Terpenoids R.A.HILL 1 Introduction The terpenoids constitute the largest class of natural products.

The great structural diversity of the terpenoids has been a challenge to the synthetic chemist and will continue to be so as more skeletal types are found. The rate of discovery of new terpenoids has increased over the last ten years largely as a result of the increase in the sophistication of separation and analytical techniques. The use of two-dimensional n.m.r. techniques, in particular, has helped the structural elucidation of new terpenoids. Crystal structure determinations have assisted when n.m.r. has failed to give an answer and many interesting new skeletons have been uncovered. This chapter can only highlight a very small proportion of the advances in terpenoid structure elucidation, synthesis and biosynthesis; however, references are given to some key reviews that provide a more comprehensive coverage. A major catalogue of natural terpenoids gives data and references to a large proportion of known terpenoids arranged in groups of related structural types. This will aid the structure elucidation of new terpenoids by providing an easy access to data on related compounds. The use of substructure or data (e.g. melting point or molecular formula) searching of a natural products computer database provides an efficient method of locating related or known terpenoids. Terpenoids are found in abundance in higher plants. The development of techniques for growing plant tissue cultures to generate terpenoids has continued, however yields of secondary metabolites are normally disappointingly low. Phytoalexins produced by plants include a large number of antifungal terpenoids. Fungi, themselves, produce a range of interesting terpenoids including trichothecanes, the protoilludane group, cyathins, fussicoccanes and many triterpenoids. Recent research into marine natural products has shown marine organisms are a prolific source of unusual terpenoids. Detailed reviews of marine natural products appear regularly and a comprehensive review of terpenoids of marine invertebrates concentrates on their biological activity. Marine organisms continue to provide new carbon skeletons. Many substituents that are rarely found in natural products occur in marine terpenoids, for example bromo- and chloro-substituents in algal terpenoids and isonitrile and isothiocyanate substituents in sponge terpenoids. The biosynthetic origin of these isonitrile groups has prompted many studies. The biosynthesis of the monoterpenoids, sesquiterpenoids and diterpenoids from all sources are covered in a series of reviews. Terpenoids are found as insect pheromones and in insect defence secretions particularly from termites. The synthesis of insect pheromones has been a particularly active area recently. Many terpenoids occur as glycosides or glycosyl esters, iridoid and triterpene glycosides being the most abundant. The biological activity of terpenoid glycosides is well established, many have been found in plants used in traditional medicine. With the increase in the isolation of terpenoid compounds from plants, the terpenoid content of a plant can be used as a taxonomic tool. Limonoids, quassinoids and iridoids have been particularly useful in the field of chemosystematics.

2 Monoterpenoids Comprehensive reviews concerning all aspects of monoterpenoids appear regularly. There has been an upturn in interest in the area of monoterpenoids over the past decade largely due to their economic importance. Volatile monoterpenoids contribute to flavours and aromas in food and are important in perfumery. Microbial transformations of monoterpenoids can produce compounds of use in the fragrance industry and plant cell cultures can also be used to form and transform monoterpenoids The importance of monoterpenoids in flavouring has renewed interest in their biosynthesis and bioformation. The monoterpenoids and their glycosides in grapes contribute to the aromas of wine and the analysis of the volatile constituents has received a lot of attention. Gas chromatography and GC-MS techniques are of particular importance in the analysis of these volatile components. Plants produce large amounts of monoterpenoids. The distinctive aroma of coniferous plantations is the result of the emission of volatile monoterpenes such as pinene(1) and Australian forests produce a high concentration of 1,8-cineole(2) from eucalyptus trees. Attention has been turned to the fate of these volatile constituents. It has been suggested that trees under attack by insects or other leaf predators may produce certain.

(1)

(2)

4 Diterpenoids Regular comprehensive reviews on the structures of new diterpenoids have appeared and a catalogue of diterpenes has been published. The diterpenoid class has one of the widest ranges of biological activity. The synthesis of diterpenoids, like other classes of terpenoids, has become an increasingly important subject. An excellent review covers the total synthesis of tricyclic and tetracyclic diterpenoids and another review covers the biotransformations of diterpenoids. Labdanes are one of the largest classes of diterpenoids and have generated much synthetic interest; however, since the discovery that forskolin(86) possesses interesting blood pressure lowering activity there has been a lot of chemistry directed towards 86 and its derivatives. Originally 86 was isolated from Coleus forskohlii. Independently coleonol was isolated from the same plant and assigned the same structure as 86 apart from the opposite stereochemistry at C-7. Both structures were assigned by X-ray crystallographic analyses. Subsequently they were shown to have the same structure (86). The biosynthesis of 86 and related labdanes from Coleus forskohlii has been studied. Over 650 members of the clerodane class of diterpenoids had been isolated up to 1991. They mainly possess the ent-clerodane skeleton (87). Confusion exists in the

literature over clerodane nomenclature. The first member of this class to be isolated was clerodin (88). It was originally assigned a structure enantiomeric with 88 and when the structure was revised the carbon skeleton (87) was designated as neoclerodane and those compounds enantiomeric to 87 as ent-neo-clerodanes. This is contrary to the practice for the rest of the diterpene classes and there have been several proposals to drop the neo-nomenclature. Thus neo-clerodanes should be known as ent-clerodanes. The clerodanes have been isolated mainly from dicotyledonous plants but also from monocotyledonous plants, liverworts, fungi and bacteria. This widespread occurrence suggests independent evolution of the ability to produce clerodanes. Teucrium species are a prolific source of highly oxygenated clerodanes, teucvin (89) is typical. They all have the ent-clerodane skeleton, oxygenation at C-6 and an equatorial methyl group at C-8.
O OH

O
OH

OAc OH
(86)
(87)

O H
O
H

O
H

O
H
8

CH2OAc

OAc

O
O
(89)

(88)

Most perhydrophenanthrene-based diterpenoids have trans-anti- trans-ring fusions as in 90. A small number including the momilactones such as momilactone A(91) possess a 9,10-syn stereochemistry. The momilactones are phytoalexins from the rice plant Oryza sativa and they have generated some synthetic and biosynthetic interest. Aphidicolin (92) has also received attention regarding its biosynthesis.

H
H

H
O

H
(90)

H O
(91)

OH
CH2OH

OAc
OAc

OH
CH2OH
(92)

OAc

H
(93)

OH

O
O

AcO

H
O

O
OH

H
(94)

OAc

OH

H
(95)

OH

Leaves of Rabdosia japonica are used as a common household medicine in Japan for gastrointestinal disorders. The drug is called enmei-so which means grass effective for prolongation of human life. Many bitter compounds have been isolated from Rabdosia species. The constituents include ent-kauranes such as shikodokaurin B (93), ent-6, 7-secokauranes such as enmein (94) and ent-8, 9-secokauranes, e.g. shikodomedin (95). The Rabdosia diterpenoids have been shown to possess antibacterial and antitumour activity and there has been much effort to investigate the structures and chemical transformations of these highly oxygenated kauranes. The gibberellins such as gibberellin A1 (96) are plant growth hormones and they arise biosynthetically by ring contraction of the ent-karane ring system. The nomenclature of the gibberellin family is well regulated and they are numbered in order of discovery. The synthesis and chemistry of the gibberellins have been expertly reviewed. The tobacco plant (Nicotiana tabacum) has been extensively studied because of its economic importance and the health factors associated with its use. One of the major groups of compounds found in tobacco are the cembranoids such as 97. The tobacco cembranoids have a close biogenetic relationship; they all possess the 1Sstereochemistry and normally have a 2E-double bond and oxygenation at C-4. Cembranoids are also found in the oleoresins of conifers and the resin coatings of the leaves of Eremophila species. The frankincense-producing Boswellia carteri produces cembranoids containing 1,12-oxygen bridges such as incensole (98) Cembrene A(99) is a trail pheromone of Nasutitermes and Trivervitermes termite species. Termites also produce defensive substances that include trinervitanes such as trinerviol (100) and kempanes such as kempene 1(101) and it is plausible that cembranes are biosynthetic intermediates for those compounds. Cembranoids are also widespread in marine organisms where they are probably biosynthetic precursors of the dolabellanes such as 102 and the dolastanes such as amijiol (103). The synthesis of cembranoids has been

recently reviewed.
OH
OH

O
OC

OH

H
H CO H 2
(96) (97)

OH

OH

(98)

(99)

O
H

OH

H
OAc H
(101)

H
OAc

(100)

H
OH

OH

OH OH
(102) (103)

The plant families Euphorbiaceae and Thymelaeaceae contain many tumour promoting and irritant diterpenoids. These compounds can all be considered as biogenetically arising from the casbane skeleton (104) as in Scheme 14. The lathyrane skeleton (105) can be formed by cyclisation of 104 and ring opening of the cyclopropane ring would lead to the jatrophane skeleton (106). Further cyclisation of 105 leads to the tigliane skeleton (107) which can undergo cyclopropane ring opening or rearrangement to give the daphnane skeleton (108) and the ingenane skeleton (109), respectively. Esters of ingol(110), a lathyrane and phorbol(111), a tigliane possess potent biological activities. The promising antitumour activity of taxol (112) has stimulated studies on its total synthesis, semi-synthesis and chemistry.

(104)

(106)

(105)

(108)

(107)

(109)

HO

OH

OH
H

H
O
HO
OH
(110)

OH

OH

OH
(111)

CH2OH

AcO

O OH

O
OC
HNOCPh

OH

HO

H
PhCO O

O
OAc

Ph
(112)

5 Sesterterpenoids Sesterterpenoids are a small group of natural products that occur mainly in marine organisms, but some are found in terrestrial life. There are only about 200 natural sesterterpenoids known but they contain a diverse array of about thirty carbon frameworks. Although they are strictly C25 compounds, there are a large number of nor-and alkylated- sesterterpenoids.

OH

(113)

O
CO2H
(114)