The development of strategies for terpenoid structure determination

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The trans A/B stereochemistry of the abietic and pimaricacids was established 46 by examining the pK values of thecarboxylic acids 37 derived by oxidative degradation. Theseresults were then extended to the triterpenes. The results ofstereochemical studies in the terpene and steroid series providedmany of the examples on which the theories of the conformationalanalysis of reactions were based.The conformational stability of trans fused α-decalones wasused to establish the B/C trans configuration in the pentacyclictriterpenes 79 and to establish the trans A/B fusion in thediterpenoids such as marrubiin 61. 80 An interesting summaryof the application of these reactions to the stereochemistry ofthe eudesmane group of sesquiterpenes appeared in 1960. 81The strategy of using cyclization reactions such as lactonizationreactions to establish the cis stereochemistry of the D/Ering junction in the pentacyclic triterpenes, in which the facileformation of the lactone 62 could only be accommodated withcis ring junction, is an example. 79,82The elucidation of the cyclization reactions of santonin togive the bridged santonic acid 63 played an interesting rolein establishing the stereochemistry of santonin. 83 Howeverthe correct configuration at C-11 was eventually establishedby X-ray analyses of 2-bromo-α-santonin and 2-bromo-βsantonin.84which was related to ()-citronellal, established 88 the absolutestereochemistry of the steroids at C-20.The extension of the method of molecular rotation differences,which had been successfully applied to correlations ofstereochemistry in the steroid series, to similar changes in thetriterpenes 89 and then to the sesqui- and diterpenes, 90 provideduseful correlations of absolute stereochemistry.13 Optical rotatory dispersion and circular dichroismThe closely related methods of optical rotatory dispersion andcircular dichroism played an important role in establishingthe absolute stereochemistry of terpenoid natural products. 91Although some of the first observations of the change ofoptical rotation with wavelength were made with camphor, theprincipal applications to stereochemistry did not begin untilthe 1950’s with the work of Djerassi and Klyne. The octantrule, for predicting the sign of the Cotton effect in the ORDcurve of ketones in a chiral environment, was based on theposition of substituents adjacent to the ketone. 92 This developmentmeant that it was possible to assign the absolute stereochemistryto a number of terpenoids. A particular impactof these studies was the demonstration that a number ofditerpenoids belonged to the antipodal series, i.e. their absolutestereochemistry at the A/B ring junction was opposite to that ofthe steroids and other diterpenoids such as abietic acid. Forexample the diterpenoid cafestol 65 was converted into theethylketone 66. 93 The ORD curve of this ketone was the mirrorimage of the curve from 4α-ethylcholestan-3-one and hence theabsolute stereochemistry of the A/B ring junction of cafestol isopposite to that of the steroids. Studies on the ring D ketonesof a number of diterpenoids were important in establishingtheir absolute stereochemistry. 76,9412 The determination of absolute stereochemistryA number of monoterpenes were known to occur in both enantiomericforms. Optically active methylsuccinic and β-methyladipicacids had been obtained as degradation products andthese were correlated with D-()-glyceraldehyde. Other interrelationshipsbetween the monoterpenoids provided usefulstereochemical correlations. 85 Hence when the absolute stereochemistryof sodium rubidium tartrate was established byX-ray crystallography and the correlation made with D-()-glyceraldehyde, 86 the absolute stereochemistry of many of themonoterpenes was established.Synthetic interrelationships between carvone and the sesquiterpenesof the eudesmane series and between eudesmol andthe steroid series led to a correlation of their absolute stereochemistry.87 An important degradation of cholest-14-en-3β-olto give a fragment 64 containing the steroid side chain and14 The absolute stereochemistry of terpenoid secondaryalcoholsA number of methods have been developed for establishing theabsolute stereochemistry of a secondary alcohol. Studies on theaddition of Grignard reagents to the α-keto-esters of opticallyactive terpenoid alcohols showed 95 that asymmetric inductioncould be used to establish the stereochemistry of a chiralalcohol. The chirality of the atrolactic acid that was formedreflected that of the original secondary alcohol. Horeau’smethod 96 was based on the kinetic resolution by the alcohol inits esterification by 2-phenylbutyric anhydride. The method isbased on using a racemic mixture of the anhydride. Oneenantiomer will react faster with the chiral secondary alcoholthan the other. The optical activity of the remaining 2-phenylbutyricacid will thus reflect the chirality of the secondaryalcohol.An NMR method based on derivatization with (R)- and (S)-α-methoxy-α-trifluoromethylphenylacetic acid (MTPA) hasbecome a popular strategy for establishing the absolute stereochemistryof terpenoid alcohols. 97 Although it was originallybased on an analysis of the 19 F NMR spectrum, a more reliable612 Nat. Prod. Rep., 2001, 18, 607–617
version uses the high field 1 H NMR spectrum. A correlationwas established between the absolute stereochemistry of terpenoidsecondary alcohols and the ∆δ (δ S δ R ) values of adjacentprotons for the (R)- and (S)-MPTA esters. This correlation wassuccessfully applied in establishing the absolute stereochemistryof a number of marine terpenoids of the cembranolide andxenicane series. 98In a few instances the absolute configuration of a terpenoidhas been determined by X-ray crystallography of a heavy atomderivative, e.g. an ester or an amide containing a bromine atom.The assumption is often made that all of a group of terpenesthat occur in a particular plant belong to the same enantiomericseries. However there have been a number of reports where,for example, enantiomeric labdane diterpenes co-occur in thewood of Oxystigma oxyphyllum 99 and in the leaves of Mimosahostilis. 100 Hence this assumption in terpenoid structureelucidaton is not always valid.15 The transition to spectroscopy driven strategiesThe elucidation of the structure of gibberellic acid 54 representsthe transition between the strategies that were dominated bychemical degradation and those that were driven by the use ofphysical methods. The work in the 1950’s concentrated onestablishing the structure of the acid-catalysed degradation andrearrangement products, allogibberic 67 and gibberic 68 acids. 73These studies utilized classical dehydrogenation reactions toform substituted fluorenes which were then synthesized, andsecondly stepwise degradative sequences in which rings C andD were cleaved. 101 This chemical work was supplemented byinformation drawn from ultraviolet and infrared spectroscopy.However several aspects of the structure of gibberellic aciditself which were described in 1958, utilized assignments of the1 H NMR spectrum. 102 The full structure and stereochemistrywas based on a combination of chemical and spectroscopicstudies in which 1 H NMR spectroscopy played an importantrole in interrelating protons, for example the trans relationshipbetween H-5 and H-6. 103 Independent X-ray crystallographicstudies of heavy atom derivatives were also published.104 More recent studies on the structures of novelgibberellins are entirely determined by physical methods,particularly mass spectrometry. 105Spectroscopic methods played a significant role in the finalelucidation of the structures of a number of highly oxygenatedterpenoid bitter principles including clerodin 69 106 andlimonin 70. 107 In these cases prior chemical work had establishedpartial structures but the evidence for the full structurehinged on the ability of 1 H NMR spectroscopy to link groupsof atoms. In the sesquiterpene area the elucidation and revisionof the structure of the trichothecenes (e.g. 71) 108 revealedthe ability of 1 H NMR spin decoupling studies to cope withhighly oxygenated compounds, thus avoiding the need forthe stepwise removal of functional groups and the structuralsimplification which characterized the earlier chemicallydriven strategies.The increasing role of X-ray crystallography in structuredetermination was also illustrated at this time. A number ofstructures, such as those of clerodin 109 and limonin, 110 were alsodetermined by crystallographic methods in ‘competition’ withthe classical chemical and spectroscopic studies. Although thetheory of non-heavy atom structure determination was known,the majority of the terpenoid structures that were reported inthe 1960’s were based on heavy atom derivatives. One of theearliest terpenoid non-heavy atom structures to be reported 111was that of rosein III (11β-hydroxyrosenonolactone) 72 in1970.16 The impact of instrumental chromatographic techniquesThe development of instrumental chromatographic techniquesfor the separation of natural products, particularly terpenoids,had widespread ramifications in structure elucidation. 112 Thegas chromatographic analysis of essential oils had revealedtheir complexity and when coupled with mass spectrometry ledto the elucidation of the structures of a number of new monoandsesquiterpenoids. The understanding of factors whichaffect the fragmentation patterns of terpenoids in the massspectrometer and the use of these as structural tools hasbecome very important. The sensitivity of the methods gave astimulus to insect chemistry in which a number of volatilemono- and sesquiterpenoids play an important role as pheromones.113 The conversion of the gibberellin plant hormones totheir esters and trimethylsilyl ethers followed by their separationand identification by gas chromatography–mass spectrometryled not only to the elucidation of the structures ofover 120 of these compounds but also to their quantitation atvarious stages of plant development. 105,114 Confirmatory syntheticand model studies have become a very important part ofthese instrumental strategies in which very small amounts ofthe natural product are examined.The development of HPLC as a separation tool and the linkwith spectroscopic methods has had a similar impact on theisolation and structure elucidation of more polar terpenoidnatural products, particularly compounds from marine sources.17 The impact of biosynthetic studiesThe development of plausible biogenetic schemes based on theisoprene rule, the cyclization of polyprenyl chains and therearrangement of carbocationic intermediates, provided themeans of evaluating terpenoid structures. 115 The discovery ofthe role of mevalonic acid in the biosynthesis of cholesterol 116and the subsequent demonstration of its incorporationin vivo into terpenoid fungal metabolites led 117 to studies whichchanged this biogenetic speculation into biosynthetic evidence.Studies in terpenoid biosynthesis may be divided into fourphases. The first phase involves the origin of the isoprene unit,Nat. Prod. Rep., 2001, 18, 607–617 613
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The development of strategies for terpenoid structure determination

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