Of muscone

This cyclization procedure was conveniently applied to the preparation of the key intermediate of a five-step synthesis of ( )-muscone [48]... 

The first two reactions (Table VII) date as far back as 1953, to Reppe s chemistry, and refer to processes occurring via metallacycles. An interesting application to natural products is the synthesis of muscone, which, however, has been obtained in a better way using alkylisonitriles (151) in place of carbon monoxide (example 3, Table VII). 

Scheme 1. Catalytic enantioselective aldehyde alkylation affords the chiral macrocyclic alcohol 3 in Oppolzer s total synthesis of muscone (1993).

Tanaka et al. (152) demonstrated that a chiral copper alkoxide could be used substoichiometrically to deliver MeLi to an enone in conjugate fashion. The precatalyst is formed from amino alcohol 221, MeLi and Cul, Eq. 123a. Under stoichiometric conditions, this catalyst mediates the conjugate addition of MeLi to the macrocyclic enone, affording muscone in 91% ee. Lower enantioselectivity is observed using a substoichiometric amount of 222 (0.5 equiv), affording a 79% yield of muscone in 76% ee, Eq. 123b. These selectivities are attained by portion-wise addition of the substrate and MeLi to the alkoxy-cuprate. This catalyst also exhibits a complex nonlinear effect (78, 153). 

A carbonium ion rearrangement, triggered by anodic oxidation of a carboxylic acid, has been used as one stage in another synthesis of muscone [118]. 

Ketones are most widely represented and include cyclopentanone derivatives, such as the jasmin fragrance substances, and cyclic ketones with 15-17-membered carbon rings, such as muscone and civetone, which are constituents of the extremely expensive animal products, musk and civet. Cyclopentadecanone, a natural musk fragrance, and the unsaturated 5-cyclohexadecen-l-one, which has not yet been found in nature, have odor characteristics similar to those of muscone and civetone and are more easily synthesized. They are, therefore, often used as substitutes. 

Tanaka reported the synthesis of (/ )-muscone (10) by an enantioselective conjugate addition of chiral alkoxydimethylcuprate, which was prepared from chiral ercdo-3-[(l-methylpyrrol-2-yl)methylamino]-l,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (9), methyllithium, and copper iodide (Scheme 9.7) [16]. In this reaction, convex deviation from a linear correlation was observed when the chiral ligand had a higher enantiopurity. This positive NLE was probably induced by the formation of a reactive homochiral dinuclear copper complex to give (R)-muscone. Rossitter also observed asymmetric amplification in a copper-catalyzed conjugate addition of methyl-... 

Interesting synthetic applications of the [4+4] and [4+4+4] cycloadditions are reported. A novel, short-step synthetic method of muscone (24) has been developed using complex 10 as a starting compound [7]. Insertion of allene to the Ni-carbon bond in 10 at low temperature gives the bis-7r-allylnickel 22. Then isonitrile is inserted to 22. When the reaction mixture is warmed, the 15-membered cyclic compound 23 is formed by reductive elimination, and conversion of 23 to muscone (24) is achieved by hydrolysis and subsequent hydrogenation in 43 % overall yield. 

Radical ring expansion1 (14, 317-318). This reaction has been used for synthesis of muscone (3) from cyclododecanone. Alkylation of the ketone with 3-chloro-... 

Scheme IV/15. Application of the enamine-ketene ring enlargement for the synthesis of ( )-muscone (IV/99) [53].

Scheme V/ll. Synthesis of ( )-muscone (V/70) from cyclododecene (V/66) including a [1.3] sigmatropic shift ring expansion [37].

Scheme VIII/8. A synthesis of muscone (VIII/48) with a fragmentation as key step [27]. a) NaNH2, toluene, reflux b) BuLi c) KOtBu...

Scheme VIII/14. Synthesis of ( )-muscone (VIII/48) using the tosylhydrazone approach of the a,/ -epoxyketone - alkynone fragmentation [38].

The transformation of cyclododecanone via IX/9 to the bicyclic intermediate, IX/10 is possible through an internal enamine reaction. Cleavage of the central ketone bridge gives the 14-membered product IX/11 [3]. This reaction was a key step in the synthesis of ( )-muscone (IX/15), Scheme IX/2, [4]. On treatment with base, the bicyclic intermediate, IX/13, prepared from 2-nitrocyclotri-decanone (IX/12), was quantitatively (R=H) [5] (or in 47 % yield (R=CH3) [4]) converted into the enlarged product IX/14. The retro aldol reaction was not... 

A Wagner-Meerwein-type rearrangement of the cation has been often observed in the oxidation of carboxylic acids (equation 59). The relative migratory aptitude of R and R has been studied, and this type of rearrangement has been applied to the synthesis of )-muscone (equation 60). ... 

Unsymmetrical compounds can also be prepared via mixed Kolbe electrolyses of different carboxylates (heterocoupling). The disadvantagous but unavoidable formation of symmetrical dimers can be suppressed to the formation of essentially one by-product if the cheapter carboxylic acid is used in a 5- to 10-fold excess. Hydrogenated carotenoids, saturated and unsaturated fatty acids, optically active )-hydroxycarboxylic acids, and intermediates for the preparation of muscone and humulene have been obtained in this way [177b]. 

Application of the above mentioned epoxy sulfone cyclization reaction has been ingeniously used in a synthesis of muscone (Scheme 113, entries c and d) and also of vitamin D3 (Scheme 113, entry e)/ In the latter case surprisingly the terminal epoxide, when subjected to the intramolecular cyclization gave a mixture of sulfonylcyclopentane and sulfonylcyclohexane derivatives arising respectively from the epoxide ring opening at the most (30%) and the least (50%) substituted carbons. ... 

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