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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Tetrahedron Lett. Author manuscript; available in PMC 2010 September 1.
Published in final edited form as:
Tetrahedron Lett. 2009 September 30; 50(39): 5482–5484.
doi:  10.1016/j.tetlet.2009.07.068
PMCID: PMC2919757

Syntheses of Isomerically Pure Reference Octalins and Hydrindanes


We describe herein the development of efficient and stereoselective synthetic routes to a range of cis- and trans- octalin and hydrindane target compounds.

In the context of a program underway in our laboratory,1 wherein we are exploring fresh extensions of Diels-Alder based strategies, we required access to several simple homogeneous, stereochemically defined unsubstituted cis- and trans-octalins and hydrindanes (compounds 1-5, Figure 1). Remarkably, a comprehensive survey of the synthetic literature revealed that only a few of the required compounds had been previously described.2a-e Moreover, the routes for the synthesis of such compounds gave mixtures of stereoisomers which were not purified. Additional reaction steps would be required to gain access to homogeneous material. For instance, the synthesis of tricyclic trans-3, accomplished through acid-catalyzed rearrangement of a precursor dodecahydroanthracene, furnished a low yield of the desired compound (15%), along with several other byproducts. An analytical sample of trans-3 could be obtained only by preparative gas chromatography. Among the target compounds, only cis-4 was obtained in a stereochemically secure manner, through Diels-Alder reaction of cyclopentadiene with 2,3-dimethyl-1,3-butadiene followed by regioselective hydrogenation of the cyclopentene olefin.

Figure 1
cis- and trans- decalins and hydrindanes prepared in this study.

In order to obtain the required quantities of our target systems through viable pathways, we were obliged to devise modified syntheses of the target compounds (15). In this Letter, we relate how these goals were accomplished.

We first describe routes to the trans-octalin derivatives, 1-3 (Scheme 1). Our key building blocks are the known cyclohexen-1,4-diones, 6a-c, themselves prepared through Diels-Alder reaction of 1,4-benzoquinone with the appropriate dienes (2,3-dimethyl-1,3-butadiene,2a isoprene2b and 1,2-dimethylenecyclohexane,3 respectively). Chemoselective reduction of 6a-c (Zn in aqueous AcOH) yielded the cis-diketones 7a-c.2a,b Following literature precedents,2a a solution of cis-diketone 7a in 1,4-dioxane was treated with 1 M NaOH (1.07 equiv) at 80 °C for 10 min, to yield the higher-melting trans-isomer, 8a. Attempts to achieve epimerization of cis-diketones 7b and 7c at comparably high temperatures were unsuccessful, leading to low recovery of the desired compounds, and formation of a variety of polar by-products. Epimerization of the cis-diketones 7b-c was preferably conducted at room temperature with 1 M NaOH (1.2 equiv) for 10 min to afford 8b and 8c in 40% and 79% yields, respectively. However, Wolff-Kishner reduction of the trans-diketones 8a-c afforded unsatisfactory mixtures of cis- and trans-olefins 1-3. Fortunately, reduction 4 of trans-bitosylhydrazones 9a-c (which were readily prepared from 8a-c) afforded pure octalin derivatives trans-1-3.

Scheme 1
Synthesis of trans-1, trans-2, and trans-3.

Having synthesized compounds 1-3 in the trans series, we next sought to prepare the corresponding cis-octalin derivatives, namely cis-1-3 (Scheme 2). The known cis-bicyclic ketones, 10a-b, 5 were prepared by Diels-Alder reaction of cyclohex-2-en-1-one with 2,3-dimethyl-1,3-butadiene and isoprene, respectively, in the presence of catalytic CH3AlCl2. The formation of the trans-isomeric cycloadducts could be suppressed by conducting the reaction at 0 °C.

Scheme 2
Synthesis of cis-1, cis-2, and cis-3.

Similarly, CH3AlCl2-catalyzed Diels-Alder reaction between cyclohex-2-en-1-one and 1,2-dimethylenecyclohexane afforded the tricyclic ketone 10c in 55% yield. Again, reduction of compounds 10a-c (NaBH4, CH3OH, −30 °C) furnished the corresponding carbinols 11a-c as diastereomeric mixtures of alcohols. All major diastereomers of 11a-c were separated from their minor isomers by simple column chromatography on silica gel.6 Actually we could not, at this stage, confidently assign the stereochemistry of the hydroxy bearing center. In any case, derived Barton-McCombie reduction 7 of xanthate esters 12a-c gave the target compounds, cis-1-3.

In accord with Casadevall’s observation,8 the ring junction carbons of cis-1-3 are more shielded than those of trans-1-3. For example, the 13C-NMR chemical shifts of the two ring junction carbons of cis-3-methylbicyclo[4.4.0]dec-3-ene (cis-2) appear at 33.65 and 33.50 ppm as singlets, whereas two singlets are observed at 38.61 and 38.15 ppm in the 13C-NMR spectrum of trans-2.6

With the target compounds in the cis- and trans-octalin series in hand, we next turned our attention to the preparation of the cis- and trans-hydrindane target compounds, 4 and 5. Our route to trans-4 and trans-5 began from the known chiral racemic diols, 14a-b, 9 themselves prepared through Diels-Alder reaction of dimethyl fumarate with the appropriate dienes, followed by LiAlH4 reduction (13→14). As shown in Scheme 3, diols 14a-b were converted to ketones 19a-b using methods analogous to those employed in the preparation of trans-bicyclo[4.3.0]non-3-en-8-one.10 Thus, treatment of 14a-b with p-TsCl in pyridine at 0 °C afforded ditosylates 15a-b, which were then subjected, without further purification, to the action of ethanolic solutions of sodium cyanide, under reflux. There were thus obtained 16a-b, which were immediately converted to the corresponding diesters 18a-b by Fisher esterification. Sequential Dieckmann cyclization, hydrolysis of the resultant β-keto esters, and decarboxylation provided tetrahydroindanones 19a-b. With the hydrocarbon skeletons of the two trans-hydrindane derivatives fully assembled, the remaining task was the deoxygenation of 19a-b. Treatment of refluxing ethanolic solutions of 19a-b with p-toluenesulfonyl-hydrazide furnished the corresponding tosylhydrazones 20a-b as white crystalline solids. Reduction of 20a-b with catecholborane4 provided the target trans-hydrindanes, trans-4 and trans-5, in 63% and 59% yields, respectively (Scheme 3).

Scheme 3
Synthesis of trans-4 and trans-5.

The availability for the first time of these reference compounds enables confident structure assignments in our ongoing Diels-Alder program, the results of which will be described in due course.

Finally, we report the syntheses of the cis-fused hydrindanes, cis-4 and cis-5. As shown in Scheme 4, the known bicyclic ketones 21a-b were reduced (NaBH4, CH3OH, −30 °C) to afford alcohols 22a-b as diastereomeric mixtures, which were then converted to 23a-b as shown. Treatment of these xanthate esters with nBu3SnH and catalytic amounts of AIBN afforded cis-4 and cis-5. The 13C-NMR spectrum of the former was identical to that reported in the literature.2e As observed in the octalin series (vide supra), the ring junction carbons of cis-4-5 are more shielded than those of the corresponding trans-isomers. For example, the 13C-NMR chemical shifts of the two ring junction carbons of cis-3-methylbicyclo[4.3.0]non-3-ene (cis-5) appear at 36.82 and 35.77 ppm as singlets, whereas two singlets are observed at 42.90 and 42.18 ppm in the 13C-NMR spectrum of trans-5.6

Scheme 4
Synthesis of cis-4 and cis-5.

In summary, we have described herein the development of workable protocols for the preparation of the cis- and trans-junction isomers of a range of octalin and hydrindane structure.

Supplementary Material



This work was supported by the NIH (HL25848 to S.J.D.). W.H.K. is grateful for a Korean Research Foundation Grant funded by Korean Government (KRF-2007-357-c00060). We thank Ms. Rebecca Wilson for valuable help in editing of this letter.


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