An Alternative Synthetic Access to cis-4 a-Methyloctahydrophenanthrene , a Biomarker of Sergipe-Alagoas Basin Petroleum in Brazil

cis-4a-Metiloctaidrofenantreno (1) foi preparado em 8 etapas (23% rendimento total) a partir do ácido 2-bromofenilacético (3) e cicloexano-1,3-diona (6). Uma reação de acoplamento do tipo Michael Heck com alta diastereosseletividade cis foi a etapa chave na montagem do esqueleto tricíclico. O composto 1 foi utilizado como padrão cromatográfico o que permitiu identificaçãoinequívoca de um biomarcador minoritário presente no petróleo de Carmópolis, Bacia de SergipeAlagoas, Brasil.


Introduction
GC/MS analyses of Brazilian petroleum 1 (Carmopolis oil field, Sergipe-Alagoas Basin, Brazil) disclosed the presence of several acids and hydrocarbons possessing alkylsubstituted monoaromatic sterane, and methyloctahydrophenanthrene (biodegraded monoaromatic sterane) skeletons, most of which require non-commercial standards for full characterization.Confirming the presence of both biomarkers, 1 and 2, possessing cis A/B-ring configuration, in the studied oils, would provide evidence for the low maturity level of the petroleum and of a common diagenetic precursor for 1 and 2 (Figure 1). 2 Preparation of cis-4a-methyloctahydrophenanthrene (1) has already been accomplished along several routes. 2 Notwithstanding these reports we proposed a new synthetic strategy assess cis-diastereomer 1 which would easily be extended to the synthesis of 2.

Results and Discussion
The most attractive synthetic strategy based on a retrosynthetic analysis called for the insertion of the arylpalladium bromide intermediate formed from the aryl bromide unit in 9 into the tethered cyclohexenone moiety (Scheme 1).This would correspond to the carbopalladation step of an intramolecular Heck reaction, one of the most versatile palladium-catalyzed carbon-carbon bond-forming processes, that has been widely applied for the construction of complex carbon skeletons, 3 and works particularly well with an electron-acceptor-substituted alkene partner.However, since the intramolecular carbopalladation in 9 generates a quaternary center, the intermediate cannot undergo β-hydride elimination, and must take the course of an overall conjugate addition, as has previously been observed for β-substituted enones. 4According to literature precedence, 5 cisconfiguration of the formed product could be expected.The pivotal intermediate 9 6 was easily prepared in three steps from 1,3-cyclohexanedione ( 6) and 1-bromo-2-(2iodoethyl)benzene ( 5) in 37% yield.The latter was obtained from (2-bromophenyl)acetic acid (3) in two steps with 78% overall yield (Scheme 1).
Applying typical conditions for a Heck reaction (Table 1), i.e. exposing 9 in DMF solution to a mixture of Pd(OAc) 2 as catalyst, triphenylphosphine as ligand, tetrabutylammonium bromide as phase transfer catalyst (Jeffery's conditions 7 ) and methanol/triethylamine as a proton source, at 80 °C for 12 h, gave a dark mixture, from which, by filtration through a pad of Celite, distribution between diethyl ether and water, and flash chromatography over silica gel of the residue from the ether solution, the cyclization product 10 was isolated.The yield, which was 36% in the first attempt (entry 1, Table 1), was only slightly improved by using twice as much Pd(OAc) 2 with the same amount of PPh 3 , yet was significantly higher with a decreased amount of PPh 3 or none at all present in the catalyst cocktail (entries 3 and 4).
Careful spectroscopic characterisation of the tricyclic compound 10 8 on the basis of one-and two-dimensional 1 H-and 13 C-NMR spectra, revealed that only a single diastereomer had formed, and it was established as the cisfused tricycle 10 by differential NOE experiments, e. g. irradiation at δ 0.87 corresponding to the methyl group on C-4a enhanced the signal of 10a-H (δ 1.20 undegassed sample) by 1.5%.From the ketone 10, the target compound 1 9 was obtained in two steps with 72% overall yield by transformation to the dithiane 11 and its reductive desulfurization with Raney nickel (Scheme 2).It is worth mentioning that the desulfurization produced a mixture of 1 with other unsaturated hydrocarbons.The crude mixture was hydrogenated, without any attempt to purify its components, to produce almost pure 1.In an alternative attempt, 10 was reduced with sodium borohydride to furnish a mixture of equatorial and axial alcohols which could be mesylated, however, reductive removal of the mesyloxy groups by treatment with LiAlH 4 failed.
Compound 1 was coinjected with the neutral aromatic fraction from one of the samples from the Carmopolis oil field from Sergipe-Alagoas Basin, Brazil, and it indeed coeluted with one of the components (relative retention index 1617). 10

Conclusion
This investigation demonstrates not only the presence of cis-4a-methyloctahydrophenanthrene, biomarker 1, in the Carmopolis oil from Sergipe-Alagoas Basin, possessing a cis-decalin moiety, but also that the Michael-type Heck reaction proceeds in high yields and with total cis stereoselectivity during the intramolecular 1,4-conjugate addition of an arylpalladium bromide intermediate to an α, β-unsaturated ketone with no hydrogen substituent at the β-position.These results add a new application to the vast repertoire of palladium-catalyzed reactions.

Figure 1 .
Figure 1.Two biomarkers detected in Brazilian petroleum.

Scheme 2. Transformation of compound 9 into the biomarker 1 Scheme 1. Synthetic route to the pivotal intermediate 9 Table 1. Optimization of the reaction conditions for the intramolecular Heck-type reaction of compound 9
a Debrominated 9 was the major by-product.b Only traces of debrominated 9 were isolated.