Civetone, synthesis

The telomer of nitromethane with four moles of butadiene 62 has a chain of 17 carbons, and this compound is a very suitable starting material with right carbon numbers and necessary functionalities for the synthesis of civetone (133), a naturally occurring fragrant compound. The telomer was converted into civetonedicarboxylic acid (132) by the following sequence of reactions ... 

Civet civetone / polyket. Q ° civetone civet cat, Civettictis [= Viverra] civetta (Schreber, 1776), Mamm./fixative in expensive perfumery trtal synthesis... 

Macrocyclic ketones. This reagent has been used for cycloolefination of acetylenic dialdehydes (Wittig-Horner reaction) as a route to muscone, exaltone, and civetone. A synthesis of the last ketone (3) is formulated (equation 1). 

Olefin metathesis has been used by a number of workers to produce macrocyclic musks. One of the earliest examples is Mol s synthesis of civetone from methyl oleate. This takes advantage of the ideally placed double bond in the starting oleic acid. Unfortunately, the ds-geometry of the olefin is lost on metathesis and a mixture of isomers results. Furthermore, almost half of the weight of the starting material is lost as the unwanted 9-octadecene. Dieckmann cyclisation of the metathetical diester, followed by hydrolysis and decarboxylation, gives a mixture of E- and Z-civetone. The synthesis is shown in Figure 4.59. 

The first documented synthetic macrocycle was synthesized by Baeyer via the condensation of pyrrole and acetone in the presence of mineral acid (Baeyer, 1886). Other examples, from a historical point of view, are listed in a review by Newkome and coworkers (Newkome et al., 1977). The aliphatic macrocycles were synthesized later as exemplified by Willstatter s synthesis of eight-membered rings (Willstatter and Veraguth, 1905) and Ruzicka s studies of the chemistry of muscone and civetone (Ruzicka, 1926). The synthesis of thiacycloalkanes using the reaction of sodium sulfide with an alkyl dihalide was also investigated early in the twentieth century (Braun and Tcherniac, 1907). A cyclam (cyclic amine) was first synthesized by Alphen (1937). The preparation of the peraza-crowns was first developed by Stetter (1953a,... 

Chromatography, 20, 21, 757 Chromogenic macrocydes, 8, 9 Cinnamates in macrocycle synthesis, 557 ds-platin, 16 Civetone, 74... 

Very pure substrate is required for the metathesis of methyl oleate. In an alternative process for the synthesis of civetone, methyl oleate was first converted to oleon (1), the doubly-unsaturated ketone 9,26-pentatriacontadien-18-one, which can be separated in pure form from the reaction mixture. Oleon was then converted into 9-cycloheptadecen-l-one (2) via-a ring-closing metathesis reaction (see Scheme 1). 

Tsuji, J. and Hashiguchi, S. (1980). Application of Olefin Metathesis to Organic Synthesis of Civetone and Macrolides, Tetrahedron Lett. 21, 2955-2958. 

After the development of the modern metathesis catalysts, [185] the synthesis of civetone was one of the first applications of ring-closing metathesis. [186] A Claisen condensation followed by metathesis can be used to prepare civetone, but even under extreme dilution (10" -10 molar), the maximum yield is only 24 %, because of considerable polymer formation. 

When the synthesis is carried out in a stepwise manner, civetone is obtained with a yield of even 74 %. 

Olefin metathesis has been exploited in a synthesis of civetone (46) from ethyl oleate (Scheme 15) and of the macrolide (47) from oleyl oleate (Scheme 16). ... 

A ring-closing metathesis strategy was first employed by Furstner and co-workers in the synthesis of civetone, a macrocyclic musk. Treatment of diene 418 using 5 mol % of 2 in refluxing dichloromethane led to the corresponding 15-member ring macrocycle 419 in 72% yield with an E Z selectivity of 4.6 to 1. 

As previously stated, mRCM is an important method for the synthesis of large rings (Sect. 3.3). Using cyclometalated catalysts, we are now able to exclusively prepare Z-macrocycles using catalyst 10 via mRCM (>95% Z) [52], Alternatively, by Z-selective ethenolysis, we are able to form the corresponding -isomer with catalyst 9 (>95% E). This was showcased in the synthesis of both - and Z-civetone (17) (Scheme 11), as well as several other macrocyclic musk compounds [51]. 

Scheme 7.8 The RCAM/Lindlar hydrogenation manifold in the synthesis of civetone.

Scheme 11.37 Synthesis of civetone 155 by an alkyne metathesis/syn-hydrogenation sequence.

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