Terpenoids and Steroids Volume 3

A Review of the Literature Published between September 1971 and August 1972

By K. H. Overton

The Royal Society of Chemistry

Copyright © 1973 The Chemical Society
All rights reserved.
ISBN: 978-0-85186-276-7

Contents

Part I Terpenoids Introduction,
Chapter 1 Monoterpenoids By A.F. Thomas,
Chapter 2 Sesquiterpenoids By J.S. Roberts,
Chapter 3 Diterpenoids By J.R. Hanson,
Chapter 4 Sesterterpenoids By J. D. Connolly, 193,
Chapter 5 Triterpenoids By J.D. Connolly,
Chapter 6 Carotenoids and Polyterpenoids By G. P. Moss,
Chapter 7 Biosynthesis of Terpenoids and Steroids By G.P. Moss,
Part II Steroids Introduction, 275,
Chapter 1 Steroid Properties and Reactions By D.N. Kirk,
Chapter 2 Steroid Synthesis in collaboration with G.A. Garcia, A. Guzman, L.A. Maldonado, G. Perez, C. Rius, and E. Santos By P. Crabbe,
Errata, 510,
Author Index, 511,

CHAPTER 1

Part I

TERPENOIDS

The interesting formal parallel that exists between the rearrangements of the chrysanthemyl cation and the conversion of presqualene alcohol into squalene (and now of prephytoene alcohol into phytoene) has been further explored. Solvolyses of the cyclopropyl (65) and cyclobutyl (63) esters both afford head-to-head coupled C10 chains analogous to squalene. A versatile new method provides access to 9-substituted p-menthanes. This starts with natural limonene and proceeds via the anion (135) which retains chirality and leads to chiral products (see below). Skeletal rearrangements in the bicycloheptane series, an historic field in the study of organic reaction mechanisms, has received a fresh impetus from the extended work of Kirmse and his colleagues, which is of preparative and mechanistic significance.

Excellence and diversity in the synthetic field again characterize the year’s work on sesquiterpenoids, with some notable examples of sophisticated methodology on the industrial scale. The production of C17 and C18 juvenile hormones and the conversion of the C17 into the C18 hormone are cases in point. The metallation of limonene referred to above has been turned to good account in stereospecific routes to bisabolane sesquiterpenoids. The unique antibiotic fumagillin has been synthesized 36 by an imaginative route. Two notable syntheses of zizaene have been reported. Wiesner’s approach utilized a synthetic route to bicyclo[3,2,1]octanes developed in the course of an approach to diterpene alkaloids. The labile trans,trans-1,5-cyclodecadiene system of hedycaryol has been successfully generated by Marshall fragmentation of the appropriate cyclo-octyl tosylate. Ourisson has described a simple two-stage procedure whereby the α-methylene-γ-butyrolactone function so widespread among natural sesquiterpenoids can be obtained from the more readily available α-methyl-γ-lactones. The method succeeds only with cis-fused lactones. The in vitro interconversion of acyclic, mono-, bi-, and tri-cyclic sesquiterpenes and their potential relevance to biosynthesis continue to attract widespread experimental attention and the complex acid-catalysed rearrangements of thujopsene have been subjected to penetrating study. An attempt to systematize the nomenclature of germacranolides should be noted by workers in the field.

Much effort in the diterpenoid field is concentrated on substances having biological activity. Thus the coleons, inumakilactones, and podofactones control the expansion and division of cells. Combined g.l.c. and mass spectrometry has played an important part in the detection and characterization of new gibberellins and there have been important advances in gibberellin synthesis. The antheridium-inducing factor of ferns has a gibberellin-like structure. Cyathin A3, isolated from the ‘bird’s nest’ fungus, represents a novel mode of cyclization of geranylgeraniol. Notable synthetic successes in the diterpene alkaloid field have come from Wiesner’s laboratory in the total synthesis of the delphinine degradation product (158) and the intermediate (159) for a synthesis of songorine.

Cheilanthatriol 1 represents a new type of sesterterpenoid whose carbon skeleton resembles that of triterpenoids.

The structure of Baccharis oxide has been revised; biosynthetically this is close to the previous structure (Vol. 2, p. 168) and therefore of comparable interest. The total laboratory synthesis of lupeol is a notable further achievement in the synthesis of unsymmetrical triterpenoids.

Cornforth and his colleagues have investigated the stereochemistry of isomerization of isopentenyl to dimethylallyl pyrophosphate in isoprenoid biosynthesis. They find that the prototropic change involved is stereochemically different from the superficially analogous association of C5 units. Bisabolene appears to be excluded as an intermediate in the biosynthesis of helicobasidin and trichothecin by recent labelling studies (see also Vol. 1, p. 232, ref. 81) and a 1,4-hydride shift in the initially formed intermediate is indicated. The loss of the C-14 methyl group in cholesterol biosynthesis differs from loss of the C-4 methyl groups. The 32-carbon atom is released at the aldehyde oxidation level as formic acid.

In the carotenoid and polyterpenoid field a number of important stereochemical studies have appeared. These include assignments of the complete stereochemistry of phytoene and lutein and the absolute configurations of absicic acid and the natural irones.

1

Monoterpenoids

BY A. F. THOMAS

The volume of work published on monoterpenoids is increasing, not only in the absolute sense, but relative to that on other natural products (including other terpenoids). There are at least three possible causes : many monoterpenoids are plentiful, further exploitation is desired, and recent refinements of analytical techniques have made possible the examination of reaction detail that was previously inaccessible. Monoterpenoids lend themselves especially well to such studies because of their suitability for gas chromatography, and also provide examples of a wide variety of structural types. Chemotaxonomy is also increasingly moving toward the use of monoterpenes because of the simplicity of analysis.

Duplication of previously published work (see Vol. 2, p. 5) is reaching new levels. It is incomprehensible that reputable journals (in some cases) with a good refereeing policy still do not detect earlier work-even when it has appeared in this and other reviews-and this year an attempt has been made to quote the earlier reference (this is rarely done by the later authors) in order to highlight the problem.

1 Analytical Methods and General Chemistry

The first of two books with monoterpenoid sections is of the ‘dictionary’ type. It would be useful were it not for the incredible number of errors. Space will not permit a full criticism, but they include incorrect formulae (carquejyl acetate, artemisia and isoartemisia ketones, linalool, linalool oxide, lippione), double bonds of incorrect geometry (yomogi alcohol, cosmene), the inclusion of many discredited or doubtful compounds (santolinenones, osmane, hymentherene, etc.), and a very unusual biogenetic scheme. The other book purports to give a brief introduction to the chemistry, but terpenoids related to chrysanthemic acid, iridoids, ortho-menthanes, and heterocyclic terpenoids are omitted, and there are only 236 references, eight of which are post-1969 and twenty post-1968. Omission of recent literature also spoils a review of photochemistry in the field of monoterpenes : although this has a large literature collection, it is mostly only up to 1969.

A method for purifying sat urated monoterpenoid hydrocarbons by multistage ex tractive crystallization with thiourea has been used for menthane, pinane, carane. and 1,1,4-trimethylcycloheptane purification. The results are analogous to distillation or liq uid-liq uid extraction with greatly increased volatility between components in the two phases in the adduct-formation process. A more specific crystallization process concerns the isolation of 98% pure (-)-menthol by crystallizing the mixture with wintergreen oil or limonene at 5 °C. Monoterpenes are also used in a discussion about physical (especially crystallographic) properties of racemates susceptible to spontaneous or ind uced resolution by crystallization, and a later paper from the same laboratory gives details of the carvoximes and camphoroximes. Gas chromatography of monoterpenoids is included in a paper concerned with an improved calculation of Kovats indices in gas chromatography and the use of various columns is discussed. Retention index data of various substituted cyclohexanes have been used to establish the stereochemistry of various p-menthanediols.

A microtechniq ue for the analysis of monoterpenoids consists of hydrogenolysis in the inlet port of a gas chromatograph and analysis of the saturated hydrocarbons. Certain ring cleavages occur, and p-alcohols lose their CH2OH group. The products obtained are identified by mass and i.r. spectrometry. The mass spectrometry of some monoterpenoid semicar bazones is reported; many mechanisms are descri bed, but without labelling evidence.

Terpenoids are frequently used to introduce asymmetry into molecules (a classic example is isopinocamphenylborane), and the use of camphor to introduce chirality into lanthanide shift reagents is now established 12 (see also the section on bicyclo[22,1]heptanes below). The difference in geminal non-equivalence of methylene hydrogens of diastereomeric (-)-menthoxyacetamides has been used as a monitor for the optical resolution of amines, 1 3 this being a development of earlier work using menthoxyacetates for diastereomeric alcohols. The optical purity of chiral amines can also be checked from the n.m.r. spectrum of the amides obtained with (+)-(1R,4R)-camphor-10-sulphonic acid. Use of a menthol ester to separate pseudoasymmetric ferrocenes has been described.

(-)-Menthyl glyoxylate has been used in an attempt to induce asymmetry during a Diels-Alder reaction between the aldehyde group of the glyoxylate and a 1-alkoxybutadiene. In the simple case the optical yield was very low, 16 but it rose to 25% when the reaction was effected in the presence of Lewis acids at low temperatures. Another attempt at inducing asymmetry in a Diels-Alder reaction used (-)-dimenthyl fumarate and isoprene. The optical yield rose from 0% at atmospheric pressure to 4.7% at 5000 atmospheres.

The preferred rotational conformations of acetyl and formyl groups can be predicted by temperature-dependent c.d. measurements, and the technique has been applied to some monoterpene aldehydes. The sign of the Cotton effect has been related to the chirality of a series of rr-molecular complexes of monoterpene (and other) hydrocarbons with tetracyanoethylene. Inconclusive results found with (+)-sabinene were ascribed to complexation with the cyclopropane ring.

2 Biogenesis, Occurrence, and Biological Activity

An excellent review, particularly where it concerns his own work, has been published by Banthorpe which covers the whole field of monoterpene biogenesis. The same author has examined the biosynthesis of (+)-pulegone in Menthapulegium, in which [2-14C]mevalonic acid gave unequal labelling, almost all the tracer being associated with the isopentenyl pyrophosphate part of the molecule, in agreement with earlier work (Vol. 2, p. 6). 3,3-Dimethyl[1-14C]acrylic acid, on the other hand, appeared to be incorporated after degradation to acetate units. The conversion of monoterpenes into carotenoids in Tanacetum vulgare and Artemisia annua has been found to occur in whole plants either as undegraded C10 units or as 3,3-dimethylallyl pyrophosphate equivalents. Some studies on in vitro tissue cultures of T. vulgare were also made.

In this plant the petals contain β-D-glucosides of isothujol, neoisothujol, and other compounds, and it is observed that [2-14C]mevalonate incorporation into the glucose portion is ten times more than into the terpenoid portion. Results not in agreement with Banthorpe’s unequal labelling have been obtained by Suga et al., who fed [2-14C]mevalonic acid to twigs of Cinnamomum camphora Sieb. var. linalooliferum and found the linalool to be equally labelled. When [2-14C]mevalonate is fed through cut stems of Mentha piperita in the presence of sucrose, the incorporation into the monoterpenes is markedly increased. This was interpreted as support for the compartmentation of sites of monoterpene biosynthesis, these sites being deficient in energy, which can be supplied by sucrose. The same group has suggested that since labelled mevalonate is readily incorporated into sesquiterpenoids but poorly into monoterpenoids in this plant, the two types of terpenoids are produced at different sites. They concur with Banthorpe’s unsymmetrical labelling results, finding that 14CO2 is incorporated into pulegone to at least 90% in the seven-carbon-ring part, with no label in the isopropyl group, which suggests that endogenous dimethylallyl pyrophosphate participates. The stereochemistry of protonation of isopentenyl pyrophosphate in its conversion into dimethylallyl pyrophosphate by isopentenyl pyrophosphate isomerase has been elucidated by Cornforth et al. Acetate is found to be a poor precursor of alkaloids in Rauwolfia serpentina and Cephaelis acuminata, and since it is a specific precursor of sitosterol in these plants it is suggested that monoterpene units in the alkaloids and the steroids must be formed by different pathways. 31 Geraniol is suspected as a natural isoprenoid inhibitor in apples; this and other known inhibitors increase the breakdown of the tissue below 5 °C. Aspects of chrysanthemate-related and iridoid biogenesis are discussed in the appropriate sections (below).

Analytical work on the natural occurrence of monoterpenoids takes three forms. Chemotaxonomy requires a study of proportions of compounds occurring in similar species in different geographical locations. Thus Zavarin’s work on Abies balsamea and A. fraseri shows that A. fraseri evolved from eastern A. balsamea by gene-loss during the xerothermic period, by following the content of the pinenes, carene, limonene, and phellandrene. This continues from earlier work on the statistical relationships of monoterpenoids (see Vol. 1, p. 7, and ref. 34). In this context the monoterpenoid composition of the cortical oleoresin of red spruce (Picea rubens) in different populations has been examined.

A second type of analysis is undertaken to ascertain the effect of some extraneous factor on a plant. Examples are the studies made on the effect of various metabolites or inhibitors that might change the monoterpenoid production of a commercial crop such as roses. Effect of seasonal change on the composition of monoterpenoids from Rosmarinus officinalis, particularly in the spring, has been examined. The fact that the bark beetles Dendroctonus brevicomis and D. ponderosae preferentially attack Pinus ponderosa trees that have been injured by photochemical air pollution suggested study of the monoterpenoid composition of the two trees (in this case there was no difference). A possible connection with the pheromones of the male boll weevil, Anthonomus grandis, led to an examination of the volatile alcohols of cotton oil (Gossypium hirsutum). Plant breeding experiments may also lead to improved commercial crops; one hybrid from M entha sachalinensia, a valuable source of (-)-menthol, inherited chemical characteristics of only the female plant, and in Mentha aquatica change in one gene altered the whole monoterpenoid composition. Analysis of the monoterpenoids in some Canadian Mentha hybrids has shown some interesting variations.

The third and most common type of chemical plant analysis sets out to find what is present. Much of this work is of poor quality, sometimes because insufficient care was given to extraction conditions but mostly because results are too meagre to warrant publication (description of only four or five compounds of the many hundreds in the essential oil of a plant is only interesting if a new substance is included). In this Report, such trivial analyses will not be included. The following analyses of monoterpenoids in plants are somewhat more useful: Amomum cardamomum and A. globosum (containing respectively 1,8-cineol and camphor as the main components among a large number listed), various analyses of plants producing non-head-to-tail linked monoterpenoids like Artemisia, Chrysanthemum, and Tagetes species, and many commercially interesting plants and oils, such as Geranium bourbon, tangerine essence, lavender and lavandin, and majoram Majorana hortensis and Origanum vulgare, where the thymol, carvacrol, and eucalyptol contents were used to distinguish between similar plants. A good analysis of parsley aroma also includes some cogent remarks on the presence of “suspect’ constituents.

The enzymic reduction of geraniol and nerol to citronellol was mentioned in Vol. 1, p. 8; Dunphy and Allcock have now isolated a solubilized enzyme reductase from rose petals that is specific for the reduction of primary terpene alcohols with either a cis- or a trans-allylic double bond. A pseudomonade has been found that converts linalool into camphor and 2,6-dimethyl-6-hydroxyocta-2,7-dienoic acid.

More epoxides (1) with juvenile hormone activity (Vol. 2, p. 7) have been made by epoxidizing the Wittig products of citronella! (2), and some of these substances also increase silk production. 54 Reduction of the double bond sometimes increases the activity against Oncopeltus fasciatus. Insecticidal activity is also reported for certain terpenoid cyclopropanes [e.g. (3), made from limonene and ethyl diazoacetate] and for isobornyl thiocyanoethyl ether (made from camphene and ethylene chlorohydrin followed by treatment with potassium thiocyanate). The insect-repelling activity shown by thujic acid amides (4) is interesting in view of the relationship with thujic acid, a component of the bark of Thuja plicata (Western red cedar), well-known to be resistant to insect attack.

Homopinane ethanolamines are said to be anticholinergic and spasmolytic.

More work on terpenoid quaternary salts as growth-retarding substances (Vol. 2, p. 7) has appeared. Reports concerning the metabolism and analysis (in the blood) of the hypoglycaemic agent ‘Glibornuride’ (5) are appearing. Bactericidal activity is claimed for another bornylamine derivative (6), and the ethylenethiol derivatives [7; X = SO3H, H, PO3H2, or C(NH2)=NH] offer protection against irradiation. Other biologically active compounds are mentioned in the appropriate sections.

(Continues…)Excerpted from Terpenoids and Steroids Volume 3 by K. H. Overton. Copyright © 1973 The Chemical Society. Excerpted by permission of The Royal Society of Chemistry.
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