Total Synthesis of Diospongin A via an Enzymatic Kinetic Resolution of (±)-Tetrahydropyranol Derived from Prins Cyclization

Abstract

A concise and efficient total synthesis of diospongin A is described; it utilizes Prins cyclization and enzymatic kinetic re­solution as key steps. This is the first report on the synthesis of ­diospongin A by means of lipase-mediated transesterification of (±)-tetrahydropyranol derived from Prins cyclization.

Prins cyclization - kinetic resolution - Mitsunobu inversion - Wacker oxidation

References and Notes

1 Yin J. Kouda K. Tezuka Y. Le Tran Q. Miyahara T. Chen Y. Kadota S. Planta Med.  2004,  70:  54 

For the Prins cyclization, see for example:

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2d Barry CS. Bushby N. Harding JR. Willis CS. Org. Lett.  2005,  7:  2683 

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2f Crosby SR. Harding JR. King CD. Parker GD. Willis CL. Org. Lett.  2002,  4:  3407 

2g Marumoto S. Jaber JJ. Vitale JP. Rychnovsky SD. Org. Lett.  2002,  4:  3919 

2h Kozmin SA. Org. Lett.  2001,  3:  755 

2i Jaber JJ. Mitsui K. Rychnovsky SD. J. Org. Chem.  2001,  66:  4679 

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2n Yadav JS. Reddy BVS. Sekhar KC. Gunasekar D. Synthesis  2001,  885 

2o Yadav JS. Reddy BVS. Reddy MS. Niranjan N. J. Mol. Catal. A: Chem.  2004,  210:  99 

2p Yadav JS. Reddy BVS. Reddy MS. Niranjan N. Prasad AR. Eur. J. Org. Chem.  2003,  1779 

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6

The enantiomeric excess of the product 6 was determined by using the Shimadzu high-performance liquid-chromatog-raphy (HPLC) system equipped with a chiral HPLC column (Eurocel 01, 5 µm OD) and a UV detector (225 nm). A solvent system of n-hexane-i-PrOH (8:2) and a flow rate of 1.0 mL/min were used.

7 Mitsunobu O. Synthesis  1981,  1 

8 For a review on Wacker oxidation: Tsuji J. Synthesis  1984,  369 

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10

( E )-2-Phenyl-6-styryl-tetrahydro-2 H -pyran-4-ol (3) Trifluoroacetic acid (16.3 mL) was added slowly to a solution of 2 (1.2 g, 8.0 mmol) and cinnamaldehyde (3.16 g, 24.0 mmol) in CH₂Cl₂ (50 mL) at r.t. under a nitrogen atmosphere. The reaction mixture was stirred for 3.0 h and then treated with sat. aq NaHCO₃ solution (40 mL) followed by Et₃N to adjust pH > 7. The organic layer was separated and then the aqueous layer was extracted with CH₂Cl₂ (3 ¥ 40 mL). The solvent was removed in vacuo and the resulting crude product was treated with K₂CO₃ (2 g) in MeOH (30 mL) over 0.5 h. Then, MeOH was removed under reduced pressure and diluted with H₂O (15 mL) and extracted with CH₂Cl₂ (3 ¥ 20 mL). The combined organic layers were dried (Na₂SO₄) and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to afford product 3 as yellow liquid (1.77 g, 78%). R _f = 0.4 (SiO₂, 30% EtOAc in hexane). IR (KBr): ν = 3420, 3029, 2922, 1717, 1602, 1494, 1450, 1063, 755, 699 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.44-7.13 (m, 10 H), 6.62 (d, J = 15.8 Hz, 1 H), 6.24 (dd, J = 15.8, 5.2 Hz, 1 H), 4.53 (d, J = 11.3 Hz, 0.5 H), 4.44 (d, J = 11.3 Hz, 0.5 H), 4.17 (dd, J = 10.5, 4.5 Hz, 1 H), 4.11-3.92 (m, 1 H) 2.33-2.10 (m, 2 H), 1.63-1.35 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 141.8, 136.7, 130.4, 129.5, 128.4, 128.3, 128.3, 127.5, 127.4, 126.4, 126.0, 125.8, 77.7, 76.3, 68.4, 42.8, 41.1. MS (EI): m/z = 281 [M + 1].
(2 S ,4 R ,6 R )-2-Phenyl-6-[( E )-styryl]tetrahydro-2 H -pyran-4-yl Acetate (4) A mixture of (±)-3 (1.5 g, 5.3 mmol) and vinyl acetate (5 mL) in cyclohexane (10 mL) was stirred with the enzyme Porcine pancreatic lipase (EC 3.1.1.3) type II (ca. 300 mg, 20% w/w) supplied by Sigma Aldrich at r.t. for 5 d. The reaction mixture was filtered through a pad of Celite. The combined filtrate and washings (EtOAc) were evaporated under reduced pressure. The residue obtained was purified by column chromatography on silica gel to furnish the required enantiomerically pure acetate 4 (759 mg, 44%) and alcohol 5 (690 mg, 46%). Compound 4: liquid; [a]_D ²⁵ -8.5 (c 1.15, CHCl₃). IR (KBr): ν = 3445, 3029, 2926, 2852, 1737, 1632, 1450, 1366, 1240, 1164, 1061, 1033, 968, 912, 754, 697 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.42-7.15 (m, 10 H), 6.63 (d, J = 16.6 Hz, 1 H), 6.23 (dd, J = 6.0, 16.6 Hz, 1 H), 5.26-5.03 (m, 1 H), 4.53 (dd, J = 1.5, 11.3 Hz, 1 H), 4.26 (dd, J = 6.0, 11.3 Hz, 1 H), 2.35-2.14 (m, 2 H), 2.04 (s, 3 H), 1.73-1.50 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 170.7, 142.0, 141.8, 137.0, 130.9, 129.5, 128.8, 128.6, 127.9, 126.8, 126.2, 126.1, 78.0, 77.8, 70.9, 70.7, 39.6, 39.3, 37.6, 21.5. MS (EI): m/z = 345 [M + 23].
Compound 5: liquid; [a]_D ²⁵ +4.5 (c 0.35, CHCl₃).
(2 S ,4 R ,6 R , E )-2-Phenyl-6-styryltetrahydro-2 H -pyran-4-ol (6) Compound 4 (500 mg, 1.5 mmol) was dissolved in MeOH (10 mL) and stirred with K₂CO₃ (214 mg, 1.5 mmol) for 15 min at r.t. Then, MeOH was removed under reduced pressure and H₂O (15 ml) was added. The mixture was extracted with CH₂Cl₂ (3 ¥ 15 mL) and the combined organic layers were dried with Na₂SO₄ and concentrated under vacuum. The crude was purified by column chromatography on silica gel to furnish desired product 6 as yellow liquid (399 mg, 92%). R _f = 0.4 (SiO₂, 30% EtOAc in hexane); [a]_D ²⁵ -5.2 (c 0.35, CHCl₃, 94% ee). IR (KBr): ν = 3420, 3029, 2922, 1717, 1602, 1494, 1450, 1063, 755, 699 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.41-7.15 (m, 10 H), 6.62 (d, J = 15.8 Hz, 1 H), 6.24 (dd, J = 5.2, 15.8 Hz, 1 H), 4.44 (dd, J = 2.2, 12.0 Hz, 1 H), 4.17 (dd, J = 4.5, 10.5 Hz, 1 H), 4.11-3.92 (m, 1 H), 2.31-2.11 (m, 2 H), 1.62-1.39 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 141.8, 136.7, 130.4, 129.5, 128.4, 128.3, 128.3, 127.5, 127.4, 126.4, 126.0, 125.8, 77.7, 76.3, 68.4, 42.8, 41.1. MS (EI): m/z = 281 [M + 1].
(2 S ,4 S ,6 R )-2-Phenyl-6-[( E )-styryl]tetrahydro-2 H -pyran-4-yl-4-nitrobenzoate (7) To a solution of compound 6 (300 mg, 1.0 mmol) in dry toluene, cooled to 0-5 °C, PPh₃ (308 mg, 1.1 mmol), p-nitrobenzoic acid (268 mg, 1.5 mmol), and DIAD (238, 1.1 mmol) were added under inert conditions and kept stirring for 3 h at r.t. After the completion of reaction toluene was removed under vacuum and the resulting crude was subjected to column chromatography that afforded the product 7 as white solid (416 mg, 90%). R _f = 0.8 (SiO₂, 20% EtOAc in hexane); mp149-151 °C(unknown); [a]_D ²⁵ -21.5 (c 1.0, CHCl₃). IR (KBr): ν = 3029, 2956, 2922, 2856, 1722, 1604, 1526, 1494, 1450, 1344, 1273, 1107, 1056, 1017, 965, 872, 750, 695 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 8.39-8.27 (m, 4 H), 7.43-7.16 (m, 10 H), 6.67 (d, J = 15.8 Hz, 1 H), 6.25 (dd, J = 5.2, 15.8 Hz, 1 H), 5.66-5.59 (m, 1 H), 4.93 (d, J = 9.8 Hz, 1 H), 4.65 (dd, J = 5.2, 11.3 Hz, 1 H), 2.33-2.13 (m, 2 H), 2.07-1.88 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 163.7, 150.6, 141.6, 136.5, 135.7, 130.7, 129.3, 128.4, 128.4, 127.7, 127.6, 126.4, 125.9, 125.7, 123.6, 74.5, 73.3, 69.7, 37.1, 35.5. MS (EI): m/z = 452 [M + 23].
(2 R ,4 S ,6 S )-2-(2-Oxo-2-phenylethyl)-6-phenyltetra-hydro-2 H -pyran-4-yl-4-nitrobenzoate (8) Oxygen was bubbled into a mixture of PdCl₂ (72 mg, 0.4 mmol), CuCl (416 mg, 2.4 mmol), DMF (7 mL), and H₂O (1 mL) at r.t. The reaction mixture was stirred at r.t. for 30 min to give a deep green mixture, and then compound 7 (350 mg, 0.8 mmol) was added. The temperature of reaction mixture was raised to 50-55 °C. The mixture was kept stirring for 3 d while maintaining the heating conditions under the atmosphere of oxygen. Then, H₂O (5 mL) was added to quench the reaction, and the resulting mixture was extracted with Et₂O (4 ¥ 15 mL). The combined organic phases were washed with H₂O (10 mL) and brine, dried over Na₂SO₄, and concentrated in vacuo. Chromatography of the residue on silica gel (PE-EtOAc, 20:1) afforded 8 (323 mg, 89%) as yellow solid. R _f = 0.5 (SiO₂, 20% EtOAc in hexane); mp 167-169 °C(unknown); [a]_D ²⁵ +31.4 (c 0.85, CHCl₃). IR (KBr): ν = 2923, 2854, 1722, 1684, 1602, 1526, 1449, 1346, 1275, 1108, 1061, 1008, 870, 784, 753 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 8.37-8.28 (m, 4 H), 7.97 (dd, J = 1.5, 6.7 Hz, 2 H), 7.61-7.35 (m, 3 H), 7.30-7.17 (m, 5 H), 5.63-5.54 (m, 1 H), 4.88 (dd, J = 2.2, 11.7 Hz, 1 H), 4.75-4.57 (m, 1 H), 3.46 (dd, J = 5.8, 16.1 Hz, 1 H), 3.04 (dd, J = 5.8, 16.1 Hz, 1 H), 2.23 (d, J = 13.9 Hz, 2 H), 2.07-1.61 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 197.8, 163.8, 150.7, 141.6, 137.2, 135.7, 133.2, 130.8, 128.5, 128.3, 128.2, 127.6, 125.7, 123.6, 74.5, 69.9, 69.6, 44.7, 36.9, 35.3, 29.6. MS (EI): m/z 468 [M + 23].
2-[(2 R ,4 S ,6 S )-4-Hydroxy-6-phenyltetrahydro-2 H -pyran-2-yl]-1-phenylethanone (1) Compound 8 (250 mg) was dissolved in MeOH (10 mL) and stirred with K₂CO₃ (77 mg, 1 equiv) for 15 min. Then MeOH was removed under reduced pressure and H₂O (15 mL) was added. The mixture was extracted with CH₂Cl₂ (3 ¥ 15 mL), the combined organic layers dried with Na₂SO₄, and concentrated under vacuum. The crude was purified by column chromatography on silica gel to furnish desired product, diospongin A(1) as colorless amorphous solid in 90% (149 mg) yield. R _f = 0.21 (SiO₂, 40% EtOAc in hexane); mp 68-70 °C(unknown); [a]_D ²⁵ -19.8 (c 0.35, CHCl₃); lit.⁹ [a]_D ²⁵ -19.6, (c 0.0084, CHCl₃). IR (KBr): ν = 3377, 2922, 1683, 1596, 1450, 1369, 1209, 1060, 998, 914, 750, 694 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.98 (dd, J = 1.0, 7.5 Hz, 2 H), 7.55 (t, J = 7.5 Hz, 1 H), 7.44 (t, J = 7.5 Hz, 2 H), 7.33-7.17 (m, 5 H), 4.93 (dd, J = 2.2, 12.0 Hz, 1 H), 4.64 (dddd, J = 1.5, 5.2, 6.0, 11.3 Hz, 1 H), 4.39-4.34 (m, 1 H), 3.41 (dd, J = 5.2, 15.8 Hz, 1 H), 3.06 (dd, J = 7.5, 15.8 Hz, 1 H), 1.96 (d, J = 14.3 Hz, 2 H), 1.80-1.57 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 198.3, 142.6, 137.2, 133.0, 128.5, 128.3, 128.2, 127.2, 125.8, 73.7, 69.0, 64.6, 45.1, 40.0, 38.4. MS (EI): m/z = 297 [M + 1].