Synthesis of unnatural pentahydroxylated pyrrolizidines: 5-epi- and 5,7a-di-epi-hyacinthacine C1

Article abstract of DOI:10.1016/j.tet.2010.07.019

Stereocontrolled synthesis of 5-epi- and 5,7a-di-epi-hyacinthacine C ₁ (7 and 8), two potential glycosidase inhibitors are described using α,β-unsaturated ketone 9 as homochiral starting material. The key step in the synthesis is the highly diastereoselective dihydroxylation reaction of 9, that allows the obtention of a single bis-hydroxylated ketone (10). Further derivatization into two epimeric mesylate esters followed by internal cyclization form the pyrrolizidinic compounds 7 and 8. This type of compounds can be useful in glycobiology due to their ability to inhibit carbohydrate-processing enzymes.

Full text of DOI:10.1016/j.tet.2010.07.019

Tetrahedron 66 (2010) 7262e7267
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of unnatural pentahydroxylated pyrrolizidines: 5-epi- and
5,7a-di-epi-hyacinthacine C1
*
*
Juan A. Tamayo , Francisco Franco , Fernando Sánchez-Cantalejo
Department of Medicinal and Organic Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 June 2010
Received in revised form 9 July 2010
Accepted 9 July 2010
Available online 16 July 2010
Stereocontrolled synthesis of 5-epi- and 5,7a-di-epi-hyacinthacine C1 (7 and 8), two potential glycosidase
inhibitors are described using a,b-unsaturated ketone 9 as homochiral starting material. The key step in
the synthesis is the highly diastereoselective dihydroxylation reaction of 9, that allows the obtention of
a single bis-hydroxylated ketone (10). Further derivatization into two epimeric mesylate esters followed
by internal cyclization form the pyrrolizidinic compounds 7 and 8. This type of compounds can be useful
in glycobiology due to their ability to inhibit carbohydrate-processing enzymes.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Azasugars
Hyacinthacines
Enantioselectivity
Synthetic methods
Enzyme inhibitors
1. Introduction
Glycosidases are enzymes involved in different and important bi-
ological processes ,such as intestinal digestion, lysosomal catabolism
and post-translational modification.1 These processes are closely re-
lated to the endoplasmic reticulum (ER) quality control and ER-asso-
ciated degradation of glycoproteins and in this respect, variation of the
glycosidase activity by inhibitors such as azasugars has enormous ap-
plications in glycobiology and drug therapy.2 Examples of these types
of compounds are isofagomine and some of its derivatives,3
nonyl-1,5-dideoxy-1,5-iminoxylitol,4 and
-1-C-octyl-1-deoxynojir-
a-1-C-
a
imycin,5 which are promising candidates in pharmacological chaper-
one therapy for the treatment of Gaucher disease and Pompe disease.
Naturally occurring iminosugars are classified into five structural
classes: polyhydroxylated pyrrolidines, piperidines, indolizidines,
pyrrolizidines and nortropanes. Among them, Hyacinthacine C1 (1)
andC5 (2)togetherwithCasuarine(3)andits3-epi-and6-epi-isomers
(4 and 5, respectively) are the most polyhydroxylated pyrrolizidine
alkaloids (PHPAs) bearing hydroxymethyl and methyl groups adja-
cent to the ring nitrogen (C-3 and C-5, Fig. 1). They are relatively un-
common in nature, where only the five compounds described below
(1e5) have been identified so far from natural sources. The first de-
scribed, PHPA 1, wasisolated by Asano et al.6 fromtheimmature fruits
and stalks of Hyacinthoides non-script and later,7 from the bulbs of
Muscari Armeniacum (Hyacinthaceae). On the other hand, PHPA 2, has
* Corresponding authors. Tel.: þ34 958 243846; fax: þ34 958 243845; e-mail
Figure 1. Some natural (1e5) and unnatural (7,8) pentahydroxylated pyrrolizidine
alkaloids and DALDP-derivative 6.
addresses: jtamayo@ugr.es (J.A. Tamayo), ffranco@ugr.es (F. Franco).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.07.019

J.A. Tamayo et al. / Tetrahedron 66 (2010) 7262e7267
7263
been recently isolated, by Kato et al.,8 from the bulbs of Scilla socialis
(Hyacinthaceae). Compounds 1 and 2 have shown a potent inhibition
activityversusAspergillusnigeramyloglucosidasewithaIC50 of84and
chemical nature of 9, we envisaged its potential use as starting ma-
terialfor thepreparationofpentahydroxylatedpyrrolizidines through
stereoselective bis-hydroxylation of its conjugated double bond. In
thisarticle, wedescribeourstudiestowardsthesynthesisofunnatural
7a-epi-hyacinthacine C1 (7) and 5,7a-di-epi-hyacinthacine C1 (8).
57
hibitory activity against intestinal rat maltase (IC50¼77
docellum saccharolyticum
-glucosidase (IC50¼48
mM, respectively. Moreover PHPA 2 has also showed a strong in-
m
M) and Cal-
b
mM). These
activities make both compounds potential candidates for the de-
velopmentof new drugs againstviralinfections, cancerand diabetes.9
From a chemical point of view, absolute configurations of 1 and
2 have not been disclosed so far, this fact, together with some
discrepancies on the actual structure of 1,10 make highly desirable
the total stereoselective syntheses of 1 and 2. Moreover, Pyne et al.
have recently reassigned the structure of uniflorine B as the known
pyrrolizidine alkaloid (þ)-casuarine (3), while the structure of
(ꢀ)-uniflorine A was suggested to be that of (þ)-6-epi-casuarine
(5).11 At the same time, stereocontrolled syntheses of new and re-
lated PHPAs are also needed to study their potential as glycosidase
inhibitors and their possible application as therapeutical agents.
Most of the synthetic routes to these iminosugars start with
a carbohydrate analogue resembling, if possible, the majority of its
stereocenters. However, non-carbohydrate approaches, such as ring
closing metathesis,11a,12 cyclization of acetylenic sulfones with
chloroamines,13 tandem inter [4þ2]/inter [3þ2] cycloaddition
process,14 cuprate chemistry15 and diastereoselective syn-dihydrox-
ylation11a,16 are becoming more popular. Supporters of non-carbo-
hydrate synthetic strategy claim that these routes are superior
because they exhibit increased stereoselectivity and are more effi-
cient at introducing the amine moiety. On the other hand, some car-
bohydrate-derivatives like polyhydroxylated pyrrolidines and
piperidines combine two desirable qualities: the presence of the
amino group and of several stereogenic centres. For these reasons,
these compounds can be considered as valuable starting material for
the synthesis of more elaborated iminosugars.
2. Results and discussion
Theretrosyntheticanalysis forthesynthesisofpyrrolizidines 7and
8, (Scheme 1)focuses onthepreparationof -dihydroxylatedketone
a,b
10 as the key intermediate. Hence, with a,b
-unsaturated ketone 917j as
starting material, stereocontrolled dihydroxylation will allow to ob-
tain the desired bis-hydroxy intermediate 10. Selective ketone re-
duction in 10, followed by cyclization to the pyrrolizidine skeleton
through the corresponding mesylate derivatives 11 and 12, and final
protecting groups removal, will render the proposed unnatural
7a-epi-hyacinthacine C1 (7) and 5,7a-di-epi-hyacinthacine C1 (8).
As described in the retrosynthetic analysis, a,b-unsaturated ke-
tone 9 was used as starting material. Catalytic dihydroxylation (DH)
of 9 with OsO4 yielded (10R,20S)-10 as a single product (Scheme 2).
The absolute configuration of the new stereogenic centres in 10 was
determined later in the synthesis. It is worth mention here the high
diastereoselectivity achieved is this reaction since, with a analogous
compound presenting a Cbz-protecting group at the amino moiety
and a benzyl group at C-50, the DH reaction in similar conditions,
leads to the obtention of a compound with (10S,20R)-configurations.19
According to the retrosynthetic plan, and in order to obtain the
mesylate intermediates 11 and 12, chemical protection of the newly
generated hydroxyl groups in derivative 10 was attempted. Several
protecting groups (BnBr, TESCl, TMSCl, TBDMSCl) were tried,
resulting in low yields or inseparable mixture of compounds. Only
acetylation with Ac2O/Py proved successful, affording di-O-acety-
lated 13 with high yield. Reduction of 13 with NaBH4 yielded a
resolvable mixture of alcohols 14 and 15 (1:1 dr). As before, the
absolute configuration of the new quiral centres in 14 and 15 was not
determined at this point but later in the synthesis.
As Figure 1 shows, PHPA 1 bears hydroxymethyl and methyl sub-
stituents at C-3 and C-5, respectively. Moreover, the stereochemistry
and functionalization at the indicated ring (dashed line) totally match
that existing in the protected DALDP-derivative 6. In this respect, our
group has been engaged in the total syntheses of different PHPAs17 by
using appropriately functionalized tetrahydroxypyrrolidines as key
intermediates18 and recently, we have described17j the use of 6 in the
synthesis of (þ)-hyacinthacine A6, (þ)-5,7a-di-epi-hyacinthacine A6
and (þ)-7a-epi-hyacinthacine A1 by means of the appropriately
functionalized a,b-unsaturated ketone 9 (see Scheme 1). Given the
Scheme 2. Reagents and conditions: (a) OsO4, NMO, Me2CO, rt; (b) Ac2O, Py, rt; (c)
NaBH4, MeOH, 0 ꢁC.
In order to build the pyrrolizidinic skeleton, alcohols 14 and 15
were separately reacted with MsCl and converted into the corre-
sponding mesylate derivatives 11 and 12, respectively. Acid-cata-
lyzed N-Boc deprotection reaction on 11 and 12 yielded
pyrrolidines 16 and 17 as shown in Scheme 3. Both amines were
refluxed with NEt3 in MeOH to obtain the pyrrolizidine skeleton
through internal nucleophilic substitution, and in situ reacted with
2 M MeONa to remove the acetyl and benzyl protecting groups and
to afford pyrrolizidines 18 and 19, respectively. The absolute
Scheme 1. Retrosynthetic analysis for the synthesis of 7a-epi-hyacinthacine C1 (7) and
5,7a-di-epi-hyacinthacine C1 (8) from -unsaturated ketone 9.
a,b

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J.A. Tamayo et al. / Tetrahedron 66 (2010) 7262e7267
Bruker AMX-300, AM-300 and ARX-400 spectrometers for solu-
tions in CDCl3 (internal Me4Si). Splitting patterns are designated as
follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet and
br, broad. IR spectra were recorded with a PerkineElmer FT-IR
Spectrum One instrument and mass spectra were recorded with
a HewlettePackard HP-5988-A and Fisons mod. Platform II and VG
Autospec-Q mass spectrometers or a NALDI ionization-time of
flight (NALDI-TOF) mass spectrometer and EI mass spectrometer.
Optical rotations were measured for solutions in CHCl3 (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). All compounds were shown to be homogeneous by chro-
matographic methods and characterized by NMR, MS and HRMS.
4.2. Synthesis and characterization
Scheme 3. Reagents and conditions: (a) MsCl, TEA, CH2Cl2, rt; (b) TFA, CH2Cl2, rt.; (c)
NEt3, THF reflux, then NaOMe, rt.
4.2.1. (2S,3S,4R,5R)-2-[(10R,20S)-10,20-Dihydroxy-30-oxobutyl]-5-
(benzoyloxymethyl)-3,4-dibenzyloxy-N-tert-butyloxy-
configuration for 18 and 19 were established on the basis of their
spectroscopic data, and their proposed structures were confirmed
by extensive NOE experiments.
Removal of the remaining O-benzyl protecting groups on in-
termediates 18 and 19 completed the synthesis and yielded the
desired (þ)-7a-epi-hyacinthacine C1 (7) and (ꢀ)-5,7a-di-epi-hya-
cinthacine C1 (8) (Scheme 4). Their analytical and spectroscopic
data were in accordance with those proposed and were confirmed
by NOE experiments.
carbonylpyrrolidine (10). To
a stirred solution of 9 (663 mg,
1.13 mmol) in acetone/water 8:1 v/v (13.5 mL) were added NMO
(266 mg, 2.27 mmol) and aqueous 1% OsO4 (1.5 mL). The mixture
was left at room temperature 7 h. TLC (Et2O/hexane, 4:1) then
revealed the presence of a new product of lower mobility. The
mixture was concentrated to a residue that was submitted to
chromatography (Et2O/hexane, 2:3/3:1) to afford syrupy 10.
25
Yield: 498 mg (71%); [
a]
þ50 (c 1, CHCl3); IR (KBr, neat) 3378
D
(OH), 1720 and 1666 cmꢀ1 (C]O); 1H NMR (400 MHz):
d
¼7.93e7.23 (m, 15H, 3Ph), 5.30 (br s, 1H, OH), 4.87 and 4.76 (2d,
2H, J¼12.2 Hz, CH2Ph), 4.61 and 4.56 (2d, 2H, J¼12.1 Hz, CH2Ph),
4.40e4.30 (m, 3H), 4.23e4.19 (m, 2H), 4.15e4.10 (m, 2H), 3.67 (m,
1H), 3.25 (br s, 1H, OH), 2.13, (s, 3H, MeCO) and 1.52 (s, 9H, CMe3);
13C NMR (100 MHz):
d
¼209.97 (C-30), 166.52 (C]O, Bz), 157.31 (C]
O, Boc), 137.85, 137.39, 133.53, 129.92, 128.68, 128.16 (Ph), 82.82
(CMe3), 76.77 and 76.24 (C-3,4), 75.21 and 72.01, (C-10,20), 64.79 and
60.62 (C-2,5), 72.11 and 71.36 (2CH2Ph), 62.00 (CH2OBz), 28.53
(CMe3) and 27.49 (C-40); HRMS (NALDI-TOF) calcd for C35H41NNaO9
[MþNa]þ 642.2679, found 642.2684 (deviation 0.8 ppm).
4.2.2. (2S,3S,4R,5R)-2-[(10R,20S)-10,20-Diacetyloxy-30-oxobutyl]-5-
(benzoyloxymethyl)-3,4-dibenzyloxy-N-tert-butyloxy-
carbonylpyrrolidine (13). Compound 10 (450 mg, 0.727 mmol) was
acetylated in dry pyridine (7.0 mL), acetic anhydride (0.275 mL,
2.91 mmol) and DMAP (cat.) at room temperature for 3 h. TLC
(Et2O/hexane, 4:1) then showed a faster-running compound. MeOH
(2 mL) was added, stirred for 10 min and the reaction mixture was
supported on silica gel and chromatographed (Et2O/hexane,
1:2/4:1) to afford pure 13 as a colourless syrup (440 mg, 86%);
Scheme 4. Reagents and conditions: (a) H2, 10% Pd/C, HCl, MeOH, rt, then Amberlite
IRA-400 (OHꢀ form).
3. Conclusions
We describe herein the synthesis of two new pentahydroxylated
pyrrolizydines: (þ)-7a-epi-hyacinthacine C1 (7) and (ꢀ)-5,7a-di-epi-
hyacinthacine C1 (8). The feasibility of the methodology employed
relies on a highly diastereoselective DH reaction that allows the
obtention of a single bis-hydroxylated ketone. In general, this is an
effective methodology for the preparation of analogues of hyacin-
thacines C. This type of compounds can be useful in glycobiology due
totheirability to inhibit carbohydrate-processingenzymes and hence
their potential as glycosidase inhibitors and therapeutical agents.
[a
]
25 þ46 (c 1, CHCl3); IR (KBr, neat) 1749, 1722 and 1666 cmꢀ1 (C]
D
O); 1H NMR (400 MHz):
d
¼8.01e7.22 (m, 15H, 3Ph), 5.27 and 5.06
(H-10,20), 4.73 (m, 2H), 4.53e4.50 (m, 3H), 4.36 (m, 3H), 4.15 and
3.76 (2 m, 2H), 2.23, 1.99 and 1.82 (3s, 9H, 3MeCO) and 1.48 (s, 9H,
CMe3); 13C NMR (100 MHz):
d
¼202.64 (C-30), 173.17 and 172.52
(2C]O, Ac), 166.52 (C]O, Bz), 156.01 (C]O, Boc), 137.85, 137.39,
133.53, 129.92, 128.68, 128.16 (Ph), 82.82 (CMe3), 76.77, 76.24, 75.21
and 72.01 (C-3,4,10,20), 64.79 and 60.62 (C-2,5), 72.11 and 71.36
(2CH2Ph), 62.00 (CH2OBz), 28.53 (CMe3), 27.49 (C-40), 20.68 and
20.49 (2CH3CO2); HRMS (NALDI-TOF) calcd for C39H45NNaO11
[MþNa]þ 726.2890, found 726.2885 (deviation ꢀ0.7 ppm).
4. Experimental section
4.1. General remarks
4.2.3. (2R,3S,4R,5R)-2-[(10R,20R,30S)-10,20-Diacetyloxy-30-hydroxy-
butyl]-5-(benzoyloxymethyl)-3,4-dibenzyloxy-N-tert-butyloxy-
carbonylpyrrolidine (14) and (2R,3S,4R,5R)-2-[(10R,20R,30R)-10,20-
diacetyloxy-30-hydroxybutyl]-5-(benzoyloxymethyl)-3,4-dibenzyloxy-
Solutions were dried over MgSO4 before concentration under
reduced pressure. The 1H and 13C NMR spectra were recorded with

J.A. Tamayo et al. / Tetrahedron 66 (2010) 7262e7267
7265
N-tert-butyloxycarbonylpyrrolidine (15). To an ice-water cooled so-
lution of 13 (895 mg, 1.27 mmol) in anhydrous MeOH (6 mL), NaBH4
(57.7 mg, 1.53 mmol) was added portionwise and the mixture was
stirred for 1.5 h. TLC (ether/hexane, 7:1) then showed the presence of
two more polar products. The reaction mixture was neutralized with
AcOH, and the mixture was supported on silica gel and chromato-
graphed (Et2O/hexane, 1;1) to afford first 14 (220 mg, 25%) as a thick
to a new residue that was supported on silica gel and chromato-
graphed (ether/hexane, 2:1) to afford 16 (130 mg, 83%). [
a
]
29 þ39 (c
D
1, CHCl3); IR (KBr, neat) 3381 (NH), 1743 and 1721 cmꢀ1 (C]O); 1H
NMR (500 MHz):
d
¼7.98e7.23 (m, 15H, 3Ph), 5.04e4.98 (m, 2H, H-
20,30), 4.88 (br d, 1H, J2,1 ¼8.4 Hz, H-1 ), 4.53 (s, 2H, CH2Ph), 4.47 and
0
0
0
0
4.45 (2d, 2H, J¼11.6 Hz, CH2Ph), 4.37 (dd, 1H, J5 a,5 b¼11.4,
J5,5 a¼5.2 Hz, H-50a), 4.17 (dd, 1H, J5,5 b¼5.1 Hz, H-50b), 3.92 (t, 1H,
0
0
syrup; [
a
]
25 þ54 (c 1, CHCl3); IR (KBr, neat) 3407 (OH),1738,1722 and
J3,4¼J2,3¼4.8 Hz, H-3), 3.82 (m, 2H, H-4,5), 3.63 (dd, 1H, H-2), 3.07 (s,
1673 cmꢀD1 (C]O); 1H NMR (400 MHz):
d¼7.88e7.17 (m, 15H, 3Ph),
3H, OMs), 2.04 and 1.92 (2s, 6H, 2MeCO) and 1.06 (d, 3H, J3 ,4 ¼6.0 Hz,
0
0
4.98e4.92 (m, 2H), 4.70 and 4.47 (2d, 2H, J¼12.5 Hz, CH2Ph),
4.61e4.55 (m, 2H), 4.56 and 4.34 (2d, 2H, J¼11.3 Hz, CH2Ph),
4.41e4.37 (m,1H), 4.12e4.07(m, 2H), 3.66 (brd,1H), 3.36(m,1H),1.98
(s, 6H, 2MeCO),1.51 (s, 9H, CMe3), 0.60 (d, 3H, J¼6.5 Hz, H-40,40,40); 13C
H-40,40,40); 13C NMR (125 MHz):
d¼170.48 and 169.98 (2C]O, Ac),
166.30 (C]O, Bz), 137.67, 137.55, 132.96, 130.00, 129.60, 128.35,
128.12,128.00,127.83 (Ph), 81.11, 78.49 and 78.08 (C-30,3,4), 72.77 (C-
20), 68.82 (C-10), 71.90 and 71.53 (2CH2Ph), 66.06 (CH2OBz), 58.66
and 58.54 (C-2,5), 38.71 (OMs), 21.17 and 20.81 (2CH3CO2) and 16.93
NMR (100 MHz):
d¼170.77 and 170.30 (2C]O, Ac), 166.10 (C]O, Bz),
157.64 (C]O, Boc), 137.33, 137.14, 133.34, 129.66, 128.41, 128.37,
128.14,128.05 (Ph), 82.53 (CMe3), 76.58, 73.48, 71.77, 71.02, 70.48 (C-
10,20,30,3,4), 72.31 and 70.76 (2CH2Ph), 61.48 and 60.40 (C-2,5), 61.62
(CH2OBz), 28.17 (CMe3), 21.25 and 20.84 (2CH3CO2) and 16.40 (C-40);
HRMS (NALDI-TOF) calcd for C39H47NNaO11 [MþNa]þ 728.3047,
found 728.3043 (deviation ꢀ0.5 ppm).
(C-40); HRMS (NALDI-TOF) calcd for C35H41NNaO11
706.2298, found 706.2304 (deviation 0.8 ppm).
S
[MþNa]þ
4.2.6. (1S,2R,3R,5R,6R,7R,7aS)-1,2-Dibenzyloxy-6,7-dihydroxy-3-hy-
droxymethyl-5-methylpyrrolizidine (18). To a solution of 16 (120 mg,
0.17 mmol) in anhydrous THF (6 mL) was added NEt3 (0.1 mL) and
the reaction mixture was refluxed for 7 h, and then treated with 2 M
NaOMe in methanol (1 mL) for 1 h. TLC (ether/MeOH,10:1) revealed
a new compound. The reaction mixture was supported on silica gel
Eluted second was 15 (198 mg, 22%) as a syrup.
26
[a]
ꢀ12 (c 1, CHCl3); IR (KBr, neat) 3474 (OH), 1750, 1724 and
D
1701 cmꢀ1 (C]O); 1H NMR (400 MHz):
5.67 (brd,1H), 5.38(m,1H), 5.18 (brd,1H), 4.93(m,1H), 4.69e3.84(m,
9H),1.99,1.97,1.91 and 1.89 (4s, 6H, 2MeCO, 2 rotamers),1.44 and 1.34
(2s, 9H, CMe3, 2 rotamers), 1.08 (m, 3H, H-40,40,40; 2 rotamers); 13C
d
¼7.93e7.19 (m, 15H, 3Ph),
and chromatographed (ether/MeOH, 8:1) to afford syrupy 18
(42 mg, 60%), [
NMR (500 MHz):
a
]
þ25 (c 1, CHCl3); IR (KBr, neat) 3378 (OH); 1H
26
D
d
¼7.36e7.26 (m, 10H, 2Ph), 4.63 and 4.49 (2d, 2H,
NMR (100 MHz):
d¼170.77 and 169.53 (2C]O, Ac),166.23 (C]O, Bz),
J¼11.70 Hz, CH2Ph), 4.58 and 4.52 (2d, 2H, J¼11.8 Hz, CH2Ph), 3.98 (t,
J1,2¼J1,7a¼4.2 Hz, H-1), 3.92 (dd, 1H, J2,3¼7.0 Hz, H-2), 3.81 (dd, 1H,
J8a,8b¼12.0, J3,8a¼4.2 Hz, H-8a), 3.74 (dd,1H, J3,8b¼6.2 Hz, H-8b), 3.56
(t,1H, J6,7¼J7,7a¼8.2 Hz, H-7), 3.47 (t,1H, J5,6¼8.2 Hz, H-6), 3.42e3.36
155.48 and 154.72 (C]O, Boc, 2 rotamers), 136.93, 133.28, 129.80,
129.72, 128.47, 128.34, 128.14, 128.05 (Ph), 81.77 (CMe3), 78.17, 75.05,
73.91, 70.03, 66.03 (C-10,20,30,3,4), 72.41, 71.86, 71.79 and 71.02
(2CH2Ph, 2 rotamers), 63.12, 62.97 (CH2OBz, 2 rotamers), 62.98 and
60.03 (C-2,5), 28.25 and 28.16 (CMe3, 2 rotamers), 20.73 (2CH3CO2)
and 16.83 (C-40); HRMS (NALDI-TOF) calcd for C39H47NNaO11
[MþNa]þ 728.3047, found 728.3054 (deviation 1.0 ppm).
(m, 2H, H-3,7a), 3.06 (m, 1H, H-5), 1.21 (d, 3H, J5,Me¼6.1 Hz, Me); 13
C
NMR (125 MHz):
d¼139.57, 129.30, 129.16, 128.66 (Ph), 83.79 (C-6),
81.10 (C-1), 80.01 (C-2,7), 73.00 and 72.27 (2CH2Ph), 71.69 (C-7a),
65.23 (C-3), 59.58 (C-8), 58.53 (C-5) and 19.33 (Me); HRMS (NALDI-
TOF) calcd for C23H29NNaO5 [MþNa]þ 422.1943, found 422.1949
(deviation 1.4 ppm).
4.2.4. (2R,3S,4R,5R)-2-[(10R,20S,30S)-10,20-Diacetyloxy-30-(meth-
anesulfonyloxy)butyl]-5-(benzoyloxymethyl)-3,4-dibenzyloxy-N-tert-
butyloxycarbonylpyrrolidine (11). To an ice-water cooled and stirred
solution of 14 (0.204 g, 0.29 mmol) in dry Cl2CH2 (7 mL) were
4.2.7. (1S,2R,3R,5R,6R,7R,7aS)-1,2,6,7-Tetrahydroxy-3-hydroxymethyl-
5-methylpyrrolizidine(7). Compound18 (40 mg, 0.10 mmol)inMeOH
(10 mL)andconc. HCl(fivedrops)washydrogenated(70 psiH2)inthe
presence of 10% Pd/C (50 mg) for 24 h. The catalyst was filtered off,
washed with MeOH, and the combined filtrate and washings were
treated with Amberlite IRA-400 resin (OHꢀ form). Evaporation of the
solvent afforded a residue that was retained on a column of Dowex
50Wx8 (200e400 mesh). The column was thoroughly washed with
MeOH, water and then with 1 N NH4OH to afford pure 7 (15 mg, 68%)
added TEA (81 mL, 0.58 mmol) and MsCl (33 mL, 0.43 mmol) and the
mixture was left at room temperature for 3 h. TLC (ether/hexane,
7:1) then showed a faster-running compound. MeOH (1 mL) was
added and after 15 min the reaction mixture was supported on
silica gel and chromatographed (ether/hexane, 2:3/1:1/ether)
to afford syrupy 11 (171 mg, 75%) as a colourless syrup. [
a
]
25 ꢀ39 (c
D
1, CHCl3); IR (KBr, neat) 1744, 1723 and 1701 cmꢀ1 (C]O); 1H NMR
(400 MHz):
d
¼8.01e7.25 (m, 15H, 3Ph), 6.01, 5.25, 5.14 and 4.93
as a colourless viscous syrup; [
a
]
29 þ7 (c 1, MeOH); IR (KBr, neat) 3384
D
(4 m, 4H), 4.71e3.93 (m, 9H), 3.05 (s, 3H, OMs), 2.19, 2.14, 2.11, 2.02
(4s, 6H, 2MeCO, 2 rotamers), 1.48 and 1.38 (2s, 9H, CMe3, 2
rotamers), 1.20 and 1.04 (2 m, 3H, H-40,40,40, 2 rotamers); 13C NMR
(OH); 1HNMR(500 MHz):
d¼4.04(dd,J1,2¼4.7, J1,7a¼2.7 Hz, H-1), 3.95
(dd,1H, J2,3¼7.9 Hz, H-2), 3.86 (dd,1H, J8a,8b¼12.1, J3,8a¼3.7 Hz, H-8a),
3.82 (dd, 1H, J3,8a¼6.0 Hz, H-8b), 3.61 (t, 1H, J6,7¼J7,7a¼8.1 Hz, H-7),
3.46(t,1H, J5,6¼8.1 Hz, H-6), 3.20(dd,1H, H-7a), 3.18(m,1H, H-3), 3.06
(m, 1H, H-5), 1.24 (d, 3H, J5,Me¼6.1 Hz, Me); 13C NMR (125 MHz):
(100 MHz):
d
¼170.85 and 169.57 (2C]O, Ac), 166.12 (C]O, Bz),
158.67 and 154.66 (C]O, Boc, 2 rotamers), 137.41, 137.02, 133.28,
129.72, 128.49, 128.28, 128.07 (Ph), 81.67 (CMe3), 81.35, 80.71,
76.90, 75.48, 75.20, 73.71, 68.51, 68.12, 67.66 (C-10,20,30,3,4, 2
rotamers), 72.28 and 71.42 (2CH2Ph), 63.28 (CH2OBz), 60.73 and
59.80 (C-2,5), 38.77 (OMs), 28.17 (CMe3), 21.08 (2CH3CO2) and 16.41
(C-40); HRMS (NALDI-TOF) calcd for C40H49NNaO13S [MþNa]þ
806.2822, found 806.2820 (deviation ꢀ0.2 ppm).
d
¼83.60 (C-6), 80.06 (C-7), 75.58 (C-1), 73.89 (C-7a), 73.51 (C-2),
66.42 (C-3), 59.78 (C-8), 58.56 (C-5) and 19.50 (Me); HRMS (NALDI-
TOF) calcd for C9H18NO5 [MþH]þ 220.1185, found 220.1186 (deviation
0.5 ppm).
4.2.8. (2R,3S,4R,5R)-2-[(10R,20S,30R)-10,20-Diacetyloxy-30-(meth-
anesulfonyloxy)butyl]-5-(benzoyloxymethyl)-3,4-dibenzyloxy-N-tert-
butyloxycarbonylpyrrolidine (12). To an ice-water cooled and stirred
solution of 15 (0.19 g, 0.27 mmol) in dry Cl2CH2 (4 mL) were added
4.2.5. (2R,3S,4R,5R)-2-[(10R,20S,30S)-10,20-Diacetyloxy-30-(meth-
anesulfonyloxy)butyl]-5-(benzoyloxymethyl)-3,4-dibenzyloxy-
pyrrolidine (16). To an ice-water cooled and stirred solution of 11
(180 mg, 0.23 mmol) in dry Cl2CH2 (3.5 mL) were added slowly TFA
(3.5 mL) and the mixture was left at room temperature for 60 min
TLC (ether/hexane, 7:1) then showed a slower-running compound.
The solvent was eliminated and the residue co-distilled with toluene
TEA (75 mL, 0.54 mmol) and MsCl (31 mL, 0.40 mmol) and the mixture
was left at room temperature for 3 h. TLC (ether/hexane,7:1) then
showed a faster-running compound. MeOH (1 mL) was added and
after 15 min the reaction mixture was supported on silica gel and
chromatographed (ether/hexane, 2:3/3:1) to afford syrupy 12

7266
J.A. Tamayo et al. / Tetrahedron 66 (2010) 7262e7267
(176 mg, 83%) as a colourless syrup. [
a
]
25 ꢀ6 (c 1, CHCl3);IR (KBr, neat)
washings were treated with Amberlite IRA-400 resin (OHꢀ form).
Evaporation of the solvent afforded a residue that was retained on
a column of Dowex 50Wx8 (200e400 mesh). The column was
thoroughly washed with MeOH, water and then with 1 N NH4OH to
D
1753, 1721 and 1701 cmꢀ1 (C]O); 1H NMR (400 MHz):
d
¼7.92e7.18
(m,15H, 3Ph), 5.76, 5.51, 5.27 and 4.96 (4 br s, 4H), 4.69e3.96 (m, 9H),
2.59 and 2.45 (2s, 3H, OMs, 2 rotamers), 2.10, 2.07, 2.04 and 2.02 (4s,
6H, 2MeCO, 2 rotamers),1.52 and 1.40 (2s, 9H, CMe3, 2 rotamers), 0.87
afford pure 8 (20 mg, 70%) as a colourless viscous syrup; [
a
]
26 ꢀ47 (c
D
(m, 3H, H-40,40,40, 2 rotamers); 13C NMR (100 MHz):
d¼170.13 and
1, MeOH); IR (KBr, neat) 3375 (OH); 1H NMR (500 MHz):
d
¼4.07 (dd,
169.76 (2C]O, Ac),166.21 (C]O, Bz),155.38 and 154.62 (C]O, Boc, 2
rotamers), 137.16, 137.04, 136.67, 133.32, 129.72, 128.42, 128.12 (Ph),
82.17 and 81.18 (CMe3, 2 rotamers), 77.42, 76.73, 76.25, 75.63, 73.63
(C-10,20,30,3,4), 71.82 and 71.09 (2CH2Ph), 68.63 and 60.20 (C-2,5),
63.18 and 62.91 (CH2OBz, 2 rotamers), 37.68 (OMs), 28.33 and 28.17
(CMe3, 2 rotamers), 20.74 and 20.64 (2CH3CO2) and 16.20 (C-40);
HRMS (NALDI-TOF) calcd for C40H49NNaO13S [MþNa]þ 806.2822,
found 806.2817 (deviation ꢀ0.6 ppm).
J1,2¼6.5, J2,3¼3.8 Hz, H-2), 3.88 (dd, 1H, J5,6¼5.9, J6,7¼3.3 Hz, H-6),
3.71 (m, 2H, H-1,7), 3.65 (d, 2H, J3,8¼3.5 Hz, H-8,8), 2.77 (quint,1H, J5,
¼J5,6¼6.4 Hz, H-5), 2.61 (t, 1H, J7,7a¼J1,7a¼8.1 Hz, H-7a), 2.48 (br d,
Me
1H, H-3), 0.92 (d, 3H, Me); 13C NMR (125 MHz):
d
¼85.65 (C-6), 80.86
(C-1), 77.81 (C-2), 77.19 (C-7a), 72.68 (C-7), 70.76 (C-3), 63.10 (C-8),
60.97 (C-5) and 14.77 (Me); HRMS (NALDI-TOF) calcd for C9H18NO5
[MþH]þ 220.1185, found 220.1188 (deviation 1.4 ppm).
Acknowledgements
4.2.9. (2R,3S,4R,5R)-2-[(10R,20S,30R)-10,20-Diacetyloxy-30-(meth-
anesulfonyloxy)butyl]-5-(benzoyloxymethyl)-3,4-dibenzyloxy-
pyrrolidine (17). To an ice-water cooled and stirred solution of 12
(160 mg, 0.20 mmol) in dry Cl2CH2 (3 mL) was added slowly TFA
(3 mL) and the mixture was left at room temperature for 45 min. TLC
(ether) then showed a slower-running compound. The solvent was
eliminated and the residue co-distilled with toluene to a new residue
that wassupported onsilicageland chromatographed (ether/hexane,
The authors are deeply grateful to Ministerio de Educación y
Ciencia (Project Ref. No. CTQ2006-14043) and Junta de Andalucía
(Group BIO-250) for financial support, and Fundación Ramón Are-
ces for a grant (F.S.-C.).
Supplementary data
2:1) to afford 17 (126 mg, 90%); [
a
]
27 þ22 (c 1, CHCl3); IR (KBr, neat)
D
3379 (NH), 1742 and 1721 cmꢀ1 (C]O); 1H NMR (400 MHz):
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.07.019.
0
0
0
0
0
d
¼7.92e7.15 (m, 15H, 3Ph), 5.20 (dd,1H, J2 ,3 ¼6.5, J1 ,2 ¼2.4 Hz, H-20),
0
0
0
0
5.08 (br d, 1H, J2,1 ¼8.0 Hz, H-1 ), 4.78 (quint, 1H, J3 ,4 ¼6.5 Hz, H-3 ),
4.47 and 4.40 (2d, 2H, J¼12.0 Hz, CH2Ph), 4.38 and 4.31 (2d, 2H,
References and notes
J¼11.4 Hz, CH2Ph), 4.30 (m, 1H, H-50a), 4.20 (br dd, 1H, J5 a,5 b¼7.9,
0
0
J5,5 b¼5.9 Hz, H-50b), 3.90 (br t,1H, J3,4¼J4,5¼6.2 Hz, H-4), 3.84 (m, 2H,
0
1. (a) Davies, G. J.; Gloster, T. M.; Henrissat, B. Curr. Opin. Struct. Biol. 2005, 15,
637e645; (b) Herscovics, A. Biochim. Biophys. Acta 1999, 1473, 96e107; (c) Stütz,
A. E. Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond; Wiley-VCH:
Weinheim, 1999; (d) Compain, P.; Martin, O. R. Iminosugars: From Synthesis to
Therapeutic Applications; Wiley: Chichester, UK, 2007; (e) Rempel, B. P.; Withers,
S. G. Glycobiology 2008, 18, 570e586; (f) Asano, N. In Modern Alkaloids: Structure,
Isolation, Synthesis and Biology; Fattorusso, E., Taglialatela-Scafati, O., Eds.; Wiley-
VCH: Weinheim, 2008; pp 11e138; (g) Asano, N. In Glycoscience: Chemistry and
Chemical Biology; Fraser-Reid, B. O., Tatsuta, K., Thiem, J., Eds.; Springer: Berlin,
2008; pp 1887e1911.
H-3,5), 2.80 (s, 3H, OMs), 2.05 and 1.81 (2s, 6H, 2MeCO) and 1.28 (d,
3H, H-40,40,40);13C NMR (100 MHz):
d
¼170.80and 170.66 (2C]O, Ac),
166.22 (C]O, Bz), 137.37, 137.14, 133.15, 129.17, 128.44, 128.07, 127.91
(Ph), 78.97 (C-4), 77.53 (C-3), 77.48 (C-30), 74.82 (C-20), 72.47 (C-10),
72.03 and 71.85 (2CH2Ph), 64.91 (CH2OBz), 58.99 and 58.83 (C-2,5),
38.47 (OMs), 20.95 and 20.88 (2CH3CO2) and 17.49 (C-40); HRMS
(NALDI-TOF) calcd for C35H41NNaO11S [MþNa]þ 706.2298, found
706.2300 (deviation 0.3 ppm).
2. (a) Nash, R. J. In Bioactive Natural Products; Colegate, S. M., Molyneux, R. J., Eds.;
Summit Wales Limited: Aberystwyth, UK, 2008; p 407; (b) Asano, N. Mod.
Alkaloids 2008, 111; Asano, N. Glycobiology 2003, 13, 93Re104R.
4.2.10. (1S,2R,3R,5S,6R,7R,7aS)-1,2-Dibenzyloxy-6,7-dihydroxy-3-hy-
droxymethyl-5-methylpyrrolizidine (19). To a solution of 17 (92 mg,
0.135 mmol) in anhydrous THF (6 mL) was added NEt3 (0.1 mL) and
the reaction mixture was refluxed for 7 h. TLC (ether/hexane, 4:1)
showed the presence of two new compounds. The reaction was
treated with 2 M NaOMe in methanol (1 mL) for 1 h. TLC (ether/
MeOH, 10:1) then revealed a new compound. The reaction mixture
was supported on silica gel and chromatographed (ether/MeOH,
3. (a) Dulsat, C.; Mealy, N. Drugs Future 2009, 34, 23e25; (b) Zhu, X.; Sheth, K. A.;
Li, S.; Chang, H. H.; Fan, J. Q. Angew. Chem., Int. Ed. 2005, 44, 7450e7453.
4. Compain, P.; Martin, O.; Boucheron, C.; Godin, G.; Yu, L.; Ikeda, K.; Asano, N.
ChemBioChem 2006, 7, 1356e1359.
5. (a) Mugrage, B. PCT Int. Appl. 2006, 102; (b) Yu, L.; Ikeda, K.; Kato, A.; Adachi, I.;
Godin, G.; Compain, P.; Martin, O.; Asano, N. Bioorg. Med. Chem. 2006, 14,
7736e7744.
6. 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. Carbohyr. Res.
1999, 316, 95e103.
7. Asano, N.; Kuroi, H.; Ikeda, K.; Kizu, H.; Kameda, Y.; Kato, A.; Adachi, I.; Waston,
A. A.; Nash, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1e8.
8. Kato, A.; Kato, N.; Adachi, I.; Hollinshead, J.; Fleet, G. W. J.; Kuriyama, C.; Ikeda,
K.; Asano, N.; Nash, R. J. J. Nat. Prod. 2007, 70, 993e997.
9. For further reviews on the chemistry and biology of pyrrolizidine alkaloids, see:
(a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
2000, 11, 1645e1680; (b) Compain, P.; Martin, O. R. Bioorg. Med. Chem. 2001, 9,
3077e3092; (c) Mroczek, T.; Glowniak, K. Proc. Phytochem. Soc. Eur. 2002, 47,
1e46; (d) Bols, M.; Lillelund, V. H.; Jensen, H. H.; Liang, X. Chem. Rev. 2002, 102,
515e553; (e) Liddell, J. R. Nat. Prod. Rep. 2002, 19, 773e781; (f) Fu, P. P.; Xia, Q.;
Lin, G.; Chou, M. W. Drug Metab. Rev. 2004, 36, 1e55; (g) Pyne, S. G.; Tang, M.
Curr. Org. Chem. 2005, 9, 1393e1418; (h) Pearson, M. S. M.; Mathé-Allainmat, M.;
Fargeas, V.; Lebreton, J. Eur. J. Org. Chem. 2005, 2159e2191; (i) Stocker, B. L.;
Dangerfield, E. M.; Win-Mason, A. L.; Haslett, G. W.; Timmer, M. S. M. Eur. J. Org.
Chem. 2010, 1615e1637; (j) Wilson, F. X.; Nash, R. J.; Horne, G.; Storer, R.; Tinsley,
J. M.; Roach, A. G. PCT Int. Appl. 2010, 202; (k) Wilson, F. X.; Nash, R. J.; Horne, G.;
Storer, R. PCT Int. Appl. 2010, 255; (l) Wilson, F. X.; Nash, R. J.; Horne, G.; Storer, R.;
Tinsley, J. M.; Roach, A. G. PCT Int. Appl. 2010, 191; (m) Wilson, F. X.; Nash, R. J.;
Horne, G.; Storer, R.; Tinsley, J. M.; Roach, A. G. PCT Int. Appl. 2010, 204.
10. Even though the structure displays for Hyacinthacine C1 in Fig. 1 was initially
reported (see Ref. 6), the same structure has been also assigned to a new hy-
acinthacine, named as Hyacinthacine C4 (see Ref. 8).
10:1/8:1) to afford syrupy 19 (36 mg, 67%), [
a
]
28 þ34 (c 1, CHCl3);
D
IR (KBr, neat) 3391 (OH); 1H NMR (500 MHz):
d
¼7.36e7.26 (m, 10H,
2Ph), 4.73 and 4.55 (2d, 2H, J¼11.90 Hz, CH2Ph), 4.65 and 4.62 (2d,
2H, J¼11.8 Hz, CH2Ph), 4.11 (dd, J1,2¼3.2, J2,3¼6.1 Hz, H-2), 3.95 (dd,
1H, J5,6¼6.6, J6,7¼3.1 Hz, H-6), 3.72 (dd, 1H, J7,7a¼7.8 Hz, H-7), 3.65
0
(dd, 1H, J1,7a¼8.2 Hz, H-1), 3.62 (dd, 1H, J3,8¼3.1, J8,8 ¼11.4 Hz, H-8),
3.47 (br d, 1H, H-80), 3.02 (t, 1H, H-7a), 2.87 (quint, 1H, J5,Me¼6.6 Hz,
H-5), 2.79 (br s, 1H, H-3), 1.07 (d, 3H, Me); 13C NMR (125 MHz):
d
¼138.21, 128.49, 127.90, 128.82, (Ph), 84.72 (C-6), 83.48 (C-2),
79.94 (C-7), 79.27 (C-1), 74.31 (C-7a), 72.73 and 71.93 (2CH2Ph),
67.07 (C-3), 61.90 (C-8), 59.19 (C-5) and 14.18 (Me); HRMS (NALDI-
TOF) calcd for C23H29NNaO5 [MþNa]þ 422.1943, found 422.1946
(deviation 0.7 ppm).
4.2.11. (1S,2R,3R,5S,6R,7R,7aS)-1,2,6,7-Tetrahydroxy-3-hydroxy-
methyl-5-methylpyrrolizidine (8). Compound 19 (52 mg, 0.13 mmol)
in MeOH (11 mL) and conc. HCl (five drops) was hydrogenated
(70 psi H2) in the presence of 10% Pd/C (50 mg) for 24 h. The catalyst
was filtered off, washed with MeOH, and the combined filtrate and
11. (a) Davis, A. S.; Ritthiwigrom, T.; Pyne, S. G. Tetrahedron 2008, 64, 4868e4879;
(b) Ritthiwigrom, T.; Pyne, S. G. Org. Lett. 2008, 10, 2769e2771; (c) Pyne, S.
Chem. Aust. 2008, 75, 13e14.

J.A. Tamayo et al. / Tetrahedron 66 (2010) 7262e7267
7267
12. For selected syntheses see: (a) White, J. D.; Hrnciar, P.; Yokochi, A. F. T. J. Am.
Chem. Soc. 1998, 120, 7359e7360; (b) Koch, D.; Maechling, S.; Blechert, S. Tet-
rahedron 2007, 63, 7112e7119; (c) Muroni, D.; Mucedda, M.; Saba, A. Tetrahe-
dron Lett. 2008, 49, 2373e2376; (d) Lesma, G.; Colombo, A.; Sacchetti, A.;
Silvani, A. J. Org. Chem. 2009, 74, 590e596.
Franco, F. Tetrahedron: Asymmetry 2004, 15, 1465e1469; (e) Izquierdo, I.;
Plaza, M.-T.; Tamayo, J. A. Tetrahedron 2005, 61, 6527e6533; (f) Izquierdo, I.;
Plaza, M.-T.; Yáñez, V. Tetrahedron: Asymmetry 2005, 16, 3887e3891; (g) Iz-
quierdo, I.; Plaza, M.-T.; Tamayo, J. A. J. Carbohydr. Chem. 2006, 25, 281e295;
(h) Izquierdo, I.; Plaza, M.-T.; Tamayo, J. A.; Rodríguez, M.; Martos, A. Tet-
rahedron 2006, 62, 6006e6011; (i) Izquierdo, I.; Plaza, M.-T.; Tamayo, J. A.;
Sánchez-Cantalejo, F. Eur. J. Org. Chem. 2007, 6078e6083; (j) Izquierdo, I.;
Plaza, M.-T.; Tamayo, J. A.; Franco, F.; Sánchez-Cantalejo, F. Tetrahedron 2010,
66, 3788e3794.
13. (a) Back, T. G.; Nakajima, K. Org. Lett. 1999, 1, 261e263; (b) Back, T. G.; Nakajima,
K. J. Org. Chem. 2000, 65, 4543e4552.
14. (a) Denmark, S. E.; Parker, D. L., Jr.; Dixon, J. A. J. Org. Chem. 1997, 62, 435e436;
(b) Denmark, S. E.; Herbert, B. J. Org. Chem. 2000, 65, 2887e2896; (c) Denmark,
S. E.; Cottell, J. J. J. Org. Chem. 2001, 66, 4276e4284.
15. (a) Dieter, K. R.; Lu, K. J. Org. Chem. 2002, 67, 847e855; (b) Dieter, R. K.; Chen, N.;
Watson, R. T. Tetrahedron 2005, 61, 3221e3230.
16. (a) Tang, M.; Pyne, S. G. Tetrahedron 2004, 60, 5759e5767; (b) Ritthiwigrom, T.;
Willis, A. C.; Pyne, S. G. J. Org. Chem. 2010, 75, 815e824.
17. (a) Izquierdo, I.; Plaza, M.-T.; Robles, R.; Franco, F. Tetrahedron: Asymmetry
2001, 12, 2481e2487; (b) Izquierdo, I.; Plaza, M.-T.; Franco, F. Tetrahedron:
Asymmetry 2002, 13, 1581e1585; (c) Izquierdo, I.; Plaza, M.-T.; Franco, F.
Tetrahedron: Asymmetry 2003, 14, 3933e3935; (d) Izquierdo, I.; Plaza, M.-T.;
18. (a) Izquierdo, I.; Plaza, M.-T.; Robles, R.; Franco, F. Carbohydr. Res. 2001, 330,
401e408; (b) Izquierdo, I.; Plaza, M.-T.; Franco, F. Tetrahedron: Asymmetry
2002, 13, 1503e1508; (c) Izquierdo, I.; Plaza, M.-T.; Rodríguez, M.; Franco, F.;
Martos, A. Tetrahedron 2005, 61, 11697e11704; (d) Izquierdo, I.; Plaza, M.-T.;
Rodríguez, M.; Franco, F.; Martos, A. Tetrahedron 2006, 62, 1904; (e) Izquierdo,
I.; Plaza, M.-T.; Rodríguez, M.; Tamayo, J. A.; Martos, A. Tetrahedron 2006, 62,
2693e2697; (f) Izquierdo, I.; Plaza, M.-T.; Yáñez, V. Tetrahedron 2007, 63,
1440e1447.
19. Yu, C.; Gao, H. Faming Zhuanli Shenqing Gongkai Shuomingshu 2008, 18.