Polyhydroxylated pyrrolizidines. Part 7. Stereoselective synthesis of unnatural analogs of (+)-casuarine from partially protected DGDP

Article abstract of DOI:10.1080/07328300600735181

A new synthetic approach to analogs of (+)-casuarine (2a and 2b), a natural pentahydroxylated pyrrolizidinic alkaloid in a highly stereocontrolled manner, is reported herein. An orthogonally protected polyhydroxylated pyrrolidine, such as (2S,3R,4R,5R)-3,

Full text of DOI:10.1080/07328300600735181

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Polyhydroxylated Pyrrolizidines. Part 7.
Stereoselective Synthesis of Unnatural
Analogs of (+)‐Casuarine from Partially
Protected DGDP
Isidoro Izquierdo a , María T. Plaza a & Juan A. Tamayo a
a Department of Medicinal and Organic Chemistry, Faculty of Pharmacy ,
University of Granada , Granada, Spain
Published online: 17 Aug 2006.
To cite this article: Isidoro Izquierdo , María T. Plaza & Juan A. Tamayo (2006) Polyhydroxylated
Pyrrolizidines. Part 7. Stereoselective Synthesis of Unnatural Analogs of (+)‐Casuarine from Partially Protected
DGDP, Journal of Carbohydrate Chemistry, 25:2-3, 281-295, DOI: 10.1080/07328300600735181
To link to this article: http://dx.doi.org/10.1080/07328300600735181
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Journal of Carbohydrate Chemistry, 25:281–295, 2006
Copyright # Taylor & Francis Group, LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300600735181
Polyhydroxylated
Pyrrolizidines. Part 7.†
Stereoselective Synthesis of
Unnatural Analogs of (1)-
Casuarine from Partially
Protected DGDP
´
Isidoro Izquierdo, Marıa T. Plaza, and Juan A. Tamayo
Department of Medicinal and Organic Chemistry, Faculty of Pharmacy, University of
Granada, Granada, Spain
A new synthetic approach to analogs of (þ)-casuarine (2a and 2b), a natural pentahy-
droxylated pyrrolizidinic alkaloid in a highly stereocontrolled manner, is reported
herein. An orthogonally protected polyhydroxylated pyrrolidine, such as
(2S,3R,4R,5R)-3,4-dibenzyloxy-20-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyr-
rolidine [3, protected DGDP (2,5-dideoxy-2,5-imino-D-glucitol)], easily available from
D-fructose, was chosen as the source of chirality and functionalization.
Keywords Stereoselective synthesis, D-Fructose, DGDP, Polyhydroxylated pyrrolizi-
dines, Alkaloids, (þ)-Casuarine analogs
Received September 26, 2005; accepted November 1, 2005.
†For Part 6 of the series, see Ref. 1.
Address correspondence to Isidoro Izquierdo, Department of Medicinal and Organic
Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain.
E-mail: isidoro@ugr.es
281

I. Izquierdo et al.
282
INTRODUCTION
Glycosidases and glycosyltransferases play an important role in molecular
biology in such a way that the interference with the enzymatic activity of
these biomolecules by inhibitors (iminosugars and related compounds) may
cause profound effects on the biological processes mediated by them, and
hence their potential applications as agrochemicals and therapeutic
agents.[2] Within this context, much attention has been paid in the last
decade to the synthesis[3] of the naturally occurring iminosugars (polyhydroxy-
lated alkaloids) as well as their analogs.
Recently, we reported on the stereoselective synthesis of (þ)-casuarine
(1),[1] which together with hyacinthacine C1[4] are the polyhydroxylated pyrro-
lizidinic alkaloids (PHPAs) with the highest degree of hydroxylation found in
nature so far. In addition, and continuing with our efforts[1,5] on the prep-
aration of PHPAs, we are interested in exploring the possibility of preparing
other unnatural synthetic isomers of 1 at the starred positions that could be
of interest for structure-activity relationship studies on glycosidase inhibition.
According to Figure 1, construction of the target PHPAs 2 could be achieved
as follows: ring A comes from an orthogonally protected derivative 3 of
2,5-dideoxy-2,5-imino-D-glucitol (DGDP), which transfers its inherent chirality
to the final compound, whereas the B ring, with the appropriate stereo-
chemistry and functionalization, would be built up following the synthetic
route outlined in Scheme 1, consisting of a carbon-chain lengthening at C(50)
of (2S,3R,4R,5R)-3,4-dibenzyloxy-20-O-tert-butyldiphenylsilyl-2,5-bis(hydroxy-
methyl)pyrrolidine (3), stereocontrolled dihydroxylation, and finally cyclization
to the pyrrolizidine skeleton.
The chiral starting compound 3 was obtained, in 30% yield, as minor
component in the synthesis from D-fructose of its related DMDP derivative[6]
when a Raney-nickel from a freshly opened can was the catalyst in the
hydrogenation step.
Figure 1: (þ)-Casuarine (1) and analogs (2).

Polyhydroxylated Pyrrolizidines
283
Scheme 1: Retrosynthesis of 2.
Since the isolation of 1 in 1994 from Casuarina equisetifolia L. (Casuarina-
ceae), only Bell et al.[7] in 1997 and very recently our group,[1] both using
carbohydrate derivatives as source of chirality and functionalization, have
reported on the synthesis of diastereomers of 1. We report herein full studies
concerning the highly stereocontrolled preparation of a new diastereomer of
1 as well as another previously described.[7]
RESULTS AND DISCUSSION
Pyrrolidine
3 was formed, as minor component, together with its
(2R,3R,4R,5R)-isomer (protected DMDP) in the hydrogenation of 5-azido-3,4-
di-O-benzyl-1-O-tert-butyldiphenylsilyl-5-deoxy-b-D-fructopyranose.[6] Treat-
ment of this mixture with benzylchloroformate (Sch. 2) followed by chromato-
graphy provided the N-Cbz protected pyrrolidine 4, which was then oxidized to
the corresponding aldehyde 5, which reacted with (methoxycarbonylmethyle-
ne)triphenylphosphorane affording, in a highly stereoselective manner,
˚
Scheme 2: Reagents and conditions: (i) CbzCl// Me2CO/K2CO3, rt; (ii) NMO/TPAP/4 A MS/
Cl2CH2; (iii) Ph3P ¼ CHCO2Me/Cl2CH2, rt.

I. Izquierdo et al.
284
methyl (E)-3-[(20R,30R,40R,50S)-30,40-dibenzyloxy-N-benzyloxycarbonyl-50-tert-
butyldiphenylsilyoxymethylpyrrolidin-20-yl]propenoate (6), in accordance
with J2,3 ¼ 15.7 Hz, as a mixture of rotamers. (The appearance of two sets of
1
peaks in the H and 13C NMR spectra indicated that rotamers were present.)
Dihydroxylation (DH) of the a,b-unsaturated ester 6 (Sch. 3) gave a resol-
vable mixture of the methyl (2S,3R)- (7) and (2R,3S)-2,3-dihydroxy-3-
[(20R,30R,40R,50S)-30,40-dibenzyloxy-N-benzyloxycarbonyl-50-tert-butyldiphenyl
silyloxymethylpyrrolidin-20-yl]propanoate (8), in a ꢀ1:3.4 diastereomeric ratio.
When the reaction was performed under the Sharpless conditions (ADH),[8]
a
modest increase of the diastereomeric ratio (1:6.9) in the presence of DHQ-
CLB catalyst was observed, whereas a lower stereoselectivity (1:2.3) was
obtained when DHQD-CLB catalyst was used, indicating a matched and
mismatched substrate-catalyst effect during the dihydroxylation process.
The absolute configurations at the new stereogenic centers in 7 could be
determined after its transformation into (1R,2S,5S,6R,7R,7aR)-6,7-dibenzy-
loxy-5-tert-butyldiphenylsilyl oxymethyl-1,2-dihydroxypyrrolizidin-3-one (10),
achieved by conventional N-deprotection to the not isolated pyrrolidinic ester
9, followed by refluxing in MeOH, under the presence of catalytic amount of
MeONa, which promoted an intramolecular g-lactamization (Scheme 4). The
structure of 10 was established on the basis of their spectroscopic data.
Thus, compound 10 showed characteristic IR g-lactam absorption at
1684 cm21, also confirmed by the presence of a resonance signal at d
172.69 ppm in its 13C NMR spectrum. Due to the overlapping of some signals
in the 1H NMR spectrum of 10, this was transformed into the related
Scheme 3: Dihydroxylation of 6.

Polyhydroxylated Pyrrolizidines
285
Scheme 4: Reagents and conditions: (i) H2/10% Pd-C/DME; (ii) MeONa (cat.)/MeOH/D; (iii)
Ac2O/py// DMAP (cat.), rt; (iv) H3B:SMe2/THF, then MeOH/D; (v) n-Bu4NþF2 3H2O/THF, rt; (vi) H2/
.
10% Pd(OH)2-C/HCl/MeOH then Amberlite IRA-400 (OH2 form).
1,2-di-O-acetyl derivative 11, which analytical and spectroscopic data were in
agreement with those expected for the proposed structure.
Extensive NOE-difference experiments (Fig. 2) confirmed the assigned
stereochemistry for 10. Thus, the definite NOE effect in 11 between C(1)H
and C(7a)H indicated 1R,2S configurations at C(1,2), while the rest of the
NOE interactions [C(7a)H ! C(6)H and C(6)H ! C(5)H] also assured the
1
total stereochemistry of 11, and hence that for 10. In addition, H-1H and
1H-13C COSY made possible the assignment of all resonance signals.
The transformation of 10 into the target molecule, (1R,2R,3S,6R,7R,7aR)-
1,2,6,7-tetrahydroxy-3-hydroxymethylpyrrolizidine (2a) (Sch. 4), was carried
out by reduction to the corresponding partially protected pyrrolizidine
12 with H3B:SMe2 complex in THF, followed by O-desilylation to 13 and
finally total deprotection to the required compound. The optical and spectro-
scopic data of compound 2a exactly matched those previously reported for
Figure 2: Main NOE interactions in 11 and 13.

I. Izquierdo et al.
286
(þ)-3,6,7-triepicasuarine.[7] Moreover, the NOE-difference interactions
displayed in Fig. 2 for the parent compound of 2a (13) also confirmed its
whole stereochemistry.
Following a similar protocol, ester 8 was transformed into (þ)-3-epicasuar-
ine (2b), the required transformations being displayed in Scheme 5. Thus, 8
was transformed into the polyhydroxylated pyrrolizidin-3-one 15, after
N-deprotection and internal g-lactamization as above. For the same reasons
invoked for 10, compound 15 was di-O-acetylated to give 16, which analytical
and spectroscopic data sufficed those expected for such molecule. NOE-
difference experiments on 16 were of significance in order to confirm again
the assigned structure, being remarkable the C(1)H ! C(7)H and the
C(2)H ! C(7a)H interactions, in order to determine the stereochemistry of
the newly formed stereogenic centres in the parent ester 8 (Fig. 3).
Reduction of 15 to pyrrolizidine 17, followed by its O-desilylation, to 18 and
total O-debenzylation, afforded the target molecule 2b slightly contaminated.
Again, and due to the overlapping of some the 1H NMR signals in 2b, this was
per-O-acetylated to 19, which analytical and spectroscopic data together with
NOE experiments (see Fig. 3) allowed its structural determination. Finally,
Zemplen de-O-acetylation of 19 and chromatography gave pure 2b.
CONCLUSIONS
We have developed a new synthetic strategy for the preparation of two unna-
tural densely polyhydroxylated pyrrolizidinic alkaloids, the already known
Scheme 5: Reagents and conditions: (i) H2/10% Pd-C/MeOH; (ii) MeONa (cat.)/MeOH/D; (iii)
Ac2O/py/DMAP (cat.); (iv) H3B:SMe2/THF, then MeOH/D; (v) n-Bu4NþF2 3H2O/THF; (vi) H2/10%
.
Pd-C/HCl/MeOH then Amberlite IRA-400 (OH2 form); (vii) MeONa (cat.)/MeOH.

Polyhydroxylated Pyrrolizidines
287
Figure 3: Main NOE interactions in 16 and 19.
(þ)-3,6,7-triepicasuarine (2a) and the new (þ)-3-epicasuarine (2b) in seven
steps at overall yield of 24% from the easily available pyrrolidine 4.
EXPERIMENTAL
General Methods
Raney-nickel was purchased from Fluka. Solutions were dried over MgSO4
1
before concentration under reduced pressure. The H and 13C NMR 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 FT-IR Spectrum One 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 (1-dm tube) with a Jasco DIP-370 polarimeter. GLC was performed on
a Hewlett-Packard 6890 gas chromatograph equipped with split/splitless
injector,
a
flame-ionisation detector, and
a
capillary HP-5 column
(30 m ꢁ 0.25 mm i.d. ꢁ 0.25 mm film thickness) at 10 min at 2308C program to
2508C, 208C/min; the He flow rate was 0.7 mL/min, the injection port and
the zone-detector temperatures were 2508C. TLC was performed on precoated
silica gel 60 F254 aluminium sheets and detection by employing a mixture of
10% ammonium molybdate (w/v) in 10% aqueous sulphuric acid containing
0.8% cerium sulphate and heating. Column chromatography was performed
on silica gel (Merck, 7734). The noncrystalline compounds, in which elemental
analyses are not included, were shown to be homogeneous by chromatographic
methods and characterized by NMR, MS, and HRMS.
(2S,3R,4R,5R)-3,4-Dibenzyloxy-N-benzyloxycarbonyl-20-O-tert-butyldi-
phenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (4). 5-Azido-3,4-di-O-benzyl-
1-O-tert-butyldiphenylsilyl-5-deoxy-b-D-fructopyranose[6] (8.7 g, 13.97 mmol) in
MeOH (70 mL) was hydrogenated at 60 psi over wet Raney-nickel (3 g,

I. Izquierdo et al.
288
freshly opened can) for 12 h. TLC (ether) then revealed the presence of a non-
mobile compound. The catalyst was removed by filtration and washed with
MeOH. The combined filtrate and washings were concentrated to a residue
(8 g) that was dissolved in dry acetone (80 mL). Anhydrous potassium carbon-
ate (5.5 g) and a solution of benzyl chloroformate (2.5 mL, 17.4 mmol) in the
same solvent (15 mL) were added and the mixture kept at rt for 6 h. TLC
(Et2O-hexane, 2:1) then revealed the presence of two faster-running com-
pounds. The mixture was filtered and the solid thoroughly washed with
acetone and the filtrate and washings concentrated to a residue that was sub-
mitted to chromatography (Et2O-hexane, 1:2). Eluted first was 4 as a colorless
syrup (2.43 g, 25%). [a]2D2 27 (c, 1); nmax (film): 3410 (OH), 3061 and 3032
(aromatic), 1683 (C ¼ O, Cbz), 736 and 700 cm21 (aromatic); dH (300 MHz),
inter alia: 7.72–7.67 and 7.49–7.23 (25H, 2 m, 5 Ph), 5.08 and 4.98 (2H, 2 d,
J ¼ 11.7, CH2Ph), 4.75 and 4.67 (2H, 2d, J ¼ 11.8, CH2Ph), 4.56 (2H, br s,
Cbz), 4.15 and 4.41–4.33 (8H, 2 m) and 1.07 (9H, s, CMe3); dC (75 MHz), inter
alia: 157.29 (C ¼ O, Cbz), 82.19 and 81.91 (C-3,4), 73.24 and 72.68 (2
CH2Ph), 67.72 (CH2Ph, Cbz), 65.42 and 61.43 (C-20,50), 64.82 and 59.90 (C-
2,5), 26.95 (CMe3), and 19.15 (CMe3); m/z (found: MNaþ, 738.3226;
C44H49NO6NaSi requires 738.3227).
Eluted second was (2R,3R,4R,5R)-3,4-dibenzyloxy-N-benzyloxycarbonyl-
20-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine as a colorless
thick syrup (6.4 g, 64%), which optical and spectroscopic data were in accord-
ance with those previously reported.[6]
Methyl (E)-3-[(20R,30R,40R,50S)-30,40-Dibenzyloxy-N-benzyloxycarbonyl-
50-tert-butyldiphenylsilyloxymethylpyrrolidin-20-yl]propenoate (6). To
a stirred solution of 4 (2.06 g, 2.9 mmol) in dry CH2Cl2 (30 mL) were added acti-
˚
vated 4 A molecular sieves (1.5 g), N-oxide-N-methylmorpholine (NMO,
420 mg, 3.56 mmol), and tetra-n-propylammonium perruthenate (TPAP,
57 mg), and the reaction mixture was kept at rt for 1 h. TLC (Et2O-hexane,
3:2) then indicated the absence of the starting material and the presence of a
faster-running compound, presumably pyrrolidinic aldehyde 5. (Methoxycar-
bonylmethylene)triphenylphosporane (1.44 g, 4.3 mmol) was added, and the
mixture was left at rt. After 48 h, TLC (Et2O-hexane, 3:2) then showed a new
compound. The reaction mixture was supported on silica gel and submitted
to chromatography (Et2O-hexane, 1:3) to afford pure 6 as colorless thick
25
405
syrup (2.07 g, 93%). [a]2D4 25.4, [a]
29.1 (c, 1.1); nmax (film): 3068 and 3032
(aromatic), 1707 (C ¼ O), 740 and 700 cm21 (aromatic); dH (400 MHz): 7.62
0
and 7.30–7.14 (25H, 2 m, 5 Ph), 7.04 (1H, dd, J2,3 ¼ 15.7, J2 ,3 ¼ 7.38, H-3),
6.04 and 5.90 (1H, 2d, J ¼ 15.0, H-2), 5.10–4.94, 4.69–4.58, 4.38–4.16 and
3.83 (12H, 4 m), 3.64 (3H, s, OMe), 1.00 (9H, s, CMe3); dC (100 MHz) inter
alia: 166.44 (C-1), 155.27 (C55O, Cbz), 147.61 and 147.03 (C-3), 122.03 and
121.99 (C-2), 85.23, 84.50, 82.24 and 81.74 (C-30,40), 73.13 and 73.00 (2

Polyhydroxylated Pyrrolizidines
289
CH2Ph), 67.27 (CH2Ph, Cbz), 62.98, 62.69, 60.01 (C-20,50), 61.34 and 61.23 (C-
500), 51.46 (OMe), 26.94 (CMe3), 19.12 (CMe3); m/z (found: MNaþ, 792.3336;
C47H51NO7NaSi requires 792.3332).
Methyl (2S,3R)- (7) and (2R,3S)-2,3-dihydroxy-3-[(20R,30R,40R,50S)-30,
40-dibenzyloxy-N-benzyloxycarbonyl-50-tert-butyldiphenylsilyloxy-
methylpyrrolidin-20-yl]propanoate (8). Dihydroxylation of 6 without chiral
catalyst: To a stirred solution of 6 (3.9 g, 5.07 mmol) in acetone-water 8:1 v/v
(40 mL) was added NMO (1.19 g, 10 mmol) and aqueous 1% OsO4 (5 mL). The
mixture was left at rt 48 h. TLC (Et2O-hexane, 3 : 1) then revealed the
presence of two new products of lower mobility. The mixture was concentrated
to a residue that was submitted to chromatography (Et2O-hexane, 1 : 3). Eluted
first was 7 as a white solid (915 mg, 22.3%). m.p. 155–1578C. [a]2D4 -31 (c, 1);
nmax (KBr): 3436 (OH), 3068 and 3032 (aromatic), 1746 (C55O, ester), 1675
(C ¼ O, Cbz), 739 and 700 cm21 (aromatic); dH (300 MHz): 7.46–7.39, 7.23–
7.05 and 6.90 (25H, 3 m, 5 Ph), 4.79 (2H, s, Cbz), 4.47 and 4.41 (2H, 2d,
J ¼ 11.4, CH2Ph), 4.42 and 4.33 (2H, 2d, J ¼ 11.8, CH2Ph), 4.17–4.02 (5H,
m), 3.79–3.70 (3H, m), 3.52 (3H, s, OMe), 0.82 (9H, s, CMe3); dC (75 MHz),
inter alia: 82.08 and 81.08 (C-30,40), 73.06 and 71.62 (2 CH2Ph), 71.96 and
70.62 (C-2,3), 67.92 (CH2Ph, Cbz), 66.54 and 62.72 (C-20,50), 61.03 (C-500),
52.37 (OMe), 26.91 (CMe3), and 19.25 (CMe3); Anal. Calcd. for C47H53NO9Si:
C, 70.21; H, 6.64; N, 1.74. Found: C, 70.61; H, 7.05; N, 1.80.
Eluted second was syrupy 8 (3.09 g, 75%). [a]2D5 221.3 (c, 1); nmax (film):
3398 (OH), 3064 and 3035 (aromatic), 1735 (C55O, ester), 1672 (C55O, Cbz),
738 and 699 cm21 (aromatic); dH (400 MHz): 7.62–7.57, 7.39–7.21 and 7.07
(25 H, 3 m, 5 Ph), 4.95 (2H, br s, Cbz), 4.64 and 4.58 (2H, 2d, J ¼ 11.5,
CH2Ph), 4.58 and 4.50 (2H, 2d, J ¼ 11.9, CH2Ph), 4.33–4.19 (5H, m), 3.99–
3.88 (3H, m), 3.69 (3H, s, OMe), and 1.00 (9H, s, CMe3); dC (100 MHz), inter
alia: 82.05 and 81.05 (C-30,40), 73.03 and 71.59 (2 CH2Ph), 71.93 and 70.58
(C-2,3), 67.90 (CH2Ph, Cbz), 66.50 and 62.70 (C-20,50), 60.99 (C-500), 52.35
(OMe), 26.89 (CMe3), and 19.23 (CMe3); m/z (found: MNaþ 826.3384,
C47H53NO9NaSi requires 826.3387).
Dihydroxylation of 6 with DHQ-CLB catalyst: To a well-stirred and cooled (ice-
water) solution of 6 (55 mg, 0.071 mmol), NMO (12 mg, 0.10 mmol) and DHQ-
CLB (9 mg, 0.02 mmol) in acetone-water (5 : 1 v/v, 6 mL) was added aqueous
0.07 M OsO4 (0.2 mL) and the mixture left for 2 days at rt, when TLC (Et2O-
hexane, 3 : 1) revealed the presence of only 7 and 8. The mixture was supported
on silica gel and chromatographed (Et2O-hexane, 1 : 3) to afford 7 (7 mg, 13%)
and 8 (48 mg, 84%).
Dihydroxylation of 6 with DHQD-CLB catalyst: Dihydroxylation of 6 (55 mg,
0.071 mmol) as above, but catalyzed with DHQD-CLB, gave 7 (15 mg, 26%)
and 8 (35 mg, 61%).

I. Izquierdo et al.
290
(1R,2S,5S,6R,7R,7aR)-6,7-Dibenzyloxy-5-tert-butyldiphenylsilyloxy-
methyl-1,2-dihydroxypyrrolizidin-3-one (10). A solution of 7 (710 mg,
0.88 mmol) in DME (25 mL) was stirred at rt with 10% Pd-C (80 mg) in an H2
atmosphere for 2 h. TLC (Et2O) then showed the presence of a compound of
lower mobility, presumably the N-deprotected pyrrolidinic ester (9). The
catalyst was filtered off, and washed with DME, and the combined filtrate
and washings were concentrated to a residue that was dissolved in MeOH
(50 mL) and treated with 2M MeONa (0.5 mL). The mixture was refluxed for
3 h. TLC (EtAcO-hexane, 1 : 1) then 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-hexane, 10 : 1) to afford 10
as a white foam (200 mg, 36%). [a]2D8 215 (c, 1); nmax (film): 3373 (OH), 3068
(aromatic), 1684 (C55O), 738 and 700 cm21 (aromatic); dH (300 MHz): 7.51–
7.46 and 7.25–7.05 (20H, 2 m, 4 Ph), 4.56 and 4.45 (2H, 2d, J ¼ 11.7,
CH2Ph), 4.53 and 4.49 (2H, 2d, J ¼ 12.0, CH2Ph), 4.30 (1H, t,
0
J6,7 ¼ J7,7a ¼ 6.5, H-7), 4.22 (1H, dd, J5,8 ¼ 5.2, J8,8 ¼ 10.7, H-8), 4.15 (1H, t,
J5,6 ¼ 6.7, H-6), 4.07 (1H, dd, J1,7a ¼ 3.6, H-7a), 3.92 (2H, m, H-1,2), 3.78
(1H, dd, J5,8 ¼ 2, H-80), 3.58 (1H, m, H-5), and 0.85 (9H, s, CMe3); dC
0
(75 MHz), inter alia: 172.69 (C-3), 84.08 (C-6), 81.30 and 73.68 (C-1 and C-2),
77.60 (C-7), 73.68 and 72.82 (2 CH2Ph), 67.34 (C-7a), 58.24 (C-8), 57.50 (C-5),
27.03 (CMe3), and 15.36 (CMe3); m/z (found: MNaþ, 660.2752;
C38H43NO6NaSi requires 660.2757).
(1R,2S,5S,6R,7R,7aS)-1,2-Di-O-acetyloxy-6,7-dibenzyloxy-5-tert-butyl-
diphenylsilyloxymethypyrrolizidin-3-one (11). Compound 10 (60 mg,
0.094 mmol) was acetylated in dry pyridine (3.0 mL), acetic anhydride
(0.5 mL), and DMAP (cat.) at rt for 4 h. TLC (Et2O) then showed a faster-
running compound. The reaction mixture was supported on silica gel and chro-
matographed (Et2O) to afford pure 11 as a colorless syrup (45 mg, 66%).
[a]2D3212.4 (c, 1); nmax (film): 3032 (aromatic), 1748 and 1715 (C55O), 743 and
700 cm21 (aromatic); dH (400 MHz): 7.75–7.67 and 7.38–7.26 (20H, 2 m, 4
Ph), 5.34 (1H, d, J1,7a ¼ 5.3, H-1), 4.98 (1H, s, H-2), 4.69 and 4.56 (2H, 2d,
J ¼ 12.0, CH2Ph), 4.66 and 4.61 (2H, 2d, J ¼ 11.8, CH2Ph), 4.45 (1H, dd,
0
J5,8 ¼ 4.2, J8,8 ¼ 11.0, H-8), 4.43 (1H, t, J6,7 ¼ J7,7a ¼ 8.0, H-7), 4.33 (1H, t,
J5,6 ¼ 7.4, H-6), 4.12 (1H, dd, H-7a), 3.85–3.79 (2H, m, H-5,80), 2.12 and
1.71 (6H, 2s, 2 Ac) and 1.02 (9H, s, CMe3); dC (100 MHz): 169.53 and 169.42
(2 COMe), 166.38 (C-3), 85.39 (C-6), 79.15 (C-2), 77.97 (C-7), 73.82 and 72.80
(2 CH2Ph), 70.49 (C-1), 63.56 (C-7a), 57.39 (C-5), 57.39 (C-8), 26.95 (CMe3),
20.64 and 20.57 (2 COMe) and 19.37 (CMe3). m/z (found: MNaþ, 744.2972;
C42H47NO8SiNa requires 744.2969).
(1R,2R,3S,6R,7R,7aR)-1,2-Dibenzyloxy-3-tert-butyldiphenylsilyloxy-
methyl-6,7-dihydroxypyrrolizidine (12). To a stirred solution of 10

Polyhydroxylated Pyrrolizidines
291
(200 mg, 0.31 mmol) in anhydrous THF (10 mL) was added dropwise a
H3B:SMe2 complex solution in the same solvent (10 M, 0.31 mL) under
argon, and the mixture was left at rt for 5 h. TLC (EtAcO-hexane, 3:1)
then revealed the absence of 10 and the presence of a faster-running
compound, presumably the borane-amine complex. MeOH (2 mL) was cau-
tiously added and the reaction mixture was concentrated to a residue that
was dissolved in MeOH (20 mL) and stirred for 12 h, when the borane-
amine complex was not observed by TLC. The reaction mixture was concen-
trated and the residue was supported on silica gel and submitted to chrom-
atography (Et2O-hexane, 10:1) to give pure 12 as a colorless syrup (164 mg,
28
405
84%). [a]2D8 27.6, [a]
-20, (c, 1); nmax (film): 3369 (OH), 3069, 738 and
701 cm21 (aromatic); dH (300 MHz): 7.60–7.57 and 7.35–7.07 (20H, 2 m, 4
Ph), 4.54 and 4.46 (2H, 2d, J ¼ 12.0, CH2Ph), 4.46 and 4.36 (2H, 2d,
J ¼ 11.4, CH2Ph), 4.16 (1H, br t, J1,2 ¼ J1,7a ¼ 1.7, H-1), 4.05 (1H, dd,
J2,3 ¼ 3.6, H-2), 3.99 (1H, br d, J5,6 ¼ 2.6, H-6), 3.95–3.83 (3H, m,
H-7,8,80), 3.81 (1H, dd, J7,7a ¼ 5.0, H-7a), 3.51 (1H, m, H-3), 3.02 (1H, dd,
0
J5,5 ¼ 10.4, H-5), 2.60 (1H, d, H-5), 2.53 (1H, br s, HO), and 0.98 (9H, s,
CMe3); dC (75 MHz) inter alia: 85.21 (C-2), 79.98 (C-1), 78.97 (C-6), 76.01
(C-7), 73.16 and 72.04 (2 CH2Ph), 72.80 (C-7a), 64.03 (C-3), 59.47 (C-8),
52.51 (C-5), 26.97 (CMe3), and 19.25 (CMe3); m/z (found: MHþ, 624.3148;
C38H46NO5Si requires 624.3145).
(1R,2R,3S,6R,7R,7aR)-1,2-Dibenzyloxy-6,7-dihydroxy-3-hydroxymethyl-
pyrrolizidine (13). To a stirred solution of 12 (150 mg, 0.24 mmol) in THF
(10 mL) was added TBAF.3 H2O (90 mg, 0.28 mmol), and the reaction
mixture was refluxed for 4 h. TLC (Et2O-MeOH, 5:1) then revealed a new
compound of lower mobility. The mixture was supported on silica gel and
chromatographed (Et2O-MeOH, 5:1) to give pure 13 as a colorless syrup
(55 mg, 59%). [a]2D9 2 19.4 (c, 1); nmax (film): 3350 (OH), 3032, 737 and
697 cm21 (aromatic); dH (400 MHz, MeOH-d4): 7.33–7.25 (10H, m, 2 Ph),
4.61 and 4.50 (2H, 2d, J ¼ 11.7, CH2Ph), 4.56 (2H, s, CH2Ph), 4.36 (1H, t,
J1,2 ¼ J1,7a ¼ 4.4, H-1), 4.18 (1H, dd, J2,3 ¼ 5.1, H-2), 4.12 (1H, m, H-6),
4.01 (1H, dd, J6,7 ¼ 2.9, J7,7a ¼ 5.3, H-7), 3.91 (1H, dd, J3,8 ¼ 3.9,
J8,8 ¼ 11.6, H-8), 3.82 (1H, dd, J3,8 ¼ 3.8, H-80), 3.63 (1H, t, H-7a), 3.35
0
0
0
(1H, q, H-3), 3.30 (1H, dd, J5,6 ¼ 5.0, J5,5 ¼ 10.5, H-5) and 2.68 (1H, dd,
J5 ,6 ¼ 2.4, H-50); dC (100 MHz, MeOH-d4), inter alia: 86.51 (C-2), 81.00 (C-
0
1), 78.86 (C-6), 76.70 (C-7), 73.29 and 72.97 (2 CH2Ph), 73.25 (C-7a), 65.08
(C-3), 58.39 (C-8), and 52.51 (C-5); m/z (found: MNaþ, 408.1785;
C22H27NO5Na requires 408.1787).
(1R,2R,3S,6R,7R,7aR)-1,2,6,7-Tetrahydroxy-3-hydroxymethylpyrrolizi-
dine [(1)-3,6,7-triepicasuarine] (2a). Compound 13 (55 mg, 0.14 mmol) in
methanol (10 mL) and conc HCl (three drops) was hydrogenated with 10%

I. Izquierdo et al.
292
Pd(OH)2-C (30 mg) at ambient pressure and rt overnight. TLC (ether-
methanol, 5:1) then revealed the absence of the starting product. The
catalyst was filtered off and washed with methanol, and the combined
filtrate and washings were treated with Amberlite IRA-400 resin (OH2
form). Evaporation of the solvent afforded pure 2a as a colorless syrup
(25 mg, 85%). [a]2D4 -13.2 (c, 1, MeOH); Lit.[7] [a]2D2 -20.1 (c, 0.93, water); dH
(400 MHz, D2O, pH 9): 4.13 (1H, t, J1,7a ¼ J1,2 ¼ 3.9, H-1), 4.10 (1H, br s,
H-6), 4.02 (1H, t, J2,3 ¼ 4.4, H-2), 3.98 (1H, br dd, J6,7 ¼ 1.7, J7,7a ¼ 4.6, H-7),
3.79 (1H, dd, J3,8 ¼ 5.3, J8,8 ¼ 11.9, H-8), 3.69 (1H, dd, J3,8 ¼ 6.0, H-80), 3.37
0
0
(1H, t, H-7a), 3.15-3.09 (2H, m, H-3,5), 2.60 (1H, d, J5,5 ¼ 11.2, H-50);
0
dC (100 MHz, D2O); 80.67 (C-2), 79.23 (C-6), 76.10 (C-7), 75.75 (C-1), 74.24
(C-7a), 65.20 (C-3), 59.01 (C-8), and 53.09 (C-5).
(1S,2R,5S,6R,7R,7aR)-6,7-Dibenzyloxy-5-tert-butyldiphenylsilyloxy-
methyl-1,2-dihydroxypyrrolizidin-3-one (15). A solution of 8 (2.9 g,
3.61 mmol) in MeOH (25 mL) was stirred at rt with 10% Pd-C (200 mg) in an
H2 atmosphere for 24 h. TLC (Et2O-hexane, 5:1) then showed the presence of
a compound of lower mobility, presumably the N-deprotected pyrrolidine
(14). The catalyst was filtered off and washed with MeOH, and the combined
filtrate and washings (50 mL) refluxed with 2M MeONa (2 mL). After 12 h,
TLC (EtAcO-hexane, 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) to afford 15 as a white foam (1.46 g,
63%). [a]1D9 þ10.2 (c, 1); nmax (film): 3368 (OH), 3069 (aromatic), 1694
(C ¼ O), 741 and 700 cm21 (aromatic); dH (400 MHz): 7.68–7.65 and 7.39–
7.16 (20H, 2 m, 4 Ph), 4.83 and 4.67 (2H, 2d, J ¼ 12.1, CH2Ph), 4.79 and 4.63
(2H, 2d, J ¼ 11.8, CH2Ph), 4.36–4.33 and 4.27–4.23 (5H, 2 m, H-1,2,6,7,8),
3.75 (2H, m, H-5,80), 3.47 (1H, t, J1,7a ¼ J7,7a ¼ 7.3, H-7a), 0.95 (9H, s, CMe3);
dC (100 MHz), inter alia: 171.46 (C-3), 83.54, 82.51, 79.72 and 78.79 (C-
1,2,6,7), 73.61 and 72.44 (2 CH2Ph), 64.48 (C-7a), 57.48 (C-5), 57.24 (C-8),
26.90 (CMe3), and 19.12 (CMe3). dH (400 MHz, Py-d5): 7.52–7.15 (20H, m, 4
Ph), 5.25 and 5.03 (5H, 2d, J ¼ 12.1, CH2Ph), 4.88–4.84 (3H, m, 1 CH2Ph,
0
H-1,2), 4.78 (1H, dd, J5,8 ¼ 3.7, J8,8 ¼ 10.2, H-8), 4.96–4.68 (2H, m, 1
CH2Ph, H-7), 4.46 (1H, t, J6,7 ¼ J5,6 ¼ 7.3, H-6), 4.00–3.95 (2H, m, H-5,80),
3.81 (1H, m, H-7a), 0.99 (9H, s, CMe3); dC (100 MHz, Py-d5), inter alia:
172.59 (C-3), 84.31 (C-6), 83.43 (C-7), 80.28 and 79.76 (C-1 and C-2), 73.47
and 72.23 (2 CH2Ph), 65.55 (C-5), 58.00 (C-8), 57.64 (C-7a) 26.99 (CMe3), and
19.24 (CMe3); m/z (found: MNaþ, 660.2758; C38H43NO6NaSi requires
660.2757).
(1S,2R,5S,6R,7R,7aS)-1,2-Di-O-acetyloxy-6,7-dibenzyloxy-5-tert-butyl-
diphenylsilyloxymethylpyrrolizidin-3-one (16). Compound 15 (50 mg,
0.078 mmol) was acetylated in dry pyridine (3.0 mL), acetic anhydride

Polyhydroxylated Pyrrolizidines
293
(0.5 mL), and DMAP (cat.) at rt for 6 h. TLC (Et2O) then showed a faster-run-
ning compound. The reaction mixture was supported on silica gel and chro-
matographed (Et2O-hexane, 1:1) to afford pure 16 as a colorless oil (40 mg,
88%). [a]2D2 211.9 (c, 1); nmax (film): 3033 (aromatic), 1749 and 1732 (C55O),
744 and 701 cm21 (aromatic); dH (300 MHz): 7.66–7.60 and 7.33–7.14 (20H,
2 m, 4 Ph), 5.72 (1H, d, J1,2 ¼ 8.5, H-2), 5.54 (1H, t, J1,7a ¼ 7.9, H-1), 4.58
and 4.48 (2H, 2d, J ¼ 11.8, CH2Ph), 4.54 (2H, s, CH2Ph), 4.41 (1H, t,
0
J6,7 ¼ J7,7a ¼ 6.8, H-7), 4.30 (1H, dd, J5,8 ¼ 4.4, J8,8 ¼ 10.7, H-8), 4.14 (1H, t,
J5,6 ¼ 7.0, H-6), 3.74–3.68 (2H, m, H-5,80), 3.55 (1H, t, H-7a), 2.05 and 2.03
(6H, 2s, 2 Ac) and 0.97 (9H, s, CMe3); dC (75 MHz): 170.11 and 170.05 (2
COMe), 166.16 (C-3), 83.70 (C-6), 82.50 (C-7), 77.15 (C-1), 75.83 (C-2), 73.51
and 73.09 (2 CH2Ph), 62.54 (C-7a), 58.26 (C-5), 57.02 (C-8), 26.91 (CMe3),
20.86 and 20.76 (2 COMe) and 19.19 (CMe3); m/z (found: MNaþ, 744.2994;
C42H47NO8SiNa requires 744.2969).
(1R,2R,3S,6S,7S,7aR)-1,2-Dibenzyloxy-3-tert-butyldiphenylsilyloxy-
methyl-6,7-dihydroxypyrrolizidine (17). To a stirred solution of 16
(700 mg, 1.1 mmol) in anhydrous THF (20 mL) was added dropwise a
H3B:SMe2 complex solution in the same solvent (10 M, 1.1 mL) under argon,
and the mixture left at rt for 4 h. TLC (EtAcO-hexane, 3:1) then revealed the
absence of 16 and the presence of a faster-running compound, presumably
the borane-amine complex. MeOH (2 mL) was cautiously added, and the
reaction mixture was concentrated to a residue that was dissolved in MeOH
(20 mL) and refluxed for 3 h, when the borane-amine complex was not
observed by TLC. The reaction mixture was concentrated and the residue
was supported on silica gel and subjected to chromatography (Et2O, Et2O-
MeOH, 1:1) to give pure 17 as a white solid foam (660 mg, 96%). [a]2D3 215.5,
(c, 1); nmax (KBr): 3350 (OH), 3070, 739 and 702 cm21 (aromatic); dH
(400 MHz): 7.64 and 7.31–7.25 (20H, 2 m, 4 Ph), 4.57 and 4.43 (2H, 2d,
J ¼ 12.0, CH2Ph), 4.52 and 4.40 (2H, 2d, J ¼ 11.9, CH2Ph), 4.10–3.98 (4H,
m, H-1,2,6,8), 3.93–3.89 (2H, m, H-7,80), 3.51–3.44 (1H, m, H-3), 3.36 (1H,
dd, J1,7a ¼ 2.1, J7,7a ¼ 6.0, H-7a), 2.97 (1H, t, J5,6 ¼ 8.4, H-5), 2.89 (1H, dd,
J5,5 ¼ 9, J5 ,6 ¼ 6.3, H-50), and 1.02 (9H, s, CMe3); dC (100 MHz), inter alia:
85.65 and 85.50 (C-1 and C-2), 80.64 (C-7), 77.59 (C-6), 75.40 (C-7a), 72.24
and 71.43 (2 CH2Ph), 65.43 (C-3), 59.46 (C-8), 52.80 (C-5), 26.88 (CMe3), and
19.20 (CMe3); m/z (found: MNaþ, 646.2972; C38H45NO5NaSi requires
646.2965).
0
0
(1R,2R,3S,6S,7S,7aR)-1,2-Dibenzyloxy-6,7-dihydroxy-3-hydroxymethyl-
pyrrolizidine (18). To a stirred solution of 17 (1.5 g, 2.4 mmol) in THF (25 mL)
was added TBAF.3 H2O (830 mg, 2.6 mmol) and the reaction mixture refluxed
for 12 h. TLC (Et2O-MeOH, 5:1) then revealed a new compound of lower
mobility. The mixture was supported on silica gel and chromatographed

I. Izquierdo et al.
294
(Et2O-MeOH, 5 : 1) to give pure 18 as a white foam (680 mg, 73%). [a]2D3 29.8
(c, 1, MeOH); nmax (film): 3368 (OH), 3064, 3031, 737 and 697 cm21
(aromatic); dH (400 MHz, MeOH-d4): 7.31–7.25 (10H, m, 2 Ph), 4.59 and 4.46
(2H, 2d, J ¼ 11.8, CH2Ph), 4.57 and 4.50 (2H, 2d, J ¼ 11.8, CH2Ph), 4.11 (1H,
s, H-1 or H-2), 4.07–4.01 (2H, m, H-6 and H-1 or H-2), 3.94 (1H, dd,
J3,8 ¼ 7.1, J8,8 ¼ 11.1, H-8), 3.91 (1H, dd, J3,8 ¼ 6.9, H-80), 3.87 (1H, t,
0
0
J6,7 ¼ J7,7a ¼ 7.8, H-7), 3.36–3.30 (2H, m, H-3,7a), 3.11 (1H, br t, J5,6 ¼ 8.5,
H-5), 3.02 (1H, dd, J5,5 ¼ 9, J5 ,6 ¼ 6.5, H-50); dC (100 MHz, MeOH-d4), inter
alia: 85.97 and 85.94 (C-1 and C-2), 80.51 (C-7), 77.00 (C-6), 75.89 (C-7a),
73.10 and 72.23 (2 CH2Ph), 66.92 (C-3), 58.08 (C-8), and 52.89 (C-5); m/z
(found: MNaþ, 408.1790; C22H27NO5Na requires 408.1787).
0
0
(1R,2R,3S,6S,7S,7aR)-1,2,6,7-Tetrahydroxy-3-hydroxymethylpyrrolizi-
dine [(1)-3-Epicasuarine] (2b). Compound 18 (680 mg, 1.77 mmol) in
methanol (15 mL) and conc HCl (three drops) was hydrogenated with 10%
Pd-C (100 mg) at ambient pressure and rt overnight. TLC (ether-methanol,
5:1) then revealed the absence of the starting product. The catalyst was
filtered off and washed with methanol, and the combined filtrate and
washings treated with Amberlite IRA-400 resin (OH2 form). Evaporation
of the solvent afforded 2b as a white foam (255 mg, 70%) slightly
contaminated.
An aliquot of 2b (45 mg, 0.22 mmol) was acetylated in dry pyridine (3.0 mL),
acetic anhydride (1.2 mL), and DMAP (cat.) at rt for 12 h. TLC (EtAcO-hexane,
1:1) then showed a faster-running compound. The reaction mixture was
supported on silica gel and chromatographed (EtAcO-hexane, 1:1) to afford
25
405
pure 19 as a colorless oil (60 mg, 66%). [a]2D5 -0.3, [a]
þ4.6 (c, 1); nmax
(film): 1760, 1755, 1747, 1738 and 1732 cm21 (C55O, acetate); dH (400 MHz):
5.33 (1H, dd, J1,2 ¼ 1.7, J2,3 ¼ 4.6, H-2), 5.30–5.25 (2H, m, H-6,7), 5.14
0
(1H, dd, J1,7a ¼ 4.5, H-1), 4.30 (1H, dd, J8,8 ¼ 11.7, J3.8 ¼ 5.9, H-8), 4.15 (1H,
dd, J3,8 ¼ 7.6, H-80), 3.57 (1H, br dt, H-3), 3.32 (1H, dd, J5,6 ¼ 6.3, J5,5 ¼ 8.9,
0
0
H-5), 3.20 (1H, t, J7,7a ¼ 4.8, H-7a), 2.92 (1H, t, J5 ,6 ¼ 8.5, H-50), 2.09,
0
2.06, 2.05, 2.047 and 2.041 (15H, 5s, 5 Ac); dC (100 MHz): 170.43, 170.29,
169.78, and 169.37 (COMe), 80.81 (C-1), 79.18 (C-2), 77.96 and 76.82 (C-6
and C-7), 73.04 (C-7a), 61.33 (C-3), 59.63 (C-8), 50.61 (C-5), 20.84, 20.81, and
20.77 (5 COMe); m/z (found: MNaþ, 438.1379; C18H25NO10Na requires
438.1376).
Conventional Zemplen deacetylation of 19 afforded pure 2b, which had
[a]2D8 þ12.6 (c, 1, MeOH); dH (400 MHz, D2O, pH 8): 4.19 (1H, s, H-1), 4.08
(1H, br d, J2,3 ¼ 3.0, H-2), 4.02–3.94 (2H, m, H-6,7), 3.87 (1H, dd, J3,8 ¼ 5.9,
J8,8 ¼ 12.2, H-8), 3.82 (1H, dd, J3,8 ¼ 8.3, H-80), 3.40 (1H, m, H-3), 3.22–3.07
(3H, m, H-5,50,7a); dC (100 MHz, D2O): 80.47 (C-1), 80.11 (C-2), 79.45 (C-6 or
C-7), 77.24 (C-7a), 76.20 (C-7 or C-6), 67.61 (C-3), 58.02 (C-8), and 52.72
(C-5); m/z (found: MHþ, 206.1027; C8H16NO5 requires 206.1028).
0
0

Polyhydroxylated Pyrrolizidines
295
ACKNOWLEDGEMENTS
´
The authors are grateful to the Spanish Ministerio de Ciencia y Tecnologıa
´
(Project PPQ2002-01303) and Junta de Andalucıa (Group CVI-250) for their
financial support.
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