Heck reaction on morita-baylis-hillman adducts: Diastereoselective synthesis of pyrrolizidinones and pyrrolizidines

Article abstract of DOI:10.1055/s-0030-1261161

An efficient approach to the diastereoselective synthesis of benzylidene-, benzyl-pyrrolizidinones, and pyrrolizidines is described. The sequence is based on a highly stereoselective Heck reaction between a hydroxylated pyrrolizidinone, prepared from a Morita-Baylis-Hillman adduct, and a suitable aryl halide, using Nájeras oxime derived palladacycle as catalyst. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1261161

Accounts and
Rapid Communications in
Synthetic Organic Chemistry
SYNLETT
SUPPORTING INFORMATION
Supporting Information
for DOI: 10.1055/s-0030-1261161
©
Georg Thieme Verlag KG Stuttgart · New York 2011
Thieme

S1
SUPPORTING INFORMATION
Heck reaction on Morita-Baylis-Hillman adduct: diastereoselective
synthesis of pyrrolizidinones and pyrrolizidines
Kristerson R. de Luna Freire, Cláudio F. Tormena and Fernando Coelho*
Universidade Campinas – UNICAMP - Instituto de Química – 13083-970 – Caixa Postal
6
154 – Campinas, SP – Brazil; E-mail: coelho@iqm.unicamp.br
Experimental procedure
Page
(
(
(
(
(
(
(
(
(
(
(
2R,4R)-tert-Butyl 2-formyl-4-hydroxypyrrolidine-1-carboxylate (7)
S4
2R,4R)-tert-Butyl
4-hydroxy-2-((S)-1-hydroxy-2- S4-S5
methoxycarbonyl)allyl)pyrrolidine-1-carboxylate (8)
1S,6R,7aR)-1,6-dihydroxy-2-methylenetetrahydro-1H-pyrrolizin-3(2H)-one (11) S5-S6
2S,4R)-tert-butyl 2-formyl-4-hydroxypyrrolidine-1-carboxylate (9)
S6
2S,4R)-tert-butyl 4-hydroxy-2-((R)-1-hydroxy-2- S6-S7
methoxycarbonyl)allyl)pyrrolidine-1-carboxylate (10)
1R,6R,7aS)-1,6-dihydroxy-2-methylenetetrahydro-1H-pyrrolizin-3(2H)-one (12)
1S,6R,7aR,E)-2-benzylidene-1,6-dihydroxytetrahydro-1H-pyrrolizin-3(2H)-one
14)
S7
S7-S8
1S,6R,7aR,Z)-1,6-dihydroxy-2-(4-hydroxybenzylidene)tetrahydro-1H-
S8
pyrrolizin-3(2H)-one (15)
1S,6R,7aR,Z)-1,6-dihydroxy-2-(4-nitrobenzylidene)tetrahydro-1H-pyrrolizin-
(2H)-ona (16)
(
S8-S9
3
(
1S,2S,6R,7aR)-2-benzyl-1,6-dihydroxytetrahydro-1H-pyrrolizin-3(2H)-one (18)
1S,2S,6R,7aR)-1,6-dihydroxy-2-(4-hydroxybenzyl)tetrahydro-1H-pyrrolizin-
S9
S9
(
3(2H)-one (20)
General experimental procedure for the amide carbonyl reduction of S9-S10
pyrrolizidinones 16, 17, 18 and 20
(1S,2R,6R,7aR)-2-benzylhexahydro-1H-pyrrolizine-1,6-diol (19)
(1S,2R,6R,7aR)-2-(4-hydroxybenzyl)hexahydro-1H-pyrrolizine-1,6-diol (21)
(1S,6R,7aR,Z)-2-benzylidenehexahydro-1H-pyrrolizine-1,6-diol (22)
S10
S10
S10

S2
(1S,6R,7aR,E)-2-(4-hydroxybenzylidene)hexahydro-1H-pyrrolizine-1,6-diol (23) S10-S11
References
S11
Table of spectra
Spectra
Pages
1
1
13
H- and C NMR spectra of cis-4-hydroxy-(D)-prolinal 7.
S12-S13
S14-S15
S16
13
H- and C NMR spectra of MBH adduct 8.
HRMS (ESI) of MBH adduct 8.
1
13
H-, C NMR spectra of pyrrolizidinone 11.
S17-S18
S19
HRMS (ESI) of pyrrolizidinone 11.
1
1
13
H and C NMR spectra of trans-hydroxy-prolinal 9.
S20-S21
S22-S23
S24
13
H and C NMR spectrum of MBH adduct 10.
HRMS (ESI) of MBH adduct 10.
1
13
H- and C NMR (500 MHz, (CD ) CO) spectrum of pyrrolizidinone 12.
S25-S26
S27
3
2
HRMS (ESI) of pyrrolizidinone 12.
nOe spectrum of pyrrolizidinone 12, irradiation at 1.59 ppm, H-7B.
nOe spectrum of pyrrolizidinone 12, irradiation at 3.73 ppm, H-5B.
nOe spectrum of pyrrolizidinone 12, irradiation at 3.89 ppm, H-7a.
nOe spectrum of pyrrolizidinone 12, irradiation at 4.53 ppm, H-1).
nOe spectrum of pyrrolizidinone 12, irradiation at 4.59 ppm, H-6).
S28
S28
S29
S29
S30
1
13
H- and C NMR spectra of benzylidene-pyrrolizidinone 14
-D NOESY spectrum of benzylidene-pyrrolizidine 14.
HRMS (ESI) of benzylidene-pyrrolizidinone 14.
S31-S32
S33
2
S34
1
13
H- and C NMR spectra of hydroxy-benzylidene-pyrrolizidinone 15.
-D NOESY spectrum of hydroxy-benzylidene-pyrrolizidinone 15.
HRMS (ESI) of hydroxy-benzylidene-pyrrolizidinone 15.
S35-S36
S37
2
S38
1
13
H- and C NMR spectra of p-nitro-benzylidene-pyrrolizidinone 16.
D-NOESY spectrum of p-nitro-benzylidene-pyrrolizidinone 16.
HRMS (ESI) of p-nitro-benzylidene-pyrrolizidinone 16.
S39-S40
S41
2
S42
1
13
H- and C NMR spectra of benzyl-pyrrolizidinone 18.
S43-S44

S3
HRMS (ESI) of benzyl-pyrrolizidinone 18.
S45
1
13
H- and C NMR spectra of hydroxy-benzyl-pyrrolizidinone 20.
HRMS (ESI) of hydroxy-benzyl-pyrrolizidinone 20.
S46-S47
S48
1
13
H- and C NMR spectra of benzylidene-pyrrolizidine 22.
D-NOESY spectrum of benzylidene-pyrrolizidine 22.
HRMS (ESI) of benzylidene-pyrrolizidine 22.
S49-S50
S51
2
S52
1
13
H- and C NMR spectra of hydroxy-benzylidene-pyrrolizidine 23.
D-NOESY spectrum of benzylidene-pyrrolizidine 23.
HRMS (ESI) of hydroxy-benzylidene-pyrrolizidine 23.
S53-S54
S55
2
S56
1
13
H- and C NMR spectra of benzyl-pyrrolizidine 19.
HMRS (ESI) of benzyl-pyrrolizidine 19.
S57-S58
S59
1
13
H- and C NMR spectra of hydroxy-benzyl-pyrrolizidine 21.
HRMS (ESI) of hydroxy-benzyl-pyrrolizidine 21.
S60-S61
S62
ATTACHMENT 1
Experimental procedure and spectra
Page
(
2R,4R)-2-(ethoxycarbonyl)-4-hydroxypyrrolidinium chloride (I)
2S,4R)-2-(ethoxycarbonyl)-4-hydroxypyrrolidinium chloride (II)
2S,4R)-1-tert-butyl 2-ethyl 4-hydroxypyrrolidine-1,2-dicarboxylate (III)
S63
S63
(
(
1
S63-S64
S65-S66
S67
13
H- and C NMR spectru of ester I.
HRMS (ESI) of ester I.
1
13
H- and C NMR (300 MHz, CD OD) spectrum of ester II.
S68-S69
S70
3
HRMS (ESI) of ester II.
1
13
H- and C NMR spectrum of ester III.
HRMS (ESI) of ester III.
S71-S72
S73

S4
Experimental procedures
(
2R,4R)-tert-Butyl 2-formyl-4-hydroxypyrrolidine-1-carboxylate (7):
A stirred solution of (2R,4R)-1-tert-butyl 2-ethyl 4-methoxypyrrolidine-
,2-dicarboxylate (0.25 g, 0.96 mmol, see attachment I for experimental
1
details) in anhydrous dichloromethane (5 mL), at -84 ºC and under argon
atmosphere, was slowly added (during 5 minutes) a toluene solution of DIBAL-H (1.0
mol/L solution, 1.9 ml, 2.89 mmol). The mixture was stirred for 20 min. At the same
temperature and the evolution was followed by TLC. The cooling bath was removed and a
saturated solution of sodium acetate (5 mL) was added. The reaction medium was poured
into a stirred mixture of ethyl ether (50 mL) and saturated ammonium chloride (10 mL).
After 2h, the gel formed was filtered over a pad of Celite® and the aqueous filtrate was
extracted again with ethyl ether. The organic phases were combined, dried over anhydrous
Na SO and evaporated. The residue was quickly filtered over a tiny amount of silica gel
2
4
(Hexane : AcOEt 40:60 to 20:80), to provide aldeyde 7, as colorless oil (0.190 g) in 92 %
yield. Hydroxy-aldehyde 7 should be stored at -20 ºC or used immediately after be
2
0
prepared. [α]D +45 (c 1.5; MeOH); IR (Film, νmax): 3377, 2974, 2931, 2838, 1728, 1646,
-
1 1
1
2
428, 1370, 1279 cm ; H NMR (250 MHz, DMSO-d , 90 ºC) δ 1.42 (9H, s), 1.89 (1H, m),
6
1
3
.23 (1H, m), 3.31 (1H, dd); 3.42 (1H, dd), 4.04 (1H, m), 4.27 (1H, m), 9.47 (1H, s); C
NMR (62.5 MHz, DMSO-d , 90 ºC) δ 28.5, 38.1, 55.2, 64.1, 68.7, 79.7, 154.7, 202.8;
6
+
HRMS (ESI-TOF) Calcd. for C H NO [M + H] 216.1236. Found 216.1245. GC
1
0
18
4
conditions: HP chiral, flow 1.5 mL/min; 100 °C; 10 °C/min up to 230 ºC; pos run: 230
°
C/15 min); T = 15.57 min (2); dr = 1:12.
R
CHO
Boc
HO
N
2
R,4R)-tert-Butyl
4-hydroxy-2-((S)-1-hydroxy-2-
(8):
HO
CO Me (methoxycarbonyl)allyl)pyrrolidine-1-carboxylate
A
2
HO
mixture of hydroxy-aldehyde 7 (0.23 g, 1.069 mmol), DABCO
N
(0.12 g, 1.069 mmol) and ethyl acrylate (2 mL) was sonicated for
Boc

S5
96 h (followed by GC). Then, the excess of methyl acrylate was removed under reduced
pressure (CAUTION: this operation should be performed under an efficient fume hood).
The residue was diluted with dichloromethane (20 mL). The organic phase was washed
with brine (3 x 30 mL), dried over anhydrous Na SO and evaporated. The crude residue
2
4
was purified by flash silica gel column chromatography (Hexane : CH Cl : AcOEt –
2
2
20
3.0:5.0:3.0) to provide adduct 8 (0.258 g), as a colorless oil, in 80 % yield. [α]D -2 (c 1.5;
MeOH); IR (Film, νmax): 3387, 2970, 2958, 2933, 2355, 2332, 1715, 1666, 1413, 1368,
1
1
155, 1090; H NMR (250 MHz, DMSO-d , 90 °C) δ 1.43 (s, 9H), 1.74 (dt, J = 13.9, 4.3
6
Hz, 1H), 1.92 (m, 1H), 3.10 (dd, J = 11.2, 3.9 Hz, 1H), 3.57 (dd, J = 11.2, 5.9 Hz, 1H), 3.71
1
3
(
s, 3H), 4.05 (m, 2H), 4.94 (m, 1H), 5.87 (t, J = 1.6 Hz, 1H), 6.17 (d, J = 1.3 Hz, 1H); C
NMR (62.5 MHz, DMSO-d , 90 ºC) δ 27.8, 32.9, 50.8, 54.8, 58.6, 67.4, 68.0, 78.0, 124.0,
6
+
1
42.2, 153.2, 165.6; HRMS (ESI-TOF) Calcd. for C H NO [M + H] 302.1604. Found
14 24 6
302.1681; GC conditions: HP chiral, flow 1.5 mL/min; 100 °C; 10 °C/min up to 230 ºC;
pos run: 230 °C/15 min); T = 22.97 min.
R
OH
O
(1S,6R,7aR)-1,6-dihydroxy-2-methylenetetrahydro-1H-pyrrolizin-
(2H)-one (11): To a stirred solution of Morita-Baylis-Hillman adduct
8 (0.20 g, 0.66 mmol) in toluene (3 mL), at 0 °C, was added
concentrated HCl (0.1 mL, 3.31 mmol). The resulting mixture was
further stirred for 5-7 min. Then, a 35% solution of NaOH was added
H
N
3
HO
(0.46 mL, 4 mmol) and the reaction was further stirred for 30 min, at room temperature.
The medium was neutralized to pH 7 (10% HCl solution) and the solvents were removed
under reduced pressure. The crude residue was purified by flash silica gel column
chromatography (CH Cl : MeOH - 95:05) to give pyrrolizidinone 11 (0.06 g) as a white
2
2
2
0
solid, in 57 % yield. [α]D -5 (c 2; EtOH); M.p. 93-94° C; IR (KBr): ν 3396, 3205, 2985,
-1 1
2
946, 2883, 1654, 1442 cm . H NMR (500 MHz, (CD ) CO) δ 1.67 (m, J = 13.4, 6.4, 4.4
3 2
Hz, 1H, H-7A), 2.35 (ddd, J = 13.4, 7.3, 5.6 Hz, 1H, H-7B), 3.17 (dd, J = 12.2, 5.2 Hz, 1H,

S6
H-5B), 3.57 (dd, J = 12.2, 2.9 Hz, 1H, H-5A), 3.62 (ddd, J = 7.3, 6.4, 5.2 Hz, 1H, H-7a),
4
1
6
1
.51 (m, J = 5.2, 3.2 Hz, 1H, H-6), 4.61 (m, J = 5.2, 2.9 Hz, 1H, H-1), 5.47 (d, J = 2.6 Hz,
1
3
H, CH ), 5.82 (d, J = 3.0 Hz, 1H, CH ); C NMR (62.5 MHz, (CD ) CO) δ 38.3, 51.6,
2
2
3 2
+
5.7, 71.9, 75.7, 114.8, 148.4, 168.3; HRMS (ESI-TOF) Calcd. for C H NO [M + H]
8
12
3
70.0817. Found 170.0864.
HO
(2S,4R)-tert-butyl 2-formyl-4-hydroxypyrrolidine-1-carboxylate (9): A
stirred solution of (2S,4R)-1-tert-butyl 2-ethyl 4-methoxypyrrolidine-1,2-
O dicarboxylate (0.25 g, 0.96 mmol, compound III, for details, see
attachment I at the end of this supporting informations) in anhydrous
dichloromethane (5 mL), at -84 ºC and under argon atmosphere, was
N
Boc
H
slowly added (during 5 minutes) a toluene solution of DIBAL-H (1.0 mol/L solution, 1.9
ml, 2.89 mmol). The mixture was stirred for 20 min. At the same temperature. The reaction
evolution was followed by TLC. The cooling bath was removed and a saturated solution of
sodium acetate (5 mL) was added. The reaction medium was poured into a stirred mixture
of ethyl ether (50 mL) and saturated ammonium chloride (10 mL). After 2h, the gel formed
was filtered over a pad of Celite® and the aqueous filtrate was extracted again with ethyl
ether. The organic phases were combined, dried over anhydrous Na SO and evaporated.
2
4
The residue was quickly filtered over a tiny amount of silica gel (Hexane : AcOEt 40:60 to
0:80), to provide aldeyde 9, as colorless oil (0.188 g) in 91 % yield. Hydroxy-aldehyde 9
2
2
0
should be stored at -20 ºC or used immediately after be prepared. [α]D -54.5 (c 1.5;
MeOH); IR (Film, νmax): 3395, 2978, 2933, 1736, 1669, 1409, 1365, 1160, 1123 cm ; H
-1 1
NMR (300 MHz, DMSO-d , 90 ºC) δ 1.42 (s, 9H), 1.96 (m, 2H), 3.43 (m, 2H), 4.14 (m,
6
1
3
1
6
2
H), 4.25 (m, 1H), 9.43 (s, 1H); C NMR (75 MHz, DMSO-d , 90 ºC) δ 28.5, 35.8, 55.5,
6
+
4.0, 68.7, 79.9, 154.2, 200.7; HRMS (ESI-TOF) Calcd. for C H NO [M + H]
1
0
18
4
16.1236. Found 216.1365. GC conditions: HP chiral, flow 1.5 mL/min; 100 °C; 10 °C/min
up to 230 ºC; pos run: 230 °C/15 min); T = 15.39 min.
R
(
(
2S,4R)-tert-butyl
methoxycarbonyl)allyl)pyrrolidine-1-carboxylate (10):
4-hydroxy-2-((R)-1-hydroxy-2-
OH
O
A
mixture of hydroxy-aldehyde 9 (0.23 g, 1.069 mmol), DABCO
0.12 g, 1.069 mmol) and ethyl acrylate (2 mL) was sonicated for
96 h (followed by GC). Then, the excess of methyl acrylate was
O
HO
(
N
Boc
removed under reduced pressure (CAUTION: this operation should be performed under an
efficient fume hood). The residue was diluted with dichloromethane (20 mL). The organic
phase was washed with brine (3 x 30 mL), dried over anhydrous Na SO and evaporated.
2
4
The crude residue was purified by flash silica gel column chromatography (Hexane :
CH Cl : AcOEt – 3.0:5.0:3.0) to provide adducts 8 (0.206 g, see above for full spectral
2
2
characterization) and 10 (0.052 g, spectral data below), as a colorless oil, in 70 % yield.
2
0
[
α]D -11 (c 1.5; MeOH); IR (Film, νmax): 3402, 2879, 2952, 1720, 1670, 1417, 1368,
-1 1
1
1
4
3
273, 1163, 1092 cm ; H NMR (250 MHz, DMSO-d , 90 °C) δ 1.45 (s, 9H), 1.52 (m,
H), 1.98 (dt, J = 12.0, 5.9 Hz, 1H), 3.30 (m, 2H), 3.71 (s, 3H), 4.07 (m, 1H), 4.23 (s, 1H),
.90 (s, 2H), 5.86 (s, 1H), 6.12 (s, 1H); C NMR (62.5 MHz, DMSO-d , 90 ºC) δ 27.8,
3.2, 50.8, 55.0, 58.4, 67.8, 68.1, 77.7, 123.6, 142.0, 153.5, 165.7; HRMS (ESI-TOF)
6
1
3
6
+
Calcd. for C H NO [M + H] 302.1604. Found 302.1634. GC conditions: HP chiral, flow
1
4
24
6
1
.5 mL/min; 100 °C; 10 °C/min up to 230 ºC; pos run: 230 °C/15 min); T = 22.09 min.
R

S7
OH
O
(
1R,6R,7aS)-1,6-dihydroxy-2-methylenetetrahydro-1H-pyrrolizin-
H
N
3
1
(2H)-one (12): To a stirred solution of Morita-Baylis-Hillman adduct
0 (0.05 g, 0.165 mmol) in toluene (1 mL), at 0 °C, was added
concentrated HCl (300 µL, 1.1 mmol). The resulting mixture was
HO
further stirred for 5-7 min. Then, a 35% solution of NaOH was added
(0.16 mL, 1 mmol) and the reaction was further stirred for 30 min, at room temperature.
The medium was neutralized to pH 7 (10% HCl solution) and the solvents were removed
under reduced pressure. The crude residue was purified by flash silica gel column
chromatography (CH Cl : MeOH - 95:05) to give pyrrolizidinone 12 (0.012 g) as a white
2
2
2
0
solid, in 55 % yield. [α]
-12 (c 2; DMSO); IR (Film, νmax): ν 3377, 3206, 2985, 2946,
D
-1 1
2
928, 1657, 1440 cm ; H NMR (500 MHz, (CD ) CO) δ 1.59 (ddd, J = 13.0, 10.8, 5.1 Hz,
3
2
H-7B), 2.16 (dd, J = 13.0, 5.6 Hz, H-7A), 3.03 (d, J = 13.1 Hz, H-5A), 3.73 (dd, J = 13.0,
5
5
.2 Hz, H-5B), 3.89 (dt, J = 10.5, 5.2 Hz, H-7a), 4.53 (dt, J = 5.1, 2.7 Hz, H-1), 4.59 (t, J =
1
3
.1 Hz, H-6), 5.49 (d, J = 2.5 Hz, 1H, CH ), 5.83 (d, J = 2.9 Hz, 1H, CH ); C NMR (62.5
2
2
MHz, (CD ) CO) δ 39.3, 51.6, 66.6, 72.8, 74.2, 116.9, 148.5, 167.9; HRMS (ESI-TOF)
3
2
+
Calcd. for C H NO [M + H] 170.0817. Found 170.0862.
8
12
3
(
1S,6R,7aR,E)-2-benzylidene-1,6-dihydroxytetrahydro-1H-
OH
H
N
pyrrolizin-3(2H)-one (14): To a solution of pyrrolizidinone 11
0.13 g, 0.77 mmol) in DMF (3 mL) was added iodobenzene
0.184 g, 0.92 mmol, 0.1 mL) de iodobenzeno, triethylamine
(
(
HO
O
(0.218 g, 2.16 mmol, 0.3 mL) and Nájera palladacycle 13 (0.5
mol%, 0.004 mmol, 0.003 g). The resulting dark brown solution was stirred for 5h, at 110-
20 °C. Then the solvent was removed under reduced pressure and the residue was purified
by flash silica gel column chromatography (CH Cl :MeOH – solvent gradient: 0:100 to
1
2
2
9
7:03), to provide benzylidene-pyrrolizidinone 14 (0.14 g), as a colorless oil, in 76 %.
2
0
[
α]D + 40 (c 1, MeOH); IR (Film, νmax): 3427, 3195, 2940, 2855, 1668, 1634, 1493, 1424,

S8
268, 1156, 1067 cm ; H NMR (400 MHz, CD CN) δ 1.30 (m, J = 13.8, 9.1, 5.4 Hz, 1H,
-1 1
1
3
H-7A), 2.38 (m, J = 13.8, 6.8 Hz, 1H, H-7B), 3.27 (dd, J = 12.3, 6.1 Hz, 1H, H-5B), 3.56
dd, J = 12.3, 3.3 Hz, 1H, H-5A), 3.69 (ddd, J = 9.1, 7.4, 1.8 Hz, 1H, H-7a), 4.47 (qd, J =
.1, 3.3 Hz, 1H, H-6), 4.91 (dd, J = 1.8 Hz, 1H, H-1), 7.35 (d, J = 2.1 Hz, 1H, CH), 7.41
(
6
1
3
(m, 3H, Ph), 7.79 (m, 2H, Ph); C NMR (62.5 MHz, (CD ) CO) δ 38.1, 52.1, 68.2, 70.1,
3 2
7
2.0, 129.2, 130.3, 131.3, 134.1, 134.2, 137.1, 172.1; HRMS (ESI-TOF) Calcd. for
+
C H NO [M + H] 246.1130. Found 246.1168.
14
16
3
1
S,6R,7aR,Z)-1,6-dihydroxy-2-(4-
OH
O
H
N
hydroxybenzylidene)tetrahydro-1H-pyrrolizin-3(2H)-one
15): To a solution of pyrrolizidinone 11 (0.25 g, 1.48 mmol)
in DMF (3 mL) was added 4-iodophenol (0.49 g, 2.22 mmol),
triethylamine (0.746 g, 7.39 mmol, 1.0 mL), Cy NMe (0.216 g,
.11 mmol, 0.24 mL) and Najera palladacycle 13 (0.5 mol%,
(
HO
2
1
OH 0.007 mmol, 0.006 g). The resulting brown solution was stirred
for 8 h, at 110-120 °C. After, the solvent was removed under reduced pressure and the
residue was purified by flash silica gel column chromatography (CH Cl :MeOH – solvent
2
2
gradient 0:100 to 97:03) to give hydroxybenzylidene-pyrrolizidinone 15 (0.20 g), as a
20
colorless oil, in 51 % yield. [α]D + 32 (c 1, MeOH); IR (Film, νmax): 3333, 2941, 1668,
-1 1
1
633, 1603, 1515, 1432, 1413, 1274, 1175, 1066 cm ; H NMR (250 MHz, D O) δ 1.36
2
(m, J = 13.3, 9.3, 5.7 Hz, 1H, H-7A), 2.50 (dt, J = 13.3, 6.8 Hz, 1H, H-7B), 3.39 (dd, J =
1
7
=
2.6, 6.3 Hz, 1H, H-5B), 3.55 (dd, J = 12.6, 3.4 Hz, 1H, H-5A), 3.78 (t, J = 8.3 Hz, 1H, H-
a), 4.60 (m, 1H, H-6), 5.07 (t, J = 1.8 Hz, 1H, H-1), 6.89 (d, J = 8.7 Hz, 2H, Ar), 7.28 (d, J
13
1.8 Hz, 1H, CH), 7.59 (d, J = 8.7 Hz, 2H, Ar); C NMR (62,5 MHz, (CD ) CO) 39.9,
3
2
5
3.5, 68.8, 70.7, 73.0, 116.4, 127.4, 132.5, 133.8, 136.3, 159.6, 172.4; HRMS (ESI-TOF)
+
Calcd. for C H NO [M + H] 262.1079. Found 262.1122.
1
4
16
4
(1S,6R,7aR,Z)-1,6-dihidroxi-2-(4-nitrobenzilideno)tetrahidro-1H-pirrolizin-3(2H)-ona
(16):
To a solution of pyrrolizidinone 11 (0.30 mmol, 0.05 g) em
DMF (3 mL) were added 4-nitro-iodobenzene (1.5 equiv.,
0
.44 mmol, 0.11 g), triethylamine (5.0 equiv., 1.48 mmol, 0.2
mL), N-Methyl-dicyclohexylamine (Cy NMe, 0.75 equiv.,
2
0.22 mmol, 0.04 mL), Nájera´s palladacycle I (13, 0.5 mol%,
0.002 mmol, 0.001 g). The resulting solution was stirred at
110-120 °C for 8 hs. After that, the solvent was removed
under reduced pressure and the residue was purified by flash silica gel column
chromatography (230-400 mesh; CH Cl : MeOH - 0:100 to 95:05) to afford 0.07 of
2
2
2
0
benzylidene-pyrrolizididinone 16, as a colorless oil, in 83% yield. [α]D + 28° (c 2,
MeOH); IR (Film, νmax): 3308, 2974, 2924, 2864, 1699, 1671, 1644, 1596, 1523, 1513,
-1 1
1
435, 1381, 1346, 1314, 1264, 1244, 1220, 1202, 1133, 1104, 1075, 1055 cm ; H NMR
(
400 MHz, CD OD) δ 1.49 (ddd, J = 13.2, 8.3, 5.1 Hz, 1H, H-7A); 2.49 (ddd, J = 13.3, 7.4,
3
6.2 Hz, 1H, H-7B); 3.38 (dd, J = 12.4, 5.8 Hz, 1H, H-5B); 3.68 (dd, J = 12.4, 3.0 Hz, 1H,
H-5A); 3.80 (td, J = 8.1, 2.4 Hz, 1H, H-7a); 4.56 (qd, J = 5.8, 3.3 Hz 1H, H-6); 5.01 (t, J =
2
8
.4 Hz, 1H, H-1); 7.45 (d, J = 2.3 Hz, 1H, CH); 8.01 (d, J = 8.8 Hz, 2H, Ar); 8.26 (d, J =
1
3
.9 Hz, 2H, Ar); C NMRN (62.5 MHz, CD CN) 39.2; 53.3; 68.4; 71.5; 72.5; 124.3;
3

S9
1
+
32.4; 133.2; 140.5; 141.8; 148.6; 170.9; HRMS (ESI-TOF) m/z Calc. for C H N O [M
H] : 291.0981. Found 291.0989.
1
4
15
2
5
+
(
1S,2S,6R,7aR)-2-benzyl-1,6-dihydroxytetrahydro-1H-
®
OH
pyrrolizin-3(2H)-one (18): In a Parr hydrogenation reactor was
H
N
added a methanolic solution (5 mL) of pyrrolizidinone 14 (0.06
g, 0.24 mmol), followed by the addition of 10% Pd/C catalyst (20
mol%, 0.012 g). The reaction was stirred under a hydrogen
pressure of 200 psi for 25 h, at room temperature. After that, the
HO
O
medium was filtered over a pad of Celite®. The solid was washed with methanol and the
combined organic phases were evaporated. The residue was purified by flash silica gel
column chromatography (CH Cl :MeOH – solvent gradient: 0:100 to 97:03) to afford
2
2
2
0
reduced benzyl-pyrrolizidinone 18 (0.06 g), as a white solid, in 97 %. [α]D + 51 (c 1,
MeOH); M. p. 135-136° C; IR (KBr, νmax): 3404, 3232, 2987, 2936, 2897, 2871, 1670,
447, 1416, 1375, 1300, 1263, 1222,1175, 1121 cm ; H NMR (500 MHz, CD OD) δ 1.55
-1 1
1
3
(
dddd, J = 13.4, 5.3, 4.0, 1.0 Hz, 1H), 2.25 (ddd, J = 13.4, 8.0, 5.4 Hz, 1H), 2.93 (m, 2H),
.02 (m, J = 7.5, 1.8 Hz, 1H), 3.08 (ddd, J = 12.0, 4.9, 1.3 Hz, 1H), 3.52 (dd, J = 12.0, 2.4
Hz, 1H), 3.64 (m, J = 8.0, 7.0, 5.3 Hz, 1H), 3.88 (dd, J = 9.4, 7.0 Hz, 1H), 4.41 (m, J = 5.1,
3
1
3
4
.0, 3.0 Hz, 1H), 7.15 (m, 1H), 7.23 (m, 2H), 7.29 (m, 2H); C NMR (62.5 MHz,
(
CD ) CO) δ 34.4, 38.6, 52.3, 54.0, 65.6, 72.4, 80.6, 126.5, 128.7, 130.3, 141.0, 175.6;
3
2
+
HRMS (ESI-TOF) Calcd. for C H NO [M + H] 248.1287. Found 248.1286.
1
4
18
3
OH
(1S,2S,6R,7aR)-1,6-dihydroxy-2-(4-
hydroxybenzyl)tetrahydro-1H-pyrrolizin-3(2H)-one (20):
The same experimental procedure described previously was
used to obtain pyrrolizidinone 20 (0.059 g), as a colorless oil,
OH
O
H
N
HO
20
in 95 % yield. Reaction time: 48 h; [α]D 185 (c 1, MeOH); IR
(
1
Film, ν ): 3351, 3031, 2923, 1669, 1515, 1443, 1366, 1237,
100 cm ; H NMR (400 MHz, (CD ) CO) δ 1.44 (m, 1H, H-
3 2
max
-
1 1
7A), 2.22 (ddd, J = 13.3, 7.0, 5.6 Hz, 1H, H-7B), 2.73 (td, J = 31.8, 7.3, 3.6 Hz, 1H, CH2),
2
.84 (m, J = 31.8, 13.3, 8.0 Hz, CH , J = 8.6, 7.0, 4.4 Hz, H-2, 2H), 3.06 (m, J = 12.1, 5.2
2
Hz, 1H, H-5B), 3.36 (dd, J = 12.1, 3.1 Hz, 1H, H-5A), 3.60 (q, J1,7a=7a,7A=7a,7B = 7.0, Hz,
1
6
H, H-7a), 3.84 (dd, J = 8.9, J = 7.0 Hz, 1H, H-1), 4.40 (m, J = 5.1, 9.0 Hz, 1H, H-6),
.65 (m, J = 5.5 Hz, 2H, Ph), 7.03 (m, J = 5.5 Hz, 2H, Ph); C NMR (62.5 MHz,
1,2 1,7a
1
3
(
CD ) CO) δ 32.5, 37.6, 50.8, 53.8, 65.0, 72.0, 78.7, 115.5, 130.5, 131.0, 155.1, 175.9;
3 2
+
HRMS (ESI-TOF) Calcd. for C H NO [M + H] 264.1236. Found 264.1318.
1
4
18
4
General experimental procedure for the amide carbonyl reduction of pyrrolizidinones
4, 15, 18, 20:
1
For example, to a solution of pyrrolizidinone 18 (0.063 g, 0.25 mmol) in anhydrous THF (5
mL) was added a freshly prepared solution of AlH in THF (1 mol/L, 10 equiv., 2.5 mmol,
3
2
.3 mL). The AlH solution was prepared as follow: A solution of LiAlH (2,4 mol/L, 2.5
3
4
mL, THF) was added, at 0° C, to a solution of AlCl (2 mmol, 0.27 g) in anydrous THF (5
3
mL). The resulting solution was stirred for 40 min). After addition, the reaction medium
was stirred for 30-60 min, at room temperature. Then, the medium was quenched with a
saturated solution of Na SO and filtered over a pad of Celite® and the solvents were
2
4
removed under reduced pressure. The residue was purified by neutral alumina column

S10
chromatography (eluting system CH Cl :MeOH 9,0:1,0) for compounds 18 and 20, and
2
2
eluting system CH Cl :MeOH:NH OH (30 %) 7,8:2,0:0,2) for compounds 16 e 17, to
2
2
4
provide the corresponding pyrrolizidines 19 in 80% yield, 21 in 53% yield, 22 in 50% yield
and 23 in 21% yield.
(
1S,2R,6R,7aR)-2-benzylhexahydro-1H-pyrrolizine-1,6-diol
2
0
OH
H
N
(19): a colorless oil; [α]D - 197 (c 1, MeOH); IR (Film, νmax):
325, 2926, 2899, 1447, 1383, 1296, 1114, 1073 cm ; H NMR
-1 1
3
HO
(
400 MHz, D O) δ 1.82 (dt, J = 13.6, 4.3 Hz, 1H, H-7A), 2.16
2
(ddd, J = 13.6, 8.3, 5.4 Hz, 1H, H-7B), 2.31 (m, 1H, H-2), 2.59
(
m, J = 14.0, 9.8 Hz (CH ), J = 11.8, 4.0 Hz (H-5B), J = 11.0 Hz (H-3) 3H), 2.92 (dd, J =
2
1
1.8, 4.5 Hz, 1H, H-5A), 3.03 (m, J = 14.0, 4.1 Hz (CH ), J = 11.0 Hz (H-3), 2H), 3.24 (td,
2
J1,7a = 7.7, 4.8 Hz, 1H, H-7a), 3.88 (dd, J1,2 = 9.5, J1,7a = 7.7 Hz, 1H, H-1), 4.39 (quin, J =
1
3
4
.5 Hz, 1H, H-6), 7.26 (t, J = 6.9 Hz, 3H, Ph), 7.35 (t, J = 7.4 Hz, 2H, Ph); C(100 MHz,
D O) δ 35.7, 37.1, 48.6, 58.0, 60.3, 68.6, 73.1, 80.8, 126.3, 128.6, 128.9, 140.2; HRMS
2
+
(
ESI-TOF) calcd for C H NO [M + H] 234.1494, found 234.1491.
14 20 2
OH
(1S,2R,6R,7aR)-2-(4-hydroxybenzyl)hexahydro-1H-
20
pyrrolizine-1,6-diol (21): a colorless oil; [α]D - 62 (c 1,
MeOH); IR (Film, νmax): 3333, 2927, 2594, 1613, 1596, 1514,
OH
H
N
-1 1
1
444, 1365, 1247, 1117, 1088 cm ; H NMR (400 MHz, D O)
2
HO
δ 1.99 (d, J = 13.2, 4.0 Hz, 1H, H-7A) 2.22 (ddd, J = 13.9, 8.9,
.0 Hz, 1H, H-7B), 2.33 (m, 1H, H-2), 2.53 (dd, J = 13.9, 8.8
Hz, 1H, CH ), 2.84 (dd, J = 12.1, 11.0 Hz, 1H, H-3), 2.91 (m, J = 13.9, 4.0 Hz (CH ), J =
5
2
2
1
1
4
2.4, 3.8 Hz (H-5A), 2H), 3.16 (dd, J = 12.4, 4.1 Hz, 1H, H-5B), 3.38 (dd, J = 10.6, 6.9 Hz,
H, H-3), 3.60 (td, J = 8.5, 3.4 Hz, 1H, H-7a), 3.98 (dd, J = 9.6, J = 8.0 Hz, 1H, H-1),
1
,2
1,7a
1
3
.49 (m, 1H, H-6), 6.78 (m, J = 8.5 Hz, 2H, Ar), 7.06 (d, J = 8.5 Hz, 2H, Ar); C(100
MHz, D O) δ 33.8, 36.5, 47.8, 58.3, 60.3, 69.9, 72.4, 79.4, 115.8, 130.1, 130.3, 155.2.
2
+
HRMS (ESI-TOF) Calcd. for C H NO [M + H] 250.1443. Found 250.1461.
1
4
20
3
(
1S,6R,7aR,Z)-2-benzylidenehexahydro-1H-pyrrolizine-1,6-
2
0
OH
diol (22): a colorless oil; [α]D -73 (c 1, MeOH); IR (Film, νmax):
406, 2925, 2855, 1646, 1495, 1448 1108, 1019 cm ; H NMR
H
N
-1 1
3
HO
(
400 MHz, (CD ) CO) δ 1.58 (m, J = 13.9, 8.4, 6.0 Hz, 1H, H-
3
2
7
A), 2.55 (m, J = 13.9, 8.4, 6.5 Hz, 1H, H-7B), 3.02 (dd, J =
1
1.9, 5.2 Hz, 1H, H-5B), 3.71 (dd, J = 11.9, 5.8 Hz, 1H, H-5A), 4.03 (d, J = 15.3 Hz, 1H,
H-3), 4.22 (t, J7a,7A=7a,7B = 8.4 Hz, 1H, H-7a), 4.50 (quin, J = 5.8 Hz, 1H, H-6), 4.57 (d, J =
5.3 Hz, 1H, H-3), 4.70 (s, 1H, H-1), 6.79 (s, 1H, CH), 7.29 (t, J = 7.3 Hz, 1H, Ph), 7.37 (t,
1
1
3
J = 7.5 Hz, 2H, Ph), 7.60 (d, J = 7.4 Hz, 2H, Ph); C NMR (62.5 MHz, (CD ) CO) δ 39.2,
3
2
6
0.0, 61.6, 71.6, 74.1, 75.8, 127.0, 127.7, 129.0, 129.6, 137.8, 142.8; HRMS (ESI-TOF)
+
Calcd. for C H NO [M + H] 232.1338. Found 232.1380.
1
4
18
2
OH
(
1S,6R,7aR,E)-2-(4-hydroxybenzylidene)hexahydro-1H-
H
N
2
0
pyrrolizine-1,6-diol (23): a colorless oil; [α]D - 48 (c 0.7,
MeOH); IR (Film, νmax): 3431, 2923, 2852, 1628, 1603, 1509,
416, 1384, 1364, 1268, 1242 cm ; H NMR (400 MHz, D O)
HO
-1 1
1
2
OH

S11
δ 1.77 (m, J = 13.6, 11.5, 5.6 Hz, 1H, H-7A), 2.46 (m, J = 13.9, 7.3 Hz, 1H, H-7B), 2.74
(dd, J = 11.5, 5.1 Hz, 1H, H-5B), 3.30 (dd, J = 11.5, 5.6 Hz, 1H, H-5A), 3.43 (m, J = 11.5,
7
4
8
6
.0, 4.3 Hz, 1H, H-7a), 3.85 (d, J = 16.0, 1.5 Hz, 1H, H-3), 4.17 (d, J = 16.0 Hz, 1H, H-3),
.47 (m, J = 5.6 Hz 1H, H-6), 4.70 (d, J = 4.3 Hz, 1H, H-1), 6.67 (s, 1H, CH), 6.83 (d, J =
1
3
.5 Hz, 2H, Ar), 7.18 (d, J = 8.5 Hz, 2H, Ar); C NMR (125 MHz, D O) δ 36.9, 55.3, 61.0,
2
9.5, 71.6, 79.5, 116.9, 126.1, 126.8, 130.6, 137.0, 159.5; HRMS (ESI-TOF) Calcd. for
+
C H NO [M + H] 248.1287. Found 248.1289.
14
18
3
References:
. Kimura, R.; Nagano, T.; Kinoshita, H. Bull. Chem. Soc. Jpn 2002, 75, 2517-2525.
1

S12
7
1
H NMR (250 MHz, DMSO-d , 90 ºC) spectrum of cis-4-hydroxy-(D)-prolinal 7.
6

S13
R103P - DMSO/250 MHz abr02KRLC 90º C
HO
O
N
Boc
H
7
200 190 180 170 160 150 140 130 120 110 100
90
80
70
60
50
40
30
20
10 ppm
1
3
C NMR (62.5 MHz, DMSO-d , 90 ºC) spectrum of cis-4-hydroxy-(D)-prolinaldehyde 7.
6

S14
8
1
H NMR (250 MHz, DMSO-d , 90 ºC) spectrum of MBH adduct 8.
6

S15
8
1
3
C NMR (62.5 MHz, DMSO-d , 90 ºC) spectrum of MBH adduct 8.
6

S16
OH
O
O
HO
N
Boc
8
HRMS (ESI) of MBH adduct 8.

S17
11
1
H NMR (500 MHz, (CD ) CO) spectrum of pyrrolizidinone 11.
3
2

S18
11
1
3
C NMR (62.5 MHz, (CD ) CO) spectrum of pyrrolizidinone 11.
3
2

S19
OH
O
H
N
HO
11
HRMS (ESI) of pyrrolizidinone 11.

S20
9
1
H NMR (300 MHz, DMSO-d , 90 ºC) spectrum of trans-hydroxy-prolinal 9.
6

S21
9
1
3
C NMR (75 MHz, DMSO-d , 90 ºC) spectrum of trans-hydroxy-prolinal 9.
6

S22
10
1
H NMR (250 MHz, DMSO-d , 90 ºC) spectrum of MBH adduct 10.
6

S23
10
1
3
C NMR (62.5 MHz, DMSO-d , 90 ºC) spectrum of MBH adduct 10.
6

S24
OH
O
O
HO
N
Boc
10
HRMS (ESI) of MBH adduct 10.

S25
12
1
H NMR (500 MHz, (CD ) CO) spectrum of pyrrolizidinone 12.
3
2

S26
12
1
3
C NMR (62.5 MHz, (CD ) CO) spectrum of pyrrolizidinone 12.
3
2

S27
OH
O
H
N
HO
12
HRMS (ESI) of pyrrolizidinone 12.

S28
2.63%
H
7A
H1
H7a
H7B
OH
HO
2.39%
N
H6
H5B
H5A
O
nOe [500 MHz, (CD ) CO)] spectrum of pyrrolizidinone 12, irradiation at 1.59 ppm, H-7B.
3
2
H7A
H1
H7a
H7B
OH
HO
0
.49%
N
H6
H5B
2.38%
H5A
O
nOe [500 MHz, (CD ) CO)] spectrum of pyrrolizidinone 12, irradiation at 3.73 ppm, H-5B.
3
2

S29
1
.60%
H7A
H1
H7a
H7B
OH
HO
0
.33%
N
H6
H5B
H5A
O
nOe [500 MHz, (CD ) CO)] spectrum of pyrrolizidinone 12, irradiation at 3.89 ppm, H-7a.
3
2
1.89%
H7A
H1
H7a
H7B
OH
HO
N
H6
H5B
H5A
O
6
.0
5.5
5.0
4.5
4.0
3.5
3.0
f1 (ppm)
2.5
2.0
1.5
1.0
0.5
0.0
nOe [(500 MHz, (CD ) CO] spectrum of pyrrolizidinone 12, irradiation at 4.53 ppm, H-1)
3
2