Terpenoids and Steroids Volume 5

A Review of the Literature Published between September 1973 and August 1974

By K. H. Overton

The Royal Society of Chemistry

Copyright © 1975 The Chemical Society
All rights reserved.
ISBN: 978-0-85186-296-5

Contents

Part I Terpenoids,
Chapter 1 Monoterpenoids By A. F. Thomas, 3,
Chapter 2 Sesquiterpenoids By T. Money, 46,
Chapter 3 Diterpenoids By J. R. Hanson, 93,
Chapter 4 Triterpenoids By J. O. Connolly, 122,
Chapter 5 Carotenoids and Polyterpenoids By G. Britton, 146,
Chapter 6 Biosynthesis of Terpenoids and Steroids By D. V. Banthorpe and B. V. Charlwood, 170,
Part II Steroids,
Chapter 1 Steroid Properties and Reactions By O. N. Kirk, 223,
Chapter 2 Steroid Synthesis By P. J. Sykes and S. J. Whitehurst, 285,
Reviews on Steroid Chemistry, 361,
Errata, 367,
Author Index, 369,

CHAPTER 1

Part I

TERPENOIDS

1

Monoterpenoids

BY A. F. THOMAS

There has been little increase in the volume of work published this year, but the space available for this Report is slightly reduced, so economy has been achieved in two ways. Papers not requiring any discussion, either because they are repetitive or because the minor point they make is evident from little more than the title, are placed at the end of each section. The number of formulae has been reduced, and more extensive use is made of names in the text. With these limitations, every effort has been made to quote all papers relevant to monoterpenoids.

1 Physical Measurements: Spectra etc.; Chirality

Titanium tetrachloride is recommended as a useful shift reagent in assigning 13C n.m.r. frequencies, particularly in αβ-unsaturated ketones such as carvone (1). which has a shift of -5.83 Hz for the β-carbon frequency, compared with -1.51 Hz using [Eu(fod)3].The C signals of the bridge methyl groups of camphor (2) (C-9 and C-10) have been assigned using another new shift reagent, tris-[4,4,4-trifluoro-1-(2-thienyl) -1,3-butadi-ene]europium(III), and [sup.13]C chemical shifts of substituted tricyclenes are discussed. The importance of non-axial symmetry in interpreting lanthanide-induced shifts in ketones has special relevance for monoterpenoids, and Newman discusses the case of camphor (2). Shifts induced by [Eu(dpm)3] in saturated o- and p-menthones, and its effect on the rotation of the isopropyl group in menthone and menthol have been measured.

Some well known mass spectra of monoterpenoid alcohols have been published again.

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The adsorption on a mercury electrode of borneol and adamantan-1-01 has been compared with that of camphor because of similar polarographic behaviour.’

The chirality of alcohols, notably (-)-linalool, (-)-menthol, and cis-menth-2-enol (3) (the name in the text is different), is rapidly established by measuring the c.d. of the complex with copper hexafluoroacetylacetonate. Photodecomposition of racemic camphor with circularly polarized light occurs enantiomerically, the optical purity of recovered camphor theoretically rising to 100 % at the end of the reaction. After 99% destruction of the ([+ or -])-camphor, the remainder has 20% optical activity.

Notable examples of the induction of asymmetry by complexing with monoterpenoids are the resolutions of the iron complex (4) and a titanium complex. The menthyl-(5;R = PPh,) and neomenthyl-(6; R = PPh2)diphenylphosphinesare epimeric, chiral ligands, suitable for asymmetric syntheses.’ Another account has appeared of an attempt to induce asymmetry by cyclization of homogeranic (-)-menthyl ester.

Various micro-organisms (Tridioderrnu, Absidia, etc.) hydrolyse some racemic acetates chirally; thus a mixture of ([+ or -])-isopulegyl acetate [([+ or -])-(7; R = COMe)] and ([+ or -])-neoisopulegyl acetate [([+ or -])-(8; R = COMe)] is converted into a separable mixture of (-)-isopulegol [(-)-[7; R = H)], (+)-isopulegyl acetate [(+)-(7; R = COMe)], and ([+ or -])-neoisopulegyl acetate. Since interconversion with citronella1 (9) is easy, this represents a practical resolution of ([+ or -])-citronellal. The acetates of menthol and carvo-menthol undergo this reaction, but not those of the stable axial alcohols, neomenthyl acetate (5; R = OCOMe) and neocarvomenthyl acetate (10). The further the acetate group is from the asymmetric centre, the lower is the optical yield.

New separation techniques for monoterpenoids are liquid chromatography on porous polymer (Hitachi gel 3010) and gas chromatography on graphitized carbon black for the notoriously delicate separation of the menthol isomers (although neo-menthol and menthol are not cleanly separated).

2 General Chemistry

Acid-catalysed isomerization of terpenoid hydrocarbons occupies much space in the literature, usually without the emergence of great novelty (see, however, pinenes). The use of mentha-2,8-diene as substrate and other hydrocarbons on TiO2–H2SO4 catalysts is described. Liquid-phase rearrangements of pinene and limonene give results varying with acid strength, and similar variations occur with basic strength in the base-catalysed rearrangements. By judicious choice of base, it is possible to prepare a particular menthene from one more accessible. Rearrangement of limonene (11) in phosphoric acid was known to yield a bicyclic hydrocarbon; the latter is shown to be a mixture of three isomers (Scheme 1). Isomerization of α-pinene over ferric phosphate at 180 — 560 °C leads to rearrangements and ring-opening to menthanes, and heating terpenes with diethyl hydrogen phosphite yields phosphonates, also with rearranged skeletons; pinenes give menthenes, camphene gives isocamphenyl ethylphosphonate, and limonene (11) gives a mixture containing a small amount of a bornyl phosphonate.

Another paper on the hydration of monoterpenoids in the presence of an ion-exchange resin has appeared (cf. Vol. 4, p. 13). Treatment of linalool (12) with chloranil results a series of dehydrations and hydrations; myrcene (13), ocimene (14), and their hydra-tion products are formed, but cyclization to menthadienes and subsequent hydration also occur. Geraniol (15), nerol (16), and linalool (12) are interconverted, and give similar products, nerol favouring the cyclized alcohol (17). The claim that β-pinene is among the dehydration products of linalool (l2) could not be confirmed using boron trifluoride or iodine as catalyst.

Of particular relevance to monoterpenoids is the comparison of reaction parameters for triphenyl phospite ozonide (TPPO) formation and those of photosensitized oxy-genation, where it has been shown that singlet oxygen cannot be a common active species for both types; limonene (11), for example, shows a very different product distribution in the two cases. TPPO oxidation occurs at lower temperatures than ozonide decomposition, and is in some cases, e.g. α-terpinene (18), more selective. A general study of epoxidation of methylenecyclohexanes, closely related to monoterpenoids, includes a discussion of the epoxide conformations. Epoxidation of ally1 alcohols with t-nutyl hydroperoxide catalysed by vanadium or molybdenum complexes has enabled the new epoxides of geraniol (19) and linalool (20) to be prepared. Oxidation of alcohols to ketones (menthol to menthone, borneol to camphor, etc.) generally occurs with N-chlorosaccharin, but limonene (11) gives a 4-chloro insertion product.

Details of the highly stereoselective reductions of ketones, (mostly bicyclic monoterpenoids) with alkylboranes are published.

A new method for alkylating methyl groups via π-allyl complexes uses geranylace-tone as a typical example; this method tackles the general difficulty of making valuable higher terpenoids from cheap monoterpenoids.

3 Occurrence, Biogenesis, and Biological Activity

A review has appeared on the distribution of terpenoids among different plant species, with sections on biosynthesis and metabolism.

Some traditional monoterpenoid plant sources are becoming rarer, adding interest to the flourishing analytical work; examples are the following species: Artemisia(several of which contain isothujone), Majurana and Origanum (containing sabinene h~drate), Citrus iyo peel oil (containing several rare oxygenated menthanes) and saffron. The C10 substance (21) from Greek tobacco is possibly not monoterpenoid but derived from a diterpene. The monoterpenoid hydrocarbon content of Cymbopogen oils varies widely with geographical source (large amounts from Ceylon, small from Java). A similar study has been made on the monoterpenoids of balsam fir.

A structure-activity correlation study of the substituted monoterpenoid type (22) of juvenile hormone attempts to show certain structural similarities with ecdysone. A juvenile hormone antibody has been developed which binds specifically with the naturally occurring hormone, thereby distinguishing it from mimics such as the monoterpenoids. A large number of variants of the geranyl part of the monoterpenoid ether juvenoids, including cyclogeranyl, linalool oxide (tetrahydrofuryl), and reduced and oxidized types, have been tested for insecticidal activity.

Pharmacological activities are reported for but-2-ynamine derivatives of borneol and menthol, and of pinol and camphene. The full paper on the repellant action of diethylthujamide against the yellow fever mosquito (Aedes aegypti) and other insects has appeared (Vol. 3, p. 10).

4 Acyclic Monoterpenoids

Terpenoid Synthesis from Isoprene. — Isoprene could be one substance affected by current raw material shortages, and its synthesis is vital for entry into the terpenoid field. Reaction of isobutylene with formaldehyde yields isoprene and 20% of a dioxan (23) which can be converted into a mixture of alcohols (Scheme 2) with oxalic acid, one of which (24) is produced industrially.

The thermodynamics of the Diels-Alder dimerization of isoprene are consistent with a one-step concerted mechanism. Dimerization of isoprene over certain palladium complexes yields only tail-to-tail-linked hydrocarbons (cf. Vol. 4, p. 11), and more has been published on the stannic chloride telomerization, giving a 61 % mixture of E- and Z-geranyl chlorides (25; R = H,) (besides tail-to-tail isomers), the 2-isomer cyclizing to 8-chloromenthene under the telomerizing conditions. Further work has appeared on the alkali-metal-catalysed dimerizations of isoprene using sodium naphthalene or lithium and t-butylamine, the latter yielding head-to-tail and tail-to-tail products in equal amounts. The dimer obtained in low yield using sodium in benzene is 92% myrcene (13).

The chloride (25; R = O) is available from the reaction between isoprene and senecioyl chloride (26) in the presence of stannic chloride. It has been converted into the ocimen-ones (27) and filifolone (28), and a similar route using isovaleroyl chloride instead of (26) leads to the tagetones (29).

Further syntheses with isoprene units are discussed in the next section.

2,6-Dimethyloctanes — Dehydroneryl isovalerate (30) [the formula (41) in Volume 4, p. 12, has wrong stereochemistry] has been synthesized from nerol (16). One of the two coumarin monoterpenoids (31) in Capnophyllum peregrinum has been synthesized directly (Scheme 3) from the tetrahydropyranyl ether of linalool (12); the other is described in the furanoid section.

The novel structure (32) reported from Psiada salvifolia is insufficiently supported (only mass and i.r. spectra).

The two allo-ocimene isomers (33) from α-pinene can be separated by allowing the E-isomer (more reactive) to form an adduct with methyl acrylate, leaving the pure Z-isomer. The reduced ocimene (34), formed by pyrolysis of pinane, can be converted into optically active citronellol (35) on hydroboration and oxidation [(+)-(35) from (-)-pinane]. Various cyclizations of the hydrocarbon (34) have been described (Scheme 4), formation of the palladium complex apparently occurring by sequential isomerization of the initially co-ordinated vinyl group, giving the strongly co-ordinated diene (36), which is reduced by available palladium hydride.

Reduction by diborane of the tricarbonyliron complexes of myrcene (13) and 2-oci-mene (37) adds hydrogen across the isopropylidene double bond; the α-phellandrene complex (see menthanes) was also examined. Multistage syntheses of α-myrcene (38), myrcene (13), and a related alcohol have been published.

Metal-catalysed addition of acetic acid to myrcene (13) yields mainly addition products to the conjugated diene system (cf. Vol. 4, p. 14). Sensitized photo-oxygenation of the diene (34) or linalool (l2) results in the introduction of oxygen on the more substituted double bond, but autoxidation of myrcene is less specific. Upwards of 42 substances are formed by oxygegation, cyclization, disproportionation, and polymerization, including pinenes, linalool oxides, camphor, and carvone, besides expected compounds. The pyrolysis of allo-ocimene peroxide (Vol. 1, p. 12) has been reinvestigated. Direct introduction of an amino-group into myrcene (13) occurs with diethyl-amine and sodium naphthalene, sodium acetate in acetic anhydride converting the products into geranyl acetate.

Access to oxygenated 2,6-dimethyloctanes can also be achieved by ring-opening of oxygenated menthanes; for example, Bayer-Villiger oxidation of (-)-menthone (39), followed by metal hydride reduction to the glycol (40) and pyrolysis over potassium bisulphite, yields 60% of (+)- citronello1 [(+)-(35)], (+)-menthone similarly giving (-)-citronellol of high optical purity. The total synthesis of tagetonol (41) in five stages from isobutyl methyl ketone has been reported, and 2-methyl-6-methyleneocta-2,7-dien-4-01 (42) was prepared following Scheme 5. Allylic rearrangement of (42) to the alcohol (43), together with polymerization, ooccurs above 100 °C. These total syntheses yield racemates, but Lefebvre et al. have made (+)-dihydrotagetone (44) by photolysis of (+)-3-methylcyclopentanone (49, followed by Grignard addition and oxidation. Natural tagetone was thus shown to be highly racemized [although some racemization occurred during irradiation of (45)].

Treatment of the dilithium salt (46) with an alkyl halide is equivalent to adding isoprene. The double-bond isomer (47) of geraniol was thus made, converted into the corresponding aldehyde and acid, and isomerized to the geraniol series. The dianion (48) of methyl acetoacetate can replace (46), the additional methyl group being added to the en01 acetate (49) to obtain a 1 :10 mixture of Z : E methyl geranates (50). Use of the enol benzoate, however, results (100%) in a Z : E ratio of 5.8 : 1. The principle of activating a methylene group with a sulphone unit (Vol. 4, pp. 15,16) has been applied to couple a second geranyl group to geranyl sulphone.

Conversion of linalool (12) into geranyl, neryl, and α-terpinyl acetates with toluene-p-sulphonic acid in acetic anhydride is less interesting than the reverse rearrangement, which occurs on heating geranyldimethylamine oxide (51). Very pure linalool (12) is obtained from the substance (52) thus obtained after reduction with zinc in acetic acid, while heating (52) results in isomerization to the corresponding nerol and geraniol isomers.

Base treatment of the sea hare monoterpenoid (Vol. 4, p. 12), a bromohydrin, yields the epoxide (53) The fact that selenium dioxide introduces oxygen on the isopropylidene terminal carbon atom of geranyl compounds in exclusively the E geometry has been used to prepare E-1-chloro-2,6-dimethyloctanes for further specific reactions.

Cyclizations of carbonium ions derived from geranyl compounds are used as ‘bio-genetic’ type models for polycyclic terpenoids. Using acetyl, crotonyl, and 2,6-dimethyl-3-methoxybenzoyl chlorides and Lewis acids (Scheme 6), geranyl acetate (54) cyclizes to (55) or (56), but methyl geranate (50) does not cyclize. Citronellol, lacking the extra double bond, gives the dimeric ether (57) with boron trifluoride etherate. A novel cyclization is discussed in the section on iridoids.

Further relevant papers in this section (besides Cookson’s syntheses noted in the previous section) concern measurement of the triplet lifetime of allo-ocimene, various Diels Alder reactions of allo-ocimene and homologues, the formation of hydro-oxycitronellal and its ethers by hydration of citronella1 imines, specific reduction of certain positions in geraniol and citral with different catalysts, epoxidation of geranyl chloride (25; R = H), and the preparation of (R)-4-methylhexane from (-)-citro-nellol[(-)-(35)].

Artemisyl, Santolinyl, Lavandulyl, and Chrysanthemyl Derivatives. — A review of rearrangements in this series has appeared.

Julia et al. have made artemisia ketone (58) from the sulphide (59) and lithium 3-methylbut-1-yn-3-yl chloride [Li-(60)], the allene (61) resulting from the sigmatropic rearrangement being readily converted into the ketone (58). Alternatively, reaction of the sulphide (59) with (60) in aqueous sodium hydroxide gives the acetylene (62; R = C [equivalent to] CH) — not, apparently, by simple alkylation of the sulphide (59), which does not react with alkyl halides under these conditions. Sigmatropic rearrangement of the ylide anion (63) is proposed. The maximum enantiomeric purity of the artemisyl product (62; R = CH=CH2) from the sigmatropic rearrangement of the salt (64) using chiral bases was only 12%.

Lavandulol (65; R = CH2OH) is produced (6 % yield) from the isoprene-magnesium complex (Vol. 2, p. 8) and prenyl chloride with air ~xidation. The nitrile (65; R = CN) smells of anise!

Details have appeared of the preparation of chrysanthemic acids from carene ozonolysis (Vol. 3, p. 23) and of the pyrethrin crystal structure. Photolysis of pyrethrin affects only the non-terpenoid portion.

Thermal or photochemical decomposition of lithium salts of the tosylates (66) gives hydrocarbons of the artemisia and

santolina series [690/, of santolinatriene (67) thermally], together with ring-expanded substances (cyclobutenes), the reaction proceeding via chrysanthemyl carbenes. Homologues of methyl chrysanthemate have been made by ozonolysis of chrysanthemate and Wittig reaction, and other related materials, some of which are both more persistent and more photostable than the natural substances, have been described.

(Continues…)Excerpted from Terpenoids and Steroids Volume 5 by K. H. Overton. Copyright © 1975 The Chemical Society. Excerpted by permission of The Royal Society of Chemistry.
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