Synthesis of Rearranged Unsaturated Drimane Derivatives

O presente trabalho relata a preparação e aplicação de três vinilcicloexenos devidamente funcionalizados (2,2-dimetil-3-vinilcicloex-3-en-1-ol, 2,2-dimetil-3-vinilcicloex-3-en-1-ona e 3,3dimetil-2-vinilcicloexeno) em reações de Diels-Alder com ésteres , -insaturados (tiglato de metila e angelato de metila). Esta abordagem levou à síntese racêmica de dez octalinas possuindo esqueleto drimânico rearranjado (4 diastereoisômeros do 1-metoxicarbonil-6-hidroxi-1,2,5,5-tetrametil1,2,3,5,6,7,8,8a-octaidronaftaleno; 1-metoxicarbonil-6-oxo-1,2,5,5-tetrametil-1,2,3,4,5,6,7,8ocataidronaftaleno; 2-metoxicarbonil-6-oxo-1,2,5,5-tetrametil-1,2,3,5,6,7, 8,8a-octaidronaftaleno; 3 diastereoisômeros do 1-metoxicarbonil-1,2,5,5-tetrametil-1,2,3,5,6,7,8,8a-octaidronaftaleno e 2-metoxicarbonil-1,2,5,5-tetrametil-1,2,3,5,6,7,8,8a-octaidronaftaleno). Para a preparação dos dienos, utilizou-se a reação de acoplamento catalisada por paládio (reação de Stille) entre enoltriflatos (preparados pelo protocolo de Stang) e tri-n-butilvinilestanana. A estereoquímica relativa dos produtos foi estabelecida a partir de métodos espectroscópicos e análise de difração de raios-X de alguns dos derivados. Estes dados podem servir para a identificação de novos produtos naturais e corrigir algumas estruturas da literatura.

The convergent construction of the octalin framework, with different side-chains at C-1 and an occasional oxo or hydroxy group at position 6, was envisioned by a Diels-Alder (DA) reaction over vinylcyclohexenes of general type 7 (Scheme 1).This synthetic approach was proved unique in the synthesis of compounds 3 6 and 4 7 .Moreover unambiguous identification of secondary metabolites occurring in minute amount is often a difficult task which can be minimized with the support of fully characterized model compounds.Herein we describe the cycloaddition of dienes (±)-7a, 7b and 7c with methyl tiglate (methyl E-2-methylbut-2-enoate) and methyl angelate (methyl Z-2methylbut-2-enoate) with a detailed spectroscopic characterization of the several adducts.

Results and Discussion
Kakisawa's 8 , Ley's 9 (modified by Mori 10 ) and Knapp's 11 methodologies are classic protocols to prepare vinylcyclohexene-type dienes, like (±)-7a, 7b and 7c.Knapp's approach to functionalize cyclohexanones seemed particularly attractive as the use of vinylmagnesium bromide, instead of sodium acetylide, avoids the use of the cumbersome liquid ammonia required in some of the above-mentioned protocols.
The synthesis of (±)-7a and 7b started from 2,2dimethylcyclohexane-1,3-dione 8a, readily available in one step (ca.82% yield) from 2-methylcyclohexane-1,3-dione, MeI and t-BuOK/t-BuOH (Scheme 2).Triton B was reported 12 as an efficient base to perform this alkylation step but, in our hands, this condition failed to produce 8a in good yield.Access to diene (±)-7a (route A, Scheme 2) was gained with a selective reduction of one carbonyl of 8a with NaBH 4 in methanol at 10 o C, protection of the resulting alcohol with TBDMSCl, followed by vinyl Grignard reagent addition (Imamoto's 13 approach) to the remaining carbonyl of ketone (±)-9 complexed with CeCl 3 and dehydration of the resulting allylic alcohol with CuSO 4 (supported on silica gel) 14 to furnish the the diene (±)-10.Attempts to perform the direct addition of the Grignard reagent to the substrate were unsuccessful, an evidence that (±)-9 is an easily enolizable ketone.
Ensuing desilylation of (±)-10 afforded the desired vinylcyclohexene (±)-7a in five steps and 18% overall yield.However, the unsatisfactory results obtained from route A prompted us to switch to an alternative method (route B, Scheme 2).Thus, (±)-7a was synthesized according to the directives given by Snyder et al. 15 in the synthesis of Scheme 1. Vinylcyclohexene derivatives: pivotal intermediates in the synthesis of relevant natural products through Diels-Alder reaction.
Reduction of 7b was accomplished with NaBH 4 to furnish (±)-7a in 97% yield.This alternative route to (±)-7a and 7b is shorter and displays a significant overall yield enhancement (49%) compared to route A. Peripheral findings from our studies in route B should be mentioned.First, to the best of our knowledge, the selective monotriflation of 8a was never reported before, therefore Stang's protocol provides an especially serviceable way to achieve the 2,2-disubstituted cyclohexane-1,3-diones selective functionalization.Second, the ketovinylcyclohexene 7b sounds a pivotal intermediate to access bicyclic terpenes possessing a ketone group at position 6, as in salmantic acid 6.
With (±)-7a , 7b and (±)-10 in hand, we turned to the crucial Diels-Alder reaction (Scheme 3).First of all, diene (±)-10 and methyl tiglate were subjected to several DA reaction conditions and in most of them the adducts were not detected (Table 1, entries 1 to 5).This problem was overcome when we applied more drastic reaction conditions.Based on the GC/MS analyses of the reaction mixtures, best results were obtained with the use of higher temperatures and pressures (Table 1, entries 6 and 7).
Thus, the presence of adducts was characterized by compounds possessing fragments of m/z 380, 323, 265, 248, 189, 171 and 119 in their mass spectra.Due to low yields the adducts were neither isolated nor further characterized.
The low reactivity of diene (±)-10 in DA reaction with methyl tiglate was assigned to the steric hindrance of the bulky TBDMS group, which was therefore removed to afford (±)-7a.In keeping with our plan, the diene (±)-7a and methyl tiglate were submitted to several DA conditions and the best results were obtained at 4 kbar and 110 o C (Table 2, entry 1).
Thus, structures for (±)-12 and (±)-13, belonging to group I (equatorial carbinolic hydrogen), and depicting H-8a chemical shifts in d 2.82 and 2.22, respectively, were established as depicted in Scheme 3.While those of (±)-14 and (±)-15, belonging to group II, (axial carbinolic hydrogen) with H-8a at d 2.72 and 2.08, respectively, were established as depicted in Scheme 3. The full assignment of the signals was only achieved with additional informations of the long range scalar interactions ( 1 H, 13 C COLOC) and nOe differential spectra.The full 1 H and 13 C chemical shifts assignments for these four octalins are shown in the experimental section.
The conformation in solution and the most significative nOe enhancements are depicted in Figure 1.Structures (±)-12 and (±)-15 were further confirmed by X-ray diffraction analysis and the ORTEP drawings are depicted in Figure 2.
Based on these results we have concluded that the regioselectivity of this reaction was maintained similar to that observed in the synthesis of mamanuthaquinone 6 (3) but the stereoselectivity exo was somewhat lost under the influence of either the hydroxyl group or the structural changes of the dienophile.
With the purpose of better understanding the stereoelectronic effects of this DA reaction we envisioned to analyse de behaviour of the ketodiene 7b with methyl tiglate and methyl angelate 20 as dienophiles.Both reactions were performed in sealed ampoules at 170 o C (7 days).
Reaction of 7b with methyl angelate furnished two products in a 2:1 ratio (Scheme 4).Total in situ isomerization of the major adduct was responsible for the isolation of compound (±)-18.The minor component (±)-19 was obtained in a 1:1 mixture with (±)-18.From the spectral data comparison of (±)-18 with those of the mixture structure of the adduct (±)-19 was established as depicted in Scheme 4. However it is worthwhile mentioning that the reaction of 7b with methyl tiglate produced two adducts in a 1:1 ratio possessing the regiochemistry of (±)-18 21 .
Thus the subtle change of the dienophile (methyl angelate® methyl tiglate) was responsible for the high regioselectivity of this reaction.
As the bicyclic framework of compound (±)-18 and that of the methyl ester 20 of salmantic acid (6) are equal the 1 H and 13 C NMR chemical shifts of the corresponding carbons and hydrogens were expected to be highly similar.Therefore some doubts about the chemical shifts of carbons 1, 6 and 7 (diterpene numbering system) of the derivative 20 were cleared by comparison with the full assignment of (±)-18 and our suggestion of assignment is depicted in structure 20a (Figure 3).
Thus based on the above results we observed that octalins possessing rings A/B of the rearranged drimane skeleton, with a C1-Me/C2-Me cis relationship, displayed a Dd about 1 ppm between the vicinal methyl groups, while for those with a trans relationship a Dd about 6 to 7 ppm, independent of the relative configuration between H-8a and C1-Me and of the C-6 substitutent, was observed.
We also realized that our set of data was not complete unless the 6-unsubstituted octalins were synthesized.The latter would provide good standards for a series of natural halimane diterpenes.We have thus embarked on the synthesis of octalin models compounds possessing C1-Me/ C2-Me cis and trans relationship (Scheme 5).Diene 7c was readily available from commercial 2,2dimethylcyclohexanone and using the previously established protocol.The DA reactions between diene 7c and methyl angelate (reaction 1) and methyl tiglate  (reaction 2) acting both as solvent and dienophiles were carried out in sealed ampoules at 170 o C for 7 days.Reactions 1 and 2 furnished mixtures of adducts (Scheme 5).Purification of the reaction mixture by preparative TLC on silica gel AgNO 3 10% (w/w) provided highly enriched major adduct (±)-22 (endo adduct) from which a full set of spectroscopic data ( 1 H NMR, 13 C NMR, gCOSY, HSQC, NOESY and MS) was obtained, allowing good structural characterization.The Dd between C1-Me and C2-Me of (±)-22 was 7 ppm in good agreement with the above mentioned trans relationship.This rule was validated by observing the reported 13 C chemical shifts of some natural products like 4 7 possessing this octalin framework.Notwithstanding this successful comparison this rule failed when applied to one of the natural products we had isolated from Vellozia flavicans, the tetra-nor-halimanoic acid (5) 4 , which depicted a Dd = 0 ppm.We have also realized that a cis relationship instead of the reported trans would better match our observations.This prompted us to reanalyse all spectroscopic data in order to ascertain that no additional misassignments were made at that time and indeed most signals were correctly assigned but for minor drawing misprinting.Thus, comparison of the spectroscopic data of (±)-22 , (±)-24 and (±)-25 (Figure 4) led us to revise the proposed structure of 5 as depicted in Figure 5.
In conclusion, we have achieved the synthesis and spectroscopic characterization of useful rearranged unsaturated drimane derivatives.This study corroborates with the idea that the regio and stereochemical outcome of the Diels-Alder reactions depend on the double bond stereochemistry of the acrilate derivatives and as a rule tiglate derivatives display high regioselectivity as observed in the synthesis of mamanuthaquinone 6 .Finally the spectrometric characterization of the compounds (±)-12, (±)-13, (±)-14, (±)-15, (±)-18, (±)-19, (±)-22, (±)-23, (±)-24 and (±)-25 is of great help to identify new natural products possessing this octalin moiety which can be so deceiving in determining its relative configuration.

Experimental
Melting points were recorded with a Kofler hot plate set up in a microscope Thermopan model (C.Reichert Optische Werke AG).FTIR Spectra were taken on a Perkin Elmer 298 spectrophotometer. 1 H NMR spectra were recorded with a Varian GEMINI 300 (300 MHz, Varian) or Bruker AC 300P(300 MHz) spectrometers.CDCl 3 was used as the solvent, with Me 4 Si (TMS) as internal standard. 13C NMR spectra were obtained with a Varian GEMINI 300 (75.5 MHz) or a Bruker AC300P (75.5 MHz) spectrometers.CDCl 3 (77.0ppm) was used as internal standard.Signals of methyl, methylene, methine and carbons nonbonded to hydrogen were recognized using DEPT 90 and 135 spectra.2D NMR spectroscopy experiments were performed with standard homonuclear H,H and heteronuclear H,X correlation pulse sequences available in the spectrometers.The GC/MS analyses were carried on a HP-5890/5970 system equipped with either a J&W Scientific DB-5 fused silica capillary column (30m X 0.25mm x 0.25 mm) or a chiral column heptakis-( 2

octahydronaphthalene (±)-(25)
A mixture of methyl tiglate (0.5 mL) and vinylcyclohexene 7c (15.00 mg, 0.11 mmol), was sealed in a glass ampoule which was introduced in an explosion protecting stainless steel tube device at 170 o C for 7 days.Before opening, the ampoule was refrigerated and the remaining methyl angelate was removed in vacuo using a kugelrohr apparatus.The residue was purified by flash chromatography on silica gel eluted with hexane/ethyl acetate 8:1 (v/v), furnishing 18 mg of a 3:2 mixture of adducts (±)-24 and (±)-25.

Figure 3 .
Figure 3. Suggested assignment (20a) for some 13 C chemical shifts reported for the salmantic acid derivative 20.