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Limonene

A. F. Thomas Firmenich SA, Research Laboratories, 12 I I Geneva 8, Switzerland

Y. Bessiere 126 I Borex, Switzerland

1 Introduction is over 95 % pure, there is sometimes doubt in the literature as 2 Hydrogen Shifts and Disproportionation ; the Action to whether the limonene that was used in any experiment was of Acids and Bases further purified or not. The major impurity in the material from 3 Addition of Water, Alcohols, and other HX-type orange oil is myrcene (3); this can be removed by clathration Molecules with tetrakis(4-methy1pyridine)di thiocyanatonickel. l1 About 4 Addition of Halogens, Sulphur, etc. 1 YOof aldehydes (mainly octanal) is also present, and there are 5 Hydrogenation of Limonene traces of other monoterpenes. The aldehydes can be removed 6 Hydroboration and Related Reactions by distillation over 0.5 YOsodium hydroxide. 7 Oxidation (except Epoxide Formation) The presence of these impurities has led to widely different 8 The Limonene Epoxides values being determined for the flavour threshold concentration 9 Addition of a C, Unit to Limonene in water. This has been given as 0.21 p.p.m., and the effect of 10 Addition of C, or More to Limonene non-volatiles on this value has been measured,12 but the 11 Pyrolysis and Miscellaneous Reactions limonene was only 96.5 YOpure, and was probably only distilled 12 Biological Reactions of Limonene orange oil, so the figures are meaningless. Values of 0.01 13 References p.p.m.13 and 229 p.p.b. (also for 96% pure limonene)" have been published, but in these papers we are not even informed which enantiomer was tested, and it is known that the organoleptic properties of the (+)- and the (-)-isomer are different.I5 Again, the promotion of mouse skin tumours by 1 Introduction orange oil was long assumed to be caused by ( + )-limonene, but The production of (+)-limonene (I) in Brazil is about 12500 pure (+)-limonene does not exert this effect.16The toxicology of tonnes per year from orange stripper oil, 15 000 tonnes per year limonene is well known;" its metabolism is mostly by allylic from cold-pressed orange oil [over 90% of which is (+)- oxidation or formation of an epoxide.lx One of the major limonene], and about 11000 tonnes per year from other metabolites, uroterpenol glycoside (4), was isolated from urine, sections of the citrus industry (orange-essence recovery water, especially of subjects with adrenal hyperplasia or in pregnancy; ete.),' making the annual world production of (+)-limonene this does not occur as an optically pure enantiomer, presumably about 50000 tonnes. Smaller amounts of more or less racemic because of the variety of enantiomers in dietary limonene.19 limonene (dipentene) are produced as a by-product from the (Uroterpenol will be discussed later.) Other metabolites are hydration of turpentine; distillation of turpentine is a source of known,')" and the conversion of (+)-limonene (I) into (+)- (-)-limonene, which can also be distilled from oil of Eucalyptus perillic acid (5)by Pseudonioncrs incognita has been described .zl sfqyriana,although the purity is not as high as that of the (+)- Limonene is reportedly insecticidal ;BB.')B it is toxic to cat fleas enantiomer. (+)-Limonene is one of the cheapest chiral starting (Ctmocephalidesjeli~),~' for example, and may play a part in materials suitable for organic synthesis, and this review is conferring resistance to trees against attack by insects.'" There intended to survey its chemistry. is a simple school experiment to demonstrate the insecticidal Until 1877, when Tilden distinguished between terpenes of properties of ( + )-limonene."' the 'turpentine group' and the 'orange group' by the characterization of crystalline nitroso-derivatives,' there was considerable confusion regarding the hydrocarbons obtained from essential oils. Wallach pointed out that hesperidene, citrene, carvene, di-isoprene, terpilene, kautschine, cynene, cajeputene, and isoterebentine were all identical to (+)- limonene.3 The discovery of ( -)-limonene (from Pinus sil- vrstrisJ)came a little later, making clear the constitution of the racemate, dipentene, which had been obtained from the distillation of rubber." The correct formula was given by Wagner in 1894,6and the first rational synthesis was by Perkin Q (3) in 1905.' Racemic limonene is one of the products of the pyrolysis of (-)-(S)-a-pinene (2),8 and the conversion of turpentine into limonene over catalysts such as sodium sulphide on alumina at 350 "C has been patented.' COOH We shall use the name 'limonene' for both the racemate and optically active forms. The major uses for limonene are in the flavour and fragrance industries, as a solvent, and in the manufacture of polymers and adhesives. Its uses as a solvent will not be discussed further but there are patents, and such use has been increasing on account of the low toxicity, pleasant odour. and bio- degradability of (+)-limonene Because ( + )-limonene that has been distilled from orange oil (4) (5) 29 1 292 NATURAL PRODUCT REPORTS. 1989

the situation is complex: this fragment does not arise in the field-free zone directly from the molecular ion that is formed by + collision-induced fragmentation.:''

2 Hydrogen Shifts and Disproportionation ; the Action of Acids and Bases The carbenium ion (a) that is derived from limonene by the (7) action of acids rearranges as shown in Scheme 1 .33 Formation of the ion (a) is also the initiation step in the Friedel-Crafts- catalysed and acid-promoted polymerization of Iim~nene,:'~the chemistry of this ion going back to 1789, when turpentine [i.cl. r-pinene (2)] was treated with sulphuric acid."' When (+)- limonene (I) is homopolymerized by Ziegler-Natta catalysts, the resulting polymer is optically inactive, and consists of both the monocyclic structure (6) and the bicyclic structure (7)."x The properties of such dipentene resins, which are used as tackifiers mainly in hot-melt adhesives (packaging materials), Q have been summarized by Ruckel et Although, in principle, all of the hydrogen shifts of Scheme 1 are reversible, in practice (a) >(I). does not occur much, because the formation of terpinolene (8) is preferred, followed by further shifts to CL- (9) and y-terpinene Other menthadienes are also formed [particularly isoterpinolene (1 1 ), which is better prepared from car-3-ene (12)"], but careful distillation of the products is necessary for preparative purposes. There is always some disproportionation (Scheme 1 ), leading to the menthenes and p-cymene (1 3), and ref. 35 notes how to avoid this. Much work has been invested in studying the differences between various acids effecting hydrogen transfers and dis- prop~rtionation,~'and the kinetics have been studied using trifluoroacetic The results vary somewhat with the + strength of the Acid forms of ion-exchange resins effect the same transformation^.“^ The chirality of limonene is lost in all of these products [ion (b) is already achiral] and the recovered limonene gradually loses optical activity because of the reaction (a) >(1). Heating limonene in dipolar aprotic solvents also causes slow rearrangement of double bonds and disprop~rtionation.~~These hydrogen shifts are encountered in many other reactions of limonene, and can significantly lower the yields of the desired products (e.g. in the hydration of Published on 01 January 1989 http://pubs.rsc.org | doi:10.1039/NP9890600291 limonene to a-terpineol, or in catalytic hydrogenation). Three isomeric dimethylbicyclo[3 .2. Iloctenes (14) were mentioned after the action on limonene of phosphoric acid on a silica support had been investigated, first in 1947 (with a different and then in 1974.47 The latter paper includes an identification of the n.m.r. spectrometer that was used, but not a single n.m.r. spectrum; one of us (AFT) repeated this work but found only the usual hydrogen shifts Scheme 1 and disproportionations. Many years earlier, phosphoric acid had been reported to give an unidentified compounddxwhich was dehydrogenated over sulphur to 2,6,9-trimethylphen- An interesting recent application of limonene is in the anth~ene,"~the structure of which was confirmed by an purification of cyclodextrins from gelatinized starch, with some independent synthesis.jn The unlikely compound (I 5) is also of which it forms filtrable solid^.^' reputed to be formed by the action of phosphoric acids5' The variation of optical activity of limonene with temperature Other reactions that have led to the isolation of dimers from is known.28Nuclear magnetic resonance spectrometry in the limonene or its disproportionation products are treatment with presence of Ag' and an optically active lanthanide complex has chloranil for 2 hours at 130-170 "C [to form (16)l" and the been used to measure the chirality,29 and the n.m.r. reaction of limonene with p-cymene (13), which has been spectrum of limonene, based on 13C-'3Ccouplings, has been reported to give the tetracyclic compound (17) in 20-25 YO reported three times"" with somewhat different figures. Natural- abundance deuterium n.m.r. spectroscopy provides a rapid means of locating the positions from which protons are lost during its biosynthesis; these positions will have excess deuterium, on account of the isotope effect. By this means, Epstein et al. have shown that C-9 and C-I0 are not equivalent during the bio~ynthesis.~'This result was suggested by feeding experiments, but difficult to prove because of the low incorporation of precursors.32 The mass spectrum of limonene appears to consist of two fragments of isoprene, one of which is charged (m/z 68),3'3but NATURAL PRODUCT REPORTS, 1989-A. F. THOMAS AND Y. BESSIERE 293

D f D

conversion of p-cymene and in over 40% selectivity.j3 The X action of BF;OEt, in CCI, or toluene apparently also gives OR !? dimerS..54.j.5 The formula in ref. 54 would be the result of the cycloaddition of the two methylene groups, to form a cyclobutane, which seems unlikely. There are a vast number of patents and publications dealing with the copolymerization of limonene with ethylene and propyIene,jfiwith norbornadiene,j7 and with other alkenes, as well as on the influence of limonene as a chain-transfer agent in the styrenation of vinyl ether polymers.j8and the polymerization of vinyl monomers (styrene, vinyl acetate, etc.)."' Double-bond rearrangement of limonene also occurs in the presence of bases3*5.fiosuch as potassium t-butoxide in dimethyl sulphoxide61 or calcium oxide at 290-380 oC.6' Dispropor- tionation to p-cymene (1 3) is readily carried out with potassium hydride in pyrrolidine or ethylenediamine,'? a reaction which led to the suggestion that limonene could be used to measure methyl ether (21 ; R = Me), had been made [by etherification of the proton-removing power of 'superbases '. The formation of a-terpineol (21 ; R = H)j2] and its odour described:" in 1883. the limonene anion (c) by metallation with butyl-lithium and Actually, a-terpineol was known before Bouchardat's N,N,N',N'- tetramethyle thylenediamine was described by experiment, having been made by the hydration of turpentine Erman et ~1.~~This anion can be transformed into mentha- with acid catalysts,j4 but the structure was only established in 1,8( IO)-dien-9-01(18)6.5 and was used in several syntheses which 1 895.75a-Terpineol was also known from dehydration of 1,8- will be referred to in later sections. Katzenellenbogen and terpin (24; X = OH),7(ithis also being obtained from turpentine. Crumrine also converted the anion (c) into the alcohol (I 8) and The a-terpineol that is obtained from limonene is generally then into the corresponding bromide for further synthesis."" (though not invariably; see below) racemic because of the Other derivatives (including some sulphides) have been made isomerizations in Scheme 1, and the racemate was one of the by Suemune et UI.,~~and tin and silicon derivatives have been first substances to be purified (m. pt 35 "C) by low-temperature prepared from the anion (c).~'In all of these reactions, the crystallization. ii chirality of limonene is retained. Some of these early experiments were conducted in glacial The dianion (d) of limonene can be formed by treatment with acetic acid, when the main product is terpenyl acetate (21 ; R = butyl-lithium and potassium t-butoxide (Lochmann's base) or Ac), from which the alcohol was obtained by potassium t-amyloxidc at reflux; quenching this dianion with Sulphuric acid in acetic anhydride also yields a- and /j-terpenyl deuterium oxide yielded 7,IO-dideuteriated limonene (1 9) and acetate^.^" The terpineols are themselves hydrated under acid some dideuteriated dimethylstyrene (20).69 conditions, 5 O/O aqueous sulphuric acid hydrating z-terpineol, with /)- and y-terpineols reacting more slowly, while Iimonene is unchanged under these conditions.x0This further hydration 3 Addition of Water, Alcohols, and other was well known to the early workers,70.i'~''who believed that HX-type Molecules a-terpineol (21 ; R = H) gave only cis-terpin [cis-(24; X = H). The carbo-cations that are formed by the action of acids on 'cis' referring to the hydroxyl and the hydroxypropyl groups] limonene (see Scheme I) can lead to addition products. Thus a- while the y-isomer (23) gave both isomers of (24; R = H).'? terpineol (21 ; R = H) can be formed by the addition of watcr; More recently it was shown that cis-terpin is the major, but not this is generally accompanied by some /j- (22) and y-tcrpineol cxclusivc, product of hydration of all of the terpineols.':' (23) from addition of water to the endocyclic double bond. The Consequently, many hydration processes of limonene produce reaction was first described by Bouchardat and Lafont in large amounts of the diols (24; R = H) besides the terpineols, 1886,"' and it is surprising that the addition of methanol was but these diols may be dehydrated to the terpineols. Sur- only described 50 years later,7' although the product, a-terpinyl prisingly, 1,4-cineole (25), but not 1,8-cineole (26), is said to be 294 NATURAL PRODUCT REPORTS, 1989

(35) R=Me R'=iPr (33) (34) (36) R=iPr R'=Me

c1 d Br (31) (32) SR formed in additi~n,'~although 1,8-cineole (26) is a major (39) component of the products resulting from treatment of a- (37) (-)-(38) R=H terpineol (21 ; R = H) with an acid.84 Surprises here are, however, common ; for example, terpin of unspecified stereo- (40) R=Ph chemistry is dehydrated by aluminium phosphate and alu- minium oxide to give limonene (l), p-cymene (13), and unidentified pr~ducts.~~The authors of this paper were surprised by the p-cymene, but we are surprised by the limonene, since we would have expected terpinolene (8) ! Innumerable different conditions have been described for the preparation of a-terpineol (21 ; R = H) from terpene hydro- carbons, mostly from turpentine. The most efficient way from NCHO limonene seems to be by using chloroacetic acids and a cation- exchange resin ; this gives optically active a-terpineol in 85 O/O conversion and 99 O/O selectivity ;*' alternatively, formic acid in the presence of zeolites gives 87-100% conversion and high selectivity.8i From limonene and acetic acid, with ferric sulphate moisture and in a solvent, e.g. carbon disulphide,99petroleum as a catalyst, a 6:4 mixture of a- and /3-terpinyl acetates is ether,'OO or dichloromethane. lnl Hydrogen bromide reacts efficiently made.8HOxymercuration of limonene followed by similarly, and the halides are converted into a-terpineol by the reduction with sodium borohydride gives a-terpineol (21 ; action of magnesium and air,'"O or with 2% potassium R = H) [70%], the rest being the diol (24; X = OH) and 1,8- hydroxide (a stronger base yields hydrocarbons, mostly cineole (26).89 In fact it has long been known that if this dipentene).lo2Zinc oxide (in 80 YOacetone for a-terpineol, or in procedure is applied to a-terpineol it leads to 1,8-~ineole.~~)If acetic acid for the acetate) has also been recommended.103 the mercuration of limonene is carried out in the presence of Because the chloride that is made in this way is optically active, sodium lauryl sulphate, the formation of micelles causes the so is the terpineo1.lo2 The di-addition products (24; X = C1) ionized part of the molecule to be exposed to attack by water and (24; X = Br) have also been known for a long time;'"' they on the periphery, and monohydration raises the yield of are best made by the action of concentrated halogen acids in terpineol to 97 methanol"" or acetic acid on limonene and can be converted The addition of methanol to limonene in the presence of an into the terpineols by adding a base.ln5The safest route from acid could not be repeated by Treibs,92who reported that there limonene to y-terpineol (23) is still the original one from was mainly dimerization with a small amount of double Baeyer,lo6consisting in brominating the dihydrobromide (24; addition. The reaction was taken up again in 1949, when X = Br), to obtain 1,4,8-tribromomenthane (32),loi and then Royals showed the reaction to be reversible by the fall in the reducing this with zinc in acetic acid to the acetate of (23), with optical activity of the product (21 ; R = Me) with increasing overall yields of 50-60 YO.'''' A method that is said to produce reaction time. Royals prepared other terpenyl ethers.93 (See 72% of y-terpineol (23) consists in dehydrating terpin (24; also refs. 54 and 71). By-products from this reaction would be X = OH) in isopropyl alcohol and 95 Yo sulphuric acid at room expected; although they have not been described, those from temperature for 80 the very similar reaction of pinene and methanol have,94 The reaction of limonene with phenols dates from 1922,"" notably the ethers (27), (28), and (29). Bicyclic systems arising and the products have been patented as resins and lacquers."' from the reaction of pinene would, of course, be absent from These products could arise either by aromatic substitution or the products from limonene. Diol monoethers are known, by formation of a phenol ether,112 further reaction giving being made, for example, from limonene and ethylene glycol in polymers.l13 The reactions are more complex than those of the presence of an ion-exchange resin.g"(See also ref. 96). The camphene or pinene (cf: the vague description of the reaction of light-induced addition of methanol to limonene takes a different limonene with 2,4-dimethylphenol compared with the precision course from the acid-catalysed reaction, yielding 52 '/o of the of the same reaction with camphene in 1960114)and while two ethers (27) and (28) with about 13 YO of mentha-1(7),8-diene products [(33) and (34)] have been described from the reaction (30).9i of phenol and limonene in the presence of boron trifluoride,'l" The microbiological addition of water to limonene is this cannot be the whole story. In the presence of a cationic ion- mentioned later. exchange resin, for instance, limonene reacts with cresols, o- The addition of hydrogen chloride to limonene to give its cresol yielding the ethers (35) and (36)11' [another surprise, monohydrochloride (31)98works well only in the absence of since these products require a carbenium ion that is derived P9890600291 NATURAL PRODUCT REPORTS, 1989-A. F. THOMAS AND Y. BESSIERE 295 from a-terpinene (9)]. Dimethylphenols with one free ortho- position"' and sesamol (3,4-methylenedioxyphenol)'18 give similar compounds. The reaction of limonene with phenol has also been studied in the USSR,"' but the publication was not available to us. Addition of nitric acid to limonene has been The ester that was obtained was reduced (by zinc dust) to a- terpineol. 120 The racemization of ( +)-limonene in sulphur dioxide occurs via the addition complex (37).122Menth- I-ene also racemizes in liquid The addition of hydrogen sulphide to limonene was shown to give menth-1-ene-8-thiol (38) in 1979,124this compound also being obtainable by the EtAlCIBr- or AlBr,-catalysed addition of H,S to pinenes.12j This compound is characteristic of grapefruit flavour, in which it occurs naturally, and has the lowest recorded flavour threshold of any naturally occurring substance.126 It is converted into 2,8-epithio-cis-p-menthane &Cl &SPhc1 (39) by radical cyclization.126The acid-catalysed addition of SPh thiophenol to limonene yields 40 YO of 8-phenylthiomenth- I - (47) X=Br ene (40), but it is difficult to purify the latter above 82%, and (48) x=€1 Fourneron et al. preferred to protect the double bond at C-1 of (+)-limonene by treating it with N-bromosuccinimide in methanol [which yielded (41)] before acid-catalysed addition of thiophenol and removal of the protecting groups (using zinc and acetic acid) to obtain ( -)-(40),12' which they required for a synthesis of car-2-ene (42). Di(p-toly1)methyl chloride adds to one double bond of limonene in the presence of zinc chloride (to the double bonds at C-8 and C-1 in the ratio of 2.5: 1).12R In three hours, at 55 "C, hydrogen cyanide in 55 YOsulphuric acid also adds to both double bonds of limonene. From the product (43), 1,8-di-isocyanomenthane was prepared by using phosgene, rearrangement of the isocyano-compounds to 13- dicyanomenthane taking place with o-dichlorobenzene at 250 "C. The stereochemistry of the products was not dis- cussed.'29 The addition of isocyanic acid in the presence of

BF, * OEt, gave only a-terpinyl isocyanate.130

4 Addition of Halogens, Sulphur, etc. The addition of halogens to limonene has been known since the time of Walla~h.'~'Addition of chlorine is not clean because of (54) the intervention of free-radical substitution. The matter was re- investigated by Carman and Venzke, who have given a method (using iodobenzene dichloride) to achieve clean formation of a sulphur with limonene was noted by Nakatsuchi in 1930,'J0 but tetrachloro-compound (44). They have also described the it was only in 1959 that Weitkamp deduced the formulae photochemical chlorination of limonene dihydrochloride (24 ; (51)-(54) and discussed the possible mechanism of their X = Cl), which leads to the 1,2,4,8-tetrachloride (45).'"2 f~rrnation.'~~Weitkamp's major product (54) is isomeric with Addition of bromine to limonene is a two-stage process,133 one of the compounds (39) that were described by Demole and but the rate slows well before the first mole has been added, and Enggist (see above).126Actually, Weitkamp had also obtained a mixture of the dibromide (46), two tetrabromides, and some this isomer (39), mixed with (54), by catalytic reduction of other compounds were identified, but no dibromide arising (53).14'These products must have been the main components of from addition only to the C(7tC(8) double bond.',' ' Limonene a mixture that had earlier been patented as a flotation agent.lJ2 tetrabromide' had long been used as a crystalline derivative of More recently, refluxing limonene with sulphur for two hours limonene (cf. Mosher13*),and Carman and Venzke showed that was shown to give a complex mixture consisting of ten the crude bromination mixture consisted of 70 YOof a crystalline hydrocarbons and 22 sulphur-containing aromatic and terpenyl tetrabromide and 30 YOof another tetrabromide which was oily compounds. The mass spectra of these substances were taken, if (+)-limonene was used but crystalline if the racemate was and proposals of several new structures were made, including used. At first, they considered the crystalline tetrabromide from the trisulphide (55),ld3but it would be desirable to have further ( + )-limonene to have the (8S)-~onfiguration,'~~but X-ray proof. Sulphurized limonene has been patented by oil com- crystallography showed it to be the (8R)-isomer (47).136 A panies as an additive in lubricating and oxidation-resistant related dichlorodibromide (48), which was made135by partial debromination of racemic limonene tetrabromide followed by The reaction of diphenyl diselenide with hydrogen peroxide chlorination of the double bond, was shown similarly to have gives phenylseleninic acid, ' PhSeOH ', which adds to limonene the same ~0nfiguration.l~~ to yield oxabicyclic selenium compounds (56), reduction of Somewhat similar to halogenation is the addition of iodine which (by tributyltin hydride) leads to 1,8-cineole (26) in high azide to both double bonds of (+)-lim~nene.'~' yield. 145 Addition of benzenesulphenyl chloride to limonene also occurs across both double bonds ;138 one mole adds 70 YOto the C(8)-C(9) double bond and the main isomers of the double 5 Hydrogenation of Limonene addition are (49) and (50).139 The first catalytic hydrogenations of limonene, which were The formation of volatile sulphides from the reaction of carried out by Sabatier and Senderens at the turn of the 296 NATURAL PRODUCT REPORTS, 1989

QOHH p.H

OH OH H (67) Rae century, yielded menth-l-ene (57) over copper"" and the (68) R=CMe2CHMe2 menthanes (58) over nickel."' These results were rapidly followed by others, e.g. the use of platinum black, which caused (71) R=H addition of hydrogen in two stages,"$ and the use of pressure."" It was soon recognized that many catalysts effccted not only hydrogenation but disproportionation (c).g. copper'"'!' and platinum on charcoal'j'). Some catalytic supports favour hydrogenation more than dehydrogenation (ZrO, and Tho,) while some favour dehydrogenation (MgO, CaO, and La20:3).'.i' The occurrence of undesired disproportionation reactions has "p led to the discovery of many methods that give high yields of (72) X=OH menth- 1-ene, for example sodium borohydride and platinum (74) salts (98 YOyield)'"" or nickel chloride and polyvinylpyrrolidone (73) X=I with hydrogen.'.j4 A catalyst that contained neodymium and a silane gave menthene after 1.5 hours'jj and a complex that contained rhodium trichloride and triphenylphosphine and times lead to the menthanes; with mesityl oxide as the hydrogen which was used as a catalyst in water give menthene after 32 acceptor, yields of up to 94% of p-cymene can be obtained.lfii hours and menthane after 76 For preparative The hydrogen that is available from limonene has also been purposes, Newhall has confirmed'"' the utility of Vavon's used in the hydrogenation of double bondslfiHand of nitriles to platinum catalystlA8rather than palladium or copper for methyl groups1"!' (both with palladium on charcoal as catalyst) menth-l-ene, and we have found that a small amount of Raney and, by adding ferric chloride to the same catalyst, of carbonyl nickel is adequate to give over 90 YOof (57).ljXThe configuration groups to hydrocarbons."" Published on 01 January 1989 http://pubs.rsc.org | doi:10.1039/NP9890600291 of the fully reduced menthanes (58) has been well established,'"!' Reductions of limonene other than catalytic ones have not and catalytic reduction generally gives preferentially the tram- been used; Semmler showed in 1904 that sodium in alcohol was isomer, but catalytic amounts of cob(1)alamin in aqueous acetic without action."' Reduction of limonene vici hydroboration is acid give nearly 70% of the cis-isomer.'"' The readiness of mentioned below. double-bond rearrangement in limonene during reduction has been exploited by using hydrogenation over a deactivated palladium catalyst; this yielded a mixture from which menth-3- 6 Hydroboration and Related Reactions ene (59) could be isolated, the unchanged limonene being The first attempted monoaddition of diborane to limonene recycled (racemization was not mentioned, but we can suppose resulted in a statistical mixture of the diols (63).li2 Using it to have occurred).161 The reason for this rearrange- disiamylborane, Brown showed how menth- 1 -en-9-01 (64) was ment-hydrogenation was to make menthone [( +)-(60)] from obtained in 79 % yield after oxidation,"" similar results having the epoxide of (59).162 been obtained with aluminium alkyls."' Brown did not mention Most of the catalytic reductions that have been mentioned the stereoisomerism at C-8 of (64), which was pointed out by yield optically active menthene, but reducing conditions Albaiges et ci1.li5 Using the addition of di-isobutylaluminium involving isomerization are known. Thus menth- 1 -ene slowly hydride to (+)-limonene followed by aerial oxidation, Ohloff et racemizes when heated in toluene with sodium and o- al. described the stereochemistry of the isomers of (64) and the chlorotoluene because of the reversible reaction that occurs corresponding aldehydes (65), a diastereoisomeric mixture of between menth- 1-ene (57) and menth-3-ene (59), the equilibrium which occurs in Bulgarian rose oil."" X-Ray crystallography of mixture containing 63% of the latter [together with 5% of the (lR,3R,4S,8R)-isomer of the diols (66)l" and of the menth-4(8)-ene (6 I )].lfi3 (4R,8R)-isomer of menth- I-en-9-01 (64)liX established the Dehydrogenation of limonene to p-cymene is reported to stereochemistry of each of them. More recently it was occur best over a catalyst of PdO and sulphur on active reported"" that boron dihydrogen chloride gave 81 '/o of the charcoal at 220-230 "C,giving 97 YOyield of p-cymene (1 3) in alcohols, although thexylboron hydrogen chloride seems to be 96% purity.164 On a small scale, iodine yields 65% of p- more stereoselective, and oxidation of the menth- 1 -en-9-yl- cymene.165 borane that was obtained with the latter gave 68% of menth- The disproportionation of limonene to p-cymene (I 3) and 1 -en-9-als directly.1H"Direct reductive alumination of limonene menthane (58) has been known since 1924, with palladium151or with aluminium and hydrogen in hexane at 160 "C and then platinum on charcoal166 as catalyst. The dehydrogenation aerial oxidation leads to (64).I8l Some methods of reduction of occurs in two stages; initially 52-53 YOof p-cymene is formed, limonene, involving boron and cobalt compounds and then an together with 4-2 O/O of menth-8-enes (62). Longer reaction acid, have been described,"' but treatment of the adduct of View Online

NATURAL PRODUCT REPORTS. 1989-A. F. THOMAS AND Y. BESSIERE 297

hydroperoxides (cis:trans = ca. 1 : 1) and racemized through the intermediacy of the radical (e). Decomposition of the hydroperoxides with heavy-metal catalysts can alter the QOl1OQ / distribution of the products (after reduction) between carvone Q [( +)-(75)] and the menthadienol(76), which has predominantly cis hydroxyl and isopropenyl There are many patents or1 and papers concerning such reactions (with Co, Mn, and Ni The products that were formed by leaving a (79) (80) (81 1 drum of limonene open in Australian sunlight included a trace of perilla alcohol (77),lg9and heating a solution of limonene in dimethyl sulphoxide at 100 "C in air for 48 hours is reported to HO #*a, OOH HO +,, OH RO.*, \ give 95 O/O of 4-methylacetophenone, via dimethylstyrene (78),'0° 2' whereas, in dimethylformamide or hexamethylphosphoric 9' 9 triamide as the solvent, cymenol (79) is the main product.'" Autoxidation in the presence of ammonia (' ammonoxidation ') yields a complex mixture of terpene hydrocarbons, pulegone 0 / (SO), and, more interestingly, some trimethylpyridines, in- cluding the 2,3,6-i~omer.~~* (83) (84) (85) Dye-sensitized photo-oxygenation (by '0,) of limonene leads to hydroperoxides, the stereoisomers of which have been separated and chara~terized.'~~The reduction products of the disiamylborane and limonene with acetic acid at 100 "C gives laiter are stereoisomers of the menthadienols -(76), (8 I), and completely racemized menth- 1 -ene.lH3 (82), but, in contrast to the autoxidation, the alcohols with cis A preliminary note by Brown and Pfaffenberger in 1967IH4 hydroxyl and isopropenyl groups are predominant, particularly was followed by a rather different full paper in 1975l"j in which (76), and they are optically active.204Improvements (of the the preparation of the cyclic boron compounds (67) and (68) is lamp or by supporting the Rose Bengal catalyst on magnesium described. The diols (69) were obtained from (67) (the oxide) have been claimed.*05 Reaction rates have been stereochemistry at C-8 again not being specified) while 83 YOof determined.206Uranyl-acetate-catalysed photochemical oxida- D-( -)-( 1 R,2R,4R)-carvornenthol (70) was obtained from (68), tion of limonene leads to a hydroperoxide (83), hydrogenation this being the most efficient way of making a single carvo- of which (over Pd) gives the tvans-menthane-trans- 1,2-diol menthol from limonene. Hydroboration of ( + )-limonene with (84).'07 Catalysis of the photo-oxidation of menth- 1-ene with BH,Cl .OEt, and then reduction with lithium aluminium ferric chloride, which has not been reported with limonene, hydride gives a borane (71) that is said to be useful for gives 38 YOof ring-opened products.'08 asymmetric induction in the hydroboration of alkenes.1N6 Oxidations that are supposed to permit greater selectivity, Acetoxyborohydride is made from NaBH, and Hg(OAc), in especially for avoiding racemization via the radical (e), include tetrahydrof~ran.'~'?This reagent hydroborates limonene on the the use of t-butyl peracetate or perbenzoate in the presence of double bond at C-1, then treatment with hydrogen peroxide cuprous bromide. The cis-carveol (82) and the trans-carveol yields dihydrocarveol (72) (stereochemistry unspecified) and (85; R = H), which are obtainable from (+)-limonene, were iodine yields 2-iodomenth-8-ene (73).lHH then converted into (-)-carvone (75).'09 Wacker conditions of Hydroboration can be used on functionalized limonenes oxidation (air and copper chloride, with a catalytic amount of such as the epoxides,lxg and the alcohol (64) can be converted palladium chloride in acetic acid) give a highly stereoselective into the corresponding chloride with CCI, and Ph3P,190leading oxidation to trans-carveyl acetate (85 ; R = Ac) in 63 YOyield,210 to a wide variety of synthetic routes. PdCl(NO,)(MeCN), being without catalytic action.'" (+)-Limonene has been silylated to (74) with triethoxysilane The oldest method of converting limonene into carvone is at 80 "C and a catalytic amount of platinum on charcoal. The through the nitroso-chlorides (86), which were first made by product was patented as a waterproofing agent for concrete. lB1 Tilden from gaseous nitrosyl chloride,212this preparation being improved by Wallach by using an alkyl nitrite and HCl."'" The action of base then gave carvone oxime,214from which carvone 7 Oxidation (except Epoxide Formation) was obtained by the action of an acid. This route is both Since 1914 it has been knownlg2that limonene is very sensitive industrialz1" and academic, there being an undergraduate to air or oxygen, rapidly acquiring a high peroxide number, and experiment for making carvone from orange There are it has been used as an anti0~idant.l~~The peroxides are slowly variants, using nitrosylsulphuric acid,"'? dinitrogen tetroxide in converted into other substances under various conditions (this formic acid,'18 and so forth. oxidation is partly responsible for the 'off-flavour' of aged Direct allylic oxidation has been carried out with t-butyl citrus oils). A full explanation has been given by Schenck et chromate, this giving 21 YO of carvone (75) and 13 YO of ~1.'~''The effect of an acid on the hydroperoxides was noticed isopiperitenone (87),'l9 with the Cr0,-pyridine complex, to by Bain,1g5.196and we have noticed that the rise in temperature give 36 YOof (75) and 31 YOof (87),220with t-butyl hydroperoxide that often occurs when limonene is hydrated under mild and hexacarbonylchromium, to give net yields of 39% of (75) conditions (weak aqueous acid in organic solvent) is due to the and 28.5% of (87) (with 47.7% of the limonene being presence of hydroperoxides. Ig7 Autoxidation is not stereo- recovered),221and with pyridinium chlorochromate, to give specific, racemic alcohols being formed after reduction of the (75) and (87) in the ratio of 2: 1 .222 Pyridinium dichromate and 298 NATURAL PRODUCT REPORTS, 1989

OH OMe

(92) (93) t-butyl hydroperoxide in the presence of Celite is reported to give a 48 YOconversion and 23 YOyield of piperitenone (88), but the 'H n.m.r. figures that are given223correspond neither to piperitenone (88) nor to isopiperitenone (87). It should be noted that (88) is readily prepared by oxidation by dichromate H-eR 0$CHO ODmEt fcHo ion of the major product (76) from the photo-oxidation of limonene.2n4 The first experiments on the electrochemical oxidation of limonene concerned the experimental technique, but no (99) R=CHO (100) (101 1 (102) products were isolated.224Later it was suggested that, in an (104) R=CH20H aqueous medium, hydration occurred before oxidation."5 In methanol, a mixture was obtained, mostly of ally1 methyl ethers;226a-terpineol (21 ; R = H) and trans-carveol (85; R = H) have also been reported."' On a graphite electrode, in NaCIO,, the major products from (+)-limonene are (-)- dihydrocarvone (89) and the trans-diol (90); both antipodes of limonene were examined.22H The cis-hydroxylating oxidant potassium permanganate yields the tetraol 'limonite' (91) (m. pt 192 0C),"9 which was also obtained with hydrogen peroxide and catalytic amounts of osmium tetroxide.'"" The 1,2-diol that is obtained by the reaction of limonene in acetic acid2"' arises by a different leads to a small amount of hydrocarbons (including mentha- mechanism from ring-opening of the epoxide (see below). 1,4,8-triene and p-cymene) and to mentha- 1,4(8)-dien-9-y1 The first work on the oxidation of limonene by selenium acetate (95) and trans-carveyl acetate (85; R = Ac).'~, Under dioxide contained no spectral data,*"' and Sakuda'"" and one of different conditions (and after reduction with NaBH,), z- showed that the main product from the reaction in terpineol (21 ; R = H) and P-terpineol (22) were obtained, the ethanol is racemic mcntha- 1,8-dien-4-01 (92), together with a terpins (24; X = H) also having been reported'lj (although the certain amount of mentha- 1,8( 1 O)-dien-9-01 (1 8) and optically authors did not seem to appreciate the instability of these on active truns-carveol (85; R = H). The isolation of supposedly gas chromatography). optically active mentha- 1,8-dien-4-01 has been described in Oxidation of limonene by thallium(III) nitrate is one of the later papers, one using the same method,':'" the other using few routes from it to the bicyclo[3.2. Iloctane structure (another H202and catalytic SeO,,':'" this reaction also being described is mentioned in Section 8, under the 8,9-epoxide). In methanol, el~ewhcrc.~"'Sharpless confirmed our work, and showed that 81 YO of the limonene was converted into a mixture of the spurious optical activity was due to The stereoisomers of (96) and (97) (1 : 4), 19 YOof the products being reaction is indeed complex (Sharpless mentions 27 products, unidentified. 246 and the carbonyl-containing products have been analysed'"!'), Early work on the oxidation of limonene by chromyl but the main product is always (92). Oxidation by selenium chloride mentioned a number of product~,'~'but later work led dioxide in acetic acid takes a different course, leading mainly to only to a small amount of dihydrocarvone (89).'48 carveyl acetate [truns (85; R = Ac)/cis = 4: 1 ; 40%], the When passed over vanadium pentoxide on pumice at 425 OC, acetate of (1 8) [30 %I, and trans-mentha- 1 (7),8-dien-2-yl acetate limonene yields maleic anhydride.249 (93) [ 10 Yo]. The action of N-bromosuccinimide on limonene should lead Oxidation of limonene by lead tetra-acetate is useful for to allylic bromination ; the first study reported unstable making optically active derivatives of mentha- 1,8( 1 O)-dien-9-01 brominated products, which were converted in 80 YOyield into (18) from the initial product (94) of the rea~tion'~'(cf: the p-cymene (13) by KOH in MeOH.'"" It is likely that the major preparation of lanceo124'),although it was first carried out on brominated product is indeed the expected one (98; X = Br), the ra~emate.'~"Although the limonene anion (c) makes this Taher and Retamar having converted limonene into carvone by reaction apparently redundant, it was still used to make the this route; they used aqueous KOH in dioxane for the aldehydes (65) in 1979.244 hydrolysis.251The action of t-butyl hypochlorite appears to be Oxidation by manganese(rr1) acetate is discussed in Section cleaner; the production of (-)-trans-carveyl chloride (98; X = 10. C1) has been optimized'"' and the latter converted into carveyl The oxidation of limonene by mercuric acetate in acetic acid esters with zinc carboxylates. 23:j View Online

NATURAL PRODUCT REPORTS, 1989-A. F. THOMAS AND Y. BESSIERE 299

(107) (108) (109) X=Se(O)Ph Y=OH (110) X=OH Y=Se(O)Ph (111) X&1 Y=OH (112) X=OH Y=C1 (114) X=NMe2 Y=OH Br (115) X=OH Y=NMe2 6 $0. -\OH OH

Early work on the ozonolysis of limonene was restricted to the possible identification of some (methyloxocyclohexenyl) acetic acids;'j4 a diozonide was also reported.255The reaction occurs very rapidly."j" The study of partial ozonolysis seems to chlorohydrins (1 11) and (1 12) with HCI in ether; only (1 12) date only from 1956, the aldehyde (99) and the corresponding [from the truns-epoxide (108)l gives a crystalline p-nitro- acid being identified after oxidative decomposition (by CrO,) benzoate, After separation, KOH in MeOH enabled the pure of the ozonide (with a small amount of 4-methylcyclohex-3- epoxides to be recovered.280The greater reactivity of the cis- enyl methyl ketone, from ozonolysis of the isopropenyl epoxide towards acids means that this isomer will give trans- group)."j' The aldehyde (100) was mentioned (without its di hydrocarvone (89) before the trans-epoxide begins to react, properties), but it was only compared with a degradation and the latter can then be isolated by fractional distillation.281 product from cembrene.'" The isolation of the C, acid, after The cis-isomer (107) also reacts more rapidly with bromine; reduction and then esterification to (IOI), rather than a C, acid treatment of the bromides (1 13) that were obtained from the of the early work'j4 was also claimed.259The cyclization of the epoxide mixture by its reaction with tributyltin hydride gives aldehyde (99) to an aldehyde (102)260or a ketone (103)''' was 1,8-cineole (26) and the trans-epoxide ( 108).2H2The products studied by Wolinsky [who made (99) from limonene epoxide]."' from treatment of the epoxide mixture with dimethylamine, The optical activity of saturated (99) has been used in further which were the amino-alcohols (1 14) and (1 15), can be readily syntheses."? Mono-ozonolysis has been exploited by a Polish separated, and the methiodides then yield the pure epoxides cgroup,?"3 who have also shown that electrochemical reduction with potassium hydroxide. 283 of the ozonide of (+)-limonene leads to the optically active The presence of the limonene 8,9-epoxides (I 16) and (1 17) alcohol (104), the latter cyclizing to the tetrahydrofuran (105) among the epoxidation products was suspected as early as in acid.?6J.?6.5See also the description of the cyclization of (99) 1926,284but they were in fact only described in 1961 as arising to a cyclopentanone (106) with a rhodium chloride catalyst."6 from the oxidation of limonene by air.lg6 They were later prepared285by using the Payne epoxidation (H,02 and PhCN), 40-50 YOof the epoxidation then occurring in the isopropenyl 8 The Limonene Epoxides group, although the conversion is very low. An alternative Direct oxidation of limonene with perbenzoic acid was first synthesis from methyl 4-methylcyclohex-3-enyl ketone and described by Prileshajew ;pfi7 peracetic acid was later used on dimethylsulphonium methylideZ8'has been preferred. 12j" Methyl (-)-limonene,'68 but only in 1957 on the ( +)-isomer.26gThese 4-methylcyclohex-3-enyl ketone is usually made from isoprene and other oxidations with peracids lead to nearly 1 : 1 mixtures and methyl vinyl ketone, and is racemic, but it can also be of the cis- and trans- I ,2-epoxides (I 07) and (I 08) or (in an early prepared from limonene in optically active form (by ozonolysis case, when H,02 in acetic acid was used) to the menth-8-ene- of limonene 1,2-epoxides and removal of the epoxides after 1,2-di0ls.'"~The cis-oxide (1 07) was prepared stereospecifically separation of the isomers).288The two 8,9-epoxides can be by Polish workers, who used the monotosylate of the 1,2- separated by careful distillation, and they were assigned diol,"O and a full investigation of the two isomers was made by configuration by Horeau's method and correlated with the Newhall."' Oxidation by a peracid gives about 10 YOof the 8,9- uroterpenols (limonene metabolites) (I 18) and (I 19) by Kergo- epoxides (see be lo^),"^ and various other methods slightly mard and Veschambre. 289 Kergomard also converted the alter this proportion. For example, epoxidation of limonene uroterpenols into the optically active a-bisabolols [u.g. (120) with sodium hypochlorite in the presence of a manganese(1rr) from (+)-1im0nene],~~~ but there was a discrepancy between porphyrin gives a ratio of 7 : 1 of l12-epoxidesto 8,9-epo~ides,~'~ the stereochemistry of these and the stereochemistry of and iodosobenzene with an iron porphyrin (which is more bisabolols that had been made in another way,290and an X-ray electrophilic than manganese) gives a ratio of nearly 20: 1 .278 study showed that the configuration of the bisabolol was not Molybdenum-hexacarbonyl-catalysed t-amyl hydroperoxide that attributed to it by Kerg~mard.~"A careful study by yielded 70 YOof the cis-isomer ( 107),274this work having been Carman has now shown that Kergomard's assignments of repeated in order to prepare the menthadienol (76) and the stereochemistries for the uroterpenols (1 18) and (1 19) are trans-isomer of (81) via the selenoxides (109) and (I (the correct (as are, therefore, the stereochemistries of the epoxides). latter had been briefly mentioned independently elsewhere2"). The mixture of uroterpenols is not separable, and neither are A 1: 1 mixture of (107) and (108) can be obtained from the dibromides of the uroterpenols. Finally, the p-nitro- limonene, in 60 Yo yield, with pertungstate-catalysed hydrogen benzoates of the uroterpenol dibromides were separable, and peroxide2" and in 87 % yield by the action of superoxide anion X-ray crystallography of the recovered uroterpenols showed (potassium superoxide and 0- or p-nitrobenzenesulphonyl clearly that the lower-melting isomer has the stereochemistry chloride) on limonene."' (1 1 8).292Carman also showed that the higher-boiling (4R,8R)- Although the isomers (107) and (108) can be separated by isomer of the epoxide (1 16) was converted into (1 18) by careful distillati~n,"~details of several chemical methods have tetramethylammonium hydroxide in dimethyl sulphoxide in 36 been published. One involved their conversion into the hours at 35-40 "C, the other epoxide (I 17) yielding (1 19) under 300 NATURAL PRODUCT REPORTS, 1989

p.. kme CIC1

the same conditions.293 The bisabolol discrepancy remains The episulphides of limonene have been prepared indirectly unexplained. from the epoxides by treating these with thiourea followed by The 8,9-epoxides have been used as intermediates in the a ba~e.~~~.~~~ conversion of limonene into the bicyclo[3.2. Iloctane system. Thermal rearrangement of the 8,9-epoxides to the menth- 1 -en- 9-als (65) was described in 1961,294and this reaction also occurs 9 Addition of a C, Unit to Limonene with acid ion-exchange resins, the reaction going further to After an early study in which no compounds were identified,"06 yield optically active 2,6-exo-dimethylbicyclo[3 .2.l]oct-2-en- Prins suggested structure (123) for a compound that was 7-endo-01 (121) as the major product together with a little of the formed by the acid-catalysed reaction of formaldehyde and 6-endo-methyl isomer.295The racemate of (1 2 1) had already limonene.,07 In 1953, Lombard re-examined the reaction ; he been prepared from geranyl acetate.29' used a zinc chloride catalyst, and suggested that the main The mixture of the four possible diepoxides has been known product was the homo-alcohol (124; R = H),8n8this structure as long as the 1,2-epo~ides.~~'Little work was carried out until being well established by Ohloff (who used an uncatalysed 1955, when it was again described,297and from 1956 onwards reaction in acetic acid)309and by Blomquist et al."" This work there are many patents describing the polymerization of was soon followed by other~,~~.~~~."'"the dioxanes (125) and ' limonene diepoxide ' with Friedel-Crafts catalysts298or photo- (126) also being identified from a perchloric-acid-catalysed sensitized cationic polymerization. 299 Although this is a major reaction.313The n.m.r. spectra of the products [including the a- use of limonene, there exists no description of the individual terpenyl ether of (124; R = H)] were measured by Blomquist, isomers of the diepoxides (122) and they have only one who obtained 80 Oh of the acetate (1 24; R = Ac) by using BF, Chemical Abstracts Service Registry Number. The 1,2-epoxide and acetic anhydride.,l4 group is more reactive towards acid than the 8,9-epoxide The alcohol (124; R = H) was oxidized by Suga and group, and the epoxides of (1 1 1) and (1 12) have been obtained Watanabe.315 The corresponding dihydrogenated aldehyde by treating the mixture of the diepoxides (1 22) with hydrochloric (127) is the main product from hydroformylation of limonene, acid under mild conditions.300When the diepoxides are used in which was first carried out over Raney In methanol synthesis, the mixture is employed without comment (e.g. the (using octacarbonylcobalt as catalyst), the main product is synthesis of hernandulcin by Mori and Kato301). the saturated methyl ether (128), and the aldehydes (129) The epoxides have been used to protect a double bond in were reported from the reaction in acetone,317 although we limonene. Thus Ohloff et al. prepared optically active mentha- question this structure. Later, rhodium catalysts, notably 1,8-dien-4-01 (92) by selenium-dioxide-catalysed oxidation of RhH(CO)(PPh,)3,31*were used, and the rate of reaction of ( + )-limonene cis- 1,2-epoxide (1 07), followed by removal of the limonene was shown to be rather low compared to those of epoxide group by treatment with zinc and acetic acid and other alkene~,~~~although the yields were After the sodium iodide,302but the yield was not good. An alternative initial patenting of (127)y other patents followed.321 suggestion is to reflux the epoxide with lithium and 1 mol % of Phosphite-modified rhodium catalysts increase the rate of biphenyl in ethylene glycol dimethyl ether.303 hydroformylation of lim~nene.~~~Esters of the acid cor- Limonene diepoxide (122) has been examined for cytotoxic responding to (1 27)323and a Mannich product (I 30)324have activity .,04 been made. NATURAL PRODUCT REPORTS, 1989-A. F. THOMAS AND Y. BESSIERE 30 1 kOH&. (145)

Although the Vilsmeier reaction of [CICH=NMe,]+[CI,PO,]- (137) distilled with the limonene that was recovered, thereby with (+)-limonene gives a yield of only 40 % after 6 days, it is lowering the observed optical This preference for very useful in that the (E)/(Z)ratio of the aldehydes (131 ; reaction on the exocyclic double bond is the contrary of that R = H) that are formed is 98 :2; this fact led Dauphin to a rapid found in 4-vinylcyclohexene, where 8 1 % of the monoaddition synthesis of (E)-atlantone (1 32).325An earlier synthesis of (1 3 1 ; takes place on the endocyclic double bond.310 R = H) was a multi-step one from methyl vinyl ketone.'s26The Addition of dihalocarbenes is difficult to stop at the stage of isomers of (131: R = H) have been patented as flavour monoaddition3-'1 unless phase-transfer conditions are em- material^."^ ployed."-', The products vary with the catalyst: PhCH,NEt,+ Delay and Ohloff used the anion (c) for adding one carbon C1- gives the diaddition products (l40), as does Me,,NC,,H,,+ atom to (+)- or to (-)-limonene. Carbonation gives the /j'y Br-,"l" the more hydrophilic Me," CI- yielding specifically unsaturated acid (1 33 ; R = OH).32HThe corresponding ester is monoaddition products, (1 39) being obtained in 68 YO yield."J-' isomerized (by MeONa in MeOH) to the thermodynamic 1,4-Diazabicyclo[2.2.2]octane leads to 100 Oh of mono- mixture of the conjugated esters (131 ; R = OMe) [(E)/(Z)= addition .:IJ5 82: 181. After separation, these were used in the synthesis of or-bisabolenes (1 34) of known stereochemistry.32'H Carbon tetrachloride reacts with limonene either in the 10 Addition of C, or More to Limonene presence of a or under the influence of ultraviolet Acetylation of limonene with acetyl chloride in the presence of light33nto yield an addition product (135), hydrolysis of which stannic chloride at - 100 "C was examined by Cookson et ctl. in (by ethanolic KOH) leads to the optically active acid (131 ; 1974. After dehydrochlorination of the product (using LiF and R = OH),330.331 which was also used331for synthesizing (R,E)- Li,CO:,) they obtained about 30% of the product (141) from atlantone from (+)-limonene. Distillation of (1 35) in ethylene reaction at the isopropenyl double bond, with 22% of the glycol (at 200-2 10 "C) gives methyl 4-methylcyclohex-3-enyl unconjugated ketone (142) and 28 '/O of the conjugated ketone ketone. 33 (143) that had been formed by reaction with the trisubstituted Carbon oxysulphide reacts with limonene in a dimethyl- or double bond."-', With senecioyl chloride (3-methylbut-2-enoyl diethyl-aluminium-catalysed ene reaction to give (I 33 ; R = chloride), the same group synthesized a-atlantone (1 32) after SH).332 dehydrochlorination, about 60 YOof the reaction occurring in The Simmons-Smith reaction of limonene was reported in the isopropenyl group against 29% in the ring."li The 1958 to yield exclusively the product (136) of addition to the acetylation was confirmed by Hoffmann, who did not, however, isopropenyl double bond, the recovered limonene having mention Cookson.:34HAcetylation on C-I0 can be effected by undergone 'little or no racemization' despite a fall by 50% trapping the limonene anion (c)~' with trimethyltin. The being recorded in the rotation.333The structure was established stannane (144) will then react with acetyl chloride to yield (133; by infrared spectrometry.""4 The same compound (1 36) was R = Me) or with senecioyl chloride to give a ratio of 25 : 75 of obtained by the palladium(n)-acetate-catalysed addition of a-atlantone and the direct coupling product (/j-atlantone).:"!' diazomethane.335Kropp et al. prepared all of the possible Erman et al. converted the anion (c) into the alcohol (145) by addition products by irradiation of methylene iodide and allowing it to react with ethylene oxide, and into a variety of limonene in chloroethane; the yields were, after three hours, sesquiterpenes (146) by its reaction with the appropriate alkyl 7% of (136), 47% of (137), and 14% of (l38).""" The halides RX."-'The anion (c) was again used for the synthesis of bicyclo[4.1. Olheptane (1 37) has also been prepared by the sesquiterpenes; its reaction with a functionalized isoprene (147) reaction of the readily accessible dichlorocarbene addition added a C, unit, giving (148), which is an intermediate in the product (I 39) with naphthalenelithi~m,:~:~~but in none of these synthesis of lanceol (146; R = CH,CH=CMeCH,OH).""" papers were the spectral properties of (137) described; a paper Oxidation of limonene by manganese(ri1) acetate in acetic in which the 13Cn.m.r. spectra of the cyclopropanes (1 37) are acid results in radical addition, giving the acid (149), in 38% given does not say how they were prepared and separated.:':'' yield,""' and the lactone (I 50).352Despite this relatively good One of us has confirmed that the major addition product from yield, the reported overall yield of the alcohol (145) was only the Simmons-Smith reaction is indeed (136), but that the two 8 Gardrat converted (149) into (150) directly by the isomers of (137) are also formed (the ratio is about 3: l), and action of formic acid, in 43% isolated yield from limonene.""" the reason that the earlier papers missed this was probably that The isopropenyl group of limonene reacts in an ene reaction View Online

302 NATURAL PRODUCT REPORTS. 1989

(154)

1,2,4-triazoline-3,5-dionewith limonene leads to a double adduct, the structure of which was reported as (160); this supposedly arises in a type of ene reaction, the initial attack on COOEt the isopropenyl double bond and transfer of the proton at C- COOEt &. ph94 being followed by a second addition on the C(4tC(8) double (159) bond.360Unfortunately, the published n.m.r. spectrum does not (157) include the signals for the vinyl protons, and it is not clear why 4 a mechanism like that proposed by Mehta and Singh for the benzyne reaction361 was not considered; this would lead to (161). This type of reaction is always complicated by the tendency of limonene to polymerize in the presence of Lewis acids or R". OH Ziegler catalysts (see above), which is the reason for using low QI. temperatures in the reactions. The ene reaction between limonene and chloral (or bromal) nevertheless gives mostly unrearranged product (1 62) in the presence of aluminium chloride, although the yield is rather In the presence of Ph acids, the tendency to rearrangement of the double bond has to I be considered, as well as the addition of water in aqueous milieu. OYNYO Despite these problems, Julia and co-workers realized the extremely simple addition of dimethylvinylcarbinol to limonene R= yN"xH in formic acid and methylene chloride. They prepared the four isomers of a-bisabolol (I 20) [( + )-(4R,8R)-a-bisabolol from (+)-limonene], and isomers of the ring-substituted alcohol with methyl acrylate if aluminium chloride is present as a (1 63).363 catalyst; the major product is the ester (151), with a small The Ritter reaction of ( +)-limonene with acetonitrile and amount of double-bond-rearranged material (1 52). This work dilute perchloric acid gives the chiral iminium salt (164). The described the preparation of P-bisabolene (1 53) from (1 5 racemate of (164) is similarly obtained from terpinolene (8), A similar reaction, using methyl vinyl ketone, yielded the while (-)-P-pinene (165) yields the enanti~mer.~'~The same ketone (1 54), which was also converted into P-bisabolene reaction, if carried out on a-terpineol (21; R = H) with (1 53),355 but this reaction is difficult to reproduce and propionitrile, is said to yield a product with the enantiomeric unsatisfactory in its application.356The corresponding reaction stereochemistry at what was C-1 of the menthene with propargylates is more successful, methyl propargylate in Cycloaddition of acetonitrile to limonene occurs exclusively on the presence of aluminium chloride giving 39% of the ester the isopropenyl double bond to give the isoxazoline (1 66).:"' (155) with smaller amounts of the two esters (156).357Snider An interesting photochemical addition of acetylacetone to has also described the Me,AICl-catalysed addition of alde- (+)-limonene has been described by a Brazilian group. The hyde~.~~*In place of a carbon-carbon double bond, a carbon- major product (167) (for which full spectral data were given) oxygen double bond has been used; thus diethyl oxomalonate was used to prepare octalones. [It would appear that they were reacts with limonene in the presence of zinc chloride to give the hoping to prepare the eudesmane skeleton; although it was diester (157) in one week.358 formed, the major isomers that were produced were the cis- and Benzyne reacts with limonene in an ene reaction to give the the trans-isomer of ( 168).]367 phenyl-substituted menthadienes (1 58) and (I 59) ; these might A reaction that has given rise to some discussion is that be optically active, because the symmetrical radical is probably between limonene and maleic anhydride. Hultzsch reported in not involved, but, while a very small optical activity was 1939 that, with maleic acid, limonene underwent rearrangement determined in the corresponding reaction with menth- I-ene, it to a-terpinene (9), which then gave a Diels-Alder product. He was not measured in the case of lirn~nene.~~~The reaction of also reported a different reaction with maleic anhydride, which NATURAL PRODUCT REPORTS, 1989-A. F. THOMAS AND Y. BESSIERE 303

S02Me S0,Me SOZCHZAc Scheme 2

starting material.3i9 The reaction of limonene(tricarbony1)iron with aryl-lithium derivatives has been described.'38o A new method for the addition of alkyl groups to the terminal isopropenyl group of limonene consists in the radical addition of methanesulphonyl iodide and elimination, to form the methyl sulphone (1 73). Deprotonation (by butyl-lithium) and alkylation, for example with prenyl bromide, leads to the C-C-coupled product (I 74). The sulphonyl group is removed from (1 74) by acylating the anion to the /?-oxosulphone (1 73, which is reduced by aluminium amalgam to the allylic sulphinic acid. This loses SO, in situ, giving a regiospecifically defined t alkene product. The (0-and (2)-a-bisabolenes (1 34) were made in this

12 Biological Reactions of Limonene It is not the intention of this article to discuss the biogenesis of limonene (leading references are given in a note about the use of natural-abundance deuterium n.m.r. spectrometry to es- tablish the difference between C-9 and C-10 during bio- genesis"82), nor do we deal in detail with its metabolic fate [although the uroterpenols (1 18) and (1 19), which are the Scheme 3 products of its mammalian metabolism, are mentioned above, and are known to play a central role in the biogenesis of other monoterpenoids, notably the 7-oxygenated menthanes of yielded an anhydride of uncertain structure.368 Alder and Perilla j,rut~scens"~].Nevertheless, certain microbial reactions Schmitz re-investigated the reaction, but apparently did not lead to possibly useful routes to optically active oxygenated obtain the same anhydride.36Y Further re-investigation by menthanes. Eschinazi and Pines led to the conclusion that limonene did not Pioneering work on the transformation of limonene by react with maleic anhydride under the conditions that were Aspergillus niger was made by Bhattacharyya et who used by Hultzsch (i.e., simple heating)."7u Radical cyclo- obtained (+)-cis-carveol (82), carvone (75), a-terpineol (2 1 ; copolymerization of limonene with maleic anhydride is well R = H), and p-mentha-2,s-dien-1-01 (76). Later, Dhavalikar known, and probable intermediates are shown in Scheme 2;3i1 isolated a strain of a member of the Enterobacteriaceae which conceivably, the product that Hultzsch obtained was an oxidized (+)-limonene to perillic acid (5) and a dihydro- anhydride, derived from one of these. acid. 38.5 This led to the definition of three pathways for the metabolism of limonene: these are ally1 oxidation, leading to carveol or to the perilla series (the latter is the main pathway), 11 Pyrolysis and Miscellaneous Reactions epoxidation, and rearrangement to dihydrocarvone.:IX6Com- The pyrolysis of limonene (I) has been known since 1884 to plete degradation by Pseudonionas PL-strain in the presence of yield primarily isoprene at 'just below red heat ';3i2 indeed, this arsenite gave a variety of ring-opened products, and ultimately was the best way of preparing isoprene for many years."7" Pines 2-methylpropionic acid, for which a mechanism was pro- and Ryer made the first serious mechanistic study, and correctly posed."8' A patent"" covers the efficient conversion of limonenc deduced that the main reaction pathway was via allo-ocimene into carvone by Corynehac.tcv-iumh)~dr.occrrboc,lustus, which was (1 69), which, at somewhat lower temperatures than those that isolated from soil. were required for a good yield of isoprene, then yielded a Limonene undergoes microbial hydroxylation with mixture of products similar to those obtained after the pyrolysis Corynespora cusiicolr, giving 80 YOof the trans- 1,2-diol from of a-pinenc (2) (Scheme 3)."i'3 The whole problem was rc- (+)-limonene and 76 YO of (90) from (-)-li~onene."~!'Other investigated by Cocker et ul., who characterized a vast number micro-organisms (members of the genera Fusarium, Cihberella, of sub~tances"~"in a mixture that was very similar to that Aspergillus, Streptomyw, and others are mentioned) also obtained from the pyrolysis of pin~ne.'~'"The pyronenes (1 70) work, and the diols can be dehydrated to mentha-2,s-dien-1-01 and (1 71) are present, and, under the conditions that were used, (76).'3X9The same workers have shown that (k)-limonene is the Irish group found up to 25 YO of compound ( 172).:j7,j converted into (+):a-terpineol (21 ; R = H) with Penicillium There are descriptions of a number of addition reactions with digitutum .'M metals scattcrcd about thc oldcr litcraturc, but mostly nothing definite was identified. We might, however, mention the reaction 13 References with antimony tri~hloride'~'~and somc colour reactions with I These figures have been made available from Brazilian sources by phosphomolybdic acid (pink or rcd-orange, dcpcnding on the A. N. Henroz, Firmenich Ltda., S. Paulo, Brazil. co nd i ti o n s ) .'' ' ' 2 W. A. Tilden and W. A. Shenstone, J. Chrm. Soc., 1877, 31, 554. With pcntacarbonyliron, limonene forms mixtures of 3 0. Wallach and W. Brass, Lic4ig.v Ann. Ch~ni.,1884, 225, 291. diene-Fe(CO),, compounds, the dienes being isomers of the 4 0. Wallach, Lic+ig.v Ann. Chem., 1888, 246, 221. 304 NATURAL PRODUCT REPORTS. 1989

5 C. J. Williams, Proc. Roy. SOC.,1860, 10, 516; G. Bouchardat, 35 R. B. Bates, E. S. Caldwell, and H. P. Klein, J. Urg. Chem., 1969, Bull. SOC.Chim. Paris, 1875, 24, 108. 34, 2615 give many earlier references. 6 G. Wagner, Ber. Dtsch. Chem. Ges., 1894, 27, 1636, 2270. 36 W. J. Roberts and A. R. Day, J. Am. Chem. Soc., 1950,72, 1226. 7 W. H. Perkin, jr., J. Chem. SOC.,1904, 85, 416; F. W. Kay and 37 E. H. Ruckel, H. G. Arlt, Jr., and R. T. Wojcik, Polymer Sci. W. H. Perkin, jr., ibid., 1906, 89, 1640. Technol., 1975, 9A, 395. 8 J. J. Gajewski and C. M. Hawkins, J. Am. Chem. Soc., 1986, 108, 38 M. Modena, R. B. Bates, and C. S. Marvel, J. Polymer Sci., Part 838. A, 1965, 3, 949. 9 L. G. Wideman and L. A. Bente (Goodyear Tire & Rubber Co.), 39 J. P. McCormick and D. L. Barton, Tetrahedron, 1978, 34, 325. U.S. P. 4508930, April 2, 1985 [Appl. 632746, July 20, 19841 40 A. N. Misra, M. R. Sarma, R. Soman, and S. Dev (Camphor and (Chem Abstr., 1985, 103, 123729). Allied Products Ltd), Indian P. 147047, Feb. 10, 1979 [Appl. 76 10 For example: in the manufacture of children’s balloons, T. B0191, June 21, 19761 (Chem. Absfr., 1980, 93, 8330); see A. F. Ishihara (Polychem. Kogyo Co. Ltd), Jpn. P. 48-40894, Nov. 27, Thomas and Y. Bessiere, in ‘The Total Synthesis of Natural 1973 [Appl. 45-68 144, Aug. 3, 19701 (Chem. Abstr., 1975, 83, Products’, ed. J. W. ApSimon, Wiley, New York, 1988, Vol. 7. 60951); in household cleaning fluids, Chem. Murk. Rep., 1987, 41 I. I. Bardyshev, A. I. Sedel’nikov, and T. S. Tikhonova, V’estsi 231, No. 21, p. 30, although the low flash point has given rise to Akad. Navuk B. SSR, Ser. Khim. Navuk, 1974, No. 5, p. 61 (Chem. discussion about complete safety in such use (see ibid., April 11, Ahstr., 1975, 82, 57954) list the action of sulphuric, phosphoric, 1988, p. 38); as solvent for cleaning paint brushes, H. Scheidel perchloric, nitric, benzenesulphonic, and toluene-p-sulphonic (Scheidel Georg Jr., GmbH), Ger. Offen. 2843764, April 10, 1980 acids. I. I. Bardyshev, L. A. Popova, E. F. Bunova, B. G. Udarov, [Appl. Oct. 6, 19781 (Chem. Abstr., 1980, 92, 217085); as solvent and Zh. F. Loiko, ibid., 1975, No. 6, p. 85 (Chem. Abstr., 1976,84, of varnishes for cleaning, restoring art objects, C. C. Goetz, Br. P. I65 038) mention salicylic acid and the isoterpinolene rearrange- 1176043, Jan. 1, 1970 (Chem. Abstr., 1970, 72, 88296). See also ment. See also I. I. Bardyshev, V. A. Barkhash, Zh. V. Dubo- Chem. Murk. Rep., Feb. 1, 1988, p. 23. venko, and V. I. Lysenkov, Zh. Org. Khim., 1978,14,1110 (Chem. 11 F. P. McCandless, Flavour Znd., 1971, 2, No. 1, p. 33. Abstr., 1978, 89, IIOOOO). This is only a minute amount of the 12 E. M. Ahmed, R. A. Dennisom, R. H. Dougherty, and P. E. work published by Bardyshev et al., but it is difficult to see any Shaw, J. Agric. Food Chem., 1978, 26, 192. useful result from it all. 13 R. G. Buttery, R. M. Seifert, D. G. Guadagni, and L. C. Ling, 42 R. M. G. Roberts, J, Chem. Soc., Perkin Trans. 2, 1976, 1374. J. Agric. Food Chem., 1971, 19, 524; R. G. Buttery, D. R. Black, This did not include identification of the products, and the D. G. Guadagni, L. C. Ling, G. Connolly, and R. Teranishi, rotation of the limonene remaining was not measured. ihid., 1974, 22, 773. 43 R. Ohnishi, K. Tanabe, S. Morikawa, and T. Nishizaki, Bull. 14 J. Pino, R. Torricella, and F. Orsi, Nuhrung, 1986, 30, 783. Chem. Soc. Jpn., 1974, 47, 571. 15 L. Friedman and J. G. Miller, Science, 1971, 172, 1044; J. 44 E. Pottier and L. Savidan, Bull. Soc. Chim. Fr., 1975, 654. Limacher, Firmenich SA, personal communication. 45 A. Matawowski, Pol. J. Chem., 1980, 54, 469. 16 J. A. Elegbede, T. H. Maltzman, A. K. Verma, M. A. Tanner, 46 V. N. Ipatieff, H. Pines, V. Dvorkovitz, R. C. Olberg, and M. C. E. Elson, and M. N. Gould, Carcinogenesis (London), 1986, 7, Savoy, J. Org. Chem., 1947, 12, 34; V. N. Ipatieff, H. Pines, J.-E. 2047. Germain, and W. W. Thomson, ibid., 1952, 17, 272. 17 D. L. J. Opdyke, Food Cosmet. Toxicol., 1978, 16, 809. 47 G. Acrombessy, M. Blanchard, F. Petit, and J.-E. Germain, Bull. 18 J. W. Regan and L. F. Bjeldanes, J. Agric. Food Chem., 1976,24, Soc. Chim. Fr., 1974, 705. 377, and references cited therein. 48 P. G. Carter, H. G. Smith, and J. Read, J. Soc. Chem. Ind., 1925, 19 A. P. Wade, G. S. Wilkinson, F. M. Dean, and A. W. Price, 44, 543T. Biochem. J., 1960, 101, 727; F. M. Dean, A. W. Price, A. P. 49 J. J. Ritter and J. G. Sharefkin, J. Am. Chem. SOC.,1940,62, 1508. Wade, and G. S. Wilkinson, J. Chem. Soc.., C, 1967, 1893. 50 J. J. Ritter and V. Bogert, J. Am. Chem. Soc., 1940, 62, 1509. 20 R. Kodama. T. Yano, K. Furukawa, K. Koda, and H. Ide, 51 Yu. P. Klyuev and A. I. Lamotkin, Izv. Vyssh. Uchebn. Zuved., Xenohiotica, 1976, 6, 377. Lesn. Zh., 1982, No. I, p. 107 (Chem. Abstr., 1982, 97, 163268). 21 J. Rama Devi and P. K. Bhattacharyya, /ndiun J. Biochem. 52 S. Fujita, Y. Kimura, R. Suemitsu, and Y. 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NATURAL PRODUCT REPORTS, 1989-A. F. THOMAS AND Y. BESSIERE 305

69 D. Wilhelm, T. Clark, T. Friedl, and P. von R. Schleyer, Chem. Natwk B. SSR, Ser. Khim. Navuk. 1985, No. 1, p. 60 (Cliem. Ber., 1983, 116, 751. Abstr., 1985, 103, 105 162). 70 G. Bouchardat and J. Lafont, C.R. Hebd. Seances Acad. Sci.. 102 0. Wallach, Liebigs Ann. Cheni.. 1906. 350, 141 ; F. W. Semmler, 1886, 102, 1555. Ber. Dtsch. Chem. Ges., 1895, 28, 2189. 71 I. W. Humphrey (Hercules Powder Co.), U.S. P. 2 151 769, March 103 S. Andaraman, K. N. Gurudutt, C. P. Natarajan, and B. Ravin- 3, 1939 (Chem. Abstr., 1939, 33, 5007'); Hercules Powder Co., Br. dranath, Tetrahedron Lerr., 1980, 21, 2189. P. 494504 and 494506, Oct. 10, 1938 (Chem. Absrr., 1939, 33, 104 F. Flawitzky, Ber. Drsch. Chem. Ges., 1879, 12. 2354. 2535,) describe the acid-catalysed reaction of methanoi (and other 105 R. Lombard and E. Geiger, Bull. Soc. Chin?. Fr., 1953, 927. alcohols) with dipentene, protecting the product as a solvent and 106 A. Baeyer, Ber. Drsch. Chem. Ges.. 1894, 27, 441. softener. 107 R. M. Bowman, A. Chambers, and W. R. Jackson. J. Cliem. Soc.. 72 A. Baeyer, Ber. Dtsch. Chem. Ges., 1893, 26, 820. C, 1966, 1296. 73 A. Baeyer, Ber. Dtsch. Chem. Ges., 1893, 26, 2558. 108 This figure is taken from J. Verghese. Indian Perfuni., 1972, 16, 35; 74 W. A. Tilden, J. Chem. Soc., 1878, 33, 247. see also C. P. Mathew and J. Verghese, J. Indian Cheni. Soc., 75 0. Wallach, Ber. Dtsch. Chem. Ges., 1895, 28, 1773. 1975, 52, 997 (Chem. Absrr., 1976, 84, 135834). 76 0. Wallach, Liebigs Ann. Chem., 1885, 230, 225. 109 G. W. Gladden, F. Johnson, and G. Watson (Cocker Chemical 77 G. Bouchardat and R. Voiry, C.R. Hebd. Seances Acad. Sci., Co.), Br. P. 1034690, June 29, 1966 [Appl. Nov. I I, 19631 (Clieni. 1887, 104, 996 carried out the first crystallization. 0. Wallach, Absrr., 1966, 65, 10630). Liebigs Ann. Chem., 1893, 275, 104 is credited with it in Beilsrein. 110 H. Wuyts, Br. P. 204754, June 29, 1922 (Cheni. Zenrralbl., 1923, but Wallach only raised the m.pt. The method has recently been IV, 951). patented by Z. P. Golovina, A. I. Bibicheva, and G. P. 11 1 J. Verghese, Perfum. Essenr. Oil Rec.. 1969, 60, 271, lists several. Kudryatseva (Kaluga Perfume), USSR P. 1066981, Dec. 30, 1981 112 K. Hultzsch, Angew. Cliem., 1938, 51, 920. (Chenz. Abstr., 1984, 100, 192 113). 113 A. L. Remmelsburg (Hercules Powder Co.), U.S. P. 2471455, 78 J. Bertram, D. R. P. 67255 (Friedl., 1892,3,892) patented what he May 31, 1949 (Chem. Ahstr., 1949, 43, 6237~). described as the process of Bouchardat and 'Dafout' (see ref. 70); 114 L. J. Kitchen, J. Am. Chem. Soc., 1948, 70, 3608. the error in the second name probably arose from mis-reading 115 Y. Watanabe, Kogyo Kagaku Zasshi, 1960, 63, 153 (CIieni. Absri-., handwritten Frakturschrift. 1962, 56, 4799~). 79 R. Luft, J. Org. Chem., 1979,44,523. This paper also describes the I16 E. Pottier and L. Savidan, Bull. Soc. Chim. Fr., Parr. 2, 1977. 557. reaction of 'acetosulfoacetic acid ' with terpinolene (8). I17 E. Pottier, Bull. Soc. Chim. Fr., Part. 2. 1981, 335. 80 0. Wallach, Liebigs Ann. Cheni., 1908, 360, 82. 118 K. L. Stevens, L. Jurd, and G. Manners, Tetraheilron, 1974, 30, 81 W. A. Tilden, J. Chem. Soc., 1879, 35, 287. 2075. 82 W. H. Perkin, J. Chem. Soc., 1907, 91, 372. 119 A. I. Sedel'nikov, T. S. Tikhonova, N. P. Polyakova, and V. P. 83 R. Lombard and E. Geiger, Bull. SOC.Chim. Fr., 1956, 1564. Larionov, Gidroliz. Lesokhim. Prom.-st.,1985, No. 4, p. 12 (Chem. 84 E. von Rudloff, Can. J. Chem., 1961, 39, 1, and references cited Ahstr., 1986, 104, 19686 gives no details). therein. 120 L. Kuczynski and H. Kuczinski, Roc:. Chem., 1951, 25, 432 85 A. Costa and J. M. Riego, Synth. Commun., 1987, 17, 1373. (Chem. Abstr., 1954, 48, 997211). 86 Y. Matsubara, K. Tanaka, M. Urata, T. Fukunaga, M. Kuwata, 121 R. M. Carman and B. N. Venzke, Ausr. J. Clieni., 1974. 27, 383. and K. Takahashi, Nippon Kagaku Kaishi, 1975, 855 (Chem. 122 D. Masilamani, E. H. Manahan, J. Vitrone, and M. M. Rogic. J. Abstr., 1976, 84, 180398); Y. Matsubara, Y. Hiraga, and M. Org. Chem., 1983, 48, 4918. Kuwata (Yasuhara Yushi Kogyo Co. Ltd), Jpn. Kokai 50- 123 M. M. Rogid and D. Masilamani, J. Am. CIiem. Soc.. 1977, 99, 131946, Oct. 18, 1975 [Appl. 49-39117, April 5, 19741 (Chem. 5220. Abstr., 1976, 84, 150791); M. Nomura and Y. Fujihara, Nippon 124 G. A. Tolstikov, F. Ya. Kanzafarov, Yu. A. Sangalov, and U. M. Kagaku Kaishi, 1983, 1818 (Chem. Abstr., 1984, 100, 192083). Dzhemilev, Neftekhimiya, 1979, 19, 425 (Cliem. Ahstr.. 1979, 91, 87 M. Nomura and Y. Fujihara, Kinki Daigaku Kogakubu Kenkyu 107 252). Hokoku, 1985, 19, 1 (Chem. Abstr., 1987, 107, 40092). 125 G. A. Tolstikov, F. Ya. Kanzafarov, U. M. Dzhemilev, R. G. 88 T. Yamanaka (Takasago Perfumery Co. Ltd), Jpn. Kokai 51- Kantyukova, and L. M. Zelenova, Zh. Org. Khini., 1983, 19, 2075 127044, Nov. 5, 1976 [Appl. 50-48595, April 23, 19751 (Chem. (Chem. Ahstr., 1984, 100, 68452). Abstr., 1977, 86, 190275). 126 E. Demole, P. Enggist, and G. Ohloff, HeIv. Chini. Actu, 1982, 65, 89 H. C. Brown, P. L. Geohegan, G. J. Lynch, and J. T. Kurek, J. 1785. Org. Chem., 1972, 37, 1941. Different proportions of products 127 J. D. Fourneron, L. M. Harwood, and M. Julia, Tetruheclron, were quoted by M. Bambagiotti, F. F. Vincieri, and S. A. Coran, 1982, 38, 693. J. Org. Chem., 1974, 39, 680, but this was not confirmed (see ref. 128 H. Mayr and R. Pock, Chem. Ber., 1986, 119, 2473. 91). 129 G. Klein, D. Arlt, and M. Jautelat (Bayer A.-G.), Ger. Offen. 90 J. Sand and F. Singer, Ber. Dtsch. Chem. Ges., 1902, 35, 3170; 3136580, March 31, 1983 [Appl. Sept. 15, 19811 (Chem. Abstr., Liebigs Ann. Chem., 1903, 329, 166; A. F. Brook and G. F. 1983, 99, 54021). Wright, 1. Org. Chem., 1957, 22, 1314. 130 T. Lesiak and W. Forys, Poi. J. Chem., 1978, 52, 927. 91 C. M. Link, D. K. Jansen, and C. N. Sukenik, J. Am. Chem. Soc., 131 0. Wallach, Liebigs Ann. Chem., 1884, 225, 304; 1885, 230, 262. 1980, 102, 7798. 132 R. M. Carman and B. N. Venzke, Aust. J. Chem., 1971, 24, 92 W. Treibs, Ber. Drsch. Chem. Ges., B, 1937, 70, 589. 665. 93 E. E. Royals, J. Am. Chem. Soc., 1949,71,2568. Some of Royals' 133 J. Verghese, Perfum. Essenr. Oil Rec., 1968, 444. references are unsatisfactory ; correct ones can be traced from 134 W. A. Mosher, J. Am. Chem. Soc., 1947, 69, 2139. Chem. Zentrulbl., 1940, I, 3851. 135 R. M. Carman and B. N. Venzke, Aust. J. Chem., 1971,24, 1727. 94 B. Burczyk, Rocz. Chem., 1970, 44, 1381. 136 R. M. Carman, C. H. L. Kennard, W. T. Robinson, G. Smith, 95 Y. Matsubara, J. Kimura, and M. Noguchi, Yukagaku, 1975,24, and B. N. Venzke, Ausr. J. Chem., 1986, 39, 2165. 166 (Chem. Abstr., 1975, 83, 10428). 137 B. Bochwic, J. Kapukinski, and B. Olejniczak, Roc. Chem., 1971, 96 D. H. Sheffield (Hercules Powder Co.), US. P. 2220462, Nov. 5, 45, 869 (Chem. Abstr., 1971, 75, 110432). 1939 (Chem. Abstr., 1941, 35, 14124). 138 N. Kharasch and C. M. Buess, J. Am. Chem. Soc., 1949,71,2724. 97 P. J. Kropp, J. Am. Chem. Soc., 1969, 91, 5783; F. P. Tise and 139 G. A. Jones, C. J. M. Stirling, and N. G. Bromby, J. Chem. Soc., P. J. Kropp, Org. Synth., 1983, 61, 112. Perkin Trans. 2, 1983, 385. The chirality of the limonene that was 98 J. Riban, C. R. Hebd. Seances Acad. Sci., 1874,79,223;Bull. Soc. used is not obvious in the formulae drawn in this paper. Chim. Paris, 1874, 22, 245. 140 A. Nakatsuchi, J. Soc. Chem. Ind. Jpn. (Suppl. Binding), 1930,33, 99 0. Wallach, Liebigs Ann. Chem., 1888, 245, 244; 0. Wallach and 408; 1932, 35, 376. ' Herr Kremers ', ibid., 1892, 270, 17 I. 141 A. W. Weitkamp, J. Am. Chem. Soc., 1959, 81, 3430, 3434, 3437. 100 R. F. Bacon, Philipp. J. Sci., Sect. A, 1909, 4, 93 (Chem. Abstr., See also C. G. Moore and M. Porter, Tetrahedron, 1959, 6, 10, 1909,3, 2856). Notwithstanding the knowledge of the superiority and a summary of earlier work by J. Verghese, Perfum. Essent. Oil of petroleum ether as a solvent, J. N. Borglin (Hercules Powder Rec., 1969, 60, 25. Co.), U.S. P. 2394359, Febr. 5, 1946, still used HCI in CS, to make 142 J. H. Werntz (E. 1. du Pont de Nemours, Inc.), US. P. 2402698 the chloride as late as 1946 (Beilstein, 4th edn., Vol. 5, p. 236); (Chem. Abstr., 1946, 40, 5765'). Chem. Abstr., 1946, 40, 2470' does not speak of CS,. 143 C. Bertaina, F. Cozzolino, R. Fellous, G. George, and E. Rouvier, 101 V. 1. Lysenkov, T. I. Pekhk, and G. N. Bazhina, Vesrsi Akud. Parfums, Cosmet., Aromes, 1986, 71, 69. 306 NATURAL PRODUCT REPORTS. 1989

144 For example: W. H. Reiland, Jr. (Sun Oil Co.), US. P. 3274 113, 184 H. C. Brown and C. D. Pfaffenberger, J. Am. Chem. Soc., 1967. Sept. 20, 1966 [Appl. Aug. 28, 19631 (Chem. Ahstr., 1966, 65, 89, 5475. 18 4074. 185 H. C. Brown and C. D. Pfaffenberger, Tetrahedron, 1975,31,925. 145 R. M. Scarborough, Jr., A. B. Smith, 111, W. E. Barnette, and 186 P. K. Jadhav and S. U. Kulkarni, Heterocycles, 1982, 18, 169. K. C. Nicolaou, J. Org. Chem., 1979, 44, 1742. 187 C. Narayana and M. Periasamy, Tetrahedron Lett., 1985, 26, 146 P. Sabatier and J. B. Senderens, C.R. Hebd. Seances Acad. Sci., 1757. 1902, 134, 1130. 188 V. K. Gautam, J. Singh, and R. S. Dhillon, J. Org. Chem., 1988, 147 P. Sabatier and J. B. Senderens, C.R. Hehd. Seunces Acad. Sci., 53, 187. 1901, 132, 1256. 89 M. Zaidlewicz and R. Sarnowski, Heterocycles. 1982, 18, 281. 148 G. Vavon, Bull. Soc. Chim. Fr.. 1914, 15, 282. 90 B. D. McKenzie, M. M. Angelo, and J. Wolinsky, J. Org. Chem., 149 W. Ipatiev, Ber. Dtsch. Cliem. Ges., 1910, 43, 3547. 1979, 44, 4042. 150 P. Sabatier and G. Gaudion, C.R. Hebd. Seances Acad. Sci., 1919, 91 R. J. De Pasquale and P. W. Kremer (SCM Corp.), U.S. P. 168, 671. 4579966, April 1, 1986 [Appl. 691 405, Jan. I, 19851 (Chem. Ahstr., 151 N. Zelinsky, Ber. Dtsch. Chem. Ges., 1924, 57, 2058. 1987, 106, 5274). 152 Y. Tanaka, H. Hattori. and K. Tanabe, Bull. Chem. Soc. Jpn., 92 A. Blumann and 0. Zeitschel, Ber. Dtsch. Chem. Ges., 1914, 47. 1978, 51. 3641. 2623. 153 C. A. Brown and H. C. Brown, J. Org. Chem.. 1966, 31, 3989. 93 N. Duffaut, Bull. Mens. lnf. ITERG, 1950, 4, 251 (Chem. Ahstr., 154 H. C. Brown, Agency of Ind. Sci. Tech. 557014537, taken from 1950, 44, 7571a). J. Syntli. Methods, 1982, 76013~. 94 G.0. Schenck, 0.-A. Neumuller, G. Ohloff, and S. Schroeter, 155 G. Jeske, H. Lauke. H. Mauermann, H. Schumann. and T. J. Liebigs Ann. Chem., 1965, 687, 26. Marks, J. An?. Cliem. Soc., 1985, 107, 8 11 I. 195 J. P. Bain, A. B. Booth, and E. A. Klein (Glidden Co.), U.S. P. 156 C. Larpent. R. Dabard, and H. Patin, Tetrtrhedron Lett., 1987, 28, 2863882, Dec. 9, 1958 (Chem. Ahstr., 1959, 53, 8194~). 2507. 196 J. P. Bain, W. Y. Gary, and E. A. Klein (Glidden Co.), U.S. P. 157 W. F. Newhall, J. Org. Chem., 1958. 23, 1274. 3014047, Dec. 19, 1961 [Appl. Aug. 27, 19531 (Chem. Ahstr., 1962, 158 W. Schenk and A. F. Thomas, unpublished work. 57, 12557~). 159 H. van Bekkum. D. Medema. P. E. Verkade, and B. M. Wepster. 197 F. Ferregutti and A. F. Thomas, unpublished work. Red. Truv. Chim. Puj9.s- Bus, 1962, 81, 269. 198 F. Matsubara and T. Kurota. Jpn. Kokai 50-149648, Nov. 29, 160 A. Fischli and P. M. Muller, Hell?. Chim. Actu, 1980. 63, 1619. 1975 [Appl. 49-55619. May 20, 19741 (Chem. Ahstr., 1976, 85, 161 H. Nagashima, T. Ogura, K. Takayama, T. Sato, and T. Matsui 5909); H. A. Taher and G. 0. Ubiergo, Essenze Deriv. Agruni., (Takasago Perfumery Co. Ltd), Jpn. Kokai Tokkyo Koho 54- 1984, 54, 122 (Chem. Ahstr.. 1985, 103, 123716). 12345, Jan. 30, 1979 [Appl. 52-78306, June 30. 19771 (Chem. 199 A. Blumann, H. Farnow, and F. Porsch. J. Cliem. Soc., 1965, Ahstr.. 1979, 91. 20802). 2990. 162 H. Nagashima. T. Ogura. K. Takayama. T. Sato. and T. Matsui 200 Y. Matsubara, M. Kaneko, and H. lwamuro (Takasago Per- (Takasago Perfumery Co. Ltd), Jpn. Kokai Tokkyo Koho 54- fumery Co. Ltd), Jpn. Kokai Tokkyo Koho 54-1 15326, Sept. 7, 9247, Jan. 24. 1979 [Appl. 52-72 77 I. June 2 I, 19771 (Chcni.Ahstr., 1979 [Appl. 53-22041, March I, 19781 (Chem. Ahstr., 1980, 92, 1979. 90, 204308). 94067). 163 H. Pines and H. E. Eschinazi, J. Am. Cliem. Soc., 1956, 78, I 178. 201 H. Iwamuro, T. Ohshio, and Y. Matsubara, Nippon Kuguku 164 R. Martin and W. Gramlich (BASF), Ger. Offen. 3607448. Sept. Kuishi. 1978, 6, 909 (Cliem.Ahstr., 1979, 90. 23267). 10, 1987 (Cliem. Ahstr., 1987, 107, 219472). 202 S. R. Dolhyj and L. J. Velenyi, Ind. Eng. Cliem.,Prod. Res. Dev., 165 T.-L. Ho, Chem Id. (London), 1987, 295. 1980, 19, 194. 166 R. P. Linstead, K. 0. A. Michaelis, and S. L. S. Thomas, J. Clwni. 203 B. 8. Jones, B. C. Clark, Jr., andG. A. lacobucci, J. Cliromutogr., Soc.. 1940, I 139. 1980, 202, 127; the paper is duplicated in Tetruhetlron. 1981, 37. 167 H. E. Eschinazi and E. D. Bergmann, J. Ani. Chcni. Soc., 1950. Suppl. No. 1. p. 405. 72. 5651. 204 S. Schroeter, Diss., Gottingen, 1962; G. 0. Schenck, K. Gollnick. 168 K. Kindler and K. Luhrs, Liebigs Ann. Ch~m.,1965, 685, 36. G. Buchwald, S. Schroeter, and G. Ohloff, Liebigs Ann. Chew.. 169 K. Kindler and K. Luhrs, Chem. Ber.. 1966, 99, 227. There are a 1964. 674. 93. few incorrect formulae in these two papers, and one in J. March. 205 Kuraray Co. Ltd, Jpn. Kokai Tokkyo Koho 56-34779, April 7. 'Advanced Organic Chemistry', 3rd edn., Wiley, New York, 1985, 1981 [Appl. 54-1 11 309. Aug. 28, 19791 (Cheni. Ahstr., 1981, 95, p. 1107, where limonene is shown to be dehydrogenated to a 133 193); Toray Industries Inc., Jpn. Kokai Tokkyo Koho 55- menthatriene instead of to p-cymene. 1 18421, Sept. 11, 1980 [Appl. 54-25649, March 7, 19791 (Chcw. 170 G. Brieger and T.-H. Fu, J. Chuw. Soc., Chrm. Commun., 1976, Ahstr.. 1981, 94, 139315). 754. 206 G. 0. Ubiergo, G. Malinskas, and H. A. Taher, €.s.sen:e Deriv. 171 F. W. Semmler. Liehigs Ann. Chem., 1904, 34, 3125. Agrum., 1986, 56, 23 (Chem. Ahstr., 1987. 107, 134504). 172 R. Dulou and Y. Chretien-Bessiere, C. R. Hrhrl. Secrncc~.~Aceid. 207 E. Murayama and T. Sato. Totrtiheeiro~iLett., 1977, 4079; Biill. Sci., 1959, 248, 216; Bull. Soc. Chim. Fr., 1959. 1362. Clicwi. Soc. Jpn.. 1978, 51. 3022. 173 H. C. Brown and G. Zweifel, J. Am. Chem. Soc., 1961, 83, 208 A. Kohda and T. Sato, J. CIwi. Soc., Cheni. Coiiimiin., 198 I, 95 I ; 1241. T. Sato, K. Maemoto, and A. Kohda. ;hid.. p. 1 116. 174 K. Ziegler, F. Krupp, and K. Zosel, Angcw~.Cliem., 1955, 67, 425; 209 C. W. Wilson, 111, and P. E. Shaw (U.S. Dept. of Agriculture). Liebigs Ann. Cheni., 1960, 629, 241 ; cf: B. A. Pawson, H.-C. U.S. Pat. Appl. 665741, March 1 I. 1976 (Chcwi. Ahstr., 1977. 87. Cheung, S. Gurbaxani, and G. Saucy, J. Am. Chem. Sol.., 1970. 136045). 92, 336. 210 A. Heumann, M. Reglier, and B. Waegell. Angeii.. Cheni..Int. Ed. 175 J. Albaiges, J. Castello, and J. Pascual, J. Org. Chmi., 1966. 31, Etigl., 1982, 21, 366. 3507. 21 I A. Heumann, F. Chauvet. and B. Waegell. Tclruhcdroti Lctt.. 176 G. Ohloff, W. Giersch, K.-H. Schulte-Elte, and E. sz. Kovlits, 1982,23,2767; F. Chauvet, A. Heumann. and B. Waegell. J. Org. Heh. Cliim. Actu, 1969, 52, 1531. CIicwi., 1987, 52, 1916. 177 K.-H. Schulte-Elte and G. Ohloff, Helv. Chin?. Actcr, 1967, 50, 212 W. A. Tilden, J. Chcwi. Soc., 1877, 31, 554. 153. 213 0. Wallach. Lic4ig.s Ann. Clwni.. 1888. 245, 255; 1889, 252. I LO; 178 J. F. Blount, B. A. Pawson, and G. Saucy, Chcw. Commun., 1969, 1904, 336, 43. 715. 2 14 A. Baeyer, Ber. Dtsch. Chem. Ges., 1896. 29, 8. 179 1. Uzarewicz and A. Uzarewicz, Pol. J. Chem., 1979, 53, 1989; see 215 C. Bordenca and R. K. Allison. Itid. Eng. Chwi., 1951. 43, 1196; also ref. 189. R. K. Allison (Food Machinery and Chemical Corp.), U.S. P. 180 H. C. Brown, S. U. Kulkarni, C. Gundu Rao, and V. D. Patil, 2485 180, Oct. 18, 1949 (Clieni.Ahstr., 1950, 44, 5291.0; A. Sattar. Tetrahedron, 1986, 42, 55 15. R. Ahmad, and S. A. Khan. Puk. J. Sci. /rid Rcs.. 1980. 23. 177 181 A. V. Kuchin, G. A. Tolstikov, V. P. Yur'ev, V. I. Ponomarenko, (Chcwi. Ahstr., 1981, 95, 49 182) report 90% of the nitroso- G. N. Kurilenko, R. A. Nurushev, and L. I. Akhmetov, Zh. chloride, from which carvone oxime is obtained in 92 '/o yield : see Obshch. Khim., 1980, 50, 91 I (Chem. Ahstr., 1980, 93, 71 842). also A. Nuiiez Selles and R. Tapanes Peraza. RPV.Cicwc. Quini.. 182 N. Satyanarayana and M. Periasamy, Tetrahedron Lett., 1984.25, 1981, 12, 165 (Chcni. Ahstr., 1983, 98, 89672). and the 74.7% yield 2501 ; P. Le Maux and G. Simonneaux, J. Mol. Cutal., 1984, 26, of (-)-carvone by M. T. Magalhaes. M. Koketsu, and V. C. 195. Wilberg (EMBRAPA). Braz. Pedido 83-00 508, Sept. 27, 1983 183 H. C. Brown and K. J. Murray, Tetrahedron, 1986, 42, 5497. [Appl. 82-508, Jan. 29, 19821 (Chcw. Ahsrr. 1984. 100. 139397). NATURAL PRODUCT REPORTS. 1989-A. F. THOMAS AND Y. BESSIERE 307

216 0. S. Rothcnburpcr. S. B. Krasnoff. and R. B. Rollins. J. Clicwi. This work seems to be based on a thesis of H. Neresheimer; cf. Etlirc.., 1981. 57. 741. Clicw. Zentrolhl.. 1916, 11. 993. 217 A. J. Mulder and R. V~III Heldcn (Shell Intern~ItionilleRcSciIrCh 255 C. C. Spencer, W. I. Weaver, E. A. Oberright, H. J. Sykes, A. L. Maatschappij B.V.), Br. P. 2008573. Junc 6. 1979 [Appl. 77- Barney. and A. L. Elder, J. Org. Clrrw., 1940. 5. 610. 43499. Oct. 19. 19773 (Chcvii. Ah.~lr..1980, 92, 76734). 256 E. P. Grinisrud, H. H. Westberg, and R. A. Rasmussen. In/. J. 218 M. Nakai. K. H>trdii. and M. Nishiniura (Ube Industries Ltd). Chcni. Kincr. Sjnip., 1975. I. 183 (quoted by R. Atkinson and Jpn. Kokai Tokkyo Koho 53-1 11 038. Sept. 8. 1978 [Appl. 52- W. P. L. Carter, Clicwi. Rev.. 1984, 84, 437). 24741. March 9, 19773 (Chwi. Ahsrr., 1979. 90. 72366). 257 S. Kataoka and Y. Hanada. Bull. Agric. Clic~m.Soc. Jpii.. 1956, 219 K. Fujita. Nippon Krrgrikii Zmdii. 1960. 81. 676 (Chern. Ahstr .. 20, 223. 196 I, 55. 65 16c.); J. Sci. Hiroshitiirr L/ni~..Scr. '4 Math.. Plij*s.. 258 D. F. Wiemer. J. Meinwald. G. D. Prestwich, and I. Miura. J. Clrcwi., 1960. 24. 691 (Clicvii. Ahti... 1962. 56. 47991). Org. Cheni., 1979, 44, 3950. 220 W. G. Dauben. M. Lorber. and D. S. Fullcrton, J. Org. Chcni., 259 S. Kataoka and Y. Hanada, Bull. Agric. Cheni. Soc. Jpn.. 1956, 1969. 34. 3587. 20. 229. 221 A. J. Pearson. Y.-S. Chcn. G. R. Han. S.-Y. Hsu. and T. Ray. J. 260 J. Wolinsky, M. R. Slabaugh, and T. Gibson, J. Org. Chem., Clicvli. Sot.. Pdin Trotis. I. 1985. 267. 1964. 29. 3740. 222 V. Niiriisimhiin. R. Rathore. and S. Chandrasekaran, Sj~/h. 261 J. Wolinsky and W. Barker, J. Am. Chcm. Soc.. 1960. 82. 636. Coiiiniiui., 1985. 15. 769. 262 For example: R. R. Heath, R. E. Doolittle, P. E. Sonnet, and J. 223 N. Chidambaram and S. Chandrasekaran. J. Org. Clieni., 1987, H. Tumlinson, J. Org. Cheni.. 1980, 45, 2910, used both (+ )- and 52. 5048. (-)-limonene for the synthesis of the sex pheromone of the white 224 S. Glasstone and H. E. Stanley. Truns. Ekt~~rroc~hmi.Soc .. 1947, peach scale (P.seuduulacaspis pentugona); L. M. Jackman, R. L. 92. 327. Webb, and H. C. Yick. J. Org. Chem., 1982,47, 1824, synthesized 225 M. Y. Duarte. H. A. Landerreche. C. M. Marschoff, and M. E. chirai 4-isopropylpiperidin-2-one from the saturated acid cor- Martins. Elec*trocliim. Acrcr. 1983. 28. 33 1. responding to (99); see also the synthesis of acorenone from the 226 T. Shono. A. Ikeda. J. Hayashi. and S. Hakozaki, J. Am. Clicwi. same acid, G. L. Lange, E. E. Neidert, W. J. Orrom, and D. J. Soc.. 1975. 97. 4261. Wallace, Can. J. Chem., 1978, 56, 1628. 227 M. Kasano. Y. Sakai, K. Yokoi, Y. Matsubara, and C. Yoshi- 263 J. Kulesza and J. Kula, Riechst., Aromen, Koerperpfiegem., 1975, mura, Kink; Daiguku Rikogakuhri Keiikjw Hokoku, 1977, 12, 93 25, 317; J. Podlejski and J. Kula, Riechsr., Aromen, Kosmet., 1980, (Chcwi. Ahsrr.. 1977, 87, 184699). 30, 41 ; J. Kula and J. Podlejski, Liebigs Ann. Chem., 1985. 2098. 228 V. Montiel. M. Lopez-Segura. A. Aldaz, M. Grande. and F. 264 J. Gora, K. Smigielski, and J. Kula, Sjnthesis, 1982, 31 I. Barba. Elecvroc-hini. Acta. 1984. 29, 1 123. 265 J. Kula, Liebigs Ann. Chem., 1983, 890. 229 G. Wagner. Ber. Dtsch. Chem. Ges., 1890, 23, 2307. 266 Tennen Yuki Kagobutsu Toronkai Koen Yoshi.shu, 26th, 1983, 230 N. A. Milas and S. Sussman, J. Am. Chem. Soc., 1937, 59, 2345. pp. 299-306 (Chem. Ahstr., 1984, 100, 192085). 231 J. Sword. J. Cheni. Soc., 1925, 127, 1682. 267 N. Prileshajew, Ber. Dtsch. Chem. Ges., 1909, 42, 4814. 232 Y. Sebe. J. Clieni. Soc. Jpn.. 1941, 62, 16 (Chem. Abstr., 1943, 37, 268 B. A. Arbusow and B. M. Michailow, J. Prukt. Chem., 1930, 127, 4063l); S. Hirayama. ihid.. 1938, 59, 229 (Chem. Abstr., 1938, 32, 92. 9072l). 269 S. M. Linder and F. B. Greenspan, J. Org. Chem., 1957, 22, 949. 233 Y. Sakuda, Bull. Chem. Soc. Jpn., 1969, 42, 3348. 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