PAPER
Synthesis of the C1–C9 Fragment of Dictyostatin
2161
13C NMR (100 MHz, CDCl3): d = –4.7, –3.8, 15.2 (epimer at C-5,
£3%), 15.6, 18.7, 18.9, 26.6, 26.7, 33.1, 37.5, 43.0, 45.1 (epimer at
C-5, £3%), 60.6, 62.3, 72.8, 73.1 (epimer at C-5, £3%), 119.4,
150.2, 167.6.
pared by slow dropwise addition of HF·py (1.3 mL) to a solution of
pyridine (5.0 mL) and THF (10.2 mL)]. The reaction mixture was
warmed to r.t. and stirred for 8 h. After quenching of the reaction by
the addition of sat. aq NaHCO3 (30 mL), the mixture was extracted
with EtOAc (4 × 20 mL). The combined organic extracts were
washed with sat. aq CuSO4 (3 × 15 mL) and brine (2 × 40 mL), dried
(Na2SO4), and evaporated under reduced pressure. Purification by
flash chromatography (hexanes–EtOAc, 2:1) gave 2.
ESI-HRMS: m/z calcd for C22H47NNaO4Si2: 468.2936; found:
468.2328.
(2E,4R,5S)-5,7-Bis(tert-butyldimethylsiloxy)-4-methylhept-2-
enal (12)
18
Yield: 218 mg (86%); colorless oil; [a]D –10.5 (c 1.00, CH2Cl2);
A stirred solution of Weinreb amide 11 (400 mg, 0.9 mmol) in an-
hyd THF (9.4 mL) was treated at –78 °C with 1 M DIBAL-H in hex-
anes (2.7 mL, 2.7 mmol). After being stirred for 90 min at –78 °C,
this solution was poured into a mixture of 1 M aq tartaric acid (12.4
mL) and EtOAc (13.8 mL). After the mixture had stirred for 1 h, the
layers were separated, the aqueous phase was extracted with Et2O
(2 × 20 mL), and the combined organic extracts were washed with
brine (2 × 25 mL), dried (Na2SO4), and evaporated under reduced
pressure; this gave crude aldehyde 12, which was used without fur-
ther purification.
[a]D24 –14.0 (c 0.20, CHCl3) {Lit.4d [a]D20 –14.3 (c = 0.21, CHCl3)};
Rf = 0.20 (hexanes–EtOAc, 8:2).
IR (CHCl3): 3418, 2954, 2929, 2885, 2857, 1719, 1637, 1601, 1439,
1256, 1197, 1176, 1082, 1031, 1005, 837, 775 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.09 (s, 3 H, MeSi), 0.10 (s, 3 H,
MeSi), 0.91 (s, 9 H, t-BuSi), 1.09 (d, J = 6.8 Hz, 3 H, CH3), 1.63–
1.74 (m, 2 H, H-8), 1.98 (br s, 1 H, OH), 2.54–2.59 (m, 1 H, H-6),
3.73 (s, 3 H, CO2CH3), 3.69–3.75 (m, 2 H, H-9), 3.85–3.88 (m, 1 H,
H-7), 5.61 (d, J = 11.2 Hz, 1 H, H-2), 6.02 (dd, J = 8.0, 15.6 Hz, 1
H, H-5), 6.56 (t, J = 11.2 Hz, 1 H, H-3), 7.38 (dd, J = 11.2, 15.6 Hz,
1 H, H-4).
Yield: 317 mg (91%); pale yellow oil; Rf = 0.81 (hexanes–EtOAc,
6:4).
13C NMR (100 MHz, CDCl3): d = –3.9, –3.7, 15.4, 18.7, 26.5, 36.3,
43.3, 51.8, 60.7, 74.4, 116.4, 127.6, 146.0, 147.7, 167.6.
1H NMR (400 MHz, CDCl3): d = 0.06 (s, 6 H, Me2Si), 0.09 (s, 6 H,
Me2Si), 0.90 (s, 9 H, t-BuSi), 0.92 (s, 9 H, t-BuSi), 1.14 (d, J = 7.2
Hz, 3 H, CH3), 1.53–1.60 (m, 1 H, H-6), 1.64–1.73 (m, 1 H, H-6),
2.57–2.67 (m, 1 H, H-4), 3.64–3.67 (m, 2 H, H-7), 3.90–3.91 (m, 1
H, H-5), 6.13 (dd, J = 7.6, 15.6 Hz, 1 H, H-2), 6.87 (dd, J = 7.6, 15.6
Hz, 1 H, H-3), 9.53 (d, J = 7.6 Hz, 1 H, H-1).
ESI-HRMS: m/z calcd for C17H32NaO4Si: 351.1962; found:
351.1957.
Acknowledgment
Methyl (2Z,4E,6R,7S)-7,9-Bis(tert-butyldimethylsiloxy)-
6-methylnona-2,4-dienoate (13)
We thank the Ministero dell’Università e della Ricerca for financial
support (PRIN prot. 2006030449) and for a postdoctoral fellowship
(‘Assegno di ricerca’ to L. Pignataro) and a PhD fellowship (Borsa
di dottorato ‘Progetto giovani’ to C. Zanato). C. Gennari gratefully
acknowledges Merck Research Laboratories for the Merck’s Aca-
demic Development Program Award. Z. Hao (Lanzhou University,
PRC) thanks the China Scholarship Council for a PhD mobility
grant.
A solution of (F3CCH2O)2P(O)CH2CO2Me (0.18 mL, 0.86 mmol)
and 18-crown-6·MeCN (1.20 g, 3.9 mmol) in anhyd THF (15.6
mL) was cooled to –78 °C, and 0.5 M KHMDS in toluene (1.72 mL,
0.86 mmol) was added dropwise. After the mixture had spent a few
min at –78 °C, a solution of aldehyde 12 (300 mg, 0.78 mmol) in an-
hyd THF (6.5 mL) was added dropwise. The mixture was stirred at
–78 °C for 1 h and then treated with sat. aq NH4Cl (20 mL) and Et2O
(20 mL). The layers were separated, the aqueous phase was extract-
ed with Et2O (2 × 30 mL), and the combined organic extracts were
washed with H2O (2 × 40 mL), dried (Na2SO4), and evaporated un-
der reduced pressure. The crude product was purified by flash chro-
matography (hexanes–EtOAc, 100:5).
References
(1) (a) Isbrucker, R. A.; Cummins, J.; Pomponi, S. A.; Longley,
R. E.; Wright, A. E. Biochem. Pharmacol. 2003, 66, 75.
(b) Madiraju, C.; Edler, M. C.; Hamel, E.; Raccor, B. S.;
Balachandran, R.; Zhu, G.; Giuliano, K. A.; Vogt, A.; Shin,
Y.; Fournier, J.-H.; Fukui, Y.; Brückner, A. M.; Curran, D.
P.; Day, B. W. Biochemistry 2005, 44, 15053.
22
Yield: 319 mg (90%); colorless oil; [a]D –2.7 (c 0.70, CH2Cl2);
24
20
[a]D –6.4 (c 0.35, CHCl3) {Lit.4d [a]D –6.6 (c = 0.36, CHCl3)};
Rf = 0.35 (hexanes–EtOAc, 100:5).
(2) Paterson, I.; Britton, R.; Delgado, O.; Wright, A. E. Chem.
IR (CHCl3): 3408, 2957, 2927, 2856, 2738, 2710, 2360, 2341, 1722,
1639, 1602, 1471, 1438, 1258, 1194, 1176, 1098, 1030, 835, 806,
775 cm–1.
1H NMR (400 MHz,CDCl3): d = 0.05 (s, 6 H, Me2Si), 0.08 (s, 6 H,
Me2Si), 0.90 (s, 9 H, t-BuSi), 0.92 (s, 9 H, t-BuSi), 1.09 (d, J = 6.9
Hz, 3 H, CH3), 1.55–1.67 (m, 2 H, H-8), 2.47–2.57 (m, 1 H, H-6),
3.63–3.68 (m, 2 H, H-9), 3.75 (s, 3 H, CO2CH3), 3.82–3.85 (m, 1 H,
H-7), 5.61 (d, J = 11.3 Hz, 1 H, H-2), 6.06 (dd, J = 8.0, 15.2 Hz, 1
H, H-5), 6.58 (t, J = 11.3 Hz, 1 H, H-3), 7.37 (dd, J = 11.3, 15.2 Hz,
1 H, H-4).
Commun. 2004, 632.
(3) (a) Paterson, I.; Britton, R.; Delgado, O.; Meyer, A.;
Poullennec, K. G. Angew. Chem. Int. Ed. 2004, 43, 4629.
(b) Shin, Y.; Fournier, J.-H.; Fukui, Y.; Brückner, A. M.;
Curran, D. P. Angew. Chem. Int. Ed. 2004, 43, 4634.
(c) O’Neil, G. W.; Phillips, A. J. J. Am. Chem. Soc. 2006,
128, 5340. (d) Ramachandran, P. V.; Srivastava, A.; Hazra,
D. Org. Lett. 2007, 9, 157.
(4) (a) Shin, Y.; Fournier, J.-H.; Balachandran, R.; Madiraju, C.;
Raccor, B. S.; Zhu, G.; Edler, M. C.; Hamel, E.; Day, B. W.;
Curran, D. P. Org. Lett. 2005, 7, 2873. (b) Fukui, Y.;
Brückner, A. M.; Shin, Y.; Balachandran, R.; Day, B. W.;
Curran, D. P. Org. Lett. 2006, 8, 301. (c) Paterson, I.;
Gardner, N. M.; Poullennec, K. G.; Wright, A. E. Bioorg.
Med. Chem. Lett. 2007, 17, 2443. (d) Jung, W.-H.;
Harrison, C.; Shin, Y.; Fournier, J.-H.; Balachandran, R.;
Raccor, B. S.; Sikorski, R. P.; Vogt, A.; Curran, D. P.; Day,
B. W. J. Med. Chem. 2007, 50, 2951. (e) Shin, Y.; Fournier,
J.-H.; Brückner, A.; Madiraju, C.; Balachandran, R.; Raccor,
13C NMR (100 MHz, CDCl3): d = –4.7, –3.8, 16.1, 18.8, 18.9, 26.6,
37.8, 43.4, 51.7, 60.5, 73.0, 116.0, 127.5, 146.3, 148.2, 167.6.
ESI-HRMS: m/z calcd for C23H46NaO4Si2: 465.2827; found:
465.2823.
Methyl (2Z,4E,6R,7S)-7-(tert-Butyldimethylsiloxy)-9-hydroxy-
6-methylnona-2,4-dienoate (2)
A solution of compound 13 (338 mg, 0.74 mmol) in THF (3.8 mL)
at 0 °C was treated with a soln of HF·py in THF–py [16.5 mL, pre-
Synthesis 2008, No. 14, 2158–2162 © Thieme Stuttgart · New York