Synthesis of (+)- and (-)-Ferruginine from L-Glutamic Acid
J . Org. Chem., Vol. 61, No. 1, 1996 321
15 min at -78 °C, at which time a solution of hydroxy ester
33 (1.47 g, 3.63 mmol) in CH2Cl2 (9.4 mL) was added at 0.84
mL/min. The reaction mixture was stirred for 1.25 h, keeping
the temperature at -78 °C, Et3N (1.47 g, 14.5 mmol) was
added dropwise, and stirring was continued for 10 min at -78
°C and for 1.5 h while allowing it to reach rt. The reaction
mixture was washed with cold 1 M KH2PO4 (100 mL), the
aqueous layer was extracted (3 × 100 mL) with CH2Cl2, the
combined organic phase was washed with saturated NaHCO3,
dried, filtered, and evaporated, and the 1.57 g of crude residue
was chromatographed (b, 7/3 to 1/1 Hex/EtOAc) to afford keto
ester 34 (1.24 g, 85%) as a 7/3 mixture of diastereomers: IR
(36). A solution of keto acids 31 (580 mg, 1.67 mmol) in 1,2-
DCE (5.0 mL) was added at 0.39 mL/min to a solution of oxalyl
chloride (291 mg, 2.29 mmol) in 1,2-DCE (9.0 mL) cooled at
-12 °C. The solution was stirred for 3 h, allowing it to reach
0 °C, 1,2-DCE (20 mL) was added, and the solution was
warmed to rt over a period of 5 min. Toluene (11 mL) was
added, the solution was immersed in a preheated bath (60 °C)
and stirred for 17 h under an Ar atmosphere, the mixture was
allowed to cool to rt and then washed with saturated NaHCO3
(93 mL), and the aqueous washing was extracted with CH2-
Cl2 (2 × 50 mL). The combined organic phase was washed
with saturated NaCl (50 mL), dried, filtered, and evaporated
to give a light brown oil (620 mg) which was chromatographed
(b, 7/3 Hex/EtOAc) to afford bicyclic ketones 35 (310 mg, 62%)-
and 36 (140 mg, 27%).
1
1720 cm-1; H NMR δ 7.27 (m, 5H), 3.98 (d, J ) 13.7, 0.7 H),
3.85 and 3.75 (2d, J ) 13.8, 2 × 0.3H), 3.70 (s, 3 × 0.7H), 3.69
(d, 0.7H, overlap) 3.64 (s, 3 × 0.3H), 3.24 (m, 0.7 and 2 × 0.3H),
3.09 (m, 0.7H), 2.61 (m, 0.7H), 2.40 (m, 2 and 0.3H), 2.11 (s,
3H), 2.20-1.77(m, 6H), 1.35 (s, 9 × 0.3H), 1.29 (s, 9 × 0.7H);
13C NMR δ 208.1 and 207.8 (0, 1C), 175.0 and 174.7 (0, 1C),
173.4 (0), 139.1 and 138.4 (0, 1C), 129.4 and 129.0 (1, 2C), 128.0
(1, 2C), 127.0 and 126.8 (1, 1C), 80.1 and 79.7 (0, 1C), 67.3,
67.0, and 66.5 (1, 2C), 59.2 and 59.1 (2, 1C), 51.4 and 51.3 (3,
1C), 48.7 and 48.5 (1, 1C) 41.8 and 41.6 (2, 1C), 29.8 and 28.0
(3, 1C), 28.7 and 28.6 (2, 1C), 27.8 (3, 3C), 27.4 and 27.0 (2,
1C), 23.5 and 20.4.(2, 1C). Anal. Calcd for C23H33NO5: C, 68.5;
H, 8.2; N, 3.5. Found: C, 68.5; H, 8.4; N, 3.8.
35: mp 69 °C; [R]21 +29.2° (c 1.15, CHCl3); IR 1730, 1705
D
cm-1; H NMR δ 7.26 (m, 5H), 3.55 (m, 1H, overlap), 3.54 (s,
1
3H), 3.51 (d, J ) 13.4, 1H), 3.49 (m, 1H, overlap), 3.37 (d, J )
13.4, 1H), 3.16 (ddd, J ) 12.3, 4.8, 2.6, 1H), 2.44 (m, 1H), 2.10
(s, 3H), 2.06 (m, 2H), 1.93 (m, 1H), 1.66 (m, 1H), 1.54 (m, 2H);
13C NMR δ 209.3 (0), 173.7 (0), 139.4 (0), 128.5 (1, 2C), 127.9
(1, 2C), 126.8 (1), 62.1 (1), 61.1 (1), 58.0 (2), 52.6 (1), 51.3 (3),
45.8 (1), 28.4 (3), 25.7 (2), 22.9 (2), 19.3 (2). Anal. Calcd for
C18H23NO3: C, 71.7; H, 7.7; N, 4.7. Found: C, 71.5; H, 7.8; N,
4.5.
36: mp 113 °C, [R]21 +34.6° (c 1.00, CHCl3); IR 1730, 1705
(2S,5R,1′R/S)-1-Ben zyl-5-[1′-(m eth oxyca r bon yl)-3′-(2′′-
m eth yl-1′′,3′′-d ioxola n -2′′-yl)p r op yl]p r olin e ter t-Bu tyl Es-
ter (30). To a degassed solution of vinylogous carbamate 10
(6.49 g, 14.6 mmol) in MeOH (200 mL) was added 10% Pd/C
(1.33 g), and the resulting suspension was hydrogenated (50
psi) for 20 h. The solution was filtered (Celite), the filter cake
was washed with warm MeOH (200 mL) and CH2Cl2 (200 mL),
and the combined filtrate was evaporated to leave a residue
which was dissolved in CH3CN (50 mL). To this solution, were
added calcined K2CO3 (6.01 g, 43.5 mmol) and BnBr (1.99 mL,
2.86 g, 16.7 mmol), and the resulting suspension was stirred
at rt overnight. The reaction mixture was poured onto H2O
(250 mL) and extracted with CH2Cl2 (3 × 250 mL), and the
combined organic solution was dried, filtered, evaporated, and
chromatographed (b, 85/15 Hex/EtOAc) to give the ketal esters
31 (5.36 g, 7/3 mixture of diastereomers by 1H NMR ratio, 82%)
D
cm-1; H NMR δ 7.31 (m, 5H), 3.64 (s, 3H) 3.63 (s, 2H), 3.48
1
(m, 2H), 2.85 (m, 2H), 2.07 (s, 3H), 1.97-1.78 (m, 4H), 1.61-
1.45 (2m, 2H); 13C NMR 8,9 δ 286.8 (0), 173.8 (0), 139.2 (0),
128.4 (1, 2C), 128.3 (1, 2C), 127.0 (1), 60.7 (1), 59.9 (1), 56.2
(1), 52.4 (1), 51.6 (3), 44.4 (1), 28.4 (3), 24.1 (2), 23.7 (2), 20.9
(2). Anal. Calcd for C18H23NO3: C, 71.7; H, 7.7; N, 4.7.
Found: C, 71.7; H, 7.8; N, 4.8.
(1R,2S,4S,5S)-4-Acetyl-8-(ter t-bu toxycar bon yl)-2-(m eth -
oxyca r bon yl)-8-a za bicyclo[3.2.1] octa n e (37). To a solu-
tion of 35 (330 mg, 1.10 mmol) in MeOH (13 mL) was added
(BOC)2O (960 mg, 4.40 mmol) followed by 10% Pd/C (70 mg),
and the resulting suspension was hydrogenated (50 psi, rt) for
3.5 h. The reaction mixture was filtered, the insoluble
material was thoroughly washed with MeOH and CH2Cl2, and
the combined filtrates were evaporated. The residue was
diluted with ether, washed with saturated NaHCO3 and
saturated NaCl, dried, and evaporated, leaving an oil which
was chromatographed (b, 7/3 Hex/EtOAc) to afford N-BOC
as a a clear oil: IR (neat) 1705 cm-1 1H NMR δ 7.40-7.20
;
(m, 5H), 4.06 (d, J ) 13, 1H), 3.89 (m, 4H), 3.72 (s, 3 × 0.7H),
3.68 (d, J ) 13, 1H), 3.64 (s, 3 × 0.3H), 3.24 (m, 1H), 3.08 (m,
1H) 2.67 and 2.45 (2m, 1H) 2.05-1.40 (m, 8H), 1.35 (s, 3H),
1.24 (s, 9H); 13C NMR δ 174.9, 173.5, 139.3, 138.6, 129.4, 128.9,
128.0, 126.9, 126.8, 109.8, 109.7, 79.8, 67.6, 67.2, 67.0, 66.7,
64.6, 64.5, 59.5, 59.2 51.4, 51.3, 49.9, 49.5, 37.1, 37.0, 28.8,
28.7, 27.9, 27.4, 27.3, 24.4, 23.8, 23.6, 21.5. Anal. Calcd for
C25H37NO6: C, 67.1; H, 8.3; N, 3.1. Found: C, 67.4; H, 8.5; N,
2.7.
carbamates 37 (310 mg, 91%) as a clear oil: [R]22 +107.2° (c
D
1.00, CHCl3); IR 1725, 1685 cm-1; H NMR δ (rotamers) 4.63
1
and 4.42 (2m, 2H), 3.70 (s, 3H), 3.32 (m, 1H), 2.55 (m, 1H),
2.19 (s, 3H), 1.92-1.82 (m, 4H), 1.63 (m, 2H), 1.46 (s, 9H); 13
C
NMR δ (rotamers) 208.2 (0), 173.5 and 173.0 (0, 1C), 152.2
(0), 79.4 (0), 54.7, 53.5, 53.3, 50.0, 44.5 and 44.1 (1, 4C), 51.7
(3), 28.7 and 28.0 (2, 1C), 28.3 (3), 28.1 (3, 3C), 24.1 and 23.4
(2, 1C), 19.5 (2). Anal. Calcd for C16H25NO5: C, 61.7; H, 8.1;
N, 4.1. Found: C, 61.4; H, 8.1; N, 4.4.
(1R,2R,4S,5S)-4-Acetyl-8-(ter t-bu toxycar bon yl)-2-(m eth -
oxyca r bon yl)-8-a za bicyclo[3.2.1] octa n e (38). Using the
procedure described above, N-Bn bicycle 36 (330 mg, 1.10
(2S,5R,1′R/S)-1-Ben zyl-5-[1′-(m eth oxyca r bon yl)-4′-oxo-
p en tyl]p r olin e (31). F r om 30. A solution of ester ketals
30 (5.3 g, 11.8 mmol) in i-PrOH (50 mL), H2O (50 mL) and
glacial acetic acid (10 mL) was refluxed for 7.5 h, cooled to rt,
poured into 1.5 M KH2PO4 (300 mL), and extracted with CHCl3
(3 × 300 mL). The combined organic phase was dried, filtered,
evaporated, and chromatographed (b, 15-35% iPrOH/CH2Cl2)
to give keto acids 31 (3.94 g, 96%).
mmol) gave the related N-BOC carbamate 38 (330 mg, 97%):
1
[R]22 +44.0° (c 1.01, CHCl3); IR 1730, 1690 cm-1; H NMR δ
D
(rotamers) 4.48 and 4.39 (2m, 2H), 3.70 (s, 3H), 2.82 (m, 2H),
2.18 (s, 3H), 2.00 (m, 4H), 1.68 (m, 1H), 1.50 (m, 1H), 1.50 (s,
9H); 13C NMR δ (rotamers) 207.3 (0), 172.6 (0), 152.8 (0), 79.9
(0), 55.0, 54.5, 54.0, 52.2, 51.2, 44.2 and 43.4 (1, 4C), 51.6 (3),
28.4, 28.3, 28.2 and 28.1 (3, 4C), 25.6, 25.0, 24.2 and 20.8 (2,
3C). Anal. Calcd for C16H25NO5: C, 61.7; H, 8.1; N, 4.1.
Found: C, 61.9; H, 8.1; N, 4.4.
From 34: Using the procedure described above, keto esters
34 (1.95 g, 4.84 mmol) provided keto acids 31 (1.42 g, 85%):
IR 3200, 1760, 1725 cm-1 1H NMR δ 7.31 (m, 5H), 4.05
;
(d, J ) 12.9, 0.7H), 3.97 (2d, J ) 13.0, 0.3H), 3.78 (s, 3 ×
0.3H), 3.75 (s, 3 × 0.7H), 3.69 (d, J ) 12.9, 0.7H, overlap),
3.64 (d, J ) 13.0, 0.3H), 3.56 (dd, J ) 9.4, 3.5, 1H), 3.32 (q, J
) 7.3, 0.3H), 3.17 (m, 0.7H), 2.82 (m, 0.7H), 2.49 (m, 2 and
0.3H), 2.14 (s, 3H), 2.14-1.80 (m, 4H), 1.71 (m, 2H); 13C NMR
δ 207.4 (0), 174.4, 174.0 and 173.2 (0, 1C), 135.7 and 135.5 (0,
1C), 129.5, 129.4, 128.7, 128.1 (1, 5C), 67.6 and 67.5 (1, 1C),
66.2 and 65.6 (1, 1C), 59.5 and 57.8 (2, 1C), 52.0 and 51.9 (3,
1C), 46.2 and 46.1 (1, 1C) 41.1 and 40.7 (2, 1C), 29.8 (3), 28.8,
28.5, 26.5, 23.3, and 22.3 (2, 3C). Anal. Calcd for
C19H25NO5‚1/3H2O: C, 64.6; H, 7.3; N, 4.0. Found: C, 64.8;
H, 7.3; N, 3.8.
(1R,2S,4S/R,5S)-4-Acetyl-8-(ter t-bu toxyca r bon yl)-2-ca r -
boxy-8-a za bicyclo[3.2.1]octa n e (39). To 1.8 M KOH/H2O
(4.90 mL, 8.82 mmol) was added a solution of keto esters 37
(270 mg, 0.87 mmol) in i-PrOH (14.0 mL) at 0 °C, and the
mixture was stirred for 40 min at 0 °C and 3.6 h at rt. Most
of the i-PrOH was evaporated, H2O (4.5 mL) was added, and
the solution was cooled at 0 °C and adjusted to pH 3.2 with 1
M H3PO4. The aqueous solution was extracted with CHCl3 (5
× 20 mL), and the combined organic phase was dried, filtered,
and evaporated to provide keto acids 39 (256 mg, 99%) as a
mixture of epimers at C-4 in an S/R ratio g 7/1: 1H NMR δ
(1R,2S,4S,5S)- a n d (1R,2R,4S,5S)-4-Acetyl-8-ben zyl-2-
(m et h oxyca r b on yl)-8-a za b icyclo[3.2.1]oct a n e (35) a n d