Linear terpenoids

The tandem zirconocene-induced co-cyclization of dienes or enynes/insertion of allyl carbenoid/addition of electrophile is a powerful method for assembling organic structures. Two illustrations of its application are the synthesis of the dollabelane natural product acetoxyodontoschismenol 99 [57,62,63] and the one-pot construction of linear terpenoids 100 (Scheme 3.25) [59,64],... 

M. Piattelli, and C. Tringali, Oxocrinol and crinitol, novel linear terpenoids from the brown alga Cystoseira crinita. Tetrahedron Lett., (1976) 937-940. 

MDLT material derived from linear terpenoids... 

The linear terpenoid precursors can undergo many different cyclization processes. The longer the chain, the more different possibilities there are for cyclized structures. The cyclization processes are essentially carbocation reactions, with the initial cation being formed by loss of the pyrophosphate residue from the parent linear structure. Some cyclization processes for monoterpenoids are shown in Fig. 8.5 and for sesquiterpenoids in Fig. 8.6. 

FIGURE 8.4. Biosynthesis of the basic linear terpenoid skeletons. 

The regioselectivity of alkene epoxidation leading to diol formation has not been examined in sufficient detail for predictive generalizations to be made, but for linear terpenoid substrates a preference for the terminal olefinic bond is often demonstrated, as discussed in Sec. III.C [8]. 

Bloch therefore suggested isoprene units could be condensed first to give squalene and then cholesterol, an extension of Ruzicka s isoprene rule for the biosynthesis of linear and cyclic terpenoids. It was then necessary to show that selectively labeled 14C-acetate could get incorporated into squalene with the correct distribution of 14C and that this squalene could give rise to cholesterol, also with the appropriate position of the 14C label. 

Earlier work by Nancy Bucher showed an ATP requirement for cholesterol biosynthesis. The involvement of phosphorylated intermediates was established by Comforth, Popjak, and their associates in the early 1960s with the discovery of kinases which successively phosphorylated MVA to MVA-P and MVA-P to MVA-PP. MVA-PP was decar-boxylated and dehydrated to give the biological C5 isoprene unit, isopentenyl pyrophosphate. This undergoes successive head-to-tail condensations to give the linear 15C terpenoid, famesyl pyrophosphate. 

Easily available advanced synthons, such as the carbohydrates, amino acids, hydroxyacids, and terpenoids, make the synthetic task easier than the complexity metrics of the target suggests this is especially true for the glycosides, if the carbohydrate portion can be introduced intactly. It must also be borne in mind that the S metric is counted in a linearly additive hion, neglecting interactions between the functional groups (Whitlock 1998) such interactions are not treated adequately by any method so far proposed to calculate the molecular complexity. Moreover, no attention was paid here to the graphic analysis of the synthesis plan based on the molecular complexity of the intermediates these aspects have recently been reviewed (Bertz 1993 Whitlock 1998 Chanon 1998). 

Sesquiterpenes are formed by the addition of one more isoprene units to a monoterpene molecule, and thus have the molecular formula C15H24 (see also Fig. 4.2). There are linear, branched or cyclic sesquiterpenes. Sesquiterpenes are unsaturated compounds. Cyclic sesquiterpenes may be monocyclic, bicyclic or tricyclic. They are the most diverse group among the volatile terpenoids [2, 3, 7-11, 13,14, 16, 20-24, 37-39, 49]. The DNP treats sesquiterpenoids in 147 different structural types [37]. Various types of sesquiterpenes (69-109) can also be seen in Structure 4.16. 

The terpenoids are secondary metabolites that are found in essential oils, resins, tissues of higher plants and micro-organisms, whilst recently some have also been located in liverworts [5,6]. The terpenoids are formed from linear arrangements of isoprene units, Fig. (1), which are derived from acetate metabolism through mevalonic acid (MVA). This pathway was found to be common to the whole range of natural terpenoid derivatives... 

Liu Y, Zhang S, Abreu PJM (2006) Heterocyclic Terpenes Linear Furano- and Pyrrolo-terpenoids. Nat Prod Rep 23 630... 

Cathenamine (100) has been identified as an early intermediate in terpenoid indole alkaloid biosynthesis (cf. Vol. 8, p. 27). It has also been isolated from Guettarda eximia. Another alkaloid, 4,21-dehydrogeissoschizine (99), has now been isolated from this plant it is readily converted into (100) in alkaline solution.29 On incubation with an enzyme preparation from Catharanthus roseus cell cultures in the presence of NADPH at pH 7, (99) was converted into ajmalicine (102), 19-ep/-ajmalicine (103), and tetrahydroalstonine (104), which are the normal products with this enzyme preparation. In the absence of NADPH, cathenamine (100) accumulated.30 The reaction to give (100) proceeded linearly with time, and was dependent on the concentration of protein and substrate. No conversion occurred in the absence of enzyme. 

Figure 2. GC-FID chromatograms for the sulfide fractions from different Alberta petroleums. The peaks labeled B13 and B20 correspond to the bicyclic terpenoid sulfides with 13 and 20 carbons, respectively. The peak labeled T23 corresponds to the tetracyclic terpenoid sulfide with 23 carbons and peaks due to the hopane sulfides are indicated at the end of the chromatograms. The clusters of peaks spaced one carbon apart on the Bellshill Lake trace correspond mainly to complex mixtures of isomeric monocyclic sulfides possessing a linear carbon framework. These sulfides have been removed by biodegradation from the upper two samples. For more complete peak identification see References 9, 10 and 35. (Reproduced from Reference 34. Copyright 1989, American Chemical Society.)...

In addition to terpene s)mthases, the construction of terpenoid carbon skeletons in plants also involves a number of prenyltransferases distinct from those that make the Cio, C15 and C20 diphosphates. One class of prenyltransferases catalyses l -4 condensations of IFF with an FFF or GGFF starter unit to make long-chain polyterpenes, such as rubber, a linear hydrocarbon with cis (Z) double bonds and as many as 30000 isoprene units. The... 

Figure 3 Biosynthetic pathways. (A) In the terpenoid coupling reaction, isomers of isopentenyl pyrophosphate are joined with the loss of pyrophosphate, leading to a linear intermediate that is cyclized to a terpenoid skeleton, as shown for the diterpene taxol. (B) In the polysaccharide coupling reaction, hexose and pentose monomers are joined with the loss of a nucleoside diphosphate, as shown for the epivancosaminyl-glucose disaccharide of vancomycin. (C) In the first step of the nonribosomal peptide coupling reaction, an aminoacyl adenylate is transferred to a carrier protein or thiolation domain (denoted T ) with loss of adenosine monophosphate. In the second step, this carrier protein-tethered aminoacyl group is coupled to the amine of an aminoacyl cosubstrate, forming a peptide bond, as shown for two residues in backbone of vancomycin. (D) In the polyketide coupling reaction, the loss of carbon dioxide from a two or three-carbon monomer yields a thioester enolate that attacks a carrier protein-tethered intermediate, forming a carbon-carbon bond as shown for the polyketone precursor of enterocin.

Two taxane alkaloids have been investigated by diffraction techniques taxine A (la) [23] and 2 deacetoxyaustrospicatine (41) [49], The results gave important information on the orientation of the side chain relatively to the terpenoid core. In both cases the aromatic ring is close to the terpenoid core, but in 4f the phenyl and the catbonyl are antiperiplanar, whereas in taxine A they are synclinal (cf. C and A in Scheme 3). As a result, the protons closer to the phenyl ring are H(6a) in taxine A and H(14a) in 4f. This is in accordance with the results of the H-NMR analysis [46], In 4f, the conformation with C-l and the phenyl antiperiplanar is stabilized by hydrophobic interactions with the methyl of the 13-acetate [49], The X-ray features of the terpenoid core of 4f and taxine A show linear strain at several carbon-carbon bonds, as generally observed in taxoids [55]. 

The past decade has seen an explosion in our understanding of enzyme pathways through which natural products are produced [6, 7]. For example, linear non-ribosomal peptide (NRP), polyketide (PK), and terpenoid (terpene) scaffolds are usually assembled from amino acids (isopenicillin) [8], acyl-CoAs (erythromycin) [9], and pentenyl pyrophosphates (artemisinin), respectively [10] (Scheme 8.1). These... 

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