Synthesis 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).

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

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-... 

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). ... 

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. ... 

A dibromomethylcycloalkanol rearranges in a similar fashion, except that a different dilithio intermediate is formed via halogen-metal exchange rather than deprotonation (Scheme 16). With unsym-metrical ketones, the more substituted group migrates. This selectivity has been applied to a synthesis of ( )-muscone (29 Scheme 17). Substituted polyhalomethyllithium species can be used in the prepara-... 

Chlorocyclopentadec-2-enone 2 was obtained in 66% yield when the dichlorocarbene adduct 1 of 1-trimethylsiloxycyclotetradecene was stirred in the presence of dilute hydrochloric acid. This is the key step in a six-step synthesis of ( + )-muscone from cyclododecanone (36% overall yield). 

The same basic methodology was used in a short synthesis of (+ )-muscone (34), starting from cyclotetradecanone. ... 

The intermediate iminocarbocation or alkylidyneammonium ion generated by an organoaluminum compound can be trapped intramolecularly by means of ole-fmic groups [186]. This interesting rearrangement-cyclization sequence was extended to an efBcient synthesis of muscone or muscopyridine (Scheme 6.147)... 

Nicolaou. K.C.. Seitz. S.P. Pavia, M.R., and Petasis, N.A.. Synthesis of macrocycles by intramolecular ketophosphonate reactions. Stereoselective construction of the "left-wing of carbomycin B and a synthesis of (//-muscone from oleic acid, J. Org. Chem.. 44. 4011. 1979. 

The acyloin condensation of a,o>-diesters in the presence of MeaSiCl represents a highly efficient method for the synthesis of large rings. The application of the convenient sequence of cyclopropanation/oxidative ring cleavage for ring expansion cf. Eq. (52) to the appropriate m a ocyclic enediol silyl ether 39 provided, a short, high-yield (23% overall) synthesis of muscone ([Pg.37]

Regioselective aldol reactions can be achieved with organoaluminum reagents, and a good example of this application is in the synthesis of muscone (131 Scheme 57). The key step involves macrocycli-... 

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