Valeranes

A new total synthesis of ( )-valerane (271) has been achieved using a reaction sequence (Scheme 31) in which the m-5,10-dimethyldecalin system is constructed... 

SYNS DI-n-BUTYLTIN DIPENTANOATE DI(PENTANOYLOXY)DIBUTYLSTANNANE VALERAN DI-n-BUTYLCINICITY (CZECH)... 

Alkoxycyclopropanes are commonly prepared from alkyl enol ethers by one of the Simmons-Smith modifications (see Chapter 7). According to Wenkert and coworkers they are cleaved by strong acids to the a-methylated carbonyl compound, thus establishing an overall a-methylation of a ketone or an aldehyde (equation 64). This method has often been used for natural product synthesis (e.g. valerane " ). 

Exo cycloalkylations have been used to synthesize ct5-1-decalones. For example, treatment of 2-methyl-3(4-tosyloxybutyl)cyclohexanone with sodium t-pentylate in benzene gave c/j-9-methyl-l-deca-lone (50) in 60% yield. Also, as shown in Scheme 28, conjugate addition-cycloalkylation was employed to synthesize a cw-fused decalone related to the sesquiterpene, ( )-valerane. Apparently, in these cases, the enolate intermediate adopts a conformation having the 4-bromobutyl side chain quasi-axial, and C—C bond formation occurs via equatorial attack to give initially a twist-boat conformation of the product. 

In addition to ( )-valerane, a wide variety of other sesquiterpenes, including ( )-ishwarane, ( )-ish-warone, ° copaene, ylangene, ( )-seychellene ( )-sativene, ( )-longifoline, " ( )-copa-camphene," ( )-damsin," ( )-A < >-capnellene, ( )-pentalenene, (-)-P-vetivone" and ( )-P-eudesmol have been synthesized by pathways involving cycloalkylation of saturated ketone enolates. 

A new annelation process involving photochemical cycloaddition of a-formyl ketones to symmetrical alkenes has provided alternative synthetic routes (Scheme 37) to valerane (385) and isovalerane (386) (cf. Vol. 5, p. 78 Vol. 6, p. 87). 

Whatever the exact mechanism of the conjugate-addition reaction, it seems clear that enolate anions are formed as intermediates and they can be trapped as the silyl enol ether or alkylated with various electrophiles. For example, addition of lithium methylvinyl cuprate (a mixed-cuprate reagent) to cyclopentenone generates the intermediate enolate 166, that can be alkylated with allyl bromide to give the product 167 (1.161). The trans product often predominates, although the transxis ratio depends on the nature of the substrate, the alkyl groups and the conditions and it is possible to obtain the cis isomer as the major product. Examples of intramolecular trapping of the enolate are known, as illustrated in the formation of the ds-decalone 168, an intermediate in the synthesis of the sesquiterpene valerane (1.162). 

In contrast, valeranes arising from migration of flie methyl group C-15 in eudesmane from C-4 to C-5, in contrast, very rarely occur. Examples include the va-lerenones from the roots of valerian Valeriana officinalis and from Nardostachys jatamansi (Valerianaceae). 

Lithium dimethyl copper reacted with (186) to introduce a methyl group stereo-selectively trans to the 5-isopropyl group. The enolate anion (187) so formed underwent intramolecular alkylation to give the cis-decalone(188), which was reduced to d/-valerane (189). Conjugate addition of lithium methyl vinyl cuprate to cyclopent-2-... 

Another example of orthoester rearrangement for the construction of a quaternary center is given in the enantioselective synthesis of (-t)-valerane 148 [34]. In this synthesis, ii-(-)-carvone 149 is used as starting material. Rearrangement of allylic alcohol 150 afforded ester 151. Diazoketone cyclization is then followed by a ring enlargement affording the bicyclo[4.4.0]decane system (Scheme 6.22). 

Conjugate addition of organocuprates to a,/S-unsaturated carbonyl compounds, followed by alkylation of the resulting enolates, leads to regiospecific ot, -dialkylation (Boeckman, 1973). This method can be applied to the synthesis of valerane (CCLIX) (Posner et al., 1974,1975a). The enolate intermediates are acylated as well. The method leads to a new synthesis of 7-oxoprosta-glandins (Tanaka et al, 1975). 

The biogenesis of the relatively rare valerane and cyperane (e.g., faurinone and cyperolone) sesquiterpenes involves rearrangement of a eudesmane precursor by shift of the C4 methyl group or ring contraction to a hydrindane nucleus, respectively. Since all of the known natural products bear oxygen functions at the site of rearrangement, an epoxide precursor is usually proposed. 

---