Pd-Catalyzed Asymmetric Synthesis of (-)-Anatoxin-a
J. Am. Chem. Soc., Vol. 121, No. 13, 1999 3063
acetate (2.33 g, 14.0 mmol) in 8 mL of acetic acid was stirred at reflux
overnight. After cooling, the reaction was cautiously added to a saturated
sodium bicarbonate solution and extracted with ether. The organic phase
was dried (MgSO4) and concentrated. Flash chromatography (0-30%
EtOAc in hexanes) yielded 2.13 g (73%) of 16 and 0.43 g (15%) of 17
as white solids.
Characterization Data for 16. Rf 0.50 (50% EtOAc in hexanes),
mp 133-135 °C. IR (neat film from CDCl3): 3278, 1741, 1238, 1160,
1047 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.75 (d, J ) 8.2 Hz, 2 H),
7.30 (d, J ) 8.0 Hz, 2 H), 5.43 (m, 1 H), 5.11 (d, J ) 7.4 Hz, 2 H),
2.38 (m, 1 H), 2.42 (s, 3 H), 2.36 (m, 1 H), 2.08 (s, 3 H), 2.03 (m, 1
H), 1.71 (br m, 4 H). 13C NMR (75.46 MHz, CDCl3): δ 171.6, 145.1,
139.0, 133.1, 131.4, 128.7, 126.7, 72.8, 53.4, 37.3, 32.0, 31.0, 26.1,
23.0, 22.3. Anal. Calcd for C17H22BrNO4S: C, 49.09; H, 5.33. Found:
C, 49.26; H, 5.21.
Characterization Data for 17. Rf 0.63 (50% EtOAc in hexanes),
mp 152-153 °C. IR (neat): 3279, 1741, 1445, 1318, 1236, 1160, 1094,
1047 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.75 (d, J ) 8.2 Hz, 2 H),
7.32 (d, J ) 8.5 Hz, 2 H), 6.16 (app t, J ) 8.7 Hz, 1 H), 5.41 (m, 1 H),
4.54 (d, J ) 8.0 Hz, 1 H), 3.21 (m, 1 H), 2.43 (s, 3 H), 2.10 (s, 3 H),
1.75 (br m, 5 H), 1.42 (m, 1 H). 13C NMR (75.46 MHz, CDCl3): δ
171.6, 145.2, 139.5, 133.8, 131.5, 128.6, 125.3, 71.8, 56.1, 38.7, 34.0,
30.2, 28.0, 23.0, 22.3. Anal. Calcd for C17H22BrNO4S: C, 49.09; H,
5.33. Found: C, 49.12; H, 5.51.
Preparation of cis- and trans-1-5-(N-Tosyl-N-boc-imido)-8-
acetoxy-(E)-cyclooctene (14). A crude 5:1 mixture of 16 and 17
obtained from a thermal electrocyclic ring opening of 2.0 g (3.72 mmol)
of a 3.5:1 mixture of exo-13 and endo-13 (vide supra) was dissolved
in CH2Cl2 (20 mL). Triethylamine (1.04 mL, 7.44 mmol), DMAP (128
mg, 1.05 mmol), and di-tert-butyl-dicarbonate (1.62 g, 7.44 mmol) were
added, and the mixture was stirred at room temperature under nitrogen
for 4 h. Evaporation of the solvent and flash chromatography (0-40%
EtOAc in hexanes) yielded 1.38 g (72%) of trans-14 and 288 mg (15%)
of cis-14 as white solids.
Preparation of Methyl cis-5-(N-Tosyl-N-boc)-8-acetoxy-1-cyclo-
octenyl Carboxylate (15a). A stainless steel autoclave was charged
with a solution of cis-14 (1 g, 1.94 mmol), Pd(PPh3)4 (112 mg, 0.097
mmol), triethylamine (405 µL, 2.90 mmol), and 1.66 mL of methanol
in 6 mL of DMPU. The autoclave was purged and pressurized with
CO at 600 psi. After the solution was stirred at 100 °C for 14 h, the
pressure was released, and the reaction mixture was diluted with water
and extracted three times with ether. The organic phases were combined,
dried (MgSO4), and concentrated in vacuo. Flash chromatography (0-
30% EtOAc in hexanes) yielded 671 mg (70%) of a white solid, mp
62-64 °C, Rf 0.32 (30% EtOAc in hexanes). IR (neat film from
1
CDCl3): 2981, 2953, 1732, 1360, 1235, 1154, 673 cm-1. H NMR
(300 MHz, CDCl3): δ 7.72 (d, J ) 8.5 Hz, 2 H), 7.29 (d, J ) 8.0 Hz,
2 H), 6.99 (dd, J ) 10.2 Hz, J ) 8.0 Hz, 1 H), 5.91 (dd, J ) 7.8 Hz,
J ) 3.3 Hz, 1 H), 4.39 (m, 1 H), 3.75 (s, 3 H), 2.86 (m, 1 H), 2.42 (s,
3 H), 2.37 (m, 2 H), 2.15 (m, 1 H), 2.02 (s, 3 H), 1.83 (m, 4 H), 1.32
(s, 9 H). 13C NMR (75.46 MHz, CDCl3): δ 171.6, 167.9,152.3, 145.7,
144.6, 139.4, 134.4, 130.9, 129.2, 85.9, 70.5, 60.4, 53.5, 34.3, 33.2,
32.5, 29.3, 25.8, 23.0, 22.4. Anal. Calcd for C24H33NO8S: C, 58.17;
H, 6.71. Found: C, 58.18; H, 6.90.
Preparation of Methyl cis-5-(N-Tosyl-N-boc-imido)-8-methoxy-
carbonyl-1-cyclooctenyl Carboxylate (15b). To a solution of 15a (287
mg, 0.580 mmol) in 2.4 mL of anhydrous methanol was added 76 mg
(0.551 mmol) of potassium carbonate. After 20 min, the reaction
mixture was filtered through a plug of silica gel, and the solvent was
removed in vacuo, yielding 254 mg (quantitative) of the desired alcohol
as a white solid. IR (neat film from CDCl3): 3526, 1732, 1694, 1644,
1598, 1435, 1360 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.75 (d, J )
8.3 Hz, 2 H), 7.30 (d, J ) 8.2 Hz, 2 H), 7.04 (app t, J ) 8.2 Hz, 1 H),
4.78 (m, 1 H), 4.30 (m, 1 H), 3.85 (d, J ) 10.7 Hz, 1 H), 3.76 (s, 3 H),
2.44 (s, 3 H), 2.35 (m, 2 H), 2.13 (m, 1 H), 1.98 (m, 1 H), 1.75 (m, 4
H), 1.34 (s, 9 H). 13C NMR (75.46 MHz, CDCl3): δ 162.2, 145.8,
139.3, 137.4, 132.9, 128.1, 124.5, 122.8, 79.6, 62.7, 55.1, 47.0, 30.5,
30.1, 28.7, 23.1, 20.9, 16.8.
To a solution of the above alcohol (245 mg, 0.56 mmol) in freshly
distilled THF at -78 °C was added dropwise 350 µL of n-butyllithium
(1.6 M, 0.56 mmol) in hexanes. After 30 s, 87 µL (1.12 mmol) of
methyl chloroformate was added rapidly, and the reaction mixture was
allowed to reach ambient temperature. Evaporation of the solvent
followed by flash chromatography (0-30% EtOAc in hexanes) gave
253 mg (91%) of a white solid. IR (neat film from CDCl3): 1732,
Characterization Data for trans-14. Mp 138-140 °C. IR (neat film
1
from CDCl3): 1728, 1357, 1281, 1237, 1154, 1089, 1047 cm-1. H
NMR (300 MHz, CDCl3): δ 7.75 (d, J ) 8.4 Hz, 2 H), 7.30 (d, J )
8.1 Hz, 2 H), 6.15 (dd, J ) 3.6 Hz, J ) 3.0 Hz, 1 H), 5.41 (d, J ) 10.4
Hz, 1 H), 4.50 (m, 1 H), 2.48 (m, 1 H), 2.43 (s, 3 H), 2.12 (s, 3 H),
1.91 (m, 2 H), 1.81 (m, 3 H), 1.36 (s, 9 H). 13C NMR (75.46 MHz,
CDCl3): δ 169.7, 150.6, 144.0, 137.6, 130.6, 129.3, 127.6, 126.2, 84.3,
72.1, 57.2, 33.2, 32.8, 31.8, 27.9, 25.7, 21.6, 20.9. Anal. Calcd for
C22H20BrNO6S: C, 51.16; H, 3.90. Found: C, 51.39; H, 5.78.
Characterization Data for cis-14. Mp 144-146 °C. IR (neat):
1732, 1455, 1360, 1235, 1151, 1089, 1046 cm-1. 1H NMR (300 MHz,
CDCl3): δ 7.74 (d, J ) 8.5 Hz, 2 H), 7.29 (d, J ) 8.0 Hz, 2 H), 6.23
(app t, J ) 8.7 Hz, 1 H), 5.59 (m, 1 H), 4.35 (m, 1 H), 2.43 (s, 3 H),
2.33 (m, 2 H), 2.11 (s, 3 H), 2.05 (m, 1 H), 1.85 (m, 5 H), 1.34 (s, 9
H). 13C NMR (75.46 MHz, CDCl3): δ 171.6, 152.3, 145.7, 139.3, 134.1,
130.9, 129.2, 125.3, 86.0, 71.5, 61.0, 36.7, 34.1, 30.6, 29.4, 29.0, 23.0,
22.3. Anal. Calcd for C22H20BrNO6S: C, 51.16; H, 5.90. Found: C,
51.42; H, 6.04.
Conversion of trans-14 to cis-14. Potassium carbonate (0.739 g,
5.35 mmol) was added to 1.38 g (2.67 mmol) of trans-14 in methanol
(40 mL). After 1 h at room temperature, the reaction mixture was
filtered through a plug of silica gel, and the solvent was removed in
vacuo, yielding 1.27 g (quantitative) of the intermediate alcohol. IR
(KBr): 1727, 1670, 1572, 1406, 1350, 1153, 1088 cm-1. 1H NMR (300
MHz, CDCl3): δ 7.75 (d, J ) 8.0 Hz, 2 H), 7.30 (d, J ) 8.5 Hz, 2 H),
6.14 (m, 1 H), 5.59 (m, 1 H), 4.50 (m, 2 H), 2.43 (s, 3 H), 2.37-2.11
(m, 2 H), 1.96-1.69 (m, 6 H), 1.34 (s, 9 H). 13C NMR (75.46 MHz,
CDCl3): δ 145.9, 139.6, 132.6, 127.4, 124.3, 124.1, 122.5, 79.1, 64.7,
52.3, 29.4, 28.5, 28.0, 21.9, 20.0, 15.3. The alcohol was dissolved in
50 mL of anhydrous benzene, and triphenylphosphine (2.10 g, 8.01
mmol) and acetic acid (0.459 mL, 8.01 mmol) were added at room
temperature. To the resulting mixture was added dropwise 1.03 mL
(5.34 mmol) of diisopropyl azodicarboxylate, and the solution was
stirred at ambient temperature for 3 h. Evaporation of solvent and flash
chromatography (0-30% EtOAc in hexanes) yielded another 1.25 g
of cis-14 (overall yield from exo-13 and endo-13, 80%). The same
protocol could be used to convert cis-14 to trans-14.
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1650, 1598, 1442, 1360 cm-1. H NMR (300 MHz, CDCl3): δ 7.72
(d, J ) 8.3 Hz, 2 H), 7.29 (d, J ) 8.1 Hz, 2 H), 7.06 (dd, J ) 10.3 Hz,
J ) 8.1 Hz, 1 H), 4.40 (m, 1 H), 3.77 (s, 3 H), 3.76 (s, 3 H), 2.88 (m,
1 H), 2.43 (s, 3 H), 2.31 (m, 3 H), 1.85 (m, 4 H), 1.33 (s, 9 H). 13C
NMR (75.46 MHz, CDCl3): δ 161.1, 150.2, 145.8, 139.3, 138.9, 132.9,
127.5, 124.5, 122.8, 79.6, 67.9, 53.9, 50.0, 47.3, 28.0, 27.1, 26.1, 23.1,
19.6, 16.8.
To a solution of 253 mg (0.519 mmol) of the above carbonate in
0.66 mL of CH2Cl2 was added 0.33 mL of TFA. After 1 h, the solvent
was evaporated, and the product was purified by flash chromatography
(0-30% EtOAc in hexanes), yielding 203 mg (95%) of a white solid,
mp 43-44 °C. IR (neat film from CDCl3): 3568, 3286, 1749, 1713,
1442 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.71 (d, J ) 8.2 Hz, 2 H),
7.29 (d, J ) 8.2 Hz, 2 H), 6.96 (dd, J ) 10.1 Hz, J ) 8.0 Hz, 1 H),
5.71 (dd, J ) 6.6 Hz, J ) 3.3 Hz, 1 H), 4.78 (d, J ) 8.5 Hz, 1 H), 3.76
(s, 3 H), 3.74 (s, 3 H), 3.27 (m, 1 H), 3.22 (m, 1 H), 2.79 (m, 1 H),
2.42 (s, 3 H), 2.15 (m, 1 H), 2.02 (m, 1 H), 1.90-1.50 (m, 4 H). 13C
NMR (75.46 MHz, CDCl3): δ 161.3, 150.0, 139.0, 138.7, 133.2, 127.3,
125.0, 122.1, 68.1, 50.1, 48.5, 47.4, 30.5, 26.1, 26.0, 18.6, 16.7. Anal.
Calcd for C19H25NO7S: C, 55.46; H, 6.12. Found: C, 55.62; H, 6.34.
Preparation of 9-Tosyl-9-aza-1-methoxycarbonylbicyclo[4.2.1]-
non-1-ene (22). To a neat mixture of 4.6 mg (0.009 mmol, 7.5 mol %)
of S,S-24 and 3.1 mg (0.003 mmol, 2.5 mol %) of Pd2(dba)3CHCl3
was added 1.2 mL of freshly distilled CH2Cl2 (thoroughly degassed by
bubbling nitrogen through it for at least 0.5 h). Note: Failure to degas
thoroughly might lead to irreproducible results. Degassing by applying
freeze-pump-thaw cycles or bubbling nitrogen through the solVent
should be done eVen though it is has been freshly distilled. After 20
min, the temperature was lowered to 0 °C, and a solution of 15b (50
mg, 0.121 mmol) in thoroughly degassed CH2Cl2 (0.7 mL) was added.