G.H. Fülep et al. / European Journal of Medicinal Chemistry 41 (2006) 809–824
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5.1.28. (1S,5R)-1-(2,5-dihydropyrrol-1-ylcarbonyl)-5,8,8-
trimethyl-3-oxabicyclo[3.2.1]octan-2-one (10)
–78 °C. After 30 min tert-butyl acetate (320 μl, 2.4 mmol)
was added and the reaction mixture was stirred for 40 min al-
lowing it to warm to –30 °C. Following addition of diethylalu-
minum chloride (2.4 ml, 2.4 mmol, 1 M in hexane), the reac-
tion mixture was stirred for additional 20 min.
A solution of carboxylic acid 8 (3.79 g, 14.4 mmol) in
CH2Cl2 (60 ml) was cooled to 0 °C. Oxalyl chloride (1.78 g,
14.5 mmol) and DMF (15 μl) were added followed by the re-
moval of the ice bath. After bubbling had stopped, the reaction
mixture was flushed with nitrogen for one hour to remove ex-
cess of HCl. The reaction mixture was cooled to 0 °C followed
by the addition of NEt3 (3.54 g, 2.5 equiv.) and 3-pyrroline
(9.1 g, 14.4 mmol). The reaction mixture was warmed to rt
and stirred for 12 h. CH2Cl2 (30 ml) was added and the organic
layers were extracted with HCl (0.5 M), dried (MgSO4), and
concentrated in vacuo. Purification by CC (petrolether/
EtOAc = 7:3) and recrystallization from petrolether/EtOAc
(7:3). Yield: 3.254 g (86%); colorless crystals, m.p. 108 °C.
[α]D20 = +97.9 (c = 0.65, CHCl3). 1H NMR (CDCl3, 0 °C):
δ = 0.91 (s, 3H, CH3), 1.09 (s, 3H, CH3), 1.38 (s, 3H, CH3),
1.86–1.97 (m, 2H, CH2CH2), 2.27 (dt, J = 11.0, 5.1 Hz, 1H,
CH2CH2), 2.43 (ddd, J = 13.9, 11.0, 5.9 Hz, 1H, CH2CH2),
3.94 (d, J = 11.3 Hz, 1H, CH2O), 4.15 (dd, J = 11.3, 2.2 Hz,
1H, CH2O), 4.12–4.18 (m, 1H, NCH2), 4.23 (ddd, J = 13.9, 5,
2.2 Hz, 1H, NCH2), 4.39 (ddd, J = 13.9, 5, 2.2 Hz, 1H, NCH2),
4.56 (ddd, J = 16.9, 5, 2.2 Hz, 1H, NCH2), 5.75 (ddd, J = 6.6, 5,
Electrophilic α-amidoalkylation: Anhydrous CH2Cl2 (1 ml
per 0.1 mmol of 11) was saturated with gaseous HCl for
20 min at –85 °C using a gas-tight syringe. Enamide 11
(0.158 g, 0.6 mmol, 0.2 M in CH2Cl2) was added dropwise
under vigorous stirring. Concurrently, the treatment of the so-
lution with gaseous HCl was continued for another 10–20 min
followed by the removal of excess of HCl in vacuo (for 1 h at
–78 °C). The organometallic reagent 13 (6.6 ml, 4 equiv.) was
added dropwise and the reaction mixture was stirred for 16 h.
The reaction was quenched with water and the aqueous layer
was extracted with CH2Cl2. The combined organic layers were
extracted with brine, dried (MgSO4) and concentrated in va-
cuo. Purification by CC (petrolether/EtOAc = 7:3). Yield:
203 mg (89%) (diastereomeric mixture of (S)-14 and (R)-14).
HPLC (n-heptane/EtOAc = 80:20; 1.5 ml min–1); (S)-14: tR
= 16.1 min, 81.2%; (R)-14: tR = 20.4 min, 18.8%. Separation
of the diastereomers by prep. HPLC (n-heptane/
EtOAc = 82:18; 13.5 ml min–1; (S)-14: tR = 33.8 min; (R)-14:
tR = 43.6 min).
2.2 Hz, 1H, HC=), 5.85 (ddd, J = 6.6, 5, 2.2 Hz, 1H, HC=). IR
–1
~
(KBr): n = 2960 cm , 2862, 1724, 1644, 1622. MS (70 eV);
(S)-14: Yield: 154 mg (67%); colorless crystals, m.p.
m/z (%): 264 (1) [M + 1]+, 235 (1), 195 (1), 168 (1), 139 (3),
135 °C. [α]D20 = +18.2 (c = 1.07, CHCl3). H NMR (CDCl3,
1
123 (3), 95 (4), 81 (11), 68 (100). C15H21NO3 (263.34).
20 °C): δ = 0.88 (s, 3H, CH3), 1.03 (s, 3H, CH3), 1.35 (s, 3H,
CH3), 1.43 (s, 9H, C(CH3)3), 1.63–1.69 (m, 1H,
NCH2CH2CH2), 1.74–1.96 (m, 4H, NCH2CH2CH2,
CH2CH2), 2.14–2.24 (m, 2H, CH2CH2), 2.31–2.43 (m, 2H, C
H2CH2, CH2COO), 2.85 (dd, J = 15.5, 3.8 Hz, 1H, CH2COO),
3.21 (td, J = 9.5, 6.5 Hz, 1H, NCH2), 3.72 (ddd, J = 9.5, 7.3,
2.4 Hz, 1H, NCH2), 3.91 (d, J = 11.0 Hz, 1H, CH2OC=O),
5.1.29. (1S,5R)-1-(2,3-dihydropyrrol-1-ylcarbonyl)-5,8,8-
trimethyl-3-oxabicyclo[3.2.1]octan-2-one (11)
A mixture of compound 10 (1.0 g, 3.8 mmol) and hydrido-
tetrakis(triphenylphosphine)rhodium(I) (15 mg) in xylene
(4 ml) was stirred in a sealed tube at 140 °C for 44 h. The
reaction mixture was filtrated and the filtrate was concentrated
in vacuo. Purification by CC (petrolether/EtOAc/ethyldimethy-
lamine = 80:20:1) and recrystallization from cyclohexene.
4.12 (dd, J = 11.0, 2.2 Hz, 1H CH2OC=O), 4.42 (qd, J = 8.1,
–1
~
3.8 Hz, 1H, NCHC). IR (KBr): n = 2980 cm , 2870, 1720,
+
1626. MS (CI, CH5 ); m/z (%): 380 (10) [M + 1]+, 360 (7),
20
324 (100), 184 (4), 128 (3). C21H33NO5 (379.50).
Yield: 700 mg (70%); colorless crystals, m.p. 105 °C. [α]D
= +46.3 (c = 0.68, CHCl3). 1H NMR (nitrobenzene-d5,
130 °C): δ = 0.91 (s, 3H, CH3), 1.07 (s, 3H, CH3), 1.35 (s, 3H,
CH3), 1.80–2.00 (m, 2H, CH2CH2), 2.18–2.33 (m, 1H,
CH2CH2), 2.45–2.70 (m, 3H, NCH2CH2, CH2CH2), 3.89–
3.96 (m, 2H, NCH2), 3.99 (d, J = 11.0 Hz, 1H, CH2O), 4.19
(dd, J = 11.0, 2.2 Hz, 1H, CH2O), 5.11–5.20 (m, 1H,
(R)-14: Yield: 36 mg (16%); colorless crystals, m.p.: 89 °C.
[α]D20 = +56.6 (c = 1.1, CHCl3). 1H NMR (nitrobenzene-d5,
140 °C): δ = 0.88 (s, 3H, CH3), 1.07 (s, 3H, CH3), 1.35 (s, 3H,
CH3), 1.51 (s, 9H, C(CH3)3), 1.82–2.06 (m, 6H,
NCH2CH2CH2, CH2CH2), 2.26 (ddd, J = 15.0, 10.0, 5.6 Hz,
1H, CH2CH2), 2.35 (dd, J = 15.6, 9.3 Hz, 1H, CH2COO),
2.61–2.72 (m, 1H, CH2CH2), 3.18 (dd, J = 15.6, 3.7 Hz, 1H,
CH2COO), 3.43–3.50 (m, 1H, NCH2), 3.62 (dt, J = 10.6,
6.9 Hz, 1H, NCH2), 3.92 (d, J = 11.1 Hz, 1H, CH2OC=O),
~
NCH=CH), 6.71–6.79 (m, 1H, NCH=). IR (KBr): n =
2973 cm–1, 2917, 2890, 1731, 1633, 1612. MS (70 eV ): m/z
(%): 263 (40) [M + 1]+, 247 (13), 195 (60), 167 (37), 139 (69),
121 (27), 81 (79), 67 (100). C15H21NO3 (263.34).
4.17 (dd, J = 11.1, 2.0 Hz, 1H, CH2OC=O), 4.60–4.67 (m,
–1
~
1H, NCHC). IR (KBr): n = 2976 cm , 2880, 1729, 1628.
MS (CI, CH5 ); m/z (%): 380 (10) [M + 1]+, 360 (4), 324
+
5.1.30. 1,1-Dimethylethyl {(2S)-1-[(1S,5R)-5,8,8-trimethyl-2-
oxo-3-oxabicyclo[3.2.1]octan-1-ylcarbonyl]pyrrolidin-2-yl}
acetate [(S)-14] and 1,1-dimethylethyl {(2R)-1-[(1S,5R)-5,8,8-
trimethyl-2-oxo-3-oxabicyclo[3.2.1]octan-1-ylcarbonyl]
pyrrolidin-2-yl}acetate} [(R)-14]
Synthesis of the organometallic reagent (13): n-butyllithium
(1.5 ml, 2.4 mmol, 1.6 M in hexane) was added to a solution of
diisopropylamine (315 μl, 2.4 mmol) in THF (2.4 ml) at
(100), 184 (3), 128 (3). C21H33NO5 (379.50).
5.1.31. Methyl {(E)-(S)-3-[1-(benzyloxycarbonyl)pyrrolidin-2-
yl]acrylate} and methyl {(Z)-(S)-3-[1-(benzyloxycarbonyl)
pyrrolidin-2-yl]acrylate} [(S)-18]
DIBAH (18 ml, 1 M in hexane) was added dropwise over
15 min to compound (S)-15 (2.346 g, 8.92 mmol) in toluene