Nerolidol synthesis

A new synthesis of nerolidol (10) from geranyl bromide has been achieved by the use of the hydroxy-sulphoxide (9)/ a new prenylating agent (Scheme 3)7 ... 

Industrial synthesis of nerolidol starts with linalool, which is converted into ger-anylacetone by using diketene, ethyl acetoacetate, or isopropenyl methyl ether, analogous to the synthesis of 6-methyl-5-hepten-2-one from 2-methyl-3-buten-2-ol. Addition of acetylene and partial hydrogenation of the resultant dehydroner-olidol produces a mixture of cis- and trans-nerolidol racemates. 

Terpenes important for both fragrances and flavours can be prepared from citral, such as citronellol, linalool, nerolidol, geraniol, farnesol and bisabolol. Citral is also an important starting material for the synthesis of vitamins A and E, carotenoids and other flavour and fragrance compounds like ionones. Most of the /3-ionone synthesised is probably used for vitamin A synthesis. 

As mentioned before (2.1.1) Arfmann et al. [133] studied the co-hydroxylation of the sesquiterpenes nerolidol and famesol and the related compounds neryl- and geranylacetone. This was done because co-hydroxylated sesquiterpenes are important intermediates in the synthesis of industrially used fragrances and flavours. Aspergillus niger ATCC 9142 and Rhodococcus rubropertinctus DSM 43197 were unable to hydroxylate nerylacetone or its -isomer geranylacetone, at the co-position of the molecule. Incubation of nerylacetone with Mucor circinelloides CBS 27749 for 25 hr resulted in seven transformation products, including one co-hydroxylation compound, in 3% yield [140]. 

With tertiary alcohols, there is even more choice. The last example in the box is a step in a synthesis of the natural product, nerolidol. But the chemists in Paris who made this tertiary alcohol could in principle have chosen any of these three routes.. three routes to a tertiary alcohol... 

This three-carbon homologation was used in a synthesis of the diterpene (— )-aplysin-20 (4) from nerolidol (equation 1). ... 

The structure of nerolidol, C]5H260, a terpene found in oil of neroli, was established by the following synthesis ... 

By contrast, acetylenic chemistry has been developed by Hofmann La Roche based on the use of propanone, diketene and acetylene as a pathway to linalol from the precursors methylheptenone and dehydrolinalol which itself has in turn been utilised for the synthesis of the (Cl3) ionones and subsequently in related methodology for the C15 alcohol, nerolidol all of which are referred to again subsequently. 

An alternative synthesis has been described also from nerolidol and although it is lengthier it comprises some unusual chemistry (ref.21). 

The synthesis of symmetrical i -carotene (152), which has 7,8 and 7, 8 single bonds, was carried out efficiently according to the C15 + C10 + C15 = C40 strategy by use of the Wittig reaction to couple the building blocks [84]. frans-Nerolidol (154) was converted, with phosphorus tribromide and triphenylphosphine, into the Ci5-phosphonium salt 155. The Wittig reaction with the Cio-dialdehyde 45 and BuLi gave -carotene (152) in an overall yield of 45% referred to 154 (Scheme 34). 

Hydroxy-frani-nerolidol (472a) is an important precursor in the synthesis of interesting avor of a-sinensal. Hrdlicka et al. (2004) reported the biotransformation of trans- (469) and CM-nerolidol (462) and cis-/trans-mixture of nerolidol using repeated batch culture of A. niger grown in... 

The utility of haloboration-conjugate addition sequence has been demonstrated in the selective synthesis of several natural products such as sulcatol, trans-geranylacetone, and trans-nerolidol (Scheme 13.4) [20]. 

Linalool can be converted to geranyl acetone by the Carroll reaction (156). After transesterification with ethyl acetoacetate, the intermediate ester thermally rearranges with loss of carbon dioxide. Linalool can also be converted to geranyl acetone by reaction with methyl isopropenyl ether. The linalyl isopropenyl ether rearranges to give geranyl acetone. Geranyl acetone is an important intermediate in the synthesis of isophytol [505-32-8], famesol [106-28-5], and nerolidol [40716-66-3]. Isophytol is used in the manufacture of Vitamin E and thus linalool is a key intermediate in the synthesis of the latter. All of these reactions are shown in Fig. 8.55 in the section on nerolidol. 

Corynebacterium sp. and Staphylococcus epidermis, the bacteria mainly responsible for the decomposition of human perspiration (348). It is available both as a homochiral isolate from plant sources and as a racemate from synthesis, through the acid-catalyzed cyclization of nerolidol (349). It is an almost colorless oil with a faint, sweet floral odor and has fixative properties in perfumery. However, its main use is as an antiphlogistic agent in cosmetics. 

Based on the fascinating biogenetic relationships that exist among monocyclic, spiro and tricyclic sesquiterpenes, several unusually simples routes have been devised to the cedrane skeleton. " One such synthesis of Q -cedrene is outlined below, and proceeds from nerolidol, presumably along lines of the proposed biogenesis. ... 

The titanium- ate complexes of a-methoxy allylic phosphine oxides, generated in situ by reaction of the corresponding lithium anion and Ti(0-i-Pr)4, condense with aldehydes exclusively at the a-position to produce homoallylic alcohols in a diastereose-lective fashion. The overall result is the three-carbon homologation of the original aldehyde, and this protocol has been used in a synthesis of (-)-aplysin-20 from nerolidol. The titanium- ate complex produced by reaction of the chiral lithium anion of an ( )-crotyl carbamate with Ti(0- -Pr)4 affords -y-condensation products (homoaldols) on reaction with aldehydes. Allyl anions produced by the reductive metalation of allyl phenyl sulfides condense with a,p-unsaturated aldehydes in a 1,2-manner at the more substituted (a) allyl terminus in the presence of Ti(0-i-Pr)4. 1,2-Addition of dialky Izincs to a,p-unsaturated aldehydes can be achieved with useful levels of enantiocontrol when the reaction is conducted using a chiral titanium(IV) catalyst in the presence of Ti(0- -Pr)4 (eq 20). Higher ee values are observed when an a-substituent (e.g. bromine) is attached to the substrate aldehyde, but a -substituent cis-related to the carbonyl group has the opposite effect. 

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