Synthesis of Bryostatin Rings A and B
FULL PAPER
dried test tube equipped with molecular sieves (4 ꢁ; 110.7 mg) and a stir-
ring bar. The catalyst was then added and the reaction was stirred at 48C
for 7 h. The reaction mixture was then poured into phosphate buffer (1m,
pH 7) and extracted with petroleum ether/diethyl ether (1:1). The organic
layer was washed twice with phosphate buffer (1m, pH 7) and once with
brine. The aqueous layers were extracted twice with diethyl ether. The
combined organic layers were dried (Na2SO4), filtered, concentrated in
vacuo, and chromatographed with a solvent gradient (2–10% v/v diethyl
ether/petroleum ether) to give compound 58 (93.1 mg, 63% yield, 94%
1092, 1037, 991, 923, 840, 768, 717, 689 cmꢀ1
C33H50O6Si: 570.3377; found: 570.3388.
; HRMS calcd for
Synthesis of compound 67: Ketal 63 (16.1 mg, 0.028 mmol) was dissolved
in methanol (0.5 mL). Camphor sulfonic acid (0.8 mg, 0.003 mmol) was
added at ambient temperature and the reaction was stirred for 3 h. The
solution was then poured over aqueous NaHCO3, diluted with diethyl
ether, washed with brine, dried (MgSO4), filtered, concentrated in vacuo,
and isocratically chromatographed (25% v/v diethyl ether/petroleum
ether) to give compound 67 (10.2 mg, 70% yield) as a yellow oil. Rf =
0.17 (10% v/v ethyl acetate/petroleum ether) [a]2D5 =9.8 (c=0.98 in
CH2Cl2); 1H NMR (500 MHz, CDCl3): d=7.24 (d, J=8.5 Hz, 2H), 6.85
(d, J=8.7 Hz, 2H), 5.83 (ddd, J=17.3, 10.6, 5.1 Hz, 1H), 5.25 (dt, J=
17.2, 1.6 Hz, 1H), 5.21 (brs, 1H), 5.06 (dt, J=10.6, 1.5 Hz, 1H), 4.53 (d,
J=11.7 Hz, 1H), 4.49 (d, J=11.7 Hz, 1H), 3.98–4.02 (m, 2H), 3.79 (s,
3H), 3.59 (ddt, J=11.0, 2.2, 5.0 Hz, 1H), 3.53–3.40 (m, 3H), 3.15 (s, 3H),
2.35–2.42 (m, 2H), 2.09 (dd, J=15.9, 5.1 Hz, 1H), 2.01–2.13 (m, 2H),
1.90–1.98 (m, 2H), 1.78 (dd, J=16.0, 5.2 Hz, 1H), 1.74 (ddd, J=12.4, 4.5,
3.1 Hz, 1H), 1.03 (s, 3H), 0.95 (s, 3H), 0.07 ppm (s, 9H); 13C NMR
(125 MHz, CDCl3): d=153.7, 138.4, 130.6, 129.1, 123.0, 114.2, 113.7,
104.1, 77.5, 75.5, 73.0, 72.9, 71.3, 68.9, 55.3, 47.9, 47.0, 43.1, 39.2, 36.6,
35.6, 29.7, 20.6, 15.5, 0.3 ppm; IR (thin film): n˜ =3456, 2952, 2925, 2854,
1618, 1514, 1465, 1362, 1302, 1248, 1114, 1038, 843 cmꢀ1; HRMS calcd for
C28H43O6Si: 503.2829 [MꢀCH3]; found: 503.2829.
ee) as a light yellow oil. HPLC: AD column, 230 nm, 1.0 mLminꢀ1
,
99.5:0.5 heptane/isopropanol, tr (minor)=11.124 min, tr (major)=
12.918 min; Rf =0.65 (20% ethyl acetate/petroleum ether); [a]2D4 =ꢀ26.0
(c=2.69 in CH2Cl2,); 1H NMR (400 MHz, CDCl3): d=6.37 (dd, J=10.5,
17.5 Hz, 1H), 6.21 (dd, J=1.1, 17.5 Hz, 1H), 5.81 (dd, J=1.1, 10.5 Hz,
1H), 4.03 (dt, J=9.6, 2.9 Hz, 1H), 3.61 (d, J=3.2 Hz, 1H), 3.44–3.46 (m,
2H), 2.72 (dd, J=9.6, 16.0 Hz, 1H), 2.63 (dd, J=2.7, 15.9 Hz, 1H), 0.88
(s, 3H), 0.85 (s, 9H), 0.81 (s, 3H), 0.020 (s, 3H), 0.019 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=201.0, 136.9, 128.5, 74.2, 71.9, 41.9, 38.4,
25.8, 21.8, 19.2, 18.2, ꢀ5.6, ꢀ5.7 ppm; IR (thin film) n˜ =3500, 2926, 2855,
1746, 1681, 1619, 1590, 1464, 1391, 1363, 1252, 1098, 1006, 984, 837, 776,
669 cmꢀ1
;
HRMS calcd for C15H31O3Si: 287.2042 [M+H]+; found:
287.2014.
Synthesis of compound 46: Tetramethylammonium triacetoxyborohy-
dride (2.8919 g, 10.99 mmol) was dissolved in acetic acid (5.5 mL) and
then cooled to ꢀ208C. Enone 58 (311.9 mg, 1.089 mmol) was then added
as a solution in acetone (5.5 mL) and the reaction was stirred for 17 h.
Sodium potassium tartrate (saturated aqueous solution, ꢁ100 mL) was
then added, as well as CH2Cl2 (ꢁ100 mL) and the thick mixture was
stirred for 2.5 h. The layers were then separated and the aqueous layer
was further extracted three times with CH2Cl2. The combined organic
layers were dried (MgSO4), filtered, concentrated in vacuo, and chroma-
Acknowledgements
We thank the National Institutes of Health (GM33049) and NSF for
their generous support of our programs. We also thank Amgen (HY),
Bristol–Myers Squibb (HY), NSF (CSB), and ARCS (CSB) for their gen-
erous financial support and fellowships. GD is a Stanford Graduate
Fellow. We appreciate the assistance of G. Wuitschik in the model study
of the bryostatin ring-B synthesis. Mass spectra were provided by the
Mass Spectrometry Regional Center of the University of California, San
Francisco, supported by the NIH Division of Research Resources. Palla-
dium and ruthenium salts were generously supplied by Johnson–Matthey.
tographed with
a solvent gradient (10–20% diethyl ether/petroleum
ether) to give diol 46 (215.6 mg, 69% yield, 5:1 d.r., as judged by integra-
tion of the olefin peak at 5.11 vs. 5.06 ppm for the diastereomer) as a
yellow oil. Rf =0.43 (20% v/v ethyl acetate/petroleum ether); [a]D24
=
ꢀ3.62 (c=2.98 in CH2Cl2); 1H NMR (400 MHz, CDCl3): d=5.93 (ddd,
J=5.0, 10.5, 17.2 Hz, 1H), 5.30 (dt, J=17.1, 1.7 Hz, 1H), 5.11 (dt, J=
10.5, 1.5 Hz, 1H), 4.45 (brs, 1H), 4.09 (d, J=2.9 Hz, 1H), 3.82 (dt, J=
12.0, 2.7 Hz, 1H), 3.50 (d, J=9.8 Hz, 1H), 3.46 (d, J=9.8 Hz, 1H), 3.12
(d, J=6.4 Hz, 1H), 1.72 (ddd, J=3.5, 11.0, 14.0 Hz, 1H), 1.56 (ddd, J=
1.4, 6.9, 14.0 Hz, 1H), 0.88 (s, 9H), 0.86 (s, 3H), 0.80 (s, 3H), 0.06 ppm (s,
6H); 13C NMR (100 MHz, CDCl3): d=141.1, 113.9, 76.3, 73.7, 70.5, 37.8,
37.1, 25.8, 22.3, 18.9, 18.1, ꢀ5.71, ꢀ5.69 ppm; IR (thin film): n˜ =3452,
2927, 2856, 1744, 1717, 1472, 1404, 1363, 1327, 1293, 1254, 1161, 1094,
1006, 990, 922, 837, 777, 669 cmꢀ1; elemental analysis calcd (%) for
C15H32O3Si: C 62.45, H 11.18; found: C 62.66, H 10.97.
[1] For bryostatin 1 isolation and structure determination, see: a) G. R.
Pettit, C. L. Herald, D. L. Doubek, D. L. Herald, E. Arnold, J.
5, 704; c) K. J. Hale, M. G. Hummersone, S. Manaviazar, M. Friger-
M. K. Hilinski, J. C. Horan, C. Kan, V. A. Verma in Drug Discovery
Research: New Frontiers in the Post-Genomic Era (Ed.: Z. Huang),
Wiley, New York, 2007, 127–162; e) R. Mutter, M. Wills, Bioorg.
H. Yang, G. Dong, Chem. Eur. J. 2011, 17, 9789–9805; B. M. Trost,
B. M. Trost, A. J. Frontier, O. R. Thiel, H. Yang, G. Dong, Chem.
Eur. J. 2011, 17, 9762–9776.
[2] a) D. A. Evans, P. H. Carter, E. M. Carreira, A. B. Charrette, J. A.
ces therein; for other examples of stereoselective formation of the
exocyclic enoate of ring B, including with chiral phosphonate re-
agents, see: b) M. OꢂBrien, N. H. Taylor, E. J. Thomas, Tetrahedron
Lett. 2002, 43, 5491; for cuprate additions to form enoates, see: c) A.
Baron, M. Ball, B. Bradshaw, S. Donnelly, O. Germay, P. C. Oller, N.
Kumar, N. Martin, M. OꢂBrien, H. Omori, C. Moore, E. J. Thomas,
radical additions to enoates, see: e) S. P. Munt, E. J. Thomas, J.
phosphonate additions, see: f) T. F. J. Lampe, H. M. R. Hoffmann,
Synthesis of compound 63: Alkene 62 (134.7 mg, 0.484 mmol) and alkyne
10 (49.7 mg, 0.17 mmol)[6] were dissolved in acetone (0.4 mL) in a flame-
dried microwave vial. [CpRuACHTUNTRGENNUG(MeCN)3]ACHTUTGNREN[NGUN PF6] (7.7 mg, 0.018 mmol) was
then added and the reaction was stirred at ambient temperature for 22 h.
The reaction was then concentrated in vacuo and chromatographed with
a solvent gradient (5–30% v/v diethyl ether/petroleum ether) to give 63
(17.6 mg, 18% yield, 2.4:1 d.r.), recovered alkene 62 (39.5 mg, 31% re-
covery) and recovered alkyne 10 (2.8 mg, 7% recovery). Rf =0.55 (10%
v/v ethyl acetate/petroleum ether); [a]2D4 =ꢀ3.2 (c=1.24 in CH2Cl2);
1H NMR (500 MHz, CDCl3): d=7.23 (d, J=7.7 Hz, 2H), 6.85 (d, J=
8.7 Hz, 2H), 5.83 (ddd, J=17.3, 10.5, 5.9 Hz, 1H), 5.25 (brs, 1H), 5.19
(dt, J=17.3, 1.6 Hz, 1H), 5.10 (ddd, J=10.5, 3.3, 1.5 Hz, 1H), 4.49 (d, J=
11.8 Hz, 1H), 4.46 (d, J=11.8 Hz, 1H), 4.19–4.23 (m, 1H), 3.97 (dd, J=
9.5, 6.3 Hz, 1H), 3.78–3.85 (m, 1H), 3.78 (s, 3H), 3.45–3.50 (m, 1H), 3.45
(dd, J=10.1, 5.2 Hz, 1H), 3.42 (dd, J=10.0, 4.3 Hz, 1H), 2.94 (ddd, J=
17.5, 10.0, 5.2 Hz, 1H), 2.58 (dd, J=17.3, 7.3 Hz, 1H), 2.37 (brd, J=
13.4 Hz, 1H), 2.20–2.24 (m, 2H), 1.95–2.00 (m, 3H), 1.86–1.42 (m, 8H),
1.302 (s, 3H), 1.298 (s, 3H), 0.06 ppm (s, 9H); 13C NMR (125 MHz,
CDCl3): d=212.5, 159.1, 152.5, 138.4, 130.3, 129.2, 123.8, 115.2, 113.7,
100.5, 77.4, 75.0, 72.9, 72.8, 70.9, 69.8, 68.1, 55.3, 50.6, 45.6, 45.1, 36.5,
32.2, 30.3, 25.3, 24.2, 20.3, 18.9, 0.3 ppm; IR (thin film): n˜ =2954, 2895,
2854, 1706, 1618, 1587, 1514, 1466, 1364, 1331, 1302, 1248, 1224, 1173,
Chem. Eur. J. 2011, 17, 9777 – 9788
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9787