Studies on the Synthesis of Bitungolides A-E: Synthesis of the C(1)-C(12) Fragment

Yanfen Xu; Xing Huo; Xinyun Li; Huaiji Zheng; Xuegong She; Xinfu Pan

doi:10.1055/s-2008-1078486

LETTER

Studies on the Synthesis of Bitungolides A-E: Synthesis of the C(1)-C(12) Fragment

Yanfen Xu^a, Xing Huo^a, Xinyun Li^a, Huaiji Zheng^a, Xuegong She*^a,b, Xinfu Pan^a
^a Department of Chemistry, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax: +86(931)8912582; e-Mail: shexg@lzu.edu.cn;
^b State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, P. R. of China

Abstract

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Abstract

Synthesis of the core segment of bitungolides A-E has been achieved in 17 steps and 4.7% overall yield. Six stereogenic centers of bitungolides A-E were established via allylation, dihydroxylation, Myers alkylation, and Evans aldol reaction

Key words

bitungolide - allylation - dihydroxylation - Myers alkylation - Evans aldol reaction

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References

References and Notes

1 Sirirath S. Tanaka J. Ohtani II. Ichiba T. Rachmat R. Ueda K. Usui T. Osada H. Higa T. J. Nat. Prod. 2002, 65: 1820

2 Brohm D. Metzger S. Bhargwa A. Müller O. Lieb F. Waldman H. Angew. Chem. Int. Ed. 2002, 41: 307

3 Davies-Coleman MT. Rivett DEA. Fortschr. Chem. Org. Naturst. 1989, 55: 1

4 Ghosh S. Kumar SU. Shashidhar J. J. Org. Chem. 2008, 73: 1582

5a Evans DA. Urpi F. Somers TC. Clark JC. Bilodeau MT. J. Am. Chem. Soc. 1990, 112: 8215

5b Harried SS. Lee CP. Yang G. Lee TIH. Myles DC. J. Org. Chem. 2003, 68: 6646

5c Crimmins MT. Carroll CA. King BW. Org. Lett. 2002, 2: 597

6 Prashad M. Har D. Kim HY. Repic O. Tetrahedron Lett. 1998, 39: 7067

7 Mancuso AJ. Huang SL. Swern D. J. Org. Chem. 1978, 43: 2480

8a Heathcock CH. Kiyooka S. Blumenkopf TA. J. Org. Chem. 1984, 49: 4214

8b Trost BM. Kondo Y. Tetrahedron Lett. 1991, 32: 1613

9 Kolb HC. Van Nieuwenhze MS. Sharpless KB. Chem. Rev. 1994, 94: 2483

10a Rychnovsky SD. Skalitzky DJ. Tetrahedron Lett. 1990, 31: 945

10b Rychnovsky SD. Rogers B. Yang G. J. Org. Chem. 1993, 58: 3511

10c Rychnovsky SD. Yang G. Powers JP. J. Org. Chem. 1993, 58: 5251

10d Rychnovsky SD. Rogers BN. Richardson TI. Acc. Chem. Res. 1998, 31: 9

10e Evans DA. Rieger DL. Gage JR. Tetrahedron Lett. 1990, 31: 7099

11 Garegg PJ. Samuelson B. J. Chem. Soc., Perkin Trans. 1 1978, 43: 2866

12a Myers AG. Yang BH. Chen H. Mckinstry L. Kopecky DJ. Gleason JL. J. Am. Chem. Soc. 1997, 117: 6496

12b Myers AG. Yang BH. Chen H. Kopeckym DJ. Synlett 1997, 457

13 Frigerio M. Santagostino M. Sputore S. Palmisano G. J. Org. Chem. 1995, 60: 7272

14 Gage JR. Evans DA. Org. Synth. 1989, 68: 83

15 Arya P. Qin H. Tetrahedron 2000, 56: 917

16a Crimmins MT. King BW. Tabet EA. J. Am. Chem. Soc. 1997, 119: 7883

16b Crimmins MT. King BW. Tabet EA. Chaudhary K. J. Org. Chem. 2001, 66: 894

17 Kaori A. J. Org. Chem. 1997, 62: 1934

18

Selected Experimental and Spectroscopic Data
Compound 19
A solution of n-BuLi in hexane (1.85 M, 15.8 mL, 29.23 mmol) was added via cannula to a suspension of LiCl (3.94 g, 92.73 mmol) and diisopropylamine (4.4 mL, 32.86 mmol) in THF (50 mL) at -78 °C. The resulting suspension was warmed to 0 °C briefly and then was cooled to -78 °C, an ice-cooled solution of amide (-)-18 (3.39 g, 15.33 mmol) in THF (50 mL, followed by a 4 mL rinse) was added via cannula. The mixture was stirred at -78 °C for 1 h, at 0 °C for 15 min and at 23 °C for 5 min. The mixture was cooled to 0 °C, and iodide 17 (3.125 g, 7.33 mmol) was added neat to the reaction via cannula. After being stirred for 18 h at 0 °C, the reaction mixture was treated with half-saturated aq NH₄Cl solution (40 mL) and the resulting mixture was extracted with EtOAc (4 × 50 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated. Purification of the residue by flash column chromatography (hexane-EtOAc, 3:1) afforded amide 19 (3.35 g, 88%); [α]_D ²⁰ +34.2 (c 7.6, CH₂Cl₂). IR (KBr): 3385, 2931, 1620, 1465, 1377, 1106, 838 cm^-1. ¹H NMR (300 MHz, CDCL₃): δ = 0.03 (s, 6 H), 0.77 (d, J = 5.7 Hz, 3 H), 0.86 (s, 9 H), 0.96-1.07 (m, 1 H), 0.99 (d, J = 7.2 Hz, 3 H), 1.11 (d, J = 6.9 Hz, 3 H), 1.27 (s, 3 H), 1.28 (s, 3 H), 1.33-1.52 (m, 4 H), 2.71-2.86 (m, 1 H), 2.82 (s, 3 H), 3.42 (dd, J = 15.3, 7.5 Hz, 1 H), 3.51 (dd, J = 10.5, 5.1 Hz, 1 H), 3.59 (dd, J = 10.5, 6.3 Hz, 1 H), 3.73-3.81 (m, 1 H), 4.38 (br s, 1 H), 4.58 (app t, J = 6.9 Hz, 1 H), 4.70 (br s, 1 H), 7.18-7.31 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = -5.3, -5.2, 14.3, 15.1, 17.1, 18.2, 24.4, 24.6, 25.8, 32.3, 34.6, 35.7, 37.7, 66.1, 67.8, 67.9, 71.2, 76.2, 100.0, 126.2, 126.8, 128.1, 142.5, 179.2. HRMS [M + H]: m/z calcd for C₂₉H₅₂NO₅Si: 522.3609; found: 522.3614.
Aldehyde 10
n-Butyllithium (1.72 M in hexanes, 19.95 mmol) was added to diisopropylamine (3.2 mL, 21.95 mmol) in THF (30 mL) at -78 °C. After stirring the mixture at -78 °C for 10 min and at 0 °C for 10 min, BH₃·NH₃ (0.631 g, 20.44 mmol) was added in one portion. After stirring the mixture at 0 °C for 15 min and then at r.t. for 15 min, (-)-19 (2.597 g, 4.98 mmol) in THF (10 mL) was added via cannula at 0 °C and the mixture was stirred at r.t. for 3 h. The reaction was quenched by slow addition of sat. NH₄Cl (20 mL) at 0 °C (gas evolution!). The aqueous phase was extracted with Et₂O (4 × 50 mL), and the combined organic layers were washed with brine (25 mL), and dried over Na₂SO₄. After concentration in vacuo, purification by flash chromato-graphy (hexane-EtOAc, 10:1) provided the alcohol (2.00 g, 92% yield) as a colorless liquid; [α]_D ²⁰ -7.7 (c 5.3, CH₂Cl₂). IR (KBr): 3368, 2931, 1465, 1225, 839 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.03 (s, 6 H), 0.80-0.92 (m, 15 H), 1.05-1.12 (m, 1 H), 1.30 (s, 3 H), 1.31 (s, 3 H), 1.34-1.40 (m, 1 H), 1.52-1.63 (m, 3 H), 1.70-1.75 (m, 1 H), 2.15 (br, 1 H), 3.39-3.50 (m, 3 H), 3.51-3.54 (m, 1 H), 3.58-3.62 (m, 1 H), 3.79-3.83 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = -5.3, -5.2, 15.0, 15.9, 18.3, 24.5. 24.7, 25.8, 32.2, 33.1, 34.5, 36.0, 66.2, 67.9, 68.6, 71.2, 100.2.
IBX (1.46g, 5.22 mmol) was added to a solution of alcohol (1.253 g, 3.48 mmol) in DMSO. After 5 h, the reaction mixture was diluted with H₂O, filtered, and extracted with Et₂O, and the organic layers were dried (Na₂SO₄) and evaporated. The crude product was purified by flash chromatography (hexane-EtOAc, 20:1) to give 10 (1.15 g, 92%); [α]_D ²⁰ -20.7 (c 8.8, CH₂Cl₂). IR (KBr): 2931, 1728, 1462, 1224, 1138, 839 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 0.04 (s, 6 H), 0.83 (d, J = 7.2 Hz, 3 H), 0.87 (s, 9 H), 1.05 (d, J = 7.2 Hz, 3 H), 1.29 (s, 3 H), 1.30 (s, 3 H), 1.39-1.65 (m, 5 H), 2.38-2.47 (m, 1 H), 3.44-3.64 (m, 3 H), 3.77-3.86 (m, 1 H), 9.61 (d, J = 1.8 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = -5.3, -5.2, 13.1, 14.5, 18.3, 24.5. 24.7, 25.8, 32.5, 33.3, 35.4, 44.1, 66.2, 67.8, 70.8, 100.2, 205.2.
Compound 21
To a cooled (0 °C) solution of the oxazolidinone 9 (364 mg, 1.47 mmol) in CH₂Cl₂ (10 mL) was added dropwise TiCl₄ (0.18 mL, 1.54 mmol) and the mixture allowed to stir for 5 min. Subsequently, (-)-sparteine (0.862 g, 3.68 mmol) was added to the yellow slurry. The dark red enolate solution was stirred for 20 min at 0 °C before aldehyde 10 (632 mg, 1.76 mmol) was added dropwise and the mixture stirred for 1 h at 0 °C The reaction was quenched with half-saturated NH₄Cl solution (6 mL). After separation of the layers, the organic layer was dried (Na₂SO₄), filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (hexane-EtOAc, 8:1) afforded (0.82 g, 90%) of 21, colorless oil; [α]_D ²⁰ +28 (c 2.30, CH₂Cl₂). IR (KBr): 3448, 2932, 1465, 1110, 1036, 704 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.04 (s, 6 H), 0.79 (d, J = 6.8 Hz, 3 H), 0.88 (s, 9 H), 0.90 (d, J = 6.4 Hz, 3 H), 0.98 (t, J = 7.2 Hz, 3 H), 1.31 (s, 6 H), 1.35-1.44 (m, 2H), 1.52-1.77 (m, 5 H), 1.89-1.97 (m, 1 H), 2.66 (br, 1 H), 2.70 (dd, J = 13.2, 10.4 Hz, 1 H), 3.37 (dd, J = 13.2, 3.2 Hz, 1 H), 3.47 (dd, J = 15.6, 6.4 Hz, 1 H), 3.54 (dd, J = 10.4, 4.8 Hz, 1 H), 3.61 (dd, J = 10.4, 6.4 Hz, 1 H), 3.78-3.83 (m, 1 H), 4.10-4.15 (m, 1 H), 4.15 (d, J = 4.8 Hz, 2 H), 4.66-4.72 (m, 1 H), 7.22-7.34 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = -5.3, -5.2, 11.8, 14.7, 15.8, 18.3, 19.3, 24.5. 24.7, 25.8, 32.3, 33.8, 34.8, 35.4, 37.9, 46.7, 55.6, 65.8, 66.2, 67.9, 71.2, 76.4,100.2, 127.3, 128.9, 129.3, 135.2, 153.0, 176.2. HRMS [M + Na]: m/z calcd for C₃₃H₅₅NO₇SiNa: 628.3640; found: 628.3652.
Compound 8
To a stirred solution of (Z)-26 (51 mg, 0.094 mmol) in anhyd THF (5 mL) at r.t. was added TBAF (59 mg, 0.188 mmol) in THF (59 mg, 0.188 mmol), and the mixture was stirred for 12 h. Then, H₂O (10 mL) was added, the layers were separated, and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried (Na₂SO₄) and concentrated in vacuo. The residue was purified by column chromatography (hexane-EtOAc, 4:1) to give 8 (36 mg, 90%) as a colorless oil; [α]_D ²⁰ -9 (c 1.00, CH₂Cl₂). IR (KBr): 3421, 2926, 1718, 1642, 1458, 1378, 1035cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 0.70 (d, J = 7.2 Hz, 3 H), 0.75 (t, J = 7.2 Hz, 3 H), 0.89 (d, J = 6.9 Hz, 3 H), 1.24 (t, J = 7.2 Hz, 3 H), 1.30 (s, 3 H), 1.31 (s, 3 H), 1.29-1.39 (m, 2 H), 1.48-1.64 (m, 4 H), 1.71-1.81 (m, 1 H), 2.24-2.28 (m, 1 H), 3.15-3.18 (m, 1 H), 3.36 (s, 3 H), 3.42-3.49 (m, 2 H), 3.52-3.56 (m, 1 H), 3.62-3.72 (m, 1 H), 3.80-3.86 (m, 1 H), 4.11 (q, J = 7.2 Hz, 2 H), 4.60 (s, 2 H), 5.80 (d, J = 11.7 Hz, 1 H), 5.96 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 11.5, 13.3, 14.2, 16.4, 22.8, 24.3. 24.8, 30.7, 33.4, 33.5, 34.7, 42.2, 56.0, 59.8, 65.4, 67.8, 70.9, 87.9, 98.5, 100.3, 120.5, 151.4, 166.2. HRMS: [M + Na]: m/z calcd for C₂₃H₄₂O₇Na: 453.2823; found: 453.2823.