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Claisen, Cope and Related Rearrangements in the Synthesis of Flavour and Fragrance Compounds

A review of the use of the Claisen, Cope and related [3,3]-sigmatropic rearrangements, sequential ("tandem") sigmatropic rearrangements and the "ene" reaction in the syntheses of flavour and fragrance compounds is presented.


Introduction
The Claisen rearrangement was discovered in 1912. Its mechanism was proposed in the 60's, just as the Cope rearrangement which involves a similar mechanism [1]. They are both [3,3]-sigmatropic rearrangements and they have been the subject of numerous reviews [2][3][4]. The Claisen rearrangement is the sigmatropic conversion of allyl vinyl ethers (1) into homoallyl carbonyl compounds (2) (Scheme1). The majority of these rearrangements require high temperatures (100-350°C), although numerous examples of catalytic syntheses are also known [5]. The common feature of all [3,3]-sigmatropic rearrangements is a six-membered transition state with a delocalised electronic structure (Scheme 2). From the kinetic point of view, a chair conformation is preferred, which makes it possible to predict the stereochemical course of the reactions [6,7]. Depending on the parent substances utilised, there exist a number of modifications, which have found a vast number of applications in laboratory-scale syntheses [8]. The most important ones are depicted in Scheme 3: Sigmatropic rearrangements are more and more frequently employed in organic syntheses, including the synthesis of natural products (eg.-terpenoids) [8], flavours and fragrances [9][10][11][12].
The Claisen as well as the Cope and Carroll rearrangements have proven very useful in the synthesis of fragrance and flavour compounds both in the laboratory and on an industrial scale. One of the first literature reports from this field referred to the synthesis of 2-methyl-2-hepten-6-one, one of the basic intermediates for the production of numerous fragrance compounds in the group of terpenoids [13].

Johnson Rearrangement
In contrast with the previous reactions, the Johnson rearrangement process yields unsaturated esters. Although not as popular as the Claisen reaction, it has found application in the synthesis of aliphatic isoprenoidal structures. This method was utilised to obtain interesting fragrances which contain the neopentyl group (25), and their silicone analogues (26)

Cope Rearrangement
Like the Claisen rearrangement, the Cope rearrangement is in most cases initiated by temperature. Yet, many catalytic processes are also known [5]. Mesityl oxide reacts with excess vinylmagnesium chloride and gives alcohol, which -under the action of temperature -undergoes the rearrangement and yields lavandulol (28), a valuable compound with a floral-rose odour [40] (Scheme 23). Interesting compounds (29) and (30) were also obtained from the reaction of allyl chloride with α,βunsaturated aldehydes and ketones [41,42] (Scheme 24). The Cope rearrangement was also utilised in the synthesis of the naturally occurring sesquiterpene -Molecules 2000, 5 elemol (31) [16], which is an essential component of galbanum oil, and many others (Scheme 25).

Oxy-Cope Rearrangement
The Oxy-Cope rearrangement involves allyl vinyl carbinols. Unstable enol derivatives of aldehydes or ketones are obtained in the first stage, which immediately undergo rearrangement and give the corresponding carbonyl compounds. The oxy-Cope rearrangement was found applicable in the synthesis of Ambretone ® (Toray Ind.) (32) and its methyl analog (33) from cyclododecanone with the intensive musk odour [43,44] (Scheme 26). The synthesis of muscone (34), a valuable compound with the odour of musk, was also described [45]

Tandem Sigmatropic Rearrangements
A product of one rearrangement frequently has a structure which under the synthesis conditions, undergoes further rearrangement(s). This is based on the "domino" effect, which is sometimes utilised in the synthesis of organic compounds [46]. Tandem rearrangements are very useful in the synthesis, and a few extensive reviews on them are available [47,48]. Within [3,3]-sigmatropic rearrangements, a system of Claisen-Cope reactions is the most frequent one, and a synthesis comprising a set of three consecutive rearrangements can also be met.
One of the earliest studies in this field referred to a very spectacular synthesis of β-sinesal (10), an important sensory component of the sweet orange oil [49] (Scheme 28). Citral (35) was also obtained in this way [50] (Scheme 29).

"Ene" Rearrangement
Alike the above mentioned reactions, the "ene" rearrangements also involve a six-membered transition state. However, the difference is that the reaction involves a hydrogen atom in the allyl position. In this way, the alicyclic alcohols (40) and (13), the so-called "plinols", were obtained from linalool and dehydrolinalool, respectively [37] (Scheme 36). The "ene" rearrangement was also employed in the series of reactions leading to compound (41) [55] (Scheme 37).

Summary
The review presented above illustrates the potential provided by sigmatropic rearrangements. Some of the products discussed possess interesting olfactory properties, although this study surely does not cover all the possibilities of utilising the sigmatropic rearrangements in the synthesis of fragrance and flavour compounds. Using these reactions many of these compounds are produced in pilot plants or on industrial scale. Some of the basic advantages offered by sigmatropic rearrangements are their good yields and the low wastes produced (many of these reactions involve no catalyst). It is thus possible to obtain a number of valuable sesquiterpenoid compounds that are present in small quantities in natural oils, wherefrom it is very difficult to separate them. Great many of them have the potential of interesting olfactory properties [37]. In view of the above, it can be concluded that sigmatropic rearrangements constitute attractive methods for the synthesis of flavour and fragrance compounds.