9542
S.M. Allin et al. / Tetrahedron 66 (2010) 9538e9544
(400 MHz, DMSO, 100 ꢀC) 1.45 (9H, s), 1.46 (9H, s), 2.31e2.35 (1H,
m), 2.72e2.78 (1H, m), 2.85e3.02 (2H, m), 3.50e3.59 (2H, m),
4.15e4.18 (1H, m), 4.41 (1H, t, J¼6.0 Hz), 4.53 (1H, dd, J¼4.4, 8.4 Hz),
4.79 (1H, t, J¼6.8 Hz), 7.18e7.26 (4H, m), 8.40 (1H, br s). 13C NMR
(100 MHz, DMSO, 100 ꢀC) 28.4 (3C), 28.5 (3C), 29.4, 30.3, 49.9, 52.7,
60.4, 61.7, 80.3, 81.2, 124.3, 126.8, 127.3, 129.4, 133.8, 137.8, 154.6,
156.0, 164.9. IR (thin film, CH2Cl2, cmꢁ1) 3409, 3273, 1697. MS (EI)
m/z 448 [MþHþ, 4%] (Calcd for C23H34N3O6: 448.2449 (MþHþ).
Found: 448.2441.).
period and the reaction stirred at room temperature for 17 h. The
reaction mixture was added to a solution of saturated brine/ethyl
acetate (1:1) (50 ml) and product extracted with ethyl acetate
(3ꢂ50 ml). The organic extracts were combined and washed with
a 1 M solution of sodium hydrosulfite, dried over anhydrous
magnesium sulfate, filtered and evaporated under reduced pres-
sure to a crude brown residue. The crude product was adsorbed
onto silica and chromatographed using silica gel as absorbent and
2:1 light petroleum/ethyl acetate as eluent to produce a yellow
solid (713 mg, 80%). The product still contained some impurities
that we were unable to remove by chromatography. For this
reason, the intermediate carboxylic acid was reacted on in its crude
state.
4.1.6. 2-((2S,5S,10bR)-5-(Hydroxymethyl)-3-oxo-1,2,3,5,6,10b-hexahy-
dropyrrolo[2,1-a]isoquinolin-2-yl)hydrazine, (6). Di-tert-butyl-1-((2S,
5S,10bR)-5-(hydroxymethyl)-3-oxo-1,2,3,5,6,10b-hexahydropyrrolo[2,
1-a]isoquinolin-2-yl)hydrazinocarboxylate, 5, (90 mg, 0.20 mmol)
and trifluoroacetic acid (0.78 ml, 10.1 mmol) were allowed to stir at
room temperature under a nitrogen atmosphere for 24 h. After this
time the mixture was concentrated under reduced pressure, and the
residue treated with an aqueous 3 M solution of HCl (15 ml) and the
solution allowed to stir for further 1 h. After this time the solution
was concentrated under reduced pressure and the residue dissolved
in water (20 ml) and washed with ethyl acetate (3ꢂ20 ml). The
aqueous phase was then evaporated to dryness using a rotary evap-
orator to yield a yellow oil (30 mg, 70%). Rf (10% MeOH/DCM) 0.11.
4.1.9. (2S,5S,10bR,30S)-2-N,N0-Bis-(3,3-tert-butyl ester)-hydrazino-2-
[(3-oxo-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline-5-car-
bonyl)-amino]-3-phenyl-propionic acid methyl ester, (8). (2S,5S,10bR)-
2-N,N0-Bis-(3,3-tert-butyl ester)-hydrazino-3-oxo-1,2,3,5,6,10b-hexa
hydro-pyrrolo[2,1-a]isoquinoline-5-carboxylic acid, 7, (713 mg,
1.55 mmol) was dissolved in anhydrous dichloromethane (30 ml)
and cooled to ꢁ15 ꢀC under nitrogen. 1-Hydroxyazabenzotriazole
(231 mg, 1.70 mmol) and 1-ethyl-3-[(dimethylamino) propyl]carbo-
diimide hydrochloride (326 mg, 1.70 mmol) were added and re-
action stirred for 20 min at ꢁ15 ꢀC. N-Methyl morpholine (172 mg,
0.19 ml, 1.70 mmol) and (S)-phenylalanine methyl ester hydrochlo-
ride (366 mg, 1.70 mmol) were added and the reaction stirred for
a further 3 h at ꢁ15 ꢀC. An ice-cold solution of 1 M HCl (6 ml) was
added and reaction extracted with dichloromethane (3ꢂ30 ml). The
organic phase was washed with saturated sodium bicarbonate, dried
over anhydrous magnesium sulfate, filtered and the solvent removed
by rotary evaporation to yield a crude orange residue. The crude
product was adsorbed onto silica and chromatographed using silica
gel as absorbent and 1:1 ethyl acetate/light petroleum as eluent to
[
a
]
20 þ14.5 [c 0.58 in MeOH]. 1H NMR (400 MHz, D2O) 2.38e2.46 (1H,
D
m), 2.51e2.58 (1H, m), 2.67 (1H, dd, J¼3.2, 16.4 Hz), 2.96 (1H, dd,
J¼6.8, 16.4 Hz), 3.51e3.59 (1H, dd, J¼8.8, 12 Hz), 3.62e3.67 (1H, dd,
J¼5.2, 12 Hz), 3.83e3.86 (1H, dd, J¼4.4, 8.8 Hz), 4.22e4.28 (1H, m),
4.92 (1 t, J¼7.2 Hz), 7.10e7.37 (4H, m). 13C NMR (100 MHz, D2O) 28.5,
29.5, 49.7, 52.7, 59.2, 60.7, 124.3, 126.9, 127.6, 129.2, 132.3, 135.4, 172.0.
IR (thin film, CH2Cl2, cmꢁ1) 3386, 1680. MS (EI) m/z 248 [MþHþ,100%]
(Calcd for C13H18N3O2: 248.1394 (MþHþ). Found: 248.1395).
4.1.7. (2S,5S,10bR)-2-N,N0-Bis-(3,3-tert-butyl
ester)-hydrazino-3-
oxo-1,2,3,5,6,10b-hexa hydro-pyrrolo[2,1-a]isoquinoline-5-carbalde-
hyde. o-Iodoxybenzoic acid (221 mg, 0.794 mmol) was added to
a solution of (2S,5S,10bR)-2-N,N0-bis-(3,3-tert-butyl ester)-hydra-
zino-5-hydroxymethyl-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]iso-
quinolin-3-one, 5, (237 mg, 0.530 mmol) in dimethyl sulfoxide
(20 ml) and the reaction stirred for 24 h at room temperature. The
reaction mixture was added to a solution of ethyl acetate/water
and the organic product extracted with ethyl acetate (3ꢂ30 ml).
The organic layer was washed with water (3ꢂ30 ml), dried over
anhydrous magnesium sulfate, filtered and evaporated to a crude
yellow solid. The crude product was adsorbed onto silica and
chromatographed using silica gel as absorbent and 1:1 ethyl ace-
tate/light petroleum as eluent to isolate the target compound as
a colourless solid (144 mg, 61%). Mp 84e87 ꢀC. Rf (2:1, petroleum
isolate the target compound as a colourless solid (549 mg, 57%). Mp
20
89e92 ꢀC. Rf (EtOAc) 0.75. [
a]
D
ꢁ28.0 [c 1.10 in CH2Cl2]. 1H NMR
(400 MHz, DMSO, 100 ꢀC) 1.48 (18H, s), 2.34 (1H, ddd, J¼6.0, 10.0,
13.6 Hz), 2.76e2.82 (1H, m), 2.91e3.05 (2H, m), 3.07e3.23 (2H, m),
3.60 (3H, s), 4.48 (1H, dd, J¼4.4, 9.6 Hz), 4.59e4.64 (1H, m),
4.67e4.72 (1H, m), 4.76 (1H, dd, J¼3.6, 7.2 Hz), 7.05e7.26 (9H, m),
7.75 (1H, d, J¼8.0 Hz), 8.62 (1H, br s). 13C NMR (100 MHz, DMSO,
100 ꢀC) 28.4 (3C), 28.6 (3C), 29.8, 30.5, 37.4, 50.8, 52.1, 52.9, 54.1, 60.9,
80.4, 81.5, 124.7, 126.8, 126.9, 127.2, 128.5 (2C), 129.0, 129.3 (2C),
132.7, 137.4, 137.6, 154.8, 155.9, 169.6, 169.8, 171.9. IR (thin film,
CH2Cl2, cmꢁ1) 3342, 1738, 1699. MS (ES) m/z 623 [MþHþ, 100%]
(Calcd for C33H43N4O8: 623.3081 (MþHþ). Found 623.3077).
4.1.10. 1-Benzyl 2-tert-butyl hydrazine-1,2-dicarboxylate10,11. A so-
lution of Boc-hydrazine (3.20 g, 24.21 mmol) in dichloromethane
(100 ml) was cooled to ꢁ78 ꢀC under a nitrogen atmosphere. Ben-
zyl chloroformate (4.09 ml, 29.06 mmol) was cautiously added
with stirring, followed by sodium carbonate (2.50 g, 24.21 mmol).
The reaction was then stirred for 24 h. After this time the reaction
mixture was evaporated to dryness and redissolved in hot ethyl
acetate (100 ml, refluxed for 1 h). The hot solution was then filtered
and the solvent removed by evaporation under reduced pressure to
yield a white solid that was used without further purification
(6.31 g, 98%). Mp 252e253 ꢀC. 1H NMR (400 MHz, CDCl3) 1.53 (9H,
s), 5.17 (2H, s), 6.33 (1H, s), 6.53 (1H, s), 7.31e7.37 (5H, m). 13C NMR
(400 MHz, CDCl3) 28.1 (3C), 67.8, 81.9,127.0,128.3, 128.4 (2C), 128.6,
135.6, 155.7, 156.7. IR (thin film, CH2Cl2, cmꢁ1) 3302, 1715. MS (EI)
m/z 266 [MþHþ, 100%] (Calcd for C13H19N2O4: 267.1339 (MþHþ).
Found: 267.13418).
ether/EtOAc) 0.6. [
a
]
20 ꢁ8.80 [c 1.00 in CH2Cl2]. 1H NMR (400 MHz,
D
DMSO, 100 ꢀC) 1.46 (18H, s), 2.31e2.38 (1H, m), 2.83e3.20 (3H, m)
4.65 (1H, dd, J¼3.2, 9.2 Hz), 4.72 (1H, dd, J¼5.2, 7.6 Hz), 4.89 (1H, t,
J¼7.2 Hz), 7.17e7.36 (4H, m), 8.57 (1H, br s), 9.64 (1H, s). 13C NMR
(100 MHz, DMSO, 100 ꢀC) 26.9, 28.4 (3C), 28.5 (3C), 31.2, 53.3, 56.7,
60.0, 80.4, 81.3, 124.7, 127.4, 127.5, 129.1, 132.3, 137.4, 154.5, 156.0,
170.0, 200.0. IR (thin film, CH2Cl2, cmꢁ1) 3281, 1730, 1700. MS (ES)
m/z 446 [MþHþ, 100%] (Calcd for C23H32N3O6: 446.2291 (MþHþ).
Found: 446.2364).
4.1.8. (2S,5S,10bR)-2-N,N0-Bis-(3,3-tert-butyl
ester)-hydrazino-3-
oxo-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline-5-carboxylic
acid, (7). A solution of (2S,5S,10bR)-2-N,N0-bis-(3,3-tert-butyl
ester)-hydrazino-3-oxo-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]iso-
quinoline-5-carbaldehyde (862 mg, 1.94 mmol) in acetonitrile
(28 ml), tert-butanol (80 ml) and 1-methyl-1-cyclohexene (28 ml)
was stirred rapidly as it cooled to 0 ꢀC. A solution of sodium chlorite
(1.68 g, 14.9 mmol) and sodium dihydrogen phosphate (1.63 g,
13.5 mmol) in water (55 ml) was added dropwise over a 10 min
4.1.11. (E)-1-Benzyl 2-tert-butyl diazene-1,2-dicarboxylate, (9)10,11. 1-
Benzyl 2-tert-butyl hydrazine-1,2-dicarboxylate (3.29 g,12.48 mmol)
wasaddedinoneportiontoasolutionofN-bromosuccinimide(1.34 g,