Of civetone

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 ... 

The preputial (musk) gland of the muskrat contains a number of macrocyclic ketones, such as isomers of civetone (cis-9-cycloheptadecenone), the main odourous component of the secretion of the civet. In the muskrat the main macrocyclic component is the cis-5-isomer of civetone (Figure 9). The glands of both animals also contain a number of other macrocyclic compounds and a variety of fatty acids (24,25,26) which could be precursors of macrocyclic ketones and alcohols as proposed by Stevens in 1945... 

The structural elucidation of civetone and muscone as large-ring ketones by Ruzicka... 

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. 

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. 

In contrast to the fatty acids, the seasonal course of civetone revealed temporal variations that displayed oscillations during April to August, but afterwards remained at a lower level until the end of the year (Figure 3). There was a significant positive correlation of civet and pregnanediol (Spearman s rho, r = 0.389, p < 0.001). 

We thank J. Streich for statistical evaluations and A. Engelhardt (Aeroxon Insect Control GmbH) for the gift of a sample of civetone. 

Relatively little is known about the biosynthesis of civetone and muscone. Ruiicka had recognised already the structural relationship of civetone and oleic acid, and so it could be imagined that civetone might be derived from oleic acid by terminal oxidation and Dieckmann cyclisation. 

The construction of muscone can be explained in this way the multienzyme complex of fatty acid biosynthesis is initiated with acetyl-CoA. Then one propi-onyl-CoA unit is incorporated, followed by six further acetyl-CoA units, resulting in the mono-branched (14S)-methylpalmitic acid. Ring closure forms an analogue of civetone. [164]... 

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. 

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). ... 

The civet cat Viverra civetta] is the originai source of civetone, a sweet and pungent ketone, now produced syntheticaiiy and used as a fixative in perfumery. 

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. 

Cp2TiMe2 and WOCI4 or WCle is an effective catalytic system for the metathesis of olefins. Importantly, the system tolerates carboxylic esters, and this enabled it to be used to effect the key steps in syntheses of civetone and other macrolides. Unsaturated ketones or acetals are not suitable substrates. 

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.

---