Polyhydroxylated pyrrolizidines. Part 4: Total asymmetric synthesis of unnatural hyacinthacines from a protected derivative of DGDP

Article abstract of DOI:10.1016/j.tetasy.2004.03.013

(1R,2R,3S,5R,7aR)-1,2-Dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine [(+)-3-epi-hyacinthacine A₃] 1 and (1R,2R,3S,7aR)-1,2-dihydroxy-3- hydroxymethylpyrrolizidine [(+)-3-epi-hyacinthacine A₂] 2 have been synthesized by Wittig's meth

Full text of DOI:10.1016/j.tetasy.2004.03.013

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1465–1469
Polyhydroxylated pyrrolizidines. Part 4: Total asymmetric
synthesis of unnatural hyacinthacines from a protected
derivative of DGDPq
*
ꢀ
Isidoro Izquierdo, Marıa T. Plaza and Francisco Franco
Department of Medicinal and Organic Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
Received 12 February 2004; accepted 10 March 2004
Abstract—(1R,2R,3S,5R,7aR)-1,2-Dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine [(þ)-3-epi-hyacinthacine A3]
1
and
(1R,2R,3S,7aR)-1,2-dihydroxy-3-hydroxymethylpyrrolizidine [(þ)-3-epi-hyacinthacine A2] 2 have been synthesized by Wittig’s
methodology using aldehyde 6, prepared from (2R,3R,4R,5S)-3,4-dibenzyloxy-N-benzyloxycarbonyl-20-O-tert-butyldiphenylsilyl-
2,5-bis(hydroxymethyl) pyrrolidine 3 (a partially protected DGDP), and the appropriated ylides, followed by cyclization through an
internal reductive amination process of the resulting a,b-unsaturated ketone 7 and aldehyde 8, respectively, and total deprotection.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
namely (þ)-3-epi-hyacinthacine A3 1 and (þ)-3-epi-
hyacinthacine A2, 2.
Previously1;2 we have reported the enantiosynthesis of
polyhydroxylated pyrrolizidine alkaloids related to
hyacinthacines,3 potent glycosidase inhibitors, using
natural carbohydrates (hexuloses) as the source of chi-
Funtionalized
rality. In these reports,
suitably protected derivatives of 2,5-dideoxy-2,5-imino-
D-fructose was transformed into
Chain-lengthening
OBn
OH
-glucitol (DGDP) 34 and into the related
D-manno
H
N
H
N
D
derivative DMDP,5 both being key intermediates in
those syntheses.
2'
TBDPSO
1
3
Several
steps
OBn
2
OH
5
Cbz
O-Protection
5'
R
OH
OH
According to Figure 1, the pivotal character of com-
pound 3, should allow the possibility of synthesizing
either pyrrolizidines structurally related to the natural
alkaloids alexine,6 by building-up the bicyclic skeleton
from C(50) or to australine7 from C(20). The former
synthetic strategy was successfully achieved and 7a-epi-
hyacinthacine A2 (7-deoxy-alexine) and 5,7a-diepi-hya-
cinthacine A3 were described.2a We report herein the
results of the application of the second strategy, con-
sisting in the C(50) O-protection, C(20) O-deprotection,
adequately functionalized chain lengthening in this
position and finally cyclization to the pyrrolizidine
skeleton to afford two new unnatural hyacinthacines,
3-Epihyacinthacine A3 ( , R = CH )
1
3
Protected DGDP ( )
from D-Fructose
3
3-Epihyacinthacine A2 (2, R = H)
Figure 1. Synthetic strategy for the preparation of hyacinthacines 1
and 2 from protected DGDP 3.
2. Results and discussion
Conventional benzoylation of (2R,3R,4R,5S)-3,4-di-
benzyloxy-N-benzyloxycarbonyl-20-O-tert-butyldiphenyl-
silyl-2,5-bis(hydroxymethyl)pyrrolidine 34 gave the total
protected derivative 4 (see Scheme 1). O-Desilylation of
4 to the corresponding partially protected pyrrolidine 5
and subsequent oxidation (TPAP/NMO) yielded the
pyrrolidinic aldehyde 6 that was not investigated, but
used in the next step. Thus, reaction of 6, with either
q For Part 3 of the series, see Ref. 1.
* Corresponding author. Tel.: +34-958-243847; fax: +34-958-243845;
e-mail: isidoro@platon.ugr.es
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.03.013

1466
I. Izquierdo et al. / Tetrahedron: Asymmetry 15 (2004) 1465–1469
1-triphenylphosphoranilydene-2-propanone or triphen-
ylphosphoranilydeneacetaldehyde gave the a,b-unsat-
urated ketone 7 and aldehyde 8, respectively. The
stereochemistry at the carbon–carbon double bond in
both compounds could not be determined due to the
existence of rotamers, which caused an extensive
broadening of the resonance signals.
In addition, the rest of the NOE interaction also con-
firmed the total stereochemistry of 9.
The high stereoselectivity found in the hydrogenation of
intermediate D5-pyrrolizine B, where 9 was the only
detected and isolated pyrrolizidine merits comment.
Formation of 9 can be attributed, according to our
previous results2 and to Figure 2, to the peculiar shape
of this kind of molecule3 where it is appreciated that the
b-face is less hindered for hydrogen attack that the a-
face is, affording only compound 9.
Cbz
N
1
R
R
BnO
OBn
H7a
H
OBn
H5
H
OBn
1
-Face
β
3 R = CH OH, R = CH OTBDPS
H3
2
2
N
H
a
b
c
1
H7
N
CH3
H
4 R = CH OBz, R = CH OTBDPS
2
2
H2
1
5 R = CH OBz; R = CH OH
CH3
2
2
8
1
6 R = CH OBz; R = CHO
OBn
2
1
BzO
d
-Face
α
BzO
OBn
e
7 R = CH OBz; R = -HC=CHCOCH3
2
H
8 R = CH OBz; R1 = -HC=CHCHO
2
9
Scheme 1. Synthesis of a,b-unsaturated pyrrolidinic ketone 7 and
aldehyde 8. Reagents and conditions: (a) BzCl/CH2Cl2/TEA; (b) n-Bu4-
Figure 2. NOE interactions in 9 and hydrogenation pathway of
intermediate D5-pyrrolizine.
þ
ꢀ
ꢁ
N F Æ3H2O/THF; (c) TPAP/NMO/CH2Cl2/4 A MS; (d) Ph3PCH-
COCH3/MePh/D; (e) Ph3PCHCHO/MePh, 60 °C.
Finally, removal of the protecting groups in 9 gave the
target molecule (þ)-3-epi-hyacinthacine A3 1, in accor-
dance with its analytical and spectroscopic data.
Catalytic hydrogenation (10% Pd–C)-cyclization of 7
afforded, in only one step, the fully protected
(1R,2R,3S,5R,7aR)-3-benzoyloxymethyl-1,2-dibenzyloxy-
5-methylpyrrolizidine 9. According to Scheme 2, for-
mation of 9 must take place as follows: initial hydro-
genation of 7 to the intermediate N-deprotected
saturated ketone A, subsequent intramolecular conden-
sation to give the D5-pyrrolizine B, which was not iso-
lated and final hydrogenation to 9.
Application of the above methodology (see Scheme 3) to
compound 8, allowed the synthesis of (þ)-3-epi-hyacin-
thacine A2, 2, where structure was established on the
basis of its analytical and spectroscopic data.
O
OBn
OBn
H
N
H
a
OBn
OBz
OBn
OBn
OBn
OBz
H
N
H
CbzN
a
-H O
2
7
OBn
OBz
OBn
OBz
HN
O
8
a
H C
3
A
B
OR
H
N
a
OR
1
OR
H
N
OR
OR
1
1
11 R = Bn; R = Bz
b
c
H C
OR
3
1
12 R = Bn; R = H
1
1
2 R = R = H
9 R = Bn; R = Bz
b
c
1
10 R = Bn; R = H
1
Scheme 3. Synthesis of (þ)-3-epi-hyacinthacine A2 2. Reagents and
conditions: (a) 10% Pd–C/H2/MeOH; (b) MeONa/MeOH; (c) 10% Pd–
C/H2/HCl, then Amberlite IRA-400 (OHꢀ form).
1 R = R = H
Scheme 2. Synthesis of (þ)-3-epi-hyacinthacine A3 1. Reagents and
conditions: (a) 10% Pd–C/H2/MeOH; (b) MeONa/MeOH; (c) 10% Pd–
C/H2/HCl, then Amberlite IRA-400 (OHꢀ form).
The stereochemistry of the new C(5) stereogenic centre
was established on the basis of extensive NOE experi-
ments. The NOE interactions are shown in Figure 2.
The definite NOE effects between C(3)H and C(5)H, and
Me(5)H and C(8)H indicate the R configuration at C-5.
3. Conclusions
Finally, two important conclusions can be stated from
the above results: that partially protected polyhydr-
oxylated pyrrolidines, derived from common hexuloses,

I. Izquierdo et al. / Tetrahedron: Asymmetry 15 (2004) 1465–1469
1467
together with a classical Wittig’s methodology are both
suitable for the enantiosynthesis of complex polyhydr-
oxylated pyrrolizidines alkaloids and that the absolute
configuration at C(5) in 5-methylpyrrolizidines is con-
trolled by that at C(7a) in such a way that C(5)Me group
and C(7a)H are always in a trans-disposition.
to a residue that was dissolved in ether, washed with
brine, concentrated and then submitted to column
chromatography (ether/hexane 2:1) to yield pure 5
(2.38 g, quantitative) as a colourless syrup, which had
25
24
½aꢁ ¼ ꢀ16:5, ½aꢁ ¼ ꢀ36:5 (c 1.5). IR (neat): 3455
D
405
(OH), 3034 (aromatic), 1711 (COPh and >NCO2Bn),
714 and 694 cmꢀ1 (aromatic). NMR data (400 MHz):
1H, d 8.15–7.20 (m, 20H, 4Ph) and 5.20–3.65 (m, 14H,
3CH2Ph, H-2,20a,20b,3,4,5,50a,50b); 13C (inter alia), d
81.85 and 81.10 (C-3,4) 73.06 and 72.73 (2OBn) 67.75
(NCbz), 64.29 and 57.29 (C-2,5), 63.72 and 63.28 (C-
20,50). Mass spectrum (LSIMS): m=z: 640.2308
[Mþ þ Na] for C35H35NO7Na 604.2311 (deviation
þ0.6 ppm).
4. Experimental
Solutions were dried over MgSO4 before concentration
1
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). Mass spectra were recorded with a Hewlett-
Packard HP-5988-A and Fisons mod. Platform II and
VG Autospec-Q mass spectrometers. Optical rotations
were measured in H2O (1 dm tube) with a Jasco DIP-370
polarimeter. 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 sulfuric acid containing 0.8% cerium sulfate (w/
v) and heating. Column chromatography was performed
on silica gel (Merck, 7734).
4.3. 4-[(20R,30R,40R,50S)-50-Benzoyloxymethyl-30,40-di-
benzyloxy-N-benzyloxycarbonylpyrrolidin-20-yl]but-3-
en-2-one 7
A solution of 5 (1 g, 1.7 mmol) in dry dichloromethane
ꢁ
(15 mL) were added activated powdered 4 A molecular
sieve (230 mg), N-methylmorpholine N-oxide (300 mg)
and TPAP (30 mg) and the reaction mixture kept at
room temperature for 30 min. TLC (ether/hexane 1:1)
then showed a faster-running compound. The reaction
was diluted with ether (20 mL), filtered through a bed of
silica gel 60 (Scharlau, 230–400 mesh) and thoroughly
washed with ether. The combined filtrate and washings
were concentrated to aldehyde 6 (780 mg, 78%) that was
used in the next step. Compound 6 (690 mg, 1.2 mmol)
was dissolved in dry toluene (20 mL) and 1-triphenyl-
phosphoranilydene-2-propanone (570 mg, 1.8 mmol)
was added and the mixture was heated at 100 °C over-
night. TLC (ether/hexane 2:1) then revealed the presence
of a new compound of lower mobility. The solvent was
eliminated and the residue supported on silica gel and
submitted to column chromatography with ether/hexane
4.1. (2S,3R,4R,5R)-20-O-Benzoyl-3,4-dibenzyloxy-N-
benzyloxycarbonyl-50-O-tert-butyldiphenylsilyl-2,5-
bis(hydroxymethyl)pyrrolidine 4
To a stirred solution of (2R,3R,4R,5S)-3,4-dibenzyl-
oxy-N-benzyloxycarbonyl-20-O-tert-butyldiphenylsilyl-
2,5-bis(hydroxymethyl)pyrrolidine 34 (1.28 g, 1.8 mmol)
in dry dichloromethane were added triethylamine (TEA,
220 lL, 2.7 mmol), DMAP (25 mg) and benzoyl chloride
(220 lL, 2 mmol) and the mixture left at room temper-
ature for 24 h. TLC (ether/hexane 1:1) then revealed a
faster-running compound. Conventional work-up of the
reaction mixture and column chromatography (ether/
hexane 1:3) afforded pure 4 (1.42 g, quantitative) as a
(1:1) as eluent to give pure 7 (660 mg, 90%) as a pale
25
D
yellow syrup, which had ½aꢁ ¼ þ17:5 (c 1). IR (neat):
3063 (aromatic), 1722, 1706 and 1700 (CO2Ph,
>NCO2Bn and a,b-unsaturated ketone), 714 and
696 cmꢀ1 (aromatic). NMR data (400 MHz): 1H, d 7.94–
7.27 (m, 20H, 4Ph), 6.58 (br s, 1H, H-4), 6.16–6.04 (br
m, 1H, H-3), 5.17 and 5.02 (2d, 2H, J 12 Hz,
>NCO2CH2Ph), 4.74–4.30 (m, 8H, 2CH2Ph, H-
30,40,500a,500b), 4.24 (br t, 1H, J 6 Hz) and 4.12 (br t, 1H,
J 5.2 Hz) for H-20,50 and 1.92 (br s, 3H, H-1,1,1); 13C
(inter alia), 197.99 (C-2), 166.19 (COPh), 155.22
(>NCO2Bn), 145.19 (C-4), 133.10 (C-3), 84.62, 84.12,
81.86 and 81.20 (C-30,40 of two rotamers) 73.11 and
72.51 (2OCH2Ph), 67.60 (>NCO2CH2Ph) 62.76 and
57.60 (C-20,50), 62.16 (C-500) and 26.75 (C-1). Mass
spectrum (LSIMS): m=z: 642.2464 [Mþ þ Na] for
C38H37NO7Na 642.2468 (deviation þ0.5 ppm).
28
28
colourless syrup, which had ½aꢁ ¼ þ7:5, ½aꢁ ¼ þ26 (c
D
1.2). IR (neat): 3078 (aromatic), 1724 and 1713 (COPh
405
and >NCO2Bn), 710 and 699 cmꢀ1 (aromatic). NMR
1
data (400 MHz): H, d 8.15–7.10 (m, 30H, 6Ph), 5.25–
3.77 (m, 14H, 3CH2Ph, H-2,20a,20b,3,4,5,50a,50b) and
13
1.07 (s, 9H, CMe3); C (inter alia), d 166.33 (COPh),
155.75 (>NCO2Bn), 72.67 and 72.08 (2OCH2Ph), 67.24
(>NCO2CH2Ph), 26.98 (CMe3) and 19.28 (CMe3). Mass
spectrum (LSIMS): m=z: 842.3491 [Mþ þ Na] for
C51H53NO7NaSi 842.3489 (deviation ꢀ0.2 ppm).
4.2. (2S,3R,4R,5R)-20-O-Benzoyl-3,4-dibenzyloxy-N-
benzyloxycarbonyl-2,5-bis(hydroxymethyl)pyrrolidine 5
To a stirred solution of 4 (3.35 g, 4.1 mmol) in THF
(20 mL) was added tetrabutylammonium fluoride tri-
hydrate (1.93 g, 6.1 mmol) and the mixture was kept at
room temperature overnight. TLC (ether/hexane 1:1)
then showed a new compound of lower mobility. The
mixture was neutralized with acetic acid, concentrated
4.4. 3-[(20R,30R,40R,50S)-50-Benzoyloxymethyl-30,40-di-
benzyloxy-N-benzyloxycarbonylpyrrolidin-20-yl]prop-2-
enal 8
To a solution of 6 (1.6 g, 2.8 mmol) in dry tolu-
ene (20 mL), triphenylphosphoranilydeneacetaldehyde

1468
I. Izquierdo et al. / Tetrahedron: Asymmetry 15 (2004) 1465–1469
(1.26 g, 4.1 mmol) was added and the mixture was
heated at 60 °C for 3 h. TLC (ether/hexane 1:1) then
revealed the presence of a new compound of lower
mobility. The solvent was eliminated and the residue
supported on silica gel and submitted to column chro-
matography with ether/hexane (1:1) as eluent to give
pure 8 (1.13 g, 67%) as a pale yellow syrup, which had
form) and concentrated. Column chromatography
(ether/methanol/TEA 5:1:0.1) of the residue gave pure 1
26
D
25
405
(64 mg, 64%), which had ½aꢁ ¼ þ17, ½aꢁ ¼ þ41 (c 1.3,
1
methanol). NMR data (400 MHz, methanol-d4): H, d
4.20 (dd, 1H, J1;2 4.4, J2;3 7.3 Hz, H-2), 3.83 (dd, 1H, J3;8
6.2, J8;8 11.1 Hz, H-8), 3.74 (dd, 1H, J3;8 4.2 Hz, H-80),
3.65 (dd, 1H, J1;7a 8.7 Hz, H-1), 2.70 (dt, 1H, H-3), 2.50
(ddd, 1H, J7a;7b 5.7, J7a;7a 10.5 Hz, H-7a), 2.45 (br sex,
1H, J5;6a ¼ J5;6b ¼ J5;Me ¼ 6:2 Hz, H-5), 2.22 (brdq, 1H,
H-6b), 1.78 (dddd, 1H, J6a;7b 2.6, J6b;7b 8.8, J7a;7b 11.6 Hz,
H-7b), 1.65 (dddd, 1H, J6a;7a 10.7, J6a;6b 13 Hz, H-6a),
1.47 (dq, 1H, J6b;7a 7.4 Hz, H-7a), and 1.19 (d, 3H, Me);
13C, d 85.30 (C-2), 81.03 (C-1), 74.47 (C-7a), 66.65 (C-3),
61.54 (C-8), 57.41 (C-5), 37.55 (C-6), 25.05 (C-7) and
21.19 (Me). Mass spectrum (LSIMS): m=z: 210.1104
[Mþ þ Na] for C9H17NO3Na 210.1106 (deviation
þ1.1 ppm).
0
0
27
1
½aꢁ ¼ þ13 (c 1). NMR data (400 MHz): H, d 9.20 (br
D
s, 1H, H-1), 7.89–7.49 (m, 20H, 4Ph), 6.56 (br s, 1H, H-
3), 6.17–6.06 (br m, 1H, H-2), 5.20–4.92 and 4.70–4.33
(2m, 10H, 3 CH2Ph, H-30,40,500a,500b), 4.22 (t, 1H, J
6.1 Hz) and 4.08 (t, 1H, J 5.4 Hz) for H-20,50. Mass
spectrum (LSIMS): m=z: 628.2313 [Mþ þ Na] for
C37H35NO7Na 628.2311 (deviation ꢀ0.3 ppm).
4.5. (1R,2R,3S,5R,7aR)-3-Benzoyloxymethyl-1,2-diben-
zyloxy-5-methylpyrrolizidine 9
Compound 7 (630 mg, 1 mmol) in dry methanol (20 mL)
was hydrogenated at 60 psi over 10% Pd–C (145 mg) for
7 h. TLC (ether/hexane 3:1) then showed the presence of
a new compound of lower mobility. The catalyst was
filtered off, washed with methanol and the filtrate and
washings concentrated to a residue that was submitted
4.7. (1R,2R,3S,7aR)-3-Benzoyloxymethyl-1,2-dibenzyl-
oxypyrrolizidine 11
Compound 8 (1.13 g, 1.9 mmol) in dry methanol (30 mL)
was hydrogenated at 60 psi over 10% Pd–C (360 mg) for
14 h. TLC (ether/TEA 1:0.1) then showed the presence
of a new compound of lower mobility. Work-up of the
reaction mixture as for 9, gave a residue that was sub-
mitted to column chromatography (ether) on silica gel,
to column chromatography (ether/hexane 1:1) to afford
25
D
pure syrupy 9 (293 mg, 61%), which had ½aꢁ ¼ þ50 (c
1.2). IR (neat): 3086, 3063 and 3028 (aromatic), 1721
(CO benzoate), 712 and 696 cmꢀ1 (aromatic). NMR
previously saturated with NH3 gas, to afford pure syr-
1
data (400 MHz): H, 8.02 (d, 2H, Jo;m 7.3 Hz, H-ortho-
25
D
upy 11 (470 mg, 55%), which had ½aꢁ ¼ þ30 (c 1.9).
Bz), 7.59 (t, 1H, Jm;p 7.2 Hz, H-para-Bz), 7.46 (t, 2H, H-
meta-Bz), 7.40–7.21 (m, 10H, 2CH2Ph), 4.73 (dd, 1H,
1
NMR data (400 MHz): H, d 8.04–7.20 (m, 15H, 3Ph),
0
4.72 (dd, 1H, J3;8 6.5, J8;8 11.4 Hz, H-8), 4.64 (dd, 1H,
0
J3;8 6.3, J8;8 11.3 Hz, H-8), 4.68 and 4.55 (2d, 2H, J
J3;8 7.2 Hz, H-80), 4.58 and 4.41 (2d, 2H, J 12 Hz,
0
12 Hz, CH2Ph), 4.62 and 4.51 (2d, 2H, J 11.7 Hz,
CH2Ph), 4.57 and 4.50 (2d, 2H, J 12 Hz, CH2Ph), 4.08
(dd, 1H, J1;2 0.7, J2;3 4.4 Hz, H-2), 3.81 (br d, 1H, H-1),
3.71 (dt, 1H, H-3), 3.55 (dt, 1H, J1;7a 3.2,
J7a;7a ¼ J7a;7b ¼ 7:5 Hz, H-7a), 3.09 (dt, 1H, J5;6 6.4,
CH2Ph), 4.52 (dd, 1H, J3;8 5.6 Hz, H-80) 4.26 (dd, 1H,
0
J1;2 3.1, J2;3 6.6 Hz, H-2), 3.81 (dd, 1H, J1;7a 8 Hz, H-1),
3.03 (br q, 1H, H-3), 2.66 (ddd, 1H, J7a;7a 10.4, J7a;7b
5.5 Hz,
H-7a),
2.51
(br
sex,
1H,
J5;6a
¼
0
0
0
0
0
J5;5 ¼ J5;6 ¼ 8:9 Hz, H-5), 2.89 (dt, 1H, J5 ;6 8.7, J5 ;6
J5;6b ¼ J5;Me ¼ 6 Hz, H-5), 2.27 (bdq, 1H, H-6b), 1.88–
1.77 (m, 1H, H-7b), 1.75–1.72 (m, 1H, H-6a), 1.65
(dq, 1H, J6b;7a 7.2, J6a;7a ¼ J7a;7b ¼ 10:7 Hz, H-7a) and
1.28 (d, 3H, Me); 13C (inter alia), d 166.37 (COPh), 89.02
(C-2), 85.35 (C-1), 73.98 (C-7a), 71.82 and 71.66 (2
CH2Ph), 63.50 (C-8), 63.27 (C-3), 55.05 (C-5), 37.16 (C-
6), 25.76 (C-7) and 21.14 (Me). Mass spectrum (LSIMS):
m=z: 494.2301 [Mþ þ Na] for C30H33NO4Na 494.2307
(deviation þ1.2 ppm).
2.3 Hz, H-50), 2.15 (ddt, 1H, J 2.5, J 7.5, J 10.2 Hz, H-
7b), 1.96–1.77 (m, 2H, H-6,60) and 1.63 (ddt, 1H, J 7.6, J
10, J 12 Hz, H-7); 13C (inter alia), d 166.51 (COPh),
88.13 (C-1), 86.55 (C-2), 71.77 and 71.48 (2CH2Ph),
70.80 (C-7a), 62.25 (C-3), 61.83 (C-8), 48.57 (C-5), 30.42
(C-7) and 26.91 (C-6). Mass spectrum (LSIMS): m=z:
458.2326 [Mþ þ H] for C29H32NO4 458.2331 (deviation
þ1.2 ppm).
4.6. (1R,2R,3S,5R,7aR)-1,2-Dihydroxy-3-hydroxy-
methyl-5-methylpyrrolizidine 1, [(+)-3-epi-hyacinthacine
A3]
4.8. (1R,2R,3S,7aR)-1,2-Dibenzyloxy-3-hydroxymethyl-
pyrrolizidine 12
Conventional debenzoylation of 11 (470 mg, 1 mmol) in
0.2 N sodium methoxide in dry methanol (7 mL) gave
after work-up and column chromatography (ether/
methanol 5:1) on silica gel, previously saturated with
To a solution of 9 (250 mg, 0.53 mmol) in anhydrous
methanol (5 mL) was added 1 N sodium methoxide
(1.2 mL) and the mixture was left for 30 min. TLC
(ether/hexane 3:1) then revealed a slower-running com-
pound, presumably 10. The mixture was acidified (concd
HCl) and hydrogenated (10% Pd–C, 110 mg) at 60 psi
for 12 h. TLC (ether/methanol/TEA 5:1:0.1) then
showed a new nonmobile compound. The catalyst was
filtered off, washed with methanol and the filtrate and
washings neutralized with Amberlite IRA-400 (OHꢀ
NH3 gas, pure syrupy 12 (330 mg, 92%), which had
28
D
½aꢁ ¼ þ19 (c 1). NMR data (300 MHz): 1H, d 7.29–7.23
(m, 10H, 2Ph), 4.61 and 4.45 (2d, 2H, J 12 Hz, CH2Ph),
4.55 and 4.49 (2d, 2H, J 12 Hz, CH2Ph), 4.10 (dd, 1H,
0
J1;2 2.1, J2;3 5 Hz, H-2), 3.97 (dd, 1H, J3;8 6.3, J8;8
11.6 Hz, H-8), 3.91 (dd, 1H, J3;8 5.8 Hz, H-80), 3.78 (dd,
0
1H, J1;7a 4.2 Hz, H-1), 3.40–3.34 (m, 2H, H-3,7a), 3.51

I. Izquierdo et al. / Tetrahedron: Asymmetry 15 (2004) 1465–1469
1469
(br s, 1H, OH), 3.03 (dt, 1H, J5a;5b 8.8, J5a;6a ¼ J5a;6b
¼
6:5 Hz, H-5a), 2.78 (bdt, 1H, J5b;6a ¼ J5b;6b ¼ 3:2 Hz, H-
5b), 2.10 (ddt, 1H, J 2.9, J 7.5, J 10.7 Hz, H-7b), 1.96–
1.72 (m, 2H, H-6a,6b) and 1.62 (m, 1H, H-7a); 13C (inter
alia), d 88.73 (C-1), 87.47 (C-2), 72.04 and 71.59
(2CH2Ph), 70.30 (C-7a), 65.03 (C-3), 59.75 (C-8), 48.01
(C-5), 30.25 (C-7) and 26.82 (C-6). Mass spectrum
(LSIMS): m=z: 354.2068 [Mþ þ H] for C22H28NO3
354.2069 (deviation þ0.2 ppm).
Acknowledgements
The authors are deeply grateful to Ministerio de Ciencia
ꢀ
y Tecnologıa (Spain) for financial support (Project
PPQ2002-01303) as well as for a grant (F. Franco).
References and notes
1. Izquierdo, I.; Plaza, M.-T.; Franco, F. Tetrahedron:
Asymmetry 2003, 14, 3933–3935.
2. (a) Izquierdo, I.; Plaza, M.-T.; Robles, R.; Franco, F.
Tetrahedron: Asymmetry 2001, 12, 2481–2487; (b)
Izquierdo, I.; Plaza, M.-T.; Franco, F. Tetrahedron:
Asymmetry 2002, 13, 1581–1585.
3. (a) Kato, A.; Adachi, I.; Miyauchi, M.; Ikeda, K.; Komae,
T.; Kizu, H.; Kameda, Y.; Watson, A. A.; Nash, R. J.;
Wormald, M. R.; Fleet, G. W. J.; Asano, N. Carbohydr.
Res. 1999, 316, 95–103; (b) Asano, N.; Kuroi, H.; Ikeda,
H.; Kizu, H.; Kameda, Y.; Kato, A.; Adachi, I.; Watson, A.
A.; Nash, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
2000, 11, 1–8; (c) Yamashita, T.; Yasuda, K.; Kizu, H.;
Kameda, Y.; Watson, A. A.; Nash, R. J.; Fleet, G. W. J.;
Asano, N. J. Nat. Prod. 2002, 65, 1875–1881; Kato, A.;
Kano, E.; Adachi, I.; Molyneux, R. J.; Watson, A. A.;
Nash, R. J.; Fleet, G. W. J.; Wormald, M. R.; Kizu, H.;
Ikeda, K.; Asano, N. Tetrahedron: Asymmetry 2003, 14,
325–331.
4. Izquierdo, I.; Plaza, M.-T.; Robles, R.; Franco, F.
Carbohydr. Res. 2001, 330, 401–408.
5. Izquierdo, I.; Plaza, M.-T.; Franco, F. Tetrahedron:
Asymmetry 2002, 13, 1503–1508.
6. Nash, R. J.; Fellows, L. E.; Dring, J. V.; Fleet, G. W. J.;
Derome, A. E.; Hamor, T. A.; Scofield, A. M.; Watkin, D.
J. Tetrahedron Lett. 1988, 29, 2487–2490.
7. Molyneux, R. J.; Benson, M.; Wong, R. Y.; Tropea, J. E.;
Elbein, A. D. J. Nat. Prod. 1988, 51, 1198–1206.
4.9. (1R,2R,3S,7aR)-1,2-Dihydroxy-3-hydroxymethyl-
pyrrolizidine 2, [(+)-3-epi-hyacinthacine A2]
Compound 12 (280 mg, 0.8 mmol) in dry methanol
(30 mL) was hydrogenated (10% Pd–C, 170 mg) in acid
medium (concd aqueous HCl, four drops) at 50 psi for
48 h. TLC (ether/methanol 3:1) then showed a not
mobile compound. The catalyst was filtered off, washed
with methanol and the filtrate and washings neutralized
with Amberlite IRA-400 (OHꢀ form), then concen-
trated. Column chromatography (ether/methanol/TEA
5:1:0.1) of the residue gave pure 2 (110 mg, 80%), which
26
D
had ½aꢁ ¼ þ2:5 (c 0.8, methanol). NMR data
(300 MHz, methanol-d4): 1H, d 4.06 (dd, 1H, J1;2 1.5, J2;3
0
3.7 Hz, H-2), 3.97 (dd, 1H, J3;8 6.6, J8;8 11.4 Hz, H-8),
3.91 (dd, 1H, J3;8 7 Hz, H-80), 3.89 (t, 1H, J1;7a 1.7 Hz, H-
1), 3.34 (dt, 1H, H-3), 3.33 (m, 1H, H-7a), 3.18 (ddd,
0
0
0
1H, J5;6 5.8, J5;6 9.1, J5;5 10.5 Hz, H-5), 2.93–2.85 (m,
1H, H-50), 2.19–2.08 (m, 1H, H-7), 1.98–1.89 (m, 1H, H-
6) and 1.82–1.62 (m, 2H, H-60,70); 13C, d 80.02 (C-1),
79.92 (C-2), 72.67 (C-7a), 65.12 (C-3), 57.57 (C-8), 48.27
(C-5), 29.66 (C-7), and 26.36 (C-6). Mass spectrum
(LSIMS): m=z: 173.1050 [Mþ] for C8H15NO3 173.1052
(deviation þ0.8 ppm).