Terpenoids

Terpenoids represent a large and structurally diverse class of natural products. Research efforts directed towards their synthesis was fueled by hypotheses on their 

The domino re-cationic cyclization popularized by Johnson and co-workers has provided a powerful stereoselective approach to the steroid subfamily of terpenoids [27]. This pioneering biomimetic work established that the entire carbocydic 

This synthesis featured a four-component coupling involving an oxidative dimerization process. Treatment of homochiral acyl silane 56 with vinyl lithium at low temperature, followed by the addition of half an equivalent of iodine to the reaction mixture, furnished tetraene 58 in high yield and with a very high level of stereoselectivity. The TBS ether was then converted to its triflate equivalent 59 in a 

72 Multicomponent Reactions in the Total Synthesis of Natural Products 

The dilithio derivative of 1,4-bisphenylsufonylbutane 61 was formed prior to the introduction of homochiral acylsilane 56 into the reaction mixture. The nucleophilic carbonyl addition/Brook rearrangement/elimination sequence delivered bis (fi)-vinyl silyl ether 64 in high yield and with very high selectivity through the putative intermediates 62 and 63. This short and effective synthesis of 55, this time made as the major isomer, was then completed as described above for 54. 

Terpenoids, especially those constituted by four mevalonate units, are among the most abundant macrocycles in Nature. There are few examples of synthetic approaches toward these compounds using RCM for the cyclization step. 

5 Terpenoids, Flavonoids, and Other Naturally occurring Analytes 4.5.5.1 Terpenoids 

Several sesquiterpene lactones (parthenin, coronopilin, tetraneurin A, hysterin, la-hydroxy-4 -0-acetylpseudoguaian-6, 12-olide, 4a-0-acetylpseudoguaian-6j -olide) 

Triterpenes were extracted fh)m Cimicifuga racemosa and separated on a Discovery Cjg column (A = 200nm and ELSD, nozzle T = 40°C, N2 pressure = 2 bar). The authors noted that other Cjg and phenyl columns could not resolve the peaks cimiracemoside A, 26-deoxyactein and actein, and five minor unidentified triterpenes. The sensitivity at 200 nm was severely compromised due to the use of a 35-min 58/21/21- 52/14/34 water/acetonitrile/ alcohol (where alcohol = 90.6/4.5/4.6 ethanol/methanol/IPA) gradient. Remember that alcohols have UV cutoff values from about 203 to 206 nm. For the ELSD, the concentration range of 8-500 pg/mL was represented in a log response vs. log concentration plot. A detection limit of 20pg/mL was reported [361]. 

Two diterpenes, cafestol and kahweol, were isolated fi om brewed coffees and separated on a C g column (A = 230 nm and 290 nm) using a 20-min 30/70 - 5/95 water/methanol gradient [362]. Peak shapes were excellent and baseline resolution was obtained. Detection limits of 50pg/L were reported and standards of 40-300 pg/g were easily detected. 

Chen et al. [365] analyzed Ginkgo biloba extracts for diterpenes (ginkgolides A, B, and C) and the sesquiterpene (bilobalide) content using a C g column (RI detector) and a 23/77 methanol/water mobile phase. Peaks were somewhat broad (perhaps due to the RI), but good resolution was achieved and elution was complete in 24min. A plot of k vs. percent methanol is,shown. A linear range of 4-60 pg 

Terpenes and terpenoids are popular chiral starting materials because they are cheap, available in bulk and chemically versatile. 

So far, the synthetic sequences have been linear. It should be clear that in a convergent synthesis, the two or more fragments to be joined must be enantiomerically pure to avoid impossible difficulties with 

We will only discuss the synthesis of lactone (36), which constitutes the C21-C25 section of milbemycin P3. (3S)-Citronellol is dehydrated to (37), which is selectively ozonised at the more electron-rich double 

See also section 7.1.1 for another application of terpenoids as chiral starting materials. 

Homopolymerization of terpenoids using C=C bonds is not as easy as homopolymerization of industrially used vinyl monomers. The trial study on 

Research on the copolymerization of terpenoids with industrially used vinyl monomers or other monomers have been often reported. Littmann introduced terpene-maleic anhydride resins for industrial use in alkyd resins in 1936. The resin was synthesized from a-terpinene and maleic anhydride via 

Synthetic Green Polymers from Renewable Monomers Terpenes from Biomass 

Nomura et achieved the polycondensation between terpene deri- 

Synthetic Green Polymers from Renewable Monomers 

The following well-known monoterpenoids have been described from lichens, but without identification of their optical rotation borneol, camphene, camphor, 1,8-cineol, p-cymene, fenchol, limonene, linalool, a-pinene, (3-pinene, terpinen-4-ol, a-terpineol, a-thujone, (3-thujone [all from Evernia prunastri [319)], and carvone [from Cetraria islandica ((555)]. 

In the Ghapter 7 Lagniappe, we looked briefly at terpenoids, a vast and diverse group of lipids found in all living organisms. Despite their apparent structural differences, all terpenoids are related all contain a multiple of five carbons 

The terpenoid precursor isopentenyl diphosphate, formerly called isopentenyl pyrophosphate and thus abbreviated IPP, is biosynthesized by two different pathways depending on the organism and the structure of the final product. In animals and higher plants, sesquiterpenoids and triterpenoids 

STEP 1 OF FIGURE 23.9 CLAISEN CONDENSATION The first step in mevalonate biosynthesis is a Claisen condensation to yield acetoacetyl CoA, a reaction catalyzed by acetoacetyl-CoA acetyltransferase. An acetyl group is first bound to the enzyme by a nucleophilic acyl substitution reaction with a cysteine -SH group. Formation of an enolate ion from a second molecule of acetyl CoA, followed by Claisen condensation, then yields the product. 

OCIaisen condensation of two molecules of acetyl CoA gives acetoacetyl CoA. 

The mevalonate pathway for the biosynthesis of isopentenyl diphosphate from three molecules of acetyl CoA. Individual steps are explained in the text. 

One of the best understood biosynthetic pathways for terpenoids is the biosynthesis for menthol in mint plants. All the enzymes are identified, cloned, and characterized [43]. Menthol plays an important role as aroma in food, cigarettes, and medications for the pulmonary tract and in cosmetics. Improvements of yield or 

Limonene as a by-product of orange juice production can be used for polymer production together with CO2 to form a polystyrol-like foam. Menthon can be used as a precursor for branched dicarbonic acids and alpha-pinen (a by-product of the forest industry) as precursor for cymol production or for enzymatic verbenone production. Other important terpenoids are phytosterols. They are used in the production of steroid hormones such as cortison or progesteron by Bayer Sobering Pharma. Probably the most important example where plant secondary metabolism and microbial fermentation are synergistically combined, steroid hormones, are produced from phytosterols. A fermentation process by Bayer Schering Pharma uses a plant metaboUte and converts it by a single-step microbial fermentation into the desired end product. 

3 Natural Product Total Synthesis Formation of Tertiary Stereocentres 16.3.1 Terpenoids 

Further optimization of asymmetric Mizoroki-Heck cyclizations of prochiral vinyl triflates focused on the effects of base, solvent and additives [30, 31]. Tertiary amine bases, such as -Pr2NEt, gave results inferior to those realized with K2CO3. In the absence of additives, reactions in toluene gave superior yields to reactions conducted in 1,2-dichloroethane (DCE) or polar solvents. However, additives such as tertiary alcohols (e.g. pinacol) or KOAc 

Recent studies by Kiely and Guiry [32] compared the utility of BINAP and diphenylphos-phinooxazoline ligands in the catalytic asymmetric synthesis of cw-decalins. Their results suggest that BtNAP provides superior conversion to Mizoroki-Heck products, although both ligand systems afford cw-decalin products with high enantioselectivities. 

Interception of the alkylpalladium intermediate in a Mizoroki-Heck cyclization can be parlayed to introduce an additional stereocentre and increase molecular complexity. Shibasaki and coworkers insightfully recognized that the linear triquinanes represent a prime opportunity for exploring the feasibility of cascade Mizoroki-Heck processes in the context of natural product synthesis, with their studies leading to the first reported asymmetric Mizoroki-Heck cyclization- ) -allyl nucleophilic trapping sequence. 

The minor isomer 60 could be converted quantitatively to the major a,)8-unsaturated lactam product 61 by subsequent reaction of the former with catalytic Pd/C in MeOH. 

Acetyl CoA is the starting material for the biosynthesis of the fatty acids. It is used for the synthesis of the fatty acids by the acetate-malonate pathway. With the terpenoids we become acquainted with a second, large group of natural products whose biosynthesis starts from acetyl CoA. The terpenoids are furnished via the acetate-mevalonate pathway. 

Isoprenoids - or polyprenoids, as they are sometimes called - comprise a large and important group of natural products that can be formally derived from isoprene (isopentane) units. This group consists of two major classes terpenoids and steroids. Although terpenoids and steroids are genetically related and such a relationship was anticipated by Heilbron as early as 1926 (187) - the chemistry of the two classes has developed fairly independently. Because of this historical fact, the two groups are usually treated separately. 

However, several natural products are known that have a number of carbon atoms which is different from those shown in Thble 8.1.1, but have a clear struc- 

Terpenoids are probably the largest single group of secondary metabolites, and at present over 7500 structurally well-defined compounds embracing a bewildering but fascinating array of skeletal types are known. 

As is the case with other classes of natural products, a trivial name based on the biological source material is invariably assigned to a new terpenoid. Thus terpenoid compounds usually carry a name derived from the family, genus, species, or local name of the raw material from which it had been isolated. Because functionality of a new compound is readily established, a trivial name is coined to indicate the dominant functionality. 

It has been suggested (212) that semisystematic names based on parent structural types be used whenever possible. The name of the parent structure is derived from the trivial name of the member first isolated. This name, when used for such derivations, besides indicating the carbon skeleton, implies, without further specification, the absolute configuration at all chiral centers of the parent. Carbon skeletons closely related to a parent structure are often named by using prefixes such as cyclo , nor , homo , seco , abeo etc. with the parent name, as indicators of modification. The prefix ent (short for enantio ) is used to indicate inversion at all chiral centers implied in the parent structure. 

Terpenes are found as constituents of essential oils and oleoresins of plants. Since antiquity they have been isolated and used in flavor and fragrance apphcations. Many important constituents of the essential oils have been identified and syntheses for them developed (see Oils, essential). 

Terpenes are characterized as being made up of units of isoprene in a head-to-tail orientation. This isoprene concept, invented to aid in the stmcture deterrnination of terpenes found in natural products, was especially useful for elucidation of stmctures of more complex sesquiterpenes, diterpenes, and polyterpenes. The hydrocarbon, myrcene, and the terpene alcohol, a-terpineol, can be considered as being made up of two isoprene units in such a head-to-tail orientation (1). 

Kirk-Othmer Encyclopedia of Chemical Technology (4th Edition) 

Terpene chemists use mainly gas chromatography in dealing with terpene mixtures in research and development as weU as in quahty control. Capillary gas chromatography with stable bonded-phase columns, the primary analytical method, is also being used more frequendy in the 1990s in product quahty control because its greater resolution is helpful in producing consistent products. 

Terpenes, biogenetically, arise from two simple five-carbon moieties. Isoprenyl-diphosphate (IPP) and dimethylallyldiphosphate (DMAPP) serve as universal precursors for the biosynthesis of terpenes. They are biosynthesised from three acetylcoenzyme A moieties through mevalonic acid (MVA) via the so-called mevalonate pathway. About 10 years ago, the existence of a second pathway leading to IPP and DMAPP was discovered involving l-deoxy-D-xylulose-5-phos-phate (DXP) and 2C-methyl-D-erythritol-4-phosphate (MEP). This so-called non-mevalonate or deoxyxylulose phosphate pathway starts off with the condensation of glyceraldehyde phosphate and pyruvate affording DXP. Through a series of reactions as shown in Fig. 4.1, IPP and DMAPP are formed, respectively [3,7, 42, 43]. 

IPP and DMAPP lead to geranylpyrophosphate (GPP), which is an immediate precursor of monoterpenes. The formation of nerylpyrophosphate (NPP) from GPP gives rise to a wide range of acyclic, cyclic, bicyclic or tricyclic skeletons. Reactions like rearrangement, oxidation, reduction and hydration via various terpene cyclases result in the formation of numerous terpene derivatives. Condensation of GPP and IPP leads to farnesylpyrophosphate (FPP), the immediate precursor of sesquiterpenoids. Likewise, FPP and IPP are conducive to diterpenoids. 

Monoterpenes are formed from two attached isoprene 3 units 2,6-dimethyloc-tane as the simplest skeleton. Thus, they can be acyclic or linear like -myrcene 4, ( )-/l-ocimene 5, (Z)-/l-ocimene 6, and allo-ocimene 7 (Structure 4.3). Or they can be cyclic, meaning ring-forming, such as in the simplest form like p-menthane 8 or p-cymene 9. Monocyclic 8, 9, bicyclic (5-3-carene 10 and tricyclic tricyclene 11 type monoterpenes are found in essential oils [1-4, 6-14, 16-23,38,39, 42, 47, 48]. 

Aromatic monoterpenes which contain a benzene ring like p-cymene 9, car-vacrol 12, thymol 13 and phenylethyl alcohol 14 (Structure 4.4) are common constituents of many essential oils, e.g. oregano (Origanum sp.), thyme (Thymus sp.), savory (Satureja sp.) and rose (Rosa sp.) oils. Another important constituent class of essential oils is phenypropanoids [36]. They are not considered as terpenoids owing to their different biogenetic origins, which will be mentioned later. 

According to the Dictionary of Natural Products (DNP), there are 25 different classes of monoterpenes [37]. 

Terpene chemists use trivial names for most of the compounds because the systematic names are much more complex. Common or trivial names, CAS Registry Numbers, and properties of selected terpenes and terpenoids are listed in Tables 2 and 3. Compounds that exhibit chirality also have other Registry Numbers for specific optical isomers. For commercial products, a material safety data sheet (MSDS), which is required by OSHA, frequendy lists multiple names such as a product name, trivial name, IUPAC name and the TSCA name. The MSDS is a good source of information about physical properties, potential health hazards, and other useful information for the safe handling of the materials. When the product is a mixture, the components and their amounts are usually listed along with their Registry Numbers. 

Cis and trans configurations describe the orientation of a functional group in the molecule. The terms cis and trans are from Latin, in which cis means on the same side and trans means on the other side or across.  

FIGURE 4.1. Repeat units of terpenoids in trans and cis configuration. 

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D-Mevalonic acid is the fundamental intermediate in the biosynthesis of the terpenoids and steroids, together classed as poly-isoprenoids. The biogenetic isoprene unit is isopentenyl pyrophosphate which arises by enzymic decarboxylation-dehydration of mevalonic acid pyrophosphate. D-Mevalonic acid is almost quantitatively incorporated into cholesterol synthesized by rat liver homogenates. 

Open-chain 1,5-polyenes (e.g. squalene) and some oxygenated derivatives are the biochemical precursors of cyclic terpenoids (e.g. steroids, carotenoids). The enzymic cyclization of squalene 2,3-oxide, which has one chiral carbon atom, to produce lanosterol introduces seven chiral centres in one totally stereoselective reaction. As a result, organic chemists have tried to ascertain, whether squalene or related olefinic systems could be induced to undergo similar stereoselective cyclizations in the absence of enzymes (W.S. Johnson, 1968, 1976). 

Similarly to alkenes. alkynes also insert. In the reaction of 775 carried out under a CO atmosphere in AcOH, sequential insertions of alkyne, CO. alkene. and CO take place in this order, yielding the keto ester 776[483]. However, the same reaction carried out in THF in the presence of LiCl affords the ketone 777, but not the keto ester[484]. The tricyclic terpenoid hirsutene (779) has been synthesized via the Pd-catalyzed metallo-ene carbonylation reaction of 778 with 85% diastereoselectivity as the key reaction[485], Kainic acid and allo-kainic acid (783) have been synthesized by the intramolecular insertion ol an alkene in 780, followed by carbonylation to give 781 and 782[486],... 

A more highly substituted analogue was successfully used in the preparation of the penitrem class of terpenoid indoles[3]. 

In a more elaborate and specific synthesis, the terpenoid indole skeleton found in haplaindole G, which is isolated from a blue-green alga, was constructed by addition of a nucleophilic formyl equivalent to enone 6.5A. Cyelization and aromatization to the indole 6.6B followed Hg -catalysed unmasking of the aldehyde group[6]. 

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