Efficient synthesis of tetrahydroxylated pyrrolizidines by nitrone cycloaddition leading to unnatural stereoisomers of 7-deoxycasuarine

Article abstract of DOI:10.1055/s-0030-1260933

A convenient and efficient method has been used for the synthesis of ten new tetrahydroxylated pyrrolizidines 12a,b, 13a-c, 14a,b, and 15a-c starting from sugar-derived cyclic nitrones prepared from d-xylose, d-arabinose, d-ribose, and l-arabinose, through a five-step reaction sequence. Pyrrolizidine 12a is an enantiomer of 7-deoxycasuarine and pyrrolizidine 12b an enantiomer of the as yet unknown 7-deoxyuniflorine A. This method expands the scope of nitrone cycloadditions and is flexible enough for the synthesis of various stereoisomers of highly polyhydroxylated pyrrolizidines. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260933

1668
LETTER
Efficient Synthesis of Tetrahydroxylated Pyrrolizidines by Nitrone
Cycloaddition Leading to Unnatural Stereoisomers of 7-Deoxycasuarine
Synthesis of
T
etrah
a
ydroxylate
b
d
Pyrrolizidi
r
nes by N
i
itrone
e
Cycloaddit
l
ion Podolan,a Lucia Kleščíková,a Lubor Fišera,*a Jozef Kožíšek,b Marek Froncb
a
Institute of Organic Chemistry, Catalysis and Petrochemistry, Slovak University of Technology,
Radlinskeho 9, 81237 Bratislava, Slovak Republic
E-mail: lubor.fisera@stuba.sk
Institute of Physical Chemistry and Chemical Physics, Slovak University of Technology,
Radlinskeho 9, 81237 Bratislava, Slovak Republic
b
Received 11 April 2011
Dedicated to Professor Heinz Heimgartner on the occasion of his 70th birthday
Nitrones have become important building blocks in or-
Abstract: A convenient and efficient method has been used for the
synthesis of ten new tetrahydroxylated pyrrolizidines 12a,b, 13a–c,
14a,b, and 15a–c starting from sugar-derived cyclic nitrones pre-
pared from D-xylose, D-arabinose, D-ribose, and L-arabinose,
ganic synthesis.7 During recent years we have developed
protocols for the preparation of optically active nitrone
templates for asymmetric 1,3-dipolar cycloadditions.8
through a five-step reaction sequence. Pyrrolizidine 12a is an enan- Enantiomerically pure polyfunctional cyclic nitrones,
tiomer of 7-deoxycasuarine and pyrrolizidine 12b an enantiomer of
the as yet unknown 7-deoxyuniflorine A. This method expands the
scope of nitrone cycloadditions and is flexible enough for the syn-
thesis of various stereoisomers of highly polyhydroxylated pyr-
rolizidines.
which have been widely used in the synthesis of various
natural and biologically active nitrogen-containing com-
pounds, are especially valuable in the synthesis of pyr-
rolizidines.4
Since the biological activity varies with the position and
stereochemistry of the hydroxy groups on the pyrrolizi-
dine skeleton,1a and as only a few syntheses of 3-(hy-
droxymethyl)-pyrrolizidine-1,2,6-triol skeletons have
been reported to date,6,7 we have focused our attention
upon developing a simple and efficient route for the syn-
thesis of these biologically important polyhydroxylated
alkaloids. In this communication we wish to describe a
synthetic strategy based on 1,3-dipolar cycloaddition of
chiral sugar-derived cyclic nitrones 4–7 (Figure 2), re-
cently described by Yu and coworkers,9 with methyl acry-
late followed by subsequent N–O bond cleavage
accompanied with spontaneous cyclization into the pyr-
rolizidine skeleton.
Key words: sugar-derived cyclic nitrones, cycloaddition, imino-
sugars, pyrrolizidines, stereoselective synthesis
Iminosugars are monosaccharide analogues with nitrogen
instead of oxygen in the ring. Due to the structural resem-
blance of polyhydroxylated alkaloids to carbohydrates,
they are considered as sugar mimics and many of them ex-
hibit promising glycosidase1 and glycosyltransferase2 ac-
tivity, making them potential drug candidates against viral
infections, cancer, and diabetes.3 Among naturally occur-
ing iminosugars, the rapidly expanding class of polyhy-
droxylated pyrrolizidines4 has attracted significant
attention because of the selective inhibitory activity asso-
ciated with several of these alkaloids.1 For example, in the
polyhydroxylated pyrrolizidine class alexine (1) has been
shown to exhibit antiviral and anti-HIV activity,5 hya-
cinthacine A2 (2) was found to be a selective inhibitor of
amyloglucosidase6 (Aspergilus niger), and 7-deoxyca-
suarine (3, Figure 1) showed specific and competitive in-
hibition activity against amyloglucosidase (Rhizopus
mould).4b–e
O–
N+
O–
N+
BnO
BnO
OBn
BnO
OBn
BnO
4
5
D-xylose
D-arabinose
O–
N+
O–
N+
BnO
BnO
OH
OH
OH
HO
H
N
H
N
H
N
BnO
BnO
OBn
OBn
OH
OH
HO
OH
6
7
D-ribose
L-arabinose
OH
7-deoxycasuarine (3)
OH
hyacinthacine A2 (2)
OH
alexine (1)
Figure 2 Sugar-derived nitrones
Figure 1 Selected polyhydroxylated pyrrolizidines
The retrosynthetic analysis is shown in Scheme 1, where
1,3-dipolar cycloaddition of chiral nitrones 4–7 derived
from corresponding sugars with methyl acrylate provides
fused isoxazolidine 8, which can be converted into a cor-
responding hydroxymethyl derivative 9. Following acti-
SYNLETT 2011, No. 12, pp 1668–1672
x
x
.x
x
.2
0
1
1
Advanced online publication: 05.07.2011
DOI: 10.1055/s-0030-1260933; Art ID: D11311ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Tetrahydroxylated Pyrrolizidines by Nitrone Cycloaddition
1669
vation with mesyl chloride gives mesylate 10, subsequent tic acid for N–O bond cleavage led to the formation of
N–O bond cleavage allows the synthesis of pyrrolizidine pyrrolizidine 11a in 93% yield after neutralization with a
skeleta 12–15 after cyclization.
saturated solution of K2CO3, extraction (EtOAc) and puri-
fication on silica gel (EtOAc). Deprotection of the benzyl
groups was achieved with H2 on Pd/C (10 mol%) in
MeOH and HCl at 50 °C overnight, to furnish the desired
polyhydroxylated pyrrolizidine 12a in 99% yield
(Scheme 2). The synthesis of 12a has thus been achieved
in five steps with an overall yield of 51% from nitrone 4.
The proposed synthetic plan, which in principle allows
access to all stereoisomers of 3-hydroxymethyl-
2,3,5,6,7,7a-hexyhydro-1H-pyrrolizine-1,2,6-triol (12–
15), if realized, could be quite general and flexible since a
variety of analogues of 7-deoxycasuarine (3) might be ac-
cessible by diversifying the starting carbohydrate-derived
nitrones.
Following the same four-step reaction sequence, the mi-
nor pyrroloisoxazolidine 8b was analogously transformed
into pyrrolizidine 12b, an enantiomer of the as yet un-
known 7-deoxyuniflorine A (Scheme 2). The latter two
pyrrolizidines 12a and 12b are epimeric at C-6, and pyr-
rolizidine 12a {[a]D25 –14.2 (c 0.4, MeOH)} is the enan-
tiomer of 7-deoxycasuarine, a more selective inhibitor4c
than casuarine, alexine, or australine. 7-Deoxycasuarine
(3) has been synthesized by Behr12 {[a]D20 +10.9 (c 0.11,
H2O)}, Goti4b,e {[a]D20 +19.8 (c 0.26, H2O)} and Carmo-
na, Vogel, and co-workers4c {[a]D25 +23 (c 0.3, MeOH)}
by a strategy employing a nitrone prepared from commer-
cially available tribenzyl D-arabinose.
OBn
OH
OBn
OBn
HO
MsOH2C
OH
N
N
O
OH
12–15
10
OBn
OBn
HOH2C
OBn
OBn
OBn
MeO2C
N
N
O
O
The relative configurations of the new compounds were
assigned on the basis of NOESY experiments of 9a, 10a,
11b, and 12b (Figure 3). The observed interactions H-4b/
H-5 and H-4a/H-3 of hydroxymethyl derivate 9a indicate
a trans relation between H-3 and H-5. The anti configura-
tion between H-3 and H-6 was established by means of a
negative mutual interaction between these protons. The
H-3/H-6 anti configuration was also assigned through H-
3/H-4a and H-6/H4b interactions of mesylate 10a. The
anti-cis configuration of the minor cycloadduct 8b was as-
signed by correlation with pyrrolizidine 11b, whose rela-
tive C6/C8 trans configuration was determined on the
basis of H-7b/H-6, H-7a/H-7a interactions. The C1/C7a
anti configuration could be seen from H-7b/H-1, H-7a/H-
7a, and H-1/H-3 interactions in addition to negative H-1/
H-7a interaction. NOE studies of the final pyrrolizidine
12b proved the trans configuration by H-6/H-7b, H-7a/H-
7a, and C1/C7a interactions and the anti configuration
OBn
8
9
BnO
O–
N+
OMe
BnO
+
O
BnO
4–7
Scheme 1 Retrosynthetic analysis
Sugar-derived cyclic nitrones 4–7 were synthesized from
the corresponding aldoses following an efficient and prac-
tical procedure described by Yu et al.9 We have modified
this
procedure
using
O-tert-butyldiphenyl-
silylhydroxylamine10 instead of NH2OMe and TBAT11 for
the cyclization, and this provided nitrone 4 with an in-
creased yield of 74%. This improved procedure was suc-
cessfully extended to the synthesis of nitrones 5–7.
H8
H5
H6
BnO
BnO
Hb4
O
The nitrone 4 was then treated with methyl acrylate in
THF at room temperature for 24 hours to give a mixture
of anti-stereoisomers 8a and 8b in a ratio of 80:20 and
combined yield of 88%. The crude esters 8a and 8b
(Scheme 2) were used directly in the reduction with
DIBAL in THF at 0 °C to room temperature without fur-
ther purification. After quenching with aqueous Rochelle
salt and extraction (EtOAc), the hydroxymethylderivates
9a and 9b were separated by MPLC on silica gel (EtOAc–
hexanes = 33:66) to give diastereomerically pure anti-
trans-isoxazolidine 9a as the major isomer and anti-cis-
isomer 9b as the minor isoxazolidine in a combined yield
of 92%. The major isomer 9a was subsequently treated
with mesyl chloride and Et3N in CH2Cl2 to furnish mesy-
late 10a in 86% yield. Exposing 10a to Zn in aqueous ace-
H8
H5
H6
BnO
BnO
Hb4
O
N
N
CH2OMs
H4a
OBn
H7
CH2OH
H4a
OBn
H7
H3
H3
9a
10a
H3
H3
H6
H1
N
HO
Hβ7
H6
H1
BnO
BnO
Hβ7
HO
N
OH
H7α
OH
H2
OH
H7α
OBn
H2
H7a
H7a
11b
12b
Figure 3 NOE experiments
Synlett 2011, No. 12, 1668–1672 © Thieme Stuttgart · New York

1670
G. Podolan et al.
LETTER
OBn
OBn
O–
N+
H
N
H
N
H
H
methyl acrylate
THF, r.t., 88%
+
OBn
MeOOC
OBn
MeOOC
BnO
BnO
O
O
OBn
OBn
OBn
8b
DIBAL
THF, –10 °C to r.t.
92%
4
8a
DIBAL
THF, –10 °C to r.t.
92%
OBn
OBn
H
N
H
N
H
H
OBn
OBn
OBn
+
HOH2C
HOH2C
O
O
OBn
9b
9a
MsCl, Et3N
MsCl, Et3N
CH2Cl2, 0 °C, 88%
CH2Cl2, 0 °C, 86%
OBn
OBn
OBn
H
H
N
H
N
H
H
Zn, AcOH, H2O
OBn
OBn
OBn
HO
OBn
MsOH2C
MsOH2C
O
60 °C, 93%
N
O
OBn
OBn
10a
10b
11a
H2, Pd/C (10 mol%)
MeOH, HCl, 50 °C
Dowex 50WX8, 97%
Zn, AcOH, H2O
60 °C, 80%
OBn
OH
H
H
N
OH
OH
H
N
H2, Pd/C (10 mol%)
MeOH, HCl, 50 °C
OBn
HO
HO
OH
HO
N
Dowex 50WX8, 96%
OBn
OH
11b
12b
OH
12a
Scheme 2
was confirmed by H-7a/H-7a, H-7b/H-1, H-7a/H-2 inter- cyclic nitrones 5–7 derived from corresponding sugars (D-
actions as well as by a negative H-1/H-7a interaction. arabinose, D-ribose, and L-arabinose; Figure 2) with me-
Subsequent X-ray analysis13–16 of the benzylated pyrroliz- thyl acrylate were analogously transformed into the novel
idine 11b confirmed the configuration of the new stereo- tetrahydroxylated pyrrolizidines 13a–c, 14a,b, and 15a–c
genic centers at C1, C2, C3, C6, and C7a (Figure 4).
(Figure 5).17
Subsequently, following the same five-step reaction se-
quence, the pyrroloisoxazolidines 8 prepared from chiral
OH
OH
OH
H
N
H
H
N
OH
OH
OH HO
HO
N
HO
OH
OH
OH
13a
13b
13c
OH
OH
H
N
H
OH
OH
OH
HO
HO
N
OH
14a
14b
OH
OH
OH
H
N
H
H
N
OH
OH
OH
OH
OH
HO
HO
HO
N
OH
15a
15b
15c
Figure 5 Novel non-natural tetratetrahydroxylated pyrrolizidines
Figure 4 The molecular structure of 11b, with the numbering
scheme16 of the asymmetric unit. Displacement ellipsoids are drawn
at the 50% probability level.
Synlett 2011, No. 12, 1668–1672 © Thieme Stuttgart · New York

LETTER
Synthesis of Tetrahydroxylated Pyrrolizidines by Nitrone Cycloaddition
E.; Gallos, J. K. Curr. Org. Chem. 2003, 7, 585.
1671
In conclusion, a convenient and efficient method has been
developed for the synthesis of a series of new tetrahydrox-
ylated pyrrolizidines 12a,b, 13a–c, 14a,b, and 15a–c
starting from sugar-derived cyclic nitrones prepared from
D-xylose, D-arabinose, D-ribose, and L-arabinose, through
a five-step reaction sequence. Pyrrolizidine 12a is an
enantiomer of 7-deoxycasuarine and pyrrolizidine 12b, an
enantiomer of the as yet unknown 7-deoxyuniflorine A.
This method expands the scope of nitrone cycloadditions
and is flexible for the synthesis of various stereoisomers
of highly polyhydroxylated pyrrolizidines.
(f) Pellissier, H. Tetrahedron 2007, 63, 3235. (g) Fišera, L.
In Topics in Heterocyclic Chemistry. Heterocycles from
Carbohydrate Precursors; El Ashry, E. S. H., Ed.; Springer:
Berlin, 2007, 287.
(8) (a) Kubán, J.; Blanáriková, I.; Fišera, L.; Jarošková, L.;
Fengler-Veith, M.; Jäger, V.; Kožíšek, J.; Humpa, O.;
Prónayová, N.; Langer, V. Tetrahedron 1999, 55, 9501.
(b) Fischer, R.; Drucková, A.; Fišera, L.; Rybár, A.;
Hametner, C.; Cyrański, M. K. Synlett 2002, 1113.
(c) Kubán, J.; Kolarovič, A.; Fišera, L.; Jäger, V.; Humpa,
O.; Prónayová, N.; Ertl, P. Synlett 2001, 1862.
(d) Blanáriková-Hlobilová, I.; Kopaničáková, Z.; Fišera, L.;
Cyrański, M. K.; Salanski, P.; Jurczak, J.; Prónayová, N.
Tetrahedron 2003, 59, 3333. (e) Fischer, R.; Drucková, A.;
Fišera, L.; Hametner, C. ARKIVOC 2002, (viii), 80.
(f) Dugovič, B.; Fišera, L.; Cyranski, M. K.; Hametner, C.;
Prónayová, N.; Obranec, M. Helv. Chim. Acta 2005, 88,
1432. (g) Rehák, J.; Fišera, L.; Kožíšek, J.; Perašínová, L.;
Steiner, B.; Koóš, M. ARKIVOC 2008, (viii), 18. (h) Rehák,
J.; Fišera, L.; Podolan, G.; Kožíšek, J.; Perašínová, L. Synlett
2008, 1260. (i) Rehák, J.; Fišera, L.; Prónayová, N.
ARKIVOC 2009, (vi), 146.
Acknowledgment
The authors are grateful to the Slovak Grant Agency (No. 1/0236/
09, No. 1/0115/10 and No. 1/0679/11). The authors thank the Struc-
tural Funds, Interreg IIIA for the financial support in purchasing the
X-ray diffractometer.
References and Notes
(9) Wang, W. B.; Huang, M. H.; Li, Y. X.; Rui, P. X.; Hu, X. G.;
Zhang, W.; Su, J. K.; Zhang, Z. L.; Zhu, J. S.; Xu, W. H.;
Xie, X. Q.; Jia, Y. M.; Yu, Ch. I. Synlett 2010, 488.
(10) Denmark, S. E.; Dappen, M. S.; Sear, N. L.; Jacobs, R. T.
J. Org. Chem. 1990, 112, 3466.
(11) Tamura, O.; Toyao, A.; Ishibashi, H. Synlett 2002, 1344.
(12) Behr, B. J.; Erard, A.; Guillerm, G. Eur. J. Org. Chem. 2002,
1256.
(1) (a) Tyler, P. C.; Winchester, B. G. In Iminosugars as
Glycosidase Inhibitors. Nojirimycin and Beyond.; Stütz, A.
E., Ed.; Wiley-VCH: Weinheim, 1999. (b)Asano, N.;Nash,
R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron:
Asymmetry 2000, 11, 1645.
(2) Compain, P.; Martin, O. R. Curr. Top. Med. Chem. 2003, 3,
541.
(3) (a) Pearson, M. S. M.; Mathé-Allainmat, M.; Fargeas, J.;
Lebreton, J. Eur. J. Org. Chem. 2005, 2159. (b) Watson, A.
A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J.
Phytochemistry 2001, 56, 265. (c) Asano, N.; Kato, A.;
Watson, A. A. Mini-Rev. Med. Chem. 2001, 1, 145.
(4) (a) Yoda, H. Curr. Org. Chem. 2002, 6, 223. (b) Cardona,
F.; Faggi, E.; Cignori, F.; Cacciarini, M.; Goti, A.
Tetrahedron Lett. 2003, 44, 2318. (c) Carmona, A. T.;
Whigtman, R. H.; Robina, I.; Vogel, P. Helv. Chim. Acta
2003, 86, 3066. (d) Brandi, A.; Cardona, F.; Cicchi, S.;
Cordero, F. M.; Goti, A. Chem. Eur. J. 2009, 15, 7808.
(e) Bonaccini, C.; Chioccioli, M.; Parmeggiani, C.; Lo Re,
D.; Soldaini, G.; Vogel, P.; Bello, C.; Goti, A.; Gratteri, P.
Eur. J. Org. Chem. 2010, 5574. (f) Hu, X.-G.; Jia, Y.-M.;
Xiang, J.; Yu, C.-Y. Synlett 2010, 982. (g) Kubán, J.;
Kolarovič, A.; Fišera, L.; Jäger, V.; Humpa, O.; Prónayová,
N. Synlett 2001, 1866. (h) Reddy, P. V.; Koóš, P.; Veyron,
A.; Greene, A. E.; Delair, P. Synlett 2009, 1141.
(13) Crystal Data of Compound 11b
C29H33NO4, M = 459.56, monoclinic, P21, a = 13.197 (2) Å,
b = 6.0914 (4) Å, c = 16.757 (3) Å, V = 1257.0(2) Å3, Z = 2,
Dx = 1.214 Mg m–3, m (Cu Ka) = 0.639 mm–1, F(000) = 492,
colorless block, 0.152 × 0.228 × 0.860 mm–3, 15292
diffractions measured (Rint = 0.026), 4082 unique,
wR2 = 0.0759, conventional R = 0.0284 on I values of 4032
diffractions with I > 2.0 s(I), (D/s)max = 0.001, S = 1.039 for
all data and 311 parameters. Unit cell determination and
intensity data collection (qmax = 74.87°) were performed on
a Gemini R diffractometer14 at 100 (1) K. Structure solution
was done using direct methods15 and refinements were
achieved by full-matrix least-squares method15 on F**2.
Further details of the crystal structure investigation can be
obtained from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge, CB2 1EZ, UK (CCDC
deposition no. 818367).
(14) Oxford Diffraction(2010). CrysAlis PRO. Oxford
Diffraction Ltd, Abingdon, England.
(15) Sheldrick, G. M. Acta Crystallogr., Sect. A: Found.
Crystallogr. 2008, 46, 112.
(16) Brandenburg, K. DIAMOND; Crystal Impact GbR: Bonn,
2006.
(17) Typical Experimental Procedure for Cycloaddition
The nitrone (5.39 mmol) was dissolved in THF (50 mL) and
methyl acrylate was added (21.56 mmol). The mixture was
stirred for 48 h at r.t. The mixture was then concentrated
under reduced pressure, and the residue was purified by
MPLC (EtOAc–hexanes = 33:66).
(i) Tamayo, J. A.; Lo Re, D.; Sánchez-Cantalejo, F. J. Org.
Chem. 2009, 74, 5679. (j) Desvergnes, S.; Py, S.; Vallée, Y.
J. Org. Chem. 2005, 70, 1459. (k) Argyropoulos, N. G.;
Gkizis, P.; Coutoli-Argyropoulos, E. Tetrahedron 2008, 64,
8752. (l) Delso, I.; Tejero, T.; Goti, A.; Merino, P.
Tetrahedron 2010, 66, 1220. (m) Koch, D.; Maechling, S.;
Blechert, S. Tetrahedron 2007, 63, 7112.
(5) Taylor, D. L.; Nash, R. J.; Fellows, L. E.; Kang, M. S.;
Tyms, A. S. Antiviral Chem. Chemother. 1992, 3, 273.
(6) Asano, N.; Kuroi, H.; Ikeda, K.; Kizu, H.; Kameda, Y.; Kato,
A.; Adachi, I.; Watson, A. A.; Nash, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1.
(7) (a) Frederickson, M. Tetrahedron 1997, 53, 403.
(b) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98,
863. (c) Merino, P.; Franco, S.; Merchan, F. L.; Romero, P.;
Tejero, T.; Uriel, T. S. Tetrahedron: Asymmetry 2003, 14,
3731. (d) Osborn, H. M. I.; Gemmel, N.; Harwood, L. M.
J. Chem. Soc., Perkin Trans. 1 2002, 2419. (e) Koumbis, A.
Representative Data for Products
Compound 9a: [a]D25 +41.6 (CHCl3, c 3.04). 1H NMR (600
MHz, CDCl3): d = 7.35–7.23 (m, 15 H, OCH2Ph), 4.60–4.48
(m, 6 H, OCH2Ph), 4.29 (m, 1 H, H-5), 4.04 (dd, 1 H, H-7,
J = 3.9, 5.6 Hz), 3.96 (dd, 1 H, H-6, J = 3.9 Hz), 3.75 (m, 2
H, H-3, H-10b), 3.66 (dd, 1 H, H-9b, J = 4.7, 10.0 Hz), 3.60
(dd, 1 H, H-9a, J = 5.6, 10.0 Hz), 3.55 (dd, 1 H, H-10a,
Synlett 2011, No. 12, 1668–1672 © Thieme Stuttgart · New York

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G. Podolan et al.
LETTER
J = 4.5, 12.3 Hz), 3.33 (dd, 1 H, H-8, J = 5.6, 10.8 Hz), 2.32
(ddd, 1 H, H-4b, J = 7.3, 8.8, 15.8 Hz), 2.16 (ddd, 1 H, H-4a,
J = 5.6, 7.3, 12.6 Hz). 13C NMR (75 MHz, CDCl3): d =
138.2–127.5 (OCH2Ph), 87.1 (C-6), 83.8 (C-7), 77.2 (C-5),
73.3, 72.3, 71.7 (OCH2Ph), 69.7 (C-9), 69.6 (C-8), 68.5 (C-
3), 63.1 (C-10), 35.4 (C-4). IR: 3238, 3032, 2921, 2852,
1496, 1454, 1357, 1143, 1093, 1078, 1025, 738, 695 cm–1.
TOF MS (ESI): m/z calcd for C29H34NO5 [MH+]: 476.2437;
found: 476.2433.
(C-1), 76.6 (C-2), 73.5 (C-6), 73.1 (C-3), 69.5 (C-7a), 62.6
(C-5), 60.6 (C-4), 38.4 (C-7). IR: 3269, 2931, 1634, 1435,
1377, 1335, 1097, 1041, 988, 927, 860, 607, 511 cm–1. TOF
MS (ESI): m/z calcd for C29H34NO4 [MH+]: 190.1079;
found: 190.1042.
Compound 13a: [a]D25 +20.4 (MeOH, c 0.83). 1H NMR (300
MHz, CD3OD): d = 4.36 (m, 1 H, H-6), 4.20 (d, 1 H, H-2,
J = 2.6 Hz), 4.08 (m, 1 H, H-7a), 3.95 (d, 1 H, H-1, J = 3.8
Hz), 3.85 (dd, 1 H, H-4b, J = 6.4, 11.1 Hz), 3.75 (dd, 1 H, H-
4a, J = 6.7, 11.1 Hz), 3.30 (m, 1 H, H-3), 3.20 (dd, 1 H, H-
5b, J = 4.1, 11.7 Hz), 2.87 (dd, 1 H, H-5a, J = 3.5, 11.7 Hz),
2.07 (m, 2 H, H-7a, H-7b). 13C NMR (75 MHz, CD3OD):
d = 79.6 (C-2), 77.0 (C-1), 73.9 (C-6), 72.0 (C-3), 68.9 (C-
7a), 62.4 (C-5), 61.4 (C-4), 32.9 (C-7). IR: 3238, 2925, 2871,
1645, 1435, 1034, 1251, 1029, 908, 674, 608, 512 cm–1. TOF
MS (ESI): m/z calcd for C29H34NO4 [MH+]: 190.1079;
found: 190.1005.
Compound 10a: [a]D25 +40.0 (CHCl3, c 0.71); mp 93–95 °C.
1H NMR (300 MHz, CDCl3): d = 7.37–7.23 (m, 15 H,
OCH2Ph), 4.56–4.50 (m, 6 H, OCH2Ph), 4.43 (m, 1 H, H-5),
4.24 (m, 2 H, H-10a, H-10b), 4.03 (dd, 1 H, H-7, J = 3.8, 5.8
Hz), 3.96 (dd, 1 H, H-6, J = 3.8 Hz), 3.75 (ddd, 1 H, H-3,
J = 3.8, 5.4, 8.9 Hz), 3.65 (dd, 1 H, H-9b, J = 5.0, 9.8 Hz),
3.57 (dd, 1 H, H-9a, J = 5.8, 9.8 Hz), 3.35 (dd, 1 H, H-8,
J = 5.8, 10.9 Hz), 3.00 (s, 3 H, OMs), 2.25 (m, 2 H, H-4a,
H-4b). 13C NMR (75 MHz, CDCl3) d = 138.1–127.5
(OCH2Ph), 86.9 (C-6), 83.9 (C-7), 74.3 (C-5), 73.2, 72.1,
71.8 (OCH2Ph), 70.0 (C-8), 69.7 (C-9), 69.3 (C-10), 68.2 (C-
3), 37.5 (OMs), 35.6 (C-4). IR: 3027, 2880, 1497, 1454,
1336, 1178, 1101, 1074, 990, 964, 908, 819, 734, 694, 526
cm–1. TOF MS (ESI): m/z calcd for C30H36NO7S [MH+]:
554.2212; found: 554.2040.
Compound 14a: [a]D25 +5.7 (MeOH, c 1.16). 1H NMR (300
MHz, CD3OD): d = 4.51 (m, 1 H, H-6), 4.21 (dd, 1 H, J = 3.6
Hz, H-2), 3.91 (m, 2 H, H-4a, H-1), 3.75 (m, 2 H, H-4b, H-
7a), 3.05 (m, 2 H, H-3, H-5a), 2.95 (dd, 1 H, J = 4.4, 11.4 Hz,
H-5b), 2.07 (ddd, 1 H, J = 4.4, 7.3, 12.4 Hz, H-7b), 1.98
(ddd, 1 H, J = 4.4, 7.3, 12.4 Hz, H-7a). 13C NMR (75 MHz,
CD3OD): d = 79.2 (C-1), 75.4 (C-2), 73.3 (C-6), 72.5 (C-3),
68.8 (C-7a), 63.2 (C-5), 61.5 (C-4), 39.1 (C-7). IR: 3329,
3209, 2974, 2910, 2876, 2738, 2475, 2399, 1460, 1323,
1226, 1140, 1098, 1057, 1031, 965, 716, 407 cm–1. TOF MS
(ESI): m/z calcd for C29H34NO4 [MH+]: 190.1079; found:
190.1070.
Compound 11a: [a]D25 –10.3 (CHCl3, c 2.10). 1H NMR (300
MHz, CDCl3): d = 7.40–7.24 (m, 15 H, OCH2Ph), 4.75–4.55
(m, 6 H, OCH2Ph), 4.36 (m, 1 H, H-6), 4.19 (dd, 1 H, H-1,
J = 6.3 Hz), 3.98 (dd, 1 H, H-2, J = 6.3, 7.6 Hz), 3.63 (dd, 1
H, H-4b, J = 4.3, 9.4 Hz), 3.55 (dd, 1 H, H-4a, J = 6.6, 9.4
Hz), 3.50 (m, 2 H, H-3, H-8), 3.10 (dd, 1 H, H-5b, J = 3.9,
11.1 Hz), 2.95 (dd, 1 H, H-5a, J = 4.0, 11.1 Hz), 2.17 (ddd,
Compound 15a: [a]D25 –15.8 (MeOH, c 1.00). 1H NMR (600
MHz, CD3OD): d = 4.55 (m, 1 H, H-6), 4.29 (dt, 1 H, J = 3.9,
8.4 Hz, H-7a), 4.22 (m, 1 H, H-2), 3.96 (d, 1 H, J = 3.9 Hz,
H-1), 3.85 (dd, 1 H, J = 5.8, 11.2 Hz, H-4a), 3.80 (dd, 1 H,
J = 8.1, 11.2 Hz, H-4b), 3.27 (dd, 1 H, J = 2.7, 11.5 Hz, H-
5a), 3.23 (ddd, 1 H, J = 3.4, 5.8, 8.1 Hz, H-3), 2.91 (dd, 1 H,
J = 4.2, 11.5 Hz, H-5b), 2.33 (ddd, 1 H, J = 5.1, 7.3, 12.3 Hz,
1 H, H-7b, J = 5.5, 8.3, 13.5 Hz), 1.90 (m, 1 H, H-7a). 13
C
NMR (75 MHz, CDCl3): d = 140.8–129.0 (OCH2Ph), 90.9
(C-1), 87.1 (C-2), 74.9 (C-6), 74.7 (C-4), 74.5, 73.8, 73.4
(OCH2Ph), 70.4 (C-3), 68.4 (C-7a), 64.1 (C-5), 41.9 (C-7).
IR: 3383, 3030, 2858, 1496, 1453, 1363, 1100, 1067, 1027,
908, 733, 695, 607 cm–1. TOF MS (ESI): m/z calcd. for
C29H34NO4 [MH+]: 460.2488; found: 460.2181.
H-7a), 1.77 (ddd, 1 H, J = 3.4, 8.4, 12.3 Hz, H-7b). 13
C
NMR (150 MHz, CD3OD): d = 80.2 (C-2), 75.7 (C-1), 74.7
(C-6), 72.5 (C-3), 69.9 (C-8), 63.6 (C-5), 60.5 (C-4), 32.6
(C-7). IR: 3261, 2927, 2866, 2709, 1417, 1309, 1282, 1231,
1036, 972, 916, 901, 773, 719, 592, 538 cm–1. TOF MS
(ESI): m/z calcd for C29H34NO4 [MH+]: 190.1079; found:
190.1132.
Compound 12a: [a]D25 –14.2 (MeOH, c 0.26). 1H NMR (300
MHz, CD3OD): d = 4.55 (m, 1 H, H-6), 4.22 (dd, 1 H, H-1,
J = 7.9 Hz), 3.87 (m, 3 H, H-2, H-4a, H-4b), 3.71 (m, 1 H,
H-7a), 3.48 (m, 1 H, H-3), 3.35 (m, 2 H, H-5a, H-5b), 2.21
(m, 2 H, H-7a, H-7b). 13C NMR (75 MHz, CD3OD): d = 81.4
Synlett 2011, No. 12, 1668–1672 © Thieme Stuttgart · New York

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