Geranyl unit

Cymopolia barbata elaborates a unique series of (20 prenylated bromohydroqui-nones called the cymopols (Hoegberg et al. 1976). Monobromination is found exclusively para (directly across) to the site of prenylation as seen in cymopolone (Fig. 1.7f). The isoprene side chains all originate from C10 geranyl units with different... 

Cyclization of homospermidine 3 via oxidative deamination of the terminal CH2NH2 groups to CHO afforded a monocyclic iminium ion 5. Nucleophilic addition of activated geranyl unit 6 to the iminuim ion 5 involves a ring closure, leading to the pyrrolo[l,2-a]azepine system (Figure 7.3) [11]. 

Stereoselective reduction of cyclic iminium ion intermediate 22 followed by a stereoselective oxidation at C-1 of propyl side chain leads to the iminium ion 23. Coupling reaction of the latter with a geranyl unit 24 provides the pyridoazepine nucleus 25 (Figure 7.8) [4]. 

The incorporation of acetate labeled with carbon-13 in Cj and C1/C2 showed that the biosynthesis of domoic acid resijlts from an original coupling between a geranyl unit and an activated form of glutamic acid (Douglas et al, 1992 Smith, Ladizinsky, and Miller, 2001). 

The enzyme catalyzed reactions that lead to geraniol and farnesol (as their pyrophosphate esters) are mechanistically related to the acid catalyzed dimerization of alkenes discussed m Section 6 21 The reaction of an allylic pyrophosphate or a carbo cation with a source of rr electrons is a recurring theme m terpene biosynthesis and is invoked to explain the origin of more complicated structural types Consider for exam pie the formation of cyclic monoterpenes Neryl pyrophosphate formed by an enzyme catalyzed isomerization of the E double bond m geranyl pyrophosphate has the proper geometry to form a six membered ring via intramolecular attack of the double bond on the allylic pyrophosphate unit... 

The conversion of isopentenyl diphosphate (IPP) to terpenoids begins with its isomerization to dimethylallyl diphosphate, abbreviated DMAPP and formerly called dimethylallyl pyrophosphate. These two C5 building blocks then combine to give the C10 unit geranyl diphosphate (GPP). The corresponding alcohol, geraniol, is itself a fragrant terpenoid that occurs in rose oil. 

The late cannabinoid pathway starts with the alkylation of ohvetolic acid (3.2 in Fig. 4) as polyketide by geranyl diphosphate (3.1) as the terpenoid unit. Terpenoids can be found in all organisms, and in plants two terpenoid pathways are known, the so called mevalonate (MEV) and non-mevalonate (DXP) pathway as described by Eisenrich, lichtenthaler and Rohdich [23,24,29,30]. The mevalonate pathway is located in the cytoplasm of the plant cells [30], whereas the DXP pathway as major pathway is located in the plastids of the plant cells [29] and delivers geranyl diphosphate as one important precursor in the biosynthesis. 

Natural products containing the isoprene unit can be prepared in this way. Methyl famesoates have been synthesized from geranyl halides and 1-carbomethoxyallylnickel halides (example 4, Table III). 

More than half of the reported secondary metabolites from macroalgae are isoprenoids. Terpenes, steroids, carotenoids, prenylated quinines, and hydroqui-nones make up the isoprenoid class, which is understood to derive from either the classical mevalonate pathway, or the mevalonate-independent pathway (Stratmann et al. 1992). Melavonic acid (MVA) (Fig. 1.2) is the first committed metabolite of the terpene pathway. Dimethylallyl (dl meth al lal) pyrophosphate (DMAPP) (Fig. 1.3) and its isomer isopentenyl pyrophosphate (IPP, Fig. 1.3) are intermediates of the MVA pathway and exist in nearly all life forms (Humphrey and Beale 2006). Geranyl (ja ran al) (C10) and famesyl (C15) units are generated by head-to-tail (Fig. 1.3) condensation of two (for C10) or three (for C15) 5-carbon DMA-like isoprene units, identifiable in final products by the characteristic fish-tail repeating units, as traced over the structure of a sesquiterpene in Fig. 1.3 (Humphrey and Beale 2006). Additional IPP condensation with famesyl pyrophosphate (FPP)... 

Hydroxy-3-methylcarbazole (52) could also function as a precursor for the formation of carbazole alkaloids with a C23 skeleton as depicted in Scheme 3.6 (370). Insertion of a Cio unit, viz., geraniol at C-1 of 2-hydroxy-3-methylcarbazole (52) would yield mahanimbinol (mahanimbilol) (56). The geranyl monoterpene unit could undergo various transformations, thus giving rise to isomeric carbazole alkaloids with a C23 skeleton, such as mahanimbine (139), cyclomahanimbine (murrayazolidine, curryanin) (151), and bicyclomahanimbine (160). Therefore, mahanimbinol (mahanimbilol) could be considered as the representative member of the carbazoles with a C23 skeleton. The occurrence of 2-hydroxy-3-methylcarbazole (52),... 

Stage (J) Condensation of Six Activated Isoprene Units to Form Squalene Isopentenyl pyrophosphate and dimethylallyl pyrophosphate now undergo a head-to-tail condensation, in which one pyrophosphate group is displaced and a 10-carbon chain, geranyl pyrophosphate, is formed (Fig. 21-36). (The head is the end to which pyrophosphate is joined.) Geranyl pyrophosphate undergoes another head-to-tail condensation with isopentenyl pyro-... 

The product of the combination of two units of the pyrophosphate, 9, through this sequence is geranyl pyrophosphate if, as shown, the proton is lost to give a trans double bond. Formation of a cis double bond would give neryl pyrophosphate (Section 30-3B). 

Continuation of the head-to-tail addition of five-carbon units to geranyl (or neryl) pyrophosphate can proceed in the same way to farnesyl pyrophosphate and so to gutta-percha (or natural rubber). At some stage, a new process must be involved because, although many isoprenoid compounds are head-to-tail type polymers of isoprene, others, such as squalene, lycopene, and /3- and y-carotene (Table 30-1), are formed differently. Squalene, for example, has a structure formed from head-to-head reductive coupling of two farnesyl pyrophosphates ... 

If sterol content and conformation are so important for membrane stability, we should study the biosynthesis of sterols (Figure 3). The first enzyme in terpenoid biosynthesis is the 3-Hydroxy-3-Methyl-Glutary1-Coenzyme A-reductase (HMG-CoA-reductase) that catalyzes the synthesis of mevalonate. Two phosphorylations and decarboxylation of mevalonate lead to isopentenylpyrophosphate, the basic C -unit in sterol synthesis. Isopentenylpyrophosphate reacts with its isomer, the dimethylally1-pyrophosphate, in a head/tail-reaction to geranyl-pyrophosphate reaction with another C -unit leads to farnesyl-pyro-phosphate, that dimerizes in a tail/tail-reaction to squalene. After expoxidation of its A -double bond, squalene cyclizes to lano-... 

The biosynthesis of monoterpenoids and camphor has been described by several authors (108-llU). Ruzicka (115,116) proposed a unified biogenetic scheme for terpenes. The biosynthetic building blocks for these terpenes are iso-prene units. The biosynthetically active isoprene units are isopentenyl pyrophosphate [l] and dimethyl allyl pyrophosphate [2] the compounds that are derived from acetate via mevalonic acid (Scheme V). Geranyl pyrophosphate [3] is the C-10 precursor for the terpenes (117). Banthorpe and Baxendale (ll8) confirmed the biosynthetic pathway of (iamphor via acetate mevalonate by conducting degradation study of camphor, biosynthesized from l c labelled mevalonic acid. The biosynthesis of camphor is summarised in Scheme VI. 

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