Polyhydroxylated pyrrolizidines. Part 5: Stereoselective synthesis of 1,2-dihydroxypyrrolizidines as a model for the preparation of densely polyhydroxylated pyrrolizidines

Article abstract of DOI:10.1016/j.tetasy.2004.10.003

The reaction of N-benzyloxycarbonyl-l-prolinal 5 with (methoxycarbonylmethylene)triphenylphosphorane in CH₂Cl₂ afforded methyl (E)-3-[(2′S)-N-benzyloxycarbonylpyrrolidin-2′-yl] propenoate 7. When the reaction was performed in MeOH, a

Full text of DOI:10.1016/j.tetasy.2004.10.003

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3635–3642
Polyhydroxylated pyrrolizidines. Part 5: Stereoselective
synthesis of 1,2-dihydroxypyrrolizidines as a model for
the preparation of densely polyhydroxylated pyrrolizidinesq
*
Isidoro Izquierdo, Marıa T. Plaza and Juan A. Tamayo
´
Department of Medicinal and Organic Chemistry, Faculty of Pharmacy, University of Granada, Granada 18071, Spain
Received 8 September 2004; accepted 1 October 2004
Abstract—The reaction of N-benzyloxycarbonyl-L-prolinal 5 with (methoxycarbonylmethylene)triphenylphosphorane in CH2Cl2
afforded methyl (E)-3-[(20S)-N-benzyloxycarbonylpyrrolidin-20-yl]propenoate 7. When the reaction was performed in MeOH, an
appreciable amountof the ( Z)-isomer 6 was obtained. Compounds 7 and 6 were dihydroxylated to the corresponding 2,3-dihydroxy
esters 8–9 and 20–21, respectively. The stereochemistry of the latter compounds could be determined after their transformations into
the corresponding 1,2-dihydroxypyrrolizidin-3-ones 11–16 and 23–25, respectively. Finally, lactams 11, 16, and 25 were reduced to
the related pyrrolizidines 14, 19, and 27.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
According to Figure 1, construction of the target
PHPAs 1 and 2 can be accomplished as follows: ring
A comes from a suitably protected polyhydroxypyrrol-
izidine4 (DGDP, DMDP, etc.), which transfers its
inherent chirality to the final compound, whereas the
B ring, with the appropriate stereochemistry, can be
built up following a synthetic route similar to that
Continuing with our efforts on the synthesis of poly-
hydroxylated pyrrolizidinic alkaloids (PHPAs), we were
interested in exploring the possibility of preparing those
with the highest degree of hydroxylation found in nature
so far, such as casuarine 12 and hyacinthacine C1 2.3
HO
H
OH
B
A
HO
HO
OH
N
(+)-Casuarine 1
Ring B synthesized according
Ring A furnished by the
to retrosynthesis in Scheme 1
appropriate pyrrolidine
HO
OH
H
N
B
A
HO
HO
OH
CH3
(+)-Hyacinthacine C1
2
Figure 1. (+)-Casuarine 1 and (+)-hyacinthacine C1 2.
q For Part4 of the series, see Ref. 1. Communicated, in part, at the XX Reunion Bienal de Quımica Organica (June 2004, Zaragoza, Spain).
*
´
Corresponding author. Tel.: +34 958 249583; fax: +34 958 243845; e-mail: isidoro@ugr.es
´
´
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.10.003

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I. Izquierdo et al. / Tetrahedron: Asymmetry 15 (2004) 3635–3642
outlined in Scheme 1, where the retrosynthesis for less
elaborated 1,2-dihydroxypyrrolizidines5 with chiralities
matching those in the target molecules is displayed, con-
sisting of a carbon-chain lengthening and subsequent
dihydroxylation under the absence and presence of chi-
ral ligands. Accordingly, the commercial N-benzyloxy-
carbonyl-L-proline 3 would be an excellent starting
material for these purposes in order to investigate not
only the suitability of the synthetic proposal, but also
the possibility of controlling its stereochemical outcomes
and hence apply these results in the preparation of 1 and
2.
formed under Sharpless conditions (ADH),12 a notable
increase in the diastereomeric ratio (1:28) in the presence
of an AD-mix aꢁ catalyst was observed, whereas a re-
verse stereoselectivity (3.5:1) was obtained when the
AD-mix bꢁ catalyst was used. These results agree with
the empirical rule outlined for ADH,13 and with those
recently reported by Robina and co-workers,14 where
a similar behavior for an analogue of 7 was observed.
The absolute configurations of the new stereogenic cen-
ters in 8 and 9 could be determined after their transfor-
mations into the related c-lactams 11 and 16. This
involved N-deprotection to 10 and 15, respectively, fol-
lowed by the corresponding cyclization promoted by
basic medium (MeONa/MeOH). Compound 16 had
spectroscopic data, which closely matched those previ-
ously reported,5b although some discrepancy occurred
OH
H
OH
N
H
1
1
with the optical data. Nevertheless, H–1H and H–13C
COSY, and extensive NOE experiments confirmed the
proposed structure for 16 and allowed the assignment
CO2H
Cbz
CO2Me
(1R,2R,7aS)-1,2-DHP 14
N
OH
H
N
Cbz
3
1
of its H and 13C NMR signals.
OH
N
(1S,2S,7aS)-1,2-DHP 19
From the above results it was concluded that the config-
urations for 8–11 mustbe ht ose shown in Scheme 3.
Scheme 1. Retrosynthesis of (1R,2R,7aS)-14 and (1S,2S,7aS)-1,2-
dihydroxypyrrolizidine 19 from N-Cbz-L-proline 3.
OH
OR
H
N
H
OH
b
2. Results and discussion
a
8
OR
NH CO2Me
With the above objective in mind, compound 3 was re-
duced6 to alcohol 4 and subsequently transformed into
the related derivative of L-prolinal 57 by oxidation with
PCC. Reaction of 5 with (methoxycarbonylmethyl-
ene)triphenyl phosphorane gave methyl (E)-3-[(20S)-N-
benzyloxycarbonylpyrrolidin-20-yl]propenoate 7 in a
highly stereoselective manner,8 which was shown to be
X
10
11 R = H; X = O
12 R = Bn; X= O
c
d
e
13 R = Bn; X = H2
14 R = H; X = H2
OH
H
OR
H
OH
b
13
a mixture of rotamers (1H and C NMR evidence).9
a
9
OR
N
NH CO2Me
Analytical and spectroscopic data for 7 are in accord-
ance with those previously reported for rac-7.10
15
X
16 R = H; X = O
OH
c
H
1
17 R = Bn; X= O
18 R = Bn; X = H2
19 R = H; X = H2
Following Scheme 2, dihydroxylation (DH) of a-b-
unsaturated ester 7 gave a resolvable mixture of the
methyl (2S,3R)-8 and (2R,3S)-2,3-dihydroxy-3-[(20S)-
N-benzyloxycarbonylpyrrolidin-20-yl]propanoate 9, in a
moderate 1:2 diastereomeric excess [GLC analysis (B)
of TMS derivatives11]. When the reaction was per-
H
7
β
d
d
e
H
2
OH
N
O
H
7a
16
Scheme 3. Reagents and conditions: (a) H2/10% Pd–C/MeOH; (b)
MeONa (cat.)/MeOH/D; (c) NaCH2SOMe/DMSO/BnBr; (d) LAH/
Et2O; (e) H2/10% Pd–C/HCl/MeOH then Amberlite IRA-400 (OHÀ
form). NOE interactions in 16.
R1
R
H
N
CO2Me
c, d, or e
7
Reduction of 16 with LAH to pyrrolizidine 19 wentot
completion (TLC analysis) but resulted in an unsatisfac-
tory recovery of the final compound. For this reason,
both 11 and 16 were transformed into the 1,2-di-O-benz-
yl derivatives 12 and 17 prior to their respective reduc-
tions affording in this case, pyrrolizidines 13 and 18 in
good yields, which were finally, O-debenzylated to the
required 14 and 19. The latter has the same spectroscopy
data to those reported for itself,5b buta discrepancy in
R
R2 R3
Cbz
Ref. 6
3
N
Cbz
8 R = R2 = OH; R1 = R3 = H
9 R = R2 = H; R1 = R3 = OH
4 R = CH2OH
5 R = CHO
a
ratio 8 : 9
b
6 R = (Z)-HC=CHCO2Me
7 R = (E)-HC=CHCO2Me
c ) OsO4/NMO/no catalyst
d ) AD-mix α : (DHQ)2-PHAL
e ) AD-mix β : (DHQD)2-PHAL
1 : 2
1 : 28
3.5 : 1
1
the optical data was found again, although H–1H and
1H–13C COSY, and NOE experiments confirmed the
proposed structure for 19 and hence that of 14.
˚
Scheme 2. Reagents and conditions: (a) PCC/4A MS/CH2Cl2; (b)
Ph3P@CHCO2Me/either CH2Cl2 or MeOH/rt.

I. Izquierdo et al. / Tetrahedron: Asymmetry 15 (2004) 3635–3642
3637
In a similar manner, the DH reaction on methyl (Z)-3-
[(20S)-N-benzyloxycarbonylpyrrolidin-20-yl]propenoate
6 afforded methyl (2S,3S)-20 and (2R,3R)-2,3-dihyd-
roxy-3-[(20S)-N-benzyloxycarbonylpyrrolidin-20-yl]pro-
panoate 21 in the ratios shown in Scheme 4 (GLC
analysis, B), depending on the reaction conditions.
spectra were recorded with Bruker AMX-300, AM-300,
and ARX-400 spectrometers for solutions in CDCl3
(internal Me4Si). IR spectra were recorded with a
Perkin–Elmer 782 instrument and mass spectra with a
Hewlett–Packard HP-5988-A and Fisons mod. Platform
II and VG Autospec-Q mass spectrometers. Optical
rotations were measured for solutions in CHCl3 (1dm
tube) with a Jasco DIP-370 polarimeter. GLC was per-
formed on a Hewlett–Packard 6890 gas chromatograph
equipped with a split/splitless injector, a flame-ioniza-
R1
R
H
N
CO2Me
c, d, or e
6
tion detector, and
a
capillary HP-5 column
R2 R3
Cbz
(30m · 0.25mm i.d. · 0.25lm film thickness) at: (A)
10min at230 ꢂC, program to 250ꢂC, 20ꢂC/min; the He
flow rate was 0.7mL/min; the injection port and the
zone-detector temperatures were 250ꢂC; (B) 3min at
110ꢂC program to 250ꢂC, 20ꢂC/min, the He flow rate
was 1.1mL/min, the injection port and the zone-detector
temperatures were 285ꢂC. TLC was performed on pre-
coated silica gel 60 F254 aluminum sheets and detection
by charring with H2SO4. Column chromatography was
performed on silica gel (Merck, 7734). The noncrystal-
line compounds were shown to be homogeneous by
chromatographic methods and characterized by NMR,
MS, and HRMS.
20 R = R3 = H; R1 = R2 = OH
21 R = R3 = OH; R1 = R2 = H
ratio 20 : 21
c ) OsO4/NMO/no catalyst
d ) AD-mix α : (DHQ)2-PHAL
e ) AD-mix β : (DHQD)2-PHAL
1 : 4
1 : 1
1 : 7
Scheme 4. Dihydroxylations of 6.
The stereochemistry of dihydroxyesters 20 and 21, were
established after their transformation into the related-
lactams 23 and 25 as above. Thus, NOE experiments
on dihydroxylactam 25 (Scheme 5) were consistent with
a (1R,2R)-configuration, lately confirmed by reduction
to the well known pyrrolizidine 27.5a On the basis of
these results the absolute configurations for 23, and
hence that for 20, must be those above mentioned.
3.1. N-Benzyloxycarbonyl-L-prolinal 5
To a stirred solution of N-benzyloxycarbonyl-L-proli-
nol6 4 (2g, 8.5mmol) in dry CH2Cl2 (30mL) were added
˚
pyridinium chlorochromate (3g, 13.8mmol) and 4A
molecular sieves (3g). Stirring was continued for 2h at
room temperature. GLC (A) showed that 4 (tR
5.66min) had disappeared and that a new compound
(tR 5.02min) was present. Et2O (30mL) was added
and after 15min, the mixture was filtered through a Sil-
ica Gel G pad and concentrated to a residue that was
percolated (Et2O) to afford pure 5 (1.8g, 90%), which
had physical and spectroscopic data in accordance with
those previously reported.7a
OH
OH
H
N
H
OH
b
a
20
OH
NH CO2Me
O
22
23
OH
H
OR
H
OH
b
a
3.2. Methyl (Z)-6 and (E)-3-[(20S)-N-benzyloxycarbon-
ylpyrrolidin-20-yl]propenoate 7
21
OR
N
NH CO2Me
24
X
OH
HO
25 R = H; X = O
26 R = Bn; X= O
3.2.1. Reaction in CH2Cl2. To a solution of 5 (1.4g,
6mmol) in CH2Cl2 (20mL) (methoxycarbonylmethyl-
enetriphenyl)phosphorane (3g, 9mmol) was added,
and the mixture left at rt. After 6h, GLC (A) showed
a new compound (tR 9.65min) and no aldehyde. The
reaction mixture was supported on silica gel and submit-
ted to chromatography (Et2O–hexane, 2:1) to afford
H
7β
c
H
2
d
H1
N
27 R = H; X = H2
H
O
5α
H
7α
H
7a
25
Scheme 5. Reagents and conditions: (a) H2/10% Pd–C/MeOH; (b)
MeONa (cat.)/MeOH/D; (c) NaH/DMSO/BnBr; (d) H3B–SMe2/THF,
rt. NOE interactions in 25.
pure 7 (1.5g, 86%) as a colorless thick syrup, which
26
D
had ½aŠ ¼ À67 (c 1.1). IR (KBr): 3032 (aromatic), 1716,
1708, and 1699 (C@O and C@C), and 696cmÀ1 (aroma-
From all the above results, it can be concluded that the
synthetic methodology reported herein, is very appropri-
ate for preparing highly hydroxylated pyrrolizidines in a
stereocontrolled manner.
tic). NMR data (400MHz): 1H, d 7.35–7.28 (m, 5H,
0
Ph), 6.84 and 6.80 (2dd, 1H, J2 ,3 5.6Hz, H-3), 5.86
and 5.76 (2d, 1H, J2,3 15.6Hz, H-2), 5.14 and 5.07 (2d,
J 12.5Hz, CH2Ph) and 5.08 (s, CH2Ph), 4.54 and 4.47
(2m, 1H, H-20), 3.76–3.62 and 3.50–3.39 (2m, 2H, H-
50a,50b), 3.70 (s, 3H, OMe), 2.12–2.01 and 1.90–1.75
(2m, 4H, H-30a,30b,40a,40b); 13C (100MHz, inter alia):
d 166.83 (C-1), 154.81 (C@O, Cbz), 148.29 and 147.83
(C-3), 120.53 (C-2), 66.95 and 66.75 (CH2Ph), 58.12
and 57.75 (C-20), 51.64 (OMe), 46.85 and 46.48 (C-50),
3. Experimental
Solutions were dried over MgSO4 before concentra-
tion under reduced pressure. The 1H and 13C NMR

3638
I. Izquierdo et al. / Tetrahedron: Asymmetry 15 (2004) 3635–3642
31.71 and 30.83 (C-40), 23.63 and 22.82 (C-30). Mass
spectrum (LSIMS): m/z: 312.1215 [M++Na] for
C16H19NO4Na 312.1212 (deviation À 1.1ppm).
Eluted second was pure 9 (1.44g, 50%); tR 18.02min, as
white crystals, mp 100–102ꢂC (from Et2O–hexane);
26
½aŠ ¼ À55 (c 1, MeOH). IR (KBr): 3300 (OH), 3010
D
(aromatic), 1752 (C@O, ester), 1691 (C@O, Cbz), and
1
700cmÀ1 (aromatic). NMR data (400MHz): H, d 7.33
(m, 5H, Ph), 5.12 (s, 2H, CH2Ph), 4.83 (d, 1H, J2,OH
3.2.2. Reaction in MeOH. To a solution of 5 (1.64g,
7mmol) in dry MeOH (50mL), (methoxycarbonylme-
thylenetriphenyl)phosphorane (3.5g, 10.6mmol) was
added, and the mixture left at rt for 3h. GLC (A)
showed no aldehyde, and the presence of 7 together with
new compound 6 (tR 8.40min) in a 1.3:1 ratio, respec-
tively. The reaction mixture was supported on silica
gel and submitted to chromatography (Et2O–hexane,
4.7Hz, HO-2), 4.27 (d, 1H, H-2), 3.90 (br t, 1H, H-20),
0
3.77 (s, 3H, OMe), 3.65 (br d, 1H, J2 ,3 8.8Hz, H-3),
3.42 (br t, 2H, J 5.5Hz, H-50a,50b), 2.74 (br s, 1H,
HO-3), 2.15 (m, 1H, H-40a), 1.92 (m, 3H, H-30a,30b,40b);
13C (100MHz): d 172.23 (C-1), 157.54 (Cbz), 136.19,
128.66, 128.33, 128.00 (Ph), 73.64 (C-3), 70.88 (C-2),
67.72 (CH2Ph), 59.74 (C-20), 52.50 (OMe), 47.24 (C-
50), 27.71 (C-40), and 23.24 (C-30). Mass spectrum
(LSIMS): m/z: 346.1261 [M++Na] for C16H21NO6Na
346.1267 (deviation + 1.6ppm). Anal. Calcd for
C16H21NO6: C, 59.43; H, 6.55; N, 4.33. Found: C,
59.57; H, 6.48; N, 3.97.
1:4) to first afford pure 6 (414mg) as a colorless syrup,
24
D
which had ½aŠ ¼ þ32 (c 1); tR 8.40min. IR (KBr):
3033 (aromatic), 1704, 1700, and 1648 (C@O and
C@C), 698cmÀ1 (aromatic). NMR data (400MHz):
1H, d 7.35–7.27 (m, 5H, Ph), 6.23 and 6.13 (2dd, 1H,
0
J2 ,3 8.2Hz, H-3), 5.78 and 5.70 (2d, 1H, J2,3 11.5Hz,
H-2), 5.35 (m, 1H, H-20), 5.10 (m, 2H, CH2Ph) 3.76
and 3.67 (m, 2H, H-50a,50b), 3.69 and 3.68 (2s, 3H,
OMe), 2.36–2.28, 1.90–1.80, and 1.75–1.60 (3m, 4H,
H-30a,30b,40a,40b); 13C (100MHz, inter alia): d 166.31
and 164.60 (C-1), 155.07 (C@O, Cbz), 152.26 and
152.01 (C-3), 118.76 and 118.35 (C-2), 66.81 and 66.69
(CH2Ph), 56.48 and 55.52 (C-20), 51.27 (OMe), 47.25
and 46.89 (C-50), 33.14 and 32.49 (C-40), 24.77
and 24.08 (C-30). Mass spectrum (LSIMS): m/z:
312.1214 [M++Na] for C16H19NO4Na 312.1212
(deviation À 0.6ppm).
A mixture of 8 and 9 (160mg, 5.5%) was also obtained.
3.3.2. Dihydroxylation of 7with chiral catalyst. Potas-
sium ferricyanide (III) (170mg, 0.52mmol), K2CO3
(67mg, 0.68mmol) and either hydroquinine-1,4-
phthalazinediyldiether
[(DHQ)2PHAL]
(1.4mg,
1.8lmol) or hydroquinidine-1,4-phthalazinediyldiether
[(DHQD)2PHAL] were stirred in 2-propanol–water
(1:1, 7mL) after which 0.071M OsO4 in water (5lL)
was added. The mixture was stirred at rt for 15min.
To this was added methanesulfonamide (18mg,
190lmol) and the mixture ice-water cooled. Compound
7 (50mg, 170lmol) in 2-propanol–water (1:1, 3mL) was
added and the mixture stirred for 2h and then allowed
to reach rt overnight. TLC (Et2O) revealed the absence
of 7 and the presence of 8 and 9. The reaction was
quenched by the addition of Na2SO3 (270mg) followed
by stirring at rt for another 30min. The mixture was
subsequently extracted with EtOAc (4 · 5mL). The
combined organic extracts were concentrated and the
residue analyzed11 by GLC (B) to give 8 and 9 in 1:28
and 3.5:1 ratios, respectively.
Eluted second was a mixture of 6 and 7 (370mg) and
finally pure 7 (1.15g). Total yield 95%.
3.3. Methyl (2S,3R)-8 and (2R,3S)-2,3-dihydroxy-3-
[(20S)-N-benzyloxycarbonylpyrrolidin-20-yl]propanoate
(9)
3.3.1. Dihydroxylation of 7without a chiral catalyst. To
a stirred solution of 7 (2.6g, 9mmol) in acetone–water
8:1 v/v (36mL), was added N-oxide-N-methylmorpho-
line (2g, 18mmol) and aqueous 1% OsO4 (4mL). The
mixture was left at room temperature overnight.
GLC11 (B) then revealed the presence of two new prod-
ucts (tR 17.73 and 18.02min) in a 1:2 ratio. The mixture
was concentrated to a residue that was submitted to
chromatography (Et2O–hexane, 4:1). Eluted first was
3.4. (1R,2S,7aS)-1,2-Dihydroxypyrrolizidin-3-one 11
A solution of 8 (730mg, 2.26mmol) in MeOH (20mL)
was stirred at rt with 10% Pd–C (90mg) in an H2 atmos-
phere for 3h. TLC (Et2O) showed the presence of a non-
mobile compound, presumably the N-deprotected
pyrrolidine 10. The catalyst was filtered off, washed with
MeOH and the combined filtrate and washings (50mL)
treated with 2M MeONa (2mL) and refluxed for 6h.
TLC (Et2O–MeOH, 1:1) revealed the presence of a
faster-running product. The mixture was neutralized
with aqueous 10% HCl, supported on silica gel and
submitted to chromatography (Et2O–MeOH, 20:1) to
pure
8 (780mg, 27%) as a colorless syrup; tR
27
D
17.73min; ½aŠ ¼ À51 (c 1). IR (neat): 3415 (OH),
3064 (aromatic), 1747 and 1669 (C@O), and 697cmÀ1
1
(aromatic). NMR data (400MHz): H, d 7.33 (m, 5H,
Ph), 5.14 and 5.10 (2d, 2H, J 12.5Hz, CH2Ph), 4.18
(dt, 1H, J 5.5, J 8.2Hz, H-20), 4.14 (s, 1H, H-2), 3.83
0
(d, 1H, J2 ,3 8.7Hz, H-3), 3.79 (s, 3H, OMe), 3.61 and
3.36 (2dt, 2H, J 6.8, J 10.8Hz, H-50a,50b), 2.16–2.07
(m, 1H, H-30a), 1.96–1.78 (2m, 2H, H-40a,40b), and
1.76–1.68 (m, 1H, H-30b); 13C (100MHz): d 173.34
(C-1), 158.54 (Cbz), 136.21, 128.62, 128.29, 128.12
(Ph), 76.96 (C-3), 72.11 (C-2), 67.83 (CH2Ph), 60.42
(C-20), 52.73 (OMe), 47.39 (C-50), 28.70 (C-30),
and 24.21 (C-40). Mass spectrum (LSIMS): m/z:
346.1261 [M++Na] for C16H21NO6Na 346.1267
(deviation + 1.7ppm).
afford 11 (220mg, 61%) as white crystals, mp 143–
23
D
144ꢂC (from EtOAc); ½aŠ ¼ þ6:3 (c 1, MeOH). IR
(KBr): 3397 (OH), and 1671cmÀ1 (C@O, lactam).
1
NMR data (400MHz, MeOH-d4): H, d 4.47 (d, 1H,
J1,2 4.0Hz, H-2), 4.30 (t, 1H, J1,7a 4.0Hz, H-1), 3.81
0
(dt, 1H, J7,7a = J7 ,7a = 7.2Hz, H-7a), 3.49–3.42 (m,
1H, H-5), 3.06–2.99 (m, 1H, H-50), 2.02–1.92 (m, 3H,
H-6,60,7), and 1.82–1.74 (m, 1H, H-70); 13C (100MHz,

I. Izquierdo et al. / Tetrahedron: Asymmetry 15 (2004) 3635–3642
3639
MeOH-d4): d 175.53 (C-3), 76.28 (C-2), 72.40 (C-1),
63.12 (C-7a), 42.90 (C-5), 26.55 (C-6), and 24.11 (C-7).
Anal. Calcd for C7H11NO3: C, 53.49; H, 7.05; N, 8.91.
Found: C, 53.57; H, 7.29; N, 8.98.
(C-3), 27.87 (C-6), and 26.12 (C-7). Mass spectrum
(LSIMS): m/z: 323.1885 [M+] for C21H25NO2 323.1885
(deviation 0.0ppm).
3.7. (1R,2R,7aS)-1,2-Dihydroxypyrrolizidine 14
3.5. (1R,2S,7aS)-1,2-Dibenzyloxypyrrolizidin-3-one 12
A solution of 13 (90mg, 0.28mmol) in MeOH (10mL)
was acidified with concd HCl and stirred at rt with
10% Pd–C (50mg) in an H2 atmosphere overnight.
TLC (Et2O–MeOH–Et3N, 2:1:0.1) then showed that 13
had disappeared. The catalyst filtered off, and washed
with MeOH. The mixture was neutralized with Amber-
lite IRA-400, the resin was filtered off washed with
MeOH and the filtrate and washings concentrated to
A stirred solution of NaH (60% oil dispersion, 90mg,
2.1mmol)) in anhydrous DMSO (6mL) was heated at
60ꢂC for 15min, then cooled at rt, and a solution of
11 (110mg, 0.7mmol) in the same solvent (4mL) added
and the mixture heated again at 60ꢂC for an additional
15min, under argon. After cooling at rt, BnBr (330 lL,
2.8mmol) was added, and the reaction mixture stirred
for 3h. TLC (Et2O) then revealed a faster-running com-
pound. The mixture was then partitioned into water
(10mL) and Et2O (40mL), the organic phase was sepa-
rated, then concentrated. Column chromatography
(Et2O–hexane, 3:1) of the residue afforded pure 12
afford 14 (22mg, 56%) as a colorless thick syrup;
22
D
½aŠ ¼ À16 (c 1, MeOH). NMR data (400MHz,
MeOH-d4): 1H, d 4.19 (ddd, 1H, H-2), 3.88 (t, 1H,
J1,2 = J1,7a = 4.0Hz, H-1), 3.55 (m, 1H, H-7a), 3.19
0
(dd, 1H, J2,3 6.5, J3,3 9.9Hz, H-3), 3.04 (dt, 1H,
0
0
(180mg, 76%) as white crystals, mp 72–73ꢂC;
J5,6 = J5,6 = 5.5, J5,5 10.1Hz, H-5), 2.62 (m, 1H, H-
21
0
½aŠ ¼ þ31 (c 1). IR (KBr): 3036 (aromatic), and
50), 2.58 (t, 1H, J2,3 9.6Hz, H-30), 2.12 (m, 1H, H-7),
D
1695cmÀ1 (C@O, lactam). NMR data (400MHz): H,
d 7.40–7.23 (m, 10H, 2CH2Ph), 5.01 and 4.78 (2d, 2H,
J 12.3Hz, CH2Ph), 4.78 and 4.58 (2d, 2H, J 12.1Hz,
CH2Ph), 4.28 (d, 1H, J1,2 3.9Hz, H-2), 4.14 (t, 1H,
1.97 (m, 1H, H-6), and 1.82–1.68 (m, 2H, H-60,70); 13C
(100MHz): d 75.34 (C-2), 72.60 (C-1), 67.73 (C-7a),
58.03 (C-3), 56.84 (C-5), 27.89 (C-6), and 25.25 (C-7).
Mass spectrum (LSIMS): m/z: 143.0945 [M+] for
C7H13NO2 143.0946 (deviation + 0.9).
1
0
J1,7a 3.7Hz, H-1), 3.67 (dt, 1H, J7,7a 3.7, J7 ,7a 7.1Hz,
0
0
H-7a), 3.60 (dt, 1H, J5,6 = J5,6 = 7.3, J5,5 11.3Hz, H-
5), 3.01 (ddd, 1H, J5 ,6 4.7, J5 ,6 8.4Hz, H-50), 2.07–
1.95 (m, 2H, H-6,7), 1.93–1.84 (m, 1H, H-60), and
1.78–1.72 (m, 1H, H-70); 13C (100MHz): d 171.86 (C-
3), 138.26, 137.92, 128.45, 128.36, 127.92, 127.82,
127.79, and 127.69 (CH2Ph), 80.92 (C-2), 77.30 (C-1),
73.33 and 72.59 (CH2 Ph), 61.03 (C-7a), 42.08 (C-5),
25.80 (C-6), and 24.16 (C-7). Anal. Calcd for
C21H23NO3: C, 74.75; H, 6.87; N, 4.15. Found: C,
74.57; H, 7.10; N, 4.08. Mass spectrum (LSIMS): m/z:
360.1572 [M++Na] for C21H23NO3Na 360.1576
(deviation + 0.9).
3.8. (1S,2R,7aS)-1,2-Dihydroxypyrrolizidin-3-one 16
0
0
0
A solution of 9 (1.33g, 4.1mmol) in MeOH (30mL) was
stirred at rt with 10% Pd–C (200mg) in an H2 atmos-
phere for 3h. TLC (Et2O) showed the presence of a
non mobile compound, presumably the N-deprotected
pyrrolidine 15. The catalyst was filtered off, washed with
MeOH and the combined filtrate and washings (50mL)
treated with 2M MeONa (4mL) and refluxed for 6h.
TLC (Et2O–MeOH, 1:1) then revealed the presence of
a faster-running product. The mixture was neutralized
with aqueous 10% HCl, supported on silica gel and sub-
mitted to chromatography (Et2O–MeOH, 20:1) to
3.6. (1R,2R,7aS)-1,2-Dibenzyloxypyrrolizidine 13
afford 16 (470mg, 72%) as white crystals, mp 168–
22
D
To a stirred solution of 12 (137mg, 0.4mmol) in anhy-
drous THF (6mL) was added LiAlH4 (35mg,
0.92mmol), and the mixture refluxed overnight. TLC
(Et2O) then revealed that the starting material was not
present. Aqueous 0.5M NaOH (2mL) was cautiously
added and the mixture partitioned into EtAcO (5mL)
and water (5mL). The organic phase was separated
and the aqueous extracted with EtAcO (3 · 5mL). The
combined extracts were concentrated and the residue
submitted to column chromatography (Et2O–MeOH,
170ꢂC (from EtOAc); ½aŠ ¼ þ17 (c 1, MeOH). {Lit.5b
22
mp 165–166ꢂC; ½aŠ ¼ þ2:4 (c 1.06, MeOH)}. IR
D
(KBr): 3364 (OH), and 1669cmÀ1 (C@O, lactam).
1
NMR data (400MHz, MeOH-d4): H, d 4.33 (d, 1H,
J1,2 8.7Hz, H-2), 3.75 (dd, 1H, J1,7a 7.3Hz, H-1), 3.52
(m, 1H, H-5), 3.49 (m, 1H, H-7a), 3.05 (m, 1H, H-50),
0
0
2.20 (ddt, 1H, J6,7 4.3, J6 ,7 = J7,7a = 6.4, J7,7 12.3Hz,
H-7), 2.04–1.98 (m, 2H, H-6,60), and 1.52 (dq, 1H,
J6,7 = J6 ,7 = J7 ,7a = 8.8Hz, H-70). 13C (100MHz,
MeOH-d4): d 173.79 (C-3), 83.17 (C-1), 80.15 (C-2),
64.33 (C-7a), 42.91 (C-5), 31.00 (C-7), and 26.67 (C-6).
Anal. Calcd for C7H11NO3: C, 53.49; H, 7.05; N, 8.91.
Found: C, 53.76; H, 6.98; N, 8.72.
0
0
0
0
20:1) to afford pure 13 (90mg, 70%) as a white syrup;
25
D
½aŠ ¼ À15 (c 0.9). IR (neat): 3031cmÀ1 (aromatic).
1
NMR data (400MHz, MeOH-d4): H, d 7.32 (m, 10H,
2CH2Ph), 4.75 and 4.57 (2d, 2H, J 11.7Hz, CH2Ph),
4.59 and 4.54 (2d, 2H, J 11.1Hz, CH2Ph), 4.07 (m,
1H, H-2), 3.97 (br s, 1H, H-1), 3.52 (br q, 1H, J
3.9. (1S,2R,7aS)-1,2-Dibenzyloxypyrrolizidin-3-one 17
0
6.5Hz, H-7a), 3.15 (dd, 1H, J2,3 5.8, J3,3 9.6Hz, H-3),
0
A stirred solution of NaH (60% oil dispersion, 150mg,
3.8mmol) in anhydrous DMSO (8mL) was heated at
60ꢂC for 15min, then cooled at rt, and a solution of
16 (200mg, 1.27mmol) in the same solvent (4mL) added
and the mixture heated again at 60ꢂC for an additional
15min under argon. After cooling at rt, BnBr (600lL,
3.00 (m, 1H, H-5), 2.74 (t, 1H, J2,3 9.2Hz, H-30), 2.61
(m, 1H, H-50), 2.20–2.07 (m, 1H, H-7), 2.00–1.88 (m,
1H, H-6), and 1.75–1.65 (m, 2H, H-60,70); 13C
(100MHz, inter alia): d 82.59 (C-2), 78.99 (C-1), 74.40
and 73.31 (CH2Ph), 66.92 (C-7a), 57.07 (C-5), 56.27

3640
I. Izquierdo et al. / Tetrahedron: Asymmetry 15 (2004) 3635–3642
5.1mmol) was added, and the reaction mixture stirred
for 3h. TLC (Et2O) then revealed a faster-running com-
pound. The mixture was then partitioned into water
(10mL) and Et2O (40mL). The organic phase was sepa-
rated and then concentrated. Column chromatography
2), 3.63 (t, 1H, J1,2 = J1,7a = 5.8Hz, H-1), 3.22 (dd, 1H,
H-3a), 3.20 (q, 1H, H-7a), 2.91 (dt, 1H, J5a,6a
=
J
5a,6b = 6, J5a,5b 10.4Hz, H-5a), 2.72 (dt, 1H,
5b,6a = J5b,6b = 6.5Hz, H-5b), 2.53 (dd, 1H, J3a,3b
6a,7a = J6b,7a
J7a,7a = 6.3, J7a,7b 13.6Hz, H-7a),1.88 (dquin, 1H,
5a,6b = J5b,6b = J6b,7b = 5.7, J6a,6b 12.0Hz, H-6b), 1.78
J
10.5Hz, H-3b), 1.96 (dq, 1H,
J
=
(Et2O–hexane, 3:1) of the residue afforded pure 17
22
(420mg, 95%) as a colorless syrupy oil; ½aŠ ¼ þ44 (c
J
D
1). IR (neat): 3032 (aromatic), and 1707cmÀ1 (C@O,
lactam). NMR data (400MHz): 1H, 7.40–7.27 (m,
10H, 2CH2Ph), 5.10 and 4.79 (2d, 2H, J 11.6Hz,
CH2Ph), 4.62 and 4.56 (2d, 2H, J 11.8Hz, CH2Ph),
4.48 (d, 1H, J1,2 8.0Hz, H-2), 3.89 (dd, 1H, J1,7a
6.5Hz, H-1), 3.61–3.54 (m, 2H, H-5,7a), 3.04 (m, 1H,
H-50), 2.10–1.86 (m, 3H, H-6,60,7), and 1.42 (dq, 1H,
(dq, 1H, J7 a,7b = J6a,7b = 6.5Hz, H-7b), and 1.70 (dquin,
1H, H-6a). 13C (100MHz), d 82.93 (C-1), 78.63
(C-2), 70.74 (C-7a), 59.62 (C-3), 56.64 (C-5), 31.43
(C-7), and 26.23 (C-6). Anal. Calcd for C7H13NO2: C,
58.72; H, 9.15; N, 9.78. Found: C, 58.45; H, 9.31; N,
10.00.
J6,7 = J6 ,7 = J7 ,7a = 8.6, J7,7 12.1Hz, H-70); 13C
(100MHz): d 170.8 (C-3), 137.80, 137.60, 128.52,
128.40, 128.26, 127.99, 127.81, and 127.78 (CH2Ph),
86.82 (C-1), 84.14 (C-2), 72.70 and 72.44 (CH2Ph),
62.03 (C-7a), 41.55 (C-5), 31.02 (C-7), and 25.82 (C-6).
Mass spectrum (LSIMS): m/z: 360.1578 [M++Na] for
C21H23NO3Na 360.1576 (deviation À 0.7).
0
0
0
0
0
3.12. Methyl (2S,3S)-20 and (2R,3R)-2,3-dihydroxy-3-
[(20S)-N-benzyloxycarbonylpyrrolidin-20-yl]propanoate
21
3.12.1. Dihydroxylation of
6 without chiral cata-
lyst. Compound 6 (1.4g, 4.84mmol) was hydroxylated
as for 7 in acetone–water 8:1 v/v (18mL), with N-oxide-
N-methylmorpholine (1.13g, 9.64mmol) and aqueous
1% OsO4 (4mL). The mixture was left at room temper-
ature overnight. GLC11 (B) then revealed the presence of
two new products (tR 17.33 and 17.67min) in a 1:4 ratio.
The mixture was concentrated to a residue that was sub-
mitted to chromatography (Et2O–hexane, 2:1). Eluted
3.10. (1S,2S,7aS)-1,2-Dibenzyloxypyrrolizidine 18
To a stirred solution of 17 (250mg, 0.74mmol) in anhy-
drous THF (6mL) was added LiAlH4 (56mg, 1.4mmol),
and the mixture refluxed overnight. TLC (Et2O) then re-
vealed that no starting material was present. Aqueous
0.5M NaOH (2mL) was cautiously added and the mix-
ture partitioned into EtAcO (5mL) and water (5mL).
The organic phase was separated and the aqueous ex-
tracted with EtAcO (3 · 5mL). The combined extracts
were concentrated and the residue submitted to column
firstwas pure 20 (160mg, 10%) as a colorless syrup; tR
25
D
17.33min; ½aŠ ¼ À51 (c 1.25). IR (neat): 3402 (OH),
3032 (aromatic), 1746 and 1669 (C@O), and 699cmÀ1
1
(aromatic). NMR data (400MHz): H, d 7.34 (m, 5H,
Ph), 5.13 (s, 2H, CH2Ph), 4.96 (br d, 1H, J 6.5Hz,
HO), 4.23 (dt, 1H, J 3.8, J 7.8Hz, H-20), 4.10 (m, 2H,
H-2, OH), 3.80 (br s, 4H, OMe, H-3), 3.59 (dt, 1H,
chromatography (Et2O–MeOH, 20:1) to afford pure 18
26
(180mg, 75%) as a colorless syrup; ½aŠ ¼ À4 (c 1). IR
J4 a,5 a = J4 b,5 a = 7.4, J5 a,5 b 10.7Hz, H-50a), 3.39
D
0
0
0
0
0
0
(neat): 3029cmÀ1 (aromatic). NMR data (300MHz):
1H, d 7.34 (m, 10H, 2CH2Ph), 4.60 and 4.57 (2d, 2H,
J 11.8Hz, CH2Ph), 4.63 (s, 2H, CH2Ph), 4.21 (q, 1H,
(ddd, 1H, J4 a,5 b 5.3, J4 b,5 b 7.3Hz, H-50b), 2.11–2.00,
1.92–1.86, and 1.84–1.75 (3m, 4H, H-30a,30b,40a,40b);
13C (100MHz), d 173.48 (C-1), 158.07 (Cbz), 136.21,
128.61, 128.26, 127.99 (Ph), 77.12 (C-3), 72.47 (C-2),
67.76 (CH2Ph), 58.48 (C-20), 52.58 (OMe), 47.83 (C-
50), 29.07 and 24.37 (C-30,40). Mass spectrum (LSIMS):
m/z: 346.1263 [M++Na] for C16H21NO6Na 346.1267
(deviation + 0.9ppm).
0
0
0
0
0
J1,2 = J2,3 = J2,3 = 5.7Hz, H-2), 3.80 (t, 1H, J1,7a 5Hz,
H-1), 3.47 (br q, 1H, J 5.0Hz, H-7a), 3.37 (dd, 1H,
0
J3,3 10.2Hz, H-3), 3.04 (m, 1H, H-5), 2.76–2.69 (m,
2H, H-30,50), 2.05–1.95 (m, 1H, H-7), 1.94–1.85 (m,
1H, H-6), and 1.83–1.64 (m, 2H, H-60,70); 13C
(75MHz, inter alia): d 88.46 (C-1), 84.99 (C-2), 72.11
and 71.83 (CH2Ph), 68.52 (C-7a), 57.13 (C-3), 55.45
(C-5), 31.18 (C-7), and 25.88 (C-6). Mass spectrum
(LSIMS): m/z: 324.1958 [M++1] for C21H26NO2
324.1964 (deviation + 1.8ppm).
Eluted second was pure 21 (1.1g, 70%) as a colorless syr-
24
D
up; tR 17.67min; ½aŠ ¼ À48 (c 1). IR (neat): 3393 (OH),
3033 (aromatic), 1742 (C@O, ester), 1674 (C@O, Cbz),
1
and 699cmÀ1 (aromatic). NMR data (400MHz): H, d
7.34 (m, 5H, Ph), 5.15 and 5.08 (2d, 2H, J 12.3Hz,
CH2Ph), 4.27 (br s, 1H, H-2), 3.99 (br s, 2H, H-3,20),
3.63 (s, 3H, OMe), 3.39 (m, 1H, H-50a), 3.16 (m, 1H,
H-50b), 2.08 and 1.90 (2m, 4H, H-30a,30b,40a,40b); 13C
(100MHz): d 172.44 (C-1), 156.96 (Cbz), 136.13,
128.59, 128.27, 128.13 (Ph), 73.75 (C-3), 73.66 (C-2),
67.80 (CH2Ph), 59.75 (C-20), 52.25 (OMe), 46.67 (C-
50), 27.73 and 23.39 (C-30,40). Mass spectrum (LSIMS):
m/z: 346.1267 [M++Na] for C16H21NO6Na 346.1267
(deviation 0.0ppm).
3.11. (1S,2S,7aS)-1,2-Dihydroxypyrrolizidine 19
A solution of 18 (275mg, 0.85mmol) in MeOH (10mL)
was acidified with concd HCl and stirred at rt with 10%
Pd–C (75mg) in an H2 atmosphere overnight. TLC
(Et2O–MeOH–Et3N, 2:1:0.1) then showed that 18 had
disappeared. The catalyst was filtered off and washed
with MeOH. The mixture was neutralized with Amber-
lite IRA-400, the resin filtered off, washed with MeOH
and the filtrate and washings concentrated to afford 19
(107mg, 88%) as white crystals, mp 164–165ꢂC
23
(from Et2O–MeOH); ½aŠ ¼ þ11 (c 0.5, MeOH). Lit.5b
3.12.2. Dihydroxylation of 6 with chiral catalyst. Com-
pound 6 (50mg, 170lmol) was dihydroxylated under the
same conditions as 7 (see above) to yield mixtures of 20
D
24
D
½aŠ ¼ À3:4 (c 0.5, MeOH). NMR data (400MHz,
1
MeOH-d4): H, d 4.03 (q, 1H, J2,3a = J2,3b = 5.8Hz, H-

I. Izquierdo et al. / Tetrahedron: Asymmetry 15 (2004) 3635–3642
3641
and 21, which were analyzed11 by GLC (B) resulting in a
1:1 (AD-mix a) and 1:7 (AD-mix b) ratios, respectively.
(CH2 Ph), 86.84 (C-1), 84.16 (C-2), 72.72 and 72.47
(CH2Ph), 62.05 (C-7a), 41.57 (C-5), 31.04 (C-7), and
25.83 (C-6). Mass spectrum (LSIMS): m/z: 360.1581
[M++Na] for C21H23NO3Na 360.1576 (deviation À 1.5).
3.13. (1S,2S,7aS)-1,2-Dihydroxypyrrolizidin-3-one 23
Compound 20 (160mg, 0.49mmol) was transformed
into 23, following the same protocol used for 9 (37mg,
48%) as white crystals, mp 130–132ꢂC (from EtOAc);
3.16. (1R,2S,7aS)-1,2-Hydroxypyrrolizidine 27
To a stirred solution of 25 (180mg, 1.14mmol) in anhy-
drous THF (6mL) added a H3B–SMe2 complex solution
in the same solvent (10M, 1.14mL) under argon, and
the mixture left at rt overnight. TLC (Et2O–MeOH,
1:1) then revealed the absence of 25. MeOH (2mL)
was cautiously added and the reaction mixture was con-
centrated to a residue that was dissolved in MeOH
(20mL) and refluxed for 6h, then concentrated. The res-
idue was supported on silica gel and chromatographed
(Et2O ! Et2O–MeOH–Et3N, 1:1:1) to give 27 (106mg,
65%) as pale yellow crystals, mp 137–138ꢂC;
24
24
½aŠ ¼ þ7, ½aŠ ¼ þ17 (c 0.6, MeOH). IR (KBr):
D
405
3305 (OH), and 1685cmÀ1 (C@O, lactam). NMR data
1
(400MHz, MeOH-d4): H, d 4.49 (d, 1H, J1,2 4.0Hz,
H-2), 4.31 (t, 1H, J1,7a 3.7Hz, H-1), 3.83 (dt, 1H,
0
J7,7a = J7 ,7a = 7.2Hz, H-7a), 3.48 (dt, 1H, J5,6
=
=
0
0
0
J5,6 = 7.5, J5,5 11.6Hz, H-5), 3.05 (dt, 1H, J5 ,6
J5 ,6 = 6.0Hz, H-50), 2.04–1.96 (m, 3H, H-6,60,7), and
1.84–1.76 (m, 1H, H-70); 13C (100MHz): d 175.57 (C-
3), 76.31 (C-2), 72.42 (C-1), 63.16 (C-7a), 42.92 (C-5),
26.56 (C-6), and 24.13 (C-7). Anal. Calcd for
C7H11NO3: C, 53.49; H, 7.05; N, 8.91. Found: C,
53.23; H, 7.40; N, 9.11.
0
0
24
D
24
405
24
D
½aŠ ¼ þ3, ½aŠ ¼ þ13, (c 1, MeOH). Lit.5a ½aŠ
¼
þ7:46 (c 0.67, MeOH). IR (KBr): 3269cmÀ1 (HO).
1
NMR data (300MHz, MeOH-d4): H, d 4.09 (q, 1H,
3.14. (1R,2R,7aS)-1,2-Dihydroxypyrrolizidin-3-one 25
0
J1,2 = J2,3 = J2,3 = 5.2Hz, H-2), 3.73 (t, 1H, J1,7a
5.2Hz, H-1), 3.33 (m, 1H, H-7a), 3.32 (dd, 1H, H-3),
0
Compound 21 (700mg, 2.16mmol) was transformed
into 25, following the same procedure used for 20
0
3.05 (dt, 1H, J5,6 = J5,6 = 5.7, J5,5 10.5Hz, H-5), 2.83
0
(dt, 1H, J5 ,6 = J5 ,6 = 6.0Hz, H-50), 2.66 (dd, 1H, J3,3
0
0
0
10.9Hz, H-30), 2.10–1.72 (m, 4H, H-7,6,70,60);
13C (75MHz): d 82.61 (C-1), 78.72 (C-2), 71.56 (C-7a),
59.69 (C-3), 56.85 (C-5), 31.23 (C-7), and 26.30 (C-6).
Anal. Calcd for C7H13NO2: C, 58.72; H, 9.15; N, 9.78.
Found: C, 58.41; H, 9.46; N, 9.91.
(230mg, 68%) as white crystals, mp 157–159ꢂC;
23
½aŠ ¼ þ11:8 (c 1, MeOH). IR (KBr): 3359 (OH), and
D
1672cmÀ1 (C@O, lactam). NMR data (400MHz,
1
MeOH-d4): H, d 4.32 (d, 1H, J1,2 8.7Hz, H-2), 3.74
(dd, 1H, J1,7a 7.1Hz, H-1), 3.54–3.47 (m, 2H, H-7a,5),
3.05 (m, 1H, H-50), 2.19 (ddt, 1H, J7,7a = J6,7 = 6.4,
J6 ,7 4.1, J7,7 12.5Hz, H-7), 2.04–1.95 (m, 2H, H-6,60),
0
0
and 1.52 (dq, 1H, J6,7 = J6 ,7 = J7 ,7a = 8.7Hz, H-70).
13C (100MHz): d 173.82 (C-3), 83.22 (C-1), 80.20 (C-
2), 64.36 (C-7a), 42.93 (C-5), 31.01 (C-7), and 26.66
(C-6). Anal. Calcd for C7H11NO3: C, 53.49; H, 7.05;
N, 8.91. Found: C, 53.31; H, 7.50; N, 8.57.
0
0
0
0
Acknowledgements
The authors are deeply grateful to Ministerio de Ciencia
´
y Tecnologıa (Spain) for financial support(Project
PPQ2002-01303).
3.15. (1R,2R,7aS)-1,2-Dibenzyloxypyrrolizidin-3-one 26
References
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60ꢂC for 15min, then cooled at rt, and a solution of
25 (110mg, 0.7mmol) in the same solvent (4mL) added
and the mixture heated again at 60ꢂC for an additional
15min, under argon. After cooling at rt, BnBr (330 lL,
2.8mmol) was added, and the reaction mixture stirred
for 3h. TLC (Et2O) then revealed a faster-running com-
pound. The mixture was then partitioned into water
(10mL) and Et2O (40mL) and the organic phase sepa-
rated and then concentrated. Column chromatography
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4. Izquierdo, I.; Plaza, M.-T.; Robles, R.; Franco, F.
Carbohydr. Res. 2001, 330, 401–408; Izquierdo, I.; Plaza,
M.-T.; Franco, F. Tetrahedron: Asymmetry 2002, 13,
1503–1508.
5. Syntheses for 1,2-dihydroxypyrrolizidines have been
previously described: (a) from 2,3-O-isopropylidene-D-
and -L-glyceraldehyde: Casiraghi, G.; Spanu, P.; Rassu,
G.; Pinna, L.; Ulgheri, F. J. Org. Chem. 1994, 59, 2906–
2909; (b) By a samarium diiodide-promoted cyclization of
N-(x-iodoalkyl)imides: Ha, D.-C.; Yun, C.-S.; Lee, Y.
J. Org. Chem. 2000, 65, 621–623; (c) From a chiral cis-a,b-
(Et2O–hexane, 3:1) of the residue afforded pure 26
23
D
(210mg, 90%) as a colorless syrup; ½aŠ ¼ þ41:6 (c 1).
IR (neat): 3031 (aromatic), and 1707cmÀ1 (C@O, lac-
1
tam). NMR data (400MHz): H, d 7.40–7.29 (m, 10H,
2CH2Ph), 5.11 and 4.79 (2d, 2H, J 11.7Hz, CH2Ph),
4.62 and 4.56 (2d, 2H, J 11.8Hz, CH2Ph), 4.47 (d, 1H,
J1,2 8.0Hz, H-2), 3.89 (dd, 1H, J1,7a 6.6Hz, H-1),
3.61–3.54 (m, 2H, H-5,7a), 3.04 (m, 1H, H-50), 2.10–
2.03 (m, 1H, H-7), 2.01–1.86 (m, 2H, H-6,60), and 1.42
´
epoxyamine: Ayad, T.; Genisson, Y.; Baltas, M.; Gorri-
(dq, 1H, J6,7 = J6 ,7 = J7 ,7a = 9.0, J7,7 12.1Hz, H-70);
13C NMR (100MHz): d 170.51 (C-3), 137.82, 137.62,
128.53, 128.42, 128.28, 128.00, 127.83, and 127.80
0
0
0
0
0
chon, L. Chem. Commun. 2003, 582–583.
6. Falorni, M.; Porcheddu, A.; Taddei, M. Tetrahedron Lett.
1999, 40, 4395–4396.

3642
I. Izquierdo et al. / Tetrahedron: Asymmetry 15 (2004) 3635–3642
7. Compound 5 was prepared by oxidation of Cbz-L-prolinol
9. In NMR spectra, two figures for the same 1H or 13C NMR
signal indicates that rotamers are present.
with: (a) SO3– Py complex: Lee, E.; Li, K.-S.; Lim, J.
Tetrahedron Lett. 1996, 37, 1445–1446; Dei, S.; Bellucci,
C.; Buccioni, M.; Ferraroni, M.; Gualtieri, F.; Guandalini,
L.; Manetti, D.; Matucci, R.; Romanelli, M.-N.; Scapec-
chi, S.; Teodori, E. Bioorg. Med. Chem. 2003, 11, 3153–
3164; (b) Swern oxidation: Nagashima, H.; Gondo, M.;
Masuda, S.; Kondo, H.; Yamaguchi, Y.; Matsubara, K.
Chem. Commun. 2003, 442–443; (c) Dess–Martin period-
inane: Gardiner, J. M.; Bruce, S. E. Tetrahedron Lett.
1998, 39, 1029–1032; (d) Reduction of Cbz-L-proline
methyl ester with DIBAL: Langley, D. R.; Thurston, D.
E. J. Org. Chem. 1987, 52, 91–97.
´
10. Barton, D. H. R.; Herve, Y.; Potier, P.; Thierry, J.
Tetrahedron 1987, 43, 4297–4308.
11. An aliquot of the reaction mixture (5mg) was persilylated
according to: Sweeley, C. C.; Bentley, R.; Makita, M.;
Wells, W. W. J. Am. Chem. Soc. 1963, 2497–2507, by
using Silylating mixture Fluka Iꢁ (500lL).
12. (a) Sharpless, K. B.; Amberg, W.; Bennari, Y. L.;
Crispino, G. A.; Hartung, J.; Jeong, K.-S.; Kwong,
H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang,
X.-L. J. Org. Chem. 1992, 57, 2768–2771; (b) Kolb, H. C.;
VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994,
94, 2483–2547.
8. When the reaction was performed in MeOH the stereo-
selectivity decreased giving an appreciable amount of the
13. Bonini, C.; Righi, G. Tetrahedron 2002, 58, 4981–
5021.
14. Carmona, A. T.; Fuentes, J.; Vogel, P.; Robina, I.
Tetrahedron: Asymmetry 2004, 15, 323–333.
´
Z-isomer. For similar results see: Herradon, B.; Mann, E.;
Salgado, A.; Sanchez-Sancho, F. Recent Res. Dev. Org.
´
Chem. 2001, 5, 49–62.