Suzuki coupling and subsequent transformations

The key Suzuki coupling was investigated within the group by Dr. Michaelis and Dr. Gebhardt and coupling product 288 was obtained in 76% yield under classical reflux (Scheme 97).^80,115 This reaction was never attempted using microwave irradiation and more investigations were necessary to try to improve the yield of this reaction.

Scheme 97 – Synthesis of coupling product 288 Reagents and conditions: a) PdCl2(dppf), K3PO4, DME, 85 °C, 12 h, 76%.

Previous results within the group revealed that coupling product 288 was isolated alongside two main side products derived from bromide 272 and identified as alcohol 281 and dimer 289 (Figure 9).^80,107 As a result, it was thought that bromide 272 could be added in larger excess in order to favor the complete completion of boronic ester 273. In addition, the synthesis of bromide 272 was much quicker and large quantities could be readily synthesized.

Figure 9 – Side products formed in the Suzuki coupling

The Suzuki coupling was attempted using the conditions optimized by Dr. Michaelis,⁸⁰ with two equivalents of bromide and the reaction was performed in a microwave (Scheme 98). Surprisingly, no reaction was observed and bromide 272 decomposed readily under these conditions (Table 11, entry a). The reaction was repeated with cesium carbonate, however, no reaction occurred and bromide 272

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decomposed (Table 11, entry b). It was thought that the base was not soluble enough in DME and as the reaction time was quicker in the microwave no reaction could occur. As a result, water was added as a co-solvent. Gratifyingly, upon treatment under the same conditions in a mixture DME/H2O (4:1), the coupling product was obtained in a moderate 45% yield (Table 11, entry c). The amount of bromide was reduced to 1.1 equivalents and the reaction was run again with potassium phosphate and the expected product 288 was obtained in a comparable yield (Table 11, entry d). Accordingly, the conditions developed by Michaelis were used for the large scale synthesis of coupling product 288.

Scheme 98 – Synthesis of coupling product 288

The next two steps towards pentacycle 290 were conducted by Dr. Michaelis and Dr. Gebhardt. The synthesis continued with the selective saponification of the methyl ester in 288. Treatment with ten equivalents of LiOH successfully afforded 271 in good yield (Scheme 99). Based on previous studies,³¹ the Friedel-Crafts acylation was planned to be performed in a three-step procedure. First, the carboxylic acid 271 would be converted into the corresponding acid chloride, the acylation would take place and finally the resulting phenol would be protected for stability purpose. Treatment of carboxylic acid 271 with Ghosez‟s reagent¹¹⁶ successfully gave the corresponding acid chloride which was treated with ZnCl2. Finally, treatment with a mixture of Ac2O and pyridine successfully afforded

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in good yield pentacycle 290, the structure of which was confirmed by X-ray crystallography (Figure 10).

Scheme 99 – Synthesis of pentacycle 290

Reagents and conditions: a) LiOH, MeOH/H2O (1:1), 48 h; b) i) Me2C(Cl)NMe2, CH2Cl2, 0 °C; ii), ZnCl2, 0 °C; iii) Ac2O, pyridine, DMAP, 12 h, 75% over two steps.

Figure 10 – X-ray structure of pentacycle 290

The synthesis continued with the oxidative demethylation to afford quinone derivative 270 (Scheme 100). Previous reported attempts for the oxidation on various model systems revealed that CAN was an excellent oxidation reagent.³¹ In addition, Behar described that the success of the CAN oxidation required the presence of the electron-withdrawing acetate protecting group on the center ring phenol;

otherwise, oxidation preferentially occurred at the central ring of the anthracene system.¹¹⁷ Pentacycle

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290 was treated with an excess of CAN at 0 °C for one hour and the reaction was warmed to room temperature for twelve hours. Surprisingly, an inseparable mixture of quinones 270 and 291 was obtained in a 1:5 ratio, respectively (Table 12, entry a). The ratio could be reduced to 1:1.7 when the reaction was conducted only at 0 °C but the undesirable quinone 291 was still obtained as the major product (Table 12, entry b). As a result, the reaction was attempted with a variety of oxidative agents.

Treatment with PIFA gave a complex mixture and quinones 270 and 291 could be isolated in a 1:10 ratio (Table 12, entry c)whereas treatment with DDQ or Ag2O gave no conversion after twelve hours (Table 12, entries d and e).¹¹⁸ Pleasingly, treatment with an excess of AgO with HNO3 at room temperature favored the formation of the desired quinone 270 and quinones 270 and 291 were obtained in a 2.7:1 ratio, respectively (Table 12, entry f).¹¹⁹ Upon treatment under the same conditions at 10 °C, the ratio was further increased to 5:1 in favor for 270 (Table 12, entry g). Finally, the reaction was conducted at 45 °C and only traces of quinone 291 were detected and quinone 270 could be obtained pure in 43% yield (Table 12, entry h).

Scheme 100 – Oxidation of pentacycle 290

Table 12 – Optimization for the formation of quinone 270

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With quinone 270 in hand, the dihydroxylation was investigated by Dr. Michaelis and Dr. Gebhardt (Scheme 101 and Table 13). Following the Danishefsky precedent,²⁴ quinone 270 was treated with a mixture of OsO4 (catalytic or stoichiometric amount) and NMO. Unfortunately, quinone 270 decomposed (Table 13, entries a and b).²⁴ Upon treatment under Sharpless conditions, no reaction took place and starting material 270 was recovered (Table 13, entry c).¹²⁰ The dihydroxylation was repeated with ruthenium tetraoxide (prepared in situ from ruthenium(III) chloride and sodium periodate), however, no reaction was observed (Table 13, entry d).⁹²

Scheme 101 – Dihydroxylation attempts on 292

Entry Conditions (eq.) Solvent Results

a OsO4 (5 mol%), NMO (1.5) acetone/H2O (9:1) Decomposition

b OsO4 (1.0) acetone/H2O (9:1) Decomposition

c K3Fe(CN)6 (3.0), K2CO3 (3.0), K2OsO2(OH)4 (5

mol%), (DHQD)2PHAL (0.1), MeSO2NH2 (2.0) tert-BuOH/H2O (1:1) No reaction

d RuCl3 (0.5 mol%), NaIO4 (0.5), H2SO4 (0.2) EtOAc/MeCN/H2O

(6:6:1) No reaction Table 13 – Dihydroxylation attempts on quinone 292

1.5 Conclusion

In summary, it was shown that pentacycle 270 can be assembled from boronic ester 273 and benzyl bromide 272 in good yield from readily synthesized components. So far, the dihydroxylation failed to be successful despite similarities with model studies. It was suggested that the dihydroxylation was not successful mainly due to the steric hindrance generated by both tert-butyl esters. In a new strategy, we sought to diminish the steric hindrance with a few modifications.

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