Terpenoids and Steroids Volume 4

A Review of the Literature Published between September 1972 and August 1973

By K. H. Overton

The Royal Society of Chemistry

Copyright © 1974 The Chemical Society
All rights reserved.
ISBN: 978-0-85186-286-6

Contents

Part I Terpenoids,
Chapter 1 Monoterpenoids By A. F. Thomas, 3,
Chapter 2 Sesquiterpenoids By R. W. Mills and T. Money, 77,
Chapter 3 Diterpenoids By J. R. Hanson, 145,
Chapter 4 Sesterterpenoids By J. R. Hanson, 171,
Chapter 5 Triterpenoids By J. D. Connolly, 183,
Chapter 6 Carotenoids and Polyterpenoids By G. Britton, 221,
Chapter 7 Biosynthesis of Terpenoids and Steroids By D. V. Banthorpe and B. V. Charlwood, 250,
Part II Steroids,
Chapter 1 Steroid Properties and Reactions By D. N. Kirk, 311,
Chapter 2 Microbiological Reactions with Steroids By L. L. Smith, 394,
Chapter 3 Steroid Conformations from X-Ray Analysis Data By C. Romers, C. Altona, H. J. C. Jacobs, and R. A. G. de Graaff, 531,
Reviews on Terpenoid Chemistry, 301,
Errata, 584,
Author Index, 585,

CHAPTER 1

Part I

TARPENOIDS

1

Monoterpenoids

BY A. F. THOMAS

This year, the section on general chemistry has been enlarged, and some reactions that are not specific to monoterpenoids have been included. Physical methods are given a separate section. Unfortunately it must be noted that Chemical Abstracts contains an increasing number of errors, as well as frequently citing insufficient information for the abstract to be useful. So far as possible, attention has been drawn to these points in each individual case.

The abstracts of the Proceedings of the 4th Congress on Essential Oils (Tbilisi, 1968) have appeared, but much of this work is now out of date.

1 Physical Measurements: Spectra etc., Chirality

The 13C n.m.r. spectra of citronellol, citronellal, and related substances have been discussed, and a study of the shifts of the alkene signals induced by AgI in the 13C n.m.r. spectra of a number of substances including the pinenes has been made. A very full discussion of the effect of shift reagents on the 1H and 13C n.m.r. spectra of borneol and isoborneol has shown that the complexes formed with the reagents are effectively axially symmetric, the magnetic axis being practically collinear with the oxygen–metal bond; an estimate of the contact contribution has been made. Coupling constants in 7,7-dimethylnorborneols have been examined using the [Eu(dpmh)3] shift agent.

In a study of the u.v. spectra of the complexes between boron trifluoride and unsaturated ketones, monoterpenoids are particularly unlucky : piperitone (1) does not fit the attempted correlation, and carvone (2) polymerizes under the conditions of measurement!

The mass spectra of monoterpenoids have been discussed, and the loss of EtCONH2 in the mass spectrum of (3) (a retro-Ritter reaction) has given rise to speculations, without the support of labelling studies. The Raman ‘circular dichroism’ of a number of optically active monoterpenoids has been examined. Circular intensity differentials (CID) Δα, = IRα – ILα/ (IRα + ILα), where (IRα, ILα) are the scattering intensities with α -polarization in right and left circularly polarized incident light, have been measured in the low-frequency Raman spectra of (+)- and (-)- α-pinene, (-)-β -pinene, (-)-borneol, and carvone. The circular differential Raman spectrum of carvone has been reported elsewhere.

Monoterpenoids are the most common of the chiral agents used for inducing asymmetry. Measurement of the n.m.r. spectra of esters of camphanic acid, such as (4), has been used to find the enantiomeric purity and absolute configuration of α-deuteriated primary alcohols, and separations of various alcohols and amines using esters of chrysanthemic acid are reported. An interesting mutual resolution can be effected with ([+ or -])-camphorsulphonic acid and α-( [+ or -])-Me2NCH2CHMeCPh(OH)CH2Ph. (+)-Carvomenthol and chloroacetic acid give carvomethylacetic acid (5), which is useful for resolving alanine. Mislow et al. have used menthyl methylphenylthioarsenite (6) in an extension to arsenic of their earlier method (see Vol. 2, p. 28) of making optically active phosphine oxides.

Probably the most interesting work taking advantage of the chirality of monoterpenoids has involved the attempts to induce asymmetry in organic synthesis. As a simple example, the rate of esterification of D-amino-acids with (-)-menthol is greater than that of L-acids, and this has led to a proposal for menthyl ester formation. The anion (8), obtained when menthyl acetate (7) is metallated, reacts with ethyl pyruvate to yield the menthyl ester of (S)-citramalic acid (9) in 26 % optical yield. Kergomard et al. found no asymmetric induction in the reaction between styrene, t-butyl hypobromite, and menthol [leading to (10)]. Oxidation of ([+ or -])-borneol with (R)-(+)-menthyl p-tolyl sulphoxide and dicyclohexylcarbodi-imide in the presence of phosphoric acid in benzene gave (-)-camphor in 7% optical yield, and the cyclization of homogeranic (-)- menthyl ester with stannic chloride to cis-tetrahydroactinidiolide (11) occurred with only ca. 12% optical yield, although this rose to 20.8% when the 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose ester was used. Asymmetric reductions of diphenylmethyl alkyl ketones by complexes of lithium aluminium hydride and cis-pinane-2,3-diol and benzyl alcohol gave up to 20% optical yields, 21 but far more successful was the reaction of ethylene and cyclo-octa-1,3-diene [to [12)], catalysed by certain π-allyl complexes of nickel where one ligand is a monoterpenoid phosphine, in which 70 % optical purity was achieved.

King and Sim have described a useful method for demonstrating the presence of a reactive intermediate in reactions involving chiral diastereomeric transition states; it provided a new piece of evidence for the intermediacy of a sulphene in the reaction between camphor-10-sulphonyl chloride and menthylamine.

The Reporter is ill-placed to criticize a chapter on the synthesis of monoterpenoids in a recently published book on the total synthesis ofnatural products.23a However, a delay of three years between the latest reference quoted and publication of a book is deplorable.

2 General Chemistry

Sukh Dev has reviewed alumina- and silica gel-induced rearrangements, many of which involve monoterpenoids. The Prins reaction of monoterpenoid hydrocarbons has also been reviewed.

Microwave discharge of carbon dioxide can function as a singlet oxygen source; photo-oxygenation by this means has been accomplished using limonene and γ-terpinene as substrates. A two-phase solvent system is useful for epoxidizing sensitive olefins (e.g. 6-methylhept-5-en-2-one) with m-chloroperbenzoic acid, but limonene gave the same epoxide in the same yield as with the single-phase system.

Several novel methods for the reduction and oxidation of oxygenated terpenoids have appeared. Potassium metal in graphite can be used to reduce camphor (a 60:40 exo : endo mixture is obtained), and oxidations of primary alcohols are effected by chromic oxide in graphite (citronellol yields 90% of the aldehyde in 24 h), but the preparation of the reagent can be dangerous. Potassium metal in hexamethylphosphoramide, with or without a co-solvent, has also been used to reduce terpenoid ketones ; with camphor, more endo- product is formed than in the potassium–graphite reduction. Hindered saturated secondary alcohols are oxidized by 2,3-dichloro-5,6-dicyano-1,4-benzo-quinone; thus borneol and isoborneol are 96% and 95 % oxidized in 8 h and neoisomenthol (i.e. the all-cis-isomer) and neoisocarvomenthol are 48% and 40% oxidized in the same time, whereas the all-equatorial alcohols menthol and carvomenthol are hardly affected in this time. Reduction of camphor with various silanes (Ph2SiH2, PhSiH3, PhMeSiH2, and Et2SiH2) in the presence of tris(triphenylphosphine)chlororhodium gives 73–90% of isoborneol (exo), but triethylsilane gives only 30% of isoborneol and phenyldimethylsilane does not reduce. Analogous results were obtained for menthone, but pulegone (13) presented some irregularities, mixtures of menthone (14) and pulegol (15) being produced in different amounts depending on the reagent. The rate of Meerwein–Ponndorf reduction (propan-2-ol–aluminium isopropoxide) for a variety of terpenoid ketones is unexpectedly high. The half-life of camphor, for example, (the slowest of those measured) was 145.8 min at 82°C. Triphenyltin hydride reduces the conjugated double bond of unsaturated aldehydes; thus citral gives citronellal, but in the case of β-cyclocitral (16), the reaction works less specifically, leading to a 1:1 mixture of the saturated aldehyde (17) and the unsaturated alcohol (18).

4-Dimethylaminopyridine is a useful catalyst in acylations; an 80% yield of linalyl acetate can be obtained (without rearrangement — see Vol. 3, p. 15) with its aid, using triethylamine as solvent and (presumably, for it is omitted from the experimental details!) acetic anhydride at room temperature for 14 h. Only catalytic amounts are needed, as was demonstrated by the preparation of menthyl monophthalate. Reaction of aminomethylene ketones with 4-aminouracil (19; X = O), the thio-analogue (20; X = S), or 2,4-diamino-6-hydroxypyrimidine (the enolized imino-analogue), yields ‘5-deazapteridines’; those corresponding to menthone (20) and camphor (21) have been reported 37 (see Vol. 3, p. 42).

The preparation of monoterpenoid aldehydes from ketones (R2CHCHO in place of R2C=O) using the Grignard reagent EtOCH2MgCl is discussed.

The Kondakov reaction is the reaction of crotonic anhydride with an olefin in the presence of zinc chloride. A number of monoterpenoid hydrocarbons react at their trisubstituted double bonds; thus 2,6-dimethylocta-2,7-diene gives the ketone (22), car-3-ene gives (23), and menth-1-ene gives both cis- and trans- isomers. Double bonds react with chlorosulphonyl isocyanate to give compounds containing a four-membered heterocyclic ring; camphene yields (24), and the products from α- and β-pinene and car-3-ene have also been described.

The reaction of vinylmagnesium bromide with unsaturated esters gives the corresponding divinylcarbinol; ethyl mentha-1,8-diene-7-carboxylate and ethyl pin-2-en-10-carboxylate have been treated in this way. A convenient method for the separation of terpenoid alcohols from mixtures via the carbamates is described.

3 Biogenesis, Occurrence, and Biological Activity

A brief section on monoterpenoids is included in a review of biogenetic-like syntheses of terpenoids. For the biosynthesis of monoterpenoids see Section 4 of Chapter 7, p. 260.

Granger and Passet have carried out a chemotaxonomic study on Thymus vulgaris, L. This plant gives very diverse essential oils, and analysis of the monoterpenoids permits the assignment of a plant to its chemotype. Somewhat similar is the approach of Banthorpe et al. in an examination of oils of Juniperus and Thuja species. The juniper leaf oils consist of two types characterized by the presence of either predominantly pinene derivatives or thujane derivatives. Blue spruce (Picea pungens) can be identified by analysis of the cortical oleoresin monoterpenoids. The genesis of monoterpenoids in the wood of common Russian conifers has been followed by direct analysis.

Attention is drawn to the remarks on straightforward chemical analysis of plant and animal material made in Volume 3 (p. 8). Among analyses that are of interest for the monoterpenoid chemist are the following : Carphephorus odoratissimus (‘deertongue’, a tobacco additive), Cinnamomum reticulatum from Taiwan [containing a remarkable 96.8% of (-)-linalool], Crocus sativus, Passiflora edulis f. flavicarpa (passion fruit), Pelargonium tomentosum [86.9% (-)-isomenthone, for which various possible stereochemical biogenetic routes are discussed], various Pinus spp. needle oils, and Pogostemon plectrantoides. A very complete analysis of certain fractions of burley tobacco has given a plethora of substances, including many 1,1,3-trimethyl- and 1,1,2,3-tetramethyl-hexane derivatives and the novel isoprenoid (25).

Secretions from the endocrine glands of staphylinid beetles, Bledius mandibularis and B. spectabilis, contain small amounts of citral and neral.

The full papers describing the preparation of the hypoglycaemically active arylsulphonylureido- and arylsulphonylamido-acyl derivatives of borneol and isoborneol (see Vol. 2, p. 7) have appeared. Details of the preparation of the juvenile hormone compounds mentioned in Vol. 3, p. 10 have been published, and some more geranylanilines (with heterocyclic substituents in the aromatic part of the molecule) having juvenile hormone activity have been made. The section on chrysanthemic acid includes other compounds having juvenile hormone activity.

Isobornyl chloroformate (26 ; R = COCl) is prepared from isoborneol and phosgene, and can be used as a protecting group for amino-acids which is removed by trift uoroacetic acid. Combined with propylenediamines, the amines (26; R = CONHCH2CH2CH2NR1R2) can be made which have local anaesthetic properties.

4 Acyclic Monoterpenoids

Terpene Synthesis from Isoprene. — The oligomerization of isoprene catalysed by nickel naphthenate and isoprenemagnesium in the presence of various phosphites as electron donors, known to give cyclic dimers (see Vol. 3, p. 12), has been re-examined. Oligomerization with cobalt chloride, sodium borohydride, and tripenylphosphine gives (27) as the main product when the ratio Ph3P: CoC12<1, but when this ratio is > 1 the tail-to-tail linked isoprenoid (28) and the 2,6-di-methyloctatriene (29) are the main products. Telomerization of isoprene by hydrogen chloride in the presence of stannic chloride is reported. Anionic telomerization with secondary amines in the presence of alkali-metal catalysts yields dimers having as their main components the ‘lavandulyl’ (30) and the ‘geranyl’ (31) structures. A similar report elsewhere contains what appears to be the incorrect structure for geranyldiethylamine. The isoprene hydrochloride dimer [(32) or (33)] can be reduced with magnesium in tetrahydrofuran containing ethyl bromide; treatment of the mixture with dry oxygen then yields lavandulol (34) and its isomers in > 40% yield. The ‘regular’ geranyl skeleton is produced when isoprene is allowed to react with alcohols over a PdC12–PhCN catalyst together with triphenylphosphine and sodium alkoxide. The main ethers thus formed have the skeleton (35). The geranyl triene (36) is also the main component of the complex mixture obtained by treating isoprene and phenol with a sodium phenate-[PdBr2L2] (L = Ph2PCH2CH2PPh2) catalyst, the amount of phenol determining the composition of the mixture of products. With sodium hydride at 40°C under pressure isoprene yields myrcene (37) and the trimer (38). Hydrative dimerization of isoprene using a cation-exchange resin catalyst is described, 71 and a review (in Japanese) on the oligomerization catalysed by lithium naphthalene has appeared.

Dienes react with β-keto-esters in the presence of P-phenyl-1-phospha-3-methylcyclopent-3-ene and palladium chloride, and the addition product (39) from isoprene and methyl acetoacetate can be readily converted into methyl-heptenone (40).

2,6-Dimethyloctanes. — The iovalerate of dehydronerol (41) has been isolated from the roots of Anthemis montana, L.; this is the first report of a dehydronerol derivative in nature. The digestive gland of the sea hare, Aplysia californica, contains brominated and chlorinated monoterpenoids characterized by the presence of a terminal vinyl bromide group, e.g. (42) and (43). These compounds and other halogenated monoterpenoids have been found in the red algae, Plocamium coccineum, on which the sea hare is known to graze. 5 The structure of one compound (44) has been fully established by X-ray diffraction. The three trienes (45), (46), and (47) have been isolated from Ledum pa lustre ; one of them (46) has been previously identified in Pinus ponderosa. A number of bifunctional carbonyl compounds (48)–(53) have been isolated from lavandin oil. They all [excepting the aldehyde acetate (48)] can be obtained by the photo-oxygenation of linalyl acetate, and, apart from (48), they may well be artefacts.

An attempt to prepare photochemically mixtures of allo-ocimenes (54) with exclusive Z-configuration about the central double bond [(54a), (54b)] failed with a variety of sensitizers, although some enrichment was noted. Vig et al. have synthesized myrcene (37) from the known ester (55; R = CO22 Et) via the corresponding aldehyde (55; R = CHO), by a vinyl Grignard reaction, oxidation, and Wittig reaction. The pyrolytic conversion of α-pinene into allo-ocimene (54) is well known ;in order to trap the intermediate ocimene, it is necessary to cool the pyrolysate very rapidly.

One method used to introduce oxygen into terpenoid hydrocarbons is by direct, acid-catalysed addition of water. With myrcene, water addition in the presence of Amberlite IR-120 gives a complex reaction mixture, consisting mostly of cyclized components; the hydrated products are mainly 1,8-cineol (56), mentha-1(7),2-dien-8-ol (57), and 2,6-dimethylocta-5,7-dien-2-ol (58). Acid-catalysed addition of acetic acid to (+)-2,6-dimethylocta-2,7-diene [(+)-(59)] gives the tertiary acetate (60) initially, but refluxing for 6–8 h causes stereo-specific cyclization to (61), together with formation of the two tetrahydroeucarvols (62). The rhodium(m) chloride-catalysed addition of ethanol to myrcene (37) leads to oligomerization and isomerization, together with a mixture of the ethyl ethers [(63), (64), (65), and (66)] but none of the derivatives corresponding to those from the palladium-catalysed addition of methanol (see Vol. 2, p. 10).

(Continues…)Excerpted from Terpenoids and Steroids Volume 4 by K. H. Overton. Copyright © 1974 The Chemical Society. Excerpted by permission of The Royal Society of Chemistry.
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