Organic Chemistry: Current Research

Organic Chemistry: Current Research
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ISSN: 2161-0401

+44 1478 350008

Research Article - (2016) Volume 5, Issue 2

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Stereoselective Total Synthesis of (-)-Anamarine from D-Mannitol

Karnekanti Rajender1*, Venkateshwarlu R2 and Venkateswara Rao P2
1Government Polytechnic, Warangal, Telangana, India
2Osmania University, Hyderabad, Telangana, India
*Corresponding Author: Karnekanti Rajender, Government Polytechnic, Warangal, Telangana-506 007, India Email:

Abstract

Stereoselective total synthesis of (-)-anamarine was achieved from D-mannitol through demonstrating the effect of electron withdrawing group in cross-metathesis reaction. The key reactions involved are regioselective ring opening, cross-metathesis and ring closing metathesis reactions.

Keywords: (-)-anamarine; D-mannitol; Cross-metathesis; Ring closing metathesis

Introduction

The δ-lactone moiety is an important structural unit found in various bioactive natural products, which show a wide range of biological activities, [1-13] such as anti-cancer and anti-leukemic activity, anti- HIV (protease), inducing apoptosis. Due to the biological importance of this class of molecules, several syntheses [14-17] were reported for the 5,6-dihydro-2H-pyran-2-one containing (-)-anamarine (2), which is a non-natural δ-lactone. Herein, I report the synthesis of (-)-anamarine from D-mannitol (Figure 1).

organic-chemistry-current-research-Structures

Figure 1: Structures of 1 and 2.

Experimental

General methods

Solvents were dried over standard drying agents and were freshly distilled prior to use. Chemicals were purchased and used without further purification. All column chromatographic separations were performed using silica gel (Acme’s, 60–120 mesh). Organic solutions were dried over anhydrous Na2SO4 and concentrated below 40°C in vacuo. 1H NMR (300 MHz and 500 MHz) and 13C NMR (75 MHz and 125 MHz) spectra were measured with a, Bruker Avance 300 MHz, 600 MHz and Varian Unity Inova-500 MHz with tetramethylsilane as an internal standard for solutions in CDCl3. J values are given in Hertz. IR spectra were recorded on at Perkin–Elmer IR-683, JASCO FT/IR- 5300 spectrophotometer with NaCl and KBr optics. Optical rotations were measured with JASCO DIP 300 digital polarimeter. Mass spectra were recorded on BRUKER MAXIS and CEC-21–11013 or Fannigan Mat 1210 double focusing mass spectrometers operating at a direct inlet system or LC/MSD Trap SL (Agilent Technologies).

(S)-1-((R)-1,4-Dioxaspiro[4.5]decan-2-yl)but-3-enyl acrylate (7)

To a stirred solution of 6 (0.74 g, 3.49 mmol) in CH2Cl2 (7.5 mL) at 0°C, Et3N (1.46 mL, 10.46 mmol), DMAP (cat.) and acryloyl chloride (0.31 mL, 3.84 mmol) were added sequentially and stirred at room temperature for 2 h. The reaction mixture was diluted with CHCl3 (10 mL) and washed with water (10 mL), brine (10 mL) and dried (Na2SO4). Solvent was evaporated and purified the residue by column chromatography (60-120 mesh Silica gel, 5% EtOAc in pet. ether) afforded 7 (0.76 g, 82%) as a pale yellow syrup; [α]28D = +17.5 (c 0.30, CHCl3); IR (neat): 2935, 2858, 2313, 1727, 1644, 1568, 1551, l516, 1466, 1449, 1406, 1367, 1264, 1047, 925, 846, 807, 772, 669 cm-1; 1H NMR (300 MHz, CDCl3): δ 6.41 (d, 1H, J = 17.4 Hz, olefinic), 6.11 (dd, 1H, J = 10.2, 17.0 Hz, olefinic), 5.88-5.69 (m, 2H, olefinic), 5.15-5.03 (m, 2H, olefinic), 4.22-3.98 (m, 3H, 3 x -OCH), 3.82 (dd, 1H, J = 6.4, 7.9 Hz, -OCH), 2.55- 2.33 (m, 2H, allylic), 1.67-1.50 (m, 8H, cyclohexyl), 1.40-1.32 (m, 2H, cyclohexyl); 13C NMR (75 MHz, CDCl3): δ 165.4, 133.0, 131.1, 128.3, 118.1, 110.1, 75.8, 72.9, 65.7, 36.0, 34.8, 35.3, 25.1, 23.9, 23.8; HRMS (ESI+): m/z calculated for C15H22O4 (M+Na)+ 289.1410, found 289.1408.

(S)-6-((R)-1,4-Dioxaspiro[4.5]decan-2-yl)-5,6-dihydro-2Hpyran- 2-one (8)

To a stirred solution of 7 (0.07 g, 0.27 mmol) in CH2Cl2 (50 mL), Grubbs-I catalyst (10 mol %) was added and stirred at reflux for 6 h. Most of the solvent was then distilled off and the concentrated solution was left to stir at room temperature for 2 h under a flow of air to decompose the catalyst. The reaction mixture was evaporated and purified the residue by column chromatography (60-120 mesh Silica gel, (60-120 mesh Silica gel, 30% EtOAc in pet. ether) afforded 8 (0.05 g, 81%) as a colorless syrup; [α]28D = -59.0 (c 0.70, CHCl3); IR (neat): 3020, 2314, 1727, 1711, 1663, 1569, 1551, 1533, 1483, 1467, 1215, 928, 742, 668 cm-1; 1H NMR (300 MHz, CDCl3): δ 6.91 (m, 1H, olefinic), 6.02 (dd, 1H, J = 2.0, 10.1 Hz, olefinic), 4.30-4.24 (m, 1H, -OCH), 4.18-4.12 (m, 2H, -OCH), 4.06-4.00 (m, 1H, -OCH), 2.61 (td, 1H, J = 5.0, 18.1 Hz, allylic), 2.48 (td, 1H, J = 3.0, 10.1 Hz, allylic), 1.65-1.53 (m, 8H, allylic), 1.48-1.32 (m, 2H, allylic); 13C NMR (75 MHz, CDCl3): δ 163.1, 144.9, 121.3, 110.6, 78.1, 75.8, 66.7, 36.6, 34.5, 26.4, 25.0, 23.7; HRMS (ESI+): m/z calculated for C13H188O4 (M+Na)+ 261.1097, found 261.1097.

(S)-6-Vinyl-5,6-dihydro-2H-pyran-2-one (5)

To a stirred solution of 8 (0.30 g, 1.27 mmol) in CH3CN (5 mL) at 0°C, CuCl2.2H2O (0.47 g, 0.35 mmol) was added and stirred at room temperature for 30 min. It was quenched with sat. NaHCO3 (1 mL), filtered through a pad of celite and washed with EtOAc (10 mL). The organic layer was dried (Na2SO4), evaporated and used as such for the next reaction. To a stirred solution above diol (0.20 g, 1.27 mmol), PH3P (1.33 g, 5.08 mmol) and imidazole (0.35 g, 5.08 mmol) in CH2Cl2 (10 mL) at 0°C, I2 (0.97 g, 3.81 mmol) was added and stirred at room temperature for 4 h. The reaction mixture was quenched with sat. aq. NaOH (1 mL) solution and extracted with CHCl3 (3 × 5 mL). The organic layers were washed with aq. hypo (4 mL), brine (4 mL) and dried (Na2SO4). Solvent was evaporated and purification of the residue by column chromatography (60-120 mesh Silica gel, 20% EtOAc in pet. ether) gave olefin 5 (0.11 g, 70%) as a colorless liquid; [α]25D = -87.5 (c 0.10, CHCl3); lit.6[α]25D = -93.4 (c 0.10, CHCl3); IR (neat): 3016, 2943, 2882, 1726, 1426, 1382, 1215, 1160, 1108, 971, 819, 748, 703, 667, 609 cm-1; 1H NMR (300 MHz, CDCl3): δ 6.89 (ddd, 1H, J = 3.8, 5.3, 9.8 Hz, olefinic), 6.10-5.90 (m, 2H, olefinic), 5.42 (d, 1H, J = 17.4 Hz, olefinic), 5.31 (d, 1H, J = 10.6 Hz, olefinic), 4.94 (m, 1H, -OCH), 2.52-2.41 (m, 2H, allylic); 13C NMR (75 MHz, CDCl3): δ 163.7, 144.4, 134.8, 121.6, 117.8, 77.7, 29.3; HRMS (ESI+): m/z calculated for C7H8O2 (M+Na)+ 147.0422, found 147.0429.

(1R)-1-((4R,4’R)-2,2,2’,2’-Tetramethyl-4,4’-bi(1,3-dioxolan)- 5-yl)ethanol (11)

To a stirred solution of 9 (21.00 g, 80.15 mmol) in CH2Cl2 (210 mL) at 0°C, Et3N (13.94 mL, 100.19 mmol) followed by n-Bu2SnO (0.50 g, 2.00 mmol) and p-TsCl (15.28 g, 80.15 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with CH2Cl2 (8 mL) and washed with water (2 × 5 mL), brine (2 × 5 mL) and dried (Na2SO4). Solvent was evaporated to give 10, which was used as such for the next step. To a stirred suspension of LiAlH4 (2.92 g, 76.92 mmol) in THF (50 mL) at 0°C, a solution of 10 (32.00 g, 76.92 mmol) in THF (100 mL) was added drop wise under nitrogen atmosphere and stirred at room temperature for 3 h, cooled to 0°C and treated with sat. Na2SO4 solution (10 mL) and filtered. Aq. layer was extracted EtOAc (50 mL) and dried (Na2SO4). Solvent was evaporated and purified the residue by column chromatography (60- 120 mesh Silica gel, 20% EtOAc in pet. ether) furnished 11 (13.9 g, 74%) as a light yellow syrup; [α]28D = +6.4 (c 0.20, CHCl3); IR (neat): 3470, 3434, 2990, 2936, 2890, 1597, 1460, 1373, 1306, 1252, 1217, 1179, 1069, 938, 841, 710, 667, 554, 513, 490 cm-1; 1H NMR (300 MHz, CDCl3): δ 4.15 (q, 1H, J = 5.7 Hz, -OCH), 4.05-4.00 (m, 2H, -OCH), 3.71 (m, 1H, -OCH), 3.67-3.57 (m, 2H, -OCH), 2.47 (br. s, 1H, -OH), 1.44 (s, 3H, Me), 1.35 (s, 6H, 2 x Me), 1.34 (s, 3H, Me), 1.24 (d, 3H, J = 6.0 Hz, Me); 13C NMR (75 MHz CDCl3): δ 110.1, 109.1, 84.4, 80.8, 76.4, 68.5, 26.8, 26.7, 26.5, 25.1, 19.5; HRMS (ESI+): m/z calculated for C12H22O5 (M+Na)+ 269.1364, found 269.1353.

tert.-Butyldiphenyl((1R)-1-((4R,4’R)-2,2,2’,2’-tetramethyl- 4,4’-bi(1,3-dioxolan)-5-yl) etho xy)silane (12)

To a stirred solution of alcohol 11 (13.80 g, 56.09 mmol) in CH2Cl2 (68 mL), imidazole (11.44 g, 168.29 mmol), TPSCl (17.61 mL, 67.31 mmol) and DMAP (cat.) were added sequentially and stirred at room temperature for 1 h. The reaction mixture was treated with water (25 mL) and extracted with CH2Cl2 (2 × 100 mL). The combined organic layers were washed with brine (65 mL) and dried (Na2SO4). Solvent was evaporated and purified the residue by column chromatography (60-120 mesh Silica gel, 5% EtOAc in pet. ether) to afford 12 (18.20 g, 66%) as a colorless syrup; [α]28D = +4.4 (c 0.10, CHCl3); IR (neat): 2930, 2859, 1659, 1462, 1428, 1379, 1240, 1152, 1111, 1057, 845, 739, 702 cm-1; 1H NMR (300 MHz, CDCl3): δ 7.69 (m, 4H, Ar-H), 7.36 (m, 6H, Ar-H), 4.06-3.92 (m, 3H, -OCH), 3.88-3.75 (m, 3H, -OCH), 1.32 (s, 6H, 2 x Me), 1.24 (s, 6H, 2 × Me), 1.06 (d, 3H, J = 6.04 Hz), 1.06 (s, 9H, 3 × Me); 13C NMR (75 MHz, CDCl3): δ 135.9, 134.4, 133.9, 129.6, 129.5, 127.5, 127.4, 109.5, 109.3, 84.4, 78.3, 76.9, 69.8, 66.8, 27.3, 27.2, 27.0, 26.4, 25.3, 19.3, 18.6; HRMS (ESI+): m/z calculated for C28H40O5Si (M+Na)+ 507.2542, found 507.2533.

(1R)-1-((4R)-5-((R)-1-(tert.-Butyldiphenylsilyloxy)ethyl)- 2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-diol (13)

To a stirred solution of 12 (18.0 g, 37.11 mmol) in CH3CN (360 mL) at 0°C, CuCl2.2H2O (5.69 g, 33.40 mmol) was added and stirred at 0°C for 30 min. It was quenched with sat. NaHCO3 (4 mL), filtered through a pad of celite and washed with EtOAc (40 mL). The organic layers were dried (Na2SO4), evaporated and purified the residue by column chromatography (60-120 mesh Silica gel, 30% EtOAc in pet. ether) afforded 13 (9.0 g, 98%, based on starting material recovery) as a colorless syrup; [α]28D = -14.6 (c 1.0, CHCl3); IR (neat): 3335, 3073, 2934, 2859, 1721, 1590, 1474, 1429, 1381, 1319, 1252, 1159, 1113, 1082, 1024, 949, 912, 872, 822, 743, 702, 612, 500 cm-1; 1H NMR (300 MHz, CDCl3): δ 7.74-7.67 (m, 4H, Ar-H), 7.43-7.35 (m, 6H, Ar-H), 3.90-3.78 (m, 3H, 3 x -OCH), 3.71-3.43 (m, 3H, 3 x -OCH), 2.69 (d, 1H, OH, J = 4.5 Hz), 1.95 (t, 1H, OH, J = 5.3 Hz), 1.34 (s, 3H, Me), 1.28 (s, 3H, Me), 1.08 (d, 3H, J = 5.3 Hz, Me), 1.05 (s, 3H, 3 x Me); 13C NMR (75 MHz, CDCl3): δ 134.8, 129. 9, 129.6, 84.1, 78.2, 76.6, 66.7, 63.6, 27.3, 26.4, 19.9, 18.6; HRMS (ESI+): m/z calculated for C25H36O5Si (M+Na)+ 467.2229, found 467.2233.

(2R)-2-((4R)-5-((R)-1-(tert.-Butyldiphenylsilyloxy)ethyl)-2,2- dimethyl-1,3-dioxol an-4-yl)-2-hydroxyethyl benzoate (14)

To a stirred and cooled (0°C) solution of 13 (2.0 g, 4.50 mmol) in CH2Cl2 (20 mL), Et3N (1.5 mL, 9.01 mmol), n-Bu2SnO (cat.) followed by BzCl (0.52 mL, 4.50 mmol) were added and stirred at room temperature for 1 h. The reaction mixture was diluted with CH2Cl2 (8 mL) and washed with water (2 × 5 mL), brine (2 × 5 mL) and dried (Na2SO4). Solvent was evaporated and purified the residue by column chromatography (60-120 mesh Silica gel, 15% EtOAc in pet. ether) afforded 14 (2.20 g, 89%) as a colorless syrup; [α]28D = +51.2 (c 0.20, CHCl3); IR (neat): 3478, 3071, 2934, 2859,1723, 1599, 1452, 1428, 1379, 1277, 1157, 1111, 822, 741 cm-1; 1H NMR (500 MHz, CDCl3): δ 8.03 (d, 2H, J = 7.4 Hz, Ar-H), 7.68 (d, 4H, J = 6.4, 22.3 Hz, Ar-H), 7.54 (t, 1H, J = 7.4 Hz, Ar-H), 7.44-7.35 (m, 8H, Ar-H), 4.53 (dd, 1H, J = 2.5, 11.9 Hz, -OCH), 4.30 (dd, 1H, J = 6.4, 11.9 Hz, -OCH), 3.94 (m, 3H, -OCH), 3.84 (m, 1H, -OCH), 2.56 (d, 1H, J = 4.5 Hz, -OH), 1.36 (s, 3H, Me), 1.31 (s, 3H, Me), 1.09 (d, 3H, J = 5.4 Hz, Me), 1.04 (s, 9H, 3 x Me); 13C NMR (75 MHz, CDCl3): δ 166.8, 135.8, 133.9, 133.3, 133.1, 129.8, 129.7, 128.3, 127.7, 127.5, 109.8, 84.0, 78.5, 71.9, 71.2, 66.5, 27.2, 26.9, 19.8, 19.2; HRMS (ESI+): m/z calculated for C32H40O6Si (M+Na)+ 571.2491, found 571.2479.

(2R)-2-((4S)-5-((R)-1-(tert.-Butyldiphenylsilyloxy)ethyl)-2,2- dimethyl-1,3-dioxola n-4-yl)-2-(tosyloxy)ethyl benzoate (15)

To a stirred and cooled (0°C) solution of 14 (2.13 g, 3.89 mmol) in CH2Cl2 (10 mL), Et3N (0.68 mL, 4.86 mmol), DMAP (cat.) and p-TsCl (0.74 g, 3.89 mmol) were added and stirred at room temperature for 5 h. Work up as described for 14 and purification of the residue by column chromatography (60-120 mesh Silica gel, 3% EtOAc in pet. ether) afforded 15 (2.30 g, 84%) as a colorless syrup; [α]25D = -6.0 (c 0.10, CHCl3); IR (neat): 3745, 3684, 3642, 3610, 3020, 2314, 1839, 1785, 1765, 1743, 1727, 1678, 1568, 1551, 1516, 1449, 1115, 929, 742, 668, 625 cm-1; 1H NMR (300 MHz, CDCl3): δ 7.93 (d, 2H, J = 7.2 Hz, Ar- H), 7.80-7.65 (m, 6H, Ar-H), 7.56 (t, 1H, J = 7.4 Hz, Ar-H), 7.49-7.30 (m, 8H, Ar-H), 7.17 (d, 2H, J = 8.1 Hz, Ar-H), 4.85 (dt, 1H, J = 2.5, 6.0 Hz, -OCH), 4.55 (dd, 1H, J = 2.5, 12.7 Hz, -OCH), 4.50-4.36 (m, 2H, -OCH), 4.01-3.87 (m, 3H, 3 x -OCH), 2.32 (s, 3H, Me), 1.38 (s, 3H, Me), 1.29 (s, 3H, Me), 1.03 (s, 9H, 3 x Me), 0.98 (d, 3H, J = 5.9 Hz, Me); 13C NMR (75 MHz, CDCl3): δ 135.9, 135.8, 133.1, 129.8, 129.7, 129.6, 128.3, 127.7, 127.6, 127.5, 110.6, 82.9, 79.0, 76.1, 69.2, 62.9, 27.9, 27.8, 27.0, 22.7, 21.6, 19.6; HRMS (ESI+): m/z calculated for C39H46O8SSi (M+Na)+ 725.2575, found 725.2580.

tert.-Butyl((1R)-1-((5R)-2,2-dimethyl-5-((S)-oxiran-2-yl)- 1,3-dioxolan-4-yl) ethox y) diph enylsilane (16)

To a stirred solution of 15 (2.20 g, 3.14 mmol) in MeOH (4 mL) at 0°C, K2CO3 (1.29 g, 9.37 mmol) was added and stirred at room temperature for 1 h. Reaction mixture was treated with aq. NH4Cl solution (3 mL), MeOH was evaporated below 40°C under reduced pressure and residue extracted with solvent ether (3 × 10 mL). Organic layer was washed with water (10 mL), brine (10 mL) and dried (Na2SO4). Solvent was evaporated and purified the residue by column chromatography (60- 120 mesh Silica gel, 8% EtOAc in pet. ether) afforded 16 (1.20 g, 90%) as a colorless syrup; [α]28D = +5.1 (c 0.10, CHCl3); IR (neat): 3077, 2984, 2934, 2894, 2861, 1730, 1649, 1590, 1472, 1428, 1379, 1254, 1161, 1109, 928, 876, 822, 741, 704 cm-1; 1H NMR (300 MHz, CDCl3): δ 7.74-7.65 (m, 4H, Ar-H), 7.44-7.32 (m, 6H, Ar-H), 4.04-3.95 (m, 2H, -OCH), 3.90 (m, 1H, -OCH), 2.99 (q, 1H, J = 3.8 Hz, epoxide), 2.66 (dq, 2H, J = 3.8, 5.3 Hz, epoxide), 1.33 (s, 6H, 2 x Me), 1.06 (s, 9H, 3 x Me), 1.04 (d, 3H, J = 6.0 Hz); 13C NMR (75 MHz, CDCl3): δ 135.8, 134.1, 133.4, 129.7, 129.6, 127.6, 127.5, 109.6, 82.4, 76.9, 69.5, 52.2, 44.5, 27.2, 27.0, 26.5, 19.8, 19.2; HRMS (ESI+): m/z calculated for C25H34O4Si (M+Na)+ 449.2124, found 449.2074.

(1S)-1-((4R)-5-((R)-1-(tert.-Butyldiphenylsilyloxy)ethyl)-2,2- dimethyl-1,3-dioxo la n-4-yl)prop-2-en-1-ol (4)

To a stirred solution of Me3SI (0.95 g, 4.67 mmol) in THF (5 mL) at -20C, n-BuLi (2.71 mL, 6.77 mmol, 2.5 molar) was added and stirred for 30 min. A solution of 16 (0.50 g, 1.16 mmol) in THF (5 mL) was added and stirred at -20°C for 30 min. The reaction mixture was quenched with aq. NH4Cl (2 mL) and extracted with EtOAc (2 × 10 mL). Organic layers were washed with water (10 mL), brine (10 mL) and dried (Na2SO4). Solvent was evaporated and purified the residue by column chromatography (60-120 mesh Silica gel, 10% EtOAc in pet. ether) afforded 4 (0.34 g, 67%) as a colorless syrup; [α]28D = +22.4 (c 0.10, CHCl3); IR (neat): 3468, 3073, 2984, 2934, 2892, 2859, 1647, 1590, 1472, 1428, 1373, 1242, 1111, 891, 822, 741, 704 cm-1; 1H NMR (300 MHz, CDCl3): δ 7.72-7.64 (m, 4H, Ar-H), 5.76 (m, 1H, olefinic), 5.27 (td, 1H, J = 2.3, 17.4 Hz, olefinic), 5.14 (td, 1H, J = 1.5, 10.6 Hz, olefinic), 4.11 (t, 1H, J = 6.0 Hz, -OCH), 3.94-3.80 (m, 3H, 3 x -OCH), 2.08 (d, 1H, J = 8.3 Hz, OH), 1.39 (s, 3H, Me), 1.28 (s, 3H, Me), 1.06 (d, 3H, J = 5.3Hz, Me), 1.04 (s, 9H, 3 x Me); 13C NMR (75 MHz, CDCl3): δ 137.6, 135.9, 135.8, 134.2, 133.5, 129.8, 129.7, 127.7, 127.5, 116.4, 109.5, 81.6, 81.3, 72.1, 71.1, 27.4, 27.3, 27.0, 20.3, 19.3; HRMS (ESI+): m/z calculated for C26H36O4Si (M+Na)+ 463.2280, found 463.2273.

(2R,3R,4R,5S)-Hept-6-ene-2,3,4,5-tetrayl tetraacetate (17)

A solution of 4 (0.20 g, 0.82 mmol) in CH2Cl2 (1 mL) at 0°C was treated with CF3COOH (1 mL) and stirred at room temperature for 15 min. Solvent was evaporated and the crude tetrol 4a was used as such for the next reaction. A solution of the above tetrol in pyridine (3 mL) was cooled to 0°C and treated with Ac2O (2 mL), DMAP (cat.) and stirred at room temperature for 20 h. Work up as described for 5 and purification of the residue by column chromatography (60-120 mesh Silica gel, 12% EtOAc in pet. ether) gave tetraacetate 17 (0.12 g, 81%) as a light yellow oil; [α]28D = -10.6 (c 0.20, CHCl3); IR (neat): 2924, 2854, 2314, 1743, 1678, 1645, 1586, 1569, 1551, 1533, 1483, 1450, 1372, 1219, 1033, 722, 687, 671 cm-1; 1H NMR (300 MHz, CDCl3): δ 5.83-5.68 (m, 1H, olefinic), 5.39-5.26 (m, 4H, 2 x olefinic, 2 x -OCH), 5.23 (m, 1H, -OCH), 4.94 (m, 1H, -OCH), 2.13 (s, 3H, OAc), 2.10 (s, 3H, OAc), 2.07 (s, 3H, OAc), 2.02 (s, 3H, OAc), 1.19 (d, 3H, J = 6.4 Hz, Me); 13C NMR (75 MHz, CDCl3): δ 170.1, 169.8, 132.4, 119.4, 79.4, 78.6, 74.0, 70.4, 27.2, 26.9, 21.1, 21.0, 15.5; HRMS (ESI+): m/z calculated for C15H22O8 (M+Na)+ 353.1207, found 353.1207.

(S)-6-((S,E)-3-((4R,5S)-5-((R)-1-(tert.-Butyldiphenylsilyloxy) ethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-hydroxyprop-1- enyl)-5,6-dihydro-2H-pyran-2-one (3)

To a mixture of olefins 5 (0.02 g, 0.04 mmol) and 4 (0.01 g, 0.08 mmol) in toluene (1 mL) under nitrogen atmosphere, Grubbs-II catalyst (0.01 g, 0.01 mmol) was added and stirred at reflux for 8 h. Work up as described for 8 and purification of the residue by column chromatography (60-120 mesh Silica gel, 35% EtOAc in pet. ether) afforded 3 (0.02 g, 81%) as a light yellow syrup; [α]25D = -52.0 (c 0.20, CHCl3); IR (neat): 3020, 2924, 2054, 2313, 1785, 1727, 1678, 1663, 1630, 1569, 1551, 1516, 1449, 1216, 929, 771, 668, 626 cm-1; 1H NMR (300 MHz, CDCl3): δ 7.75-7.66 (m, 4H, Ar-H), 7.47-7.36 (m, 6H, Ar-H), 6.87 (ddd, 1H, J = 3.4, 5.1, 8.5 Hz, olefinic), 6.06 (td, 1H, J = 1.5, 9.8 Hz, olefinic), 5.92-5.76 (m, 2H, olefinic), 4.91 (m, 1H, -OCH), 4.22 (t, 1H, J = 3.8 Hz, -OCH), 4.01-3.85 (m, 3H, -OCH), 2.86-2.37 (m, 2H, allylic), 1.40 (s, 3H, Me), 1.27 (s, 3H, Me), 1.09 (d, 3H, J = 5.7 Hz, Me), 1.04 (s, 9H, 3 x Me); 13C NMR (75 MHz, CDCl3): δ 163.8, 144.5, 135.9, 135.8, 133.9, 133.4, 133.3, 129.8, 129.7, 128.4, 127.7, 127.5, 121.5, 109.6, 81.4, 81.0, 77.0, 71.3, 70.6, 29.6, 29.5, 27.2, 27.0, 20.7, 19.3; HRMS (ESI+): m/z calculated for C31H40O6Si (M+Na)+ 559.2486, found 559.2487.

(2R,3R,4R,5S,E)-7-((S)-6-oxo-3,6-dihydro-2H-pyran-2-yl) hept-6-ene-2,3,4,5-tetrayl tetraacetate ((-)-Anamarine) (2)

A solution of 3 (0.05 g, 0.09 mmol) in CH2Cl2 (1 mL) at 0°C was treated with CF3COOH (0.3 mL) and stirred at room temperature for 15 min. Evaporation of the solvent gave tetrol 3a, which was used as such for the next reaction. To a solution of the above tetrol 3a in pyridine (2 mL) at 0°C, Ac2O (0.5 mL) and DMAP (cat.) were added and stirred at room temperature for 20 h. Work up as described for 17 and purification of the residue by column chromatography (60-120 mesh silica gel, 28% EtOAc in pet. ether) gave tetraacetate 2 (0.03 g, 86%) as a gummy liquid; [α]25D = -17.8 (c 0.30, CHCl3); IR (neat): 3751, 3656, 3574, 3019, 2313, 1742, 1727, 1550, 1532, 1215, 1058, 929, 747, 668, 626 cm-1; 1H NMR (300 MHz, CDCl3): δ 6.90 (ddd, 1H, J = 9.6, 4.7, 3.8 Hz, olefinic), 6.06 (td, 1H, J = 1.9, 9.8 Hz, olefinic), 5.86-5.76 (m, 2H, olefinic), 5.37 (dd, 1H, J = 5.3, 7.2 Hz, -OCH), 5.31 (dd, 1H, J = 3.4, 7.2 Hz, -OCH), 5.18 (dd, 1H, J = 3.4, 6.8 Hz, -OCH), 5.04-3.87 (m, 2H, 2 x -OCH), 2.46 (m, 2H, allylic), 2.13 (s, 3H, OAc), 2.08 (s, 6H, 2 x OAc), 2.03 (s, 3H, OAc), 1.18 (d, 3H, J = 6.4 Hz, Me); 13C NMR (75 MHz, CDCl3): δ 170.0, 169.9, 169.8, 169.7, 163.5, 144.5, 133.0, 125.5, 121.4, 75.8, 71.9, 71.6, 70.4, 67.3, 29.1, 21.0, 20.9, 20.8, 20.6, 15.8; HRMS (ESI+): m/z calculated for C20H26O10 (M+Na)+ 449.1418, found 449.1420.

(2R,3R,4R,5S,E)-7-((S)-6-oxo-3,6-dihydro-2H-pyran-2-yl) hept-6-ene-2,3,4,5-tetrayl tetraacetate ((-)-Anamarine) (2)

To a solution of 5 (0.02 g, 0.12 mmol) and 17 (0.02 g, 0.06 mmol) in CH2Cl2 (2 mL) under nitrogen atmosphere, Grubbs-II catalyst (0.01 g, 0.01 mmol) was added and stirred at reflux for 5 h. Work up as described for 16 and purification of the residue by column chromatography (60- 120 mesh Silica gel, 28% EtOAc in pet. ether) afforded 2 (0.02 g, 68%), whose spectral data was comparable with 2 synthesized from 8.

Results and Discussion

Retrosynthesis

The retrosynthetic analysis of 2 revealed that 3 (Scheme 1) is the late stage intermediate. Olefin 3 could be realized by a cross-metathesis of olefin 4 and lactone 5. The requisite lactone 5 and olefin 4 could be prepared from D-mannitol.

organic-chemistry-current-research-Retrosynthetic-strategy-anamarine

Scheme 1: Retrosynthetic strategy of (-)-anamarine 2.

Synthesis of vinyl lactone fragment 5

Vinyl lactone 5 was achieved from D-mannitol (Scheme 2). Accordingly, reaction of alcohol 69 (6 was achieved from D-Mannitol in two steps with overal yield 70%) with acryloyl chloride and Et3N in CH2Cl2 furnished the acrylate 7 in 82% yield, Which on RCM reaction with Grubbs-I10 catalyst gave α,β-unsaturated lactone 8 in 81% yield (exclusively Z-olefin). Grubbs-I10 catalyst for RCM is more prior for construction of Z-olefin while compared to Wittig or related strategies for synthesis of olefin. Treatment of 8 with CuCl2.2H2O in CH3CN afforded the diol, which on subsequent treatment with Ph3P, iodine and imidazole11 in CH2Cl2 furnished 5 in 70% yield, [α]25D = -87.5 (c 0.10, CHCl3); lit. [17] [α]25D = -93.4 (c 0.10, CHCl3).

organic-chemistry-current-research-Reagents-acryloyl-chloride

Scheme 2: Reagents and conditions: a) acryloyl chloride, Et3N, cat. DMAP, CH2Cl2, 0°C-rt, 2 h; b) Grubss-I catalyst, CH2Cl2, reflux, 6 h; c) CuCl2.2H2O, CH3CN, 0°C, 30min; d) PH3P, I2, imidazole, CH2Cl2, 0°C-rt, 2 h.

Synthesis of tetraacetate fragment 4

For the synthesis of 4, diol 912 (9 was achieved from D-Mannitol in one step with 80% yield) was subjected to reaction with p-TsCl in the presence of Et3N and n-Bu2SnO in CH2Cl2 13 to give tosylate 10, which on further deoxygenation with LiAlH4 in THF furnished 11 in 74% yield (Scheme 3). Treatment of the alcohol 11 with TPSCl and imidazole in CH2Cl2 afforded 12 in 66% yield. Selective deprotection of 12 using CuCl2.2H2O14 in CH3CN furnished diol 13, which on treatment with benzoyl chloride in the presence of Et3N and n-Bu2SnO in CH2Cl2 to give 14 in 89% yield (Scheme 3). Reaction of alcohol 14 with p-TsCl, Et3N and cat. DMAP in CH2Cl2 furnished 15 in 84% yield. Treatment of tosylate 15 with K2CO3 in MeOH afforded 16 (90%), which on reaction with Me3SI and n-BuLi in THF at -20°C gave 4 in 67% yield. Treatment of 4 with CF3COOH in CH2Cl2 gave tetrol 4a, which on treatment with Ac2O and pyridine in CH2Cl2 furnished tetraacetate 178 in 81% yield.

organic-chemistry-current-research-Reagents-conditions

Scheme 3: Reagents and conditions: a) p-TsCl, Et3N, n-Bu2SnO, CH2Cl2, 0°C-rt, 1 h; b) LiAlH4, THF, 0°C-rt; c) TPSCL, imidazole, CH2Cl2, 0°C-rt 1 h; d) CuCl2.2H2O, CH3CN, 0°C, 30 min; e) BzCl, Et3N, CH2Cl2, n-Bu2SnO, 0°C-rt, 1 h; f) p-TsCl, Et3N, cat. DMAP, CH2Cl2, rt, 12 h; g) K2O3, MeOH, 0°C-rt, 1 h; h) Me3Sl, n-BuLi, -20°C, 30 min; i) CF3COOH, CH2Cl2, 0°C-rt, 15 mn; j) Ac2O, pyridine, cat. DMAP, CH2Cl2, rt, 20 h.

Synthesis of 2

Finally, for the synthesis of (-)-anamarine 2, olefins 17 and 5 were subjected to olefin cross-metathesis conditions using Grubbs-II catalyst in toluene at reflux to give 3 (81%) yield (Scheme 4). Cross-metathesis conditions using Grubbs-II catalyst favours more percentage of E-olefin while compared to other strategies for synthesis of olefin. Compound 3 was treated with CF3COOH in CH2Cl2 to give tetrol 3a by the simultaneous deprotection of silyl and acetonide groups. Finally, reaction of 3a with Ac2O and pyridine in CH2Cl2 furnished (-)-anamarine 2 (86%). The spectral data of 2 was in accordance with the literature values [17-31] (Tables 1 and 2). [α]25D=-17.8 (c 0.3, CHCl3); lit.5 [α]24D = -16.0 (c 0.5, CHCl3). Alternatively, coupling of 5 with 4 under cross-metathesis conditions using Grubbs-II catalyst [26] afforded (-)-anamarine 2 (68%) (Scheme 4). Though 2 could be obtained from the alternative coupling, the yields were albeit less when compared to the earlier experiments. From the above studies, it is evident that, in the absence of acetyl group at allylic position, cross metathesis reaction is facilitated for higher yields.

organic-chemistry-current-research-Reagents-Grubbs-toluene

Scheme 4: Reagents and conditions: a) Grubbs-II catalyst, toluene reflux, 8 h; b) CF3COOH, CH2Cl2, 0°C-rt, 15 min; c) Ac2O, pyridine, cat. DMAP, CH2Cl2, rt, 20 h; d) Grubbs-II catalyst, CH2Cl2, reflux, 5 h.

S. No Protan Spectral data for (-)-anamarine from literature(Meshram et al.)[17] (-) - anamarine
1 olefinic 6.89 (ddd, 1H, J = 9.3, 5.0, 3.5 Hz, olefinic), 6.90 (ddd, 1H, J = 9.6, 4.7, 3.8 Hz, olefinic),
2 olefinic 6.07 (d, 1H, J = 9.5 Hz, olefinic), 6.06 (td, 1H, J = 9.8, 1.9 Hz, olefinic),
3 olefinic   5.90-5.75 (m, 2H, olefinic), 5.86-5.76 (m, 2H, olefinic),
4 -OCH 5.36 (dd, 1H, J = 7.0, 6.0 Hz, -OCH), 5.37 (dd, 1H, J = 7.2, 5.3 Hz, -OCH),
5 -OCH 5.31 (dd, 1H, J = 7.3, 3.5 Hz, -OCH), 5.31 (dd, 1H, J = 7.2, 3.4 Hz, -OCH),
6 -OCH 5.18 (dd,1H, J = 6.9, 3.5 Hz, -OCH), 5.18 (dd, 1H, J = 6.8, 3.4 Hz, -OCH)
7 -OCH 4.97 (td, 1H, J = 12.6, 7.7 Hz, -OCH), 4.91 (quint, 1H, J = 6.5 Hz, -OCH), 5.04-3.87  (m, 2H, 2 x -OCH),
8 allylic  2.50-2.40(m, 2H, allylic) 2.46 (m, 2H, allylic),
9 OAc 2.13 (s, 3H, OAc), 2.13 (s, 3H, OAc),
10 OAc 2.07 (s, 6H, 2 x OAC),
2.03 (s, 3H, OAc),		 2.08 (s, 6H, 2 x OAc),
2.03 (s, 3H, OAc)
11 methyl 1.18 (d, 3H, J = 6.42 Hz, Me), 1.18 (d, 3H, J = 6.4 Hz, Me)

Table 1: Comparison table of 1H NMR.

S. No 13C Spectral data for (-)-anamarine from literature (Meshrametal.) (-) - anamarine
1 C-OAc 170.0 170.0
2 C-OAc 169.8 169.9
3 C-OAc 169.83 169.8
4 C-OAc 169.76 169.7
5 C1 163.5 163.5
6 C3 144.5 144.5
7 C7 133.0 133.0
8 C6 125.5 125.5
9 C2 121.5 121.4
10 C5 75.8 75.8
11 C8 71.9 71.9
12 C10 71.6 71.6
13 C9 70.4 70.4
14 C11 67.3 67.3
15 C4 29.1 29.1
16 C-CO 21.0 21.0
17 C-CO 20.91 20.9
18 C-CO 20.86 20.8
19 C-CO 20.6 20.6
20 C12 15.8 15.8

Table 2: Comparison table of 13CNMR.

Conclusion

In conclusion, an efficient convergent synthetic strategy is developed for the synthesis of (-)-anamarine from D-mannitol and explicated the effect of electron withdrawing group in cross-metathesis reaction. Vinyl lactone and olefinic acyclic fragments were synthesized and coupled to give (-)-anamarine. This approach is adoptable for the diversity oriented efficient synthesis of such relevant lactone class of compounds.

Acknowledgments

The author (K. R.) thanks the UGC, New Delhi, India for the financial support in the form of a fellowship.

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Citation: Rajender K, Venkateshwarlu R, Rao VP (2016) Stereoselective Total Synthesis of (-)-Anamarine from D-Mannitol. Organic Chem Curr Res 5: 166.

Copyright: © 2016 Rajender K, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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