Terpenes and the Isoprene Rule

Problem 9.35 Pick out the isoprene units in the terpenes limonene, myrcene and a-pheliandrene, and in vitamin A, shown below, 

In the structures below, dashed lines separate the isoprene units. 

Problem 9.36 Draw formulas for (o) isopropylcyclopentane, b) c -l,3-dimethylcyclooctane, (c) bicyclo[4.4. l]undecane, (d) rrarw-l-propyl-4-butylcyclohexane. 

Problem 9.37 Name each of the following compounds and indicate which, if any, is chiral. 

Problem 9.38 Draw the structural formulas and give the stereochemical designation meso, rac, cis, trans, achiral) of all the isomers of trichlorcyclobutane.  

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Two units of isoprene combine to form terpenes, Cjo compounds such as geraniol. Three isoprene units form sesquiterpenes, C15 compounds such as famesol. Diterpenes are C20 compotmds, triterpenes are C30 compounds, and so on. Myriad terpenoid compounds are known, and most can be traced to derivatives of isoprene as starting material. Most terpenes follow the isoprene rule, which dictates the head-to-t ul formation described earlier. AH of the terpenes shown in Figure 12.76 do not stricdy follow the pattern, but each has at least one head-to-tail connection. 

The German chemist Otto Wallach (Nobel Prize m chemistry 1910) determined the structures of many terpenes and is credited with setting forth the isoprene rule ter penes are repeating assemblies of isoprene units normally joined head to tail... 

Exercise 30-1 a. Write out all of the possible carbon skeletons for acyclic terpene and sesquiterpene hydrocarbons that follow the isoprene rule. Do not consider doublebond position isomers. 

The sesquiterpenes, diterpenes, and poly terpenes can be considered most simply from a structural point of view as products composed of multiple units of isoprene. Structures currently assigned to some of the sesquiterpenes may have to be revised as the study of terpene chemistry advances, since many of these have been based on the validity of the isoprene rule for terpene structures and exceptions to this rule are becoming known (37). 

Figure 1.25 The isoprene rule for classifying compounds as terpenes. To apply the rule one ignores the double bonds (see myrcene) and in some cases it is also necessary to distort the isoprene structure (see a-pinene)...

Ruzicka, L. (1953). The isoprene rule and the biogenesis of terpenic compounds. Experi-entia 9 357-367. 

All terpenes are related, regardless of their apparent structural differences. According to the isoprene rule proposed by Leopold Ruzicka, terpenes can be thought of as arising from head-to-tail joining of five-carbon isoprene 2-methyl-1,3-butadiene) units. Carbon 1 is called the head and carbon 4 is the tail. For example, myreene contains two isoprene units joined head to tail, forming an eight-carbon chain with two one-carbon branches. of-Pinene similarly contains two isoprene units assembled into a more complex cyclic structure. 

The isoprene rule is a convenient formalism, but isoprene itself is not the biological precursor of terpenes. Nature instead uses two isoprene equivalents —isopentenyl pyrophosphate and dimethylallyl pyrophosphate. These five-carbon molecules are themselves made from condensation of three acetyl CoA units (Section 21.9). 

Biosynthesis In contrast to steroids and terpenes, there is no equivalent to the isoprene rule for alkaloids as a useful aid for structure determination and biogenetic investigations. It is generally accepted today that A. are formed in cyclization, condensation, and dimerization reactions from amino acids and biogenic amines with biogenic aldehydes and ketones. 

Polyterpenes (polyterpenoids). Natural products made up of n C lo units (= 2 n isoprene building blocks) with n>4, the biogenesis of which generally obeys the isoprene rule. The most important P. are the tetra-terpenes (n=4) including carotinoids, ficaprenols, natural rubber, balata, and gutta-percha. The name is also used for hydrocarbon resins (terpene resins) prepared synthetically by polymerization of monoter-penes. 

About 30 000 terpenes are known at present in the literature Their basic structure follows a general principle 2-Methylbutane residues, less precisely but usually also referred to as isoprene units, (Cs), build up the carbon skeleton of terpenes this is the isoprene rule found by Ruzicka and Wallach (Table 1). Therefore, terpenes are also denoted as isoprenoids. In nature, terpenes occur predominantly as hydrocarbons, alcohols and their glycosides, ethers, aldehydes, ketones, carboxylic acids and esters. 

Most terpenes share isoprene (2-methyl-1,4-butadiene) as a common carbon skeleton building block. This structural relationship was identified by Wallach in 1887, who recognized that most terpenic structures result from the head-to-tail condensation of isoprene units and this became known as the isoprene rule . Based on this generic rule, terpenes can be classified according to the number of isoprene units (Table 2.1). 

Early studies indicated that terpenes were composed of five carbon units. By 1860, isoprene, a compound with the empirical formula C5H8, could be derived by pyrolysis of turpentine and rubber. Further, isoprene could be transformed into a C10H16 compound that subsequently decomposed back to the original five-carbon unit. Wallach recognized that terpenes could be subdivided into several groups hemiterpenes, true terpenes, sesquiterpenes, and diterpenes. In 1887, he proposed that monoterpenes (true terpenes) as well as other terpenoids were composed of isoprene units, a concept that became known as the isoprene rule (Wallach, 1887). The structure of isoprene was not solved until much later (Spurgeon and Porter, 1981). 

Explain how caryophyllene fits the isoprene rule (see essay, "Terpenes and Phenylpropanoids"). 

Wallach proposed that one isoprene (2-methyl-l, 3-butadiene) unit of five carbon atoms could serve as this function. This idea was eventually elaborated on by Ruzicka and Bloch into the isoprene rule. Eventually, as we will see, the family of terpenes (Cio), sesquiterpenes (C15), diterpenes (C20), sesterpenes (C25), triter-penes (C30), and truly large compounds (polymers) found in latex and gutta-percha comprises tens of thousands of individual, unique compounds all of which may be considered as derived from isoprene (2-methyl-l,3-butadiene) and that the pair of C5 isomers, isopentenyl diphosphate and dimethylallyl diphosphate, compounds linked by interconversion (Scheme 11.41) under the influence of the isopentenyl isomerase (EC 5.3.3.1) serve as the biochemical parents to the family. ... 

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