Myrcene synthesis

The production of myrcene (7) from P-pinene is important commercially for the synthesis of a wide variety of flavor and fragrance materials. Some of those include nerol and geraniol, citroneUol (27) and citral (5). 

Another synthesis of Lyral (51) consists of the reaction of myrcene with acrolein to give the myrac aldehyde [37677-14-8] (52). The aldehyde group, which is sensitive to acid hydration conditions with strong acids, has to be protected by formation of the morpholine enamine. The enamine is then hydrolyzed on workup after the acid-catalyzed hydration to produce Lyral (93—95). 

A synthesis of optically active citroneUal uses myrcene (7), which is produced from P-piaene. Reaction of diethylamine with myrcene gives A/,A/-diethylgeranyl- and nerylamines. Treatment of the aHyUc amines with a homogeneous chiral rhodium catalyst causes isomerization and also induces asymmetry to give the chiral enamines, which can be readily hydrolyzed to (+)-citroneUal (151). 

The above system has been used for the reaction of EtjNH with myrcene to give a mixture of hydroamination products (53% yield) containing 80% of N,N-diethylgeranylamine [208], a key intermediate for the synthesis of industrially important monoterpenes [208, 209-211], including (-)-menthol (Tagasako process) [212]. 

The synthesis of a variety of chiral aliphatic aldehydes of high optical purity through the enantioselective isomerization of allylamines found many applications in organic synthesis. The enantioselective isomerization of diethylgeranylamine, which was prepared from myrcene, furnished (R, )-diethylenamine in >98% yield with >98% ee. This enamine is converted to (—(-menthol stereospecifically in high chemical yield (yield of each step >92%, Scheme 4).9 11... 

Isomerization of allylic amines is another example of the application of the BINAP complex. Rh BINAP complex catalyzes the isomerization of N,N-diethylnerylamine 40 generated from myrcene 39 with 76-96% optical yield. Compound (R)-citronellal (R)-42. prepared through hydrolysis of (R)-41, is then cyclized by zinc bromide treatment.49 Catalytic hydrogenation then completes the synthesis of (—)-menthol. This enantioselective catalysis allows the annual production of about 1500 tons of menthol and other terpenic substances by Takasago International Corporation.50... 

Synthesis from (3-Pinene. Pyrolysis of /3-pinene yields myrcene, which is converted into a mixture of predominantly geranyl, neryl, and linalyl chloride by addition of hydrogen chloride in the presence of small amounts of catalyst, e.g., copper(I) chloride and an organic quaternary ammonium salt [29]. After removal of the catalyst, the mixture is reacted with sodium acetate in the presence of a nitrogen base (e.g., triethylamine) and converted to geranyl acetate, neryl acetate, and a small amount of linalyl acetate [30]. 

Synthesis from (3-Pinene. For a description of this route, see under Geraniol. Addition of hydrogen chloride to myrcene (obtained from /3-pinene) results in a mixture of geranyl, neryl, and linalyl chlorides. Reaction of this mixture with acetic acid-sodium acetate in the presence of copper(I) chloride gives linalyl acetate in 75-80% yield [37]. Linalool is obtained after saponification. 

The raw material, myrcene (15 FF/Kg), is significantly cheaper than linalool (40 FF/Kg), the feedstock in the existing process.54 Furthermore, the intermediate P-ketoesters can be used for the synthesis of pseudoionone a key intermediate for the manufacture of vitamin A (world market for vitamin A 3 000 t/a at a price of 40-50 /kg).54>504... 

As is indicated in Fig. 22-3, the same intermediate cation can yield a variety of end products. For example, pure geranyl diphosphate pinene cyclase catalyzes formation of several other terpenes in addition to a-pinene.89 Another aspect of terpene synthesis is that insects may convert a plant terpene into new compounds for their own use. For example, myrcene, which is present in pine trees, is converted by bark beetles to ipsenol (Fig. 22-3), a compound that acts as an aggregation pheromone.90... 

Allylic double bonds can be isomerized by some transition metal complexes. Isomerization of alkyl allyl ethers 480 to vinyl ethers 481 is catalysed by Pd on carbon [205] and the Wilkinson complex [206], and the vinyl ethers are hydrolysed to aldehydes. Isomerization of the allylic amines to enamines is catalysed by Rh complexes [207]. The asymmetric isomerization of A jV-diethylgeranylamine (483), catalysed by Rh-(5)-BINAP (XXXI) complex to produce the (f )-enaminc 484 with high optical purity, has been achieved with a 300 000 turnover of the Rh catalyst, and citronellal (485) with nearly 100% ee is obtained by the hydrolysis of the enamine 484 [208]. Now optically pure /-menthol (486) is commerically produced in five steps from myrcene (482) via citronellal (485) by Takasago International Corporation. This is the largest industrial process of asymmetric synthesis in the world [209]. The following stereochemical corelation between the stereochemistries of the chiral Rh catalysts, diethylgeranylamine (483), diethylnerylamine (487) and the (R)- and (5)-enamines 484... 

Noyori s BINAP catalysts deserve special attention because their chirality is based on the bulkiness of the naphthalene groups, rather than on carbon or phosphorus asymmetric centers (Figure 3.28, inset) [77]. One of the many examples of asymmetric catalysis using BINAP is the synthesis of (—)-menthol, an important additive for flavors, fragrances, and pharmaceuticals. Starting from myrcene, the process is carried out by Takasago International on a multi-ton scale. The key step is the isomerization of geranyldiethylamine to (R)-citronellal enamine [78], which is then hydrolyzed to (R)-citronellal with nearly 99% ee. 

But it is not this step that makes the synthesis remarkable, but rather Takasago s route focitronel lal. Pinene is another terpene that is produced in only low enantiomeric excess by pine trees (and indeed, which is the major enantiomer depends on whether it is a European or a North Americar pine tree). But in the menthol process none of this matters, and cheap, enantiomerically impure pinene can be used, because the first step is to convert it to an achiral terpene, myrcene. Lithium diethylamide adds to this diene to give an allylic amine. 

Cross-coupling ofallyl bromides with allyltins (cf. 10, 26). The coupling of prenyl bromide with the tin reagent 1 in the presence of 10% ZnCh gives myrcene (2) in high yield. This coupling also provides a synthesis of vitamin K, (3). ... 

N.N-Dialkylgeranylamines have been prepared by the reaction of dialkyl amines with geranyl halides. The procedure described here is a modification of one we reported earlier. It is a simple, one-step synthesis of N,N-dialkylgeranylamines from myrcene and dialkylamines which are readily available bulk chemicals. The reaction proceeds stereoselectively, and yields are high. 

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