Synthesis of Biologically Important Tetrapyrroles
J . Org. Chem., Vol. 65, No. 1, 2000 211
mmol, 1.0 equiv) of isobutyl chloroformate in a dropwise
fashion over a period of 5 min. The resulting solution was
stirred at 0 °C for 40 min. The solution was cooled to -78 °C,
and NH3, from NH4OH dried through a CaCl2 drying tube,
was bubbled into the solution for 1 h. The reaction solution
was allowed to warm to room temperature and stirred over-
night. Solvent was removed under reduced pressure, the
residue was taken up in 50 mL of H2O and 50 mL of EtOAc
and extracted with EtOAc, and the combined organic extracts
were dried over anhydrous Na2SO4, concentrated under re-
duced pressure, and chromatographed (silica gel, EtOAc) to
afford 0.25 g (90%) of amide (()-27a . Recrystallization from
EtOAc/hexanes afforded this compound as colorless needles:
mp 81-82 °C; Rf 0.61 (silica gel, EtOAc); IR (CCl4) 3514.5,
(t, J ) 7.2 Hz, 3H), 1.28 (d, J ) 6.9 Hz, 3H), 1.38 (d, J ) 6.9
Hz, 3H), 1.64 (m, 3H), 1.85 (m, 1H), 2.01 (s, 3H), 2.05 (s, 3H),
2.18 (m, 1H), 2.38 (m, 1H), 2.51 (m, 4H), 2.89 (m, 5H), 3.01 (s,
1H), 3.64 (s, 3H), 3.65 (s, 3H), 5.48 (s, 1H), 5.59 (br s, 1H),
6.63 (s 1H), 7.12 (br s, 1H), 8.5-9.2 (br s, 2H); 13C NMR
(CDCl3) δ 10.21\ , 10.2, 11.5, 12.7, 18.5, 20.0, 20.4, 20.5, 23.1,
24.2, 29.8, 30.0, 35.7, 35.9, 39.7, 50.3, 52.1, 54.4, 74.0, 92.2,
101.1, 113.3, 119.8, 125.5, 128.9, 130.4, 132.3, 143.5, 149.1,
153.9, 167.7, 173.6, 173.7, 177.3, 179.3; FAB HRMS, m/z
619.3487, M + H calcd for C35H47N4O6 619.3496.
(2R,3R,17R,18R)-2,18-Dieth yl-8,12-bis[2-(m eth oxyca r -
bon yl)eth yl]-3,7,13,17-tetr a m eth yl-2,3,17,18-tetr a h yd r o-
bilin -1,19(21H,24H)-d ion e (30). A solution of 10 mg (0.016
mmol, 1 equiv) of 29 and 0.13 mL (0.13 mmol, 8 equiv) of 1 M
n-Bu4NF/THF in 0.5 mL of THF was purged with argon and
heated at reflux under argon for 30 min. The reaction mixture
was diluted with EtOAc, washed with saturated NaHCO3
solution and brine, dried over anhydrous Na2SO4, and con-
centrated in vacuo. Flash chromatography (4:1 hexanes/
acetone) gave 4.1 mg (41%) of 30 as a purple solid: 1H NMR
(CDCl3) δ 1.02 (t, J ) 7.5 Hz, 6H), 1.44 (d, J ) 6.9 Hz, 6H),
1.53-1.69 (m, 2H), 1.75-1.91 (m, 2H), 2.05 (s, 6H), 2.19-2.28
(m, 2H), 2.53-2.58 (m, 4H), 2.88-3.00 (m, 6H), 3.67 (s, 6H),
5.52 (s, 2H), 6.75 (s, 1H); 13C NMR (CDCl3) δ 10.0, 11.8, 20.1,
20.6, 23.9, 36.0, 40.0, 49.8, 52.2, 91.1, 112.7, 125.6, 137.4, 138.6,
148.7, 150.2, 173.8, 179.5; FAB HRMS, m/z 619.34, M + H
calcd for C35H47N4O6 619.3496.
3398.8, 3309.8, 2968.9, 2360.0, 1693.8, 1586.1, 1552.1 cm-1
;
1H NMR (CDCl3) δ 1.06 (t, J ) 8.0 Hz, 3H), 1.35 (d, J ) 7.0
Hz, 3H), 1.70-1.85 (m, 2H), 2.23 (m, 1H), 2.28 (d, J ) 2.5 Hz,
1H), 2.83 (dt, J ) 7.0, 3.0 Hz, 1H), 5.42 (br. s, 1H), 5.99 (br. s,
1H); 13C NMR (CDCl3) δ 11.9, 18.4, 23.8, 27.7, 53.7, 70.7, 86.3,
176.6. Anal. Calcd. for C8H13NO: C, 69.03; H, 9.41. Found:
C, 68.90; H, 9.38.
(2R,3R)-2-Eth yl-3-m eth ylpen t-4-yn e Car boxam ide (27a).
This compound was prepared from the homochiral alkyne acid
(2R,3R)-2-ethyl-3-methylpent-4-yne carboxylic acid23 following
a procedure identical to that described above for (()-27a ;
identical spectral data as for (()-27a .13a-c
(()-syn -N-(4-Met h oxyb en zyl)-2-et h yl-3-m et h ylp en t -4-
yn e Ca r boxa m id e ((-27b). A total of 1.00 g (7.14 mmol, 1.0
equiv) of (()-2-ethyl-3-methylpent-4-yne carboxylic acid23 and
2 mL of oxalyl chloride (22.9 mmol, 3.2 equiv) were mixed and
stirred for 7 h at room temperature. Excess oxalyl chloride
was removed in vacuo, and the residue was dissolved in CH2-
Cl2 (10 mL). The resulting solution was added to an ice-cold
solution of 4-methoxybenzylamine (4.7 mL, 36.0 mmol, 5.0
equiv) and Et3N (3 mL, 21.5 mmol, 3 equiv) in CH2Cl2 (10 mL).
The mixture was stirred for 30 min, poured into H2O, and
extracted with CH2Cl2. The organic extracts was washed with
brine, dried (MgSO4), and concentrated in vacuo. Flash chro-
matography (silica gel, EtOAc/hexanes 3:1) afforded 1.13 g
(61%) of (()-27b as colorless needles: Rf 0.28 (silica gel, EtOAc/
hexanes 3:1); 1H NMR (CDCl3) δ 0.95 (t, 3H), 1.25 (d, 3H),
1.60-1.80 (m, 3H), 2.10 (m, 1H), 2.75 (m, 1H), 3.81 (s, 3H),
4.43 (d, 2H), 6.09 (br s, 1H), 6.87 (d, 2H), 7.25 (d, 2H).
(2R,3R)-N-(4-Meth oxyben zyl)-2-eth yl-3-m eth ylp en t-4-
yn e Ca r boxa m id e (27b). This compound was prepared from
the homochiral alkyne acid (2R,3R)-2-ethyl-3-methylpent-4-
yne carboxylic acid23 following a procedure identical to that
described above for (()-27b; identical spectral data as for (()-
27b.
Dia m id e 28. A mixture of 51 mg (0.086 mmol, 1 equiv) of
19a , 47.6 mg (0.343 mmol, 4 equiv) of acetylenic amide 27a ,
and 6.0 mg (0.0086 mmol, 0.1 equiv) of PdCl2(Ph3P)2 in Et3N
(1.0 mL) and 1,4-dioxane (0.5 mL) was degassed by freeze-
thaw cycle (three times) and then stirred at 50 °C under argon
for 14 h. The reaction mixture was diluted with EtOAc, washed
with saturated NaHCO3 solution and brine, dried over anhy-
drous Na2SO4, and concentrated in vacuo. Flash chromatog-
raphy (3:2 hexanes/acetone) afforded 21.7 mg (77%) of 28 as
an orange solid: mp 193-95 °C; 1H NMR (CDCl3) δ 0.98 (t, J
) 7.5 Hz, 6H), 1.33 (d, J ) 6.9 Hz, 6H), 1.67 (m, 4H), 2.00 (s,
6H), 2.15 (m, 2H), 2.49 (t, J ) 7.5 Hz, 4H), 2.86 (t, J ) 7.5 Hz,
4H), 2.98 (m, 2H), 3.63 (s, 6H), 6.07 (br s, 2H), 6.70 (s, 1H),
7.45 (s,1H); 13C NMR (CDCl3) δ 10.3, 12.4, 19.1, 20.5, 24.3,
29.6, 35.7, 52.2, 54.7, 77.1, 101.3, 117.6, 129.5, 137.2, 137.9,
139.3, 173.6, 177.5. Anal. Calcd for C35H46N4O6: C, 67.94; H,
7.49; N, 9.05. Found: C, 67.82; H, 7.48; N, 8.99.
Am id e 31a . A mixture of 102.8 mg (0.17 mmol, 2 equiv) of
19a , 12 mg (0.086 mmol, 1 equiv) of the alkyne amide 27a ,
and 12.0 mg (0.01 mmol, 0.12 equiv) of Pd(Ph3P)4 in Et3N (1
mL) and 1,4-dioxane (0.5 mL) was degassed by freeze-thaw
cycle (three times) and then stirred at 50 °C under argon for
11 h. The reaction mixture was diluted with EtOAc, washed
with saturated NaHCO3 solution and brine, dried over anhy-
drous Na2SO4, and concentrated in vacuo. Flash chromatog-
raphy (4:1 hexanes/acetone) afforded 34.0 mg (65%) of 31a as
an orange solid, which was recrystallized from EtOAc/hexane
to give orange needles: mp 157-58 °C; 1H NMR (CDCl3) δ
1.03 (t, J ) 7.5 Hz, 3H), 1.37 (d, J ) 7.2 Hz, 3H), 1.74 (m,
2H), 1.96 (s, 3H), 2.06 (s, 3H), 2.25 (m, 1H), 2.52 (m, 4H), 2.91
(m, 4H), 3.06 (m, 1H), 3.64 (s, 3H), 3.66 (s, 3H), 5.50 (br s,
1H), 5.88 (br s, 1H), 6.71 (s, 1H); 13C NMR (CDCl3) δ 10.1,
12.6, 13.0, 18.7, 20.3, 20.7, 24.0, 29.8, 35.5, 35.6, 52.2, 52.2,
54.5, 74.9, 101.0, 117.1, 122.2, 125.9, 129.1, 131.2, 132.8, 134.9,
141.7, 149.4, 173.4, 173.5, 176.6. Anal. Calcd for C27H34
-
IN3O5: C, 53.38; H, 5.64; N, 6.92. Found: C, 53.28; H, 5.68;
N, 6.87.
Am id e 31b. This material was prepared following a pro-
cedure identical to that described above for 31a , using 381.2
mg (0.64 mmol, 2 equiv) of 19a , 83.2 mg (0.32 mmol, 1 equiv)
of the alkyne amide 27b, 40.0 mg (0.034 mmol, 0.1 equiv) of
Pd(Ph3P)4, 5 mL of Et3N, and 2.5 mL of 1,4-dioxane. After the
mixture was stirred at 50 °C under argon for 16 h, workup
and purification by flash chromatography (1:1 hexanes/EtOAc)
afforded 142.7 mg (61%) of 31b as an orange-brown solid: 1H
NMR (CDCl3) δ 0.98 (t, J ) 7.5 Hz, 3H), 1.35 (d, J ) 7.2 Hz,
3H), 1.74 (m, 2H), 1.96 (s, 3H), 1.97 (s, 3H), 2.18 (m, 1H), 2.52
(m, 4H), 2.90 (m, 4H), 3.07 (m, 1H), 3.64 (s, 3H), 3.67 (s, 3H),
3.70 (s, 3H), 4.45 (m, 2H), 6.04 (t, J ) 5.4 Hz, 1H), 6.71 (s,
1H), 6.72 (d, J ) 8.7 Hz, 2H), 7.19 (d, J ) 8.7 Hz, 2H); 13C
NMR (CDCl3) δ 10.1, 12.7, 13.1, 10.0, 20.4, 20.7, 24.1, 30.0,
35.5, 35.6, 43.6, 52.2, 52.2, 55.2, 55.7, 75.0, 101.3, 114.5, 117.1,
122.3, 126.1, 129.2, 129.6, 131.0, 131.3, 132.8, 135.0, 141.7,
149.5, 159.4, 173.4, 173.5, 173.8; FAB HRMS, m/z 728.2196,
M + H calcd for C35H43IN3O6 728.2197.
Dia m id e 33a . A mixture of 70.0 mg (0.115 mmol, 1 equiv)
of 31a , 35.8 mg (0.23 mmol, 2 equiv) of the alkyne amide
32a ,13b and 15.0 mg (0.013 mmol, 0.11 equiv) of Pd(Ph3P)4 in
Et3N (1 mL), 1,4-dioxane (0.5 mL), and DMF (0.5 mL) was
degassed by freeze-thaw cycle (three times) and then stirred
at 50 °C under argon for 10 h. The reaction mixture was
diluted with EtOAc, washed with saturated NaHCO3 solution,
water, and brine, dried over anhydrous MgSO4, and concen-
trated in vacuo. Flash chromatography (2:1, 1:1, 1:2 hexanes/
acetone) afforded 24.0 mg (33%) of 33a as an orange-brown
Am id e 29. A solution of 20 mg (0.032 mmol, 1 equiv) of 28,
0.26 mL (0.26 mmol, 8 equiv) of 1 M n-Bu4NF solution in THF,
and 0.2 mL of Et3N in 2 mL of THF was purged with argon
and stirred at room temperature under argon for 1.5 h. The
reaction mixture was then diluted with EtOAc, washed with
saturated NaHCO3 solution and brine, dried over anhydrous
Na2SO4, and concentrated in vacuo. Flash chromatography (4:1
hexanes/acetone) gave 17.8 mg (89%) of 29 as a purple solid:
mp 53-5 °C; 1H NMR (CDCl3) δ 0.97 (t, J ) 7.2 Hz, 3H), 1.05