2016 Volume 64 Issue 4 Pages 366-370
A versatile synthetic procedure for a sulfur analogue of pachastrissamine (jaspine B), which involves the tandem thiolation–cyclization of a 1,4-ditosylate to construct a tetrahydrothiophene ring, was developed. Nucleophilic amino substitution of a tetrahydrothiophene-4-sulfonate with unexpected retention of the configuration afforded the sulfur analogue of 4-epi-pachastrissamine.
Pachastrissamine (1, jaspine B) is a natural anhydrophytosphingosine derivative that has an all-cis-2,3,4-trisubstituted tetrahydrofuran structural framework and was isolated from the marine sponges Pachastrissa sp.1) and Jaspis sp.2) in 2002 and 2003, respectively (Fig. 1). It exhibits cytotoxic activity against various cancer cell lines1–9) and induces programmed cell death, such as autophagy6) and apoptosis7–10) in some cancer cells. Owing to its interesting structural features and significant biological properties, many researchers have reported the total synthesis of 13–7,11–31) and its stereoisomers5,6,20–29,31–41) to date. In addition, several analogues of 1 have been synthesized and their biological activities have been investigated.7,42–47) Kim and colleagues reported the synthesis of the sulfur analogue 4 from D-ribo-phytosphingosine and 4 exhibited higher cytotoxicity against several cancer cell lines than 1.46) Because sulfur-containing heterocycles such as thiosugars often exhibit various interesting biological activities48) and a sulfur atom can exist in multiple oxidized forms, replacement of the oxygen atom in the ring of 1 by a sulfur atom serves as a potential way to produce new drug candidates. Very recently, we succeeded in the synthesis of 1, 2-epi-pachastrissamine 2, and the 2-epi-aza analogue 3.31) Our synthetic route to 1–3 would be useful for the synthesis of their derivatives bearing various alkyl side chains, because inexpensive diethyl D-tartrate is employed as a starting material and the alkyl side chain is introduced at a later stage. Here, we report studies on the synthesis of a sulfur analogue of pachastrissamine, which is based on the synthetic strategy for 1–3, and the synthesis of the 4-epi-sulfur analogue 5.
Our strategy to synthesize 4 is outlined retrosynthetically in Chart 1. On the basis of our previous syntheses of 1–3,31) the desired analogue 4 would be derived from the tetrahydrothiophene 6 via SN2-type amination at the 4-position. Because olefin cross-metathesis of sulfur-containing compounds is often problematic,49–52) we planned to extend the alkyl side chain before the introduction of a sulfur atom. The thiophene ring system would be created by stepwise thiolation–cyclization via the 4-mercapto-1,2-diol 7 from 8, which would be converted from the 3,4-anti-homoallylic alcohol 9 using olefin cross-metathesis. Compound 9 has already been prepared from commercially available diethyl D-tartrate (10).31)
The synthesis was started from 9,31) as shown in Chart 2. Treatment of 9 with 1-tridecene in the presence of Grubbs second-generation catalyst in CH2Cl2 under reflux conditions generated a mixture of the (E)- and (Z)-isomers of the alkene 11, which was hydrogenated using Pd/C in EtOAc to afford 8. Tosylation of 8 with p-toluenesulfonyl chloride (TsCl) afforded 12 in 67% yield from 9. We next examined the nucleophilic substitution of 12 with a thiolate anion as a nucleophile. Treatment of 12 with sodium sulfide pentahydrate (Na2S·5H2O) in N,N-dimethylformamide (DMF) at room temperature to 100°C afforded not the desired thiol 13 but the eliminated product 14, in contrast to our previous case of the aza analogue 3,31) in which the reaction of the tosylate of the 4-epimer of 9 with sodium azide furnished the corresponding nucleophilic substitution product in high yield.31)
Reagents and conditions: (a) 1-Tridecene, Grubbs 2nd catalyst, CH2Cl2, reflux, 24 h; (b) H2, Pd/C, EtOAc, r.t., 4.5 h; (c) TsCl, 4-dimethylaminopyridine (DMAP), pyridine, r.t., 60 h, 67% (3 steps); (d) Na2S·5H2O, DMF, r.t., 1 d, 50 to 100°C, 3 d.
This unfortunate result made us investigate an alternative synthetic procedure to 4 using tandem thiolation–cyclization from 12 via the ditosylate 15 (Chart 3). Deprotection of the diol-protecting group of 12 was performed using 50% aqueous trifluoroacetic acid (TFA) in CH2Cl2 at room temperature for 1.5 h to afford the tetrahydrofurans 1753) and 18 in 9% and 48% yields, respectively, via deprotection followed by spontaneous cyclization. After milder treatment of 12 with p-toluenesulfonic acid monohydrate (TsOH·H2O) in a mixture of MeCN and water54) at room temperature for 20 min, reaction with TsCl and triethylamine (Et3N) in the presence of a catalytic amount of dibutyltin oxide (Bu2SnO) under reflux conditions55) for 0.5 h afforded the desired 15 in 27% yield as a minor product and the cyclized product 17 in 63% yield as the major product. Improvement of the yield of 15 was accomplished by a one-pot procedure involving the deprotection of 12 and subsequent selective tosylation of the primary alcohol. Thus, the reaction of 12 with copper(II) chloride dihydrate (CuCl2·2H2O) in CH3CN at room temperature56) for 1 h followed by treatment with TsCl, Et3N, and a catalytic amount of Bu2SnO under reflux for 0.5 h generated 15 in 56% yield, accompanied by 19% of 17. We next examined a tandem thiolation–cyclization reaction of 15. Although a similar attempt to cyclize a sulfonate of a 1,4-diol derivative was troublesome in the synthesis reported by Kim and colleagues,46) fortunately, the treatment of the ditosylate 15 with an excess amount of Na2S·5H2O in DMF at 105°C easily proceeded to afford the tetrahydrothiophene 6 in 81% yield. According to the syntheses of 1–3, triflation of 6 followed by treatment with benzylamine (BnNH2) afforded a complex mixture. However, reaction via the mesylate 19 led to the introduction of an amino group. After mesylation of 6 with mesyl chloride (MsCl) and pyridine in the presence of DMAP in CH2Cl2, the resulting 19 was reacted with BnNH2 at 150°C for 12 h to generate a 67% yield of the amination product. The use of chloromethanesulfonate57) 20 for the amination slightly improved the yield (75%) of the same product. Unfortunately, the product was unexpectedly the 4-epimer 23, whose stereochemistry was confirmed by a nuclear Overhauser effect (NOE) experiment; a NOE was observed between the H-4 proton and the methylene proton that was directly attached to the C-2 carbon.58) This unfortunate, but interesting, retention of configuration in nucleophilic substitution can be rationalized by a double-inversion procedure. Intramolecular substitution by the neighboring S or O atoms may have formed sulfonium 2159,60) or oxonium 22 intermediates with inversion of configuration at the C-4 position followed by nucleophilic attack of BnNH2 on 21 or 22 with further inversion of configuration. Protection of the amino group of 23 with di-tert-butyl dicarbonate [(Boc)2O] and Et3N in CH2Cl2 produced the fully protected amine 24 in 90% yield. Treatment of 24 with sodium in liquid ammonia at −78°C for 0.5 h cleanly removed both benzyl and p-methoxybenzyl groups to afford the N-Boc protected tetrahydrothiophene 25 in 61% yield. Removal of the Boc group under acidic conditions successfully afforded 5 in 83% yield.
Reagents and conditions: (a) 50% TFA, CH2Cl2, r.t., 1.5 h, 17 (9%), 18 (48%), 12 (37%); (b) 1) TsOH·H2O, MeCN–H2O (9 : 1), r.t., 20 min; 2) TsCl, Bu2SnO, Et3N, CH2Cl2, reflux, 0.5 h, 15 (27%, 2 steps) 17 (63%, 2 steps); (c) 1) CuCl2·2H2O, MeCN, r.t., 1 h; 2) TsCl, Bu2SnO, Et3N, reflux, 0.5 h, 15 (56%, 2 steps) 17 (19%, 2 steps); (d) Na2S·5H2O, DMF, 105°C, 2.5 h, 81%; (e) MsCl, pyridine, DMAP, CH2Cl2, r.t., 3 d, 51%; (f) chloromethanesulfonyl chloride, Et3N, CH2Cl2, 0°C to r.t., 3 h, 73%; (g) benzylamine, 150°C, 12 h, 67%; (h) benzylamine, 70°C to 120°C, 35 h, 75%; (i) (Boc)2O, Et3N, CH2Cl2, 0°C to r.t., 10 h, 90%; (j) Na, liq. NH3, THF, −78°C, 0.5 h, 61%; (k) TFA, CH2Cl2, 0°C to r.t., 40 min, 83%.
In summary, we have attempted a versatile procedure for the synthesis of the pachastrissamine sulfur analogue 4. Tandem thiolation–cyclization of the ditosylate 15, which was derived from the 3,4-anti-homoallylic alcohol 9, generated the tetrahydrothiophene 6 in high yield. Unexpected retention of configuration was observed in the nucleophilic substitution of the sulfonates 19 and 20 with BnNH2, leading to the successful synthesis of the 4-epimer 5. Considering the reported biological activities of the stereoisomers of 1 and 2, 5 is expected to have potent biological activities. Biological evaluation of 5 and further studies toward the synthesis of 4 are currently under way.
Copper(II) chloride dihydrate (155 mg, 0.91 mmol) was added to a solution of 12 (340 mg, 0.51 mmol) in MeCN (5 mL) under a nitrogen atmosphere. After stirring at room temperature for 1 h, Bu2SnO (113 mg, 0.46 mmol), p-toluenesulfonyl chloride (130 mg, 0.68 mmol), and Et3N (0.14 mL, 1.00 mmol) were added to the mixture. After heating under reflux with stirring for 0.5 h, the resulting mixture was cooled to room temperature and then filtered through a pad of silica gel and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EtOAc–hexane=1 : 4) to give 15 (212 mg, 56%) and 17 (40 mg, 19%). Compound 12 (9 mg, 3%) was recovered.
15: Colorless oil. [α]D25 +1.5 (c=0.95, CHCl3). 1H-NMR (400 MHz, CDCl3) δ: 0.88 (3H, t, J=6.9 Hz), 0.99–1.32 (24H, m), 1.54–1.62 (1H, m), 1.65–1.74 (1H, m), 2.44 (6H, s), 2.52 (1H, d, J=6.4 Hz), 3.70 (1H, dd, J=4.1, 2.8 Hz), 3.77–3.94 (3H, m), 3.80 (3H, s), 4.35 (1H, d, J=11.0 Hz), 4.65 (1H, d, J=11.0 Hz), 4.67 (1H, dt, J=8.2, 3.7 Hz), 6.83–6.86 (2H, m), 7.14–7.18 (2H, m), 7.33 (2H, d, J=8.2 Hz), 7.34 (2H, d, J=8.2 Hz), 7.76–7.81 (4H, m). 13C-NMR (100 MHz, CDCl3) δ: 14.1, 21.6 (2C), 22.6, 24.9, 29.1, 29.32, 29.37, 29.43, 29.6 (2C), 29.7 (3C), 29.8, 31.9, 55.2, 68.2, 69.8, 74.0, 77.7, 83.4, 113.9 (2C), 127.8 (2C), 128.0 (2C), 129.1, 129.8 (2C), 129.9 (4C), 132.4, 133.7, 144.9, 145.1, 159.5. IR (neat) cm−1: 3526 (br), 2925, 2853, 1613, 1598, 1515, 1465, 1363, 1305, 1250, 1189, 1177, 1096, 1036, 980, 901, 815, 666. MS (FAB) m/z: 747 ([M+H]+). High resolution (HR)-MS (FAB) Calcd for C40H59O9S2 m/z: 747.3600 [M+H]+. Found 747.3594.
17: Colorless solid. mp 37–38°C. [α]D20 +21.3 (c=1.10, CHCl3). 1H-NMR (400 MHz, CDCl3) δ: 0.88 (3H, t, J=6.9 Hz), 1.19–1.43 (24H, m), 1.57–1.72 (2H, m), 1.74 (1H, br d, J=4.6 Hz), 3.61 (1H, dd, J=10.1, 1.8 Hz), 3.71 (1H, dd, J=3.7, 0.9 Hz), 3.81 (3H, s), 3.96 (1H, td, J=6.9, 3.7 Hz), 4.15 (1H, dd, J=10.1, 4.6 Hz), 4.33–4.36 (1H, br m), 4.46 (1H, d, J=11.9 Hz), 4.59 (1H, d, J=11.9 Hz), 6.86–6.90 (2H, m), 7.24–7.28 (2H, m). 13C-NMR (100 MHz, CDCl3) δ: 14.1, 22.7, 26.4, 28.5, 29.3, 29.60 (2C), 29.65 (2C), 29.68 (3C), 29.8, 31.9, 55.3, 71.7, 73.4, 75.3, 80.7, 84.2, 113.8 (2C), 129.3 (2C), 130.1, 159.3. IR (KBr) cm−1: 3373 (br), 2919, 2850, 1614, 1586, 1516, 1468, 1423, 1349, 1304, 1250, 1174, 1102, 1086, 1065, 1036, 924, 870, 813, 721, 670, 657. MS (FAB) m/z: 421 ([M+H]+). HR-MS (FAB) Calcd for C26H45O4 m/z: 421.3318 [M+H]+. Found 421.3303.
(3S,4S,5S)-4-[(4-Methoxybenzyl)oxy]-5-tetradecyltetrahydrothiophen-3-ol (6)Sodium sulfide pentahydrate (308 mg, 1.83 mmol) was added to a solution of 15 (137 mg, 0.18 mmol) in DMF (5 mL) under a nitrogen atmosphere. After heating at 105°C with stirring for 2.5 h, the resulting mixture was cooled to room temperature and diluted with Et2O. The organic layer was washed with water and brine; dried over MgSO4; filtered; and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EtOAc–hexane=1 : 4) to give 6 (65 mg, 81%) as a colorless oil. [α]D21 −55.7 (c=1.04, CHCl3). 1H-NMR (500 MHz, CDCl3) δ: 0.88 (3H, t, J=6.9 Hz), 1.15–1.40 (24H, m), 1.50–1.58 (1H, m), 1.75–1.82 (1H, m), 1.97 (1H, br d, J=5.2 Hz), 2.69 (1H, dd, J=11.5, 3.4 Hz), 3.17 (1H, dd, J=11.5, 5.2 Hz), 3.43 (1H, dt, J=9.7, 5.2 Hz), 3.79–3.81 (1H, m), 3.81 (3H, s), 4.36–4.39 (1H, m), 4.51 (1H, d, J=11.5 Hz), 4.52 (1H, d, J=11.5 Hz), 6.87–6.90 (2H, m), 7.25–7.28 (2H, m). 13C-NMR (100 MHz, CDCl3) δ: 14.1, 22.7, 28.7, 29.3, 29.53, 29.58 (2C), 29.63 (3C), 29.66 (2C), 30.7, 31.9, 34.5, 47.7, 55.2, 72.1, 75.4, 85.4, 113.8 (2C), 129.5 (2C), 129.9, 159.4. IR (neat) cm−1: 3419 (br), 2924, 2852, 1613, 1586, 1514, 1465, 1303, 1249, 1173, 1101, 1063, 1038, 822, 756, 721. MS (FAB) m/z: 437 ([M+H]+). HR-MS (FAB) Calcd for C26H45O3S m/z: 437.3090 [M+H]+. Found 437.3130.
(3S,4S,5S)-N-Benzyl-4-((4-methoxybenzyl)oxy)-5-tetradecyltetrahydrothiophen-3-amine (23)Benzylamine (3 mL) was added to 20 (46 mg, 0.084 mmol). After stirring at 70°C for 10 h, the resulting mixture heated to 120°C over a period of 25 h. The mixture was purified by silica gel column chromatography (eluent: EtOAc–hexane=1 : 9) to give 23 (33 mg, 75%) as a colorless oil. [α]D21 −67.4 (c=0.75, CHCl3). 1H-NMR (500 MHz, CDCl3) δ: 0.88 (3H, t, J=6.9 Hz), 1.12–1.50 (25H, m), 1.67 (1H, br s), 1.75–1.82 (1H, m), 2.60 (1H, dd, J=10.9, 5.7 Hz), 3.01 (1H, dd, J=10.9, 5.7 Hz), 3.34 (1H, quint, J=5.2 Hz), 3.39 (1H, q, J=5.7 Hz), 3.74–3.83 (3H, m), 3.80 (3H, s), 4.46 (2H, s), 6.85–6.88 (2H, m), 7.21–7.34 (7H, m). 13C-NMR (100 MHz, CDCl3) δ: 14.1, 22.7, 28.5, 29.3, 29.59 (2C), 29.64 (2C), 29.67 (2C), 29.69 (2C), 31.2, 31.9, 32.3, 47.6, 52.3, 55.2, 62.5, 71.8, 85.1, 113.8 (2C), 127.0, 128.0 (2C), 128.4 (2C), 129.6 (2C), 130.0, 140.1, 159.3. IR (neat) cm−1: 3312, 3062, 3028, 2999, 2924, 2852, 1612, 1586, 1514, 1465, 1455, 1302, 1249, 1173, 1087, 1038, 822, 735, 699. MS (FAB) m/z: 526 ([M+H]+). HR-MS (FAB) Calcd for C33H52NO2S m/z: 526.3719 [M+H]+. Found 526.3747.
(2S,3S,4S)-4-Amino-2-tetradecyltetrahydrothiophen-3-ol (4-epi-Pachastrissamine Sulfur Analogue, 5)Trifluoroacetic acid (10 µL, 0.13 mmol) was added to a solution of 25 (4.0 mg, 0.01 mmol) in anhydrous CH2Cl2 (0.8 mL) at 0°C under a nitrogen atmosphere. After stirring at room temperature for 40 min, the resulting mixture was treated with methanolic NaOH (2.5 M, 0.15 mL) at 0°C. The mixture was stirred at room temperature for 15 min and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: MeOH–CH2Cl2–NH4OH=10 : 100 : 1) to give 5 (2.5 mg, 83%) as a colorless amorphous solid. [α]D21 −83.6 (c=0.11, CHCl3). 1H-NMR (400 MHz, CDCl3) δ: 0.88 (3H, t, J=6.9 Hz), 1.26–1.45 (24H, m), 1.50–1.60 (1H, m), 1.60 (3H, br s), 1.77–1.86 (1H, m), 2.55 (1H, dd, J=11.0, 3.2 Hz), 3.20 (1H, dd, J=11.0, 6.0 Hz), 3.47–3.52 (1H, m), 3.52–3.55 (1H, m), 3.89 (1H, t, J=4.1 Hz). 13C-NMR (100 MHz, CDCl3) δ: 14.1, 22.7, 28.8, 29.4, 29.51, 29.58, 29.62, 29.64 (3C), 29.68 (2C), 30.3, 31.9, 35.7, 49.5, 59.9, 80.2. IR (KBr) cm−1: 3339 (br), 2956, 2920, 2850, 1655, 1629, 1592, 1468, 1377, 1310, 1261, 1086, 1036, 964, 929, 721. MS (FAB) m/z: 316 ([M+H]+). HR-MS (FAB) Calcd for C18H38NOS m/z: 316.2674 [M+H]+. Found 316.2690.
The authors declare no conflict of interest.
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