Cuparene synthesis

For synthesis of the sesquiterpene ( )-cuparene (2-358) [192] using this method, 2-355 was reacted with 2-354 and 2-356 to give 2-358 via 2-357 in 45 /o overall yield. 

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... 

A large number of tertiary alkyl chlorides has been methylated. Equations 77-79 are typical41,74). The simple synthesis of (i)-cuparene 252 is an application in terpene chemistry 35). 

A novel radical anion (LDMAN) methodology developed by Cohen and coworkers (see Section IILA.2) was then applied efficiently for the two-pot synthesis of the sesquiterpene ( )-cuparene, 184, starting from the allyl reagent 180118. The tandem addition/cyclization... 

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... 

Ring-closing metathesis has also been applied to the synthesis of a number of terpene derivatives containing six-membered rings. The terpene derivatives prepared by this approach have been as simple as cuparene and as complex as tricycloillicinone. Several key examples are illustrated below. 

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. 

Paul, T, Pal, A., and Mukherjee, D. (2003) Stereocontrolled total synthesis of ( )-tochuinyl acetate and facile total synthesis of ( )-a-cuparenone and (ib)-cuparene. ARKIVOC, 104—114. 

Photo-mediated asymmetric synthesis of (2)-cuparene has been studied by Grainger and Patel (2003). In this procedure, generation of a benzylic quaternary stereocenter via the photo-mediated cyclization of a chiral (aminobutyl) styrene followed by a microwave-assisted Cope elimination led to a total synthesis of the sesquiterpene... 

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