Stereoselective synthesis of novel tetrahydroxypyrrolizidines

Article abstract of DOI:10.1016/j.tetasy.2003.11.022

N-Benzyloxycarbonyl-2,5-dideoxy-2,5-imino-3,4-O-isopropylidene-L-ribose 12a has been converted into (1R,2S,6R,7S,7aS)-5 and (1R,2S,6S,7R,7aR)-1,2,6,7- tetrahydroxypyrrolidin-5-ones 6 and (1R,2S,6S,7S,7aS)-7 and (1R,2S,6R,7R,7aS)-1, 2,6,7-tetrahydroxypyrrolizidines 8 following stereoselective paths. These new compounds have been assayed for their inhibitory activities towards 25 glycosidases. Pyrrolizidines 7 and 8 are moderate but selective inhibitors of amyloglucosidase from Rhizopus mold (7: IC₅₀=130μM, K _i=120μM; 8: IC₅₀=200μM, K_i=180μM, mixed type of inhibition).

Full text of DOI:10.1016/j.tetasy.2003.11.022

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 323–333
Stereoselective synthesis of novel tetrahydroxypyrrolizidines
a
Ana T. Carmona, Jose Fuentes, Pierre Vogel and Inmaculada Robina
a
b
a,
*
ꢀ
a
ꢀ
ꢀ
ꢀ
Departamento de Quımica Organica, Facultad de Quımica, Universidad de Sevilla, Apartado 553, E-41071 Sevilla, Spain
bInstitute of Molecular and Biological Chemistry, Swiss Federal Institute of Technology (EPFL), BCH, CH 1015 Lausanne-Dorigny,
Switzerland
Received 7 October 2003; accepted 17 November 2003
Abstract—N-Benzyloxycarbonyl-2,5-dideoxy-2,5-imino-3,4-O-isopropylidene-L-ribose 12a has been converted into (1R,2S,6R,
7S,7aS)-5 and (1R,2S,6S,7R,7aR)-1,2,6,7-tetrahydroxypyrrolidin-5-ones 6 and (1R,2S,6S,7S,7aS)-7 and (1R,2S,6R,7R,7aS)-1,2,6,7-
tetrahydroxypyrrolizidines 8 following stereoselective paths. These new compounds have been assayed for their inhibitory activities
towards 25 glycosidases. Pyrrolizidines 7 and 8 are moderate but selective inhibitors of amyloglucosidase from Rhizopus mold
(7: IC50 ¼ 130 lM, Ki ¼ 120 lM; 8: IC50 ¼ 200 lM, Ki ¼ 180 lM, mixed type of inhibition).
ꢀ 2003 Elsevier Ltd. All rights reserved.
1. Introduction
include the cis-allylation of a chiral lactam skeleton
derived from
-malic acid,8 cyclizations of acetylenic
D
Pyrrolizidine alkaloids form a class of important natural
compounds.1 Their common skeleton (1-azabicyclo-
[3.3.0]octane) can be hydroxylated at different positions
and possess a further hydroxymethyl group at C-1
(necines), at C-3 (alexines), or at C-3 and C-5 (hyacin-
thacines). Many pyrrolizidine alkaloids are selective
glycosidase inhibitors, and, as consequence, display a
range of important biological activities.2 This fact,
together with their functional and stereochemical com-
plexities, has promoted the development of a variety of
synthetic routes and a number of synthetic analogues
has been prepared.3 The formation of the pyrrolizidine
framework generally takes place by cyclization of a
conveniently substituted pyrrolidine moiety. Several
types of processes, for example, radical and ionic cycli-
zations, carbene insertions and acylimmnium cycliza-
tions have been reviewed.4 Other procedures such
as Claisen-like intramolecular acylation involving
a-pyrrolidinyl sulfones,5 ring-closing metathesis of
disubstituted ethenyl pyrrolidines,6 or intramolecular
titanium-mediated coupling reactions of a-substituted
succinimides7 have been described. Other processes
sulfones with b-chloroamines,9 cyclizations of N-prop-
argylaminyl radicals10 and cycloaddition processes
including tandem inter[4+2]/inter[3+2],11 hetero Diels–
Alder reactions,12 and [2+2],13 and 1,3-dipolar cyclo-
additions.14–16 Recently a chemo-enzymatic process
involving an enzymatic aldol reaction followed by
double reductive amination has been described for the
synthesis of several tetrahydroxylated pyrrolizidine
alkaloids, such as 3-epi-australine, australine and 7-epi-
alexine.17
Sugars have been extensively used as starting materials
in most syntheses in this area, and highly stereocon-
trolled routes for the preparation of new series of pyr-
rolizidine alkaloids using readily available carbohydrates
have been reported. For instance,
L-xylofuranose
derivatives have been used for the preparation of
novel pyrrolizidines structurally related to (+)-alexine
and (+)-australine.18
D-arabinose has been used for the
preparation of (+)-hyacinthacine.19 The syntheses of
7a-epi-hyacinthacine A2, 5,7a-diepi-hyacinthacine A3
20
and (+)-hyacinthacine A3
starting from
synthesis of 1,2,6,7-tetrahydroxypyrrolizidines 1 and 2
starting from -glycero-
-gulo-heptono-1,4-lactone21
and -glycero-
-talo-heptono-1,4-lactone,22 respec-
have been carried out
D
-fructose. Fleet et al. have described the
D
D
Keywords: Pyrrolizidines; Enzymatic inhibitors; Azasugars; Enzyme
inhibition; Sharpless asymmetric dihydroxylation; Pyrrolidines;
Iminosugars; Pyrrolizidinones.
D
D
tively. The synthesis of four diastereoisomers of
(+)-casuarine, starting from octonolactones23 has also
been reported. Some of the above syntheses imply the
* Corresponding author. Tel.: +34-954557150; fax: +34-954624960;
e-mail: robina@us.es
0957-4166/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.11.022

324
A. T. Carmona et al. / Tetrahedron: Asymmetry 15 (2004) 323–333
preparation of iminoalditols as intermediates such as
1,4-imino- -glycero- -ido 3 and 1,4-imino- -glycero-
-glucoheptitols 424 presenting these compounds the
additional advantage of being good and selective
hydroxylation reaction on 13a with osmium tetroxide
and morpholine-N-oxide gave a mixture of the corre-
sponding syn-diastereoisomers 15 and 16 in a ratio 1:1,
indicating that the sugar moiety does not exert any
induction onto the stereoselectivity. When the reaction
was carried out in the presence of the commercially
available catalysts for asymmetric Sharpless dihydr-
oxylations, good yields and a moderate selectivity were
observed in both cases. syn-Diols 15 and 16 were
obtained in a ratio 3.4:1 using AD-mixa and 1:4 with
AD-mixb. In the case of the reaction using AD-mixb
12% of the starting material was recovered (Scheme 1).
L
D
L
D
inhibitors of a- and b-
D
-glucosidases (Fig. 1).
OH
OH
5
6
7
N
N
OH
OH
3
7a
H
H
2
1
HO
OH
HO
OH
2
1
The relative configurations of the polyhydroxylated
pyrrolidine derivatives are based upon the empirical
mnemonic device proposed by Sharpless28 and have
been confirmed by deprotection and cyclization reac-
tions. Thus treatment of 15 and 16 with aq TFA, fol-
lowed by hydrogenolysis and refluxing with ethanol
gave pyrrolizidinones 5 and 6 in 52% and 68% yield,
respectively.
OH
H
N
H
N
OH
H
OH
OH
OH
OH
HO
OH
HO
OH
3
4
Figure 1.
1
The H NMR data of 5 and 6 confirmed the proposed
It is known that small modifications on the structure of
iminosugars may significantly change their enzymatic
inhibitory properties,25 therefore the development of
new stereocontrolled synthetic routes for the prepara-
tion of novel natural polyhydroxylated pyrrolizidine
alkaloids or of their unnatural isomers, is a task of
interest for SAR studies.
structures (Fig. 3, see experimental). In the case of
compound 5 an NOE between pair of protons H-7a
(d ¼ 3:53)/H-6 (d ¼ 4:33) confirmed the (R)-configura-
tion of C-6. In addition, for compound 6 dihedral
angle between H-6/H-7 on the one hand and between
H-1/H-7a on the other hand must both approach 90ꢁ
as J6;7 ¼ J1;7a ¼ 0 Hz were observed. For compound 5,
an antiperiplanar relationship between proton pairs H-
6/H-7 and H-1/H-7a (J6;7 ¼ 8:6 Hz, J1;7a ¼ 6:9 Hz) is
confirmed. These data are compatible with an envelope
conformation for both five-membered rings in the
pyrrolizidine moiety occupying C-2 and C-6 the apical
positions in 5 and C-1 and C-6 in compound 6.
Recently we have described26 a stereoselective method
for the preparation of hydroxylated indolizidines from
the readily available 3,6-imino-2,3,6-trideoxy-L-arabino
and D-arabino-hexose. By using a similar approach we
describe herein a stereoselective route for the synthesis
of two new enantiopure tetrahydroxy pyrrolizidin-5-
ones 5 and 6 and two tetrahydroxypyrrolizidines 7 and
In order to improve the diastereoselectivity in the
Sharpless dihydroxylation with the commercial reagents
AD-mixa and AD-mixb, we decided to carry out the
reaction with the p-methoxybenzoylic ester 18 obtained
after reduction and protection. Compound 18 is a good
substrate for asymmetric dihydroxylation, because it is
known that aromatic moieties attached to allylic alco-
hols exert an excellent control of the diastereoselectivity
when using the pseudoenantiomeric Cinchona alkaloid
ligands for Sharpless reagents.29 In the case of the
reaction with AD-mixa, compound 19 was obtained as
major compound, with a 90% d.e. Reaction with AD-
mixb gave diastereoisomer 20 with a d.e. of 99%.
Hydroxylation with osmium tetroxide gave a 1:1 mix-
8, starting from D-allitol and based on elongation of
azasugar–carbaldehydes followed by stereoselective
hydroxylation and cyclization (Fig. 2).
O
N
O
N
OH
OH
OH
OH
OH
OH
OH
OH
N
N
H
H
H
H
OH
HO
OH
HO OH
HO
HO OH
8
6
7
5
Figure 2.
ꢀ
ture of diastereoisomers. Zemplen methanolysis of 19
and 20 gave 21 and 22 in 91% and 84% yield, respec-
tively, that after acidic deprotection gave the iminoald-
itols 23 and 24 (Scheme 2).
2. Results and discussion
The synthesis begins from 2,5-imino- -ribose 12a and
L
12b that were obtained according to FleetÕs methodol-
The configurations for the glycol moieties were based
on the Sharpless mnemonic device27 and have been
confirmed by cyclization into different pyrrolizidine
derivatives. This has been carried out by regioselec-
tive tosylation and Boc cleavage of 19 and 20. The
pyrrolizidines 7 and 8 were obtained in quantitative
yields.
ogy.27 Compound 12a was prepared starting from 1,4-
dideoxy-1,4-imino-2,3:5,6-di-O-isopropylidene-D
-allitol26
9 by protection with benzyloxycarbonyl group to give
successively compound 11. Wittig reaction on 12 with
two different protecting groups for nitrogen gave a
mixture of alkenes 13 and 14 in a ratio E/Z 10:1. Direct

A. T. Carmona et al. / Tetrahedron: Asymmetry 15 (2004) 323–333
325
Cbz
Cbz
Cbz
N
H
N
N
N
NaIO4
CbzCl
NaHCO3
99%
PTSA
CHO
O
O
OH
O
O
OH
MeOH/H2O
THF/H2O
95%
O
O
O
O
O
O
O
O
12a
11
9
10
R
R
N
R
N
COOEt
N
Ph3P=CHCOOEt
CH2Cl2, 90%
CHO
COOEt
+
O
O
O
O
O
O
E:Z = 10:1
13a, R = Cbz
13b, R = Boc
14a, R = Cbz
14b, R = Boc
12a, R = Cbz
12b, R = Boc
Cbz
N
Cbz
N
Cbz
N
OH
COOEt
OH
Dihydroxylation
COOEt
COOEt
+
OH
OH
O
O
O
O
O
O
16
15
13a
(i) TFA, 80%
68%
52%
(ii) H2/Pd
(iii) EtOH, reflux
OH
OH
OH
OH
O
N
O
ratio 14 : 15 yield 14 +15
N
OsO4, NMO, no ligand
1 : 1
93%
H
H
AD-mixα : (DHQ)2-PHAL 3.4 : 1
AD-mixβ : (DHQD)2-PHAL 1 : 4
80%
HO
OH
HO
OH
76% + (12% 13a)
6
5
Scheme 1.
NOE
Compounds 5, 6, 7 and 8 were assayed as enzymatic
inhibitors towards 25 commercially available glycosid-
ases. These compounds did not show any inhibitory
activity at 1 mM concentration towards the following
H
H
O
H
O
N
N
HO
HO
HO
HO
H
OH
OH
H
7a
R
7a
2
2
1
7
H
enzymes: a-L-fucosidase from bovine epididymis, and
1
H
7
H
H
OH
HO
H
human placenta, a-galactosidases from coffee beans,
Aspergillus niger and from Escherichia coli, b-galacto-
sidases from E. coli, A. niger, Aspergillus orizae
and from ÔJack beanÕ, a-glucosidase (maltase) from
yeast, a-glucosidase (isomaltase) from baker yeast,
amyloglucosidase from A. niger, b-glucosidase from
almond, a-mannosidase from ÔJack beanÕ and from
almond, b-mannosidase from Helix pomatia, b-xylosi-
dase from A. niger, a-N-acetylgalactosaminidase from
chicken liver and b-N-acetylglucosaminidase from ÔJack
beanÕ and bovine epididymis A and B. Furthermore
pyrrolizidinones 5 and 6 ignored a-glucosidase from rice
and amyloglucosidase from Rhizopus mold, presenting
only weak inhibition activity towards b-galactosidase
6
5
Figure 3.
1
The H NMR data of 7 and 8 are in accordance with
the proposed structure (Fig. 4, see experimental).
The NOE observed between the H NMR signals of
1
H-7 (d ¼ 4:16)/H-7a (d ¼ 3:99) indicated the R con-
figuration for C-6 and C-7 in compound 8. For
compound 7, NOEs observed between pairs of protons
H-1 (d ¼ 4:26)/H-7 (d ¼ 4:07) and H-6 (d ¼ 4:13)/H-7a
(d ¼ 3:41) are compatible with the proposed S con-
figuration for C-7. The average coupling constant
values for these pyrrolizidines indicate higher confor-
mational flexibility than in the case of pyrrolizidinones
5 and 6.
from bovine liver (IC50 ¼ 305 lM for
5
and
IC50 ¼ 470 lM for 6). Compound 6 presented a com-
petitive inhibition towards b-glucosidases from Caldo-
cellum saccharolyticum (IC50 ¼ 365 lM, Ki ¼ 117 lM).
Pyrrolizidines 7 and 8 did not inhibit b-galactosidase

326
A. T. Carmona et al. / Tetrahedron: Asymmetry 15 (2004) 323–333
Boc
N
Boc
N
(i) DIBALH, CH2Cl2
OpMBz
OsO4, NMO
-15οC, 50%
(ii) 4-MeOBzCl,
TEA, DMAP
81%
17
COOEt
19 + 20
O
O
O
O
18
(ratio: 1:1)
1b
Boc
N
Boc
OH
OH
N
OpMBz
OpMBz
OH
OH
O
O
19
(d.e. = 90%)
(d.e. > 99%)
O
O
20
NaOMe
MeOH
NaOMe
MeOH
84%
91%
Boc
N
Boc
N
OH
OH
OH
OH
OH
OH
O
O
O
O
22
21
ClTs/py
50%
ClTs/py
50%
-15 °C, 47%
Ts-8
-15 °C, 58%
Ts-7
(i) TFA
(i) TFA
100%
100%
(ii) NH4OH
(ii) NH4OH
OH
OH
N
N
OH
H
OH
H
OH
HO
OH
HO
8
7
amyloglucosidase
Rhizopus mold
76% Ki = 180 µM
amyloglucosidase
Rhizopus mold
80% Ki =120 µM
H
OH
H
N
OH
N
(i) TFA
(i) TFA
OH
OH
(ii) Dowex
(ii) Dowex
21
22
88%
100%
OH
OH
OH
OH
HO
HO
24
23
Scheme 2.
NOE
activities towards amyloglucosidase from Rhizopus mold
[IC50 ¼ 130 lM, Ki ¼ 120 lM (M) for 7; IC50 ¼ 200 lM,
Ki ¼ 180 lM (M) for 8]. Compound 7 additionally pre-
sented a weak inhibition activity towards a-glucosidase
from rice (IC50 ¼ 325 lM).
NOE
H
N
N
H
HO
HO
HO
H
HO
OH
OH
H
2
7a
7a
2
1
1
H
7
7
H
H
H
OH
HO
H
H
7
8
NOE
The methodology presented here has given access to
novel pyrrolizidine derivatives, important compounds
for structure–activity studies in the inhibition of glyco-
sidases. Modification of the configuration of the tetra-
hydroxypyrrolizidines may induce significant changes
in their inhibitory activities as demonstrated in this
work.
Figure 4.
from bovine liver and b-glucosidase from C. saccharo-
lyticum, but presented moderate and specific inhibition

A. T. Carmona et al. / Tetrahedron: Asymmetry 15 (2004) 323–333
327
3. Experimental
ether/acetone 6:1 fi 4:1), gave 11 (0.76 g, 37%) as an oil
22
and 1.26 g (55%) of recovered 10. ½aꢀ ¼ )34.5 (c 1.3,
D
3.1. General
CH2Cl2). IR (film) 3347 (OH), 2938, 1676 (C@O), 1433,
1109, 1063, 756, 698 cmꢁ1. 1H NMR (300 MHz, CDCl3,
d ppm, J Hz) d 7.37–7.26 (m, 5H, Ph), 5.17 (s, 2H, CH2-
Ph), 4.87 (d, 1H, J3;2 ¼ 5:9, H-3), 4.74 (td, 1H, J2;1 ¼ 0:8,
Optical rotations were measured in a 1.0 cm tube with a
Perkin–Elmer 241 MC spectropolarimeter. 1H NMR
and 13C NMR spectra were obtained for solutions in
CDCl3, DMSO-d6, CD3OD and D2O, J values are given
in Hz and d in ppm. All the assignments were confirmed
by two-dimensional NMR experiments. The FAB mass
spectra were obtained with glycerol or 3-nitrobenzyl
alcohol as matrix. TLC was performed on silica gel
HF254 (Merck), with detection by UV light and Pancaldi
reagent ((NH4)6MoO4, Ce(SO)4, H2SO4, H2O). Silica gel
60 (Merck, 230 mesh) was used for preparative chro-
matography. Anhyd solvents and reagents were freshly
distilled under N2 prior to use. The inhibition constants
(Ki) and the type of inhibition (competitive, noncom-
petitive, mixed) were determined from Lineweaver–Burk
plots.30 For each plot, a blank and two concentrations
of inhibitor were used corresponding to IC50 and IC50/2.
0
J2;1 ¼ 5:8, H-2), 4.07 (d, 1H, J4;5 ¼ 8:9, H-4), 3.97 (dd,
1H, 2J1;1 ¼ 13:0, H-1), 3.60–3.55 (m, 2H, H-6, OH), 3.38
0
(dd, 1H, H-10), 3.41–3.35 (m, 1H, H-5), 2.91 (br s, 1H,
OH), 1.42 and 1.35 (2s, 3H each, C(CH3)2). 13C NMR
(75.4 MHz, CDCl3, d ppm) d 156.1 (C@O), 136.1 (C-1 of
Ph), 128.4, 128.0, 127.5 (Ph), 111.7 (C(CH3)2), 81.9 (C-
3), 79.0 (C-2), 70.4 (C-5), 67.4 (CH2-Ph), 65.1 (C-4), 62.5
(C-6), 52.0 (C-1), 26.7 and 24.6 (C(CH3)2). FABMS m=z
338 [90%, (M+H)þ], 360 [100%, (M+Na)þ]. Anal. Calcd
for C17H23NO6: C, 60.52; H, 6.87; N, 4.15. Found: C,
60.27; H, 7.17; N, 4.21.
3.4. N-Benzyloxycarbonyl-2,5-dideoxy-2,5-imino-3,4-
O-isopropylidene-L-ribose 12a
A solution of NaIO4 (1.31 g, 6.14 mmol) in water
(20 mL) was added dropwise to a solution of 11 (1.03 g,
3.07 mmol) in THF (15 mL) cooled at 0 ꢁC. After stirring
for 1.5 h at that temperature, THF was evaporated and
the residue dissolved in CH2Cl2 (80 mL) and washed
successively with water, satd aq soln of NaHCO3 and
brine. The organic phase was dried, filtered and con-
centrated to afford crude aldehyde 12a (0.88 g, 95%)
which was used for the next step without further puri-
fication. FABMS m=z 306 [50%, (M+H)þ], 328 [100%,
(M+Na)þ]. CIMSHR m=z found 306.1344 (calcd for
C16H19NO5+H: 306.1341).
3.2. N-Benzyloxycarbonyl-1,4-dideoxy-1,4-imino-2,3:5,6-
di-O-isopropylidene-D-allitol 10
To a stirred solution of 1,4-dideoxy-1,4-imino-2,3:5,6-
di-O-isopropylidene-
-allitoll26 (1.50 g, 6.17 mmol) in
D
EtOH/H2O 1:1 (40 mL), NaHCO3 (0.88 g, 10.5 mmol)
and CbzCl (0.96 mL, 6.8 mmol) were added. After stir-
ring for 2 h at rt, the mixture was poured into satd aq
soln of NaHCO3 (130 mL) and extracted with AcOEt
(3 · 100 mL). The organic phases were dried over
Na2SO4, filtered and concentrated. Column chromato-
graphy (ether/petroleum ether 1:3 fi 1:1), afforded 10
22
(2.30 g, 99%). ½aꢀ ¼ )60.5 (c 1.2, CH2Cl2). IR (film)
D
2986, 2940, 1707 (C@O), 1418, 1103, 1057, 760,
698 cmꢁ1. 1H NMR (300 MHz, DMSO-d6 90 ꢁC, d ppm,
J Hz) d 7.36–7.31 (m, 5H, Ph), 5.14 (d, 1H, 2JH;H ¼ 12:8,
CH-Ph), 5.09 (d, 1H, CH-Ph), 4.73 (td, 1H, J2;1 ¼ 0:8,
3.5. Ethyl (E) and (Z)-N-benzyloxycarbonyl-2,3,4,7-
tetradeoxy-4,7-imino-5,6-O-isopropylidene-L-ribo-hept-
2-enonate 13a and 14a
0
J2;3 ¼ J2;1 ¼ 5:8, H-2), 4.68 (d, 1H, H-3), 4.16 (q, 1H,
To a solution of 12a (0.88 g, 2.88 mmol) in dry CH2Cl2
(20 mL), ethoxycarbonyltriphenylmethylenephospho-
0
J5;4 ¼ J5;6 ¼ J5;6 ¼ 5:8, H-5), 4.02–3.93 (m, 2H, H-4, H-
2
0
6), 3.77 (dd, 1H, J1;1 ¼ 12:8, H-1), 3.75 (dd, 1H,
rane (1.5 g, 4.30 mmol) was added and the mixture was
heated under reflux for 2 h. After evaporation of the
solvent, the residue was treated with ether, filtered and
concentrated. Column chromatography (ether/petro-
leum ether 1:5 fi 1:2) afforded 13a (956 mg, 88%) and
14a (96 mg, 9%), both as oils.
J6 ;6 ¼ 11:7; H-60), 3.42 (dd, 1H, H-10), 1.37 and 1.30
2
0
(2s, 3H each, C(CH3)2). 13C NMR (75.4 MHz, DMSO-
d6 90 ꢁC, d ppm) d 153.9 (C@O), 136.4 (C-1 of Ph),
127.8, 127.2, 126.8 (Ph), 110.3 (C(CH3)2), 108.4
(C(CH3)2), 80.2 (C-2), 78.5 (C-3), 74.1 (C-5), 65.8, 65.7,
65.3 (CH2-Ph, C-4, C-6), 51.8 (C-1), 26.2, 25.8 and 24.2
(2C(CH3)2). FABMS m=z 378 [100%, (M+H)þ], 400
[20%, (M+Na)þ]. CIMSHR m=z found 378.1913 (calcd
for C20H27NO6+H: 378.1916).
23
D
Data for 13a: ½aꢀ ¼ )47 (c 1, CH2Cl2). IR (film) 2984,
2936, 1715 (C@O), 1663 (C@C), 1109, 1051, 976, 750,
700 cmꢁ1. 1H NMR (300 MHz, DMSO-d6 90 ꢁC, d ppm,
J Hz) d 7.35–7.28 (m, 5H, Ph), 6.79 (dd, 1H, J3;2 ¼ 15:7,
4
J3;4 ¼ 5:7, H-3), 5.85 (dd, 1H, J2;4 ¼ 1:6, H-2), 5.14 (d,
2
3.3. N-Benzyloxycarbonyl-1,4-dideoxy-1,4-imino-2,3-O-
isopropylidene-
1H, JH;H ¼ 12:7, CH-Ph), 5.08 (d, 1H, CH-Ph), 4.77
0
D
-allitol 11
(ddd, 1H, J6;5 ¼ 5:7, J6;7 ¼ 4:9, J6;7 ¼ 0:7, H-6), 4.66–
3
4.63 (m, 2H, H-4 and H-5), 4.15 (q, 2H, JH;H ¼ 7:1,
2
0
To a solution of 10 (2.30 g, 6.10 mmol) in MeOH/H2O
9:1 (30 mL), PTSA (115 mg, 0.61 mmol) was added.
After 16 h at rt the reaction mixture was neutralized with
IRA-68 (OHꢁ) resin. Filtration of the resin and evapo-
ration of the filtrate gave a residue that, after column
chromatography (ether/petroleum ether 1:2 fi 3:1 and
CH2CH3), 3.77 (dd, 1H, J7;7 ¼ 12:9, H-7), 3.47 (dd,
1H, H-70), 1.27 and 1.25 (2s, 3H each, C(CH3)2), 1.23 (t,
3H, CH2CH3). 13C NMR (75.4 MHz, DMSO-d6 90 ꢁC, d
ppm) d 164.6 (COOEt), 153.7 (C@O of Cbz), 142.8 (C-
3), 127.8, 127.2, 126.8 (Ph), 121.5 (C-2), 110.7
(C(CH3)2), 82.9 (C-5), 70.1 (C-6), 65.9 (CH2-Ph), 63.9

328
A. T. Carmona et al. / Tetrahedron: Asymmetry 15 (2004) 323–333
2
J7;7 ¼ 13:0, H-7), 3.46 (dd, 1H, H-70), 1.36 (s, 9H,
C(CH3)3), 1.38 and 1.25 (2s, 3H each, C(CH3)3), 1.25 (t,
3H, CH2CH3). 13C NMR (75.4 MHz, DMSO-d6 90 ꢁC,
d ppm) d 164.4 (COOEt), 153.2 (C@O of Boc), 144.7 (C-
3), 120.4 (C-2), 110.5 (C(CH3)2), 84.7 (C-5), 78.5
(C(CH3)3), 77.9 (C-6), 61.4 (C-4), 59.3 (CH2CH3), 50.4
(C-7), 27.6 (C(CH3)3), 26.3 and 24.6 (C(CH3)2), 13.4
(CH2CH3). FABMS m=z 242 [60%, (M)Boc+H)þ], 364
[100%, (M+Na)þ]. Anal. Calcd for C17H27NO6: C,
59.81; H, 7.97; N, 4.10. Found: C, 59.52; H, 8.01; N,
4.16.
0
(C-4), 59.6 (CH2CH3), 51.0 (C-7), 26.3 and 24.4
(C(CH3)2), 13.5 (CH2CH3). FABMS m=z 376 [10%,
(M+H)þ], 398 [60%, (M+Na)þ]. Anal. Calcd for
C20H25NO6: C, 63.98; H, 6.71; N, 3.73. Found: C, 63.75;
24
D
H, 6.78; N, 3.69. Data for 14a: ½aꢀ ¼ +65.6 (c 1.8,
CH2Cl2). IR (film) 2986, 2940, 1713 (C@O), 1196, 1117,
1
1053, 824, 760, 700 cmꢁ1. H NMR (300 MHz, DMSO-
d6 90 ꢁC, d ppm, J Hz) d 7.36–7.25 (m, 5H, Ph), 6.13 (dd,
1H, J3;2 ¼ 11:6, J3;4 ¼ 8:7, H-3), 5.88 (dd, 1H,
4J2;4 ¼ 1:5, H-2), 5.49 (dd, 1H, H-4), 5.06 (s, 2H, CH2-
0
Ph), 4.76 (dd, 1H, J6;5 ¼ 5:2, J6;7 ¼ 4:9, H-6), 4.45 (d,
3
1H, H-5), 4.13 (q, 2H, JH;H ¼ 7:0, CH2CH3), 3.74 (d,
1H, 2J7;7 ¼ 12:9, H-7), 3.56 (dd, 1H, H-70), 1.35 and 1.25
0
(2s, 3H each, C(CH3)2), 1.22 (t, 3H, CH2CH3). 13C
NMR (75.4 MHz, DMSO-d6 90 ꢁC, d ppm) d 164.4
(COOEt), 153.7 (C@O of Cbz), 144.3 (C-3), 136.5 (C-1
of Ph), 127.8, 127.2, 126.7 (Ph), 120.9 (C-2), 110.6
(C(CH3)2), 84.8 (C-5), 77.9 (C-6), 65.7 (CH2-Ph), 61.6
(C-4), 59.4 (CH2CH3), 50.7 (C-7), 26.3 and 24.5
(C(CH3)2), 13.5 (CH2CH3). FABMS m=z 376 [100%,
(M+H)þ], 398 [30%, (M+Na)þ]. Anal. Calcd for
C20H25NO6: C, 63.98; H, 6.71; N, 3.73. Found: C, 63.89;
H, 6.81; N, 3.75.
3.7. Asymmetric dihydroxylation reactions. General
procedure
To a solution of the olefin (1 mmol) in t-BuOH/H2O 1:1
(10 mL), AD-mix (a or b) (1.4 g/mmol olefin) and
MeSO2NH2 (1 mmol) were added. The reaction mixture
was stirred at 0 or 25 ꢁC until no more evolution was
detected by TLC. After that, Na2SO3 (1.1 g/g AD-mix)
was added at 0 ꢁC and the mixture was stirred at 25 ꢁC
for 45 min. Then, it was diluted with AcOEt (20 mL) and
extracted. The organic phases were washed with KOH
2 N and brine, dried over Na2SO4, filtered and concen-
trated.
3.6. Ethyl (E) and (Z)-N-(tert-butoxycarbonyl)-2,3,4,7-
tetradeoxy-4,7-imino-5,6-O-isopropylidene-L-ribo-hept-
2-enonate 13b and 14b
3.8. General procedure for the deacylations
To a solution of 12b31 (1.30 g, 4.8 mmol) in dry CH2Cl2
(30 mL), ethoxycarbonyltriphenylmethylenephospho-
To a solution of the substrate (0.1 mmol) in dry MeOH
(7 mL), NaOMe/MeOH (1 M) (0.03 mmol) was added
until basic pH. After stirring for 3 h at 25 ꢁC, the mixture
was neutralized with IR-120 (Hþ) resin, filtered and
concentrated.
rane (2.34 g, 6.72 mmol) was added and the mixture was
heated under reflux for 2 h. After evaporation of the
solvent, the residue was treated with ether, filtered and
concentrated. Column chromatography (ether/petro-
leum ether 1:5 fi 1:2) afforded 13b (1.27 g, 78%) and 14b
(119 mg, 7%), both as oils.
3.9. Boc and isopropylidene groups hydrolysis. General
procedure for deprotection
24
Data for 13b: ½aꢀ ¼ )39 (c 1, CH2Cl2). IR (film) 1701
D
1
(C@O), 1663 (C@C), 1167, 1051, 976 cmꢁ1. H NMR
(300 MHz, DMSO-d6 90 ꢁC, d ppm, J Hz) d 6.77 (dd,
1H, J3;2 ¼ 15:7, J3;4 ¼ 5:8, H-3), 5.82 (dd, 1H, 4J2;4 ¼1:7,
The protected pyrrolidine (0.05 mmol) was stirred in a
solution of 80% aqueous TFA (1.5 mL) for 2 h at 25 ꢁC.
The mixture was then poured into a Dowex 50WX8
(100–200 mesh) ion-exchange column and sequentially
washed with MeOH (30 mL), H2O (30 mL) and NH4OH
10% (50 mL). The fractions containing the unprotected
product were concentrated under vacuum.
0
H-2), 4.72 (ddd, 1H, J6;5 ¼ 5:2, J6;7 ¼ 0:8, J6;7 ¼ 4:9, H-
6), 4.61 (dd, 1H, J5;4 ¼ 1:0, H-5), 4.53 (dd, 1H, H-4),
3
4.14 (q, 2H, JH;H ¼ 7:1, CH2CH3), 3.67 (dd, 1H,
2
J7;7 ¼ 12:9, H-7), 3.34 (dd, 1H, H-70), 1.39 (s, 9H,
0
C(CH3)3), 1.36 and 1.25 (2s, 3H each, C(CH3)2), 1.22 (t,
3H, CH2CH3). 13C NMR (75.4 MHz, DMSO-d6 90 ꢁC,
d ppm) d 164.8 (COOEt), 153.4 (C@O of Boc), 143.6 (C-
3), 121.3 (C-2), 110.8 (C(CH3)2), 83.0 (C-6), 79.0 (C-5),
78.3 (C(CH3)3), 63.9 (C-4), 59.8 (CH2CH3), 51.0 (C-7),
27.8 (C(CH3)3), 26.5 and 24.6 (C(CH3)2), 13.8
(CH2CH3). EIMS m=z 341 [7%, (M)þÅ], 326 [15%,
(M)CH3)þÅ]. Anal. Calcd for C17H27NO6: C, 59.81; H,
7.97; N, 4.10. Found: C, 59.96; H, 7.90; N, 4.08.
3.10. Ethyl N-benzyloxycarbonyl-4,7-dideoxy-4,7-imino-
5,6-O-isopropylidene-
and ethyl N-benzyloxycarbonyl-4,7-dideoxy-4,7-imino-
5,6-O-isopropylidene- -glycero- -gluco-heptanonate 16
L
-glycero-
L
-altro-heptanonate 15
L
L
Asymmetric
dihydroxylation of
13a (156 mg,
0.416 mmol) with AD-mixa (16 h, rt) afforded, after
work-up and column chromatography (CH2Cl2/acetone
25:1 fi 20:1), 15 (123 mg, 61%) and 16 (40 mg, 20%).
Same reaction of 13a (156 mg, 0.416 mmol) with AD-
mixb (20 h, rt) afforded, after work-up and column
chromatography (CH2Cl2/acetone 25:1 fi 20:1), 16
(103.2 mg, 61%), 15 (25.8 mg, 15%) and a 12% of
recovered 13a.
24
Data for 14b: ½aꢀ ¼ +115 (c 1, CH2Cl2). IR (film) 2985,
D
2936, 1715 (C@O), 1182, 1167, 1119, 1053, 714 cmꢁ1. 1H
NMR (300 MHz, DMSO-d6 90 ꢁC, d ppm, J Hz) d 6.07
(dd, 1H, J3;2 ¼ 11:6, J3;4 ¼ 8:8, H-3), 5.88 (dd, 1H,
4J2;4 ¼ 1:4, H-2), 5.40 (ddd, 1H, J4;5 ¼ 0:8, H-4), 4.72
0
(td, 1H, J6;5 ¼ J6;7 ¼ 5:1, J6;7 ¼ 1:1, H-6), 4.42 (dd, 1H,
2
H-5), 4.16 (q, 2H, JH;H ¼ 7:1, CH2CH3), 3.65 (dd, 1H,

A. T. Carmona et al. / Tetrahedron: Asymmetry 15 (2004) 323–333
329
25
Data for 15: ½aꢀ ¼ )32 (c 0.6, CH2Cl2). IR (film) 3443
d ppm) d 153.3 (C@O of Boc), 131.6 (C-2), 124.9 (C-3),
110.3 (C(CH3)2), 83.7 (C-5), 78.23 (C(CH3)3), 78.16 (C-
6), 63.7 (C-4), 60.3 (C-1), 50.7 (C-7), 27.6 (C(CH3)3),
26.3 and 24.5 (C(CH3)2). FABMS m=z 322 [60%,
(M+Na)þ], 200 [70%, (M)Boc+H)þ]. Anal. Calcd For
C15H25NO5: C, 60.18; H, 8.42; N, 4.68. Found: C, 59.90;
H, 8.55; N, 4.66.
D
(OH), 2986, 2938, 1738 (C@O), 1703 (C@O), 1125,
1
1055, 862, 766, 698 cmꢁ1. H NMR (300 MHz, DMSO-
d6 90 ꢁC, d ppm, J Hz) d 7.36–7.30 (m, 5H, Ph), 5.10 (s,
2H, CH2-Ph), 4.95 (d, 1H, J5;6 ¼ 5:9, H-5), 4.93 (br d,
1H, JOH;3 ¼ 6:5, OH-3), 4.87 (br d, 1H, JOH;2 ¼ 6:8, OH-
0
2), 4.69 (ddd, 1H, J6;7 ¼ 5:1, J6;7 ¼ 1:3, H-6), 4.11 (q,
2H, 3JH;H ¼ 7:1, CH2CH3), 4.14–4.05 (m, 2H, H-4, H-2),
3.86 (m, 1H, H-3), 3.69 (dd, 1H, 2J7;7 ¼ 12:4, H-7), 3.48
0
(dd, 1H, H-70), 1.29 and 1.25 (2s, 3H each, C(CH3)2),
1.20 (t, 3H, CH2CH3). 13C NMR (125.7 MHz, DMSO-
d6 90 ꢁC, d ppm) d 171.5 (COOEt), 153.8 (C@O of Cbz),
136.6 (C-1 of Ph), 127.8, 127.2, 126.7 (Ph), 109.7
(C(CH3)2), 80.3 (m, C-5), 78.7 (m, C-6), 71.9, 65.9 (C-4,
C-2), 71.3 (m, C-3), 65.6 (CH2-Ph), 59.8 (CH2CH3), 52.3
(C-7), 26.4 and 24.4 (C(CH3)2), 13.5 (CH2CH3). CIMS
m=z 410 [65%, (M+H)þ]. CIMSHR m=z found 410.1818
(calcd for C20H27NO8+H: 410.1815).
3.12. (E)-N-(tert-Butoxycarbonyl)-2,3,4,7-tetradeoxy-
4,7-imino-5,6-O-isopropylidene-1-O-(p-methoxybenzoyl)-
L
-ribo-hept-2-enitol 18
A solution of allylic alcohol 17 (222.5 mg, 0.744 mmol)
in dry CH2Cl2 (3.5 mL) was treated with Et3N (210 lL),
p-methoxybenzoyl chloride (152 mg, 0.89 mmol) and
DMAP (cat). After stirring for 4 h at 25 ꢁC, the mixture
was diluted with CH2Cl2 (30 mL), poured into water
(40 mL) and extracted with CH2Cl2. The organic phase
was washed with 1 M HCl (20 mL), satd aq soln of
NaHCO3 (2 · 30 mL) and brine (30 mL), dried, filtered
and concentrated. Chromatography purification (ether/
19
Data for 16: ½aꢀ ¼ )47 (c 1, CH2Cl2). IR (film) 3499,
D
3324 (OH), 1725 (C@O), 1678 (C@O), 1105, 1069, 878,
1
764, 698 cmꢁ1. H NMR (300 MHz, DMSO-d6 90 ꢁC, d
ppm, J Hz) d 7.35–7.28 (m, 5H, Ph), 5.10 (s, 2H, CH2-
Ph), 4.95 (d, 1H, J5;6 ¼ 6:0, H-5), 4.92 (br d, 1H,
JOH;2 ¼ 7:3, OH-2), 4.86 (br d, 1H, JOH;3 ¼ 6:4, OH-3),
petroleum ether 1:3 fi 1:2) of the residue afforded 18
23
(261 mg, 81%) as an oil. ½aꢀ ¼ )19 (c 1.5, CH2Cl2). IR
D
(film) 1715 (C@O), 1597, 1404, 1260, 1165, 1066, 851,
1
4.68 (ddd, 1H, J6;7 ¼ 5:1, J6;7 ¼ 0:9, H-6), 4.17 (d, 1H,
768, 723 cmꢁ1. H NMR (300 MHz, DMSO-d6 90 ꢁC,
0
J4;3 ¼ 6:0, H-4), 4.12 (q, 2H, 3JH;H ¼ 7:1, CH2CH3), 4.05
d ppm, J Hz) d 7.93–7.89 (m, 2H, Ph), 7.05–7.00 (m, 2H,
Ph), 5.80 (dt, 1H, J2;3 ¼ 15:6, J2;1 ¼ 4:5, H-2), 5.73 (ddt,
1H, J3;4 ¼ 5:8, 4J3;1 ¼ 1:0, H-3), 4.76 (dd, 2H, H-1), 4.72
(ddd, 1H, J3;2 ¼ 3:2, H-3), 3.98 (dd, 1H, H-2), 3.73 (dd,
1H, 2J7;7 ¼ 12:4, H-7), 3.48 (dd, 1H, H-70), 1.30 and 1.24
0
(2s, 3H each, C(CH3)2), 1.20 (t, 3H, CH2CH3). 13C
NMR (125.7 MHz, DMSO-d6 90 ꢁC, d ppm) d 171.7
(COOEt), 154.1 (C@O of Cbz), 136.7 (C-1 of Ph), 127.8,
127.1, 126.6 (Ph), 109.8 (C(CH3)2), 80.3 (m, C-5), 78.6
(m, C-6), 70.4 (C-4), 69.6 (C-3), 66.0 (C-2), 65.6 (CH2-
Ph), 59.8 (CH2CH3), 52.6 (C-7), 26.4 and 24.3
(C(CH3)2), 13.5 (CH2CH3). FABMS m=z 432 [100%,
(M+Na)þ]. Anal. Calcd For C20H27NO8: C, 58.67; H,
6.65; N, 3.42. Found: C, 58.43; H, 6.84; N, 3.66.
(ddd, 1H, J6;5 ¼ 5:8, J6;7 ¼ 5:0, J6;7 ¼ 0:8, H-6), 4.54
0
(dd, 1H, J5;4 ¼ 0:6, H-5), 4.42 (br d, 1H, H-4), 3.85 (s,
2
0
3H, CH3O), 3.65 (dd, 1H, J7;7 ¼ 12:8, H-7), 3.32 (dd,
1H, H-70), 1.38 (s, 9H, C(CH3)3), 1.36 and 1.26 (2s, 3H
each, C(CH3)2). 13C NMR (75.4 MHz, DMSO-d6 90 ꢁC,
d ppm) d 164.6 (C@O), 162.9 (C-1 of Ph), 153.3 (C@O of
Boc), 130.7 (Ph), 129.8 (C-3), 125.3 (C-2), 121.7 (C-4 of
Ph), 113.6 (Ph), 110.4 (C(CH3)2), 83.4 (C-5), 78.4
(C(CH3)3), 78.1 (C-6), 63.8 (C-4), 63.3 (C-1), 55.1
(CH3O), 50.7 (C-7), 27.6 (C(CH3)3), 26.3 and 24.5
(C(CH3)2). FABMS m=z 456 [10%, (M+Na)þ], 334
[25%, (M)Boc+H)þ]. Anal. Calcd For C23H31NO7: C,
63.72; H, 7.21; N, 3.23. Found: C, 63.17; H, 7.30; N,
3.17.
3.11. (E)-N-(tert-Butoxycarbonyl)-2,3,4,7-tetradeoxy-
4,7-imino-5,6-O-isopropylidene-L-ribo-hept-2-enitol 17
To a solution of 13b (600 mg, 1.76 mmol) in dry CH2Cl2
(12 mL), cooled at )20 ꢁC, DIBALH (1 M in CH2Cl2,
3.5 mL) was added dropwise under argon. After 20 min,
the reaction was quenched with MeOH (3 mL) and
allowed to warm to 25 ꢁC. The mixture was diluted with
ether (15 mL), satd aq soln of NaCl (3 mL) and MgSO4
(3 g) were added and stirred for 1 h at 25 ꢁC. After fil-
tration and evaporation, the residue was chromato-
3.13. N-(tert-Butoxycarbonyl)-1,4-dideoxy-1,4-imino-2,3-
O-isopropylidene-7-O-(p-methoxybenzoyl)-
allo-heptitol 19
L
-glycero-D-
To a solution of 18 (83.5 mg, 0.193 mmol) in t-BuOH/
H2O 1:1 (2 mL) stirred at 0 ꢁC, AD-mixa (0.270 g) and
MeSO2NH2 (18 mg, 0.193 mmol) were added. The mix-
ture was vigorously stirred at 0 ꢁC for 5 d and quenched
by addition of Na2SO3 (0.35 g). After warming to 25 ꢁC,
the mixture was stirred for 45 min, diluted with AcOEt
(10 mL) and H2O (5 mL) and extracted with AcOEt
(3 · 25 mL). The organic phase was dried (Na2SO4), fil-
tered and concentrated. Column chromatography
graphed on silica gel (CH2Cl2/acetone 20:1 fi 12:1) to
25
give 17 (260 mg, 50%) as an oil. ½aꢀ ¼ )30.2 (c 1.8,
D
CH2Cl2). IR (film) 3486 (OH), 2980, 2934, 1694 (C@O),
1
1410, 1215, 1165, 1055, 972 cmꢁ1. H NMR (300 MHz,
DMSO-d6 90 ꢁC, d ppm, J Hz) d 5.63 (dddd, 1H,
4
0
J2;3 ¼ 15:5, J2;1 ¼ J2;1 ¼ 4:7, J2;4 ¼ 1:2, H-2), 5.53
4
4
0
(dddd, 1H, J3;4 ¼ 5:4, J3;1 ¼ J3;1 ¼ 1:3, H-3), 4.70
0
0
(ddd, 1H, J6;5 ¼ 5:8, J6;7 ¼ 5:2, J6;7 ¼ 0:9, H-6), 4.49 (d,
(CH2Cl2/acetone 20:1) afforded 19 (67 mg, 74%, d.e.:
22
D
1H, H-5), 4.38 (m, 2H, H-4 and OH), 3.96–3.92 (m, 2H,
0
90%) as a solid. ½aꢀ ¼ )20 (c 1, CH2Cl2). IR (film) 3436
H-1, H-10), 3.64 (dd, 1H, J7;7 ¼ 12:8, H-7), 3.28 (dd,
(OH), 1667 (C@O), 1605, 1420, 1105 (C–O), 870,
770 cmꢁ1. 1H NMR (300 MHz, DMSO-d6 90 ꢁC, d ppm,
J Hz) d 7.98–7.92 (m, 2H, Ph), 7.06–6.98 (m, 2H, Ph),
2
1H, H-70), 1.40 (s, 9H, C(CH3)3), 1.35 and 1.25 (2s, 3H
each, C(CH3)2). 13C NMR (75.4 MHz, DMSO-d6 90 ꢁC,

330
A. T. Carmona et al. / Tetrahedron: Asymmetry 15 (2004) 323–333
2
0
4.94 (br d, 1H, J3;2 ¼ 5:8, H-3), 4.79 (br d, 1H,
JOH;5 ¼ 5:8, OH-5), 4.67 (m, 2H, H-2, OH-6), 4.23 (d,
2H, J7;6 ¼ 5:9, H-7), 4.01 (br d, 1H, J4;5 ¼ 3:7, H-4), 3.84
(s, 3H, CH3O), 3.80 (m, 1H, H-6), 3.64 (m, 1H, H-5),
3.94 (d, 1H, J4;5 ¼ 4:4, H-4), 3.60 (dd, 1H, J1;1 ¼ 12:5,
H-1), 3.53 (dd, 1H, J5;6 ¼ 3:5, H-5), 3.47–3.43 (m, 2H,
H-7, H-6), 3.39 (dd, 1H, J7 ;6 ¼ 3:5, J7 ;7 ¼ 11:3, H-70),
3.36 (dd, 1H, H-10), 1.39 (s, 9H, C(CH3)3), 1.31 and 1.23
(2s, 3H each, C(CH3)2). 13C NMR (75.4 MHz, DMSO-
d6 90 ꢁC, d ppm) d 153.6 (C@O of Boc), 109.6 (C(CH3)2),
80.6 (C-3), 78.7 (C-2), 78.2 (C(CH3)3), 71.6 (C-6), 70.5
(C-5), 65.6 (C-4), 62.5 (C-7), 52.2 (C-1), 27.6 (C(CH3)3),
26.4 and 24.5 (C(CH3)2). CIMS m=z 334 [20%,
(M+H)þÅ], 234 [100%, (M)Boc+H)þÅ]. CIMSHR m=z
found 334.1861 (calcd for C15H27NO7+H: 334.1866).
Anal. Calcd For C15H27NO7: C, 54.04; H, 8.16; N, 4.20.
Found: C, 53.62; H, 7.98; N, 4.19.
2
0
0
3.61 (dd, 1H, J1;2 ¼ 0:8, 2J1;1 ¼ 12:4, H-1), 3.41 (dd, 1H,
0
J1 ;2 ¼ 5:0, H-10), 1.38 (s, 9H, C(CH3)3), 1.33 and 1.25
0
(2s, 3H each, C(CH3)2). 13C NMR (75.4 MHz, DMSO-
d6 90 ꢁC, d ppm) d 164.9 (C@O), 162.8 (C-1 of Ph), 153.7
(C@O of Boc), 130.9 (Ph), 121.9 (C-4 of Ph), 113.4 (Ph),
109.7 (C(CH3)2), 80.5 (C-3), 78.7 (C-2), 78.6 (C(CH3)3),
69.0 (C-5, C-6), 65.2 (C-4, C-7), 55.1 (CH3O), 52.0 (C-1),
27.6 (C(CH3)3), 26.4 and 24.6 (C(CH3)2). FABMS m=z
490 [70%, (M+Na)þ], 368 [80%, (M)Boc+H)þ]. CIMS
m=z 468 [10%, (M+H)þÅ]. CIMSHR m=z found 468.2225
(calcd for C23H33NO9+H: 468.2233).
3.16. N-(tert-Butoxycarbonyl)-1,4-dideoxy-1,4-imino-2,3-
O-isopropylidene-
D
-glycero-L-talo-heptitol 22
3.14. N-(tert-Butoxycarbonyl)-1,4-dideoxy-1,4-imino-2,3-
-
O-isopropylidene-7-O-(p-methoxybenzoyl)-
talo-heptitol 20
D
-glycero-
L
Conventional deacylation of 20 (212 mg, 0.454 mmol)
with NaOMe/MeOH following the general procedure
afforded, after chromatography column (CH2Cl2/MeOH
28
D
To a 0 ꢁC solution of 18 (100 mg, 0.231 mmol) in
t-BuOH/H2O 1:1 (3 mL), AD-mixb (0.323 g) and
MeSO2NH2 (22 mg, 0.231 mmol) were added. The mix-
ture was vigorously stirred at 0 ꢁC for 3 d and quenched
by addition of Na2SO3 (0.35 g). After warming to 25 ꢁC,
the mixture was stirred for 45 min, diluted with AcOEt
(10 mL) and H2O (5 mL) and extracted with AcOEt
(3 · 25 mL). The organic phase was dried (Na2SO4), fil-
tered and concentrated. Column chromatography
25:1 fi 20:1), 22 (126.5 mg, 84%) as a solid. ½aꢀ ¼ )53.8
(C@O), 1593, 1219, 1167, 1057 cmꢁ1
(c 1.3, CH2Cl2). IR (film) 3407 (OH), 2978, 2930, 1674
.
1H NMR
(300 MHz, DMSO-d6+D2O 90 ꢁC, d ppm, J Hz) d 4.75
(d, 1H, J3;2 ¼ 5:9, H-3), 4.67 (td, 1H, J2;1 ¼ 5:7,
0
J2;1 ¼ 0:6, H-2), 4.02 (d, 1H, J4;5 ¼ 4:6, H-4), 3.66–3.62
(m, 2H, H-5, H-1), 3.49 (dd, 1H, J7;6 ¼ 5:4, 2J7;7 ¼ 10:8,
0
H-7), 3.43 (dd, 1H, J7 ;6 ¼ 6:0, H-70), 3.41–3.33 (m, 2H,
0
H-6 and H-10), 1.37 (s, 9H, C(CH3)3), 1.29 and 1.21 (2s,
3H each, C(CH3)2). 13C NMR (75.4 MHz, DMSO-d6
90 ꢁC, d ppm) d 153.2 (C@O), 109.7 (C(CH3)2), 82.0 (C-
3), 78.9 (C(CH3)3), 78.3 (C-2), 70.6 (C-6), 69.6 (C-5),
65.3 (C-4), 62.5 (C-7), 52.9 (C-1), 27.7 (C(CH3)3), 26.4
and 24.5 (C(CH3)2). CIMS m=z 334 [50%, (M+H)þÅ].
(CH2Cl2/acetone 20:1), afforded 20 (90.3 mg, 84%,
23
D
d.e. > 99%) as a solid. ½aꢀ ¼ )37 (c 0.5, CH2Cl2). IR
(film) 3464 (OH), 1697 (C@O), 1605, 1408, 1262, 1167,
1
1045, 853, 768, 694 cmꢁ1. H NMR (300 MHz, DMSO-
d6 90 ꢁC, d ppm, J Hz) d 7.96–7.91 (m, 2H, Ph), 7.04–
6.99 (m, 2H, Ph), 4.70–4.60 (m, 3H, H-2, OH-5, OH-6),
CIMSHR
m=z
found
334.1869
(calcd
for
4.34 (dd, 1H, 2J7;7 ¼ 11:1, J7;6 ¼ 6:0, H-7), 4.72 (dd, 1H,
C15H27NO7+H: 334.1866).
0
J7 ;6 ¼ 5:0, H-70), 4.11 (br d, 1H, J4;5 ¼ 4:8, H-4), 3.85 (s,
0
3H, CH3O), 3.82–3.71 (m, 2H, H-5, H-6), 3.68 (br d, 1H,
2
J1;1 ¼ 12:6, H-1), 3.44 (dd, 1H, J1 ;2 ¼ 5:0, H-10), 1.39
(s, 9H, C(CH3)3), 1.33 and 1.25 (2s, 3H each, C(CH3)2).
13C NMR (75.4 MHz, DMSO-d6 90 ꢁC, d ppm) d 164.9
(C@O), 162.8 (C-1 of Ph), 153.8 (C@O of Boc), 130.8
(Ph), 122.0 (C-4 of Ph), 113.5 (Ph), 110.0 (C(CH3)2),
81.9 (C-3), 78.9 (C-2), 78.4 (C(CH3)3), 69.6 (C-5), 68.0
(C-6), 65.3 (C-4, C-7), 55.1 (CH3O), 52.9 (C-1), 27.6
(C(CH3)3), 26.4 and 24.5 (C(CH3)2). FABMS m=z 490
[100%, (M+Na)þ], 368 [15%, (M)Boc+H)þ]. CIMSHR
m=z found 468.2226 (calcd for C23H33NO9+H:
468.2234).
3.17. 1,4-Dideoxy-1,4-imino-
L
-glycero-D-allo-heptitol 23
0
0
Conventional acidic deprotection of 21 (20 mg,
0.06 mmol) with 80% aqueous TFA gave 23 (10.2 mg,
25
D
88%) as a solid. ½aꢀ ¼ +17 (c 1, H2O). 1H NMR
(300 MHz, D2O, d ppm, J Hz) d 4.14–4.08 (m, 2H, H-2,
H-3), 3.77 (ddd, 1H, J6;7 ¼ 4:6, J6;H ¼ 3:2, J6;H ¼ 7:2, H-
2
0
6), 3.66 (dd, 1H, J7;7 ¼ 11:6, H-7), 3.64–3.57 (m, 2H,
H-5, H-70), 3.14 (t, 1H, J4;5 ¼ J4;3 ¼ 6:0, H-4), 3.11 (dd,
2
0
1H, J1;2 ¼ 5:2, J1;1 ¼ 12:1, H-1), 2.82 (dd, 1H,
J1 ;2 ¼ 3:7, H-10). 13C NMR (75.4 MHz, D2O, d ppm) d
0
75.3, 73.8 (C-2, C-3), 74.1 (C-6), 73.5 (C-5), 65.2 (C-4, C-
7), 52.1 (C-1). CIMS m=z 194 [100%, (M+H)þÅ]. CI-
MSHR m=z found 194.1027 (calcd for C7H15NO5+H:
194.1028).
3.15. N-(tert-Butoxycarbonyl)-1,4-dideoxy-1,4-imino-2,3-
O-isopropylidene-
L
-glycero-D-allo-heptitol 21
Conventional deacylation of 19 (43.6 mg, 0.093 mmol)
with NaOMe/MeOH following the general procedure
afforded, after chromatography column (CH2Cl22/5MeOH
3.18. 1,4-Dideoxy-1,4-imino-
D
-glycero-L-talo-heptitol 24
25:1 fi 20:1), 21 (28.4 mg, 91%) as a solid. ½aꢀ ¼ )17
Conventional acidic deprotection of 22 (24 mg,
0.093 mmol) with 80% aqueous TFA gave 24 (14 mg,
D
(c 0.77, CH2Cl2). IR (film) 3441 (OH), 2920, 1665
22
D
1
1
(C@O), 1111 (C–O), 1053 cmꢁ1. H NMR (300 MHz,
100%) as a solid. ½aꢀ ¼ +27 (c 1, MeOH). H NMR
DMSO-d6+D2O 90 ꢁC, d ppm, J Hz) d 4.84 (d, 1H,
(300 MHz, MeOD, d ppm, J Hz) d 4.07 (td, 1H,
0
0
J3;2 ¼ 5:9, H-3), 4.64 (td, 1H, J2;1 ¼ 5:9, J2;1 ¼ 0:9, H-2),
J2;1 ¼ 3:0, J2;1 ¼ J2;3 ¼ 4:8, H-2), 3.96 (dd, 1H,

A. T. Carmona et al. / Tetrahedron: Asymmetry 15 (2004) 323–333
331
J3;4 ¼ 7:6, H-3), 3.77 (t, 1H, J5;4 ¼ J5;6 ¼ 3:0, H-5), 3.69–
added. After 1.5 h at )20 ꢁC, water was added (0.5 mL)
and the mixture was allowed to warm to 25 ꢁC. Solvent
was removed and the residue was diluted with AcOEt,
washed successively with 1 M HCl, satd aq soln of
NaHCO3 and brine, dried and concentrated. Purifica-
tion by column chromatography (CH2Cl2/MeOH
80:1 fi 20:1) afforded tosylate Ts-7 (78 mg, 58%) and
17 mg (18%) of recovered 21. Tosylate Ts-7 (59.3 mg,
0.122 mmol) was then treated with TFA 80% at 25 ꢁC
for 2 h and then evaporated. The residue was dissolved
in water and treated with NH4OH until basic pH. Sol-
vent evaporation and purification by column chroma-
3.59 (m, 3H, H-6, H-7, H-70), 3.17 (dd, 1H, H-4), 3.18
2
(dd, 1H, J1;1 ¼ 12:1, H-1), 2.90 (dd, 1H, H-10). 13C
0
NMR (75.4 MHz, MeOD, d ppm) d 75.0 (C-3), 74.8 (C-
6), 72.1 (C-2), 70.3 (C-5), 65.0 (C-4), 64.0 (C-7), 52.4 (C-
1). CIMS m=z 194 [100%, (M+H)þÅ]. CIMSHR m=z
found 194.1034 (calcd for C7H15NO5+H: 194.1028).
3.19. (1R,2S,6R,7S,7aS)-1,2,6,7-Tetrahydroxypyrrol-
izidin-5-one 5
A suspension of 15 (60 mg, 0.147 mmol) in 80% aqueous
TFA (1.5 mL) is stirred at 25 ꢁC for 2 h. Evaporation of
the solvent gave a residue that after column chroma-
tography (CH2Cl2/MeOH 25:1) afforded a crude prod-
uct that was hydrogenated for 4 h (abs EtOH, 3 mL;
Pd/C, 10%, 18 mg). The reaction mixture was filtered
and the filtrate heated under reflux for 24 h. Evaporation
of the solvent and column chromatography (CH2Cl2/
tography (CH2Cl2/MeOH/NH4OH 10% 4:2:0.5)
22
afforded 7 (21 mg, 100%). ½aꢀ ¼ +24 (c 0.72, MeOH).
D
1H NMR (300 MHz, MeOD, d ppm, J Hz) d 4.26 (dd,
1H, J7;7a ¼ 6:9, J7;6 ¼ 4:1, H-7), 4.20 (ddd, 1H, H-6),
4.13 (ddd, 1H, H-2), 4.07 (t, 1H, J1;2 ¼ J1;7a ¼ 2:8, H-1),
3.41 (dd, 1H, H-7a), 3.34 (dd, 1H, J3;2 ¼ 4:3,
2
0
J3;3 ¼ 11:8, H-3), 3.30 (dd, 1H, J5;6 ¼ 2:6, H-5), 3.09
(dd, 1H, J5 ;5 ¼ 11:4, J5 ;6 ¼ 3:9, H-50), 2.83 (dd, 1H,
2
0
0
J3 ;2 ¼ 3:1, H-30). 13C NMR (75.4 MHz, MeOD, d ppm)
0
MeOH/NH4OH 10% 4:2:0.5) led to 5 (9 mg, 52%).
22
D
½aꢀ ¼ +25 (c 0.24, MeOH). IR (film) 3333 (OH), 1688
d 80.0 (C-1), 79.3 (C-2), 76.7 (C-7a), 76.4 (C-7), 73.4 (C-
6), 61.5 (C-5), 60.2 (C-3). CIMS m=z 176 [100%,
(M+H)þÅ]. CIMSHR m=z found 176.0921 (calcd for
C7H13NO4+H: 176.0923).
(C@O), 1441, 1379, 1115 (C–O) cmꢁ1
.
1H NMR
(300 MHz, MeOD, d ppm, J Hz) d 4.33 (br d, 1H,
0
J6;7 ¼ 8:6, H-6), 4.15 (td, 1H, J2;3 ¼ J2;1 ¼ 4:9, J2;3 ¼ 2:7,
H-2), 3.90 (dd, 1H, J7;7a ¼ 7:0, H-7), 3.85 (dd, 1H,
2
0
J1;7a ¼ 6:9, H-1), 3.75 (dd, 1H, J3;2 ¼ 5:2, J3;3 ¼ 12:5,
H-3), 3.53 (t, 1H, H-7a), 3.03 (dd, 1H, H-30). 13C NMR
(75.4 MHz, MeOD, d ppm) d 175.2 (C@O), 82.3 (C-7),
80.2 (C-6), 77.6 (C-1), 73.5 (C-2), 67.4 (C-7a), 50.0 (C-3).
CIMS m=z 190 [100%, (M+H)þÅ]. CIMSHR m=z found
190.0717 (calcd for C7H12NO5+H: 190.0715).
3.22. (1R,2S,6R,7R,7aS)-1,2,6,7-Tetrahydroxypyrrolizi-
dine 8
To a solution of 22 (75 mg, 0.225 mmol) in dry pyridine
(2 mL) stirred at )20 ꢁC, TsCl (85.8 mg, 0.45 mmol) was
added. After 1.5 h at )20 ꢁC, water was added (0.5 mL)
and the mixture was allowed to warm to 25 ꢁC. Solvent
was removed and the residue was diluted with AcOEt,
washed successively with 1 M HCl, satd aq soln of
NaHCO3 and brine, dried and concentrated. Purification
by column chromatography (CH2Cl2/MeOH 80:1 fi
20:1) afforded the corresponding tosylate Ts-8 (51 mg,
47%) and 21 mg (28%) of recovered 22. Tosylate Ts-8
(35.6 mg, 0.073 mmol) was then treated with 80%
aqueous TFA at 25 ꢁC for 2 h and then evaporated. The
residue was dissolved in water and treated with NH4OH
until basic pH. Solvent evaporation and purification by
3.20. (1R,2S,6S,7R,7aS)-1,2,6,7-Tetrahydroxypyrrol-
izidin-5-one 6
A suspension of 16 (60.8 mg, 0.149 mmol) in 80%
aqueous TFA (1.5 mL) is stirred at 25 ꢁC for 2 h.
Evaporation of the solvent gave a residue that after
column chromatography (CH2Cl2/MeOH 30:1) afforded
a crude product that was hydrogenated for 4 h (abs
EtOH, 3 mL; Pd/C, 10%, 18 mg). The reaction mixture
was filtered and the filtrate heated under reflux for 24 h.
Evaporation of the solvent led to 6 (15 mg, 68%).
column chromatography (CH2Cl2/MeOH/NH4OH 10%
23
D
23
D
½aꢀ ¼ )5.4 (c 0.75, MeOH). IR (film) 3360 (OH), 1676
4:2:0.5) afforded 8 (12.8 mg, 100%). ½aꢀ ¼ +31 (c 0.9,
1
1
(C@O), 1451, 1090 (C–O) cmꢁ1. H NMR (500 MHz,
MeOH). H NMR (300 MHz, MeOD, d ppm, J Hz) d
MeOD, d ppm, J Hz) d 4.25 (td, 1H, J2;1 ¼ J2;3 ¼ 4:8,
4.46 (t, 1H, J1;2 ¼ J1;7a ¼ 4:4, H-1), 4.38 (q, 1H,
0
0
J2;3 ¼ 2:7, H-2), 4.21 (dd, 1H, J1;7a ¼ 7:0, H-1), 4.17
J2;3 ¼ J2;3 ¼ 4:5, H-2), 4.25 (br t, 1H, H-6), 4.16 (dd, 1H,
(dd, 1H, J7a;7 ¼ 3:8, H-7a), 4.14 (d, 1H, H-7), 3.92 (s,
J7;7a ¼ 4:4, J7;6 ¼ 1:5, H-7), 3.99 (t, 1H, H-7a), 3.38 (dd,
2
2
0
0
1H, H-6), 3.66 (dd, 1H, J3;2 ¼ 5:1, J3;3 ¼ 12:7, H-3),
1H, J3;3 ¼ 11:5, H-3), 3.35 (dd, 1H, J5;6 ¼ 1:4, H-5),
3.08 (dd, 1H, J3 ;2 ¼ 2:6, H-30). 13C NMR (75.4 MHz,
3.08 (dd, 1H, J5 ;6 ¼ 3:1, 2J5 ;5 ¼ 11:6, H-50), 3.00 (dd, 1H,
H-30). 13C NMR (75.4 MHz, MeOD, d ppm) d 79.2 (C-6),
75.1 (C-7a), 74.6, 74.5 (C-2, C-7), 70.6 (C-1), 60.7 (C-5),
59.3 (C-3). CIMS m=z 176 [100%, (M+H)þÅ]. CIMSHR
m=z found 176.0920 (calcd for C7H13NO4+H: 176.0923).
0
0
0
MeOD, d ppm) d 175.8 (C@O), 82.9 (C-6), 74.5 (C-2),
73.0 (C-7), 69.9 (C-1), 69.0 (C-7a), 49.2 (C-3). CIMS m=z
190 [100%, (M+H)þÅ]. CIMSHR m=z found 190.0716
(calcd for C7H12NO5+H: 190.0715).
3.21. (1R,2S,6S,7S,7aS)-1,2,6,7-Tetrahydroxypyrrol-
izidine 7
Acknowledgements
ꢀ
ꢀ
We thank the Direccion General de Investigacion
ꢀ
ꢀ
To a )20 ꢁC solution of 21 (91.5 mg, 0.275 mmol) in dry
pyridine (2.5 mL), TsCl (104.8 mg, 0.55 mmol) was
Cientıfica y Tecnica of Spain for financial support (grant
nos BQU 2001-3740 and BQU 2001-3779) and for the

332
A. T. Carmona et al. / Tetrahedron: Asymmetry 15 (2004) 323–333
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Swiss National Science Foundation and the ÔOffice
ꢀ
Federal de lÕEducation et de la ScienceÕ (Bern). This
work is part of the European COST Program, working
groups COST-D13-0001/98 and D25-0001/02.
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