HETEROCYCLES

Note | Regular issue | Vol. 78, No. 9, 2009, pp. 2369-2376
Received, 22nd April, 2009, Accepted, 21st May, 2009, Published online, 21st May, 2009.
DOI: 10.3987/COM-09-11741

■ A Concise Synthesis of Solamin and cis-Solamin, Mono-THF Acetogenins from Annona muricata

Hidefumi Makabe,* Asuka Kuwabara, Yasunao Hattori, and Hiroyuki Konno

Shinshu University, 8304 Minamiminowa-mura, Kamiina-gun, Nagano 399-4598, Japan

Abstract

A concise total synthesis of solamin (1) and cis-solamin (2) was performed using an epoxy alcohol (11) as a versatile chiral building block for synthesizing the stereoisomers of the mono-THF annonaceous acetogenins.

The annonaceous acetogenins, which are endemic to certain plants of the Annonaceae, are of much interest especially due to their unique structural features and significant biological activities such as cytotoxic, antitumoral, pesticidal, antiinfective, and antifeedant ones. Biochemical studies have shown that acetogenins are the most potent inhibitors of the mitochondrial respiratory enzyme complex I (NADH-ubiquinone oxidoreductase). More than 430 compounds belonging to this family have been isolated to date, and most of them possess tetrahydrofuran (THF) or tetrahydropyran (THP) rings, hydroxyl, keto and epoxy group, double and triple bonds together with a terminal α,β-unsaturated γ-lactone unit on a C-35 or C-37 long carbon chain.1 Consequently, significant effort has been devoted toward the total synthesis of annonaceous acetogenins.2 Solamin (1) is a mono-THF acetogenin, isolated from Annona muricata in 1991.3 cis-Solamin (2) is a diastereomer of 1 and it was isolated in 1998 from same plants.4 Several syntheses of 1 and 2 were reported including our previous syntheses.5,6 In our previous syntheses, it was necessary to get rid of undesired diastereomer of the THF part. As to the synthesis of 1, low stereoselectivity of the epoxidation of 3 and the difficulty to separate 4a and 4b caused serious problem. To separate undesired product 4b, benzoylation of the hydroxyl group followed by careful purification with preparative TLC was necessary.5c For the synthesis of 2, although the stereoselectivity to construct ent-4b was improved using TBHP in the presence of VO(acac)2 as a catalyst, it was still necessary to introduce benzoyl group for careful separation.6a Thus it was difficult to synthesize mono-THF moiety in large scale (Scheme 1).

To solve these problems, we have developed a concise synthesis of solamin (1) and cis-solamin (2) using systematic and stereoselective construction of the mono-THF moieties without separating undesired diastereomers from chiral epoxy alcohol 11.8 The synthetic strategy of 1 and 2 is shown in Scheme 2. The mono-THF moieties were synthesized from epoxy alcohol 11 using Sharpless AD mix β for threo-trans-threo moiety 8 and AD mix α for threo-cis-threo THF moiety 9 (Scheme 2).

As shown in Scheme 3, the THF part 8 and 9 were synthesized from acrolein and laurylmagnesium bromide as we prepared before through 8 steps in 50 and 52 % yield, respectively (Scheme 3).7,8

The α, β-unsaturated γ-lactone segment was synthesized as shown in Scheme 4. We selected vinyl iodide 14 as the coupling partner. Vinyl iodide 14 was derived from 1-bromohexane and propargyl alcohol as we reported before.5c We examined the alkylation of γ-lactone 15 (prepared by the method of White et al.9) with diiodide 14 using LDA, LHMDS, NHMDS, and KHMDS as a base. In the case of LDA and/or LHMDS, yield of product was very poor. On the other hand, NHMDS and KHMDS resulted in moderate yield. The counter cation of the base was extremely important for the alkylation of 15. Oxidation with m-CPBA following thermal elimination of sulfoxide gave γ-lactone moiety 10 (Scheme 4).

The THF moiety 8 and γ-lactone 10 were coupled by the Sonogashira cross-coupling reaction to give 17 in 78% yield. Diimide reduction with p-TsNHNH2 and AcONa in ethylene glycol diethyl ether under reflux afforded saturated product 18. Finally, deprotection of the MOM-protected ethers with BF3·Et2O afforded 1 in 72% yield. The synthesis of 2 was also carried out as described for 1. The spectral and physical data of the synthetic 1 and 2 were in good agreement of those of reported values (Scheme 5).3,4

In conclusion, a concise synthesis of 1 and 2 was accomplished through 18 steps in 15% and 18% yield, respectively. The overall yields of 1 and 2 were much higher than those of our previous synthesis (19 steps, 0.86% yield for 1,5c 20 steps, 3.5% for 26a,6b).

EXPERIMENTAL
General. All melting points were uncorrected. 1H and 13C NMR spectra were measured with a Bruker Avance DRX 500 FT-NMR spectrometer in CDCl3 at 500 and 125 MHz, respectively. Chemical shifts were relative to tetramethylsilane as an internal standard. The coupling constants were given in Hz. Mass spectra were obtained on JEOL JMS-700 mass spectrometer. IR spectra were recorded with JASCO FT-IR 480 Plus infrared spectrometer. Optical rotations were determined with a JASCO DIP-1000 polarimeter.

(8’EZ)-3-(Iodonon-9’-enyl)-5-methyl-2,5-dihydrofuran-2-one (10). To an ice-cooled solution of compound 15 (200 mg, 1.0 mmol) in THF (5 mL) was added sodium bis(trimethylsilyl)amide (1.0 M solution in THF, 1.0 mL). After the mixture had been stirred for 30 min at 0 oC, the diiodide 14 (396 mg, 1.0 mmol) in HMPA (2 mL) was added to it and the whole was allowed to warm to rt. The reaction mixture was then poured into saturated aqueous NH4Cl (5 mL), and the mixture was extracted with Et2O. The organic phase was washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was roughly purified with silica gel column chromatography (hexane/AcOEt = 8:1) to afford 16 (274 mg, 60%) as a colorless oil. This compound was used for the next step without further purification. Compound 16 (114 mg, 0.25 mmol) was dissolved in CH2Cl2 (5 mL) and m-CPBA (65%, 66 mg, 0.25 mmol) was added at 0oC. After the mixture was stirred for 20 min at this temperature, saturated aqueous Na2S2O3 and NaHCO3 (1:1, 5 mL) were added. The mixture was stirred for 1 h and extracted with Et2O. The organic phase was washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified with preparative TLC (toluene/AcOEt = 15:1) to afford 10 (71 mg, 82%) as a colorless oil. IR(film)νmax: 3073, 2978, 2927, 2854, 1752, 1653, 1607, 1453, 1318, 1199, 1118, 1100, 1085, 1069, 1026, 949, 860 cm-1. 1H NMR (500 MHz, CDCl3) δ: 1.20-1.55 (10H, m), 1.41 (3H, d, J = 7.0 Hz), 2.05-2.20 (2H, m), 2.26 (2H, t, J = 7.0 Hz), 5.00 (1H, qd, J = 7.0, 1.5 Hz), 5.98 (0.67H, dt, J = 15.8, 1.5 Hz), 6.18 (0.67H, m), 6.50 (0.67H, dt, J = 15.8, 6.8 Hz), 7.00 (1H, d, J = 1.5 Hz). 13C NMR (125 MHz, CDCl3) δ: 19.19, 25.11, 27.30, 27.33, 27.83, 28.24, 28.35, 28.54, 28.71, 28.89, 28.97, 28.99, 29.02, 29.03, 29.05, 29.62, 34.59, 35.95, 74.35, 77.39, 82.23, 134.20, 141.32, 146.63, 148.90, 173.84 ppm. HREIMS Calcd for C14H21IO2 [M]+ 348.0586, found 348.0590.

(1’’’R,2”R,5S,5”R,13’R)-3-{13’-Methoxymethoxy-13’-[5”-(1’’’-methoxymethoxytridecyl)tetrahydr-ofuran-2”-yl]tetradec-8’-en-10’-ynyl}-5-methyl-2,5-dihydrofuran-2-one (17). Cl2Pd(PPh3)2 (2.5 mg, 3.5 μmol) was added to a solution of 10 (25 mg, 0.07 mmol) in Et3N (0.15 mL). After the solution had been stirred for 30 min, a solution of 8 (30 mg, 0.07 mmol) in Et3N (0.15 mL) and CuI (1.5 mg, 8 μmol) was added. After the mixture had been stirred for 12 h, the reaction was quenched with saturated aqueous NH4Cl (3 mL), and the mixture was extracted with Et2O. The organic phase was washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified with preparative TLC (toluene/AcOEt = 10:1) to afford 17 (35 mg, 78%) as a colorless oil. IR(film)νmax: 3052, 2924, 2853, 1758, 1654, 1465, 1318, 1205, 1150, 1102, 1035, 955, 918 cm-1. 1H NMR (500 MHz, CDCl3) δ: 0.88 (3H, t, J = 6.8 Hz), 1.25-1.80 (34H, m), 1.41 (3H, d, J = 6.8 Hz), 1.95-2.10 (4H, m), 2.26 (2H, t, J = 7.2 Hz), 2.45-2.65 (2H, m), 3.38 (3H, s), 3.39 (2H, s), 3.40 (1H, s), 3.46 (1H, m), 3.64 (1H, m), 3.98 (1H, m), 4.12 (1H, m), 4.67 (1H, d, J = 6.8 Hz), 4.73-4.78 (2H, m), 4.84 (1H, m), 5.00 (1H, qd, J = 6.8, 1.5 Hz), 5.42 (0.67H, dd, J = 15.8, 1.8 Hz), 5.81 (0.67H, m), 6.03 (0.67H, dt, J = 15.8, 7.4 Hz), 6.99 (1H, d, J = 1.5 Hz) ppm. 13C NMR (125 MHz, CDCl3) δ:14.11, 19.19, 22.42, 22.50, 22.66, 25.12, 25.46, 25.49, 27.33, 28.03, 28.10, 28.44, 28.69, 28.73, 28.92, 29.07, 29.33, 29.60, 29.62, 29.65, 29.79, 31.16, 31.89, 55.77, 66.64, 74.03, 77.65, 79.56, 80.09, 80.21, 81.70, 81.79, 96.37, 96.47, 96.65, 109.64, 134.21, 143.77, 148.89, 173.89 ppm. HRFABMS Calcd for C39H67O7 [M+H]+ 647.4886, found 647.4890.

(1’’’R,2”R,5S,5”R,13’R)-3-{13’-Methoxymethoxy-13’-[5”-(1’’’-methoxymethoxytridecyl)tetrahydr-ofuran-2”-yl]tetradecyl}-5-methyl-2,5-dihydrofuran-2-one (18). A solution of sodium acetate (371 mg, 4.52 mmol) in H2O (12 mL) was added to a solution of 17 (16 mg, 0.025 mmol) and p-toluenesulfonylhydrazide (733 mg, 3.73 mmol) in diethoxyethane (8 mL) under reflux over 5 h. After being cooled to rt, the mixture was extracted with Et2O. The organic phase was washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified with preparative TLC (hexane/AcOEt = 4:1) to afford 18 (13 mg, 78%) as a colorless oil. [α]25D +28 (c 0.30, CHCl3), IR(film)νmax: 3052, 2925, 2854, 1759, 1654, 1466, 1373, 1318, 1203, 1149, 1102, 1033, 919, 722 cm-1. 1H NMR (500 MHz, CDCl3) δ: 0.88 (3H, t, J = 6.7 Hz), 1.25-1.50 (46H, m), 1.41 (3H, d, J = 6.8 Hz), 1.92 (2H, m), 2.26 (2H, t, J = 6.7 Hz), 3.39 (6H, s), 3.46 (2H, m), 3.98 (2H, m), 4.67 (2H, d, J = 6.8 Hz), 4.84 (2H, d, J = 6.8 Hz), 5.00 (1H, qd, J = 6.8, 1.5 Hz), 6.99 (1H, d, J = 1.5 Hz) ppm. 13C NMR (125 MHz, CDCl3) δ:14.13, 19.21, 22.69, 25.16, 25.52, 27.38, 28.44, 29.18, 29.31, 29.35, 29.52, 29.61, 29.64, 29.80, 31.22, 31.91, 55.71, 77.41, 79.60, 81.49, 96.67, 134.31, 148.86, 173.93 ppm. HREIMS Calcd for C38H69O6 [M−OMe]+ 621.5094, found 621.5086.

Solamin (1). BF3·Et2O (0.02 mL) was added to a solution of 18 (5 mg, 0.076 mmol) in dimethyl sulfide (0.4 mL) at 0oC. After the mixture was stirred for 10 min at this temperature, the reaction was quenched with saturated aqueous NaHCO3 (1 mL), and the mixture was extracted with Et2O. The organic phase was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified with preparative TLC (hexane/AcOEt = 1:2) to afford 1 (3.0 mg, 72%) as a colorless waxy solid. Mp 67-69 oC, [α]25D +22 (c 0.20, MeOH), IR(KBr)νmax: 3438, 3052, 2918, 2850, 1737, 1653, 1468, 1374, 1203, 1115, 1082, 1028, 961, 890, 721 cm-1. 1H NMR (500 MHz, CDCl3) δ: 0.88 (3H, t, J = 7.1 Hz), 1.21-1.58 (44H, m), 1.41 (3H, d, J = 6.8 Hz), 1.68 (2H, m), 2.00 (2H, m), 2.25-2.31 (4H, m), 3.40 (2H, m), 3.80 (2H, m), 5.00 (1H, dd, J = 6.8, 1.4 Hz), 6.99 (1H, d, J = 1.4 Hz) ppm. 13C NMR (125 MHz, CDCl3) δ:14.09, 19.22, 22.68, 25.19, 25.61, 27.43, 28.73, 29.18, 29.30, 29.35, 29.50, 29.59, 29.62, 29.64, 29.72, 31.92, 33.56, 74.04, 77.36, 81.83, 134.40, 148.79, 173.84 ppm. HRFABMS Calcd for C35H64O5Na [M+Na]+ 587.4651, found 587.4650.

(1’’’S,2”R,5S,5”S,13’R)-3-{13’-Methoxymethoxy-13’-[5”-(1’’’-methoxymethoxytridecyl)tetrahydr-ofuran-2”-yl]tetradec-8’-en-10’-ynyl}-5-methyl-2,5-dihydrofuran-2-one (19). The procedure was the same as that used for the preparation of 17. Compound 19 (97 mg, 84%) was prepared from 10 (75 mg, 0.45 mmol) and 9 (90 mg, 0.21 mmol) as a colorless oil. IR(film)νmax: 3052, 2925, 2853, 1758, 1654, 1466, 1318, 1204, 1150, 1102, 1041, 955, 918 cm-1. 1H NMR (500 MHz, CDCl3) δ: 0.88 (3H, t, J = 7.0 Hz), 1.25-1.95 (39H, m), 2.07 (2H, m), 2.26 (2H, t, J = 7.0 Hz), 2.48-2.74 (2H, m), 3.39 (3H, s), 3.40 (1H, s), 3.41 (2H, s), 3.51 (1H, m), 3.68 (1H, m), 3.92 (1H, m), 4.08 (1H, m), 4.67 (1H, d, J = 6.8 Hz), 4.73-4.78 (3H, m), 5.00 (1H, qd, J = 7.0, 1.5 Hz), 5.42 (0.67H, dd, J = 15.5, 1.5 Hz), 5.81 (0.67H, m), 6.03 (0.67H, dt, J = 15.5, 7.0 Hz), 6.99 (1H, d, J = 1.5 Hz) ppm. 13C NMR (125 MHz, CDCl3) δ:14.09, 19.18, 22.39, 22.56, 22.65, 25.12, 25.14, 25.40, 27.33, 27.46, 27.73, 28.69, 28.85, 28.90, 29.06, 29.15, 29.32, 29.59, 29.60, 29.63, 29.78, 30.10, 31.20, 31.88, 32.87, 55.67, 66.64, 77.80, 77.89, 79.76, 80.33, 80.58, 82.01, 84.85, 96.39, 96.67, 109.16, 109.68, 134.22, 142.94, 143.71, 148.87, 173.84 ppm. HREIMS Calcd for C39H67O7 [M]+ 646.4809, found 646.4793.

(1’’’S,2”R,5S,5”S,13’R)-3-{13’-Methoxymethoxy-13’-[5”-(1’’’-methoxymethoxytridecyl)tetrahydro-furan-2”-yl]tetradecyl}-5-methyl-2,5-dihydrofuran-2-one (20). The procedure was the same as that used for the preparation of 18. Compound 20 (85 mg, 85%) was prepared from 19 (96 mg, 0.15 mmol) as a colorless oil. [α]19D +4.5 (c 0.87, CHCl3), IR(film)νmax: 3052, 2924, 2853, 1760, 1654, 1466, 1318, 1149, 1102, 1078, 1041, 918 cm-1. 1H NMR (500 MHz, CDCl3) δ: 0.88 (3H, t, J = 6.8 Hz), 1.25-1.50 (46H, m), 1.41 (3H, d, J = 7.0 Hz), 1.86 (2H, m), 2.26 (2H, t, J = 7.5 Hz), 3.39 (6H, s), 3.50 (2H, m), 3.89 (2H, m), 4.67 (2H, d, J = 7.0 Hz), 4.83 (2H, d, J = 6.5 Hz), 5.00 (1H, qd, J = 7.0, 1.5 Hz), 6.99 (1H, d, J = 1.5 Hz) ppm. 13C NMR (125 MHz, CDCl3) δ:14.10, 19.21, 22.67, 25.17, 25.44, 27.39, 27.60, 29.25, 29.34, 29.52, 29.61, 29.65, 29.66, 29.81, 31.23, 31.91, 55.68, 77.38, 79.81, 81.83, 96.70, 134.33, 148.82, 173.88 ppm. HREIMS Calcd for C38H69O6 [M−OMe]+ 621.5094, found 621.5090.

cis-Solamin (2). The procedure was the same as that used for the preparation of 1. Compound 2 (36 mg, 76%) was prepared from 20 (55 mg, 0.84 mmol) as a colorless waxy solid. Mp. 70-72 oC, [α]19D +21 (c 0.34, MeOH), IR(KBr)νmax: 3422, 3052, 2918, 2849, 1739, 1653, 1469, 1081, 1029, 969, 721 cm-1. 1H NMR (500 MHz, CDCl3) δ: 0.88 (3H, t, J = 6.8 Hz), 1.21-1.58 (44H, m), 1.41 (3H, d, J = 6.8 Hz), 1.75 (2H, m), 1.94 (2H, m), 2.26 (2H, t, J = 7.0 Hz), 2.55 (2H, brs. –OH), 3.42 (2H, m), 3.82 (2H, m), 5.00 (1H, dd, J = 6.8, 1.5 Hz), 6.99 (1H, d, J = 1.5 Hz) ppm. 13C NMR (125 MHz, CDCl3) δ:14.10, 19.19, 22.66, 25.14, 25.69, 27.36, 28.09, 29.05, 29.15, 29.21, 29.27, 29.33, 29.39, 29.47, 29.57, 29.60, 29.62, 29.64, 29.65, 29.66, 29.68, 31.89, 34.07, 74.33, 77.39, 82.69, 134.30, 148.84, 173.89 ppm. HREIMS Calcd for C35H64O5 [M]+ 564.4753, found 564.4720.

References

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