Palladium-Catalyzed DYKAT Reactions
FULL PAPER
10 min. Butadiene monoxide 4 (16.5 g, 0.235 mol) was added and the
yellow solution stirred at RT for 12 h. The reaction was concentrated and
the orange residue purified by flash chromatography (silica gel, Et2O) to
yield 7 (49.79 g, 99.6%) as a white solid. Enantiomeric excess was deter-
mined to be 94.4% ee by chiral HPLC (Chiralpak OD, heptane/iPrOH
90:10, 1.0 mLminÀ1, tR[(R)-7] = 13.75 min and tR[(S)-7] = 16.75 min).
The spectral data agreed with that previously reported.[14a]
H2O)];[37] 1H NMR (400 MHz, D2O): d = 3.82 (dt, J=7.3, 2.0 Hz, 2H),
3.70 (dd, J=11.7, 4.1 Hz, 2H), 3.62 (dd, J=11.5, 6.4 Hz, 2H), 3.03–2.89
(m, 2H) ppm; 13C NMR (100 MHz, D2O): d = 78.1, 62.3, 61.8 ppm; IR
(NaCl, thin film); n˜ = 3314, 2924, 1543, 1412 cmÀ1; elemental analysis
calcd (%) for C6H13NO4: C 44.16, H 8.03, N 8.58; found: C 44.48, H 7.79,
N 8.50.
4-[(R,7R)-1,6-Dioxaspiro[4.5]dec-7-yl]-butan-1-ol (51); A flame-dried
G
250 mL flask with triol 50 (7.5 g, 35 mmol) in CH3CN/THF 3:2 (175 mL)
ACHTREUNG
was degassed with Ar by bubbling for 5 min. To this solution was quickly
ACHTREUNG
added solid [PdCl2(PhCN)2] (268 mg, 0.7 mmol, 2 mol%) and the reac-
A
(R,R)-6 (819 mg, 1.04 mmol, 0.75 mol%) was flushed with argon. Dry
CH2Cl2 (400 mL, degassed with argon for 30 min) was added followed by
8 (15.5 g, 137 mmol) and DBU (208 mg, 1.37 mmol, 1 mol%) and the sus-
pension stirred 5 min. Butadiene monoxide 4 (9.75 g, 139 mmol) was
added and the solution stirred at room temperature for 8 h. The reaction
was concentrated in vacuo. The orange residue was purified by flash
chromatography (silica gel, Et2O/MeOH 50:1) to yield anti-9 (22.6 g,
90%, 123 mmol) as a clear, light yellow oil. 1H NMR indicates the prod-
uct is ꢀ97% pure with minor contamination by syn-9. The minor syn-di-
astereomer syn-9 (1.06 g, 4.2%, 5.8 mmol), was also isolated at this stage.
The diastereoselectivity of the reaction was determined by GC analysis
tion was stirred at RT under Ar balloon 13 h. The resulting yellow/green
solution was concentrated and purified by flash column chromatography
(silica gel, Et2O/PE 4:1) to yield 51 (6.37 g, 85%, 29.8 mmol) as a clear,
colorless, oil. [a]2D9 = +76 (c 1.24, MeOH); Rf =0.51 (CH2Cl2/MeOH
1
10:1); H NMR (500 MHz, CDCl3): d = 3.88 (m, 2H), 3.71 (m, 1H), 3.65
(t, J=7.0 Hz, 2H), 2.04 (m, 1H), 1.94–1.81 (m, 3H), 1.72–1.35 (m, 12H)
1.20 (ddd, J=16.5, 13.0, 3.5 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3): d
= 105.8, 70.1, 66.6, 37.7, 35.7, 32.7, 32.5, 30.8, 23.6, 21.7, 20.3 ppm; IR
(thin film); n˜ = 3406, 2937, 1457, 1386, 1310, 1271, 1215, 1161, 1115,
1008, 960, 918 cmÀ1; HRMS (EI+): m/z: calcd for C12H21O3: 213.1491,
found: 213.1491 [MÀH]+. Diastereomeric excess determined by GC of
of the crude reaction mixture (Varian 3600, 100/3-10-250/2; tR
C
crude product (HP 5973 GC/MS, 100/3-10-250/2; tR
A
7.19 min tR
ACHTREUNG
1
tR(S,R) = 7.69 min; 97:3.
AHCTREUNG
CH2Cl2); Rf =0.50 (Et2O/MeOH 20:1); H NMR (300 MHz, CDCl3): d =
5.90 (ddd, J=17.4, 10.2, 7.5 Hz, 1H), 5.74 (ddd, J=17.7, 9.3, 8.7 Hz, 1H),
5.38 (d, J=10.2 Hz, 1H), 5.37 (d, J=16.8 Hz, 1H), 5.29 (d, J=10.2 Hz,
1H), 5.21 (d, J=17.4 Hz, 1H), 4.48 (t, J=8.7 Hz, 1H), 4.32 (dd, J=8.7,
8.1 Hz, 1H), 4.02 (dd, J=8.4, 7.8 Hz, 1H), 3.90 (m, 3H), 3.57 (dd, J=8.4,
4.8 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3): d = 158.5, 134.9, 132.3,
121.7, 118.9, 67.6, 62.8, 59.6, 59.2 ppm; IR (thin film): n˜ = 3418, 3085,
2985, 2912, 1732, 1644, 1480, 1417, 1336, 1253, 1064, 1030, 992, 936, 764,
706 cmÀ1; HRMS (EI+): m/z: calcd for C9H13NO3: 184.0974, found
184.0969 [M+H]+.
(+)-Broussonetine G (3); 10% Pd/C (15 mg, 0.014 mmol, 25 mol%) was
added to a vial with triol 61 (32.1 mg, 0.055 mmol). The flask was flushed
with N2, and MeOH (1 mL) was added via syringe, followed by 3 drops
concentrated HCl. A baloon of H2 was bubbled through the stirring solu-
tion 5 min, then the reaction stirred under H2 at RT for 3 h. The reaction
was filtered through a plug of Celite, the plug rinsed with MeOH
(10 mL), and the combined filtrates concentrated. Purification of the
product by ion exchange chromatography (DOWEX50W-X2 (H+ form),
gradient elution H2O then 1m aqueous NH4OH) provides 3 (18.8 mg,
95%, 0.052 mmol) as a white film. [a]2D5 = +19.3 (c 0.74, MeOH); Rf =
0.80 (CHCl3/MeOH/56% aq. NH4OH 5:1:1); 1H NMR (500 MHz,
[D5]pyridine): d = 6.95 (brs, 1H, OH), 6.78 (brs, 1H, OH), 6.30 (brs,
1H, OH), 6.01 (brs, 1H, OH), 4.95 (t, J=6.4 Hz, 1H), 4.72 (t, J=6.4 Hz,
1H), 4.28 (dd, J=10.8, 5.5 Hz, 1H), 4.24 (dd, J=10.8, 3.8 Hz, 1H), 4.11
(ddd, J=6.4, 4.8, 4.8 Hz, 1H), 3.83 (m, 4H), 3.64 (dd, J=6.5, 4.8 Hz,
1H), 2.00–1.71 (m, 6H), 1.71–1.54 (m, 7H), 1.48–1.37 (m, 4H), 1.13 (m,
1H) ppm; 13C NMR (125 MHz, [D5]pyridine): d = 105.91, 80.55, 80.31,
74.03, 70.31, 67.53, 66.77, 65.88, 63.48, 38.19, 36.73, 35.05, 33.39, 31.38,
26.85, 26.31, 24.17, 20.99 ppm; IR (thin film): n˜ = 3356, 2937, 1683, 1458,
1202 cmÀ1; HRMS (EI+): m/z: calcd for C18H33NO6: 359.2308, found:
359.2284 [M]+.
A
A
ACHTREUNG
(S,S)-6 (42 mg, 0.053 mmol, 3 mol%) was flushed with argon. Dry
CH2Cl2, 4.5 mL, (degassed with argon for 10 min) was added followed by
8 (200 mg, 1.77 mmol) and DBU (27 mg, 0.18 mmol, 10 mol%) and the
suspension stirred 5 min. Butadiene monoxide 4 (123 mg, 1.77 mmol) was
added and the solution stirred at room temperature for 6 h. The reaction
was concentrated in vacuo. The orange residue was purified by flash
chromatography (silica gel, Et2O/MeOH 50:1) to yield syn-9 (245.8 mg,
76%) as a clear, light yellow oil, the minor anti-9 diastereomer was not
isolated, but was determined to be 10% by GC (Agilent 6850 A, 100/5-
20-250/5; tR
[a]2D5
C
G
=
(500 MHz, CDCl3): d = 5.94 (ddd, J=17.6, 10.5, 7.1 Hz, 1H), 5.85 (m,
1H), 5.30 (m, 4H), 4.50–4.44 (m, 2H), 4.14 (m, 1H), 4.00 (m, 1H), 3.94
(m, 1H), 3.74 (m, 1H) ppm; 13C NMR (125 MHz, CDCl3): d = 158.2,
135.7, 132.2, 120.7, 119.2, 67.4, 62.8, 60.2, 58.7 ppm.; IR (thin film): n˜ =
3435, 3085, 2984, 2911, 1732, 1644, 1480, 1416, 1337, 1248, 1062, 1030,
994, 936, 764 cmÀ1; elemental analysis calcd (%) for C9H13NO3: C 59.00,
H 7.15, N 7.65; found: C 59.16, H 7.20, N 7.77.
Acknowledgements
We thank the NIH (GM 13598), the Eli Lilly Corporation (fellowship to
D.B.H.), and the Deutsche Forschungsgemeinschaft (fellowship to
M.J.W.) for their support of our research. We also thank Prof. Maiko Shi-
bano (Osaka University of Pharmaceutical Sciences) for NMR spectra
and donation of a sample of natural broussonetine G. Mass spectra were
provided by the Mass Spectrometry Regional Center of the University of
California/San Francisco supported by the NIH Division of Research Re-
sources.
(2R,3R,4R,5R)-2,5-Dihydroxymethyl-3,4-dihydroxypyrrolidine
[(+)-
DMDP] (1); 10% Pd/C (7.5 mg, 0.007 mmol, 5 mol%) was added to a
vial with 16a (54.3 mg, 0.14 mmol). The vial was flushed with N2, then
1 mL MeOH was added followed by two drops concentrated HCl. A
baloon of H2 was bubbled through the reaction 5 min, then the reaction
was stirred under H2 balloon 2.5 h. The reaction was filtered through a
plug of Celite and the plug washed with 23 mL MeOH. The filtrates
were combined and concentrated to yield the crude HCl salt as yellow
oil/solid. 1H NMR (400 MHz, D2O): d = 4.07 (dt, J=8.1, 4.4 Hz, 2H),
3.91 (dd, J=12.8, 3.5 Hz, 2H), 3.84 (dd, J=12.8, 5.8 Hz, 2H), 3.57–3.53
(m, 2H) ppm. Purification by ion exchange chromatrography
(DOWEX50W-X2) by dissolving in 1 mL H2O with 1 drop 10% aqueous
HCl, and gradient elution with 20 mL H2O, then 20 mL 1m NH4OH. The
NH4OH fractions were collected and concentrated to yield 1 (22 mg,
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96%) as
a
white oily solid. M.p. 112–1158C (H2O) [lit. m.p. 115–
1178C];[37] [a]2D8
=
+55.4 (c 1.25, H2O), [lit. [a]D20
=
+53.8 (c 0.32,
Chem. Eur. J. 2006, 12, 6607 – 6620
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6619