Total Synthesis of (()-Cylindrospermopsin
J. Am. Chem. Soc., Vol. 122, No. 21, 2000 5023
65.29), 64.5, (60.95, 60.89), (54.68, 54.67), 53.8, (42.54, 42.53), (38.45,
38.34), (33.35, 33.24), 25.7 (6 C), (18.2, 17.9) (2 C), (11.42, 11.40),
-4.68, -4.70, -5.04, -5.18; IR (neat) 1706, 1696, 1573, 1461, 1357,
HRMS (FAB) calcd for C37H58N3O6Si2 (MH+) 696.3864, found
696.3850.
(125.4-127.4) (10 C), 97.2, (74.5, 74.3), (68.9, 68.8), 67.9, 67.0, 56.7,
54.5, 53.5, (51.89, 51.82), (47.77, 47.69), (39.00, 38.97), 38.2, (34.28,
34.12), (27.47, 27.37), (25.7-25.6) (6 C), (17.95, 17.85) (2 C), (13.55,
13.50), (-4.5, -5.2) (4 C); IR (neat) 1758, 1594, 1355; HRMS (FAB)
calcd for C45H68N5O8Si2 (MH+) 682.4606, found 682.4603.
Formation of Aldehyde 24. A stream of ozone was introduced into
a solution of 23 (3.56 g, 5.11 mmol) in CH2Cl2 (200 mL) at -78 °C
for about 20 min until the solution turned bluish. Nitrogen was bubbled
through the solution for 10 min to purge the excess ozone. Me2S (1.50
mL, 20.5 mmol) was added, and the mixture was then stirred at -78
°C for 20 min. The solution was concentrated, and the residue was
purified by flash chromatography on silica gel (5:1 hexane/EtOAc) to
provide 2.56 g (72%) of 24 as a 1:1 mixture of diastereomers: 1H
NMR 9.77 (s, 1 × 0.5), 9.67 (s, 1 × 0.5), 7.36-7.26 (m, 5), 6.57 (s,
1 × 0.5), 6.55 (s, 1 × 0.5), 5.35-5.13 (m, 5), 4.60-4.38 (m, 1), 3.96-
3.92 (m, 6), 2.72-2.53 (m, 1), 1.95-1.52 (m, 2), 0.90 (d, 3, J ) 6.8),
Data for the benzyl methylene groups of the byproduct: 5.04 (d, 1,
J ) 12.4), 4.98 (d, 1, J ) 12.4), 4.24 (d, 1, J ) 14.8), 4.19 (d, 1, J )
14.8).
Formation of Diol 29. A solution of 28 (370 mg, 0.429 mmol) and
TBAF (1 M in THF, 900 µL, 0.90 mmol) in THF (10 mL) was stirred
at room temperature overnight. The solution was concentrated, and the
residue was purified by flash chromatography on silica gel (10:1 CH2-
Cl2/MeOH) to give 226 mg (83%) of 29 as a 1:1 mixture of
diastereomers: 1H NMR 7.44-7.22 (m, 10), 6.44 (s, 1 × 0.5), 6.42 (s,
1 × 0.5), 5.13 (s, 2), 5.05 (br s, 2), 4.56-4.48 (m, 1), 3.958 (s, 3 ×
0.5), 3.955 (s, 3 × 0.5), 3.924 (s, 3 × 0.5), 3.920 (s, 3 × 0.5), 3.96-
3.92 (m, 1), 3.77-3.67 (m, 1), 3.58-3.48 (m, 3), 2.55-2.30 (m, 1),
2.20-1.50 (m, 5), 0.94 (d, 3, J ) 6.8); 13C NMR (174.05, 173.94),
172.2, 164.8, 159.0, 151.5, (149.9, 149.8), 137.1, 135.1, 128.6-127.6
(10 C), (97.30, 97.29), (72.53, 72.36), (68.29, 68.31), (67.94, 67.91),
67.3, (56.4, 56.3), 54.7, 53.8, (51.9, 51.7), (48.1, 47.9), (39.1, 38.9),
(38.45, 38.37), (33.7, 33.5), (27.7, 27.6), (13.00, 12.93); IR (neat) 1752,
1596, 1570, 1355; HRMS (DCI/NH3) calcd for C33H40N5O8 (MH+)
634.2877, found 634.2874.
0.89 (s, 9), 0.83 (s, 9 × 0.5), 0.82 (s, 9 × 0.5), 0.15-0.05 (m, 12); 13
C
NMR (201.1, 200.7), (172.5, 172.4), (170.6, 170.5), 165.1, (159.80,
159.78), (135.9, 135.8), (128.6, 128.5) (2 C), (128.3, 128.2), (127.86,
127.82) (2 C), (97.24, 97.18), (84.1, 83.9), 83.3, (68.23, 68.15), 66.7
(br), (65.14, 65.11), 64.5, (54.8, 54.7), (53.89, 53.87), (43.9, 42.8), 38.4,
(32.8, 32.3), (25.67, 25.64) (6 C), (18.2, 17.9) (2 C), (10.0, 9.1), (-4.8,
-5.1) (2 C), (-5.1, -5.2) (2 C); IR (neat) 1709, 1595, 1574, 1358;
HRMS (DCI/NH3) calcd for C36H56N3O7Si2 (MH+) 698.3657, found
698.3698.
Formation of Ketone 30. Activated MnO2 (200 mg, 2.00 mmol)
was added to a solution of 29 (160 mg, 0.253 mmol) in 6 mL of CH2-
Cl2 at room temperature. The reaction mixture was stirred at room
temperature for 1 h and filtered through a plug of Celite. The filtrate
was concentrated and purified on silica gel (1:1 hexane/EtOAc, EtOAc)
to give 138 mg (87%) of 30 as an oil: 1H NMR 7.37-7.20 (m, 10),
6.89 (s, 1), 5.13 (s, 2), 4.97 (s, 2), 3.99 (s, 3), 3.98 (s, 3), 3.99-3.97
(m, 1), 3.96-3.90 (m, 1), 3.82-3.74 (m, 1), 3.58-3.55 (m, 1), 3.55
(ddd, 1, J ) 10.8, 8.0, 5.6), 3.27 (br t, 2, J ) 7.0, 7.0, 1.2), 2.78-2.69
(m, 1), 2.26-2.17 (m, 1), 1.96 (ddd, 1, J ) 13.0, 11.0, 3.1), 1.82 (ddd,
1, J ) 13.0, 3.2, 3.2), 1.71-1.64 (m, 1), 0.95 (d, 3, J ) 6.7); 1H NMR
(C6D6) 7.40-7.00 (m, 11), 5.33 (s, 2), 5.02 (d, 1, J ) 12.2), 4.96 (d,
1, J ) 12.2), 3.78 (s, 3), 3.50 (s, 3), 3.55-3.40 (m, 2), 3.20 (dd, 1, J
) 10.0, 8.0), 3.18-3.12 (m, 1), 2.99 (dd, 1, J ) 10.0, 5.6), 2.98-2.91
(m, 1), 2.84 (ddd, 1, J ) 12.8, 7.2, 5.6), 2.38-2.32 (m, 2), 1.5-1.2
(m, 3), 0.34 (d, 3, J ) 7.3); 13C NMR 200.4, 172.9, 165.6, 161.5, 158.9,
151.5, 149.2, 137.1, 135.2, 128.6 (2 C), 128.49, 128.47, 128.1 (2 C),
127.9 (2 C), 127.4 (2 C), 99.1, 68.3, 68.1, 67.2, 56.5, 55.1, 54.3, 51.4,
47.8, 38.5, 38.1, 35.2, 25.8, 12.9; IR (neat) 1752, 1707, 1592, 1566,
1387, 1357, 1254; HRMS (FAB) calcd for C33H38N5O8 (MH+)
632.2720, found 632.2718.
Acetate 31. To a solution of 30 (138 mg, 0.218 mmol) in pyridine
(5 mL) was added acetic anhydride (62 µL, 0.656 mmol). The mixture
was stirred at room temperature overnight and concentrated under
reduced pressure. Purification of the residue on silica gel (1:1 hexane/
EtOAc) provided 130 mg of a 5:1 mixture of acetate 31 and enol acetate
of 31 (87%) as an oil that was used for the next step.
The data for 31 determined from the mixture: 1H NMR 7.36-7.21
(m, 10), 6.90 (s, 1), 5.15 (br s, 1), 5.13 (s, 2), 4.99 (s, 2), 3.99 (s, 3),
3.98 (s, 3), 3.95-3.92 (m, 1), 3.71-3.63 (m, 1), 3.56 (dd, 1, J ) 10.0,
5.5), 3.48 (ddd, 1, J ) 11.0, 8.8, 6.1), 3.27 (dd, 2, J ) 7.0, 7.0), 2.71
(dddd, 1, J ) 13.4, 7.0, 7.0, 6.7), 2.22 (dddd, 1, J ) 13.4, 8.0, 7.0,
7.0), 2.08 (s, 3), 1.96 (ddd, 1, J ) 14.6, 3.7, 3.7), 1.88 (ddd, 1, J )
14.6, 11.0, 3.1), 1.80 (ddq, 1, J ) 11.0, 3.7, 6.8), 0.88 (d, 3, J ) 6.8);
13C NMR 200.2, 172.9, 170.1, 165.6, 161.4, 158.8, 151.5, 148.8, 137.1,
135.1, 128.6-127.5 (10 C), 99.1, 70.4, 68.4, 67.2, 57.1, 55.1, 54.3,
51.9, 47.9, 37.0, 34.9, 34.8, 25.8, 21.0, 12.6; IR (neat) 1752, 1798,
1590, 1566, 1387, 1358; HRMS (DCI/NH3) calcd for C35H40N5O9
(MH+) 674.2826, found 674.2807.
Benzylamine 25. To a solution of 24 (2.56 g, 3.67 mmol) in toluene
(40 mL) containing Na2SO4 (5 g) was added benzylamine (2.0 mL,
18.4 mmol) and HOAc (1.3 mL, 22.0 mmol) under nitrogen. The
solution was stirred at room temperature for 2 h. MeOH (50 mL) and
NaCNBH3 (1.20 g, 18.4 mmol) were then added and the resulting
mixture was stirred at room temperature for another 2 h. Saturated
NaHCO3 solution (60 mL) was added, and the solution was extracted
with EtOAc (3 × 80 mL). The combined organic layers were washed
with brine (100 mL), dried (Na2SO4), and concentrated. Flash chro-
matography of the residue on silica gel (3:1 hexane/EtOAc) gave 1.97
g (68%) of 25 as a 1:1 mixture of diastereomers: 1H NMR 7.40-7.23
(m, 10), 6.65 (s, 1 × 0.5), 6.47 (s, 1 × 0.5), 5.30-5.13 (m, 4), 4.34-
4.16 (m, 2), 3.97 (s, 3), 3.94 (s, 3), 3.82-3.60 (m, 2), 3.30-3.08 (m,
1), 2.94-2.82 (m, 1), 2.20-2.07 (m, 1), 1.97-1.80 (m, 1), 1.75-1.60
(m, 1), 1.00-0.80 (m, 18), 0.20-0.00 (m, 12); 13C NMR 172.4, (171.11,
171.06), (165.1, 165.0), (140.6), 139.0, (136.49, 136.46), (128.6-126.6),
(10 C), 97.3, (85.7, 85.6), 81.3, 67.5, (65.31, 65.25), 64.6, (58.6, 58.5),
51.2, 51.1, 49.5, 42.5, 35.3, 33.1, 27.4, (25.71, 25.68) (6 C), (18.2,
18.0) (2 C), (11.6, 11.5), (-4.7, -4.9) (2 C), (-5.0, -5.1) (2 C); IR
(neat) 3320, 1946, 1700, 1574, HRMS (FAB) calcd for C43H65N4O6Si2
(MH+) 789.4443, found 789.4475.
Bis-Cbz-Protected Guanidine 28. A suspension of 25 (1.97 g, 2.49
mmol) and 5% Pd/C (1.00 g) in MeOH (70 mL) was stirred at room
temperature under H2 (1 atm) overnight. The Pd catalyst was filtered
off, and the filtrate was concentrated to provide 1.02 g of crude 26.
To a solution of crude 26 (1.02 g) in toluene (80 mL) was added
slowly a solution of CNBr (170 mg, 1.61 mmol) in toluene (40 mL)
over 3 h. The mixture was stirred at room temperature for 2 h and
concentrated to provide crude 27.
To a solution of crude 27 in THF (20 mL) was added excess NaH
(400 mg, 9.60 mmol) and CbzCl (914 µL, 6.40 mmol) at 0 °C. The
mixture was stirred at room temperature for 8 h. Unreacted NaH was
filtered off and quenched carefully with 2-propanol. The filtrate was
concentrated and purified by flash chromatography on silica gel (10:1
hexane/EtOAc, then 2:1 hexane/EtOAc) to give 880 mg (45% from
25) of 28 as a 1:1 mixture of diastereomers followed by 190 mg (10%)
of a byproduct with one Cbz group and one benzyl group on the
guanidine.
The data for 28: 1H NMR 7.45-7.30 (m, 10), 6.58 (s, 1 × 0.5),
6.56 (s, 1 × 0.5), 5.19-5.05 (m, 4), 4.65 (dd, 1 × 0.5, J ) 7.2, 3.6),
4.64 (dd, 1 × 0.5, J ) 7.2, 3.6), 3.99 (s, 3 × 0.5), 3.98 (s, 3), 3.97 (s,
3 × 0.5), 3.94-3.91 (m, 1), 3.70-3.40 (m, 4), 2.62-2.54 (m, 1), 2.40-
2.30 (m, 1), 2.22-2.10 (m, 1), 2.05-1.54 (m, 4), 0.95 (s, 9), 0.94 (s,
9), 0.91 (d, 3, J ) 6.8), 0.11 (s, 6 × 0.5), 0.09 (s, 6 × 0.5), 0.084 (s,
6 × 0.5), 0.075 (s, 6 × 0.5); 13C NMR (175.57, 175.46), (172.00,
171.97), (164.69, 164.65), 158.8, 151.4, (149.15, 149.12), 137.1, 135.1,
The data for the enol acetate were determined from the mixture:
1H NMR 7.36-7.20 (m, 10), 6.72 (dd, 1, J ) 7.7, 7.3), 6.24 (s, 1),
5.15 (br s, 1), 5.14 (s, 2), 5.04 (s, 2), 4.06 (m, 1), 3.94 (s, 6), 3.67 (m,
1), 3.54-3.44 (m, 2), 3.26 (ddd, 1, J ) 14.4, 7.7, 4.8), 2.84 (ddd, 1, J
) 14.4, 7.3, 7.0), 2.25 (s, 3), 2.07 (s, 3), 1.94 (ddd, 1, J ) 14.8, 4.0,
4.0), 1.86 (ddd, 1, J ) 14.8, 10.4, 3.2), 1.78 (ddq, 1, J ) 10.4, 3.1,
6.7), 0.88 (d, 3, J ) 6.7); 13C NMR 120.9, 96.3, 68.7, 68.1, 67.5, 56.9,
54.9, 54.3, 51.1, 48.7, 37.4, 35.0, 29.5, 21.0, 20.6, 12.7 (the carbons