Monoterpenes industrial syntheses

Citral a doubly unsaturated monoterpene aldehyde, M, 152.24. A mixture of cis and Irons isomers is a component of many essential oils. C.A (trans-C., geranial) b.p.,2 110-112 "C, P20 0.8898, n J 1.4894. CB (cis-C., neral) b.p.12 102-104°C, pjo 0.8888, /Id 1.4891. C. is a component of complex insect pheromone mixtures. When heated, it is converted to isocitral, and it undergoes photocyclization to photocitral A. Conversion of C. to pseudoionone with acetone is important as the first step in the industrial synthesis of vitamin A. In the perfume and food industries C. is the most important of the aliphatic monoterpenes. 

Experimental procedures have been described in which the desired reactions have been carried out either by whole microbial cells or by enzymes (1—3). These involve carbohydrates (qv) (4,5) steroids (qv), sterols, and bile acids (6—11) nonsteroid cycHc compounds (12) ahcycHc and alkane hydroxylations (13—16) alkaloids (7,17,18) various pharmaceuticals (qv) (19—21), including antibiotics (19—24) and miscellaneous natural products (25—27). Reviews of the microbial oxidation of aUphatic and aromatic hydrocarbons (qv) (28), monoterpenes (29,30), pesticides (qv) (31,32), lignin (qv) (33,34), flavors and fragrances (35), and other organic molecules (8,12,36,37) have been pubflshed (see Enzyp applications, industrial Enzyt s in organic synthesis Elavors AND spices). 

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]. 

Despite their low cost and abundant availability, the applications of monoterpenes as chiral synthons or building blocks for synthesis of chiral fine chemicals on an industrial scale have lagged far behind amino acids and carbohydrates. Most of the work in this area is related to multi-step total synthesis of complex natural products in laboratory scale. With the structures of new drug candidates in the research and development pipeline of pharmaceutical companies getting bigger and more complicated, the application of more sophisticated chiral building blocks such as the terpenes will... 

One of the earliest industrial applications of monoterpenes is in the steroid synthesis. Robinson annelation is used frequently in these transformations as a key step. The first example of this reaction was by Robinson himself to synthesize a-cyperone from dihydrocarvone.56 This synthesis has been shown to follow a stereospecific course to give (+)-a-cyperone (37) from (+)-dihydrocar-vone (38) (Scheme 5.14).57-59 Since then, numerous modifications and improvements have been made to apply this type of reaction for syntheses of a variety of natural and unnatural products.60... 

All the optically active terpenes mentioned in this chapter are commercially available in bulk (>kg) quantities and are fairly inexpensive. Although many of them are isolated from natural sources, they can also be produced economically by synthetic methods. Actually, two thirds of these monoterpenes sold in the market today are manufactured by synthetic or semi-synthetic routes. These optically active molecules usually possess simple carbocyclic rings with one or two stereo-genic centers and have modest functionality for convenient structural manipulations. These unique features render them attractive as chiral pool materials for synthesis of optically active fine chemicals or pharmaceuticals. Industrial applications of these terpenes as chiral auxiliaries, chiral synthons, and chiral reagents have increased significantly in recent years. The expansion of the chiral pool into terpenes will continue with the increase in complexity and chirality of new drug candidates in the research and development pipeline of pharmaceutical companies. 

Although advances in monoterpene chemistry have dominated the industrial scene, significant developments have taken place in other categories. Sesquiterpene chemistry contains many examples where semi-synthesis has been adopted. 

N,N-Diethy1gerany1am1ne is a key intermediate for the synthesis of Industrially Important acyclic monoterpenes such as geranyl acetate, llnalooicitral and cltronellal... 

One of the earliest industrial applications of monoterpenes is in the steroid synthesis. Robinson annelation is used frequently in these transformations as a key step. 

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