Part I

TERPENOIDS

Monoterpenoids

BY R. B. YEATS

This Report covers the primary literature from August 1975 up to August 1976; literature available only as a Chemical Abstract after September 1st 1976 is not included.

Two useful supplementary volumes update the corresponding chapters in the second edition of Rodd on acyclic and monocyclic monoterpenoids, on bicyclic monoterpenoids, and on the biogenesis of mevalonate, hemiterpenoids, and monoterpenoids. A useful textbook on natural plant constituents includes some biochemistry and chemistry of monoterpenoids.

1 Physical Measurements: Spectra [etc.; Chirality

13C N.m.r. assignments for campholenic aldehyde, car-3-ene, β-cyclocitral, three lavandulyl derivatives, and nerol oxide, as well as for 24 acyclic, 39 p-methane, six bicyclo[3,1,0]hexane, twelve bicyclo[2,2,1]heptane, and eight bicyclo[3,1,1]heptane monoterpenoids are recorded.

The use of trichloroacetyl isocyanate to generate carbamates in situ can be used to identify methyl groups adjacent to a tertiary alcohol (downfield shift of 0.29–0.44 p.p.m.) and to assign the geometry of double bonds in allylic alcohols. Similarities in the 1H n.m.r. and infrared spectra of monoterpenoids may be valuable in identifying new sesquiterpenoid analogues.

Mass spectral papers include another compilation of monoterpenoid alcohol spectra, a comparison of fragmentation patterns for camphor and menthone with their oxime, semicarbazone, and nitrophenylhydrazone derivatives, and a comparison of collisional activation mass spectra of ten related acyclic, monocyclic, and bicyclic monoterpenoid hydrocarbons together with derived C7H9+ ions.

The c.d. spectra of N-salicylidene derivatives of p-menthane, thujane, and fenchane amines correlate with known absolute configurations, and a new octant rule for nitramines is illustrated with N-nitrocamphidine. In measuring the fluorescent-detected c.d. spectrum of camphor, differences in the fluorescence intensity of the chromophore may result from restricted Brownian rotation during the lifetime of the excited state rather than from the circular dichroism of the chromophore. Differences in the absorption and fluorescence c.d. spectra of a number of bicyclo[2,2,1]heptanones have been exp1ained. The greater sensitivity of vibrational c.d. to structural changes than absorption spectra should make it a valuable tool for determining molecular stereochemistry; some C — H data are provided for borneol, camphor, menthol, and the pinenes.'

Alkylation of the Schiff base derived from (1S,2S,5S) -2-hydroxypinan-3-one and glycinet-butylester has yielded D-amino-acids in high optical purity (e.g. D-alanine, 83%), and asymmetric hydrogenolysis of the chiral hydrazone derived from (2S)-bornylamine and ethyl pyruvate yields L-alanine in 46.5% optical purity. In another model system for the action of NAD(P)H, (-)-menthyl benzoylformate is reduced with (-)-menthy1 Hantzsch ester, catalysed by Zn2+ under Reformatsky-type conditions, in 77% optical yield to (-)-menthyl (2R)-mandelate (cf. Vol. 6, p. 6). (+)-8- Phenylmenthyl acrylate is dramatically superior to (-)-menthyl acrylate in chiral directing ability in Diels-Alder cycloaddition reactions. The substituted caprolactam available from (-)-menthone oxime by Beckmann rearrangement is used to oxidize sulphides in low optical yields. Other syntheses of chiral sulphur compounds based upon (-)-menthol include the synthesis of O-substituted diary1 sulphilimines, sulphonium ylides, and sulphoxides from the corresponding (O)-(-) -menthoxydiarylsulphonium salts, the synthesis of thiirans in low optical yield using S-lithiomethyl O-(-)-menthy1 dithiocarbonate, and the straightforward dias-tereomeric preparation of chiral benzyl thiols from sodium O-(-)-menthyl dithixcarbonate. Other asymmetric induction reactions involving monoterpenoids include the synthesis of a chiral Dewar-benzene, a one-step synthesis of S-(+)- 2,2,2-trifluorophenylethanol of sufficient purity for direct use as a chiral n.m.r. solvent, two routine investigations using chiral lithium aluminium hydride complexes, and a report of acetophenone reduction with monoterpenoid glycol-lithium aluminium hydride complexes.

Chromatography of radiochemically homogeneous terpenoids has been reviewed; useful gas-chromatographic techniques reported include the use of polyphenyl ether in g.c.-m.s. of 23 monoterpenoid hydrocarbons, the use of 3,4,5-trimethoxybenzylhydrazine for pre-column removal of aldehydes and ketones, and the resolution of some bicyclic alcohols and ketones by co-injection with a volatile chiral resolving agent.

2 General Synthetic Reactions

Some useful reviews which discuss applications from, or are of value to, monoterpenoid chemistry include applications of singlet oxygen, manganese dioxide,di-isobutylaluminium and tri-isobutylaluminium hydrides, catecholborane, and chlorosulphonyl isocyanate, discussions of functional group selectivity of complex hydride reducing agents, hydrozirconation, selenium reagents, and the photochemistry and spectroscopy of βγ-unsaturated carbonyl compounds; an interesting, but non-novel, account of industrial terpenoid synthesis has also appeared.

Epoxidation of tetrahydropyranyl ethers (e.g. isopentenyl tetrahydropyranyl ether) produces readily detonatable peroxides which are stable to many commonly used methods of destruction.

Thermal and mercury(II)-catalysed [3,3]sigmatropic rearangement of allylic trichloroaxetimidates and allylic pseudo-ureas (e.g. geraniol, linalool) are useful for the 1,3-transposition of hydroxy- and amino-groups; the former is synthetically preferred. The [2,3]sigmatropic rearrangement of allylic sulphoxides has been used to effect an alkylative 1,3-carbonyl transposition of enones (e.g. carvene).

A 1,3-hydroxy-transposition [e.g. geraniol to linalool, (+)-cis-carveol to (-)-cis- carveol has been accomplished via the previously reported (Vol. 5, p. 6) metal-catalysed epoxidation and sodium–ammonia reduction of the corresponding α-epoxymesylate. The full paper (Vol. 6, p. 7) on bromine-trialkyltin alkoxide oxidation of alcohols has appeared and includes a one-step procedure using bromine-bis(tributyltin) oxide; related work using N-bromosuccinimide reports oxidation of primary allylic alcohols (e.g. geraniol) to aldehydes, but in the presence of aldehydes, non-allylic alcohols yield esters. Chromyl chloride oxidation of alcohols (citronellol, geraniol, pinocarveol) to aldehydes is difficult to control and led to a new method of preparing pure di-t-butyl chromate, the use of which is also reviewed (with only four references post-1969!); oxidation of allylic alcohols is less satisfactory than with Collins oxidation because of double-bond isomerization and allylic oxidation. Chromium trioxide in hexamethylphosphoramide (HMPA) readily oxidizes geraniol to geranial although menthol oxidation proceeds only in moderate yield; geranial is also obtained in high yield from geranyl bromide by the use of chromate ion as a nucleophile in HMPA in the presence of dicyclohexyl-18-crown-6. Corey has used potassium superoxide as a nucleophile in DMSO-DMF in the presence of polyether-18-crown-6 to convert geranyl bromide directly into geraniol; in benzene, potassium superoxide-18-crown-6 readily cleaves α-keto-(e.g. camphorquinone), α-hydroxy-, and α-kalogeno-ketones (e.g. 3-bromo-camphor), -esters, and -carboxylic acids to the corresponding carboxylic acids.

In connection with atmospheric pollution by monoterpenoids, α-pinene, β-pinene, and (+)-limonene have been shown to be extremely reactive towards O(3P) atoms, with rate constants an order of magnitude higher than that for the reaction of O(3P) with propylene; a second paper reports the Arrhenius expressions. Acid-catalysed oxidation of borneol to camphor using m-chloroperbenzoic acid is less efficient than the corresponding nitroxide-catalysed oxidation. Two very mild method? for oxidizing alcohols to aldehydes or ketones without double-bond isomerization or epimerization are the use of N-methylmorpholine N-oxide, catalysed by [RUCl2(PP3)3], and photochemical cleavage of pyruvate esters. The 'forbidden' insertion of triplet oxygen into cis-1,3-dienes by photochemical irradiation in the presence of trityl cation gives 1,4-peroxido-cis-2-enes (e.g. α-terpinene to ascaridole) in high yield. Hydroxylation of (1) with ozone on silica gel proceeds in low yield but with high retention of configuration to yield dihydrolinalool (2) after debromination.

Further investigations of selective reductions include 1,4-reduction of enones (e.g. carvone) as well as reductive alkylation, using Li- and K-Selectrides, and the use of 9-borabicyclo[3,3,1]nonane, which in the case of camphor yields only 75% of the exo-isoborneol compared with 99.3% using the very sterically hindered lithium trisiamylborohydride; bornan-2-exo-yloxyaluminium dichloride reduces (-)-menthone to a 95:5 mixture of (+)-neomenthol (3; X = S-OH) and (-)-menthol (3; X = R-OH). Silver-ion-induced oxidation of acyclic and cyclic organoboranes is a useful method for cyclizing dienes; geranyl acetate, after cis-elimination, yields (4; X = cis-H), and linalyl acetate yields (4; X = cis-OH) and (4; X = trans-OH). Non-rearranged allylic ethers [e.g. (5)] are formed in good yield on treating the p-tosylhydrazones of αβ-unsaturated aldehydes and ketones with sodium borohydride-methanol owing to decreased C=N reactivity favouring base-catalysed elimination. Only the olefinic bond in αβ-unsaturated carbonyl compounds (e.g. carvone) is reduced in high yield using Na[HFe2(CO)8], whereas only the carbonyl group in citral (the formula is incorrect in this paper) is reduced using propan-2-ol on dehydrated alumina.'

Other synthetically useful reactions are allylic amination using TsN=Se=NTsand TsN=S=NTS, photolysis of αβ-unsaturated ketones in the presence of UO2Cl2-methanol [e.g. to give (6); cf. Vol. 6, p. 10], halogenation of enol silyl ethers, terminal double bond (e.g. geranyl cyanide, carvone)bromination with (7) in CH2Cl2 chlorination of tertiary alcohols with PCl5 an improved synthesis of alkyl iodides via hydroboration and reaction with iodine-sodium methoxide which proceeds by inversion, regeneration of ketones from tosylhydrazones, aryl-hydrazones, and oximes, ether cleavage using di-iodomethyl methyl ether in acetonitrile, and the protection of hydroxy-groups as methylthiomethyl ethersand as β-methoxyethoxymethyl ethers.

3 Biogenesis, Occurrence, and Biological Activity

A monograph on fragrance raw materials has been published as well as two useful, if dated, collections of papers on essential oils.

(2-13C]Mevalonolactone is synthesized in two steps from [2-13C]acetic acid and 4-benzyloxybutan-2-one although a longer route is required for [3,4-13C2]mevalono1actone. The structure of the hemiterpenoid mustelan (8) from the anal glands of the mink (Mustela vison) and the polecat (Mustela putorius) has been confirmed by X-ray analysis of the corresponding thietan 1,1-dioxide and by synthesis.

There has been considerable progress in the study of monoterpenoid biosynthesis. This is reviewed in Chapter 6.

Fungal metabolism of methyl geranate by Colletotrichum nicotianae affords methyl R-(+)-6,7-dihydroxygeranate in 85% yield via methyl S-(-)-6,7-epoxygeranate. Pseudomonas aeruginosa converts α-terpineol into p-mentha-1,4(8)-diene and borneol.

Further oxygenated monoterpenoids have been reported from pine beetles. It is suggested that micro-organisms introduced by Dendroctonus frontalis may be responsible for the conversion of the aggregation pheromone trans-verbenol into verbenone which inhibits further attack by the pine bark beetle (cf. Vol, 6, pp. 13, 179, 180).

Fourteen anticipated mammalian metabolites of (+)-limonene may result from allylic oxidation or epoxide formation.

Essential oil analyses of note this year are of Buchu leaf (some p-menthane sulphur derivatives), Hyssopus officinalis (methyl myrtenate, 2-hydroxyisopinocamphone, pink acid, and pinonic acid), Laggera auritu (m-menth-6-en-S-ol), some Cymbopogon species (up to 89% of unusual p-menthadienols), and Trichostema lanceolatum (55% p-menthen-4-ol). There have been repor:s of wide variations of composition within a species, for example, Majorana hortensis and Hungarian Tanacetum vulgare (e.g. 82% artemisia ketone, 64% piperitone, 94% thujone, 84% thujyl alcohol, 81% umbellulone, and in some samples such high percentages of unidentified components).

The crystal structures of three pyrethroid insecticides have been determined. The syntheses of phenothrin analogues of lower insecticidal activity and of other chrysanthemate esters have been reported. Further pyrethroid papers concern the relationship between insecticidal toxicity and cyclopropane substituents in pyrethroids, the photochemistry of the most potent known pyrethroid, and the metabolism of permethrin in rats (cf. Vol. 6, p. 13).

Further papers on monoterpenoid ether juvenoids have appeared and metabolic investigation now extends to steers (cf. Vol. 5, p. 7, ref. 48).

4 Acyclic Monoterpenoids

Tergenoid Synthesis from Isoprene. — Co-oxidation of thiophenol and isoprene with oxygen yields the synthons (9) and (10) in useful yields' and the isoprene epoxide (11) is a useful hemiterpenoid synthon with carbanions.

The full paper on Cookson's syntheses of ocimenones, filifolene, and the tagetones has appeared (Vol. 5, p. 8). One-pot syntheses of the predominantly trans-isomers (>80%)of (12; X = CH2OH) and (13; named lavandurol), (12; X = CO2H), and (12; X = CHO) result from [(η5-C5H5)2TiCl2]--catalysed regioselective isoprene insertion into 2-methylallyl Grignard reagent, followed by appropriate elaboration. A report of geraniol, nerol, and 3,7-dimethyloct-2-ene-1, 7-diol synthesis simply combines previously reported telomerization and amino-oxide rearrangement reactions (Vol. 4, p. 10; Vol. 5, p. 12) and an earlier paper in the same series has come to light – the sodium-initiated telomerization with NN-diethylallylic amines to yield NN-diethyl-lavandulylamine and NN-diethylnerylamine (cf. Vol. 6, p. 15). Dimerization of isoprene with TiCl4-Et3Al-sulpholan gives a 2:1 ratio of (14) and (15). Electronic and steric factors have been examined in the amine-[NiCl2(PPh3)2]-NaBH4 dimerization of isoprene to both linear and cyclic dimers; for example, (15) is favoured with n-propylamine but cyclic dimers are preponderant with β-picoline. In a similar system, Baker reports 61% head-to-tail dimerization [e.g. (16)] using NiCl2-PPh3-NaBH4, reporting the same results again in a communication including isoprene dimerization with cyclododecatriene(triphenyl-phosphine)nickel and acetaldehyde (the preferred reaction is at the σ-allyl site of the nickel complex). Exclusive head-to-head dimerization of isoprene occurs with (17) in the presence of [(PPh3)2PdCl2] to give (18); reaction with the homologue of (17) proceeds similarly but in lower yield, and acyclic organodisilanes again give head-to-head linking but with trans-double bonds. Isoprene dimerization over lithium (or sodium) followed by oxidation to give Co-alcohols and -diols is similar to that reported earlier [Vol. 1, p. 18; formula (71) is obviously incorrect] and formation of carboxylic acids by quenching with carbon dioxide is of little novelty. Telomerization of 1-chloro-3-methylbut-2-ene with 2-methylbut-2-ene in the presence of SnCl4 and of isoprene with its hydrochlorides (to give linalool, α-terpineol, and m-menth-6-en-8-ol after saponification) have been reinvestigated. Isoprene telomerization with acetic acid is reported. Further papers in this section report quantitative cyclodimerization [catalyst: Ni(acac)2-P(OPh)3-perhydro-9b-alumo-phenalene] to (19; 95%) (cf. Vol. 3, p. 12), head-to-tail dimerization (80%) with mesityl oxide [catalyst: Ni(acac)2-PPh3-AlEt 3] and the formation of (20; 62%) [catalyst: Mg-(Ph3P)2NiCl2], allo-ocimene (95%) (catalyst: Ni naphthenate-Ph2PH-LiAlH4), 2,7-dimethylocta-1,3,7-triene or 2,7-dimethylocta-1,4,6-triene (catalyst: Pd acetonylacetonate-tricyclohexylphosphine-H3PO4), and a mixture of myrcene (21; 39%) and cis- and trans-ocimene (22; 52%) (Pd catalysts-NaOPh).

2,6-Dimethyloctanes. — Minor components in Cinnamomum camphora are reported to be 3,7-dimethylocta-1,7-dien-3,6-diol and 3,7-dimethylocta-1,5-dien-3,7-diol, and in Mentha x gentilis nm. hirtella, tetrahydrogeranyl acetate.

Electron-impact and photo-ionization mass spectra of geraniol, linalool, and nerol have been reported. Enantiomeric composition studies using chiral europium shift reagents include data on ipsdienol and citronellic acid.