Synthetic Approaches to the Bottom Half Fragment for Bryostatin 11

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.

Key words

bryostatin 11 - bottom half fragment - asymmetric aldol - Saksena-Evans reduction - thioketalization-lactonization

References and Notes

• For recent reviews on bryostatin chemistry and biology, see:
• 2a Mutter R. Wills M. Bioorg. Med. Chem.  2000,  8:  1841 
• 2b Hale KJ. Hummersone MG. Manaviazar S. Frigerio M. Nat. Prod. Rep.  2002,  413 
• 2c Sun MK. Alkon DL. CNS Drug Rev.  2006,  12:  1 
• 2d Abadi G. Palen W. Geddings J. Irwin T. Kasali N. Colyer J. Goodson F. Sith J. Jone K. Hester J. Noble L. Groundwater PW. Phillips D. Manning TJ. Natural Products I, In Recent Progress in Medical Plants   Vol. 15:  Govil JN. Singh VK. Ahmad K. Sharma RK. Studium Press; New Delhi: 2006.  p.363 
• 2e Hale KJ. Manaviazar S. Chem. Asian J.  2010,  5:  704 
• 2f Green AP. Hardy S. Lee ATL. Thomas EJ. Phytochem. Rev.  2010,  9:  501 
• 2g Szpilman AM. Carreira EM. Angew. Chem. Int. Ed.  2010,  49:  9592 
• 4a Etcheberrigaray R. Tan M. Dewachter I. Kuip_eri C. Van der Auwera I. Wera S. Qiao L. Bank B. Nelson TJ. Kozikowski AP. Van Leuven F. Alkon DL. Proc. Natl. Acad. Sci. U.S.A.  2004,  101:  11141 
• 4b Alkon DL. Sun M.-K. Nelson TJ. Trends Pharmacol. Sci.  2007,  28:  51 
• 5a Pettit GR. J. Nat. Prod.  1996,  59:  812 ; and references cited therein
• 5b Lopanik N. Gustafson KR. Lindquist N. J. Nat. Prod.  2004,  67:  1412 
• 6 Kageyama M. Tamura T. Nantz MH. Roberts JC. Somfai P. Whritenour DC. Masamune S. J. Am. Chem. Soc.  1990,  11:  27407 
• 7a Evans DA. Carter PH. Carreira EM. Angew. Chem. Int. Ed.  1998,  37:  2354 
• 7b Evans DA. Carter PH. Carreira EM. Charette AB. Prunet JA. Lautens M. J. Am. Chem. Soc.  1999,  121:  7540 
• 8 Ohmori K. Ogawa Y. Obitsu T. Ishikawa Y. Nishiyama S. Yamamura S. Angew. Chem. Int. Ed.  2000,  39:  2290 
• 9 Manaviazar S. Frigerio M. Bhatia GS. Hummersone MG. Aliev AE. Hale KJ. Org. Lett.  2006,  8:  4477 
• 10a Trost BM. Dong G. Nature (London)  2008,  456:  485 
• 10b Trost BM. Dong G. J. Am. Chem. Soc.  2010,  132:  16403 
• 11 Keck GE. Poudel YB. Cummins TJ. Rudra A. Covel JA. J. Am. Chem. Soc.  2011,  133:  744 
• 12a Wender PA. Baryza JL. Bennett CE. Bi FC. Brenner SE. Clarke MO. Horan JC. Kan C. Lacote E. Lippa B. Nell PG. Turner TM. J. Am. Chem. Soc.  2002,  124:  13648 
• 12b Hale KJ. Frigerio M. Manaviazar S. Hummersone MG. Fillingham IJ. Barsukov IG. Damblon CF. Gescher A. Roberts GCK. Org. Lett.  2003,  5:  499 
• 12c Trost BM. Yang H. Thiel OR. Frontier AJ. Brindle CS. J. Am. Chem. Soc.  2007,  129:  2206 
• 12d Keck GE. Li W. Kraft MB. Kedei N. Lewin NE. Blumberg PM. Org. Lett.  2009,  11:  2277 
• 12e

  See also ref. 2e-g.

• Thomas and Trost reported an unsuccessful trial of the RCM method for C16-C17 double-bond construction:
• 13a Ball M. Bradshaw BJ. Dumeunier R. Gregson TJ. MacCormick S. Omori H. Thomas EJ. Tetrahedron Lett.  2006,  2223 
• 13b Trost BM. Yang H. Thiel OR. Frontier AJ. Brindle CS. J. Am. Chem. Soc.  2007,  129:  2206 
• 14 Nakata T. Takao S. Fukui M. Tanaka T. Oishi T. Tetrahedron Lett.  1983,  24:  3873 
• 15a Saksena AK. Mangiaraeina P. Tetrahedron Lett.  1983,  24:  273 
• 15b Evans DA. Dimare M. J. Am. Chem. Soc.  1986,  108:  2476 
• 16a Heathcock CH. Kiyooka S. Blumenkopf TA.
  J. Org. Chem.  1984,  49:  4214 
• 16b Gerlach K. Quitschalle M. Kalesse M. Tetrahedron Lett.  1999,  40:  3533 
• The constructions of similar aldehydes via anti-selective allylation have been reported by other groups. See:
• 17a De Brabander J. Vandewalle M. Synthesis  1994,  855 
• 17b Wender PA. Brabander JD. Harran PG. Jimenez JM. Koehler MFT. Lippa B. Park CM. Shiozaki M. J. Am. Chem. Soc.  1998,  120:  4534 
• 17c Keck GE. Truong AP. Org. Lett.  2005,  7:  2149 
• 18 Brownbridge P. Chan TH. Brook MA. Kang GJ. Can. J. Chem.  1983,  61:  688 
• 19a Baxter J. Mata EG. Thomas EJ. Tetrahedron Lett.  1998,  54:  14359 
• 19b Voight reported that the use of TiCl_{2 (}Oi-Pr)₂ as a Lewis acid provided a 5:1 selectivity ratio. See: Voight EA. Roethle PA. Burke SD. J. Org. Chem.  2004,  69:  4534 
• 20 Gennari C. Cozzi PG. Tetrahedron  1988,  44:  5965 
• 25 Yoda H. Mizutani M. Takabe K. Heterocycles  1998,  48:  679 

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): ν_max = 2951.1, 2927.9, 2851.7, 1737.9, 1249.9, 1240.2, 1222.9, 1101.4, 1076.3, 835.2, 775.4 cm^-¹. HRMS: m/z calcd for C₂₅H₄₀O₄S₂SiNa [M + Na]⁺: 519.2030; found: 519.1979. [α]_D ^²³ +31.2 (c 3.31, CH₂Cl₂).