3792
I. Izquierdo et al. / Tetrahedron 66 (2010) 3788–3794
0
0
0
mobility. The catalyst was filtered off, washed with MeOH and the
filtrate and washings were concentrated to a residue that was
dissolved in DCM (8 mL) and cooled (ice-water). To this stirred
solution, TFA (8 mL) was added and the mixture left for 1.5 h. TLC
(Et2O/hexane, 2:1, v/v) then revealed a non-mobile compound. The
solvent was eliminated and the residue co-distilled with toluene to
a new residue, which was dissolved in MeOH and basified by ad-
dition of 2 N MeONa/MeOH and refluxed for 2 h. TLC (Et2O/MeOH,
20:1, v/v) showed a slower running compound. The reaction mix-
ture was neutralized and submitted to column chromatography
(Et2O/MeOH, 20:1/10:1, v/v) to afford pure 14 (270 mg, 86% from
J3,8¼4.1, J8,8 ¼12.1 Hz, H-8), 3.81 (dd, 1H, J3,8 ¼8.0 Hz, H-8 ), 3.76
0
(dd, 1H, H-1), 3.39 (dt, 1H, J1,7a¼2.4, J7a,7¼J7a,7 ¼7.9 Hz, H-7a), 3.21
0
(dt,1H, H-3), 2.91 (ddd,1H, J¼2.1, 9.0 Hz, H-5), 2.79 (dt,1H, J5,5 ¼9.8,
J¼5.8 Hz, H-50), 2.14 (ddt, 1H, J¼2.5, 7.6, J7,7 ¼12.6 Hz, H-7), 1.87 (m,
0
1H, H-6), 1.69 (m, 1H, H-60) and 1.50 (ddt, 1H, J¼7.6, J¼10.4 Hz, H-
70) ppm; 13C NMR:
d 76.9 (C-1), 72.5 (C-2), 72.1 (C-7a), 67.1 (C-3),
60.9 (C-8), 49.1 (C-5), 30.9 (C-7) and 27.4 (C-6) ppm; HRMS
(LSIMS): calcd for C8H15NO3 [Mþ] 173.1050; found 173.1052 (de-
viation þ0.8 ppm).
4.2.8. 4-[(3E,20S,30S,40R,50R)-50-(Benzoyloxymethyl)-30,40-bis(di-
benzyloxy)-N0-(tert-butyloxycarbonyl)pyrrolidin-20-yl]but-3-en-2-
one (16). To a stirred solution of 8 (785 mg, 1.44 mmol) in dry DCM
(15 mL) were added activated 4 Å molecular sieves (100 mg), NMO
(250 mg, 2.15 mmol) and TPAP (100 mg) and the reaction mixture
was kept at rt for 90 min. TLC (Et2, 3:1, v/v) then indicated the
absence of the starting material and the presence of a faster-
running compound. The reaction was diluted with Et2O (50 mL),
filtered through a bed of Silica gel 60 (Scharlau, 230–400 mesh) and
thoroughly washed with Et2O. The combined filtrate and washings
were concentrated to afford presumably aldehyde 9. This material
was used in the next step.
To a stirred solution of the above 9 in dry toluene (20 mL) 1-
(triphenylphosphoranyliene)-2-propanone (685 mg, 2.15 mmol)
was added and the mixture refluxed. After 8 h, TLC (Et2O/hexane,
3:1, v/v) revealed the presence of a new compound of slightly lower
mobility. The solvent was eliminated and the residue was sup-
ported on silica gel and chromatographed (Et2O/hexane, 1:5, v/v) to
27
27
12) as a colourless syrup, which had [
CHCl3); IR (neat): 3365 (OH), 3031 (aromatic), 1667 (C]O lactam),
739 and 698 cmꢀ1 (aromatic); 1H NMR (500 MHz):
7.40–7.28 (m,
a
]
ꢀ6, [
a
]
ꢀ10 (c 1,
D
405
n
d
10H, 2Ph), 4.66 and 4.63 (2d, 2H, J¼12.0 Hz, CH2Ph), 4.61 and 4.50
(2d, 2H, J¼11.9 Hz, CH2Ph), 4.21 (m, 1H, H-7a), 3.93 (dd, 1H, J3,8¼2.6,
0
J8,8 ¼12.0 Hz, H-8), 3.86 (dd, 1H, J1,2¼5.5, J2,3¼3.0 Hz, H-2), 3.83 (m,
0
0
1H, H-3), 3.68 (dd, 1H, J3,8 ¼7.9 Hz, H-8 ), 3.51 (dd, 1H, J1,7a¼7.9 Hz,
0
0
0
H-1), 2.68 (ddd, 1H, J6,6 ¼16.7 Hz, H-6), 2.44 (dd,1H, J6 ,7 ¼8.9 Hz, H-
60), 2.28 (br dt, 1H, J6,7¼J7,7a¼7.8, J7,7 ¼12.3 Hz, H-7), 1.74 (tt, 1H,
0
J6,7 ¼12.3, J7 ,7a¼9.2 Hz, H-70) ppm; 13C NMR (inter alia):
d
174.5 (C-
0
0
5), 81.9 (C-2), 81.0 (C-1), 72.5 and 72.4 (2CH2Ph), 65.6 (C-7a), 64.7
(C-3), 63.0 (C-8), 35.7 (C-6) and 26.9 (C-7) ppm; HRMS (LSIMS):
calcd for C22H25NO4Na [MþNa]þ 390.1675; found 390.1681 (de-
viation þ1.7 ppm).
4. 2. 6. (1S, 2R, 3R, 7aS)-1, 2-Bis(benzyloxy)-3-(hydroxy-
methyl)pyrrolizidine (15). An H3B$SMe2 complex solution in an-
hydrous THF (10 M, 670
m
L) was added dropwise to a stirred
give pure 16 (600 mg, 71% from 8) as a colourless syrup, which had
26
solution of 14 (247 mg, 0.67 mmol) in anhydrous THF (10 mL) un-
der argon and the mixture left at rt for 1.5 h. TLC (Et2O/MeOH, 5:1,
v/v) then revealed the absence of 14 and the presence of a faster-
running compound, presumably the borane/amine complex. MeOH
(1 mL) was cautiously added, and the reaction mixture was con-
centrated to a residue, which was dissolved in MeOH (5 mL) and
refluxed for 12 h, by which time the borane–amine complex was no
longer observed by TLC. The reaction mixture was concentrated,
and the residue was purified by chromatography on silica gel (Et2O/
[
a
]
ꢀ30 (c 1, CHCl3); IR (neat):
n
3063 and 3031 (aromatic), 1722
-unsaturated ketone and >NBoc), 738 and
712 cmꢀ1 (aromatic); 1H NMR (400 MHz):
D
and 1699 (BzO,
a,b
d
7.79 (d, 2H, Jo,m¼7.2 Hz,
ortho-H, Bz), 7.49 (t,1H, Jm,p¼7.2 Hz, para-H, Bz), 7.32 (t, 2H, meta-H,
0
Bz), 7.30–7.18 (m, 10H, 2Ph), 6.46 (dd, 1H, J2 ,4¼6.0, J3,4¼16 Hz, H-4),
6.08 (d, 1H, H-3), 4.78–3.79 (4br m, 10H, 2CH2Ph and H-
20,30,40,50,500a,500b), 2.00–1.90 (2br s, 3H, H-1,1,1, two rotamers), 1.41
and 1.32 (2br s, 9H, CMe3, two rotamers) ppm; 13C NMR (inter alia):
d
197.7 (C-2), 166.1 (Bz), 155.1 (Boc), 145.9 and 144.2 (C-3,4), 81.0,
MeOH, 15:1, v/v/Et2O/MeOH/NH4OH, 5:1:0.5, v/v) to give pure 15
78.4, 76.9 and 75.7 (C-30,40, two rotamers), 71.6 (2CH2Ph), 63.1 (C-
500), 61.8 and 60.3 (C-20,50), 28.0 (CMe3) and 27.2 (C-1) ppm; HRMS
(LSIMS): calcd for C35H39NO7Na [MþNa]þ 608.2621; found
608.2624 (deviation þ0.6 ppm).
29
(140 mg, 59%) as a colourless viscous syrup. [
IR (neat):
(500 MHz, MeOH-d4):
a]
þ91 (c 1, MeOH);
D
n
3330 (OH), 3031, 737 and 698 cmꢀ1 (aromatic); 1H NMR
7.37–7.22 (m, 10H, 2Ph), 4.58 and 4.51 (2d,
d
J¼11.5 Hz, 2H, CH2Ph), 4.57 and 4.53 (2d, J¼11.8 Hz, 2H, CH2Ph),
3.86 (dd, J1,2¼5.1, J2,3¼8.4 Hz, 1H, 2-H), 3.82 (dd, J3,8¼4.1,
4.2.9. (1S,2R,3R,5S,7aS)-1,2-Bis(benzyloxy)-3-(hydroxymethyl)-5-
methylpyrrolizidine (19). Compound 16 (600 mg, 1.03 mmol) in
MeOH (20 mL) was hydrogenated with H2 from a balloon over 10%
Pd/C (100 mg) for 2 h. The reaction mixture was filtered and an
aliquot was concentrated to afford intermediate saturated ketone
(IR evidence). The reaction mixture was then acidified with concd
HCl (0.2 mL) and left at rt for 72 h. Neutralization of the reaction
mixture with 2 N MeONa/MeOH and subsequent hydrogenation in
the presence of 10% Pd/C (100 mg) for 12 h, gave after removal of
the catalyst and column chromatography (Et2O/hexane 1:3/Et2O)
compound 18 (150 mg) slightly contaminated. Finally, Zemplen
debenzoylation of 18 with 2 N MeONa/MeOH (0.5 mL) for 12 h
0
0
0
J8,8 ¼12.1 Hz, 1H, 8-H), 3.75 (dd, J3,8 ¼8.0 Hz, 1H, 8 -H), 3.74 (dd, 1H,
0
1-H), 3.57 (dt, J1,7a¼3.1, J7a,7¼J7a,7 ¼8.0 Hz, 1H, 7a-H), 3.43 (dt, 1H, 3-
0
H), 2.89 (ddd, J¼6.7, J¼2.4, J5,5 ¼9.5 Hz, 1H, 5-H), 2.79 (dt, J¼9.8,
J¼5.6 Hz, 1H, 50-H), 2.09 (ddt, J¼2.4, 7.4, J7,7 ¼12.6 Hz, 1H, 7-H), 1.85
0
(m, 1H, 6-H), 1.70 (m, 1H, 60-H), 1.42 (ddt, J¼7.7, 10.6 Hz, 1H, 70-
H) ppm; 13C NMR (inter alia):
d 85.2 (C-1), 82.4 (C-2), 75.9 and 75.5
(2CH2Ph), 72.1 (C-7a), 68.7 (C-3), 63.6 (C-8), 51.6 (C-5), 33.9 (C-7),
30.3 (C-6) ppm; HRMS (LSIMS): calcd for C22H28NO3 [MþH]þ
354.2069; found 354.2068 (deviation ꢀ0.2 ppm).
4.2.7. (1S,2R,3R,7aS)-1,2-Dihydroxy-3-hydroxymethylpyrrolizidine
[(þ)-7a-epi-hyacinthacine A1 (3)]. Compound 15 (120 mg,
0.34 mmol) in MeOH (15 mL) and concd HCl (five drops) was hy-
drogenated (482 kPa H2) in the presence of 10% Pd/C (50 mg) for
20 h. The catalyst was filtered off, washed with MeOH and the
combined filtrate and washings treated with Amberlite IRA-400
resin (OHꢀ form). Evaporation of the solvent afforded a residue
that was retained on to a column of Dowex 50Wx8 (200–
400 mesh). The column was thoroughly washed with MeOH, water
and then with 1 N NH42O7H to afford pure 3 (55 mg, 93%) as a col-
followed by column chromatography (Et2O/hexane, 1:1/2:1, v/v)
24
then afforded pure 19 (90 mg, 24% from 16) as a syrup. [
1, CHCl3); IR (neat):
(aromatic); 1H NMR (500 MHz):
a]
þ35 (c
D
n
3441 (OH), 3063, 3031, 736 and 697 cmꢀ1
7.36–7.26 (m, 10H, 2Ph), 4.79 and
d
4.57 (2d, 2H, J¼11.8 Hz, CH2Ph), 4.60 and 4.58 (2d, 2H, J¼12.5 Hz,
CH2Ph), 4.20 (dd, 1H, J1,2¼6.0, J2,3¼3.7 Hz,0 H-2), 3.71 (dd, 1H,
0
J3,8¼3.2, J8,8 ¼11.0 Hz, H-8), 5.53 (m, 2H, H-1,8 ), 3.16 (m, H-7a), 2.78
0
(br s, 1H, H-3), 2.56 (br sex, 1H, J5,6¼J5,6 ¼6.0 Hz, H-5), 2.21 (m, 1H,
H-6), 1.79 (m, 1H, H-7), 1.78 (m, 1H, H-60), 1.44 (m, 1H, H-70) and 1.13
ourless thick syrup. [
a
]
þ47 (c 0.65, water); 1H NMR (500 MHz,
(d, 3H, JMe,5¼6.0 Hz, Me) ppm; 13C NMR:
¼138.7, 128.5, 128.18 and
d
D
MeOH-d4):
d
3.88 (dd, 1H, J1,2¼5.5, J2,3¼9.0 Hz, H-2), 3.84 (dd, 1H,
127.75 (CH2Ph), 85.3 (C-2), 80.2 (C-1), 73.1 and 72.1 (2CH2Ph), 72.7