Linalool cyclization

Tetrabromocyclohexa-2,5-dienone in methylene chloride promotes the biomimetic cyclization of linalool and dehydrolinalool to (60 R=vinyl or ethynyl) as the major product with minor amounts of (61 X = Br, R = vinyl or ethynyl) in contrast to brominative cyclization with A/ -bromosuccinimide when (61 X = Br,... 

Esterification of linalool requires special reaction conditions since it tends to undergo dehydration and cyclization because it is an unsaturated tertiary alcohol. These reactions can be avoided as follows esterification with ketene in the presence of an acidic esterification catalyst below 30 °C results in formation of linalyl acetate without any byproducts [71]. Esterification can be achieved in good yield, with boiling acetic anhydride, whereby the acetic acid is distilled off as it is formed a large excess of acetic anhydride must be maintained by continuous addition of anhydride to the still vessel [34]. Highly pure linalyl acetate can be obtained by transesterification of tert-butyl acetate with linalool in the presence of sodium methylate and by continuous removal of the tert-butanol formed in the process [72]. 

Acid-catalyzed cyclization and dehydration of citral and linalool give rise to several compounds that occur at comparatively high concentrations and contribute to the typical aroma of distilled lime oil (e.g., 1,4-cineole [470-67-0], 1,8-cineole [470-82-6], 2,2,6-trimethyl-6-vinyltetrahydropyran [7392-19-0], and 2-(2-buten-2-yl)-5,5-dimethyltetrahydrofuran [7416-35-5]) [406-406b, 408-412a]. 

The synthesis of tetrahydrofurans through cyclization via epoxide ring opening has been well investigated and has been applied to the preparation of a-bisabolol oxides (69IJC1060) and linalool oxides (77H(6)1365) and by Kishi et al. in the synthesis of lasalocid A (195), where the epoxide pathway resulted in a stereospecific construction of six out of the ten chiral centers (Scheme 93) (78JA2933). 

Cyclization of unsaturated epoxides.1 Reaction of the epoxy alcohol (2) derived from linalool with cobaloxime(I), (1), forms the P-hydroxycobaloxime 3. 

Arigoni and co-workers128 used isotopic labeling experiments to show that the cyclization of linalool to a-terpineol occurs at the center of the double bond rather than at its extremities. In principle, the intermediate cation 30 could adopt an elongated conformation 31 leading to 33 (which is not found) or the folded conformation 32, where attack of the carbocation at the center of the double bond gives the observed product 34. 

Three new monoterpenoid lactones, (28)—(30), isolated from the urine of koala bears fed on Eucalyptus punctata, appear to have arisen from the cyclization of carboxylic acids formed as hydrolysis products of glucuronide conjugates from the metabolism of a- and /3-pinenes.70 Linalool injected into various plant species has been claimed to be converted into a-terpineol and other monoterpenoids.71 However, direct interconversions cannot be inferred from this type of non-radioactive tracer study. The terpenoids alleged to be produced may well be stress metabolites or be formed b secondary processes that perturb the usual pattern of terpenoid formation. 

This new cyclization was used for synthesis of eucalyptole (equation I) and linalool (equation II). 

Polyene cyclization. Cyclization of dienes by oxymercuration ordinarily is not stereoselective. However, the presence of an allylic hydroxyl groups can increase the stereoselectivity. Thus oxymercuration-demercuration of linalool (1) under the best conditions leads mainly to the iridanols 2 and 3, which constitute 85% of the... 

The one-pot epoxidation/cyclization of unsaturated terpene alcohols, for example linalool and a-terpineol, to mono- and bicyclic derivatives also required the catalysis of large-pore Ti,Al-P (Scheme 18.10) [93, 107]. 

Two isomers of linalool oxide have been isolated from lilac Syringa vulgaris L.) flower oil, " and their syntheses from ( + )-linalyl acetate have been effected following Scheme 19 the four diastereoisomers of the lilac alcohols (323) were separated by gas chromatography.It should be added that the aldehydes in this series were prepared elsewhere by direct cyclization with sodium carbonate in methanol of the selenium oxide oxidation product of linalyl acetate. " ... 

In their strategy, three methods were investigated for the synthesis of aldehyde 86. Initially, linalool was selected as the starting material (Scheme 19). Cyclization with TBCO afforded a mixture of tetrahydropyrans (89 and 90, 10 6.9) and tetrahydrofurans (88) in 56% and 24% yields respectively. The preference for the stereoselective formation of pyran 89 over the desired compound 90 was postulated to be associated with the chair transition states shown in Scheme 19. Presumably, the diaxial interaction between the Ci methyl group and the vinyl substituent R in intermediate 92 is less severe than those between the two methyl groups in intermediate 93, leading to the undesired tetrahydropyran 89 as the major product [51]. 

Biomimetic cyclization of polyenes as routes to diterpenoids continues to be explored. The brominative cyclization of geranyl-linalool afforded160 the 3-bromo-manoyl oxide and the boron trifluoride-catalysed cyclization of the diepoxide of p-homogeranylanisole gave 13-methoxy-A-homo-4a-oxopodocarpatrienol.161 Some further synthetic studies of anhydroverticillol have been reported.162... 

Two elements of the cyclization have yet to be addressed the isomerization of geranyl pyrophosphate to linalyl pyrophosphate (or the equivalent ion-pair) and the construction of bicyclic skeleta. Studies on the biosynthesis of linalool (61), and on the analogous nerolidyl system in the sesquiterpene series (52), have shown this allylic transposition to occur by a net suprafacial process, as expected. On the other hand, the chemical conversion of acyclic or monocyclic precursors to bicyclic monoterpenes, under relevant cationic cyclization conditions, has been rarely observed (47,62-65) and, thermodynamic considerations notwithstanding (66), bicyclizations remain poorly modeled. 

Finally, let us consider the by-products of linalool transformation by I3 cinerea. The formation of 3,9-epoxy-p-menth-l-ene (27), the character impact compound of fresh dill herb (14), can be understood by allylic rearrangement of (E)-2,6-dimethyl-2,7-octadiene-1,6-diol (19) to the corresponding hydroxygeraniol (-nerol). This compound is known to undergo cyclization to the epoxy derivative (27) under acidic conditions (15). 

Many hydroxylated linalools [including compounds 105, 106, 108, and 110, both (Z)- and ( )-isomers], as well as the epoxides of both furanoid (109) and pyranoid (see section on pyrans) linalyl oxides, have been identified in papaya fruit (Carica papaya). At the same time, the first reported occurrence of die two linalool epoxides (112) in nature was made. These epoxides are well known to be unstable and easily cyclized (see Vol. 2, p. 165) and have been made by careful peracid oxidation of linalool. An interesting new method has now been described. While the vanadium- or titanium-catalyzed epoxidation of geraniol (25) gave the 2,3-epoxide (see above), as does molybdenum-catalyzed epoxidation with hydrogen peroxide, the epoxidation of linalool (28) with molybdenum or tungsten peroxo complexes and hydrogen peroxide led, by reaction on the 6,7-double bond, to 112. ... 

The plinols (355), thermal cyclization products of linalool (28) (Vol. 2, p. 61, Refs. 208 and 216 Vol. 4, p. 494, Ref, 285), have been synthesized by a new route, starting with Diels-Alder additions to 2,5-dimethylfuran. The adduct with maleic anhydride was said to be exo-, 356, although no evidence was given, and the only reference quoted concerning this compound does not refer to stereochemistry. The adduct of furan and maleic anhydride is indeed known to be entirely converted to the exo-isomer after initial formation of the endo-... 

There are many compounds closely related to natural products that are associated with novel syntheses. Dehydrated linalool oxide 891, for example, is conveniently made by chlorination of linalool acetate (28 acetate) with calcium hypochlorite, then cyclization of the allyl chloride 892 with sodium hydroxide and Aliquat 336 in methanol. Once obtained 891 was converted to the dehydrogenated lilac alcohols 893 (R = H). The monoepoxides (on the isopropenyl group) were transformed in a mixture of diacetates that were pyrolyzed to the acetates 893 (R = Ac). Linalool oxide epoxides (894) have... 

Attention is drawn to the synthesis the oxygenated linalool oxide 896. This compound (and other stereoisomers) is not a naturally occurring monoterpenoid, but a fragment required in the synthesis of a calcium ion-selective ionophore, ionomycin, and was made from hydroxygeranyl acetate (113, R = Ac), then Sharpless conditions for introducing a chiral epoxide were used. The vital step is the cyclization of 897 by epoxidizing again under Sharpless conditions (titanium tetraisopropoxide and diethyl tartrate) when the product 896 is obtained. ... 

Aldol condensation of acetone with formaldehyde gives methyl vinyl ketone. This can undergo the ene reaction with isobutylene to give an isomer of methylheptenone, 2-methylhept-l-en-6-one. Isomerization to methylheptenone is easy using an acidic catalyst, and acetylene can be added to either isomer. From methylheptenone, the process leading to linalool is the same as in the examples above. If the acetylene is added to 2-methylhept-l-en-6-one, then isodehydrolinalool results. This is actually advantageous when the monoterpene unit is to be used as a precursor for ionones and vitamins, since the 1,1-disubstituted double bond is more reactive in the cyclization reaction than is the normal 1,1,2-trisubstituted bond. (The cyclization reaction is described in detail below.) The preparation of these two acetylenic ketones is shown in Scheme 4.9 and is the basis of a process commercialized by BASF. 

Ionization of allylic systems, generating stabilized ions, is one of the most successful methods of inducing cyclization. On treating chiral linalool with protic acids, a 6-exo reaction takes place via a chairlike transition state (concerted mechanism) but the configuration is inverted on building chiral limonene (10)14. 

The predominant product of polyphosphoric acid cyclization of dehydro-linalool (cf. Vol. 1, p. 9) is dependent upon the amount of acid and upon the reaction temperature. ... 

The kinetics of the solvolysis of linalyl p-nitrobenzoate were published in note form 18 years ago, but a full discussion of the reaction, including the mechanism for retention of optical activity in the cyclized products, has now been published as one of the Winstein memorial papers. Another paper on the reaction of linalool with phosphorus pentachloride reports 88 % yield of a ca. 3 1 mixture of geranyl and linalyl chlorides (after 4 h at —10 °C). Acetylation of linalool is notoriously fickle on account of ready rearrangements now a method using t-butyl acetate and sodium methoxide is said to give a 90% yield of the unrearranged acetate. The rearrangements involved in the acid decomposition of the... 

The biogenetic pathway of formation of cleomeolide may be envisaged to arise either by the oxidative cyclization of geranyl linalool expoxide [10] as outlined in Scheme 1 or via head-to-tail cyclization of geranyl geranyl pyrophosphate [11] as shown in Scheme 2. However, one would be tempted to prefer the former considering the oxygenation pattern in the molecule. 

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