Professor Hanson is Emeritus Professor of Chemistry at the University of Sussex.

Terpenoids and Steroids Volume 12

A Review of the Literature Published between September 1980 and August 1981

By J. R. Hanson

The Royal Society of Chemistry

Copyright © 1983 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85186-356-6

Contents

Part I Terpenoids,
Chapter 1 Monoterpenoids By D. V. Banthorpe and S. A. Branch, 3,
Chapter 2 Sesquiterpenoids By J. S. Roberts, 75,
Chapter 3 Diterpenoids By J. R. Hanson, 186,
Chapter 4 Triterpenoids By R. B. Boar, 207,
Chapter 5 Carotenoids and Polyterpenoids By G. Britton, 235,
Part II Steroids,
Chapter 1 Physical Methods By D. N. Kirk, 269,
Chapter 2 Steroid Reactions and Partial Syntheses By B. A. Marples, 288,
Author Index, 330,

CHAPTER 1

Part I

TERPENOIDS

1

Monoterpenoids

BY D. V. BANTHORPE AND S. A. BRANCH

1 Introduction

Owing to a chain of misfortunes, this subject has not been reviewed since Volume 9. Consequently the present survey has to cover the literature from autumn 1978 to that dated 31.12.81 (as recorded in Chemical Abstracts and Current Contents up to 1.6.82). Dr A. F. Thomas of Firmenich SA, Geneva, kindly gave access to his card index covering the period and we are extremely grateful to him: we also thank the Royal Society of Chemistry for providing selected abstracts.

The present half-litre pot has to contain the distillate of some 6000 monoterpenoid-related papers: although most are trivial for the present, or indeed any, purpose, there has obviously had to be a change of presentation from that usual in these Reports. We have had to abandon all pretence of comprehensive coverage, and in particular have had to be highly selective in the following categories: (a) the vast patent literature which, although no doubt of industrial importance, often seems to cynical eyes to be vague, trivial, and repetitive; (b) the seemingly endless reports on occurrence and distribution of monoterpenes in plants; (c) studies on analogues of monoterpenes (e.g. homologues of pyrethrinoids and cannabinoids); and (d) reports in journals unavailable in the U.K., and inadequately abstracted. Iridoids are discussed but terpene alkaloids are excluded.

Even with the above restrictions, rigorous selection had to be made on the remaining bulk of the literature. Lack of space has precluded much criticism, cross-reference, and magisterial comment that are such a feature of previous Reports. We have made an attempt to select salient papers — often those giving leading references to earlier work within the period — but we would urge any authors who feel that their contributions have been ignored or maltreated to send in reprints for transmission to future Reporters.

In the following sections, the plant species that are sources of monoterpenes are not recorded unless of some special significance, and similarly for points of stereo-chemistry, absolute configuration, reagents, and reaction conditions.

Excellent reviews have appeared on the synthesis of monoterpenoids, of cannabinoids, and of the use of isoprene in terpenoid synthesis, and also on terpenoids from marine sponges, the base-catalysed isomerization of monoterpenes, and iridoids. Books on secondary metabolism in plants contain chapters on monoterpenes, and detailed but overlapping reviews deal with the biosynthesis of mono and other terpenoids, others cover the stereochemistry of chain-lengthening and cyclization, the importance of membrane systems in monoterpene biosynthesis, the metabolism of monoterpene epoxides, the production of monoterpenes (inter alia) in tissue culture, chemotaxonomy, and the functions of terpenoids in plants.

2 Physical Measurements: Chirality

Spectral and Other Physical Data. — 13C N.m.r. studies on hydroxy-and chloro-menthanes have revealed that certain shifts are very sensitive and reliable probes for ring conformation, 25 and similar studies are available of menthylenol ethers and of 13C-13C coupling in limonene and carvone. A detailed analysis of relaxation times has been made from the 13C spectrum for solid camphor, and such spectra of norpinanes and homopinanes have been fully analysed. 1H N.m.r. studies with shift reagents have enabled the conformations of the verbenols to be elucidated and the stereochemistry of derivatives of camphor oxime has been analysed. Corrected structures for the isomeric bornane-trans-2,3-diols have been proposed. Analysis of the n.m.r. frequencies of the methyl groups of fenchone has assisted analysis of the structure of the sesquiterpene cedranone. 13C and 1H n.m.r. spectra of a variety of iridiols and their glycosides have been investigated and spectra of methylcyclopentanes have been analysed for use as models in the interpretation of those of iridiols.

Routine, but useful, interpretations of the mass spectral fragmentation patterns under electron impact have been reported for esters of the menthane and camphane series, for thioketones with the thujane, pinane, camphane, and fenchane skeleta, for [2H]limonene, for cannabinoids, and for the volatile components from Pinus seedlings.

Raman optical activity of menthane derivatives and of pinenes, carenes, and related compounds50 has been studied. The technique has been used to investigate the interconversion of the pseudoaxial and pseudoequatorial forms of α-phellandrene at low temperatures. Chiroptical methods have enabled the assignment of absolute configurations and of conformations of iridoid glycosides, of allylic alcohols of the menthane and pinane classes (as their p-nitrobenzoates), and of camphor derivatives (1). Methylpulegene (2) is anomalous in showing no absorption maximum above 210 nm (pulegene; λmax 232 nm), but it does exhibit a c.d. Cotton effect: presumably the 3-methyl substituent prevents the diene system from attaining planarity. The relationship between the polarizibility ellipsoids of the C=C and the C4 ring in pinenes, the absolute configurations, and the optical rotations has been theoretically explored. Detailed and impressive consistent force-field calculations have been made on the c.d. of menthane derivatives.

Several important studies have appeared concerning the detailed geometry of certain monoterpene skeletons. Almost always (one exception; cf. ref. 58) the thujane skeleton has been previously shown to adopt a boat conformation. A 1H n.m.r study of a variety of bicyclo[3.1.0]hexanes and thujane derivatives, allied to calculations of the effect of ring buckling, has suggested that an alkyl substituent at the bridgehead of the [3.1.0)-bicyclo-system (as in the thujanes) causes the boat to twist, although this can be reduced by an axial substituent at C-4. More refined analysis suggests that in the thujanes the C5 ring is much flatter than in less substituted bicyclo[3.1.0)hexanes: e.g. in (3), α is 10–13°, rather than 24–30° in the latter. In particular, α was deduced to be -3° for (+)-thujone (4) (cf. ref. 59); i.e. the C5 ring was virtually planar! This compares with values of 25° and 15° for α in (+)-thujone and the epimeric (-)-isothujone deduced from microwave spectroscopy. It was suggested that the latter analysis was in error as the spectra were interpreted using the parameters determined for the parent bicyclo[3.1.0]hexane and no allowance was made for twisting of the ring in the more substituted derivatives. Computed dihedral angles for the C4 rings of pinanols were in quantitative agreement with those determined by X-ray diffraction. The preferred conformations of trans- and cis-2-pinanol are chair and boat respectively (with reference to the C6 ring carrying one methyl substituent), and both pino-campheols that were studied also favoured the boat conformation — but these boats were best described as ‘twisted semi-boats’. Theoretical calculations on the conformations of chrysanthemyl compounds were reported, and both the favoured conformations and also the configurations at C-1 and C-8 of certain iridoid glucosides have been elucidated by use of 1H or 13C n.m.r. and m.s. Details of the stereochemistry of the adducts of Fe(CO)3 with α-terpinene and σ-menthadienes have appeared. X-Ray studies of (5)–(7) gave the expected information.

G.c.–Fourier-transform i.r. appears to be a technique of great potential for the identification of monoterpenes in plant extracts: in some cases it is claimed to be superior to g.c.–m.s. but generally the methods are complementary. Another recent procedure is droplet counter-current chromatography which is a modification of counter-current distillation. This has been applied very successfully to the bulk separation of iridoid glucosides. A method has been claimed for the identification of terpene alcohols at the µg level: this involved g.c.–m.s. after reduction over platinum with lithium aluminium hydride. As a result, different substrates were said to give a pattern of products with characteristic skeleta: thus borneol yielded camphane or tetramethylcyclopentanes.

Photoelectron spectra of fenchone derivatives and e.s.r. spectra of the para-magnetic adducts between organic Si-, Ge-, and Sn-centred radicals and camphor and thiocamphor have been studied:

Chirality. — The simultaneous presence of (8) and (9) (L= YbIII, GamIII, or PrIII splits the 1H and 13C n.m.r. signals of chiral α-pinene, limonene, and camphene. As a consequence the enantiomeric purities could be readily determined: previously, hydrocarbons were not amenable to such techniques. Compound (9) augmented the Ag salt shift but did not interact alone.

Allyl boronates of substituted camphor diols (10) added to acetaldehyde to yield (11), which on base treatment cleaved to give 86 % optically pure pent-4-en-2-ol: pinane diols were less effective. B-3-Pinanyl-9-borabicyclo[3.3.1]nonane [prepared from (+)-α-pinene] proved an exceptionally effective reagent for the stereospecific reduction of [1-2H1]-aldehydes to [2H1]-primary alcohols: thus [CHO-2H1]benzaldehyde was converted into optically-pure (+)-[1-2H1]benzyl alcohol. A detailed mechanistic discussion of the reaction was appended. The chiral titanium compound (12) converted benzaldehyde into 1-phenylethanol in low (ca.] 14%) optical yield. Chiral amines, e.g. N-isopropyl-(-)-menthylamine, were used as bases in asymmetric condensations between bromoacetates and ketones in Reformatsky-type reactions, but the optical yields were generally poor, at a maximum 40%. The rhodium complex (13) was resolved: the enantiomers were both yellow, although the racemic mixture was red-green.

3 General Synthetic Methods

Monoterpenes are widely used as substrates in the development of new synthetic reagents and routes. However, many of these studies refer to a one-off use of a particular compound as one of many models and such are not discussed here unless of especial interest. We rather review the salient work involving specific functionalization and modification of the class.

The ene reaction of aldehydes with alkenes provides a potentially valuable route to homoallylic alcohols [cf. (14a) -> (14b)]. Coupling of isoprene with 3-methyl-butan-1-al yielded (15) in excellent yield, and limonene similarly, reacted (at the exocyclic double bond) to yield a hydroxybisabolane. Dimethylaluminium chloride (a mild Lewis acid and also a proton scavenger) catalysed the process and proton-initiated reactions did not occur. A novel synthetic method has been developed for the synthesis of optically active terpenes by the ring-opening of (R)-(+)-β-methyl-propiolactone: the sequence to citronellic acid (16) and pulegone (17) utilized the previously developed step whereby a regiospecific attack of a Grignard reagent on the substrate was catalysed by cuprous iodide. An elegant new route to monoterpenes could possibly be developed to give specific labelling with tracer: the key intermediate was an oxonium salt (18), and pathways to cis-terpin (19), 1,8-cineole (20), and α-terpineol (21) are shown in Scheme 1. An effective method of converting camphor into epicamphor and menthone into carvomenthone involved the route (22)->(23). A very detailed study has been made of the linkage of C5 units, viathe elaboration of a C10-cyclopropyl intermediate (24) formed from reaction of C5-carbenes and a C5-alkene. Typically, acid treatment of (24) led to a product showing head-to-tail linkage of the units (25), whereas base treatment followed by acidification gave irregular structures (26) (Scheme 2): treatment of (24) and its analogues with dissolving metals or peracids also led to novel, functionalized but regular structures. Methods for the formation of allylsilanes from geraniol, linalool, and myrtenol and from verbenol have been reported. The gem-di-(trimethylsilane) derived from geraniol reacts with acid to yield citronellene (3,7-dimethylocta-1,6-diene) A general route has been developed to α,β-unsaturated aldehydes of homomonoterpenes, and various monoterpene γ- and δ-lactones have been synthesized by the Wittig-Homer reaction. Geraniol and also pinane derivatives have been elaborated into α-substituted methylacrylates via a Claisen-o-ester rearrangement with trimethyl β-methoxyorthopropionate using trimethylbenzoic acid as catalyst, e.g. (27)->(28), and the epoxides of pulegone and piperitone have been prepared by the Wittig reaction. Treatment of allyl acetates of the menthane and pinane classes (e.g. those of carveols and myrtenol) with sodium diethylmalonate in the presence of diphenylphosphinoethane and a Pd catalyst effected the transformation (29)->(30), with obvious scope for further modification. Another reaction leading to valuable synthetic intermediates is the addition of dichlorocarbene to camphene followed by reduction to yield (31) and (32); β-pinene and limonene behaved similarly.

The reactions of metal complexes of monoterpenes continue to be actively explored and many specific examples will be found in later sections. Of general interest are the dimerization of π-allyl-Pd complexes of α- and β-pinenes and of carvone that are effected by irradiation at 366 nm and the thermal decompositions of (π-allyl)nickel halide complexes of, e.g., isoprene (33), to form myrcene. Hydrosilylation of 1,3-dienes (e.g. isoprene, myrcene, ocimene) was found to be a regiospecific 1,4-addition for Pd complexes but followed the alternative route for Rh compounds; a good discussion is appended. A series of dimers of isoprene bonded at 1–2, 1–3, 1–4, 2–4, 3–4, and 4–4 positions were prepared by suitable regiocontrolled catalysis by transition metals of the coupling of 2-methylbut-2-ene-1,4-diylmagnesium or 3-methylbut-2-enylmagnesium chloride with C5-alkenyl halides. Various terpene amines have been obtained in excellent yields by Pd-catalysed telomerization of isoprene with NH3.

Conditions have been worked out for the conversion of allylic alcohols into 1,3-dienes (e.g. nerol->myrcene, geraniol->trans->β-ocimene) by a sequence involving epoxidation, trimethylsilylation, ring-opening, desilylation, formation of diol, then of dibromides, and debromination, e.g. (34)->(35). Reaction of a variety of monoterpenes with HOCl-CH2Cl2 resulted in addition of chlorine followed by shift of the double bond: dechlorination (Zn) led to α-olefins (60–80%), and the chloro-derivative of citronellol could be efficiently converted into rose oxide [2-(2-methylprop-1-enyl)-4-methyltetrahydropyran) by successive treatment with acid and base. Dehydrations of allylic monoterpenols with carbodi-imides and anhydrous CuSO4 were effective. Hydroalumination of β-pinene, camphene, and α-thujene in the presence of O2 gave after work-up the product of anti-Markovnikov addition (73% trans-product, 85% endo, and non-stereoselective, respectively). In contrast, hydroboronation (TiCl4–NaBH44) gave 85% cis-product from β-pinene and mainly isopinocampheol from α-pinene.

A very useful functionalization of the isopropylidene terminus of isoprenoids led to the formation of terminal trans-allylic alcohols (36)->(37), e.g. 10-hydroxy-geraniol. Step (i) was highly regioselective and (ii) could be very effectively carried out by the Evans procedure. Preoccupations with the reactions of monoterpenes (thujenes, menthenes, and carenes) and other 1-methylcyclohexenes has obscured the fact that 1-methylcycloalkenes with four-, five-, seven-, eight-, or twelve-membered rings show predominantly syn-side addition in the ene oxidation with photo-chemically generated singlet oxygen (38; route i). 1-Methylcyclohexenes, however, show anti-side addition (route ii): the theoretical reasons for this dichotomy have been very convincingly discussed. The PdCl2 complex from carvone was converted by irradiation in the presence of O2 into (39) whereas treatment of carveol or myrtenol with Pd in the presence of PPh3 and a base yielded the ketone. Geraniol and carveol were oxidized at the alcohol group by O2 in the presence of [RuCl2(PPh3)3] and menthol was converted into menthone by MoO2. Methods have been developed for the epoxidation of a variety of types of mono-terpenes with t-butyl hydroperoxides over metal catalysts.

(Continues…)Excerpted from Terpenoids and Steroids Volume 12 by J. R. Hanson. Copyright © 1983 The Royal Society of Chemistry. 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.