Synthesis of the KLMN Fragment of Gymnocin-A ... - ACS Publications

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Synthesis of the KLMN fragment of gymnocin-A from the FGH fragment Takeo Sakai, Aoi Ishihara, and Yuji Mori J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00232 • Publication Date (Web): 09 Mar 2017 Downloaded from http://pubs.acs.org on March 9, 2017

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The Journal of Organic Chemistry

Synthesis of the KLMN fragment of gymnocin-A from the FGH fragment

Takeo Sakai, Aoi Ishihara, Yuji Mori* Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan Email: [email protected] RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the journal that you are submitting your paper to)

ABSTRACT

An improved route for the synthesis of the KLMN fragment of gymnocin-A was developed through the oxiranyl anion coupling of the FGH fragment with a chiral C3 epoxy sulfone, followed by 6-endo cyclization. This straightforward approach reduced the number of synthetic steps by fourteen compared with a previous route using alternative building blocks.

Marine polycyclic ether natural products have gained significant interest from organic chemists due to their complex structures and potent bioactivities.1 For example, gymnocin-A (1, Fig. 1) is a polycyclic ether isolated from the extract of cultured cells from the notorious red tide dinoflagellate Karenia mikimotoi,2 and it exhibits a potent cytotoxicity against P388 mouse leukemia cells (IC50 1.3 µg/mL). However, both the cytotoxic mode of action of gymnocin-A and the mechanisms behind its other ACS Paragon Plus Environment


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bioactivities remain unclear due to the difficulty of obtaining sufficient amounts of this material from its natural source. In addition, due to the large molecular weight of 1 (i.e., >1000 amu) and its stunning array of 14 adjoining ether rings, which constitutes the third largest number of rings identified among known natural products, its synthesis is extremely challenging, and requires an efficient strategy with high convergence, including preparation of the necessary fragment molecules.3 Indeed, in 2003, Tsukano and Sasaki reported the first complete synthesis of gymnocin-A, which was based on repeated Suzuki couplings.4 In addition, we recently achieved the total synthesis of 15 using a convergent oxiranyl anion strategy in a unified manner to construct and assemble fragments 2, 3, and 4 (Scheme 1).6 In this case, the synthesis of the ABC fragment (2) was achieved by the coupling of triflate 5 with epoxy sulfone 6, which were prepared from D-glucose and 2-deoxy-D-ribose, respectively. 7 Furthermore, the KLMN fragment (4) was constructed from triflate 7 and epoxy sulfone 9, both of which were derived from 2deoxy-D-ribose.8 This synthetic strategy was also applied for the construction of the FGH fragment (3). Finally, three fragments, 2–4, were assembled into the target molecule,5 achieving the complete synthesis of 1 over a long linear sequence of 60 steps starting from 2-deoxy-D-ribose. However, the total number of synthetic steps required was 122, one-third of which constituted the preparation of the KLMN fragment (4). We therefore sought a more efficient route to the synthesis of fragment 4.

Figure 1. Structure of gymnocin-A.

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Scheme 1. Total synthesis of gymnocin-A (1). The inherent substructure of 1 contains a twice-repeating 6–7–6 tricyclic ring system motif with the same substitution pattern and stereochemistry as those present in the FGH and KLM ring systems. Thus, we designed a new synthetic route to KLMN fragment 4 starting from FGH fragment 3. A related idea was presented previously in Sasaki’s synthesis where both the GHI and KLMN fragments were prepared divergently.4a However, our novel approach is advantageous in that it avoids the preparation of building block 9 and subsequent construction of the fused LM ring system. Thus, we herein report the straightforward synthesis of fragment 4 from fragment 3.

We envisioned that the stereoselective installation of the N-ring moiety on the FGH tricyclic system could be achieved using a 6-endo cyclization approach, where the optically pure cis-β-epoxy sulfone 109 could be employed as a building block for the synthesis of the polytetrahydropyran moiety (Scheme 2). Thus, lithiation of 10 with n-BuLi in the presence of 3 resulted in the formation of a single coupling product 11 in 88% yield. Exposure of the product to p-TsOH·H2O at 60 °C in chloroform resulted in ACS Paragon Plus Environment


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acid-promoted desilylation and smooth 6-endo cyclization via the chair-like transition state 12 10 to furnish the 6-membered ketone 13 in 89% yield, which corresponded to the tetracyclic ring system of the KLMN fragment. In contrast to this one-pot procedure, an alternative two-step method based on treatment with pyridinium p-toluenesulfonate (PPTS) followed by BF3·OEt211 gave an unsatisfactory overall yield of 48%, thereby indicating the efficiency of our novel one-pot process. Subsequently, the stereoselective NaBH4 reduction of ketone 13 at −80 °C led to the formation of alcohol 14 in 89% yield, whose desilylation using TBAF later afforded diol 15. Conversion of the hydroxymethyl group on the terminal N-ring into a methyl group was conducted via a one-pot triflation of the primary alcohol and TBS protection of the secondary alcohol to give 16 in 81% yield. This was then followed by reduction with LiBEt3H to afford the KLMN ring system 17.

Scheme 2. Divergent synthesis of KLMN epoxy sulfone 4 from FGH triflate 3. Hydrogenolysis of the two benzyl groups of 17 generated the corresponding diol 18. To differentiate between the two resulting hydroxy groups, the diol was initially bis-silylated prior to selective monodesilylation with p-TsOH·H2O in MeOH to afford the known alcohol 19. Finally, conversion of 19 into KLMN fragment 4 was accomplished through a previously reported three-step sequence involving a


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Dess–Martin oxidation, a Horner–Wadsworth–Emmons reaction with TolSO2CH2P(O)(OEt)2, and epoxydation with t-BuOOH under basic conditions. In conclusion, we developed a straightforward synthetic route for the preparation of the tetracyclic KLMN fragment (4) of gymnocin-A from the FGH fragment (3) using the optically active epoxy sulfone 10. The present synthesis enabled the formation of 4 in only 12 steps from the intermediate fragment 3, thereby omitting the 12 reaction steps required for the synthesis of building block 9, in addition to the 14 steps required for the formation of the fused LM ring system from compounds 7 and 9. The present concise route therefore ensures a more readily available supply of fragments for the synthesis of gymnocin-A and its analogs for use in biological investigations.

Experimental Section General Information. All air- and moisture-sensitive reactions were carried out under an argon atmosphere in dry, freshly distilled solvents under anhydrous conditions. Throughout the experimental methods described herein, the term “dried” refers to the drying of an organic solution over MgSO4 followed by filtration. Flash chromatography was carried out using silica gel (spherical, neutral, particle size 40–50 mm). Melting points are uncorrected. Chemical shifts are reported in ppm relative to internal TMS (δ 0.00 ppm) for 1H NMR spectra, and to the solvent signal (δ 77.0 ppm, CDCl3) for

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C NMR

spectra. Data are reported as follows: chemical shift, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad). All high-resolution mass spectra were recorded on a magnetic sector FAB mass spectrometer.

Coupling product 11. To a solution of the FGH-triflate 3 (135 mg, 0.177 mmol) and cis-β-epoxy sulfone 10 (160 mg, 0.354 mmol) in a mixture of THF (2.0 mL) and HMPA (0.154 mL, 0.885 mmol) at −100 °C was added n-BuLi (0.206 mL of a 1.63 M solution in hexane, 0.336 mmol), and the reaction ACS Paragon Plus Environment


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mixture was stirred at −100 °C for 0.5 h. After this time, the reaction was quenched using a saturated aqueous NH4Cl solution and extracted with EtOAc. The resulting extract was washed with brine, dried, and concentrated under reduced pressure. Purification by flash chromatography (2% EtOAc in benzene) afforded the coupling product 11 (166 mg, 88%) as a colorless amorphous solid. [α]22D +29.9 (c 1.28, CHCl3); IR (film) 2953, 2874, 1325, 1111, 1082 cm−1; 1H NMR (CDCl3, 600 MHz) δ 7.85 (2H, dd, J = 8.4, 1.2 Hz), 7.72–7.67 (4H, m), 7.64 (1H, tt, J = 7.5, 1.2 Hz), 7.52 (2H, t, J = 7.8 Hz), 7.46–7.37 (6H, m), 7.35–7.22 (10H, m), 4.59 (1H, d, J = 11.4 Hz), 4.53 (1H, d, J = 12.1 Hz), 4.47 (1H, dd, J = 13.0, 5.8 Hz), 4.46 (1H, d, J = 12.1 Hz), 4.42 (1H, dd, J = 13.2, 2.6 Hz), 4.41 (1H, d, J = 11.4 Hz), 3.71 (1H, dd, J = 5.8, 2.5 Hz), 3.60 (2H, dd, J = 7.5, 6.1 Hz), 3.39 (1H, ddd, J = 10.9, 9.3, 4.8 Hz), 3.30 (1H, td, J = 9.0, 2.4 Hz), 3.22 (1H, ddd, J = 10.9, 9.4, 4.7 Hz), 3.18 (1H, ddd, J = 10.9, 8.9, 4.6 Hz), 3.04 (1H, dd, J = 8.7, 5.5 Hz), 3.03 (1H, dt, J = 9.2, 6.6 Hz), 2.73 (1H, td, J = 8.8, 2.7 Hz), 2.26 (1H, dd, J = 12.1, 4.8 Hz), 2.23 (1H, dtd, J = 13.9, 7.7, 2.6 Hz), 2.09 (1H, dd, J = 15.4, 2.7 Hz), 2.08 (1H, dd, J = 15.4, 8.7 Hz), 2.04 (1H, dt, J = 12.3, 4.6 Hz), 1.95 (1H, dq, J = 14.4, 7.2 Hz), 1.68–1.56 (4H, m), 1.48 (1H, t, J = 11.6 Hz), 1.37 (1H, dt, J = 12.1, 11.2 Hz), 1.16 (3H, s), 1.10 (9H, s), 0.81 (9H, t, J = 7.9 Hz), 0.40 (3H, dq, J = 15.2, 7.9 Hz), 0.38 (3H, dq, J = 15.2, 7.9 Hz); 13C NMR (CDCl3, 150 MHz) δ 138.6, 138.1, 137.3, 135.6, 135.5, 134.0, 133.5, 133.1, 129.8, 129.7, 129.1, 129.0, 128.4, 128.3, 127.82, 127.75 (×2), 127.66, 127.6, 127.4, 82.9, 79.2, 78.1, 77.2, 76.8, 76.1, 76.0, 75.4, 75.1, 72.8, 70.7, 69.5, 69.0, 66.8, 66.5, 61.5, 44.7, 41.6, 32.3, 30.9, 29.4, 26.8, 25.2, 19.3, 16.2, 6.8, 4.9; HRMS (FAB) m/z: [M + Na]+ Calcd for C61H80O10SSi2Na 1083.4908; Found 1083.4927.

One-pot operation for the desilylation–6-endo cyclization of 11 to 13. To a solution of TES ether 11 (207 mg, 0.195 mmol) in CHCl3 (5 mL) was added p-TsOH·H2O (56 mg, 0.29 mmol), and the reaction mixture was stirred at 60 °C for 3.5 h. After cooling to room temperature, the reaction was quenched using a saturated aqueous NaHCO3 solution. The resulting mixture was extracted with EtOAc, ACS Paragon Plus Environment

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and the extract was washed with water and brine, dried, and concentrated under reduced pressure. Purification by flash chromatography (20% EtOAc in hexane) afforded ketone 13 (140 mg, 89%) as a colorless oil. [α]26D −15.9 (c 0.25, CHCl3); IR (film) 2930, 2857, 1726, 1106 cm−1; 1H NMR (CDCl3, 600 MHz) δ 7.72–7.60 (2H, m), 7.69–7.66 (2H, m), 7.44–7.40 (2H, m), 7.40–7.36 (4H, m), 7.36–7.26 (10H, m), 4.63 (1H, d, J = 11.6 Hz), 4.53 (1H, d, J = 12.1 Hz), 4.45 (1H, d, J = 12.1 Hz), 4.44 (1H, d, J = 11.6 Hz), 3.99 (1H, dd, J = 10.8, 2.8 Hz), 3.97 (1H, dd, J = 10.8, 4.4 Hz), 3.94 (1H, dd, J = 4.4, 2.8 Hz), 3.63 (1H, ddd, J = 10.8, 9.2, 4.8 Hz), 3.59 (2H, dd, J = 7.5, 5.9 Hz), 3.38 (1H, ddd, J = 10.8, 9.2, 6.0 Hz), 3.37–3.29 (3H, m), 3.26 (1H, ddd, J = 11.0, 9.5, 4.8 Hz), 3.12 (1H, dd, J = 8.9, 5.2 Hz), 2.93 (1H, dd, J = 16.8, 6.0 Hz), 2.38–2.30 (3H, m), 2.24 (1H, dtd, J = 14.0, 7.7, 2.6 Hz), 2.15 (1H, dq, J = 14.8, 6.9 Hz), 1.77–1.67 (3H, m), 1.67–1.58 (2H, m), 1.55 (1H, q, J = 11.3 Hz), 1.23 (3H, s), 1.01 (9H, s);

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C NMR (CDCl3, 150 MHz) δ 205.6, 138.7, 138.1, 135.67, 135.66, 133.4, 133.3, 129.6 (×2),

128.4, 128.3, 127.9, 127.71, 127.66, 127.6 (×2), 127.4, 83.6, 83.0, 79.5, 78.2, 76.2, 75.6, 74.9, 74.5, 72.8, 70.8, 69.0, 66.8, 63.3, 44.9, 44.7, 37.6, 32.4, 29.5, 26.7, 25.2, 19.2, 16.3; HRMS (FAB) m/z: [M + Na]+ Calcd for C49H60O8SiNa 827.3955; Found 827.3951.

Two-step operation of desilylation–6-endo cyclization of 11 to 13

(1) Removal of the TES group. To a solution of TES ether 11 (49 mg, 0.046 mmol) in a mixture of CH2Cl2 (0.5 mL) and MeOH (0.5 mL) was added PPTS (12 mg, 0.047 mmol), and the reaction mixture was stirred at room temperature for 2.0 h. After this time, the reaction was quenched with Et3N, and concentrated under reduced pressure. Purification by flash chromatography (40% EtOAc in hexane) afforded the epoxy alcohol (31 mg, 71%) as a pale yellow oil. [α]28D +11.8 (c 1.09, CHCl3); IR (film) 3445, 2931, 2858, 1111, 1082 cm−1; 1H NMR (CDCl3, 600 MHz) δ 7.87 (2H, dd, J = 8.4, 1.1 Hz), 7.73 (4H, dd, J = 8.0, 1.4 Hz), 7.68 (1H, tt, J = 7.5, 1.2 Hz), 7.56 (2H, ddt, J = 8.3, 7.7, 1.5 Hz), 7.51–7.46 (2H, m), 7.46–7.41 (4H, m), 7.38–7.27 (10H, m), 4.63 (1H, d, J = 11.6 Hz), 4.57 (1H, d, J = 11.9 Hz), ACS Paragon Plus Environment


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4.50 (1H, d, J = 11.9 Hz), 4.45 (1H, dd, J = 12.8, 3.2 Hz), 4.45 (1H, d, J = 11.6 Hz), 4.42 (1H, dd, J = 13.0, 5.7 Hz), 3.83 (1H, dd, J = 5.6, 3.2 Hz), 3.63 (2H, dd, J = 7.5, 6.1 Hz), 3.47 (1H, ddd, J = 10.8, 9.2, 4.8 Hz), 3.33 (1H, td, J = 9.5, 3.3 Hz), 3.33 (1H, ddd, J = 11.4, 9.1, 4.8 Hz), 3.26 (1H, ddd, J = 10.9, 9.4, 4.6 Hz), 3.12 (1H, dt, J = 9.0, 7.0 Hz), 3.09 (1H, t, J = 7.2 Hz), 2.91 (1H, ddd, J = 9.1, 8.2, 2.6 Hz), 2.31–2.25 (3H, m), 2.24 (1H, dt, J = 12.3, 4.7 Hz), 2.15 (1H, dd, J = 15.6, 2.6 Hz), 2.03 (1H, dq, J = 14.5, 7.7 Hz), 1.81 (1H, br s), 1.72–1.59 (4H, m), 1.52 (1H, t, J = 11.6 Hz), 1.38 (1H, q, J = 11.4 Hz), 1.18 (3H, s), 1.13 (9H, s); 13C NMR (CDCl3, 150 MHz) δ 138.6, 138.1, 136.9, 135.5 (×2), 134.2, 133.3, 133.1, 129.8 (×2), 129.2, 129.1, 128.4, 128.3, 127.82, 127.76 (x2), 127.7, 127.6, 127.4, 82.8, 79.4, 78.1, 76.6, 76.1, 75.4, 74.7, 72.8, 70.8, 69.0, 68.4, 66.8, 66.5, 61.3, 44.6, 41.2, 32.3, 32.0, 29.4, 26.8, 25.1, 19.2, 16.2; HRMS (FAB) m/z: [M + Na]+ Calcd for C55H66O10SSiNa 969.4044; Found 969.4031. (2) 6-Endo cyclization to 13. To a solution of the above epoxy alcohol (5.2 mg, 0.0055 mmol) in CH2Cl2 (1 mL) was added BF3·OEt2 (6.8 µL, 0.055 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 1.0 h. After this time, the reaction was quenched using a saturated aqueous NaHCO3 solution, and the resulting mixture was extracted with EtOAc. The extract was washed with brine, dried, and concentrated under reduced pressure. Purification by flash chromatography (30% EtOAc in hexane) afforded ketone 13 (3.0 mg, 68%) as a colorless oil.

Alcohol 14. To a solution of ketone 13 (274 mg, 0.341 mmol) in a mixture of CH2Cl2 (3.4 mL) and MeOH (3.4 mL) was added NaBH4 (39 mg, 1.0 mmol) at −80 °C, and the reaction mixture was stirred at this temperature for 40 min. After this time, the mixture was quenched using a saturated aqueous NH4Cl solution. The resulting mixture was then extracted with EtOAc, and the extract was washed with water and brine, dried, and concentrated under reduced pressure. Purification by flash chromatography (30% EtOAc in hexane) afforded ketone 14 (245 mg, 89%) and epi-14 (18 mg, 7%). Data for ketone 14:


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Colorless oil; [α]26D −18.9 (c 1.07, CHCl3); IR (film) 3460, 2932, 2858, 1113, 1061 cm−1; 1H NMR (CDCl3, 600 MHz) δ 7.69–7.65 (4H, m), 7.47–7.43 (2H, m), 7.42–7.38 (4H, m), 7.34–7.26 (10H, m), 4.60 (1H, d, J = 11.4 Hz), 4.52 (1H, d, J = 12.1 Hz), 4.44 (1H, d, J = 12.1 Hz), 4.40 (1H, d, J = 11.4 Hz), 3.92 (1H, dd, J = 10.4, 4.5 Hz), 3.79 (1H, dddd, J = 10.8, 9.4, 4.8, 1.8 Hz), 3.77 (1H, dd, J = 10.3, 7.3 Hz), 3.58 (2H, dd, J = 7.5, 5.9 Hz), 3.54 (1H, ddd, J = 10.9, 9.2, 4.9 Hz), 3.41 (1H, d, J = 1.8 Hz, OH), 3.31 (1H, ddd, J = 9.4, 7.3, 4.6 Hz), 3.31–3.24 (2H, m), 3.23 (1H, ddd, J = 11.0, 9.3, 4.8 Hz), 3.07 (1H, dd, J = 9.7, 4.6 Hz), 2.97 (1H, ddd, J = 11.6, 9.0, 4.2 Hz), 2.92 (1H, ddd, J = 11.4, 9.0, 4.0 Hz), 2.38 (1H, dt, J = 11.6, 4.4 Hz), 2.27 (1H, dd, J = 12.0, 4.7 Hz), 2.22 (1H, dtd, J = 14.0, 7.7, 2.6 Hz), 2.16–2.08 (2H, m), 1.76–1.65 (3H, m), 1.60 (1H, ddt, J = 14.1, 9.0, 5.7 Hz), 1.49 (1H, t, J = 11.6 Hz), 1.46 (1H, q, J = 11.4 Hz), 1.38 (1H, q, J = 11.4 Hz), 1.17 (3H, s), 1.06 (9H, s);

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C NMR

(CDCl3, 150 MHz) δ 138.6, 138.1, 135.6, 135.5, 132.5, 132.4, 130.0 (×2), 128.4, 128.3, 127.83 (×2), 127.82, 127.7 (×2), 127.4, 83.1, 79.8, 79.1, 78.1, 76.2, 75.9, 75.4, 75.2, 72.8, 70.7, 69.7, 69.2, 66.8, 66.4, 44.6, 37.48, 37.46, 32.3, 29.6, 26.8, 25.2, 19.1, 16.2; HRMS (FAB) m/z: [M + Na]+ Calcd for C49H62O8SiNa 829.4112; Found 829.4141.

1

H NMR Coupling constants of 14

Isomer of Alcohol 14 (epi-14): Colorless oil; [α]25D −5.0 (c 1.02, CHCl3); IR (film) 3482, 2931, 2858, 1104 cm−1; 1H NMR (CDCl3, 600 MHz) δ 7.73–7.70 (2H, m), 7.68–7.66 (2H, m), 7.45–7.42 (2H, m), 7.41–7.37 (4H, m), 7.34–7.26 (10H, m), 4.61 (1H, d, J = 11.4 Hz), 4.53 (1H, d, J = 12.1 Hz), 4.45 (1H, d, J = 12.1 Hz), 4.41 (1H, d, J = 11.4 Hz), 4.20 (1H, tdd, J = 3.5, 2.8, 1.0 Hz), 3.88 (1H, dd, J = 11.0,



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4.4 Hz), 3.87 (1H, dd, J = 11.0, 5.3 Hz), 3.58 (2H, dd, J = 7.6, 6.0 Hz), 3.56 (1H, ddd, J = 11.0, 9.4, 5.0 Hz), 3.42 (1H, ddd, J = 5.3, 4.4, 1.0 Hz), 3.38 (1H, ddd, J = 11.7, 9.1, 4.5 Hz), 3.33 (1H, dt, J = 8.8, 6.8 Hz), 3.30 (1H, td, J = 9.2, 2.6 Hz), 3.24 (1H, ddd, J = 11.0, 9.3, 4.8 Hz), 3.10 (1H, dd, J = 8.8, 5.3 Hz), 3.04 (1H, d, J = 3.5 Hz, OH), 3.03 (1H, ddd, J = 11.7, 9.2, 4.2 Hz), 2.30 (1H, dd, J = 12.0, 4.7 Hz), 2.27–2.20 (2H, m), 2.18–2.11 (2H, m), 1.74–1.57 (5H, m), 1.53 (1H, dt, J = 12.7, 11.4 Hz), 1.49 (1H, ddd, J = 12.8, 12.0, 2.8 Hz), 1.19 (3H, s), 1.05 (9H, s); 13C NMR (CDCl3, 150 MHz) δ 138.6, 138.2, 135.8, 135.5, 133.0, 132.5, 129.85, 129.83, 128.4, 128.3, 127.82, 127.76, 127.72, 127.65 (×2), 127.4, 83.1, 80.1, 78.3, 78.1, 77.0, 76.2, 75.4, 73.0, 72.8, 70.7, 69.5, 68.0, 66.8, 64.7, 44.6, 37.8, 36.3, 32.4, 29.7, 26.7, 25.2, 19.2, 16.2; HRMS (FAB) m/z: [M + Na]+ Calcd for C49H62O8SiNa 829.4112; Found 829.4093.

1

H NMR Coupling constants of epi-14

Diol 15. To a solution of TBDPS ether 14 (245 mg, 0.303 mmol) in THF (3 mL) was added Bu4NF (0.455 mL of a 1.0 M solution in THF, 0.455 mmol), and the reaction mixture was stirred at room temperature for 1.0 h. After this time, the reaction was quenched using a saturated aqueous NH4Cl solution, and the reaction mixture was extracted with EtOAc. After washing the organic extract with brine, it was dried and concentrated under reduced pressure. Purification by flash chromatography (90% EtOAc in hexane) afforded diol 15 (161 mg, 94%) as a colorless oil. [α]26D −18.9 (c 1.08, CHCl3); IR (film) 3418, 2943, 2870, 1455, 1102, 1064 cm−1; 1H NMR (CDCl3, 600 MHz) δ 7.34–7.26 (10H, m), 4.61 (1H, d, J = 11.4 Hz), 4.53 (1H, d, J = 12.1 Hz), 4.44 (1H, d, J = 12.1 Hz), 4.41 (1H, d, J = 11.4 Hz), 3.85 (1H, dd, J = 11.6, 4.0 Hz), 3.77 (1H, dd, J = 11.6, 5.0 Hz), 3.68 (1H, ddd, J = 11.1, 9.4, ACS Paragon Plus Environment

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4.7 Hz), 3.58 (2H, dd, J = 7.7, 5.9 Hz), 3.56 (1H, ddd, J = 10.8, 9.2, 4.8 Hz), 3.30 (1H, td, J = 9.2, 2.6 Hz), 3.28 (1H, dt, J = 9.0, 6.8 Hz), 3.24 (1H, ddd, J = 11.0, 9.4, 4.8 Hz), 3.21 (1H, ddd, J = 9.4, 5.0, 4.0 Hz), 3.08 (1H, dd, J = 9.2, 5.1 Hz), 3.03 (1H, ddd, J = 11.6, 8.9, 4.2 Hz), 2.93 (1H, ddd, J = 11.5, 9.0, 4.2 Hz), 2.36 (1H, dt, J = 11.5, 4.4 Hz), 2.28 (1H, dd, J = 12.0, 4.7 Hz), 2.26 (1H, br s), 2.23 (1H, dtd, J = 14.1, 7.5, 2.4 Hz), 2.18 (1H, dt, J = 12.0, 4.4 Hz), 2.13 (1H, dddd, J = 14.0, 8.5, 7.5, 7.0 Hz), 1.74 (1H, br s), 1.74–1.65 (3H, m), 1.61 (1H, ddt, J = 14.3, 8.8, 5.8 Hz), 1.50 (1H, t, J = 11.6 Hz), 1.443 (1H, q, J = 11.4 Hz), 1.440 (1H, q, J = 11.4 Hz), 1.19 (3H, s);

13

C NMR (CDCl3, 150 MHz) δ 138.6,

138.1, 128.4, 128.3, 127.8, 127.68, 127.65, 127.4, 83.0, 81.1, 79.8, 78.1, 76.23, 76.15, 75.4, 75.3, 72.7, 70.8, 69.2, 66.81, 66.75, 63.0, 44.6, 38.2, 37.5, 32.3, 29.6, 25.2, 16.2; HRMS (FAB) m/z: [M + Na]+ Calcd for C33H44O8Na 591.2934; Found 591.2936.

Triflate 16. To a solution of diol 15 (84 mg, 0.147 mmol) in 2,6-lutidine (69 µL, 0.59 mmol) and CH2Cl2 (1.5 mL) at −80 °C was added Tf2O (25 µL, 0.155 mmol), and the reaction mixture was stirred at −80 °C for 40 min. TBSOTf (68 µL, 0.29 mmol) was then added, and the reaction mixture was stirred at 0 °C for 45 min. After this time, the reaction was quenched using a saturated aqueous NaHCO3 solution, and the reaction mixture was extracted with EtOAc. The extract was washed with water and brine, dried, and concentrated under reduced pressure. Purification by flash chromatography (20→25% EtOAc in hexane) afforded triflate 16 (97 mg, 81%) as a pale yellow solid. Mp 119–120 °C; [α]26D +8.2 (c 1.67, CHCl3); IR (film) 2952, 2933, 2859, 1415, 1208, 1146, 1079, 945 cm−1; 1H NMR (CDCl3, 600 MHz) δ 7.34–7.26 (10H, m), 4.71 (1H, dd, J = 10.3, 1.9 Hz), 4.60 (1H, d, J = 11.6 Hz), 4.53 (1H, d, J = 12.1 Hz), 4.52 (1H, dd, J = 10.3, 5.5 Hz), 4.44 (1H, d, J = 12.1 Hz), 4.41 (1H, d, J = 11.4 Hz), 3.60 (1H, ddd, J = 10.8, 9.4, 4.8 Hz), 3.58 (2H, dd, J = 7.5, 5.9 Hz), 3.55 (1H, ddd, J = 11.0, 9.4, 5.0 Hz), 3.40 (1H, ddd, J = 9.2, 5.5, 1.9 Hz), 3.30 (1H, td, J = 9.2, 2.6 Hz), 3.28 (1H, dt, J = 9.1, 6.6 Hz), 3.23 ACS Paragon Plus Environment


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(1H, ddd, J = 11.0, 9.4, 4.6 Hz), 3.08 (1H, dd, J = 8.8, 5.3 Hz), 3.04 (1H, ddd, J = 11.6, 9.0, 4.2 Hz), 2.93 (1H, ddd, J = 11.6, 8.9, 4.0 Hz), 2.33 (1H, dt, J = 11.6, 4.4 Hz), 2.28 (1H, dd, J = 12.1, 4.6 Hz), 2.26–2.20 (2H, m), 2.13 (1H, dq, J = 14.7, 7.3 Hz), 1.74–1.58 (4H, m), 1.50 (1H, t, J = 11.0 Hz), 1.47 (1H, q, J = 11.4 Hz), 1.46 (1H, q, J = 11.4 Hz), 1.18 (3H, s), 0.87 (9H, s), 0.09 (3H, s), 0.07 (3H, s); 13C NMR (CDCl3, 150 MHz) δ 138.6, 138.1, 128.4, 128.3, 127.8, 127.68, 127.65, 127.4, 118.6 (q, JC-F = 319.5 Hz), 82.9, 79.9, 79.1, 78.1, 76.2, 76.2, 75.4, 75.3, 74.7, 72.7, 70.8, 69.1, 66.8, 66.1, 44.6, 38.8, 37.3, 32.3, 29.5, 25.6, 25.1, 17.8, 16.2, −4.1, −5.1; HRMS (FAB) m/z: [M + Na]+ Calcd for C40H57O10F3SSiNa 837.3291; Found 837.3286.

Reduction product 17. To a solution of diol 16 (95 mg, 0.12 mmol) in THF (1.2 mL) at 0 °C was added LiBEt3H (0.223 mL of a 1.05 M solution in THF, 0.223 mmol), and the reaction mixture was stirred at room temperature for 1.0 h. After this time, the reaction was quenched using a saturated aqueous NH4Cl solution, and the reaction mixture was extracted with EtOAc. The extract was washed with water and brine, dried, and concentrated under reduced pressure. Purification by flash chromatography (15% EtOAc in hexane) afforded the reduction product 17 (76 mg, 98%) as a colorless solid. Mp 93–94 °C; [α]26D +0.9 (c 0.83, CHCl3); IR (film) 2951, 2857, 1455, 1079 cm−1; 1H NMR (CDCl3, 600 MHz) δ 7.34–7.26 (10H, m), 4.61 (1H, d, J = 11.4 Hz), 4.53 (1H, d, J = 12.1 Hz), 4.44 (1H, d, J = 12.1 Hz), 4.41 (1H, d, J = 11.4 Hz), 3.58 (2H, dd, J = 7.5, 5.9 Hz), 3.54 (1H, ddd, J = 10.8, 9.3, 4.9 Hz), 3.32–3.25 (3H, m), 3.23 (1H, ddd, J = 10.8, 9.2, 4.6 Hz), 3.19 (1H, dq, J = 8.8, 6.2 Hz), 3.08 (1H, dd, J = 10.0, 4.1 Hz), 2.99 (1H, ddd, J = 11.6, 9.0, 4.2 Hz), 2.93 (1H, ddd, J = 11.4, 9.0, 4.2 Hz), 2.29 (1H, dd, J = 12.1, 4.6 Hz), 2.26–2.20 (2H, m), 2.17 (1H, dt, J = 12.0, 4.4 Hz), 2.12 (1H, m), 1.76–1.65 (3H, m), 1.62 (1H, m), 1.50 (1H, t, J = 11.7 Hz), 1.44 (1H, q, J = 11.4 Hz), 1.42 (1H, q, J = 11.4 Hz), 1.21 (3H, d, J = 6.1 Hz), 1.18 (3H, s), 0.87 (9H, s), 0.07 (3H, s), 0.06 (3H, s);


13

C NMR

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(CDCl3, 150 MHz) δ 138.6, 138.2, 128.4, 128.3, 127.8, 127.7 (×2), 127.4, 83.1, 79.8, 78.5, 78.1, 76.3, 76.1, 75.8, 75.3, 72.8, 72.1, 70.7, 69.3, 66.8, 44.6, 39.2, 37.8, 32.3, 29.7, 25.7, 25.2, 18.2, 17.9, 16.2, −4.2, −4.8; HRMS (FAB) m/z: [M + Na]+ Calcd for C39H58O7SiNa 689.3850; Found 689.3865.

Diol 18. A mixture of dibenzyl ether 17 (69 mg, 0.104 mmol) and 20% Pd(OH)2–C (50 mg) in EtOAc (3 mL) was stirred under a hydrogen atmosphere at room temperature for 1.5 h. The resulting gray suspension was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (EtOAc) afforded diol 18 (49 mg, 97%) as a colorless solid. Mp 192–194 °C; [α]26D +42.6 (c 1.03, CHCl3); IR (film) 3368, 2952, 2933, 2858, 1104, 1070 cm−1; 1H NMR (CDCl3, 600 MHz) δ 3.82 (1H, ddd, J = 11.0, 7.3, 3.8 Hz), 3.78 (1H, ddd, J = 11.0, 7.0, 2.9 Hz), 3.54 (1H, ddd, J = 10.7, 9.2, 4.9 Hz), 3.50 (1H, ddd, J = 11.2, 9.4, 4.8 Hz), 3.29 (1H, ddd, J = 10.7, 8.7, 4.6 Hz), 3.25 (1H, dt, J = 9.2, 7.3 Hz), 3.22 (1H, ddd, J = 9.2, 7.5, 4.6 Hz), 3.19 (1H, dq, J = 9.0, 6.2 Hz), 3.17 (1H, dd, J = 10.3, 4.0 Hz), 2.99 (1H, ddd, J = 11.7, 9.2, 4.2 Hz), 2.92 (1H, ddd, J = 11.6, 8.8, 4.0 Hz), 2.72 (1H, br s), 2.37 (1H, br s), 2.23 (1H, dt, J = 11.6, 4.4 Hz), 2.18 (1H, dt, J = 12.0, 4.4 Hz), 2.14 (1H, dd, J = 11.9, 4.6 Hz), 2.13 (1H, dq, J = 13.3, 7.7 Hz), 2.01 (1H, ddt, J = 14.7, 7.5, 3.9, 3.9 Hz), 1.84–1.73 (3H, m), 1.70 (1H, m), 1.51 (1H, t, J = 11.9 Hz), 1.43 (1H, q, J = 11.6 Hz), 1.42 (1H, q, J = 11.5 Hz), 1.24 (3H, s), 1.21 (3H, d, J = 6.2 Hz), 0.87 (9H, s), 0.06 (3H, s), 0.06 (3H, s); 13C NMR (CDCl3, 150 MHz) δ 83.2, 83.0, 79.6, 78.5, 76.0, 75.8, 75.2, 72.1, 69.7, 69.2, 61.0, 48.0, 39.2, 37.7, 34.9, 29.5, 25.7, 25.4, 18.2, 17.9, 16.1, −4.2, –4.8; HRMS (FAB) m/z: [M + Na]+ Calcd for C25H46O7SiNa 509.2911; Found 509.2919.



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Alcohol (19). To a mixture of diol 18 (48 mg, 0.099 mmol) in CH2Cl2 (1.5 mL) and 2,6-lutidine (57 µL, 0.49 mmol) at 0 °C was added TBSOTf (68 µL, 0.30 mmol), and the reaction mixture was stirred at room temperature for 40 min. After this time, the reaction was quenched with saturated aqueous NaHCO3 solution, and the mixture was extracted with EtOAc. The extract was washed with brine, dried, and concentrated under reduced pressure. Purification by flash chromatography (6→10% EtOAc in hexane) afforded tri-TBS ether (71 mg, quant.) as a colorless solid. To a mixture of this triTBS ether (69 mg, 0.097 mmol) in a mixture of CH2Cl2 (1 mL) and MeOH (1 mL) was added pTsOH·H2O (17 mg, 0.091 mmol), and the reaction mixture was stirred at 0 °C for 20 min. After this time, the reaction was quenched with Et3N, and the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (25→30% EtOAc in hexane) afforded alcohol 19 (55 mg, 94%) as a colorless solid. All spectroscopic data were identical to those previously reported.8

Supporting Information Copies of 1H and

13

C NMR spectra of all new compounds. This material is

available free of charge via the Internet at http://pubs.acs.org.

Notes The authors declare no competing financial interest.

Acknowledgments This research was partially supported by Grant-in-Aids for Scientific Research (C) (16K08182 and 16K08183) from the Japan Society for the Promotion of Science (JSPS).

1

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Products; Wiley-Blackwell: Weinhein, Germany, 2010; Vol. 1, Chapter 11, pp 212−220. (b) Shimizu, Y.


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Dinoflagellate Toxins. In Marine Natural Products; Scheuer, P. J., Ed.; Academic Press: New York, 1978; Vol. 1. (c) Shimizu, Y. Chem. Rev. 1993, 93, 1685−1698. (d) Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93, 1897−1909. (e) Murata, M.; Yasumoto, T. Nat. Prod. Rep. 2000, 17, 293−314. (f) Yasumoto, T. Chem. Rec. 2001, 1, 228−242. (g) Daranas, A. H.; Norte, M.; Fernández, J. J. Toxicon 2001, 39, 1101−1132. (h) Satake, M. In Topics in Heterocyclic Chemistry; Kiyota, H., Ed.; Springer: Berlin, Heidelberg, 2006; Vol. 5, pp 21−51. 2

(a) Satake, M.; Shoji, M.; Oshima, Y.; Naoki, H.; Fujita, T.; Yasumoto, T. Tetrahedron Lett. 2002,

43, 5829−5832. (b) Tanaka, Y.; Satake, M.; Yotsu-Yamashita, M.; Oshima, Y. Heterocycles 2013, 87, 2037−2046. 3

For reviews of polycyclic ether syntheses, see: (a) Inoue, M. Chem. Rev. 2005, 105, 4379−4405. (b)

Nakata, T. Chem. Rev. 2005, 105, 4314−4347. (c) Nicolaou, K. C.; Frederick, M. O.; Aversa, R. J. Angew. Chem., Int. Ed. 2008, 47, 7182−7225. (d) Sasaki, M.; Fuwa, H. Nat. Prod. Rep. 2008, 25, 401−426. For recent total synthesis, see: (e) Fuwa, H.; Ishigai, K.; Hashizume, K.; Sasaki, M. J. Am. Chem. Soc. 2012, 134, 11984−11987. (f) Ishigai, K.; Fuwa, H.; Hashizume, K.; Fukazawa, R.; Cho, Y.; Yotsu-Yamashita, M.; Sasaki, M. Chem.–Eur. J. 2013, 19, 5276−5288. 4

(a) Sasaki, M.; Tsukano, C.; Tachibana, K. Org. Lett. 2002, 4, 1747–1750. (b) Sasaki, M.; Tsukano,

C.; Tachibana, K. Tetrahedron Lett. 2003, 44, 4351–4354. (c) Tsukano, C.; Sasaki, M. J. Am. Chem. Soc. 2003, 125, 14294−14295. (d) Tsukano, C.; Ebine, M.; Sasaki, M. J. Am. Chem. Soc. 2005, 127, 4326−4335. 5

Sakai, T.; Matsushita, S.; Arakawa, S.; Mori, K.; Tanimoto, M.; Tokumasu, A.; Yoshida, T.; Mori,

Y. J. Am. Chem. Soc. 2015, 137, 14513–14516. 6

(a) Sakai, T.; Sugimoto, A.; Mori, Y. Org. Lett. 2011, 13, 5850−5853. (b) Sakai, T.; Sugimoto, A.;

Tatematsu, H.; Mori, Y. J. Org. Chem. 2012, 77, 11177−11191. ACS Paragon Plus Environment


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