Terpenoids and Steroids Volume 2

A Review of the Literature Published Between September 1970 and August 1971

By K. H. Overton

The Royal Society of Chemistry

Copyright © 1972 The Chemical Society
All rights reserved.
ISBN: 978-0-85186-266-8

Contents

Part I Terpenoids,
Introduction, 3,
Chapter 1 Monoterpenoids By A. F. Thomas,
Chapter 2 Sesquiterpenoids By J. S. Roberts,
Chapter 3 Diterpenoids By J. R. Hanson,
Chapter 4 Triterpenoids By J. D. Connolly,
Chapter 5 Carotenoids and Polyterpenoids By G. P. Moss,
Chapter 6 Biosynthesis of Terpenoids and Steroids By G. P. Moss,
Part II Steroids,
Introduction, 227,
Chapter 1 Steroid Properties and Reactions By D. N. Kirk,
Chapter 2 Steroid Synthesis By P. Crabbé In collaboration with G. A. Garcia, J. Haro, L. A. Maldonado, C. Rius, and E. Santos,
Errata, 435,
Author Index, 436,

CHAPTER 1

Part I

TERPENOIDS

Introduction

Unexpected results have come to light bearing on monoterpenoid biosynthesis (Chapter 1). Banthorpe’s group have shown that in the formation of the thujane and camphor skeletons, activity from labelled mevalonic acid can appear predominantly in the C5 unit supposedly derived from isopentenyl pyrophosphate and only to a minor extent in the dimethylallyl pyrophosphate-derived portion. Banthorpe has also presented evidence for a chrysanthemyl intermediate, analogous to presqualene alcohol, in the biosynthesis of artemesia ketone.

Laboratory synthesis again dominates the year’s activity in the sesquiterpenoid field (Chapter 2) and continues to elicit much ingenuity. Notable are the routes developed by Corey’s group to the C17 and C18 Cecropia juvenile hormones, the synthesis of trichodermin, the first member of the trichothecane group to be synthesized, syntheses of copacamphor, copacamphene, and cyclocopacamphene, and extension of Money’s camphor synthesis to campherenone and campherenol with potential for further elaboration to e.g. longifoline and sativine. Routes to nootkatone and α-vetivone, zizanoic acid, and patchoulenone also merit mention among a long list of synthetic achievements. The structure of bilobalide, a highly oxygenated sesquiterpenoid containing the unusual t-butyl group, is of special interest. It could be derived from the structurally related C20 gingkolides, whose biosynthesis has been clarified.

X-Ray analysis, increasingly by the direct method, is coming into routine use for structure determination. A notable concentration of effort is evident in the phorbol, grayanotoxin and taxane series of diterpenoids (Chapter 3), where novel skeletons and complex functionality make pre-X-ray methods quite unsuitable. But the relatively ready access to X-ray facilities is underlined by analyses (e.g. grayanotoxin-1, and taxinine) undertaken to establish doubtful points of stereochemistry.

The structure of presqualene alcohol has been established beyond reasonable doubt by three independent rational syntheses (Chapter 4). As the last isolable intermediate between acetate and squalene to be formulated, its structure has been a subject of controversy since its isolation in 1966. Its formulation therefore represents a major advance which makes it possible to consider its mode of formation from farnesol and its transformation into squalene. Enzymic and non-enzymic cyclizations of oxidosqualene and related substances continue with vigour. ([+ or -])-Malabaricanediol is the first natural product to be formed in vitro by cyclization of a squalene derivative. On the basis of numerous in vivo and in vitro experiments, van Tamelen has delineated the minimum substrate requirements of the enzyme 2,3-oxidosqualene sterol cyclase. New skeletal types of triterpenoids now appear only rarely. Baccharis oxide is such a type, but its structure is readily derivable from an intermediate cation, the result of squalene cyclization, which is assumed to lead to the lupane, oleanane, and ursane families of triterpenoids. The total synthesis of unsymmetrical triterpenoids has represented a major challenge for many years ; this year has seen the completion of total syntheses of germanicol and alnusenone.

The unusual structure of the carotenoid pigment peridinin required for its solution the collaboration of four laboratories and a combination of all available physical techniques (Chapter 5).

The problem of whether cis– or trans-olefinic double bonds are involved in any particular polyisoprenoid biosynthesis has been brought into prominence this year (Chapter 6). Thus the sesquiterpenoid dimer gossypol is biosynthesized from cis, cis-farnesyl pyrophosphate. However, it is not clear whether the central cis-unit is incorporated as such (as in the case of rubber) or whether geranyl pyrophosphate is isomerized to neryl pyrophosphate before the third C5 unit is added. Nero I itself is formed, like geraniol, initially from all-trans units and must therefore include an isomerization step in its genesis. These results raise the interesting possibility that any of the appropriate geometrically isomeric open-chain polyenes may be involved in a particular polyisoprenoid biosynthesis. The long-postulated 1,2-hydrogen shift from C-13 to C-17 in the biosynthesis of lanosterol and β-amyrin has been demonstrated directly by incorporation of the appropriately tritiated oxidosqualene. Euphol is excluded as a biosynthetic precursor of the quassinoid bitter principle glaucaroubolone by incorporation experiments with the appropriately tritiated mevalonic acid, and lanosterol has been similarly excluded from curcurbitacin biosynthesis. An interesting result to emerge from biosynthetic studies with mycophenolic acid is that the side chain represents a degraded farnesyl rather than geranyl unit. Nakanishi and his colleagues have proposed a most ingenious biogenetic derivation for gingkolide B from a pimarane; the unusual t-butyl group is formed from an isopropylidine group (ex C-4) and methionine.

1

Monoterpenoids

BY A. F. THOMAS

Although this report covers the period from September 1970 to August 1971, certain earlier publications that came too late for inclusion in the previous Specialist Report in this series will be mentioned. It is depressing to find, among the papers reviewed, several reporting works that had been previously published.

1 Analytical Methods and General Chemistry

The problems associated with lability of double bonds during the mass spectro-metric examination of monoterpenes have been discussed. The mass spectra of ketones are not as easy to interpret as those of thioketones, the latter having a higher proportion of heteroatom-containing fragments. They are readily available by reaction of the ketones either with phosphorus pentasulphide, or with hydrogen sulphide and dry hydrogen chloride, and are recommended for the study of bicyclic ketones in the norbornane series.

The mass spectra of many monoterpenoids have been published. Analysis by gas chromatography of the mixture which constitutes the sex pheromone of the boll weevil (Anthonomus grandis Boheman) has been described. It consists of a cyclobutane monoterpenoid (Vol. 1, p. 18), and three 3,3-dimethyl-Δ1, α-cyclohexane-ethanols and -acetaldehydes.

Scott and Wrixon have developed a quadrant rule for the c.d. of platinum(II)–olefin complexes that depends on d–d orbital transitions. Application of the rule to monoterpenes was considered, and generally conformed to expectations based on known absolute configurations, but in some cases (notably β-pinene) the results were not satisfactory. The complex measured may be that of α-pinene, for which a Cotton curve of the opposite sign is predicted. Further work on the use of 19F n.m.r. spectra of terpene alcohol derivatives has appeared. The interaction of epoxide with the hydroxy-group in the epoxypulegols has been examined by following the i.r. frequency of the OH band.

In the course of an examination of the autoxidation of terpene hydrocarbons, Bardyshev and Shavyrin have found, predictably, that those containing conjugated double bonds (e.g. allo-ocimene, myrcene) are oxidized most rapidly, those with isolated double bonds or cyclopropane rings more slowly (e.g. limonene, carene), and those with a single double bond slowest (e.g. pinene). The effect of light, heat, and inhibitors was studied.

The rearrangement of monoterpenoid epoxides on alumina and silica gel surfaces has been studied. On the latter support, the rearrangements are typical of carbonium ions.

2 Biogenesis and Biological Activity

The main advances in monoterpenoid biogenesis have been achieved by Banthorpe’s group, who have extended their work (published earlier in note form) on the thujane derivatives obtained from Thuja, Tanacetum, and Juniperus species. More than 90% of the label from [2-14C]mevalonic acid is incorporated in that part of the skeleton derived from isopentenyl pyrophosphate, the part supposedly derived from 3,3-dimethylallyl pyrophosphate being essentially unlabelled. These results are not consistent with the accepted view that both isopentenyl and 3,3-dimethylallyl pyrophosphates are directly derived from mevalonic acid. However, in a second experiment concerned with the incorporation of [2-14C]-mevalonic acid into the petals of rose flower heads, the results accorded with the accepted pattern, geraniol being labelled as in (1), with a similar distribution being found in nerol. The anomaly in the thujane experiments could be explained by the existence of a metabolic pool of dimethylallyl pyrophosphate, by compartmentation effects, or by a non-mevaloid source for the compound. In this connection it is possibly significant that the leaf and stem tissues employed in the thujane work contain discrete oil glands not seen in petal tissue. In the biosynthesis of (+)- and (-)-camphor in Artemisia, Salvia, and Chrysanthemum species, 73—83% of the label is incorporated from [2-14C]mevalonic acid at C(6) as shown in (2) ; again, that part of the skeleton supposedly derived from 3,3-dimethylallyl pyrophosphate was not equivalently labelled. The biogenesis of the artemisia monoterpenoids is mentioned later.

Zavarin has continued his chemotaxonomic approach to biogenetic problems with a study of the leaf monoterpenes of some Cupressus species.

Tidd has clarified the role of pyrophosphates in terpene biogenesis by measuring the hydrolysis rate of isopentenyl pyroph0sphate and related pyrophosphates over the physiological pH range. Potty and Bruemmer, continuing their search for enzymes causing transformations of terpenes in citrus fruits, have discovered a system that reduces (+)-limonene [but not (-)-limonene] in the orange.

Because of their ready availability, there is a constant search for possible uses for the more common naturally occurring terpenes and their simple derivatives. This year has seen the claim of insecticidal and juvenile hormone activity for esters of geraniol and its epoxide (see below). Pharmacological (hypo -glycaemic) activity was found in the piperidinesulphonamide of D-camphor endo-3-carbonic acid, but less successful were the esters of guaiacol, thymol, and carvacrol, which were almost non-toxic. Some of the 1-(1′-hydroxyethyl)-2,2-dimethyl -3-(2′-dialkylaminoethyl)cyclobutanes (3), obtained from the reduction of pinonic acid amides, are reported to show antiparkinson activity. Quaternized 2-dimethylaminomenth-8-en-1-ols (4) are claimed to be growth regulants, nematicides, and fungicides, 22 and Β-pinene resins are said to potentiate a herbicide.

3 Acyclic Monoterpenoids

Telomerization of Isoprene. — Reviews have appeared on isoprene and chloroprene, and on the complex reactions of isoprene to form terpenoids (in Japanese). Isoprene reacts with magnesium, especially in the presence of Lewis acids, and the resulting complex gives adducts with aldehydes. As usual in this type of reaction, a very complex mixture is obtained. The palladium-chloride -catalysed reaction of isoprene with acetic acid gives different products in differentsolvents. Monomers predominate in benzene [2-methylbut-2-enyl acetate (5) and 3-methylbut-2-enyl acetate (6)] while dimers [(7), (8), neryl (9), and geranyl (10) acetates] tend to be formed in tetrahydrofuran. Further details of the synthesis of C10 alcohols from isoprene and naphthyl-lithium are available, as well as of the in situ oxidation, but there is little of novelty (see Vol. 1, p. 17).

2,6-Dimethyloctanes. — The full account of the synthetic work on achillene (see Vol. 1, p. 9) includes a technique for improvement of the yield of natural cis-achillene (12) by irradiation of the trans-compound (11), in the presence of benzophenone, the equilibrium mixture containing 45% cis-achillene. Thermal isomerization of cis-β-ocimene (13) [[equivalent to] (16)] yields 6-cis-allo-ocimene (14) without any trans-isomer (15); this is presumably because the preferred conformer (16) has the bulky isobutenyl group in a pseudo-equatorial position (the 6-trans-product would require the pseudo-axial position for this group). The 6-trans- isomer (15) can be made by treating cis-β-ocimene (13) with potassium t-butoxide, both isomers then being formed. Sasaki et al. have examined the 1,4-cyclo-additions of nitrosobenzene with isoprene, chloroprene, and myrcene (17). The proportions of the two products (18) and (19) from the latter compound vary with temperature. The same authors have found that the 1,4-cycloaddition reactions of allo-ocimene [a mixture of (14) and (15)] with a variety of dienophiles all appear to occur via the trans-compound (15). Cyclization of allo-ocimene in sodium and isopropylamine leads to a mixture of alkylated cycloheptadienes (20)—(23), only 5% possessing the eucarvone skeleton (23).

Further investigations with palladium-myrcene complexes show that, in acetic acid, a mixture of acetates [linalyl (24), neryl (9), geranyl (10), (25), and (26)] is formed, 36 while a cyclic complex (27) is formed in methanol. Analogous complexes of ocimene have been studied, and found to yield geranyl methyl ether with methanol, and a dimer of limonene with acetone. An interesting method proposed for the removal of myrcene from a terpene mixture is selective clathration with nickel tetra-(4-methylpyridine)dithiocyanate.

According to de Haan, confirmation of the stereochemistries of geraniol and nerol was obviously needed, and it is gratifying that his n.m.r. spectral measurements using tris(dipivalomethanato)europium(III) as a shift reagent support the commonly accepted assignments (nerol = cis, geraniol = trans).

When geraniol and phenol react together in the presence of 85 % phosphoric acid, there are formed, in addition to o– and p-geranylphenols, the singly cyclized chroman (28) and the doubly cyclized hexahydroxanthene (29).

Several simple p-alkylphenyl ethers of geraniol epoxide have been found to possess juvenile hormone activity. The p-ethylphenyl ether, tested on the yellow mealworm (Tenebrio molitor) was 1000 times more active than the Cecropia hormone, although it seems that it acts on many other insects too.

Epoxidation of the appropriate geranyl ether and acid hydrolysis to the corresponding glycol affords the natural products marmin (30) and severin (31); leading references to this type of substance are given by Dreyer. Citronellyl acetate glycol (32) reacts with toluene-p-sulphonic acid in benzene; the ketone (33) which is first produced, on further acid treatment, cyclizes to the cyclopentyl ketone (34). The reaction of geraniol with boron trifluoride etherate has been reported to give, after seven days, digeranyl ether, linalyl geranyl ether, various hydrocarbons, α-terpineol, and much unchanged geraniol. The complexing of linalyl acetate with Pd11 has been examined.

Yet another method for the preparation of hydroxycitronellal (35) has been developed; it depends on the fact that the immonium salt (36) is hydrated by aqueous sulphuric acid, hydrolysis of the imine group taking place with sodium hydroxide. The effect of catalysts supported on silica gel on the well-known thermal conversion of citronellal to isopulegol has been studied. The abstract of a Russian Patent for the preparation of citral (following a well-known route from isoprene) appears to be incorrect, so the novelty of the process cannot be assessed. In the presence of magnesium oxide, citral reacts with unsaturated ketones to give substituted acetophenones. The two geometric isomers of citral react differently, neral (cis-citral) giving mixtures of an acetophenone (37) and its dihydro-analogue (38), geranial (trans-citral) giving an isomeric acetophenone (39).

Solvolysis of (S)-2,6-dimethyloct-5-yl toluene-p-sulphonate gives a tetrahydro-linalool, (R)-2,6-dimethyloctan-6-ol, with about 60% retention of asymmetry. Kirmse and Arold have described several other similar reactions and suggest that a hydrophobic anchimeric interference of alkyl residues persists during the rearrangement, giving chirality to the carbonium ion.

Analysis of Tagetes minuta. L. (Compositae) revealed the presence of cis– (40a) and trans– (40b) -ocimenones (= tagetenones), in addition to the previously known tagetones and dihydrotagetones. The new compounds were synthesized by treatment of a mixture of 3-methylbut-2-enoyl chloride and isoprene with a Lewis acid, e.g. SbCl5.

(Continues…)Excerpted from Terpenoids and Steroids Volume 2 by K. H. Overton. Copyright © 1972 The Chemical Society. Excerpted by permission of The Royal Society of Chemistry.
All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
Excerpts are provided by Dial-A-Book Inc. solely for the personal use of visitors to this web site.