Ketones macrocyclic

In addition to large-scale process work, there is also some effort expended in providing synthetic methods for producing small amounts (<100 kg/yr) of materials needed for replacement of naturals that are being discontinued or in short supply. Examples are ambrinol (59) and dihydro-y-ionone (60) for the replacement of ambergris. More recendy, tincture of tonquin musk has been replaced by using, among other materials, mixtures of macrocyclic ketones and alcohols which have been found in the natural substance. 

I E G L E R Macrocyclic synthesis Synthesis ol macrocyclic ketones from dinitnles using high dilution... 

Raney nickel desulfurization of the macrocyclic ketones or their reduction products confirmed the structures assigned to these compounds and simultaneously offers new methods for the synthesis of macrocyclic alicyclic compounds. =°... 

Electrophilic substitution reactions on alkynylsilanes are also known. In 1978 K. Ultimootd, M. Tanaka and coworkers by an intramolecular reaction carried out the synthesis of a macrocyclic ketone. 

Challenging applications in the field of macrocyclic furans have been investigated. The major synthetic advantage is the cyclization to the furan after the macro-cyclization. This will avoid a problematic ring closure to macrocycles (to 1,3-furano-phanes) with a furan substrate ( furan latest strategy ). Test substrates demonstrated the viability of this concept [50], as shown below for the synthesis of the [8]furano-phane 91 from the macrocyclic ketone 90 (Scheme 15.22) [39]. 

Zheng W, Seletsky BM, Palme MH, Lydon PJ, Singer LA, Chase CE, Lemelin CA, Shen Y, Davis H, Tremblay L, Towle MJ, Salvato KA, Weis BF, Aalfs KK, Kishi Y, Littlefield BA, Yu MJ. (2004) Macrocyclic ketone analogues of halichondrin. Bioorg Med Chem Lett 14 5551-5554. 

The classical scent of the sea is afforded by ambergris, which is also the best fixative for perfumes. Once secured from whales, ambergris can now be legally provided by chemical synthesis (Science whaling 2000). Other fixatives are obtained from land animals, such as castoreum, civet, and musk. The first one is a phenolic substance and the latter two macrocyclic ketones that have stimulated the earfy methodologies for the synthesis of macrocyclic conqjoimds... 

Imines derived from macrocyclic ketones (C10 to C 15 ) and (- )-(S)-a-(methoxymcthyl)benzene-ethanamine are successfully deprotonated using LDA ( —25 JC. THF. 1 h)9. In contrast to azaenolates of C0- to C8-membered cyclic ketones, which show only E geometry, Z-isomers are observed with macrocyclic imines. As evident from H-NMR data, azaenolates of cyclodecanone imines generated under these conditions are a mixture of E- and Z-isomers (33 66), whereas azaenolates of cyclododecanone and cyclopenladecanone imines arc formed as the pure. E-isomers (see Table 3). Upon heating the solutions of metalated imines to reflux for 1 hour, complete isomerization to the thermodynamically more stable Z-isomers occurs. 

Table 3. ot-Alkylated Macrocyclic Ketones by Alkylation of Chiral Macrocyelie Ketimines, Followed by Hydrolysis9... 

Alkyl halides possessing / -hydrogens are usually poor substrates for carbonylative cross-coupling due to competitive / -hydride elimination/ Allyl chlorides can be used in carbonylative cross-coupling with allylstannanes/ phenyl-, 3-furyl, or vinylstannanes " to afford allylketones in modest to good yields. Divinylketones can be accessed through the reaction of vinylstannanes with vinyl iodides or vinyl triflates, with the latter requiring the addition of LiCl. Synthetic potential of this method has been proved in the formation of macrocyclic ketone jatrophone. In the reaction of vinyl triflates with tetramethyltin or aryltrimethylstannanes the additional activation by ZnCle is required. 

Cyclohexadecen-l-one can be added to perfume compositions as a substitute for the natural macrocyclic ketone musks. 

The macrocyclic esters hold a special position among the industrially produced lactone fragrance materials. Like the well-known macrocyclic ketones, they have outstanding odor properties as musks. However, the lactones can be prepared more easily than the ketones, for example, by depolymerization of the corresponding linear polyesters. Since replacement of a methylene unit by oxygen affects the odor of these compounds very little, oxalactones with 15-17-membered rings... 

The animals are kept in cages, and the fresh secretion is taken from the pouches at regular (about one-week) intervals. Civet is almost liquid with a light yellow color. It darkens when exposed to light and takes on a consistency like salve. In dilutions (e.g., as an alcoholic tincture), civet has a pleasant, sweetish odor. A resinoid prepared by extraction with acetone is a dark brown-red mass [257]. Civetone (see p. 88) is the main odoriferous constituent of civet (2.5-3.4%). Civet contains other macrocyclic ketones such as cyclohexa- and cycloheptadecanone and 6-cw-cycloheptadecenone. Traces of indole and skatole contribute to the animal note [258]. 

Muscone and related macrocyclic ketones are responsible for the odor of musk [260,261]. Like other animal secretions, musk was preferentially used as an alcoholic tincture in fine fragrances. FCT 1983 (21) p. 865 [68991-41-3], [90064-09-8]. 

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). 

Nitropyrimidine reacts in analogous fashion with enamines based on macrocyclic ketones (94TL2075). Quaternization makes it possible for 1-methylpyridinium iodide to react with enaminoesters with the formation of... 

Lithium o-lithiophenoxide, 166 Macrocyclic ketones Tributyltin hydride, 316 Methyl ketones... 

ZIEGLER METHOD. Cydization of dinitriles at high dilution in dialkyl ether in the presence of ether-soluble metal alkylamlide and hydrolysis of the resultant imino-nitril with formation of macrocyclic ketones in good yields. 

Free radical reactions have been used in organic synthesis not only for ring expansion, but also for formation of macrocyclic ketones [48] [51]. 

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... 

In 1973, Van Dorp et al. found a number of interesting macro-cyclic compounds, including some with both double and triple unsaturated bonds (26), but made no attempt to determine their biological significance. They compared the macrocyclic ketones and the fatty acids found in civet and muskrat gland and concluded that there is evidently no correlation between the macrocyclic ketone composition and the fatty acid composition. For example, cycloheptadecanone was the most prominent peak in the muskrat gland (41% of the macrocyclic ketones), whereas the stearic acid from which it could have been formed, was among the minor components (3%) of the fatty acids. 

We cannot, however, support the opinion that there is no correlation between the ketones and fatty acids. Analyses made over a one year period seem to indicate that the percentage of macrocyclic ketones is often high when that of the acids is low and vice versa. This would support Stevens hypothesis, which was challenged by Van Dorp et al. (26), that the ketones are formed by cyclization and decarboxylation of fatty acids (25). 

We wish to thank Unilever, Vlaardingen for supplying samples of macrocyclic ketones and Dr. P.E.J. Verwiel and Ing. A. Lakwijk for carrying out GC/MS experiments. The work was supported by a grant from the Dutch Departments of Wildlife Management and Public Works. We also thank Dr. W.J. Doude van Troostwijk and his collaborators of the Committee for Muskrat Control for their valuable help and advices. 

Figure 9. Structures of the main macrocyclic ketones of the civet (left) and the...

Whilst catalysts are not normally required for Baeyer-Villiger oxidation using peracids, boron trifluoride etherate has been used to activate peracetic acid in the preparation of macrocyclic ketones (Figure 3.57).256... 

Figure 3.57 Activation of peracetic acid with BFyOEt for macrocyclic ketone oxidation.

In another work, Meyers and coworkers found that in asymmetric synthesis of macrocyclic ketones and a-alkyl ketones by using chiral imines, two intermediate lithioenamines were obtained. One of them was formed in the reaction with LDA at — 30 C and is the kinetically controlled is-isomer 36. The second product formed on reflux with LDA is the Z-isomer 37, which is the thermodynamically more stable isomer. Both formed anion 38 on heating (equation 10). 

The preparation of doubly unsaturated macrocyclic ketones is provided (3). The synthesis of functionalized macrocycles by ring closing metathesis methods are described (4). 

This method provides an attractive route to unsaturated macrocyclic ketones. Example ... 

Macrocyclic ketones. A recent method for synthesis of macrocyclic ketones involves intramolecular alkylation of protected cyanohydrins. Sodium hexamethyidisilazide... 

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