HETEROCYCLES

Short Paper | Regular issue | Vol. 83, No. 11, 2011, pp. 2601-2605
Received, 27th July, 2011, Accepted, 5th September, 2011, Published online, 14th September, 2011.
DOI: 10.3987/COM-11-12321

■ Synthesis of (R)-(+)-Tanikolide, a Toxic and Antifungal δ-Lactone from the Marine Cyanobacterium Lyngbya majuscula

Keizo Matsuo,* Junko Hikita, and Keiji Nishiwaki

Faculty of Pharmaceutical Sciences, Kinki University, 3-4-1, Kowakae, Higashi-Osaka 577-8502, Japan

Abstract

(R)-(+)-Tanikolide, a brine-shrimp toxic and antifungal marine metabolite, isolated from the lipid extract of a blue green algae, cyanobacterium, Lyngbia mujuscula, was synthesized starting from (-)-quinic acid.

(R)-(+)-Tanikolide (1) is a brine-shrimp toxic and antifungal marine metabolite, isolated from the lipid extract of a blue green algae, cyanobacterium, Lyngbia mujuscula Gomont (Oscillatoriaceae), from a species collected on the Tanikeli Island, Madagascar.1 Although more than twenty methods for its synthesis have so far been appeared,2 in the course of our synthetic studies on biologically active natural products using (-)-quinic acid (2) as a chiral source,3 we planned to synthesize (R)-(+)-tanikolide (1).
We thought that it might be possible to introduce the stereogenic center at C1 of (-)-2 into the C5 asymmetric center of (+)-1 using the same synthetic intermediate lactol (4),3b which was prepared for our synthesis of (-)-malyngolide (3),4 although 3 possessed the opposite stereochemistry at C5 stereogenic center in (+)-1. The lactol (4) was derived easily from (-)-quinic acid (2).3b For the preparation of a chiral lactol such as 4, an enantioselective enzymatic hydrolysis (e.g. with lipases) of a prochiral meso-diesters may also be a good method.5

The lactol (4) was treated with nonyltriphenylphosphonium bromide in the presence of n-BuLi to give an alkene-alcohol (5) as a mixture of E and Z-isomers (25:75) in 90% yield.6 The alcohol (5) was successively oxidized with PDC to an aldehyde (6) in 76% yield. Horner-Wadsworth-Emmons reaction of 6 with triethyl phosphonoacetate in the presence of NaH gave an unsaturated ester (7) in 90% yield,7 whose newly formed alkene possessed E-form exclusively. The ester (7) was successively hydrogenated under H2 atmosphere in the presence of Pd/C catalyst to form a saturated ester (8) in 82% yield. Finally,basic hydrolysis of theester group of 8 with NaOH followed by acidic work-up involving deprotection and subsequent lactone formation afforded (R)-(+)-tanikolide (1);8 [α]D22 +1.98 (c 0.0365, CHCl3) (lit.,1 [α]D25 +2.3 (c 0.65, CHCl3) ) in 76% yield. IR, 1H-NMR and 13C-NMR spectral data of the synthesized (+)-1 are identical to those of the natural one.1 Thus, it was demonstrated that the chiral lactol (4) was the useful common synthon for the preparation of both (+)-tanikolide (1) and (-)-malyngolide (3), which have the opposite absolute stereochemistry on their stereogenic centers each other.

EXPERIMENTAL
Melting points were determined using a Round Science micro-melting point apparatus, model RFS-10, and are uncorrected. IR spectra were measured with a JASCO FT/IR-460 plus infrared spectrophotometer. NMR spectra were recorded on a JEOL AL 400 (400 MHz 1H, 100 MHz 13C) spectrometer using tetramethylsilane as an internal standard. Chemical shifts (δ) are given in ppm. Low- and high-resolution mass spectra (HRMS) were measured with a JEOL JMS-700TKM instrument at 70 eV. Optical rotation was measured with a JASCO DIP-370 digital polarimeter.

(R)-2-(2,2-Dimethyl-4-(undec-2-enyl)-1,3-dioxolan-4-yl)ethanol (5)
n-Butyllithium (1.6 M in hexane solution, 3.53 mL, 5.64 mmol) was added to a solution of nonyl-triphenylphosphonium bromide (2.70 g, 5.64 mmol) in dry THF (5 mL) under ice cooling and the mixture was stirred at rt under N2 for 1.5 h. A solution of 4 (0.54 g, 2.82 mmol) in dry THF (5 mL) was added to the above reaction mixture under ice cooling and the whole was stirred at rt under N2 for 2 h. The mixture was concentrated under reduced pressure to leave a residue, which was treated with CHCl3. The solution was washed with H2O and brine, successively, and then dried over anhydrous Na2SO4．Evaporation of the solvent under reduced pressure gave the residue (3.80 g), which was chromatographed on SiO2 (AcOEt : hexane = 1 : 1) to afford 5 (0.3 g, 90%) as a colorless oil. IR (neat) cm-1: 3433, 2925, 2855, 1456, 1369, 1525, 1213, 1158, 1057, 897, 865, 832, 722. 1H NMR (CDCl3) δ: 0.88 (3H, t, J = 6.8 Hz, -C(14)-H), 1.27 (12H, br.s, C(8~13)-H), 1.42 (3H, s, -CH3), 1.44 (3H, s, -CH3), 1.85 (2H, m, -C(2)-H), 2.02 (2H, m, -C(7)-H), 2.40 (2H, m, -C(4)-H), 2.72 (1H, br.s, -OH), 3.77 (2H, m, -CH2OH), 3.87 (2H, m, -C(3’)-H), 5.28-5.35 (1H, m, -C(6)-H), 5.50-5.56 (1H, m, -C(5)-H). 13C NMR (CDCl3) δ: 14.0, 22.6, 26.8, 27.0, 27.5, 29.1, 29.3 (2C), 31.8, 32.6, 35.5, 38.3, 59.2, 72.6, 83.7, 109.5, 123.5, 133.4. MS (m/z): 283, 223, 146, 145, 87, 59. HRMS (m/z): Calcd for C17H31O3 (M+-CH3): 283.2273. Found: 283.2255. [α]D22 +0.53 (c 0.041, CHCl3).
(R)-2-(2,2-Dimethyl-4-(undec-2-enyl)-1,3-dioxolan-4-yl)acetaldehyde (6)
To a solution of 5 (1.0 g, 3.33 mmol) in dry CH2Cl2 (50 mL) were added PDC (1.9 g, 5.0 mmol) and dry ground MS (1.9 g) and the whole was stirred at rt overnight. After the mixture was diluted with Et2O, the whole was filtered by the aid of Celite.® The filtrate was concentrated under reduced pressure to give the residue, which was chromatographed on SiO2 (AcOEt : hexane = 1 : 4) to furnish 6 (0.752 g , 76 %) as a colorless oil. IR (neat) cm-1: 2986, 2925, 2855, 1724, 1456, 1380, 1370, 1254, 1213, 1158, 1059, 975, 895, 847, 723. 1H NMR (CDCl3) δ: 0.88 (3H, t, J = 6.8 Hz, -C(14)-H), 1.26 (12H, br.s, C(8~13)-H), 1.406 (3H, s, -CH3), 1.413 (3H, s, -CH3), 2.00 (2H, m, -C(7)-H), 2.35 (2H, m, -C(4)-H), 2.62 (1H, dd, J =15.8, 2.4 Hz, -C(2)-H), 2.72 (1H, dd, J = 15.8, 2.4 Hz, -C(2)-H), 3.86 (1H, d, J = 9.1 Hz, -C(3’)-H), 3.92 (1H, d, J = 9.1 Hz, -C(3’)-H), 5.35-5.41 (1H, m, -C(6)-H), 5.48-5.61 (1H, m, -C(5)-H), 9.81 (1H, t, J = 2.4 Hz, -CHO). 13C NMR (CDCl3) δ: 14.1, 22.6, 26.8, 26.9, 27.4, 29.1, 29.2, 29.3, 29.4, 31.8, 36.0, 50.9, 72.4, 81.3, 109.8, 122.9, 123.7, 201.1. MS (m/z): 278, 252, 221, 220, 144, 143, 85, 83, 57. HRMS (m/z): Calcd for C18H30O2 (M+-H2O): 278.2246. Found: 278.2237. [α]D23 +1.94 (c 0.037, CHCl3).
(R)-Ethyl 4-(2,2-dimethyl-4-(undec-2-enyl)-1,3-dioxolan-4-yl)but-2-enoate (7)
To a suspension of NaH (60% oil dispersion, 0.122 g, 2.95 mmol) in dry THF (20 mL) was added triethyl phosphonoacetate (0.61ml, 2.95 mmol) and the mixture was stirred at 0 oC under N2 for 1 h. A solution of 6 (0.73 g, 2.46 mmol) in dry THF (20 ml) was added to the reaction mixture and the whole was stirred at rt under N2 for 2 h. After the reaction was quenched by addition of s.NH4Cl aq. (6 ml), the whole was extracted with AcOEt. The combined organic layer was washed with s.NaCl aq. and dried over anhydrous Na2SO4. Removal of the solvent under reduced pressure gave the residue (1.30 g), which was chromatographed on SiO2 (AcOEt : hexane = 1 : 9) to yield 7 (0.81 g, 90 %) as a colorless oil. IR (neat) cm-1: 2983, 2926, 2855, 1723, 1654, 1456, 1369, 1261, 1212, 1181, 1059, 983, 889, 722. 1H NMR (CDCl3) δ: 0.88 (3H, t, J = 6.8 Hz, -C(16)-H), 1.26-1.41 (21H, m, -CH3, -C(10~15)-H), 2.04 (2H, m, -C(9)-H), 2.26-2.42 (2H, m, -C(6)-H), 2.45-2.52 (2H, m, -C(4)-H), 3.80 (2H, m, -C(5’)-H), 4.19 (2H, q, J = 7.3 Hz, -CO2CH2CH3), 5.35 (1H, m, -C(8)-H), 5.55 (1H, m, -C(7)-H), 5.87 (1H, d, J=15.6 Hz, C(2)-H), 6.96 (1H, m, C(3)-H). 13C NMR (CDCl3) δ: 14.0, 14.2, 22.6, 27.0, 27.1, 27.5, 29.2, 29.3, 29.4, 29.5, 31.8, 35.5, 40.1, 60.2, 71.8, 82.6, 109.7, 123.2, 124.5, 133.5, 144.0, 166.1. MS (m/z): 351, 253, 213, 195, 155, 127, 85, 83. HRMS (m/z): Calcd for C21H35O4 (M+-CH3): 351.2535. Found: 351.2565. [α]D24 +1.51 (c 0.0425, CHCl3).

(R)-Ethyl 4-(2,2-dimethyl-4-undecyl-1,3-dioxolan-4-yl)butanoate (8)
A solution of 7 (0.738 g, 1.93 mmol) in EtOH (28 mL) was stirred under H2 atmosphere in the presence of 10% Pd/C (300 mg) at rt for 3 h. The catalyst was removed by filtration and the filtrate was connected under reduced pressure to give the residue, which was chromatographed on SiO2 (AcOEt : hexane = 1 : 6) to yield 8 (0.606 g, 82 %) as a colorless oil. IR (neat) cm-1: 2983, 2926, 2855, 1737, 1456, 1368, 1252, 1212, 1183, 1060, 983, 877, 817. 1H NMR (CDCl3) δ: 0.88 (3H, t, J = 6.8 Hz, -C(16)-H), 1.24-1.30 (21H, m, -C(7-15)-H, -CO2CH2CH3), 1.379 (3H, s, -CH3), 1.384 (3H, s, -CH3), 1.47-1.75 (6H, m, -C(3, 4, 6)-H), 2.32 (2H, t, J = 6.8 Hz, -C(2)-H), 3.75 (2H, s, -C(5’)-H), 4.13 (2H, q, J = 7.2 Hz, -CO2CH2CH3). 13C NMR (CDCl3) δ: 14,1, 14.2, 19.7, 22.6, 24.2, 27.2, 27.4, 29.3, 29.5, 29.6 (3C), 30.1, 31.9, 34.5, 36.6, 37.3, 60.2, 72.9, 83.2, 108.9, 173.4. MS (m/z): 355, 325, 295, 255, 215, 157, 85, 83, 57. HRMS (m/z): Calcd for C21H39O4 (M+-CH3): 355.2848. Found: 355.2854. [α]D28 +0.68 (c 0.025, CHCl3).
(R)-(+)-Tanikolide (1)
To a solution of 8 (0.54 g, 1.45 mmol) in EtOH (14.3 mL) was added a solution of KOH (3.78 g) in H2O (14.3 mL) and the whole was stirred at rt for 2 h. After the reaction mixture was adjusted to pH3 by the addition of 2N HCl aq. (50 mL) under ice-cooling, the whole was stirred at rt for 1.5 h. The reaction mixture was salted out and then extracted with AcOEt. The combined organic layer was washed with brine and dried over anhydrous Na2SO4. Removal of the solvent under reduced pressure leaved the residue (0.532 g), which was dissolved in CH3CN (20 mL). Amberlyst15 (0.213 g) was added to the solution and the whole was stirred at rt for 3 h. The whole was filtered and the filtrate was concentrated under reduced pressure to give the residue which was dissolved in Et2O. The solution was washed with s.NaHCO3 aq. and then s.NaCl aq. and dried over anhydrous Na2SO4. Removal of the solvent under reduced pressure furnished the residue (0.457 g) which was chromatographed over SiO2 (CHCl3 : acetone = 4 : 1) to give 1 (0.312 g, 76 %) as colorless crystals. Mp 40-41 oC. IR (Nujol) cm-1: 3394, 2922, 2852, 1713, 1466, 1330, 1247, 1196, 1049, 927, 855, 755, 722, 641. 1H NMR (CDCl3) δ: 0.88 (3H, t, J = 6.8 Hz, -C(16)-H), 1.26 (18H, br.s, -C(7-15)-H), 1.58~1.77 (3H, m, -C(6)-H, -C(4)-Ha), 1.80-1.94 (3H, m, -C(3)-H, -C(4)-Hb ), 2.42-2.54 (2H, m, -C(2)-H), 3.55 (1H, dd, J = 12.0, 6.0 Hz, -CH2OH), 3.66 (1H, dd, J = 12.0, 6.0 Hz, -CH2OH). 13C NMR (CDCl3) δ: 14.0, 16.6, 22.6, 23.3, 26.6, 29.2, 29.4, 29.5 (2C), 29.7 (2C), 29.9, 31.8, 36.8, 67.3, 86.6, 172.1. HRMS (m/z): Calcd for C16H29O2 (M+-CH2OH): 253.2167. Found: 253.2192. [α]D22 +1.98 (c 0.0365, CHCl3).

ACKNOWLEDGMENTS
This work was supported by ‘High-Tech Research Center’ Project for Private Universities: matching fund subsidy from MEXT (Ministry of Education, Culture, Sports, Science and Technology, Japan), 2007-2011.

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