Diels-Alder reactions using 4,7-dioxygenated indanones as dienophiles for regioselective construction of oxygenated 2,3-dihydrobenz[f]indenone skeleton

Regioselective construction of 4,8,9-trioxygenated 2,3-dihydrobenz[f]indenones, key intermediates for the synthesis of kinamycin antibiotics, was achieved via Diels-Alder reactions (DAR) using 4,7-dioxygenated indanone-type compounds as dienophiles. Reaction of indanetrione with 1-methoxybutadiene gave a 1 : 1 mixture of undesired 4,5,9-trioxygenated 2,3-dihydrobenz[f]indenone and [4.4.3]propellane. The addition of Lewis acid did not affect the product ratio, whereas the use of the 6-bromoindanetrione exclusively afforded the latter propellane. On the other hand, DAR of benzyne derived from bromoindan and furan gave 5,8-epoxy-2,3-dihydrobenz[f]indene, which was subjected to acid-induced ring opening to give 2,3-dihydrobenz[f]indenone with undesired 4,5,9-trioxy functions.


Results and Discussion
In the quinone route, we designed several indanetriones to modulate steric and electronic factors; i.e. 1,4,7-indanetrione 8, the 6-brominated quinone 12, and the corresponding 4-monoacetals 13 and 14 (Scheme 2). Intramolecular Friedel-Crafts reaction of 2,5-dimethoxybenzenepropanoic acid (15) and the 4-brominated derivative 16 [31], by a procedure modified from the synthesis of 4 [23], afforded the corresponding indanones 17 and 18. Cerium ammonium nitrate (CAN) oxidation [32] of indanone 17 smoothly afforded indanetrione 8, but attempts with bromoindanone 18 resulted in no reaction even under reflux. Utilization of a milder oxidant phenyliodosyl bis(trifluoroacetate) (PIFA) [33] for the oxidation of phenolic indanone 20, derived from 18 by selective demethylation with magnesium iodide (MgI 2 ) [34], gave bromoquinone 12 after modification of the workup protocol without aqueous sodium bicarbonate. The PIFA oxidation of phenols 19 [35] and 20 in the presence of methanol gave the corresponding monoacetals 13 and 14.  Table 1). Both compounds were obtained as single diastereoisomers. The former was determined as an undesired 5-methoxy derivative 21, the structure of which was deduced by HMBC correlations and NOE enhancement (Figure 2a). The latter structure 22 was also determined by HMBC and NOE experiments ( Figure 2b); however, the relative configuration of the carbon connected to the methoxy group could not be determined because of lacking NOE data. Next, the effect of Lewis acid on the regioselectivity was examined. At first, zinc chloride (ZnCl 2 ), an effective cata- lyst on DAR of benz[f]indenone and Danishefsky-type diene [21], was chosen. Addition of a catalytic amount of ZnCl 2 at −78 °C did not affect the regioselectivity (entry 2). An increase in the amount of ZnCl 2 led to the formation of a complex mixture containing a small amount of propellane 22 (entry 3).
Next, instead of ZnCl 2 , which is only slightly soluble in CH 2 Cl 2 , boron trifluoride etherate (BF 3 · OEt 2 ) was applied as a soluble Lewis acid; however, similar results were obtained to those with ZnCl 2 (entries 4, 5). Interestingly, when bromoquinone 12 was reacted under the conditions of entry 1,   DAR at the ring junction proceeded exclusively to give bromopropellane 23 in high yield as the sole product (entry 6). The yield was slightly reduced and the regioselectivity was not affected in the reaction in the presence of a catalytic amount of BF 3 · OEt 2 (entry 7).
We next turned to the use of quinone monoacetals 13 and 14 as dienophiles [36]. No adduct was formed on reaction of 13 in CH 2 Cl 2 without a catalyst at room temperature (rt) (entry 8), whereas refluxing in toluene gave deprotected propellane 22 (16%) together with phenol 19 (23%), a synthetic precursor of 13 (entry 9). Stirring bromoquinone monoacetal 14 in CH 2 Cl 2 at rt yielded only a small amount of propellane 23 (entry 10). The regioselectivity and the yield were not improved by the addition of ZnCl 2 , from which the phenol 20 and propellane 23 were isolated in low yields as conversion products (entry 11  Table 2). The yield was still low (12%) under microwave irradiation (entry 2). The use of lithium diisopropylamide (LDA) [42] in THF slightly increased the yield of 26 to 25% (entry 3). Although no improvement was observed after increasing the quantity of the base (entry 4), the yield was slightly improved to 30% on decreasing the quantity of furan (9) to two equivalents (entry 5). Bases derived from tetramethylpiperidine (TMP) [43] were not effective (entries 6, 7). Thus, the desired improvement of the yield was not observed for the synthesis of the 5,8-epoxybenz[f] indene derivative 26; nevertheless, the ring-opening step was examined. Treatment of 26 with hydrochloric acid in a mixture of methanol and THF after deprotection of the ketal unit [41] afforded a ring-opened product 27 in 39% yield with recovery of epoxy ketone 11 (42%). The structure of 27 was determined to be the 5-hydroxylated compound, not 8-oxygenated isomer 28, by HMBC and NOE experiments (Figure 3). In the former quinone route, the regioselectivity on the introduced methoxy group in 2,3-dihydrobenz[f]indenone was examined. 4,5,9-Trioxygenated 2,3-dihydrobenz[f]indenone derivative 21 was exclusively formed on DAR of indanetrione 8 and diene 7 because of selective activation of the C6 carbon due to the presence of additional cross conjugation between the C1 and the C4 carbonyl groups (TS-A, Figure 4). Semiempirical calculation [44] of molecular orbitals of quinone 8 supported this proposal, in which a larger LUMO coefficient (0.295) was obtained at C6 compared with C5 (0.244, Figure 5a). On the other hand, the reverse of the selectivity was expected when Lewis acid is coordinated with two carbonyls at C1 and C7 to positively activate the C5 carbon (TS-B, Figure 4); however, the addition of a catalytic amount of Lewis acid did not affect the regioselectivity. Similar reversal of the selectivity was also expected on using a quinone monoacetal to mask the ketone functionality at the 4 position (TS-C); however, the desired 2,3dihydrobenz[f]indenone-type compound was not obtained.
On the other hand, propellane-type product 22 was obtained as a by-product in DAR of 8. In the case of reaction of bromoquinone 12, propellane 23 was the sole product. Larger coefficients at C3a and C7a carbons compared with those of C5 and C6 ones supported this phenomenon (Figure 5a). The steric bulk of the bromine atom in 12 can assist the selective formation of 23 (Figure 5b).

Scheme 4:
The proposed mechanism for the acid-induced ring opening of epoxynaphthalene 29 by Giles et al. [19]. ives were obtained; however, this finding could be applied to the synthesis of regioisomeric kinamycin analogues in each experiment. In the quinone route, the DAR has occurred mainly at the ring juncture of indanetriones to furnish propellane-type compounds [45]. This interesting framework of the products would be applicable to not only synthesis of other natural product but also preparation of newly designed functional molecules.