Synthesis of a Mumbaistatin Analogue through Cross-Coupling

Abstract

Studies on the total synthesis of mumbaistatin, the ­strongest natural inhibitor of G6P-T1, have culminated in the synthesis of a 4′′,8-dideoxy analogue. Key steps include a Diels-Alder reaction for the construction of the functionalized anthraquinone, a palladium-catalyzed Stille coupling to generate a tetra-ortho-sub­stituted diarylmethane, and a titanium-mediated alkynylation of an aldehyde to complete the carbon skeleton of mumbaistatin. Radical bromination of the methylene bridge afforded a lactone, which ­resembles the target structure in its cyclized form.

mumbaistatin - diabetes - anthraquinone - benzo­phenone - natural product - Diels-Alder reaction - Stille reaction - ­titanium

References and Notes

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25

3-Hydroxy-1-methyl-9,10-dioxo-9,10-dihydro-anthracene-2-carboxylic Acid tert -Butyl Ester (10): To a solution of naphthoquinone 5 (6.20 g, 32.3 mmol, 1.0 equiv) in toluene (220 mL) was added the diene 6 (22.25 g, 64.6 mmol, 2.0 equiv) and the mixture was refluxed for 36 h. Then the solvent was removed in vacuo and the oily residue was dissolved in THF (100 mL), containing H₂O (5.0 mL). The black solution was allowed to stir for 15 h at r.t., before silica gel 60 (50 g) was added and the suspension was evaporated to dryness in vacuo. The silica-containing crude product was added to the top of a flash SiO₂ column and the product was eluted with cyclohexane-EtOAc (4:1). Evaporation of the solvent afforded a crude product, which was recrystallized from cyclohexene-EtOAc (4:1) to yield the anthraquinone 10 (6.80 g, 20.1 mmol, 62%) as a yellow solid; TLC: R _f 0.18 (cyclohexane-EtOAc, 4:1); mp 250 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 1.59 (s, 9 H, OMe₃), 2.62 (s, 3 H, Me), 7.59 (s, 1 H, H-4), 7.59-7.88 (m, 2 H, H-6, H-7), 8.06-8.10 (m, 2 H, H-5, H-8), 11.35 (s, 1 H, OH). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 18.74 (q, Me), 27.68 (q, OCMe₃), 82.09 (s, OCMe₃), 111.60 (d, C-4), 123.03 (s, C-2), 125.91, 126.63 (2 × s,C-5, C-8), 130.58, 131.32 (3 × s, C-4a, C-9a), 133.32, 134.45 (2 × s, C-6, C-7), 136.08 (s, C-8a, C-10a), 139.56 (s, C-1), 157.80 (s, C-3), 165.82 [C(O)Ot-Bu], 182.30, 182.85 (2 × s, C-9, C-10). IR: 3366 (br m), 2976 (w), 1725 (s), 1665 (vs), 1570 (vs), 1365 (m), 1308 (s), 1249 (s), 1146 (s), 712 (vs) cm^-1. MS (EI-DIP; 70 eV): m/z (%) = 338 (1) [M]⁺, 282 (54) [M-C₄H₈]⁺, 264 (100), 236 (18), 180 (12), 152 (38), 76 (12), 57 (72). HRMS (EI, 70 eV): m/z [M]⁺ calcd for C₂₀H₁₈O₅: 338.1154; found: 338.115 ± 0.002. The X-ray crystal structure data of compound 10 has been deposited at the Cambridge Crystallographic Data Centre and was allocated the deposition number 632347.
1-(2-Hydroxymethyl-6-methoxybenzyl)-3-methoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic Acid tert -Butyl Ester (14): A Schlenk flask was charged under argon with degassed NMP (7 mL) and THF (7 mL), bromide 4 (415 mg, 0.96 mmol, 1.0 equiv), Pd₂(dba)₃ (8.9 mg, 9 µmol, 1 mol%), AsPh₃ (11.6 mg, 38 µmol, 4 mol%) and copper(I) iodide (3.5 mg, 19 µmol, 2 mol%) was added. Then (3-methoxy-2-tributylstannanylphenyl)methanol (13; 530 mg, 1.24 mmol 1.3 equiv) was added and the reaction mixture was stirred at 75 °C for 20 h. Then, EtOAc (30 mL) was added, the layers were separated, and the aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine and dried over MgSO₄. Removal of the solvent under reduced pressure gave a brown residue, which was purified by column chromatography (silica gel, cyclohexane-EtOAc, 7:3). After evaporation of the solvent the desired product 14 (183 mg, 376 µmol, 39%; still contaminated with impurities) was obtained as a yellow solid in a total weight of 250 mg along with the debrominated compound 11 (141 mg, 327 µmol, 34%). Usually, the product 14 was used for the next step (Swern oxidation) without further purification. For analytical purposes a small sample of pure 14 was prepared by column chromatography (silica gel, CH₂Cl₂-EtOAc, 30:1-10:1); TLC: R _f 0.24 (cyclohexane-EtOAc, 2:1); mp 195 °C. ¹H NMR (250 MHz, CDCl₃): δ = 1.38 (s, 9 H, OCMe₃), 2.99 (t, ³ J _H,H = 5.0 Hz, 1 H, CH₂OH), 3.42 (s, 3 H, OMe at C-2′), 4.01 (s, 3 H, OMe at C-3), 4.64 (d, ³ J _H,H = 4.5 Hz, 2 H, CH₂OH), 4.68 (s, 2 H, CH₂-at C-1), 6.66 (dd, ⁴ J _H,H = 1.0 Hz, ³ J _H,H = 8.0 Hz, 1 H, H-3′), 7.01 (dd, ⁴ J _H,H = 1.0 Hz, ³ J _H,H = 7.5 Hz, 1 H, H-5′), 7.12 (app t, ³ J _H,H = 8.0 Hz, 1 H, H-4′), 7.63-7.69 (m, 2 H, H-6, H-7), 7.73 (s, 1 H, H-4), 7.95-8.02, 8.13-8.20 (2 × m, 1 H, H-5, H-8), ¹³C NMR (75 MHz, CDCl₃): δ = 27.88 (q, COMe₃), 30.22 (t, CH₂ at C-1), 55.53 (q, OMe at C-2′), 56.27 (q, OMe at C-3), 63.30 (t, CH₂OH), 83.01 (s, OCMe₃), 107.20 (d, C-4), 110.98 (d, C-3′), 121.91 (d, C-5′), 125.70, 126.08 (2 × s, C-4a, C-9a), 126.08, 126.37, 126.98 (3 × d, C-4′, C-5, C-8), 132.15 (s, C-2), 133.05, 134.17 (2 × d, C-6, C-7), 135.00 (s, C-8a, C-10a), 136.79 (s, C-1), 140. 55 (s, C-6′), 144.67 (s, C-1′), 157.88 (s, C-2′), 159.44 (s, C-3), 166.40 [s, C(O)Ot-Bu], 183.11, 183.41 (2 × s, C-9, C-10). IR: 3533 (br m), 3071 (w), 2976 (m), 1716 (s), 1667 (s), 1574 (vs), 1461 (s), 1280 (vs), 1141 (vs), 1097 (s), 1097 (s), 1020 (m), 713 (vs) cm^-1. MS (EI-DIP; 70 eV): m/z (%) = 488 ([M]⁺; 414, >1), 414 (35), 369 (100), 355 (11), 339 (9), 226 (8), 57 (33). HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₉H₂₈O₇: 511.1733; found: 511.173 ± 0.002.
1-[2-(1,6-Dihydroxyhexyl)-6-methoxybenzyl]-3-methoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic Acid tert -Butyl Ester (15): A solution of pent-4-yn-1-ol (210 mg, 2.39 mmol, 4.0 equiv) in THF (4 mL) was cooled to 0 °C. Then a 1.6 M solution of n-BuLi in hexane (3.0 mL, 4.77 mmol, 8.0 equiv) was added slowly. After 15 min, the stirred reaction mixture was cooled to -60 °C, and TiCl(Oi-Pr)₃ (1.32 g, 4.95 mmol, 8.3 equiv) dissolved in THF (2 mL) was added. The solution was stirred at -60 °C for further 1.5 h and aldehyde 3 (290 mg, 0.60 mmol, 1.0 equiv) in THF (6 mL) was added via cannula. The reaction mixture was stirred at -60 °C for 30 min, warmed from -60 °C to -20 °C, stirred for 15 h, quenched with sat. NH₄Cl, warmed to r.t., and diluted with CH₂Cl₂. The aqueous phase was extracted with CH₂Cl₂ (2 ×), the combined organic extracts were dried over MgSO₄, concentrated and purified by column chromatography (silica gel, cyclohexane-EtOAc, 4:6) to give the corresponding addition product(alkyne) as a yellow oil (305 mg, 0.54 mmol). To a solution of the alkyne (305 mg, 0.54 mmol, 1.0 equiv) in toluene (15 mL), Rh(PPh₃)₃Cl (52 mg, 0.06 mmol, 9 mol%) was added under argon. The resulting suspension was then stirred under an atmosphere of hydrogen (3 atm) at r.t. for 15 h. Then the solvent was evaporated and the residue was purified by column chromatography (silica gel, cyclohexane-ethyl acetate, 4:6) to give compound 15 (298 mg, 0.52 mmol, 87% overall yield) as a yellow solid; TLC: R _f 0.31 (cyclohexane-EtOAc, 4:6); mp 66.0 °C. ¹H NMR (250 MHz, CDCl₃): δ = 1.27-1.54 [m, 4 H, HO(CH₂)_{2 (}CH₂)₂], 1.40 (s, 9 H, COMe₃), 1.55-1.90 (m, 4 H, HOCH₂CH₂, HOCHCH₂), 3.38 (s, 3 H, OMe), 3.56 (t, J _H,H = 6.5 Hz, 2 H, HOCH₂), 4.00 (s, 3 H, OMe), 4.43 (d, J _H,H = 16.0 Hz, 1 H, CH₂Ar₂), 4.83 (d, J _H,H = 16.0 Hz, 1 H, CH₂Ar₂), 5.12-5.19 (m, 1 H, HCOH), 6.55-6.60 (m, 1 H, H-5′), 7.11-7.14 (m, 2 H, H-3′, H-4′), 7.63-7.68 (m, 2 H, H-6, H-7), 7.74 (s, 1 H, H-4), 7.90-7.95, 8.13-8.17 (2 × m, 2 H, H-5, H-8). ¹³C NMR (75 MHz, CDCl₃): δ = 25.60 (t, CH₂), 25.90 (t, CH₂), 28.01 (q, OCMe₃), 29.80 (t, CH₂Ar₂), 32.67 (t, CH₂), 37.48 (t, CH₂), 55.23 (q, OMe at C-6′), 56.29 (q, OMe at C-3), 62.79 (t, HOCH₂), 69.94 (d, CHOH), 82.98 (s, OCMe₃), 107.18 (d, C-4), 109.93 (d, C-5′), 118.55 (d, C-3′), 120.39 (s, C-2), 125.10, 125.66 (2 × s, C-4a, C-9a), 126.45, 127.02, 127.21 (3 × d, C-4′, C-5, C-8), 132.19 (s, C-1′), 133.11, 134.25 (2 × d, C-6, C-7), 135.11, 136.90 (2 × s, C-8a, C-10a), 145.40, 145.51 (2 × s, C-2′, C-1), 157.42 (s, C-6′), 159.59 (s, C-3), 166.47 (s, CO₂ t-Bu), 183.14, 183.59 (2 × s, C-9, C-10). IR: 3406 (m, br), 2936 (m), 1719 (s), 1668 (s), 1574 (vs), 1462 (s), 1330 (s), 1281 (vs), 1142 (vs), 1090 (s), 1088 (s), 714 (vs) cm^-1. MS (EI-DIP; 70 eV): m/z (%) = 220, 205, 181, 177, 145, 91, 57. HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₄H₃₈O₈: 597.2465; found: 597.246 ± 0.002.
6-{3-Methoxy-2-(4-methoxy-3,6,11-trioxo-1,3,6,11-tetrahydroanthra[1,2- c ]furan-1-yl)-phenyl}-6-oxohexanoic Acid Methyl Ester (2): Compound 16 (165 mg, 0.28 mmol, 1.0 equiv), N-bromosuccinimide (98 mg, 0.55 mmol, 2.0 equiv) and benzoyl peroxide (3.3 mg, 0.01 mmol, 5 mol%) were dissolved in CCl₄ (15 mL) and refluxed under irradiation with a 150-W lamp for 3 h. After this time, the reaction mixture was quenched with a sat. solution of NaHCO₃ and extracted with CH₂Cl₂. The organic layers were dried over MgSO₄, concentrated and purified by column chromatography (silica gel, cyclohexane-EtOAc 3:7) to yield lactone 2 (124 mg, 0.23 mmol, 83%) as a yellow solid; TLC: R _f 0.39 (cyclohexane-EtOAc, 3:7); mp 142.5 °C. ¹H NMR (250 MHz, CDCl₃): δ = 1.70-2.00 [m, 4 H, MeO₂CCH_{2 (}CH₂)₂], 2.35-2.45 (m, 2 H, MeO₂CCH₂CH₂), 3.25-3.45 (m, 2 H, ArCOCH₂CH₂), 3.35 (s, 3 H, OMe), 3.62 (s, 3 H, CO₂Me), 4.19 (s, 3 H, OMe), 6.77-6.80 (m, 1 H, H-5′), 7.23-7.32 (m, 2 H, H-3′, H-4′), 7.49 (s, 1 H, CHOHAr₂), 7.68-7.74 (m, 2 H, H-6, H-7), 7.83 (s, 1 H, H-4), 7.95-8.00, 8.18-8.23 (2 × m, 2 H, H-5, H-8). ¹³C NMR (75 MHz, CDCl₃): δ = 23.53 (t, CH₂), 24.61 (t, CH₂), 33.99 (t, CH₂), 41.71 (t, CH₂), 51.45 (q, CO₂Me), 55.68 (q, OMe at C-6′), 56.88, 57.14 (d, q, CHOAr₂, OMe at C-3), 109.30 (d, C-4), 114.19 (d, C-5′), 119.61 (d, C-3′), 120.56, 120.84 (2 × s, C-2, C-1′), 127.08, 127.40, 129.73 (3 × d, C-4′, C-5, C-8), 132.75, 133.15 (2 × s, C-4a, C-9a), 133.91, 134.49 (2 ×d, C-6, C-7), 139.43, 142.98 (2 × s, C-8a, C-10a), 155.98, 158.63 (2 × s, C-2′, C-1), 161.36 (s, C-6′), 167.25 (s, C-3), 173.95 (s, CO₂Me), 180.43 (s, ArCO₂), 182.35, 182.46 (2 × s, C-9, C-10), 204.76 (s, COCH₂). IR: 3093 (w), 2944 (m), 1763 (vs), 1733 (s), 1674 (vs), 1597 (vs), 1583 (vs), 1456 (s), 1333 (vs), 1292 (vs), 1275 (vs), 1060 (vs), 1009 (vs), 712 (s) cm^-1. HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₁H₂₆O₉: 565.1475; found: 565.147 ± 0.002. The X-ray crystal structure of compound 2 has been deposited at the Cambridge Crystallographic Data Centre and was allocated the deposition number 632345.