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30.E: Natural Products and Biosynthesis (Exercises)

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    84775
  • 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 double-bond position isomers.

    b. Do the same for monocyclic terpenes with a six-membered ring.

    Exercise 30-2 The terpene known as alloöcimene \(\left( \ce{C_{10}H_{16}} \right)\) shows \(\lambda_\text{max}\) at \(288 \: \text{nm}\) and gives among other products 1 mole of 2-propanone and 1 mole of ethanal on ozonization. What is a likely structure for alloöcimene? Show your reasoning.

    Exercise 30-3 Write structures for each of the optical and cis-trans isomers that would be expected for the following isoprenoid compounds (refer to Table 30-1):

    a. myrcene
    b. \(\alpha\)-farnesene
    c. limonene
    d. zingiberene
    e. sabinene
    f. \(\alpha\)-pinene
    g. camphene
    h. selinene
    i. caryophyllene

    Exercise 30-4* Optically active camphene racemizes on heating with weak acids. Write a mechanism for this racemization that is in harmony with the acid-catalyzed character of the reaction. (We suggest that you review Sections 8-9B and 15-5E.)

    Exercise 30-5

    a. Nerol and geraniol cyclize under the influence of acid to yield \(\alpha\)-terpineol. How could the relative ease of cyclization of these alcohols, coupled with other reactions, be used to establish the configurations at the double bond of geraniol, nerol, geranial, and neral? Write a mechanism for the cyclizations.

    b. Acidic cyclization of optically active linaloöl produces optically active \(\alpha\)-terpineol. Explain how this can come about.

    Exercise 30-6 Reduction of the ketone group of \(\left( - \right)\)-menthone, which has its alkyl groups trans to one another, gives two products, known as \(\left( - \right)\)-menthol and \(\left( + \right)\)-neomenthol. These two substances differ considerably in their reactions. \(\left( + \right)\)-Neomenthol undergoes dehydration either in methanoic acid or when treated with phosphorus pentachloride, whereas \(\left( - \right)\)-menthol gives a methanoate ester with methanoic acid and a chloride with phosphorus pentachloride. What is the relationship between neomenthol and menthol, and why do they behave differently with methanoic acid and phosphorus pentachloride? What is the likely structure of the menthene from dehydration of neomenthol? (Review Sections 8-8D, 12-3D, and 12-5.)

    Exercise 30-7* Camphor can be made on an industrial scale from \(\alpha\)-pinene (turpentine) by the following reactions, some of which involve carbocation rearrangements of a type particularly prevalent in the bicyclic terpenes and the scourge of the earlier workers in the field trying to determine terpene structures.

    Write mechanisms for the rearrangement reactions, noting that hydrated titanium oxide is an acidic catalyst.

    Exercise 30-8 One route for the synthesis of \(D\),\(L\)-fenchone is through the following steps. Show the reagents, conditions, and important reaction intermediates you expect would be successful in achieving each of the indicated transformation, noting that more than one step may be required (all the reactions necessary have been described in previous chapters).

    Exercise 30-9 The synthesis of Cecropia juvenile hormone outlined below was designed by E. J. Corey and co-workers. Draw in the structure of the product (as i, ii, etc.) at each stage where this has been omitted, and write above the arrows the reagents and conditions necessary to accomplish reactions where these have been omitted. (To save space, the abbreviation \(\ce{R}\) and \(\ce{R'}\) are used to designate parts of the structure that do not change in later steps.)

    Exercise 30-10 How many optical isomers are possible for cholic acid?

    Exercise 30-11 Assuming cholesterol has the following stereochemical configuration, draw a similar configurational structure for cholic acid (including the hydroxyl groups).

    Exercise 30-12 Reduction of the double bond of cholesterol can be carried out so as to produce either 5\(\alpha\)- or 5\(\beta\)-cholestanol. Equilibration of 5\(\alpha\)-cholestanol with a trace of 5\(\alpha\)-cholestanone and base (Section 16-4E) gives \(90\%\) 5\(\alpha\)-cholestanol and \(10\%\) of a stereoisomer known as epicholestanol. Similar equilibration of 5\(\beta\)-cholestanol (in the presence of 5\(\beta\)-cholestanone) gives \(10\%\) 5\(\beta\)-cholestanol and \(90\%\) of a stereoisomer of 5\(\beta\)-cholestanol known as epicoprostanol. Write the configurations of each of these compounds and explain the orders of stabilities that are observed.

    Exercise 30-13

    a. The structure of Terramycin (an oxytetracycline antibiotic) is shown below. This substance is a mold metabolite and shows extensive incorporation of \(\ce{^{14}C}\) when \(\ce{CH_3-^{14}CO_2H}\) is introduced into the culture medium. Indicate positions expected for introduction of the \(\ce{^{14}C}\)-label in Terramycin using \(\ce{CH_3-^{14}CO_2H}\).

    b. Erythromycin A is an example of a large group of antibiotics known as macrolides. They are medium-ring lactones. Erythromycin A is biosynthesized from propanoate. Show the expected distribution of deuterium and \(\ce{^{14}C}\) labels in erythromycin grown in a medium containing \(\ce{CD_3CH_2^{14}CO_2H}\).

    Exercise 30-14 Show the position(s) of an isotopic carbon label such as \(\ce{^{14}C}\) in geranyl pyrophosphate biosynthesized from carboxyl-labeled \(\ce{CH_3C}^* \ce{O_2H}\) by way of \(8\) and \(9\).

    Exercise 30-15 Show by a reasonable mechanism how myrcene, ocimene, and limonene might arise from \(\ce{CH_3CO_2H}\) by way of the pyrophosphate ester, \(9\).

    Suppose one started with \(\ce{CH_3CO_2H}\) labeled at the methyl with \(\ce{^{14}C}\); where would each product be labeled?

    Exercise 30-16 An ingenious and highly practical synthetic procedure for forming the steroid ring system has been developed by W. S. Johnson that closely mimics the squalene cyclization without the need for enzymes. The cyclizations occur by carbocationic intermediates under rather strictly defined conditions that are designed to prevent the reactants from being diverted to nucleophilic substitution or elimination products until the desired additions have occurred. Devise a course for each of the following Johnson reactions:

    The following problems illustrate the steps taken in several important syntheses of naturally occurring substances. Show the reagents, conditions, and important intermediates you expect to be successful in achieving each of the indicated transformations, noting that more than one step may be required. Except where conditions and reagents already are supplied, all the reactions necessary have been discussed in previous chapters. We suggest that the reasons for the stereospecificity of the reactions (if any) be considered carefully. See Table 30-2 for steroid structures.

    Exercise 30-17 Equilenin was synthesized by Bachmann, Cole, and Wilds in 1939. This was the first total synthesis of a steroid. The route follows:

    Exercise 30-18 The total synthesis of cortisone has been achieved from an intermediate prepared by Woodward and co-workers in 1951 by the following route:

    Exercise 30-19 W. S. Johnson and co-workers have produced several elegant syntheses of estrone. One of the shortest and most stereospecific follows:

    Exercise 30-20 Cantharidin, a bicyclic "head-to-head" monoterpene (Section 30-3A) that is the irritant principle of the Spanish fly, would seem to be easy to synthesize by hydrogenation of the Diels-Alder adduct of dimethylbutenedioic anhydride and oxacyclopentadiene (furan):

    However, this route fails because the Diels-Alder reaction with the particular set of reagents has a very unfavorable equilibrium constant. Even if the addition were successful, it is possible also that the stereochemistry (exo or endo) of the adduct would not be the same as that of the natural product.

    An ingenious synthesis of cantharidin that gives the correct stereochemistry was reported by Stork, van Tamelen, Friedman, and Burgstahler (1953) by way of the following intermediates:

    Exercise 30-21 Cedrene (oil of cedar) has been synthesized by Stork and Clarke (1955) by way of the following intermediates:

    Exercise 30-22 A synthesis of the alkaloid morphine (Section 23-2) was completed by Gates and Tschudi in 1952 by way of the following key intermediates, starting from naphthalene. Show the reagents, conditions, and important reaction intermediates that you expect would be successful in achieving each of the indicated transformations, noting that more than one synthetic step may be required between each key compound and considering carefully the order in which the operations should be carried out. Indicate those reactions that may be expected to give mixtures of stereo- or position-isomers. All the reactions involved have analogy in reactions that have been discussed in this or previous chapters, except where conditions and reagents are specified.

    Exercise 30-23 Synthesis of the alkaloid reserpine was reported in 1956 by R. B. Woodward and co-workers through the following intermediates from 2,4-pentadienoic acid. Show the reagents, conditions, and important reaction intermediates that you expect would be successful in achieving each of the indicated transformations, noting that more than one synthetic step may be required between each key compound and considering carefully the order in which the operations should be carried out. Indicate those reactions that may be expected to give mixtures of stereo- or position-isomers. All the reactions involved have analogy in reactions that have been discussed in this or previous chapters, except where the reagents and conditions are specified. The beauty of this synthesis lies in the control that it provides over the stereochemistry of the transformations involved, and it is worthwhile to give this detailed attention (with the aid of models, if possible).

    Reserpine has important clinical use in the treatment of high blood pressure (hypertension) and also as a tranquilizer for the emotionally disturbed.

    Exercise 30-24 The need for adequate amounts of prostaglandins has led to several total syntheses of these substances. A stereospecific synthesis reported by E. J. Corey and co-workers in 1968 is outlined below. Complete the sequence as in Exercise 30-9 by showing the reagents and conditions needed for each step. Note that \(\wr\) implies a mixture of epimers.

    Contributors

    • John D. Robert and Marjorie C. Caserio (1977) Basic Principles of Organic Chemistry, second edition. W. A. Benjamin, Inc. , Menlo Park, CA. ISBN 0-8053-8329-8. This content is copyrighted under the following conditions, "You are granted permission for individual, educational, research and non-commercial reproduction, distribution, display and performance of this work in any format."