Development of Novel Reactions Using Hypervalent Iodine(III) Reagents: Total Synthesis of Sulfur-Containing Pyrroloiminoquinone Marine Product, (±)-Makaluvamine F

Abstract

Novel and efficient intramolecular nucleophilic substitution reactions of phenol ethers using activated hypervalent iodine species have been developed and their application to the total synthesis of strongly cytotoxic makaluvamine F (1), a member of sulfur-containing pyrroloiminoquinone marine products, is described.

Biomimetic Synthesis of (.+-.)-Galanthamine and Asymmetric Synthesis of (-)-Galanthamine Using Remote Asymmetric Induction

“…The reaction with PIDA produced a moderate yield of 20b, compared to the reaction with PIFA (Table 2, Entries 2, 3, 5). As previously predicted, [33][34][35][36][37] considerable amounts of by-products 21a-d were obtained in cases using acetic acid, acetonitrile, dimethoxyethane, and isopropanol as solvents due to the gen- eration of a cation (22) or a radical followed by nucleophilic attack of the solvents (Table 2, Entries 4-8). Fortunately, the best yield (85%) was obtained in the reaction conducted with PIFA in trifluoroethanol at room temperature ( Table 2, Entry 1).…”

“…Next, the PIFA-mediated intramolecular phenol couplings of 7a and 7b were attempted and were found to afford good yields (75 and 95%, respectively) of dienone (11a, b) when the reaction was carried out at Ϫ40°C in trifluoroethanol, where low nucleophilicity is believed to increase in the chemical yield of the oxidative coupling (Chart 1). [33][34][35][36][37] Herein, we were able to show that the use of the PIFA-mediated phenol coupling, where the substrates had a tri-Omethyl pyrogallol ring instead of a catechol moiety in the norbelladine skeleton, could provide an excellent method for the synthesis of 1. However, the attempted demethylation of 11a and 11b with boron tribromide at Ϫ78°C to afford tetrahydrodibenzofuran derivatives (8a, b) was unsuccessful because of difficulties in the selective cleavage of methyl ethers and the occurrence of side-reactions such as dienonephenol rearrangement.…”

“…However, chemical yields of the coupling could not be increased to more than 50%. [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] In addition, the coupling reaction using metal oxidants had the practical disadvantages of releasing toxic chemicals as waste reagents, e.g., cyanides from potassium ferricyanide or heavy metal ions.…”

“…38,39) Moreover, phenyliodine(III) bis(trifluoroacetate) (PIFA) was chosen as the oxidative reagent for the phenol coupling based on reports that in addition to the coupling product only volatile products, i.e., iodobenzene and trifluoroacetic acid, remained after the PIFA-induced reaction. [33][34][35][36][37][43][44][45][46][47][48][49] At an initial stage of pretesting, we focused on the PIFAinduced phenol coupling of tri-O-methylated derivatives (7a, b) of pyrogallol-type norbelladine (6) to synthesize key intermediates 8a and 8b, and began with the preparation of 7a and 7b. 3,4,5-Trimethoxybenzaldehyde (9) was treated with tyramine in the presence of sodium borohydride to afford 10, which was derived to trifluoroacetamide 7a and formamide 7b.…”

“…Reductive amination of 14a with tyramine in the presence of sodium borohydride and successive treatment of the product 12b with trifluoroacetic anhydride produced a good yield of trifluoroacetamide 12a. However, solubility of 12a in trifluoroethanol, the most suitable solvent for PIFA-mediated reaction, [33][34][35][36][37] was quite poor and the reaction attained in trifluoroacetic acid produced a low yield (12%) of 8a probably due to sidereactions triggered by the generation of a radical species on the pyrogallol moiety.…”