New synthetic approach to C5-hydroxymethyl-substituted polyhydroxylated pyrrolizidines

Article abstract of DOI:10.1055/s-0033-1339123

A new approach to C5-hydroxymethyl-substituted pyrrolizidines involving 1,3-dipolar cycloaddition of a d-mannose-derived cyclic nitrone and the S _N-reaction of a silyl ketene acetal is presented. The synthesis shows good stereoselectivity as a result of the presence of a dioxolane substituent at C5 of the nitrone, the bulkiness of the silyl ketene acetal, and the shape of the pyrrolizidinylium intermediate formed during intramolecular reductive amination. This approach provides access to pyrrolizidines with the same relative configuration as that found in hyacinthacines C₂ and C ₃, and in (+)-pochonicine.Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1339123

1616▌
LETTER
lNetteerw Synthetic Approach to C5-Hydroxymethyl-Substituted Polyhydroxylated
Pyrrolizidines
Hydroxymethyl-Substituted Polyhydroxylated Pyrrolizidines
Daniela Beňadiková,a Michal Medvecký,a Alexandra Filipová,a Ján Moncoľ,b Milan Gembický,c Naďa Prónayová,d
Robert Fischer*a
a
Institute of Organic Chemistry, Catalysis and Petrochemistry, Slovak University of Technology, Radlinského 9, SK-812 37 Bratislava,
Slovak Republic
E-mail: robert.fischer@stuba.sk
b
Institute of Inorganic Chemistry, Technology and Materials, Slovak University of Technology, Radlinského 9, SK-812 37 Bratislava,
Slovak Republic
c
Bruker AXS Inc., 5465 East Cheryl Parkway, Madison, WI 53711-5373, USA
d
Institute of Analytical Chemistry, Department of NMR Spectroscopy and Mass Spectrometry, Slovak University of Technology,
Radlinského 9, SK-812 37 Bratislava, Slovak Republic
Received: 20.03.2014; Accepted after revision: 21.04.2014
isms, including insects, fungi, mammals, and a plant.4
Abstract: A new approach to C5-hydroxymethyl-substituted pyr-
Structurally, the compound was shown to be the first poly-
rolizidines involving 1,3-dipolar cycloaddition of a D-mannose-de-
hydroxylated pyrrolizidine alkaloid containing an acet-
rived cyclic nitrone and the SN-reaction of a silyl ketene acetal is
presented. The synthesis shows good stereoselectivity as a result of
amide group. Later, Takahashi and co-workers5 reported a
the presence of a dioxolane substituent at C5 of the nitrone, the total synthesis of the compound, revised its originally
bulkiness of the silyl ketene acetal, and the shape of the pyrrolizidi-
nylium intermediate formed during intramolecular reductive amina-
tion. This approach provides access to pyrrolizidines with the same
inhibitory activity of the compound against various β-N-
relative configuration as that found in hyacinthacines C2 and C3, and
in (+)-pochonicine.
published structure, and proposed its absolute configura-
tion. This absolute configuration, as well as the nanomolar
acetylglucosaminidases [for example, that of jack bean
(1.6 nM)], was confirmed by Kato and Yu and their co-
Key words: carbohydrates, heterocycles, nitrones, pyrrolizidines,
workers,6 who first synthesized natural (+)-pochonicine
stereoselective synthesis
(3; Figure 1), together with its enantiomer and other epi-
mers.
Polyhydroxylated pyrrolizidine alkaloids are an important
HO
OH
HO
HO
OH
OH
H
N
H
N
H
N
class of naturally occurring iminosugars that possess sig-
nificant biological activity as inhibitors of glycosidases.1
As a result, many routes have been developed for their
synthesis,2 including many total syntheses of hyacintha-
cines. New members of this class of compounds, namely
the hyacinthacines C2 (1) and C3 (2) have been isolated
from the bulbs of the plant Ledebouria socialis (formerly
Scilla socialis), and their structures were assigned as pen-
tahydroxylated pyrrolizidines with a hydroxymethyl sub-
stituent at C5 (Figure 1).3a Hyacinthacine C2 was found to
be a good inhibitor of bacterial β-glucosidase (IC50 = 13
μM) and human placenta α-L-fucosidase (IC50 = 17 μM).
Hyacinthacine C3 showed good inhibitory activity toward
bovine liver β-galactosidase (IC50 = 52 μM).3a The abso-
lute configuration of hyacinthacine C2 was confirmed by
synthesis but, unfortunately, the NMR spectra of synthetic
hyacinthacine C3 were not consistent with those of the
natural sample.3b Recently, Usuki et al. isolated a new al-
kaloid, pochonicine, from a solid fermentation culture of
the fungal strain Pochonia suchlasporia var. suchlasporia
TAMA 87.4 Pochonicine showed potent inhibitory activi-
ty against β-N-acetylglucosaminidases of various organ-
OH
OH
OH
HO
OH
HO
HO
OH
NHAc
1
2
3
hyacinthacine C2
hyacinthacine C3
(+)-pochonicine
Figure 1 C5-Hydroxymethyl-substituted naturally occurring poly-
hydroxylated pyrrolizidine alkaloids
As a part of our continuing interest in asymmetric 1,3-di-
polar cycloadditions, we have developed protocols for the
preparation of optically active nitrone templates from
sugars7 and we have used them in various transformations
to give analogues of alkaloids.8 In general, five-mem-
bered cyclic nitrones derived from monosaccharides (usu-
ally pentoses) permit short and efficient syntheses of
polyhydroxylated pyrrolizidine alkaloids.9a The stereose-
lectivity is controlled by the stereocenter at the C3 atom
of the nitrone, although in some cases the stereochemical
outcome can also depend on the relative configuration of
substituents at C3 and C5 (Scheme 1). Thus, attack of a di-
polarophile on a 3,5-cis-nitrone proceeds with high selec-
tivity from the less-hindered side, affording 3a,4-anti
pyrroloisoxazolidines,2b,j,o,9 whereas cycloadditions of
3,5-trans-nitrones provide both 3a,4-anti and 3a,4-syn
isomers with poor to moderate anti selectivity.2m,n,10 Most
SYNLETT 2014, 25, 1616–1620
Advanced online publication: 03.06.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339123; Art ID: st-2014-d0242-l
© Georg Thieme Verlag Stuttgart · New York

LETTER
Hydroxymethyl-Substituted Polyhydroxylated Pyrrolizidines
1617
of the cycloadditions proceed through an exo approach to synthetic strategy towards C5-hydroxymethyl-substituted
give the major 2,3a-trans-isomer.
pyrrolizidines A (Scheme 2) is based on a cascade/tandem
intramolecular reductive amination and N–O bond cleav-
age of the bicyclic isoxazolidine B. Isoxazolidine B might
be prepared by a Lewis acid-catalyzed SN-reaction of a si-
lyl ketene acetal with acetoxyisoxazolidine C bearing a
good leaving group at C2, which should be readily avail-
able by a 1,3-dipolar cycloaddition of the cyclic nitrone D.
O
1N
preferred exo-anti
approach
dipolarophile
O1
R1O
R1O
7
N
R2
5
6
2
R1O
2
5
3a
4
3
3
R1O
OR1
R3
4
H
OR1
3a,4-anti-2,3a-trans
R1O
3,5-cis nitrone
In this communication, we wish to report a new synthetic
approach to C5-hydroxymethyl-substituted pyrroli-
zidines, with a focus on the stereochemical outcome of the
key steps of the synthesis.
O
R2
N
2
3a
R1O
R3
4
First, we examined the reaction of the silyl ketene acetal 5
with a 5-acetoxyisoxazolidine to give a masked α-keto es-
ter, suitable as an intermediate for intramolecular reduc-
tive amination (Scheme 2). Previously, similar SN-
reactions catalyzed by Lewis acids have been reported
only for a few furanose derivatives.12 Silyl ketene acetal 5
was prepared by the method described in the literature,13
and it was treated with isoxazolidine 4a,b in the presence
of trimethylsilyl triflate (Scheme 3). The reaction was car-
H
OR1
O
3a,4-anti-2,3a-trans
N
5
dipolarophile
R1O
+
3
R1O
R1O
O
R2
R1O
OR1
N
2
3,5-trans nitrone
3a
R3
4
H
OR1
3a,4-syn-2,3a-trans
Scheme 1 The stereoselectivity of 1,3-dipolar cycloadditions de- ried out at –80 °C in anhydrous dichloromethane and, af-
pends on the relative configuration at the C3 and C5 positions of the
five-membered cyclic nitrene.
ter one hour, gave the isomeric isoxazolidines (±)-6a,b in
a 90:10 in favor of the 3,5-trans-isomer 6a, which was
isolated by flash column chromatography in 67% yield.14
The high stereoselectivity is probably the result of the for-
2. intramolecular
reductive
amination
3. reduction
of ester group
mation of the thermodynamically more stable product.
1. N–O bond
Having obtained these results, we focused our interest on
the synthesis of pyrrolizidine derivatives (Scheme 4). The
known nitrone 7, derived from D-mannose, which has the
desired relative configuration at C1, C2, and C3 for sub-
sequent synthesis of pyrrolizidines similar to alkaloids 1–
3, was prepared in six steps by a slight modification of a
procedure described elsewhere.15 To the best of our
knowledge, the use of vinyl acetate in 1,3-dipolar cyclo-
addition reactions of cyclic nitrones has not previously
been documented. Moreover, the use of nitrone 7 in cyclo-
additions has not been examined; only its 1,3-dipolar ad-
ditions have been reported.16 The bulky dioxolane
substituent might play an important role in the stereo-
chemical course of the cycloaddition reaction to achieve
better 3a,4-syn selectivity. The dioxolane substituent can
later be transformed into C3-hydroxymethyl or amino-
methyl substituents on the target pyrrolizidines by reduc-
tion or reductive amination, respectively, of the
corresponding aldehyde formed by oxidative cleavage of
the diol after deprotection.
cleavage
O
OMe
O
HO
OH
RO
4
N
O
3
1
5
N
2
HO
6
OH
7
7a
RO
HO
OR
A
B
O
N
RO
O
OAc
N
RO
RO
RO
OR
OR
C
D
Scheme 2 Retrosynthetic analysis of C5-hydroxymethyl-substituted
pyrrolizidines from five-membered cyclic nitrone.
In line with our initial research in the field of stereoselec-
tive synthesis of 5-substituted isoxazolidines by using in-
termediate
5-acyloxyisoxazolidines11a,b
and
4,5-
unsubstituted 2,3-dihydroisoxazoles,11c we became inter-
ested in pyrroloisoxazolidines as promising precursors for
the preparation of pochonicine-related compounds. Our
The 1,3-dipolar cycloaddition was performed in neat vinyl
acetate in a sealed tube and gave a mixture of two isoxa-
O
OMe
OTMS
OMe
TMSOTf
(1 equiv)
O
O
Bn
OAc
Bn
OMe
MeO
N
N
+
OMe
CH2Cl2 (0.5 M)
–80 °C, 1 h
6a (67%)
OMe
Ph
Ph
4a,b
1 equiv
5
( )-6a,b
3,5-trans-a/3,5-cis-b (90:10)
2 equiv
Scheme 3
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1616–1620

1618
D. Beňadiková et al.
LETTER
O
O
O
O
O
OMe
OMe
OTBDPS
OMe
O
O
O
1
O
O
O
O
O
H
O
H
N
H
N
H
N
H
N
O
H
O
H
O
H
N
2
OAc
OAc
6
a
b
c, d
5
OMe
OMe
+
3
3a H
O
O
O
O
from 8a
4
O
O
O
O
O
7
8a
8b
9
10
OH
HO
O
O
H
H
H
OTBDPS
HO
O
O
g
e
H
f
h
HO
HO
HO
O
H
OH
N
N
N
N
H
H
O
H
TBDPSO
HO
OH
HO
OH
OH
O
O
OH
OH
OH
11
12
13
14
Scheme 4 Reagents and conditions: (a) vinyl acetate, sealed tube, 75 °C, 18 h, 8a/8b 87:13, 8a 78%; (b) (MeO)2C=C(OTMS)(OMe) 5 (2
equiv), TMSOTf (1 equiv), CH2Cl2 (0.5 M), –80 °C, 1 h, 9 dr >95:5, 69%; (c) LiAlH4 (2 equiv), THF (0.1 M), 0 °C, 30 min, 89%; (d) TBDPSCl
(2 equiv), imidazole (4.2 equiv), CH2Cl2 (0.5 M), r.t. 12 h, 94%; (e) 80% aq AcOH, 60 °C, 16 h, 55%; (f) H2 (1 atm), Pd/C (10%), EtOH, r.t.,
12 h, 79%; (g) TBAF (1.5 equiv), THF (0.1 M), r.t., 2 h, 80%; (h) TFA–H2O (1:1), r.t., 12 h then Dowex (Marathon MSC, H+ form), 95%. The
8a/8b ratio was determined by 1H and 13C NMR spectroscopic analysis of the crude reaction mixture.
zolidines 8a and 8b in a ratio of 87:13. The major isomer ried out by hydrogen-mediated intramolecular reductive
8a was separated by flash column chromatography in 78% amination2d,i,l,n and gave a single isomer of pyrrolizidine
yield. Its structure was assigned by NMR studies, includ- 12, which was isolated by flash column chromatography
ing nuclear Overhauser effect (NOE) experiments, and its in 79% yield. Removal of the silyl protecting group with
absolute configuration was confirmed by X-ray crystallo- tetrabutylammonium fluoride followed by hydrolysis of
graphic analysis (Figure 2).17 In accord with our expecta- the remaining isopropylidene group gave the hexahydrox-
tions, the reaction predominantly proceeds from the less- ylated pyrrolizidine 14 in 76% yield over two steps.
hindered face opposite the dioxolane substituent through
exo attack to provide the desired 3a,4-syn-2,3a-trans-
isoxazolidine 8a with excellent syn selectivity.
The structure of pyrrolizidine 13 was characterized spec-
troscopically by a series of selective one-dimensional
NOESY experiments and two-dimensional ROESY ex-
periments.19 The spectra showed strong NOE interactions
between H-5 and H-6, H-6 and H-7a, H-7a and H-7a, H-1
and H-7a, H-1 and H-2, and H-2 and H-1′ (Figure 3). The
3,5-trans-5,6-cis relative configuration was also con-
firmed by the presence of interactions between H-3 and
H-CH2OH and between H-7b and H-CH2OH.
β-face
Ha
H
O
H
H
H
N
O
O
O
Hb
HO
7
1
7a
O
HO
2
Figure 2 Molecular geometries, thermal ellipsoids, and numbering
scheme for 8a
H
5
N
H
H
TBDPSO
H
H
1'
HO
OH
2'
O
H
α-face
H
H
A subsequent SN-reaction of compound 8a with silyl ke-
tene acetal 5 gave the single 2,3a-trans-isoxazolidine 9
exclusively in 69% yield.18 Unfortunately, we experi-
enced serious difficulties with the hydrolysis of the di-
methyl acetal group adjacent to the ester group. We
therefore first reduced the methyl ester with lithium alu-
minum hydride in tetrahydrofuran at 0 °C; subsequent
protection with tert-butyl(diphenyl)silyl chloride gave the
isoxazolidine 10 in a total yield of 84% after two steps. Fi-
nally, the dimethyl acetal was readily removed in aqueous
acetic acid at 60 °C. The reduced yield of compound 11
(55%) was the result of further hydrolysis of the second
isopropylidene group. Subsequent ring closure was car-
OH
intramolecular
reductive amination of 11
13
Figure 3 NOE enhancements observed in compound 13, and the
proposed attack of hydrogen during intramolecular reductive amina-
tion of 11
The stereoselectivity of the intramolecular reductive ami-
nation can be explained in terms of the shape of the pyrro-
lizidinylium intermediate (Figure 3). This predominantly
allows hydrogen to approach from the less-hindered α-
face,2e affording the desired isomer 12, whereas attack
from the β-face seems to be disfavored.
Synlett 2014, 25, 1616–1620
© Georg Thieme Verlag Stuttgart · New York

LETTER
Hydroxymethyl-Substituted Polyhydroxylated Pyrrolizidines
1619
Moreno-Clavijo, E.; Robina, I.; Cardona, F. Eur. J. Org.
Chem. 2011, 7155. (n) Gkizis, P.; Argyropoulos, N. G.;
Coutouli-Argyropoulou, E. Tetrahedron 2013, 69, 8921.
(o) Martella, D.; Cardona, F.; Parmeggiani, C.; Franco, F.;
Tamayo, J. A.; Robina, I.; Moreno-Clavijo, E.; Moreno-
Vargas, A. J.; Goti, A. Eur. J. Org. Chem. 2013, 4047.
(p) Marjanovic, J.; Divjakovic, V.; Matovic, R.; Ferjancic,
Z.; Saicic, R. N. Eur. J. Org. Chem. 2013, 5555.
(q) Rajender, A.; Rao, J. P.; Rao, B. V. Eur. J. Org. Chem.
2013, 1749. (r) Xu, W.-Y.; Iwaki, R.; Jia, Y.-M.; Zhang, W.;
Kato, A.; Yu, C.-Y. Org. Biomol. Chem. 2013, 11, 4622; and
references cited therein.
In conclusion, we have developed a new synthetic ap-
proach to C5-hydroxymethyl-substituted pyrrolizidines.
The presence of a dioxolane substituent at C5 of the five-
membered cyclic nitrone 7, derived from D-mannose, in-
duced excellent syn-selectivity in the 1,3-dipolar cycload-
dition with vinyl acetate. The novel nucleophilic
substitution of acetoxyisoxazolidine 8a with the silyl ke-
tene acetal 5, derived from α,α-dimethoxyacetate, pro-
ceeded exclusively from the less-hindered side of the
pyrroloisoxazolidine. Finally, hydrogen-mediated intra-
molecular reductive amination predominantly gave the
pyrrolizidine 12 with the desired 5,7a-cis relative config-
uration.
(3) (a) 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, 993. (b) Sengoku, T.; Satoh, Y.; Takahashi,
M.; Yoda, H. Tetrahedron Lett. 2009, 50, 4937.
(4) Usuki, H.; Toyo-oka, M.; Kanzaki, H.; Okuda, T.; Nitoda, T.
Bioorg. Med. Chem. 2009, 17, 7248.
Acknowledgment
(5) Kitamura, Y.; Koshino, H.; Nakamura, T.; Tsuchida, A.;
Nitoda, T.; Kanzaki, H.; Matsuoka, K.; Takahashi, S.
Tetrahedron Lett. 2013, 54, 1456.
(6) Zhu, J.-S.; Nakagawa, S.; Chen, W.; Adachi, I.; Jia, Y.-M.;
Hu, X.-G.; Fleet, G. W. J.; Wilson, F. X.; Nitoda, T.; Horne,
G.; van Well, R.; Kato, A.; Yu, C.-Y. J. Org. Chem. 2013,
78, 10298.
(7) (a) Fišera, L. In Heterocycles from Carbohydrate
Precursors; El Ashry, E. S. H., Ed.; Springer: Berlin, 2007,
287. (b) Dugovič, B.; Fišera, L.; Reißig, H.-U. Eur. J. Org.
Chem. 2008, 277.
(8) (a) Rehák, J.; Fišera, L.; Kožíšek, J.; Bellovičová, L.
Tetrahedron 2011, 67, 5762. (b) Podolán, G.; Kleščíková,
L.; Fišera, L.; Kožíšek, J.; Fronc, M. Synlett 2011, 1668.
(c) Podolán, G.; Fišera, L.; Kožíšek, J.; Fronc, M.
Heterocycles 2012, 84, 683.
(9) (a) Brandi, A.; Cardona, F.; Cicchi, S.; Cordero, F. M.; Goti,
A. Chem. Eur. J. 2009, 15, 7808. (b) Carmona, A. T.;
Whigtman, R. H.; Robina, I.; Vogel, P. Helv. Chim. Acta
2003, 86, 3066. (c) Toyao, A.; Tamura, O.; Takagi, H.;
Ishibashi, H. Synlett 2003, 35. (d) Cardona, F.; Parmeggiani,
C.; Faggi, E.; Bonaccini, C.; Gratteri, P.; Sim, L.; Gloster, T.
M.; Roberts, S.; Davies, G. J.; Rose, D. R.; Goti, A. Chem.
Eur. J. 2009, 15, 1627.
(10) Holzapfel, C. W.; Crous, R. Heterocycles 1998, 48, 1337.
(11) (a) Fischer, R.; Drucková, A.; Fišera, L.; Hametner, C.
ARKIVOC 2002, (viii), 80. (b) Fischer, R.; Stanko, B.;
Prónayová, N. Synlett 2013, 24, 2132. (c) Fischer, R.;
Lackovičová, D.; Fišera, L. Synthesis 2012, 44, 3783.
(12) (a) Narasaka, K.; Ichikawa, Y.-i.; Kubota, H. Chem. Lett.
1987, 16, 2139. (b) Ichikawa, Y.-i.; Kubota, H.; Fujita, K.;
Okauchi, T.; Narasaka, K. Bull. Chem. Soc. Jpn. 1989, 62,
845. (c) Mukaiyama, T.; Uchiro, H.; Hirano, N.; Ishikawa,
T. Chem. Lett. 1996, 25, 629.
The authors are gratefully to the Slovak Grant Agencies (APVV,
Bratislava, project No. APVV-0203-10; VEGA, projects No.
1/0972/12 and No. 1/0488/14 and ASFEU, Bratislava, ITMS pro-
jects No. 26240120001, 26240120025).
References
(1) (a) Asano, N.; Kuroi, H.; Ikeda, H.; Kizu, H.; Kameda, Y.;
Kato, A.; Adachi, I.; Watson, A. A.; Nash, R. J.; Fleet, G. W.
J. Tetrahedron: Asymmetry 2000, 11, 1. (b) Asano, N.; Nash,
R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron:
Asymmetry 2000, 11, 1645. (c) Compain, P.; Martin, O. R.
Bioorg. Med. Chem. 2001, 9, 3077. (d) Watson, A. A.; Fleet,
G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J.
Phytochemistry 2001, 56, 265. (e) Iminosugars: From
Synthesis to Therapeutic Applications; Compain, P.; Martin,
O. R., Eds.; Wiley: Chichester, 2007. (f) Asano, N. In
Modern Alkaloids: Structure, Isolation, Synthesis and
Biology: Fattorusso E; Taglialatela-Scafati, O., Ed.; Wiley-
VCH: Weinheim, 2008. (g) Winchester, B. G. Tetrahedron:
Asymmetry 2009, 20, 645. (h) Gloster, T. M.; Davies, G. J.
Org. Biomol. Chem. 2010, 8, 305. (i) Best, D.; Wang, C.;
Weymouth-Wilson, A. C.; Clarkson, R. A.; Wilson, F. X.;
Nash, R. J.; Miyauchi, S.; Kato, A.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2010, 21, 311. (j) Horne, G.;
Wilson, F. X. Prog. Med. Chem. 2011, 50, 135. (k) Nash, R.
J.; Kato, A.; Yu, C.-Y.; Fleet, G. W. J. Future Med. Chem.
2011, 3, 1513. (l) Gloster, T. M. Biochem. Soc. Trans. 2012,
40, 913; and references cited therein.
(2) (a) Davis, B. J. Tetrahedron: Asymmetry 2009, 20, 652.
(b) Tamayo, J. A.; Franco, F.; Lo Re, D.; Sánchez-Cantalejo,
F. J. Org. Chem. 2009, 74, 5679. (c) Affolter, O.; Baro, A.;
Frey, W.; Laschat, S. Tetrahedron 2009, 65, 6626. (d) Ribes,
C.; Falomir, E.; Carda, M.; Marco, J. A. Tetrahedron 2009,
65, 6965. (e) Izquierdo, I.; Plaza, M.; Tamayo, J. A.; Franco,
F.; Sánchez-Cantalejo, F. Tetrahedron 2010, 66, 3788.
(f) Tamayo, J. A.; Franco, F.; Sánchez-Cantalejo, F.
Tetrahedron 2010, 66, 7262. (g) Delso, I.; Tejero, T.; Goti,
A.; Merino, P. Tetrahedron 2010, 66, 1220.
(13) Malhiac, C.; Tekin, J.; Ramiandrasoa, G.; Leveque, H.;
Combret, J.-C. Phosphorus, Sulfur Silicon Relat. Elem.
1995, 102, 127.
(14) Methyl (±)-(2-Benzyl-3-phenylisoxazolidin-5-
yl)(dimethoxy)acetate (6a); Typical Procedure
The reaction flask was charged with 5-
(h) Ritthiwigrom, T.; Nash, R. J.; Pyne, S. G. Tetrahedron
2010, 66, 9340. (i) Garrabou, X.; Gómez, L.; Joglar, J.; Gil,
S.; Parella, T.; Bujons, J.; Clapés, P. Chem. Eur. J. 2010, 16,
10691. (j) Bonaccini, C.; Chioccioli, M.; Parmeggiani, C.;
Cardona, F.; Lo Re, D.; Soldaini, G.; Vogel, P.; Bello, C.;
Goti, A.; Gratteri, P. Eur. J. Org. Chem. 2010, 5574.
(k) Brock, E. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.;
Thomson, J. E. Org. Lett. 2011, 13, 1594. (l) Tamayo, J. A.;
Franco, F.; Sánchez-Cantalejo, F. Eur. J. Org. Chem. 2011,
7182. (m) D’Adamio, G.; Goti, A.; Parmeggiani, C.;
acetoxyisoxazolidines 4a,b (1.13 g, 3.80 mmol), sealed with
a rubber septum, and filled with argon. Anhydrous CH2Cl2
(8 mL) was added and the solution was cooled to –80 °C.
Silyl ketene acetal 5 (1.57 g, 7.61 mmol) and TMSOTf (0.69
mL, 3.80 mmol) were added successively and the mixture
was stirred at –80 °C for 1 h. When the starting material had
disappeared (TLC; hexanes–EtOAc, 70:30), the reaction
was quenched by adding sat. aq NaHCO3 (10 mL). The
mixture was allowed to warm to r.t., CH2Cl2 (10 mL) was
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1616–1620

1620
D. Beňadiková et al.
LETTER
added, and the mixture was vigorously stirred for 5 min. The
organic layer was then separated and the aqueous layer was
extracted with CH2Cl2 (2 × 10 mL). The organic layers were
combined, washed with H2O, dried (Na2SO4), filtered, and
concentrated in vacuo. Column chromatography [silica gel,
hexanes–EtOAc (80:20)] gave a colorless solid; yield: 0.95
g (2.56 mmol, 67%); mp 78–80 °C (hexanes); 1H NMR (600
MHz, CDCl3): δ = 2.63 (ddd, J = 12.8, 8.4, 7.1 Hz, 1 H, H-
4a), 2.75 (ddd, J = 12.8, 10.2, 7.0 Hz, 1 H, H-4b), 3.28 (s, 3
H, OCH3), 3.41 (s, 3 H, OCH3), 3.61 (s, 3 H, OCH3), 3.68–
3.73 (m, 2 H, H-3, CH2Ph), 3.94 (d, J = 14.5 Hz, 1 H,
CH2Ph), 4.52 (dd, J = 8.4, 7.0 Hz, 1 H, H-5), 7.17–7.41 (m,
10 H, Ph); 13C NMR (150.1 MHz, CDCl3): δ = 39.8, 50.4,
50.8, 52.7, 59.2, 70.0, 76.8, 102.0, 127.0, 127.9 (2 C), 128.0,
128.6, 129.5, 136.9, 138.4, 167.9.
–0.03(12); maximum and minimum residual densities 0.15
and –0.15 eÅ–3, respectively.
Crystallographic data for compound 8a have been deposited
with accession number CCDC 883297, and can be obtained
free of charge from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax:
+44(1223)336033; E-mail: deposit@ccdc.cam.ac.uk; Web
site: www.ccdc.cam.ac.uk/conts/retrieving.html.
(18) Methyl {(3aS,4S,7S,8aS,8bR)-4-[(4S)-2,2-Dimethyl-1,3-
dioxolan-4-yl]-2,2-dimethylhexahydro[1,3]dioxolo[3,4]-
pyrrolo[1,2-b]isoxazol-7-yl}(dimethoxy)acetate (9)
Colorless oil; yield: 430 mg (69%); [α]D20 +59.80 (c 0.99,
CHCl3). 1H NMR (600 MHz, CDCl3): δ = 1.29 (s, 6 H, 2 ×
CH3), 1.34 (s, 3 H, CH3), 1.47 (s, 3 H, CH3), 2.62 (ddd, J =
12.8, 8.9, 1.3 Hz, 1 H, H-3a), 2.81 (ddd, J = 13.0, 8.3, 5.5 Hz,
1 H, H-3b), 3.30 (s, 3 H, OCH3), 3.40 (s, 3 H, OCH3), 3.77–
3.68 (m, 2 H, H-6, H-3a), 3.82 (s, 3 H, OCH3), 3.96 (d, J =
7.1 Hz, 2 H, H-5′a,b), 4.24 (td, J = 7.1, 2.8 Hz, 1 H, H-4′), 4.42
(dd, J = 8.9, 5.5 Hz, 1 H, H-2), 4.66 (dd, J = 5.4, 6.1 Hz, 1
H, H-4), 4.82 (dd, J = 6.3, 1.4 Hz, 1 H, H-5). 13C NMR
(150.1 MHz, CDCl3): δ = 24.4, 25.0, 26.0, 26.5, 31.0, 50.3,
50.7, 52.9, 66.2, 69.6, 71.7, 76.4, 77.1, 83.1, 86.1, 101.8,
109.5, 112.9, 167.6.
(19) (1S)-1-[(3aS,4S,6S,7S,8aS,8bR)-7-Hydroxy-6-(hydroxy-
methyl)-2,2-dimethylhexahydro-4H-[1,3]dioxolo[4,5-a]-
pyrrolizin-4-yl]ethane-1,2-diol (13): Selected NMR Data
1H NMR (600 MHz, CDCl3): δ = 1.35 (s, 3 H, CH3), 1.57 (s,
3 H, CH3), 2.06 (td, J = 14.1, 3.7 Hz, 1 H, H-7b), 2.26 (ddd,
J = 14.1, 7.7, 6.4 Hz, 1 H, H-7a), 3.43 (dd, J = 10.5, 4.9 Hz,
1 H, H-5), 3.56 (dd, J = 9.7, 4.7 Hz, 1 H, H-1′), 3.64 (dd, J =
11.5, 4.7 Hz, 1 H, H-2′a), 3.68 (d, J = 4.7 Hz, 1 H, H-3), 3.71
(dd, J = 11.5, 4.7 Hz, 1 H, H-2′b), 3.82–3.87 (m, 2 H, H-7a,
CH2OH), 3.97 (dd, J = 12.3, 4.7 Hz, 1 H, CH2OH), 4.35 (dd,
J = 9.7, 5.0 Hz, 1 H, H-6), 4.59 (t, J = 5.2 Hz, 1 H, H-1), 4.73
(dd, J = 5.7, 1.3 Hz, 1 H, H-2). 13C NMR (150.1 MHz,
CDCl3): δ = 23.7, 25.5, 33.2, 61.0, 64.2, 65.3, 66.1, 66.6,
73.0, 74.0, 82.4, 86.9, 112.8.
(15) Tamura, O.; Toyao, A.; Ishibashi, H. Synlett 2002, 1344.
(16) (a) Masson, G.; Cividino, P.; Py, S.; Vallée, Y. Angew.
Chem. Int. Ed. 2003, 42, 2265. (b) Kaliappan, K. P.; Das, P.;
Chavan, S. T.; Sabharwal, S. G. J. Org. Chem. 2009, 74,
6266. (c) Li, X.; Qin, Z.; Wang, R.; Chen, H.; Zhang, P.
Tetrahedron 2011, 67, 1792. (d) Bandaru, A.; Kaliappan, K.
P. Synlett 2012, 23, 1473. (e) Fu, Y.; Liu, Y.; Chen, Y.;
Hügel, H. M.; Wang, M.; Huang, D.; Hu, Y. Org. Biomol.
Chem. 2012, 10, 7669. (f) Kui, E. L.; Kanazawa, A.;
Poisson, J.-F.; Py, S. Tetrahedron Lett. 2013, 54, 5103.
(g) Khangarot, R. K.; Kaliappan, K. P. Eur. J. Org. Chem.
2013, 2692.
(17) Crystallographic Data Collection and Refinement
X-ray data were collected on a Bruker Kappa APEX Ultra
diffractometer with mirror-monochromated Cu Kα radiation
with a rotating anode Nonius FR951 at 100 K. The structure
was solved by direct methods using SHELXS-97 [see ref.
20a], refined by a full-matrix least-squares procedure with
CRYSTALS [ver. 14.43; see ref. 20b], and drawn with the
OLEX2 package [see ref. 20c]. The chirality of carbon atoms
was confirmed by using the PLATON program [see ref. 20d]
for C1(S), C3(S), C4(R), C5(S), C6(S), and C7(S).
X-ray Data for C16H25NO7 (8a)
(20) (a) Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112.
(b) Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout,
K.; Watkin, D. J. J. Appl. Crystallogr. 2003, 36, 1487.
(c) Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard,
J. A. K.; Puschmann, H. J. Appl. Crystallogr. 2009, 42, 339.
(d) Spek, A. L. Acta Crystallogr., Sect. D 2009, 65, 148.
Monoclinic, space group, P21, a = 8.6080(5), b = 9.8526(6),
c = 10.6718(6) Å, β = 103.018(2)°, V = 881.83(9) Å3, Z = 2;
final R = 0.0255, Rw = 0.0657, S = 1.004, Flack parameter
Synlett 2014, 25, 1616–1620
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.