Monoterpene synthesis

Another reason for the increase in interest in monoterpene synthesis is caused by the use of chiral monoterpenes as synthetic auxiliaries. This has led to the study of the chiral synthesis of some monoterpenoids, which is discussed in the relevant sections. 

This volume contains a chapter updating monoterpene synthesis and reviews the newer areas of leukotrienes and macrocyclic lactones. My grateful thanks are due to the authors of these contributions for their efforts in producing definitive work on their specialty areas. 

BOUVIER, F., SUIRE, C., D HARLINGUE, A., BACKHAUS, R.A., CAMARA, B., Molecular cloning of geranyl diphosphate synthase and compartmentation of monoterpene synthesis in plant cells., Plant J, 2000,24, 241-252. 

At the moment our work concentrates on the characterisation of this branch point of monoterpene synthesis and phytoene synthesis, respectively. Both ways can be activated by different means. Phytoene synthesis is stimulated by 3 mM ATP and liposomes whereas optimal monoterpene synthesis occurs in the absence of ATP and liposomes. 

Another access to the enzymes responsible for monoterpene synthesis is provided by dimethylaminoethyl diphosphate, an analogon of dimethylallyl diphosphate which inhibits the iso-pentenyl diphosphate A-isomerase at very low concentrations (Muhlbacher and Poulter 1985). This inhibitor was tested for its influence on monoterpene biosynthesis using radioactively labeled IPP and nonlabeled dimethylallyl diphosphate as substrates and optimized monoterpene conditions as mentioned above, Monoterpene synthesis was inhibited up to 50at an inhibitor concentration of 2 pM whereas the synthesis of di- and tetra-terpenes and geranylgerany 1 diphosphate was not impaired (Fig. 3). 

Experimental procedures have been described in which the desired reactions have been carried out either by whole microbial cells or by enzymes (1—3). These involve carbohydrates (qv) (4,5) steroids (qv), sterols, and bile acids (6—11) nonsteroid cycHc compounds (12) ahcycHc and alkane hydroxylations (13—16) alkaloids (7,17,18) various pharmaceuticals (qv) (19—21), including antibiotics (19—24) and miscellaneous natural products (25—27). Reviews of the microbial oxidation of aUphatic and aromatic hydrocarbons (qv) (28), monoterpenes (29,30), pesticides (qv) (31,32), lignin (qv) (33,34), flavors and fragrances (35), and other organic molecules (8,12,36,37) have been pubflshed (see Enzyp applications, industrial Enzyt s in organic synthesis Elavors AND spices). 

One method of synthesis of taxol analogues starts with a-pinene (8), the readily available and inexpensive monoterpene derived from the processing of turpentine from the pine tree (200). The a-pinene is oxidized to verbenone, which is then alkylated and converted to taxol analogues in a multistep process. 

Another monoterpene used as a starting material for taxol analogues is camphor (43), which is readily available naturally or can be produced synthetically (201,202). Total synthesis of taxol analogues may be the answer toward finding new compounds for the treatment of many types of cancer. 

Since the chemical addition of HCN always results in mixtures of cis/trans-isomers, the stereoselective HNL-catalyzed addition is of great advantage in the synthesis of natural products. The syntheses of the natural monoterpenes cis-p-menth-8-ene-l,7-diol and cA-/ -menthane-l,7,8-triol are interesting examples for the application of this methodology (Scheme 9). ... 

The above system has been used for the reaction of EtjNH with myrcene to give a mixture of hydroamination products (53% yield) containing 80% of N,N-diethylgeranylamine [208], a key intermediate for the synthesis of industrially important monoterpenes [208, 209-211], including (-)-menthol (Tagasako process) [212]. 

The activity of the FePeCli6-S/tert-butyl hydroperoxide (TBHP) catalytic system was studied under mild reaction conditions for the synthesis of three a,p-unsaturated ketones 2-cyclohexen-l-one, carvone and veibenone by allylic oxidation of cyclohexene, hmonene, and a-pinene, respectively. Substrate conversions were higher than 80% and ketone yields decreased in the following order cyclohexen-1-one (47%), verbenone (22%), and carvone (12%). The large amount of oxidized sites of monoterpenes, especially limonene, may be the reason for the lower ketone yield obtained with this substrate. Additional tests snggested that molecular oxygen can act as co-oxidant and alcohol oxidation is an intermediate step in ketone formation. 

Allylation of acyloyl-imidazoles and pyrazoles61 with allyl halide mediated by indium in aqueous media provides a facile regioselective synthesis of P, y-unsaturated ketones (Scheme 11.1), which has been applied to the synthesis of the monoterpene artemesia ketone. The same product can be obtained by indium-mediated allylation of acyl cyanide (Eq. 11.35).62 Samarium, gallium, and bismuth can be used as a mediator for the allylation of nitrones and hydrazones to give homoallylic hydroxylamine and hydrazides in aqueous media in the presence of Bu4NBr (Scheme 11.2).63 The reaction with gallium and bismuth can be increased dramatically under microwave activation. 

Evidence for de novo synthesis of pheromone components was obtained by showing that labeled acetate and mevalonate were incorporated into ipsdienol by male Ips pini [103,104]. Similarly, labeled acetate and other labeled intermediates were shown to be incorporated into frontalin in a number of Dendroctonus species [105]. Possible precursors to frontalin include 6-methyl-6-hep-ten-2-one, which was incorporated into frontalin by D. ruffipennis [106]. The precursor 6-methyl-6-hepten-2-one also was shown to be converted to bre-vicomin in the bark beetle, Dendroctonus ponderosae [107]. In addition, the expression patterns of HMG-CoA reductase and HMG-CoA synthase are tightly correlated with frontalin production in Dendroctonus jeffreyi [108, 109]. A geranyl diphosphate synthase cDNA from I. pini was also isolated, functionally expressed, and modeled [110]. These data indicate that the de novo isoprenoid biosynthetic pathway is present in bark beetles. A variety of other monoterpene alcohols such as myrcenol, pityol, and sulcitol are probably synthesized through similar pathways [111]... 

The biosynthesis of monoterpenes, the major components of peppermint essential oils, can be divided into four stages (Fig. 9.4). Stage 1 includes the formation of isopentenyl diphosphate (IPP) and dimethylallyl alcohol (DMAPP). In plants, two separate pathways are utilized for the synthesis of these universal C5 intermediates, with the cytosolic mevalonate pathway being responsible for the formation of sterols and certain sesquiterpenes, and the plastidial mevalonate-independent pathway being involved in the biosynthesis of isoprene, monoterpenes, certain sesquiterpenes, diterpenes, tetraterpenes, as well as the side chains of chlorophyll and plastoquinone.16 In peppermint oil gland secretory cells, however, the mevalonate pathway is blocked and the biosynthesis of monoterpenoid essential... 

During the past two decades a great number of papers have been published on the isolation, structure elucidation, synthesis and transformation, biogenesis, chemotaxonomy, and pharmacology of indole alkaloids. In this chapter we summarize the new results that appeared from 1968 to mid 1984 for the cory-nantheine-yohimbine group of monoterpene indole alkaloids with greater emphasis on their chemistry, excluding the related oxindoles and heteroyohimbines. 

Another large volume monoterpene is (—)-menthol, a compound that belongs to a family of eight stereoisomers. Only (—)-menthol (1 R,2S,3R-configuration) possesses the characteristic peppermint odor and exerts the unique cooling sensation on the skin. Most (—)-menthol is obtained by freezing peppermint or cornmint oil, followed by recrystallization. Besides this natural menthol some 20% or 3000 t a-1 is made by (semi)-synthesis. 

Hudlicky, T., Reddy, D.B., Govindan, S.V., Kulp, T., Still, B. and Sheth, J.P., Intramolecular cyclopentene annulation. 3. Synthesis and carhon-13 nuclear magnetic resonance spectroscopy of bicyclic cyclopentene lactones as potential perhydroazulene and/or monoterpene synthons. J. Org. Chem., 1983, 48, 3422. 

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