolides (equation 10). The substrate in this case contains two double bo and several allylic positions. This oxidation is reported to be even more selective than the aiudogous oxidation of geranyl acetate originally reported by Sh less. 

Membrane attachment of Ras requires covalent addition of lipids. Virtually all members of the Ras superfamily are prenylated.io Farnesylation is essential. Defects in lipid modification make Ras non-functional. A 15-carbon farnesyl or 20-carbon geranyl-geranyl chain is attached to a cysteine in the COOH-terminus of Ras. The linkage is by a thioether bond and irreversible, and therefore not a point of regulatory control, n ... 

N.N-Dialkylgeranylamines have been prepared by the reaction of dialkyl amines with geranyl halides. The procedure described here is a modification of one we reported earlier. It is a simple, one-step synthesis of N,N-dialkylgeranylamines from myrcene and dialkylamines which are readily available bulk chemicals. The reaction proceeds stereoselectively, and yields are high. 

The next series of steps involves the combination of IPP units to form geranyl diphosphate, famesyl diphosphate, and geranylgeranyl diphosphate, which serve as the precursors of the mono-, sesqui- and diterpene families, respectively [Figure 4.9]. In effect, all of the other members of these families arise from the cyclization or secondary modification of these three precursors. 

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