Synthesis of Porphobilinogen
J. Am. Chem. Soc., Vol. 123, No. 38, 2001 9311
formed by decomposition of formic anhydride).22 Finally,
addition of acetoxy radical from the R-face would afford the
more stable cis-fused product 32. An analogous mechanism,
but involving initial cleavage of bond b in 26, would lead to
the regioisomeric bis-acetal 33.
Further studies of this mechanism are in progress, and we
expect that conversions of type 7a f 32 might be of general
use in natural product synthesis.
2H), 3.38 (d, J ) 14.4 Hz, 1H), 3.70 (s, 3H), 3.79 (d, J ) 14.4 Hz,
1H), 4.76 (dd, J ) 1.8 Hz, 4.5 Hz, 1H), 5.75 (d, J ) 5.7 Hz, 1H), 6.24
(dd, J ) 1.8 Hz, 5.7 Hz, 1H), 7.14-7.30 (m, 7H), 7.41-7.58 (m, 2H);
13C NMR (CDCl3) δ 27.5, 33.2, 35.3, 35.5, 38.4, 43.4, 46.2, 47.0, 52.0,
62.1, 80.8, 87.3, 126.9, 127.0, 128.1, 128.1, 130.2, 130. 5, 132.2, 132.6,
134.7, 136.5, 137.1, 138.4, 141.5, 141.9, 171.3, 173.6 (restricted rotation
of the dibenzosuberyl group leads to observance of all carbons). HRMS-
(EI) calcd for (C28H29NO4) ([M+]) 443.2097; found 443.2104.
Also obtained from this reaction was 1.23 g (17%) of 6-[(10,11-
dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)furan-2-ylmethylcarbam-
oyl]hex-4-enoic acid, methyl ester (6c): colorless oil; 1H NMR (CDCl3)
δ 2.38 (m, 4H), 3.14 (d, J ) 6.0 Hz, 2H), 2.93-3.35 (m, 4H), 3.69 (s,
3H), 4.50(s, 2H), 5.40-5.48 (m, 2H), 5.62-5.71 (m, 1H), 6.13 (dd, J
) 1.5 Hz, 3.0 Hz, 1H), 6.84 (br s, 1H), 7.09-7.23 (m, 7H), 7.38-
7.41 (m, 2H); 13C NMR (CDCl3) δ 28.5, 34.4, 34.6, 38.9, 44.2, 52.2,
52.4, 107.6, 111.0, 111.2, 127.0 (2C), 128.6 (2C), 130.7 (2C), 132.1,
132.2, 132.9, 137.7 (2C), 141.2 (2C), 142.2 (2C), 151.9, 173.1, 174.2.
HRMS(EI) calcd for (C28H29NO4) ([M+]) 443.2097; found 443.2094.
3-[4-Oxo-11-oxa-3-aza-tricyclo[6.2.1.0]undec-9-en-7-yl]propion-
ic Acid, Methyl Ester (7a). A solution of 4.19 g (9.4 mmol) of 7c and
1.02 g (9.4 mmol) of anisole in 5 mL of CH2Cl2 was cooled to 0 °C
under Ar, and was treated dropwise with vigorous stirring with 5 mL
of trifluoroacetic acid (TFA). After being stirred 1 h at 0 °C, the reaction
mixture was allowed to warm to room temperature for 2 h, and was
then concentrated to dryness under reduced pressure A small amount
of residual TFA was removed by concentration from benzene. The
residue was chromatographed (silica gel, 1:20 MeOH/EtOAc) to yield
2.07 g (88%) of 7a as a colorless solid: mp 124.0-0.8 °C; IR (TCE)
3204, 3091, 1728, 1655 cm-1; 1H NMR (CDCl3) δ 1.49-1.62 (m, 3H),
1.90-1.94 (m, 1H), 2.24-2.38 (m, 3H), 2.68 (dd, J ) 5.4 Hz, 15.6
Hz, 1H), 3.71 (s, 3 H), 3.71 (dd, J ) 1.8 Hz, 14.4 Hz, 1H), 3.92 (dd,
J ) 3.6 Hz, 14.4 Hz, 1H), 4.88 (dd, J ) 1.5 Hz, 4.2 Hz, 1H), 6.35 (d,
J ) 5.7 Hz, 1H), 6.44 (dd, J ) 1.5 Hz, 5.7 Hz, 1H), 6.48 (br s, 1H);
13C NMR (CDCl3) δ 27.6, 33.2, 37.1, 42.8, 44.3, 48.5, 52.0, 80.9, 86.0,
135.6, 138.0, 173.6, 174.1. Anal. Calcd for C13H17NO4: C, 62.14; H,
6.82; N, 5.57. Found: C, 62.12; H, 6.69; N, 5.58.
3-(2-Acetoxy-7a-formyloxy-5-oxooctahydrofuro[2,3-c]pyridin-3-
yl)propionic Acid, Methyl Ester (32); 3-(7a-Acetoxy-2-formyloxy-
5-oxooctahydrofuro[2,3-c]pyridin-3-yl)propionic Acid, Methyl Ester
(33); 3-(2,7a-Diacetoxy-5-oxooctahydrofuro[2,3-c]pyridin-3-yl)pro-
pionic Acid, Methyl Ester (16a). A solution of 470 mg (1.87 mmol)
of 7a in 25 mL of CH2Cl2 was cooled to -78 °C, and was treated with
a finely dispersed stream of O3 until the blue color just persists. Excess
O3 was then removed by purging with O2. The reaction mixture was
allowed to warm to room temperature and was treated with vigorous
stirring with 3.62 g (11.2 mmol) of iodosylbenzene diacetate and 1.90
g (7.48 mmol) of I2 in one portion. The resulting dark solution was
irradiated with stirring at room temperature for 4.5 h using a 200 W
tungsten lamp. At the end of this period the reaction was treated
dropwise with saturated aqueous Na2S2O3 until the solution turned
colorless. The resulting precipitate was filtered, and the aqueous phase
was extracted with 5 × 20 mL of CH2Cl2. The combined organic
extracts were washed with 10 mL of saturated brine, dried over
anhydrous MgSO4, and concentrated to dryness under reduced pressure.
The residue was chromatographed (silica gel, EtOAc) to yield 400 mg
(65%) of a mixture of 32, 33, and 16a.26 Further chromatography
allowed separation into two components: 16a and combined 32/33.
Acetals 32 and 33 (yellow oils): 1H NMR (CDCl3) δ 1.88-1.94
(m, 2H), 2.11 (s, 3H), 2.14 (s, 1H), 2.38 (t, J ) 7.5 Hz, 2H), 2.43 (t,
J ) 3 Hz, 1H), 2.71 (dd, J ) 2.5 Hz, 5.5 Hz, 1H), 3.04 (d, J ) 5.5 Hz,
1H), 3.69 (s, 3H), 3.71 (d, J ) 5.5 Hz, 2H), 5.83 (br s, 1H), 6.43 (d,
J ) 4.8 Hz, 1H), 8.16 (s, 1H); 13C NMR (CDCl3) δ 22.0, 23.0, 32.3,
33.8, 46.4, 47.2, 48.3, 52.2, 97.8, 112.0, 159.9, 170.0, 172.9, 173.0.
HRMS (EI) calcd for (C14H19NO8 + H) ([M + H+]) 330.1189; found
330.1186.
Experimental Section
N-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-N-furan-2-
ylmethylacetamide (12c). A solution of 6.35 g (65.5 mmol) of
furfurylamine (4a) and 18.2 mL (131 mmol) of Et3N in 150 mL of
CH2Cl2 was cooled to 0 °C, and treated with vigorous stirring with
15.0 g (65.5 mmol) of 5-chlorodibenzosuberane. After addition was
complete, the reaction was stirred for an additional 30 min at 0 °C,
and then at room temperature for 5 h before concentrating under reduced
pressure. The residue, consisting of crude 4c, was taken up in 13.4 g
(131 mmol) of acetic anhydride and 15.9 mL (197 mmol) of pyridine.
The reaction was then heated at 100 °C for 5 h, cooled to room
temperature, and diluted with 100 mL of Et2O. The resulting solution
was washed with 20 mL each of 1 N NaOH, 1 N HCl, and saturated
brine. After being dried over anhydrous MgSO4, the organic layer was
concentrated and the residue chromatographed (silica gel; pet ether/
EtOAc, 5:1) to afford 21.80 g (93%) of 12c as a crystalline solid: mp
90.0-0.5 °C (colorless crystals from Et2O); IR (TCE) 2922, 1644, 1438
1
cm-1; H NMR (CDCl3) δ 2.17 (s, 3H), 2.94-3.02 (m, 2H), 3.33-
3.36 (m, 2H), 4.51 (s, 2H), 5.50 (br s, 1H), 6.14 (dd, J ) 1.5 Hz, 2.1
Hz, 1H), 6.88 (br s, 1H), 7.10-7.20 (m, 7H), 7.40-7.43 (m, 2H); 13
C
NMR (CDCl3) δ 23.2, 34.3 (2C), 44.3, 64.4, 107.1, 110.6, 126.5 (2C),
128.1 (2C), 130.3 (2C), 132.4, 137.4 (2C), 140.8 (2C), 141.7 (2C),
151.5, 171.9. Anal. Calcd for C22H21NO2: C, 79.73; H, 6.39; N, 4.23.
Found: C, 79.75; H, 6.40; N, 4.23.
3-Hydroxypent-4-enoic Acid (10,11-Dihydro-5H-dibenzo[a,d]cy-
clohepten-5-yl)furan-2-ylmethylamide (13c). A solution of 19.36 g
(58.1 mmol) of 12c in 100 mL of THF was cooled to -78 °C under
Ar, and was treated dropwise, with vigorous stirring, with 43 mL (58.1
mmol) of 1.36 M lithium diisopropylamide/heptane/tetrahydrofuran/
ethylbenzene.6a After addition was complete, the reaction was stirred
at -78 °C for an additional 1 h, and was then treated in one portion
with 7.7 mL (116.2 mmol) of acrolein. The resulting solution was stirred
for 30 min at -78 °C, allowed to warm slowly to room temperature,
and quenched with 50 mL of saturated NH4Cl. After filtration, the
aqueous layer was extracted with 4 × 50 mL of EtOAc, and the
combined organic extracts were washed with 15 mL of saturated brine,
dried over anhydrous MgSO4, and concentrated to dryness under
reduced pressure. Chromatography (silica gel, 5:1 pet ether/EtOAc)
then afforded 21.03 g (93%) of 13c as a colorless oil: IR (neat) 3433,
3056, 1733, 1633 cm-1; 1H NMR (CDCl3) δ 2.50-2.70 (m, 2H), 2.93-
3.06 (m, 2H), 3.25-3.37 (m, 2H), 4.37 (s, 1H), 4.51 (s, 2H), 4.59 (br
s, 1H), 5.13 (dt, J ) 1.5 Hz, 10.5 Hz, 1H), 5.30 (d, J ) 16.5 Hz 1H),
5.49 (br s, 1H), 5.86 (ddd, J ) 5.1 Hz, 10.5 Hz, 16.5 Hz, 1H), 6.12
(dd, J ) 1.8 Hz, 3 Hz, 1H), 6.89 (br s, 1H), 7.10-7.25 (m, 7H), 7.35-
7.43 (m, 2H); 13C NMR (CDCl3) δ 34.3 (2C), 43.5, 69.5, 107.4, 110.6,
115.0, 126.6, 126.7, 128.3, 128.3, 130.4 (2C), 136.9 (2C), 136.9 (2C),
139.3 (2C), 140.7, 140.8, 141.9 (2C), 150.8, 173.8. HRMS(EI) calcd
for (C25H25NO3-H) ([M - H+]) 386.1755; found 386.1758.
3-[3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-4-oxo-11-
oxa-3-azatricyclo[6.2.1.0]undec-9-en-7-yl]propionic Acid, Methyl
Ester (7c). A solution of 6.20 g (16.0 mmol) of 13c, 9.9 mL (80 mmol)
of trimethylorthoacetate (MOA), and 15 mL of toluene was thoroughly
degassed with Ar, and was divided into three thick-walled reaction tubes
containing a catalytic amount of pivalic acid and tert-butylcatechol.
The tubes were sealed under Ar and heated with stirring at 130 °C for
90 h. After being cooled to room temperature, the reaction mixture
was concentrated under reduced pressure, and the residue was chro-
matographed (silica gel, 4:1 pet ether/EtOAc) to give 5.08 g (72%) of
7c as an amorphous solid: IR (neat) 3463, 1728, 1638 cm-1; 1H NMR
(CDCl3) δ 1.29-1.60 (m, 3H), 1.82-1.88 (m, 1H), 2.24-2.37 (m, 3H),
2.76 (dd, J ) 5.1 Hz, 4.5 Hz, 1H), 3.01-3.06 (m, 2H), 3.25-3.34 (m,
16a (yellow oil): 1H NMR (CDCl3) δ 1.86-2.07 (m, 2H), 2.10-
2.14 (m, 6H), 2.34-2.45 (m, 3 H), 2.70-2.80 (m, 2H), 3.03-3.09 (m,
1H), 3.48-3.70 (m, 2H), 3.72 (s, 3H), 6.31 (br s, 1H), 6.36 (d, J ) 5.1
Hz, 1H); HRMS (FAB) Calcd for (C15H21NO8 + H) [(M + H+)]
344.1345; found 344.1346.
(26) Comparable yields were obtained on 2-3 g scales (not optimized).