8668
A. Kiriazis et al. / Tetrahedron 67 (2011) 8665e8670
Powel algorithm. Flexibility of the ligand was considered during
followed by evaporation of the solvents by a rotary evaporator to
docking simulations by Gold v4.1. The binding cavity was defined
centered on oxygen atom 101 of threonine 242 with a radius of 10 A.
Ten docking runs were performed (100.000 runs of the genetic al-
gorithm each), leading to the same binding pose for each run.
yield carboxylic acid (7) as a white crystalline solid (2.39 g, 92%).
ꢀ
ꢁ
Mp 110e111 C. IR:
674 cm ; H NMR (300 MHz, CDCl
n
3200e2800 (br), 2969, 1742, 1694, 1195,
): 10.57 (1H, br s), 5.90e5.80
(2H, m), 3.63 (3H, s), 3.09 (1H, dd, J¼3.6,11.4 Hz), 3.01 (1H, dd, J¼4.1,
ꢀ1 1
3
d
11.4 Hz), 2.34e2.25 (2H, m), 2.24e2.10 (4H, m), 1.95 (1H, d,
.1.2. endo-Norbornene-5,6-cis-dicarboxylic anhydride (4)25. Maleic
J¼10.8 Hz), 1.62e1.46 (2H, m), 1.23 (1H, d, J¼10.8 Hz); C NMR
13
4
anhydride (30.0 g, 306 mmol) briquettes were ground in mortar
and dried 2e3 h in vacuo and then dissolved in anhydrous
dichloromethane (60 mL). Cyclopentadiene (freshly distilled)
3
(75 MHz, CDCl ) d 179.1, 173.4, 129.6, 129.5, 52.2, 48.1, 48.0, 47.9,
18 4
47.8, 37.3, 37.1, 35.8, 28.2, 28.1. Anal. Calcd for C14H O (250.12): C,
67.18; H, 7.25. Found: C, 67.03; H, 7.22. GCeMS: The carboxylic acid
(
22.2 g, 337 mmol) in dichloromethane (10 mL) was added drop-
(7) was O-methylated with diazomethane in Et
responding diester: [M] , m/z 264.
2
O to give the cor-
ꢁ
þ
wise to the solution of maleic anhydride at 0 C under argon. After
2
4 h the white precipitate was collected and washed with diethyl
2
5
ether (2ꢃ20 mL) and dried in vacuo to give known 4 as a white
4.1.6. (ꢂ)-cis-Methyl 3-[[(benzyloxy)carbonyl]amino]decahydro-1,4-
methanonaphthalene-2-carboxylate (8). Carboxylic acid (6) (1.57 g,
6.24 mmol), triethylamine (1.26 g, 12.5 mmol, 2.0 equiv), and
diphenylphosphoryl azide (2.06 g, 7.56 mmol, 1.2 equiv) were dis-
1
3
crystalline solid (47.0 g, 94%). H NMR (300 MHz, CDCl ): d 6.30 (2H,
m), 3.58e3.55 (2H, m), 3.52e3.47 (2H, m), 1.77 (1H, dd, J¼1.8,
þ
9
.3 Hz); 1.57 (1H, dd, J¼1.8, 9.3 Hz). GCeMS: [M] , m/z 164.
ꢁ
solved in anhydrous toluene (40 mL) and heated at 100 C for 2 h
4
.1.3. meso-1,2,3,4,4a,5,8,8a-Octahydro-4,9-methanonaphtho[2,3-c]
under argon. Then benzyl alcohol (3.26 g, 30.2 mmol, 5.0 equiv) was
added and the resulting reaction mixture was heated at 110 C for
26
ꢁ
furan-1,3-dione (5) . endo-Norbornene-5,6-cis-dicarboxylic anhy-
dride (4) (6.00 g, 36.6 mmol) was dissolved in a solution of anhy-
drous degassed p-xylene (12 mL) and 3-sulfolene (14.0 g, 119 mmol,
3 d. The reaction mixture was cooled to ambient temperature and
the solvents were evaporated by a rotary evaporator. The oily res-
idue was purified by column chromatography on silica gel (eluent:
EtOAc/n-Hex 1:3) to produce (8) as a colorless oil (1.24 g, 50%). IR
3
.2 equiv) and phenothiazine (0.500 g, 2.60 mmol, 0.07 equiv) were
added. The reaction mixture was heated in a sealed tube at
ꢁ
ꢀ1
1
165e170 C for 48 h under argon. After 48 h, GCeMS analysis from
(ATR):
n
3379, 2965, 1745, 1705, 1195 cm
; H NMR (300 MHz,
the reaction mixture showed a formation of the DielseAlder
product together with some side products and starting material.
Dichloromethane (20 mL) was added and the crude reaction mix-
ture was hot filtrated and concentrated on a rotary evaporator. The
crude product was recrystallized from acetone to yield the known
meso-anhydride (5) as white thin needles (1.58 g, 20%). Mp
CDCl ):
3
d
7.42e7.28 (5H, m), 6.86 (1H, br d, J¼7.8 Hz), 5.12 (1H, d,
J¼12.3 Hz), 5.07 (1H, d, J¼12.3 Hz), 4.16e4.08 (1H, m), 3.65 (3H, s),
2.97 (1H, dd, J¼4.4, 11.0 Hz), 2.20e2.14 (2H, m), 1.94e1.84 (1H, m),
13
1.76 (1H, d, J¼10.8 Hz) 1.70e1.54 (4H, m), 1.42e1.08 (6H, m);
C
3
NMR (75 MHz, CDCl ) d 174.9, 157.0, 137.6, 129.2, 128.9, 128.8, 67.3,
52.9, 52.4, 48.4, 48.1, 45.9, 37.3, 34.4, 33.2, 23.6, 23.5, 19.9,19.8.
GCeMS: [M] , m/z 357.
ꢁ
ꢁ
26 1
þ
2
(
06e208 C (lit. 208 C).
2H, m), 3.43 (1H, d, J¼2.1 Hz), 3.42 (1H, d, J¼2.1 Hz), 2.58e2.55 (2H,
m), 2.34e2.22 (2H, m), 2.12 (1H, 1H, d, J¼10.8 Hz), 1.88e1.76 (2H,
H NMR (300 MHz, CDCl
3
):
d
5.97e5.85
4.1.7. (ꢂ)-cis-Methyl 3-[[(benzyloxy)carbonyl]amino]-1,2,3,4,4a,5,8,
8a-octahydro-1, 4-methanonaphthalene-2-carboxylate
(9). Carboxylic acid (7) (1.12 g, 4.48 mmol), triethylamine (905 mg,
8.96 mmol, 2.0 equiv), and diphenylphosphoryl azide (1.48 g,
5.37 mmol, 1.2 equiv) were dissolved in anhydrous toluene (20 mL)
13
m), 1.62e1.54 (2H, m), 1.50 (1H, td, J¼1.8, 10.8 Hz); C NMR
(
75 MHz, CDCl 172.5, 129.2, 50.8, 47.3, 39.3, 38.6, 28.0. Anal.
3
)
d
Calcd for C13H O (218.09): C, 71.54; H, 6.47. Found: C, 70.94; H,
14 3
þ
6
.43. GCeMS: [M] , m/z 218.
ꢁ
and heated at 100 C for 3 h under argon. Then benzyl alcohol
4
.1.4. (ꢂ)-cis-3-(Methoxycarbonyl)decahydro-1,4-methanonaphtha-
(2.42 g, 22.4 mmol, 5.0 equiv) was added and the resulting reaction
ꢁ
lene 2-carboxylic acid (6). meso-Anhydride (5) (1.00 g, 4.59 mmol)
was dissolved in an equimixture of methanol and EtOAc (35 mL)
followed by addition of the palladium catalyst (Pd 10 wt % on ac-
tivated carbon). The reaction mixture was stirred under hydrogen
mixture was heated at 90 C for 48 h. The reaction mixture was
ꢁ
cooled to 20 C and all volatiles were evaporated by a rotary
evaporator. The oily residue was purified by column chromatog-
raphy on silica gel (eluent: EtOAc/n-Hex 1:3) to yield (9) as a col-
ꢁ
atmosphere (H
2
balloon) for 24 h at ambient temperature. Then
orless oil (1.09 g, 68%), which crystallized on standing at ꢀ20 C. Mp
ꢁ
hydrogenation was stopped and the reaction mixture was heated at
7
by filtration through Celite and the resulting filtrate was concen-
96e97 C. A sample of (9) for single crystal X-ray analysis was
ꢁ
0 C for another 24 h under argon. The catalyst was then removed
recrystallized from n-hexane. IR (ATR):
1264, 1049, 698 cm ; H NMR (300 MHz, CDCl ): 7.40e7.22 (5H,
n
3365, 2933, 1741, 1708,
ꢀ1 1
3
d
trated on a rotary evaporator to yield carboxylic acid (6) as a white
m), 6.85 (1H, br d, J¼7.5 Hz), 5.90e5.78 (2H, m), 5.12 (1H, d,
J¼12.3 Hz), 5.07 (1H, d, J¼12.3 Hz), 4.13 (1H, m), 3.64 (3H, s), 3.00
(1H, dd, J¼4.4, 11.0 Hz), 2.30e1.98 (5H, m), 1.87 (1H, d, J¼10.8 Hz)
ꢁ
crystalline solid (1.03 g, 89%). Mp 111e113 C. IR:
n
3300e2700 (br),
): 9.29 (1H,
br s), 3.64 (3H, s), 3.06 (1H, dd, J¼3.6, 11.4 Hz), 3.01 (1H, dd, J¼4.2,
1.7 Hz), 2.99 (1H, dd, J¼3.6, 11.7 Hz), 2.26e2.18 (2H, m), 2.12e1.98
2H, m), 1.85 (1H, d, J¼10.2 Hz), 1.64e1.54 (2H, m), 1.42e1.28 (4H,
ꢀ1 1
2
964, 1734, 1697, 1178 cm ; H NMR (300 MHz, CDCl
3
d
13
1.84e1.74 (1H, m), 1.60e1.48 (2H, m), 1.30 (1H, d, J¼10.8 Hz);
C
1
NMR (75 MHz, CDCl
3
) d 174.7, 157.0, 137.6, 129.8, 129.3, 129.2, 128.9,
(
128.7, 67.3, 53.0, 52.5, 49.3, 48.8, 46.1, 37.9, 34.6, 33.6, 27.9, 27.8.
1
3
m), 1.19 (1H, d, J¼10.2 Hz), 1.18e1.06 (2H, m); C NMR (75 MHz,
CDCl 179.2, 173.8, 52.1, 48.1, 47.8, 47.1, 47.0, 37.0, 36.9, 35.3, 23.9,
3.8, 19.9, 19.8. Anal. Calcd for C14 (252.14): C, 66.65; H, 7.99.
Found: C, 66.58; H, 7.99. GCeMS: The carboxylic acid (6) was O-
Anal. Calcd for C21
C, 71.04; H, 7.15; N, 3.93. GCeMS: [M] , m/z 355. Crystallographic
H
25NO
4
(355.18): C, 70.96; H, 7.09; N, 3.94. Found:
þ
3
)
d
2
H
20
O
4
data of (9):
C
21
H
25NO
4
,
M¼355.42, orthorhombic, Pbca,
ꢀ ꢀ
ꢀ1
3
a¼12.1273(3), b¼15.3221(5), c¼19.7539(6) A, V¼3670.59(19) A ,
ꢀ
3
methylated with diazomethane in Et
diester: [M] , m/z 266.
2
O to give the corresponding
Z¼8, D
c
¼1.286 g cm
,
m
(Mo K
a)¼0.089 mm , F(000)¼1520,
þ
block, colorless, size¼0.40ꢃ0.20ꢃ0.20 mm, 11,378 reflections
measured (Rint¼0.0296), 3574 unique, wR
conventional R¼0.0362, [( max¼0.001] on F-values of 2439 re-
flections with I>2
2
¼0.0876 for all data,
4
.1.5. (ꢂ)-cis-3-(Methoxycarbonyl)-1,2,3,4,4a,5,8,8a-octahydro-1,4-
methanonaphthalene-2-carboxylic acid (7). meso-Anhydride (5)
2.26 g, 10.4 mmol) was dissolved in anhydrous methanol (90 mL)
D/s)
s
(I), S¼0.993 for all data and 239 parameters.
(
and refluxed for 18 h under argon. The reaction mixture was cooled
to ambient temperature and filtered through a pad of charcoal