Synlett 2011(11): 1555-1558  
DOI: 10.1055/s-0030-1260784
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthetic Approaches to the Bottom Half Fragment for Bryostatin 11

Kyoko Nakagawa-Goto*, Michael T. Crimmins
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Fax: +1(919)9663893; e-Mail: goto@email.unc.edu;
Further Information

Publication History

Received 31 January 2011
Publication Date:
10 June 2011 (online)

Abstract

An approach towards the stereoselective synthesis of the bottom half fragment of bryostatin 11 is described. Key steps ­include asymmetric aldol and Saksena-Evans reduction reactions ­to construct multiple stereogenic centers and thioketalization-­lactonization reactions to form the thioketal-protected C-ring.

    References and Notes

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1

Current address: K. Nakagawa-Goto, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill,
NC 27599, USA.

3

For current information, see: http://clinicaltrials.gov.

21

Lactone 24 To an ice-cold solution of anti-diol 23 (260 mg, 0.8 mmol) in CH2Cl2 (5.0 mL), TFA (0.6 mL, 7.8 mmol) was added. The mixture was stirred at r.t. for 2.5 h, and then quenched with sat. NaHCO3 at 0 ˚C. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by flash chromatography gave lactone 24 (189 mg, 95%) as a colorless oil. ¹H NMR (400 MHz, CDCl3):
δ = 7.40-7.25 (m, 5 H), 4.63 (d, J = 11.7 Hz, 1 H), 4.54 (d, J = 11.7 Hz, 1 H), 4.32-4.18 (m, 2 H), 3.76-3.68 (m, 1 H), 2.87 (ddd, J = 17.2, 5.7, 1.2 Hz, 1 H), 2.48 (dd, J = 17.2, 7.8 Hz, 1 H), 2.26-2.18 (m, 2 H), 1.82-1.71 (m, 1 H), 1.27 (d, J = 6.4 Hz, 3 H). HRMS: m/z calcd for C14H18O4Na [M + Na]+: 273.1103; found: 273.1100.

22

Methyl Acetal 25 To a solution of lactone 24 (171 mg, 0.7 mmol) in CH2Cl2 (2.0 mL), 2,6-lutidine (0.2 mL, 1.7 mmol), and TESOTf (0.2 mL, 0.9 mmol) were added at -78 ˚C. After 0.5 h, the mixture was quenched with sat. NaHCO3 and then extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by flash chromatography gave TES ether (205 mg, 92%) as a colorless oil. To a solution of (i-Pr)2NH (0.25 mL, 1.8 mmol) in THF (1.5 mL), n-BuLi (1.5 M in hexane, 1.2 mL, 1.8 mmol) was added dropwise at -30 ˚C and stirred 10 min. After addition of tert-butyl acetate (0.25 mL, 1.9 mmol) at -78 ˚C, the mixture was stirred for 1 h, and the TES ether (205 mg, 0.6 mmol) in THF (2.0 mL) was added slowly. The mixture was stirred for 10 min, quenched with H2O, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by flash chromatography gave tert-butyl ester (253 mg, 0.5 mmol, 97%) as a colorless oil, which was dissolved in benzene (2.0 mL) and MeOH (0.5 mL). Methylorthoformate (0.6 mL, 5.5 mmol) and PPTS (14 mg, 0.055 mmol) were added. After stirring at r.t. for 2 h, the mixture was quenched with sat. NaHCO3. The whole was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, and concen-trated in vacuo. Purification by flash chromatography gave methyl acetal 25 (153 mg, 91%) as a colorless oil. ¹H NMR (400 MHz, CDCl3): δ = 7.40-7.25 (m, 5 H), 4.66 (d, J = 12.0 Hz, 1 H), 4.60 (d, J = 12.0 Hz, 1 H), 4.16-4.04 (m, 1 H), 3.64-3.50 (m, 2 H), 3.23 (s, 3 H), 2.71 (d, J = 13.7 Hz, 1 H), 2.51 (d, J = 13.7 Hz, 1 H), 2.32 (ddd, J = 12.5, 4.7, 1.8 Hz, 1 H), 1.94-1.87 (m, 1 H), 1.60-1.52 (m, 1 H), 1.46 (s, 9 H), 1.35-1.24 (m, 1 H), 1.19 (d, J = 6.4 Hz, 3 H). HRMS:
m/z calcd for C27H46O6SiNa [M + Na]+: 517.2961; found: 517.2974.

23

Thioketal 26 A solution of methyl acetal 25 (175 mg, 0.46 mmol) in MeNO2 (2.0 mL) and CH2Cl2 (1.0 mL) was cooled to -45 ˚C. 1,3-Propanedithiol (0.15 mL, 1.5 mmol) and BF3˙OEt2 (0.3 mL, 2.4 mmol) were added in succession. The mixture was gradually warmed to 0 ˚C over 1 h and purified directly by column chromatography to obtain thioketal 26 (160 mg, 91%).

24

TBS ether 27
To a solution of thioketal 26 (226 mg, 0.59 mmol) in DMF (2.0 mL), imidazole (320 mg, 4.7 mmol) and TBSCl (304 mg, 2.0 mmol) were added, and the mixture was stirred at r.t. overnight. After quenching with sat. NaHCO3, the mixture was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by flash chromatography gave TBS ether 25 (254 mg, 87%) as a colorless oil. ¹H NMR (400 MHz, CDCl3): δ = 7.36-7.33 (m, 3 H), 7.31-7.25 (m, 2 H), 4.87-4.78 (m, 1 H), 4.55 (s, 2 H), 4.21 (ddd, J = 10.5, 4.5, 2.0 Hz, 1 H), 3.20 (dd, J = 17.2, 2.2 Hz, 1 H), 3.02-2.78 (m, 5 H), 2.45 (ddd, J = 14.1, 2.6, 2.2 Hz, 1 H), 2.17 (s, 2 H), 2.10-1.91 (m, 1 H), 2.34-2.21 (m, 4 H), 1.64-1.55 (m, 1 H), 1.13 (d, J = 6.5 Hz, 3 H), 0.86 (s, 9 H), 0.07 (s, 3 H), 0.01 (s, 3 H). ¹³C NMR (400 MHz, CDCl3): δ = 167.9, 138.7, 128.5, 127.8, 127.7, 76.6, 73.3, 71.2, 68.0, 45.3, 43.8, 42.0, 36.5, 31.1, 26.9, 26.7, 26.2, 26.0, 24.8, 18.1, 13.4, -4.3, -4.7. MS (ESI+): m/z = 519 [M+ + Na]. IR (film): νmax = 2951.1, 2927.9, 2851.7, 1737.9, 1249.9, 1240.2, 1222.9, 1101.4, 1076.3, 835.2, 775.4 cm. HRMS: m/z calcd for C25H40O4S2SiNa [M + Na]+: 519.2030; found: 519.1979. [α]D ²³ +31.2 (c 3.31, CH2Cl2).