Of cuparene

The AE reactions on 2,5,5-trisubstituted allyl alcohols have received little attention, due in part the limited utility of the product epoxides. Selective ring opening of tetrasubstituted epoxides are difficult to achieve. Epoxide 39 was prepared using stoichiometric AE conditions and were subsequently elaborated to Darvon alcohol. Epoxides 40 and 41 were both prepared in good selectivity and subsequently utilized in the preparation of (-)-cuparene and the polyfunctoinal carotenoid peridinin, respectively. Scheme 1.6.12... 

Despite the favorable thermodynamics associated with the cyclization of unsaturated organolithiums, the isomerization is often sluggish when the ring closure involves generation of a quaternary center or formation of a strained framework. In such cases it has been found that addition of lithiophilic Lewis bases such as THF or TMEDA facilitate the reaction.7 9 The preparation of cuparene, a sterically congested sesquiterpene possessing two adjacent quaternary centers, illustrates the methodology.11... 

Dipolar cycloaddition. Arylthiomethyl chlorides (1) in the presence of a Lewis acid can undergo a [4 + 2]cycloaddition to a tetrasubstituted alkene. They can be prepared by reaction of thiophenol with BrCH2Cl in the presence of DBU in CH,CN. C2H5A1C12 is preferred over A1C1, SnCl4, or TiCl4 as the Lewis acid. This reaction provides a short synthesis of cuparene (2). 

Scheme 9 Photomediated and microwave-assisted synthesis of Cuparene...

When the alkene trap is 1,1-disubstituted, cyclisation of a tertiary benzylic organolithium gives a product with two adjacent quaternary centres. Krief applied this type of cyclisation to the synthesis of cuparene 244136 using a different disconnection from the one used by Bailey (above). Though it is irrelevant to the synthesis of cuparene, the cyclisation of 257 to 258 is also stereoselective and produces a single stereoisomer of 259 on carbonation of the cyclised organolithium. The tertiary organolithium is too basic to cyclise in THF and in this solvent... 

The isolation of -(-)-cuparene (77), and f -(-)-S-cuparenol (78) from the liverwort, Bazzania pompeana, is consistent with the general tendency of this type of plant to produce sesquiterpenoids enantiomeric with those found in higher plants38... 

CpTiCl3/LiAlH4. Titanium-based reagents have also been employed in a new approach to propellane systems, including the quadrone ring skeleton (equation 35). More recently Takeshita et al. demonstrated the chemoselectivity of such reagents in a formal synthesis of cuparene (18 equation 36). Similar chemoselectivity is observed in pinacolic cyclizations promoted by TMSCl/Zn (equation... 

The direct geminal dimethylation of ketones using dimethyltitanium dichloride has provided an extremely simple synthesis of cuparene (120) from the ketone (121).77 This efficient procedure should prove useful in other sesquiterpenoid syntheses in view of the fact that the gem-dimethyl group is a common feature in a number of such compounds. A new sesquiterpene, (—)-herbertene (122), has been... 

Rh2(OAc)4-catalyzed decomposition of diazoester 352a results in intramolecular C/S insertion, whereby a quaternary benzylic carbon atom without a heterosubstituent is generated. This transformation was used in a synthesis of (+)-cuparene... 

With cations ranked according to their relative stability, we then assume that given a choice, the more stable cation will be formed in a reaction because it is lower in energy. The addition of HCl to methylenecyclobutane (100) illustrates this point, where the final product is 1-chloro-l-methylcyclobutane (103), used by Fitjer in a synthesis of cuparene. 29 7 0 n bond reacts as a base, donating a pair of electrons to the acid (H+ = HCl). When the new C—H bond is formed, a carbocation is generated at the other carbon of the jt bond, leading to... 

U 18. Bailey, W.F. Khanolkar, A.D. Construction of a Sterically Congested Carhon Framework via 5-Hexenyllithium Cyclization. Synthesis of (+/-)-Cuparene Tetrahedron Lett. 1990, 47(37), 7727-7738... 

A short synthesis of the ketone (95) has been reported and this constitutes a formal synthesis of cuparene (96), since (95) has been converted into (96) previously. As an alternative strategy to the cuparane skeleton a three-carbdn... 

From (a)-cuparene, six metabolites (333-338) were obtained. These are structurally very similar to those found in the metabolites of (-)-cuparene, except for the presence of an acetonide (336), but they are not identical. All metabolites possess benzoic acid moiety. 

The possible biogenetic pathways of (+)-cuparene (324) have been proposed in Figure 20.97. Unfortunately, none of the metabolites show strong mossy odor (Hashimoto et al., 2006). The presence of an acetonide in the metabolites has also been seen in those of dehydronootkatone (25) (Furusawa et al., 2003) (Figure 20.98). 

The liverworts Herbertus aduncus, Herbertus sakurai, and Mastigophora diclados produce (-)-herbertene, the C3 methyl isomer of cuparene, with its hydroxy derivatives, for example, her-bertanediol (339), which shows no production inhibitory activity (Harinantenaina et al., 2007), and herbertenol (342). Treatment of compound (339) in P. sclerotiorum in Czapek-polypeptone medium gave two dimeric products, mastigophorene A (340) and mastigophorene B (341), which showed neurotrophic activity (Harinantenaina et al., 2005). 

FIGURE 20.98 Possible pathway of biotransformation of (+)-cuparene (324) yy Aspergillus niger. 

SCHEME 17.15 Synthesis of ( )-cuparene. (Adapted with permission from Ref. [10]. Copyright (2009) American Chemical Society). 

In the last few years, several groups have developed enantioselective domino reactions catalysed by combinations of organocatalysts with palladium complexes. As an example, Murkheqee and List have reported a domino synthesis of p-all earbon quaternary amines on the basis of a highly enantioseleetive a-allqrlation of a-branched aldehydes, involving an achiral palladium catalyst and a chiral phosphoric acid. Under the catalysis of phosphoric acid, a secondary allylamine reacted with an a-branehed aldehyde to form an enammonium phosphate salt, which upon reaction with palladium catalyst afforded a cationic 7t-allyl palladium complex (Scheme 7.2). This intermediate resulted in the formation of an a-allylated iminium ion, whieh eould be reduced to the corresponding final chiral amine in high yield and exeellent enantioselectivity of 97% ee. The synthetic utility of this transformation was also demonstrated hy a formal synthesis of (+)-cuparene. 

MeCOCl, AICI3/CS2 2) CF3CO3H/CH2CI2 3) K2C03/Me0H Scheme 29. Conversion of (—)-cuparene to (—)-2-hydroxycuparene References, pp. 269—285... 

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