Synthesis of trihydroxylated pyrrolizidine and indolizidine alkaloids based on SmI2-induced reductive coupling of chiral nitrones with methyl acrylate

Article abstract of DOI:10.1016/j.tet.2011.05.129

Synthesis of trihydroxylated pyrrolizidines, the enantiomer of 2-epihyacinthacine A₂ and indolizidine analogues of the natural alkaloids is reported. The key step of these syntheses is the stereoselective samarium diodide-induced coupling of th

Full text of DOI:10.1016/j.tet.2011.05.129

Tetrahedron 67 (2011) 5762e5769
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Synthesis of trihydroxylated pyrrolizidine and indolizidine alkaloids based on
SmI2-induced reductive coupling of chiral nitrones with methyl acrylate
a
a
,
b
ꢀ b
*
ꢀ
ꢁ
ꢁ ꢁ
ꢁ
Juraj Rehak , Lubor Fisera , Jozef Kozísek , Lenka Bellovicova
a Institute of Organic Chemistry, Catalysis and Petrochemistry, Slovak University of Technology, SK-812 37 Bratislava, Slovak Republic
b Institute of Physical Chemistry and Chemical Physics, Slovak University of Technology, SK-812 37 Bratislava, Slovak Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of trihydroxylated pyrrolizidines, the enantiomer of 2-epihyacinthacine A2 and indolizidine
analogues of the natural alkaloids is reported. The key step of these syntheses is the stereoselective
Received 22 March 2011
Received in revised form 11 May 2011
Accepted 31 May 2011
samarium diodide-induced coupling of the chiral nitrone prepared from
D-ribose with methyl acrylate.
The nitrone derived from -ribose possessing C2/C3 syn configuration reacted with methyl acrylate in the
D
Available online 13 June 2011
presence of samarium diiodide in excellent yield and diastereoselectivity, with only the anti-di-
astereomer being detected.
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Pyrrolizidine
Indolizidine
Alkaloids
Nitrones
Samarium diiodide
1. Introduction
synthesis of chiral pyrrolidines from sugar-derived nitrones.
Recently we have found that the reaction course of samarium
The polyhydroxylated alkaloids are a group of biologically active
natural compounds that inhibit glycosidases and glycosyl-
transferases.1 Selective inhibition of these enzymes is used in
treating viral or microbial diseases and to treat cancer and meta-
bolic disorders.2 Asano et al. isolated a group of promising natural
polyhydroxylated pyrrolizidines from plants of the genus Hyacen-
thacea.3 These trihydroxylated alkaloids were found to inhibit
diiodide-induced reductive coupling of chiral nitrones with methyl
acrylate is dependent on the structure of the starting chiral nitrone.
Nitrones possessing a C2/C3 syn configuration reacted with
methyl acrylate to give g-N-hydroxylamino esters with high dia-
stereocontrol.11 On the other hand, the coupling of nitrones pos-
sessing C2/C3 anti-configuration with methyl acrylate proceeded
more slowly and the g-N-hydroxylamino esters were obtained as
minor products along with products resulting from an unexpected
reductive deoxygenation of the starting nitrone.
4
a broad range of glycosidases and subsequently hyacinthacine A1
5
and hyacinthacine A2 were synthesized. In addition, to the natu-
ral products, attention has been paid to the preparation of stereo-
Herein we report the synthesis of trihydroxylated pyrrolizidine
and indolizidine alkaloids, in particular the enantiomer of
2-epihyacinthacine 2 and indolizidine 20,11 structurally related to
the hyacinthacine alkaloids.3 Retrosynthetic analysis of target
products 1 and 2 provided a suitably functionalized precursor
pyrrolidine 3 (Scheme 1). The intermediate 3 possesses a primary
hydroxyl group in position 1 protected as its tert-butyldimethylsilyl
ether and a secondary hydroxyl group on carbon 2 activated for SN2
substitution as a mesylate. For the preparation of 7a-epi-hyacin-
thacine A1 1, a double inversion at the stereogenic center of the
pyrrolidine 3 in position 2 is necessary. Alternatively, 3,7a-di-epi-
hyacinthacine A1 2 could be available from the pyrrolidine 3 after
a single inversion at the stereogenic center in position 2. In-
termediate 3 can be prepared relatively straightforwardly from
isomeric trihydroxylated pyrrolizidine analogues.6
Nitrones have become important building blocks in organic
synthesis.7 During recent years we have developed protocols for
the preparation of optically active nitrone templates for the
asymmetric 1,3-dipolar cycloadditions.8 These nitrones have re-
cently been used in a samarium diiodide-induced umpolung pro-
cedure, undergoing reductive coupling with
a,b-unsaturated
esters,9aed ketones or aldehydes9eeg and alkylsulfinyl imines9h to
afford intermediates suitable for the preparation of biologically
active substances.5d,10 Since this methodology represents a general
route to g-N-hydroxylamino esters, we turned our attention to the
g
-N-hydroxyamino ester 4, which can be obtained by SmI2 induced
* Corresponding author. Tel.: þ421 2 59325169; e-mail address: lubor.fisera@
reaction of nitrone 5 with methyl acrylate. On the basis of our
ꢁ
stuba.sk (L. Fisera).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.129

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J. Rehak et al. / Tetrahedron 67 (2011) 5762e5769
5763
the treatment with HgCl2 and HgO in acetone.15 The reaction
afforded the chiral aldehyde that was directly used in condensation
with N-benzylhydroxylamine to give 5 in 82% yield over two steps
(Scheme 2).16 The nitrone 5 was then used in the samarium
diiodide-induced reductive coupling with methyl acrylate.9e11 This
reaction provided the expected adduct 4 in the excellent 95% yield
and diastereoselectivity greater than 95:5, with only the anti-di-
OH
OH
H7a
N
H7a
N
N
7
7
1
1
PG
MsO
TBDMSO
6
6
OH
OH
2
2
2
O
3
3
5
5
1
O
OH
OH
8
8
7a-epi-hyacinthacine A1
1
3
3,7a-di-epi-hyacinthacine A1
2
astereomer being detected (Scheme 2). The chiral pure
g-N-
hydroxylamino ester 4 was next transformed to the chiral pyrroli-
dinone 9 by reductive cleavage of the NeO bond of the N-hydrox-
ylamino group with zinc in acetic acid in 82% yield (Scheme 3).
Subsequent X-ray analysis of the pyrrolidinone 9 confirmed the
anti-configuration of the new stereogenic centers at C3/C4, which is
consistent with our previous observation,9 as well as the results
presented by Py and Vallee (Scheme 3, Fig. 1).10,11
MeO2C
Bn
N
O
O
OH
4
5
O
O
4
O
Bn
N
HO
4
N
N
Bn
O
Bn
O
O
O
O
O
LiAlH4, THF,
reflux, 94%
Zn, AcOH, H2O,
THF, 50 °C, 82%
OH
O
4
O
CO2Me
+
5
O
O
O
O
O
HO
OH
O
10
9
5
AcOH, H2O,
40 °C, 47%
Scheme 1. Retrosynthetic pathway for 7a-epi-hyacinthacine A1 1 and 3,7a-di-epi-hy-
acinthacine A1 2.
O
H
N
N
Bn
Bn
HO
HO
previous results we expected that g-N-hydroxyamino ester 4 thus
formed would have an anti-configuration for the new stereogenic
centers.
MsCl, pyridine,
from -20 °C to rt.
TBDMSCl, DCM,
O
HO
N
O
imidazole, rt,
O
99%
Bn
O
TBDMSO
O
Cl
OTBDMS
13
12
11
TEA, toluene,
KI, 165 °C, two
steps, 79%
2. Results and discussion
The chiral
that had been initially protected with propane-2-thiol in concen-
trated hydrochloric acid.12 The
-ribo diisopropyl dithioacetal 6
D
-ribo nitrone 5 was prepared starting from
D-ribose
OH
O
O
H
H
1) HCl, H2O, MeOH, rt.
2) Amberlite©, 99%
D
OH
OH
N
N
obtained in 63% yield was next protected with 2,2-
dimethoxypropane in THF in the presence of a catalytic amount
OTBDMS
14
2
of PTSA;4a the desired 2,3:4,5-di-O-isopropylidene-
D
-ribose diiso-
propyl-dithioacetal 7 being obtained in 79% yield. In addition to the
expected product 7 2,5:3,4-di-O-isopropylidene- -ribose dithioa-
Scheme 3. Preparation of pyrrolizidine 2.
D
The pyrrolidinone 9 was finally reduced to pyrrolidine 10 using
LiAlH4 in an excellent yield of 94%. Next, we tried to remove the
terminal isopropylidene group from the 10 using Zn(NO3)2$6H2O17
and InCl3,18 unsuccessfully with decomposition being observed.
The required dihydroxypyrrolidine 11 could however be prepared
cetal 8 was also isolated in a yield of 13% (Scheme 2).
S
S
O
O
O
HO
OH OH
O
O
OH
HO
(CH3)2C(OCH3)2,
(CH3)2CHSH,
HCl, rt, 63%
S
7
THF, PTSA, 60 °C,
OH
S
HO
OH
7: 79%, 8: 13%
6
D-Ribose
O
O
S
S
O
O
8
MeO2C
Bn
N
Bn
1) HgCl2, HgO,
N
OH
O
O
O
O
methyl acrylate,
acetone, reflux
O
7
SmI2, H2O, THF,
-80 °C, 99%,
d.r.: >95:5
2) BnNHOH, MgSO4,
DCM, rt, 82%
O
O
O
O
5
4
Scheme 2. Preparation of nitrone 5, followed by SmI2 induced cross-coupling.
This finding is consistent with results of Edgar13 and Kumar.14
The structure of 7 and 8 was deduced by NMR spectroscopic
analysis and definitively determined by X-ray structural analysis of
the pyrrolidinones 9 and 23. Next the dithioacetal protecting group
was removed from di-O-isopropylidene- -ribose dithioacetal 7 by
D
Fig. 1. X-ray structure of pyrrolidinone 9.

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J. Rehak et al. / Tetrahedron 67 (2011) 5762e5769
5764
only byslow hydrolysis of pyrrolidine 10 in 80% acetic acid at 40 ꢀC in
47% yield and 85% conversion (Scheme 3). It should be mentioned
that the temperature control is essential since the temperatures
higher than 40 ꢀC resulted in substantial decrease in yield. The pri-
mary hydroxyl group on dihydroxypyrrolidine 11 was subsequently
selective protected with TBDMSCl in quantitative yield. For the final
step, we had planned to activate the secondary hydroxyl group of
TBDMS-pyrrolidine 12 as its mesylate and prepare the cyclization
precursor by the reductive elimination of the benzyl group. Contrary
to our expectations, in the reaction of 12 with MsCl in pyridine, in-
stead of the mesyl activated intermediate we isolated directly the
cyclized pyrrolizidine quaternary salt 13 (Scheme 3). This result
shows that the benzyl protective group is not optimal for protecting
the pyrrolidine in conditions where nucleophilic substitution is
possible. Transformation of the pyrrolizidine quaternary salt 13 to
pyrrolizidine 14 by Pd/C catalyzed reductive cleavage of benzyl
group was not successful, but the required pyrrolizidine 14 was
obtained by thermal decomposition of the quaternary pyrrolizidine
salt 13 in the presence of triethylamine.19 The yield of the 14 was 79%
over two steps (Scheme 3). The final steps in the preparation of the
trihydroxylated pyrrolizidine hyacinthacine analogue 2, involved
removing the isopropylidene and TBDMS protecting groups. The
reaction was carried out in a methanolic solution of hydrochloric
acid. This reaction provided the desired product 2 as its hydrochlo-
ride salt and the free pyrrolizidine was liberated by treatment with
AmberliteÒ base in 99% yield (Scheme 3). The final product 2 was
N
N
Boc
Boc
HO
O
Pd(OH)2/C, H2, Boc2O,
AcOEt, EtOH, rt, 99%
InCl3, H2O,
CH3CN, rt, 83%
HO
O
10
O
O
O
O
16
15
TBDMSCl, DMF,
imidazole, rt, 91%
N
N
Boc
Boc
MsO
TBDMSO
HO
TBDMSO
MsCl, pyridine,
DMAP, rt, 93%
O
O
O
O
18
17
1) TBAF, H2O, THF, r.t.
2) K2CO3, MeOH, r.t, 82%
N
OH
OH
H
Boc
H
O
1) TMSI, DCM, rt.
2) HCl, MeOH, rt.
3) Amberlite©, 71%
HO
HO
OH
OH
O
N
N
O
1
19
20
Scheme 4. Preparation of indolizidine 20.
hydroxyl group 17 was activated with mesyl chloride in pyridine
giving 18 in 93% yield. Synthesis of pyrrolizidine 1 requires a double
inversion of mesylate activated stereogenic center of the pyrroli-
dine 18. An earlier procedure for the synthesis of similar com-
pounds used a desilylation and subsequent cyclization of the free
hydroxyl group to the corresponding oxirane with a double in-
version. The intramolecular opening of the oxirane with sub-
sequent cyclization gave the appropriate bicycle.4a In our case we
were able to prepare the activated pyrrolidine 19 by desilylation of
TBDMS-pyrrolidine 18 with TBAF in THF followed by alkaline acti-
vated cyclization. The yield of the oxirane 19 was 82% over two
steps. The best method for preparation of the pyrrolizidine 1
appeared to be removal of the Boc group from 19 with TMSI in DCM
followed by cyclization. Surprisingly, the reaction of the oxirane 19
with TMSI provided instead of the expected 7-epi-hyacinthacine A1
1, a trihydroxyindolizidine 20 (Scheme 4). The syntheses of several
stereoisomeric trihydroxyindolizidines have been published,21 the
product 20 has been described by Koskinen.22
The formation of 6-endo-tet product 20 is not in accordance with
Baldwin’s rules and therefore we assume that the addition of iodine
occurred to the less substituted and sterically hindered primary
oxirane carbon,23 followed by intramolecular nucleophilic sub-
stitution of iodine with the free-amine group.
Next we decided to convert the side product 8, obtained in the
protection of the free hydroxy groups of dithioacetal 6, to the
nitrone 21 and then examine the impact of its configuration on the
SmI2 induced cross-coupling with methyl acrylate. Removal of the
dithioacetal from 8 by HgO/HgCl2 in acetone15 gave a chiral alde-
hyde that was directly used for the preparation of the desired
nitrone 21 in 60% overall yield over two steps (Scheme 5). In the
samarium diiodide-induced reaction with methyl acrylate chiral
nitrone 21 afforded the expected adduct 22 in an excellent 88%
yield and 95:5 diastereoselectivity. This enantiomerically pure ad-
duct was then converted to the pyrrolidinone 23 by Mo(CO)6
cleavage of NeO bond in 60% yield.
obtained in an overall yield of 13% from D-ribose.
The relative configuration at the stereogenic centers in pyrroli-
zidine 2 was determined by extensive NOE experiments (Fig. 2).
Strong NOE effects between H-1 and H-2, between H-2 and H-3 and
also between H-3 and H-1 indicate that H-1, H-2, and H-3 are on the
same side of the ring. Irradiation of H-7a enhanced only the signal
intensity of H-7. This indicates that H-7a and H-7 are on the same
side of the ring. Thus, pyrrolizidine 2 was determined to be
(1S,2R,3S,7aS)-1,2-dihydroxy-3-hydroxymethylpyrrolizidine. The
ꢀ
opposite enantiomer of 2 was described by Clapes, [
a
]
20 ꢁ34.0 (c
D
0.9, MeOH).6d The comparison of the optical rotation of our product
20
2 [
a
]
D
þ32.0 (c 0.2, MeOH) confirmed the preparation of the
opposite enantiomer.
H-7
H-5
H-1
H-3
H-6
H-2
N
H-7
OH
OH
H-6
H-7a
H-5
OH
Fig. 2. NOE effects of pyrrolizidine 2.
Next we have focused our attention on the synthesis of pyrro-
lizidine 1 (Scheme 4). We decided to change the benzyl protecting
group of pyrrolidine 10 to a Boc group due to the observation of
generation of the pyrrolizidine quaternary ammonium salt 13 on
mesylation of 12. Boc-protected pyrrolidine 15 was prepared in
quantitative yield by (Pd/CeH2) N-debenzylation of pyrrolidine 12
and in situ Boc-protection.20 Next we used two Lewis acids for the
selective deprotection of the terminal isopropylidene group of Boc-
pyrrolidine 15. Zn(NO3)2$6H2O in acetonitrile provided selective,
but deprotected pyrrolidine 16 only in 50% yield at 67% conver-
sion.17 Better results for selective deprotection of the pyrrolidine 15
were achieved with InCl3 in acetonitrile. The dihydroxypyrrolidine
16, obtained in 83% yield, was selectively protected with TBDMSCl
in the presence of imidazole and DMF to provide the desired
TBDMS protected pyrrolidine 17 in 95% yield. The free secondary
X-ray analysis of 23 confirmed the anti-configuration of the new
formed stereogenic center (Fig. 3).24
3. Conclusions
The synthesis of trihydroxylated pyrrolizidine 2, 3,7a-di-epi-
hyacinthacine A1 the enantiomer of 2-epihyacinthacine A2 in
overall yield 13% from commercial available D-ribose is reported.

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J. Rehak et al. / Tetrahedron 67 (2011) 5762e5769
5765
(10 mL) and this solution was cooled in an ice bath to 5 ꢀC. Propane-
2-thiol (10.1 g, 133.2 mmol, 12.3 mL) was then added dropwise. The
temperature was kept at 5 ꢀC for 40 min, and then the reaction
mixture was stirred at room temperature for 1 h, progress of the
reaction being monitored by TLC (EtOAc). After completion of the
reaction, water (150 mL) was added, and solution was neutralized
with PbCO3 to pH 7. During addition of PbCO3 CO2 was evolved
carrying with it excess propane-2-thiol. This gas was scrubbed by
bubbling through an aqueous solution of NaClO4. Inorganic solids
were removed by filtration through a pad of CeliteÒ and the solvent
was removed under reduced pressure. The residue was separated
by flash chromatography (silica gel, EtOAc) and 6 was obtained as
colorless solid (12.0 g, 63%), mp 96e98 ꢀC (lit.:12 97e97.5 ꢀC); Rf
1) HgCl2, HgO,
acetone, reflux
O
N
O
O
O
O
O
O
O
O
CO2Me
methyl acrylate,
Bn
8
2) BnNHOH, MgSO4,
DCM, rt, 60%
SmI2, H2O, THF,
-80 °C, 88%,
d.r.: >95:5
N
OH
Bn
21
22
Mo(CO)6, H2O,
CH3CN, reflux,
60%
O
O
O
N
O
O
Bn
(EtOAc) 0.26; [
a
]
25 ꢁ63 (c 1, MeOH); nmax (KBr): 3346, 3239, 2952,
23
D
2915, 2863, 1452, 1444 cmꢁ1
; dH (300 MHz, CD3OD) 1.24e1.31 (m,
Scheme 5. Preparation of pyrrolidinone 23.
12H), 3.02e3.22 (m, 2H), 3.66 (dd, J¼6.0, 11.3 Hz, 1H), 3.75 (dd,
J¼3.3, 11.3 Hz, 1H), 3.79e3.84 (m, 1H), 3.88e3.91 (m, 2H), 3.33 (d,
J¼1.6 Hz, 1H); dC (75 MHz, CD3OD) 23.7, 23.9, 24.1, 24.3, 35.9, 36.2,
54.1, 64.1, 73.1, 75.1, 77.1.
4.1.2. (4R,40R,5R)-5-(bis(Isopropylthio)methyl)-2,2,20,20-tetramethyl-
4,40-bi(1,3-dioxolane) (7) and (3aR,4R,8aR)-4-(bis(Isopropylthio)
methyl)-2,2,6,6-tetramethyltetrahydro-[1,3]dioxolo[4,5-e][1,3]dioxe-
pine (8). Substrate 6 (5.0 g, 17.6 mmol) was dissolved in THF
(100 mL) and 2,2-dimethoxypropane (20 mL) and PTSA (0.5 g) were
added to the solution. The reaction mixture was stirred at 60 ꢀC for
3 h. The reaction was confirmed to be complete by TLC analysis,
whereupon a solution of Na2CO3 (100 mL, 1 M in water) was added.
The mixture was extracted with EtOAc (4ꢂ100 mL) and the com-
bined organic layers were washed with brine (100 mL), dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (silica
gel: 100 g, 20% EtOAc/hexanes), 5.1 g (79%) of (4R,40R,5R)-5-(bis(I-
sopropylthio)methyl)-2,2,20,20-tetramethyl-4,40-bi(1,3-dioxolane) (7)
was isolated as pale yellow crystals, mp 30e35 ꢀC; Rf (20% EtOAc/
Fig. 3. X-ray structure of 23.
hexanes, 1:4) 0.25; [a]
25 ꢁ132.2 (c 0.202, CHCl3); nmax (KBr) 2985,
The key step of this synthesis is the samarium diodide-induced
coupling of the chiral nitrone prepared from -ribose with methyl
acrylate. The nitrone derived from -ribose possessing C2/C3 syn
D
2958, 2929, 2867, 1455, 1381, 1371, 1255 cmꢁ1
; dH (600 MHz, CDCl3)
D
D
1.27 (d, J¼6.7 Hz, 3H), 1.29 (d, J¼6.7 Hz, 3H), 1.31e1.35 (m, 12H), 1.41
(s, 3H), 1.51 (s, 3H), 3.16 (septet, J¼6.7 Hz, 1H), 3.25 (septet,
J¼6.7 Hz, 1H), 3.91 (dd, J¼5.3, 8.7 Hz, 1H), 4.09 (dd, J¼6.9, 9.3 Hz,
1H), 4.16 (dd, J¼6.2, 8.7 Hz, 1H), 4.38 (d, J¼2.7 Hz, 1H), 4.60 (dd,
J¼2.7, 6.9 Hz, 1H), 4.72 (ddd, J¼5.5, 6.0, 11.5 Hz, 1H); dC (150 MHz,
CDCl3) 22.8, 23.2, 23.3, 23.6, 24.4, 25.3, 26.1, 26.8, 34.7, 35.2, 48.7,
68.5, 73.1, 79.0, 81.3, 109.3, 109.6; HRMS calcd for: C17H32O4S2Na
(MNa)þ: 387.1640, found: 387.1642 and 0.8 g (13%) of (3aR,4R,8aR)-
4-(bis(Isopropylthio)methyl)-2,2,6,6-tetramethyltetrahydro-[1,3]dio-
configuration reacted with methyl acrylate in the presence of
samarium diiodide in excellent yield and diastereoselectivity,
with only the anti-diastereomeric adduct being detected.
Furthermore, we have also prepared the (6S,7R,8S,8aS)-6,7,8-
trihydroxyindolizidine 20 in 12% overall yield from D-ribose. The
formation of the uncommon seven membered ring in product 8
was confirmed by X-ray analysis of the derived pyrrolidinone 23.
4. Experimental section
4.1. General methods
xolo[4,5-e][1,3]dioxepine (8) was isolated as pale yellow crystals, mp
25
58e60 ꢀC; Rf (20% EtOAc/hexanes) 0.16; [
a
]
ꢁ58.4 (c 0.209,
D
CHCl3); nmax (KBr) 2989, 2962, 2948, 1456, 1441, 1369, 1336,
1296 cmꢁ1
;
dH (600 MHz, CDCl3) 1.25 (d, J¼6.7 Hz, 3H), 1.29 (d,
Melting points were determined using a Kofler hot-stage ap-
paratus and are uncorrected. TLC analysis was carried out using
Merck TLC silica gel 60 F254 aluminum sheets and visualized by UV
light or oxidized in KMnO4 solution (NaOH/KMnO4/K2CO3/H2O
J¼6.7 Hz, 3H), 1.32 (d, J¼6.7 Hz, 3H), 1.33 (d, J¼6.7 Hz, 3H), 1.34 (s,
3H), 1.37 (s, 3H), 1.45 (s, 3H), 1.48 (s, 3H), 3.02 (septet, J¼6.7 Hz, 1H),
3.15 (septet, J¼6.7 Hz, 1H), 3.95 (ddd, J¼1.9, 14.2, 33.1 Hz, 2H), 4.00
(dd, J¼1.2, 9.5 Hz, 1H), 4.10 (d, J¼1.2 Hz, 1H), 4.14 (td, J¼1.6, 5.7 Hz,
1H), 4.28 (dd, J¼5.7, 9.5 Hz,1H); dC (150 MHz, CDCl3) 22.8, 23.1, 23.3,
24.1, 23.6, 25.3, 25.7, 28.3, 34.9, 35.1, 50.0, 58.2, 72.6, 76.2 (C-4),
101.8, 108.2; HRMS calcd for: C17H32O4S2Na (MNa)þ: 387.1640,
found: 387.1644.
1:8:80:1200). Specific rotations [
a
] were measured on an IBZ
line (589 nm)
Messtechnik Polar-L P polarimeter at the sodium
m
D
using a 1 dm cell. 1H NMR and 13C NMR spectra were recorded on
the Varian VRX-300 and Varian INOVA-600 in CDCl3 or CD3OD
solution using TMS as internal standard. Chemical shifts are
reported in ppm. IR spectra were recorded on an FTIR NICOLET
MAGNA 750 instrument. HRMS analyses were determined on
a Shimadzu, AXIMA TOF (MALDI-TOF/RTOF-MS). Elemental analy-
ses were conducted using a Fisons EA 1108 Analysator.
4.1.3. (Z)-1-Phenyl-N-(((4S,40R,5S)-2,2,20,20-tetramethyl-4,40-bi(1,3-
dioxolan)-5-yl)methylene)methanamine oxide (5). Compound
7
(3.64 g, 10 mmol) was dissolved in acetone (150 mL), water (4 mL),
HgO (4.33 g, 20 mmol) and HgCl2 (5.43 g, 20 mmol) were added and
the resultant slurry was stirred at reflux for 2 h. Progress of the
reaction was monitored by TLC (50% EtOAc/hexanes). On comple-
tion of reaction the mixture was cooled to room temperature, solids
4.1.1. (2R,3R,4R)-5,5-bis(Isopropylthio)pentane-1,2,3,4-tetraol
(6). D-Ribose (10.0 g, 66.6 mmol) was dissolved in hydrochloric acid

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J. Rehak et al. / Tetrahedron 67 (2011) 5762e5769
5766
were removed by filtration through a pad of CeliteÒ and the solvent
was removed under reduced pressure. The residue was shaken with
CHCl3 (100 mL) resulting in a white precipitate. The mixture was
filtered through a pad of CeliteÒ and the filtrate was washed with
aqueous KI (2ꢂ100 mL, 1 M) and brine (100 mL). The organic ex-
tracts were dried with Na2SO4, filtered and evaporated under re-
duced pressure. The residual yellow oil was dissolved in
dichloromethane (100 mL) and anhydrous MgSO4 (6 g, 50 mmol)
and N-benzylhydroxylamine (1.35 g, 11 mmol) were added and the
reaction mixture was stirred at room temperature for 15 h. After
this period the MgSO4 was filtered off and the solvent was removed
under reduced pressure. The residue was purified by flash chro-
matography (silica gel: 100 g, 75% EtOAc/hexanes then EtOAc) and
and 9 was isolated as colorless crystals (1.18 g, 83%), mp 89e91 ꢀC;
25
Rf (80% EtOAc/hexanes) 0.36; [
a
]
D
þ4.8 (c 0.206, CHCl3); nmax
(KBr) 2993, 2941, 2917, 2872, 1678, 1497, 1455, 1435, 1420 cmꢁ1
;
dH
(300 MHz, CDCl3) 1.22 (s, 3H), 1.25 (s, 3H), 1.31 (s, 3H), 1.43 (s, 3H),
1.96e2.16 (m, 2H), 2.30e2.40 (m, 1H), 2.56e2.67 (m, 1H), 3.85 (dd,
J¼4.3, 8.4 Hz, 1H), 3.95e3.98 (m, 2H), 3.99e4.02 (m, 1H), 4.08 (dd,
J¼5.4, 8.4 Hz, 1H), 4.16 (d, J¼15.1 Hz, 1H), 4.41 (d, J¼5.7 Hz, 1H), 4.94
(d, J¼15.1 Hz, 1H), 7.24e7.34 (m, 5H); dC (75 MHz, CDCl3) 19.8, 24.3,
25.1, 26.3, 26.8, 30.8, 44.5, 56.7, 68.4, 73.3, 75.1, 77.3, 105.6, 108.9,
127.3, 128.1, 128.4, 136.6, 175.4; Anal. Calcd for: C21H29NO5: C, 67.18;
H, 7.79; N, 3.73; Found: C, 66.97; H, 7.81; N, 3.61.
4.1.6. 1-Benzyl-2-((4S,40R,5S)-2,2,20,20-tetramethyl-4,40-bi(1,3-
dioxolan)-5-yl)pyrrolidine (10). Pyrrolidinone 9 (1.14 g, 3.03 mmol)
was dissolved in dry THF (40 mL) and the mixture cooled in an ice
nitrone 5 was obtained as colorless solid (2.75 g, 82%), mp
25
129e131 ꢀC; Rf (50% EtOAc/hexanes) 0.2; [
a
]
D
þ108.4 (c 0.201,
CHCl3); nmax (KBr) 3081, 3031, 2979, 2951, 2928, 2875, 1609, 1498,
bath to 0 a nitrogen atmosphere. LiAlH4 (0.576,
ꢀC under
1454, 1421 cmꢁ1
;
dH (300 MHz, CDCl3) 1.23 (s, 3H), 1.29 (s, 3H), 1.34
12.12 mmol) was added and the reaction mixture was heated to
reflux for 2.5 h when reaction was confirmed to be complete by TLC
analysis. The mixture was cooled to room temperature, MeOH
(5 mL) and silica gel were added and the resultant slurry was dried
under reduced pressure and the residue purified by column chro-
matography (silica gel: 50 g, 33% EtOAc/hexanes). Pyrrolidine 10
(s, 3H), 1.41 (s, 3H), 3.82e3.93 (m, 3H), 4.35 (t, J¼7.1 Hz, 1H),
4.81e4.93 (2ꢂ d, J¼13.9 Hz, 2H), 5.40 (t, J¼6.2 Hz, 1H), 6.81 (d,
J¼6.1 Hz, 1H), 7.37e7.43 (m, 5H); dC (75 MHz, CDCl3) 24.9, 25.3,
26.5, 27.4, 66.6, 69.4, 72.3, 74.0, 77.4, 109.3, 109.5, 128.9, 129.1, 129.7,
132.0, 134.6; Anal. Calcd for: C18H25NO5: C, 64.46; H, 7.51; N, 4.18;
Found: C, 64.73; H, 7.43; N, 3.96.
was isolated as yellow oil (1.09 g, 94%), Rf (50% EtOAc/hexanes)
25
0.43; [
a
]
ꢁ34.2 (c 0.202, CHCl3); nmax (KBr) 3027, 2985, 2937,
D
4.1.4. Methyl 4-(benzyl(hydroxy)amino)-4-((4S,40R,5S)-2,2,20,20-tet-
ramethyl-4,40-bi(1,3-dioxolan)-5-yl)butanoate (4). A stirred and
carefully deoxygenated solution of nitrone 5 (1.34 g, 4 mmol) in dry
THF (40 mL) was cooled to ꢁ82 ꢀC under a nitrogen atmosphere.
Methyl acrylate and water were degassed by refluxing under
a stream of nitrogen for 20 min, then methyl acrylate (0.504 mL,
5.6 mmol), water (0.574 mL, 32 mmol) and a solution of SmI2
(120 mL, 0.1 M in THF) were added to the nitrone solution. The
temperature was kept between ꢁ88 and ꢁ81 ꢀC for 1 h, whereupon
a solution of Na2S2O3 (100 mL) was added. The mixture was
extracted with EtOAc (4ꢂ100 mL) and the combined organic ex-
tracts were washed with brine (100 mL), dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (silica gel: 50 g, 33%
EtOAc/hexanes) and the adduct 4 was isolated as a colorless oil
2875, 2788, 1494, 1454, 1380, 1371 cmꢁ1
; dH (300 MHz, CDCl3) 1.31
(s, 3H), 1.34 (s, 3H), 1.41 (s, 3H), 1.43 (s, 3H), 1.67e1.87 (m, 3H),
1.94e2.04 (m, 1H), 2.27 (dd, J¼9.0, 16.0 Hz, 1H), 2.96e3.02 (m, 1H),
3.10e3.17 (m, 1H), 3.60 (d, J¼13.0 Hz, 1H), 3.86 (dd, J¼5.7, 8.3 Hz,
1H), 3.90e3.97 (m, 2H), 4.00e4.05 (m, 1H), 4.09 (dd, J¼6.0, 8.7 Hz,
1H), 4.26 (dd, J¼1.3, 6.4 Hz, 1H), 7.21e7.37 (m, 5H); dC (75 MHz,
CDCl3) 23.9, 24.6, 25.5, 26.8, 26.9, 25.8, 53.9, 59.1, 61.1, 68.5, 73.7,
77.7, 78.2, 108.1, 109.5, 126.8, 128.0, 129.5, 138.7; HRMS calcd for:
C21H32NO4 (MH)þ: 362.2331, found: 362.2336.
4.1.7. (1R)-1-((4R,5S)-5-(1-Benzylpyrrolidin-2-yl)-2,2-dimethyl-1,3-
dioxolan-4-yl)ethane-1,2-diol (11). Pyrrolidine 10 (0.51 g,
1.41 mmol) was dissolved in a mixture of AcOH (20 mL) and water
(5 mL) and the mixture was heated to 40 ꢀC for 3 days monitoring
by TLC. When a bis-deprotected product was detected, the reaction
was quenched by adding water (100 mL) and treating with K2CO3
until basic (pH>10). The solution was extracted with EtOAc
(5ꢂ60 mL), and the combined organic extracts were washed with
brine (60 mL), dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by column chroma-
tography (silica gel: 50 g, 50% EtOAc/hexanes, then EtOAc) to fur-
(1.68 g, 99%, dr: >95:5), Rf (20% EtOAc/hexanes) 0.66; [
a
]
25 þ23.3
D
(c 0.223, CHCl3); nmax (KBr) 3449, 3030, 2987, 2938, 2885, 1737,
1497, 1455 cmꢁ1
; dH (300 MHz, CDCl3) 1.41 (s, 3H), 1.36 (s, 6H), 1.29
(s, 3H), 1.85e1.97 (m, 1H), 2.21e2.31 (m, 1H), 2.45e2.65 (m, 2H),
3.28e3.35 (m, 1H), 3.63 (s, 3H), 3.84e3.98 (m, 3H), 4.07e4.23 (m,
3H), 4.61 (t, 1H, J¼6.2 Hz, 1H), 5.10e5.20 (br s, 1H), 7.22e7.37 (m,
5H); dC (75 MHz, CDCl3) 23.2, 25.2, 25.5, 26.6, 27.6, 31.5, 51.6, 60.5,
62.9, 68.2, 73.7, 75.3, 79.3, 107.8, 109.8, 127.0, 128.1, 128.9, 138.3,
175.0; Anal. Calcd for: C22H33NO7: C, 62.39; H, 7.85; N, 3.31; Found:
C, 62.18; H, 7.92; N, 3.24.
nish starting material 10 (0.08 g 15%) and desired pyrrolidine 11
25
(0.213 g, 47%) as colorless oils, Rf (80% EtOAc/hexanes) 0.25; [a]
D
ꢁ13.0 (c 0.2, CHCl3); nmax (KBr) 3396, 2994, 2949, 2891, 1496, 1453,
1379, 1368 cmꢁ1
dH (300 MHz, CDCl3) 1.34 (s, 3H), 1.44 (s, 3H),
;
1.72e1.92 (m, 2H), 1.94e2.14 (m, 2H), 2.50 (td, J¼7.3, 11.6 Hz, 1H),
2.79 (ddd, J¼6.1, 8.0, 11.6 Hz, 1H), 3.25 (q, J¼6.6 Hz, 1H), 3.41 (d,
J¼12.7 Hz, 1H), 3.69 (dd, J¼5.8, 10.7 Hz, 1H), 3.78e3.84 (m, 1H), 3.89
(dd, J¼3.42, 10.7 Hz, 1H), 4.08e4.16 (m, 2H), 4.22 (d, J¼12.7 Hz, 1H),
7.25e7.40 (m, 5H); dC (75 MHz, CDCl3) 21.1, 25.6, 28.3, 25.9, 51.5,
59.8, 63.9, 64.6, 68.4, 77.7, 78.2, 108.1, 127.5, 128.5, 129.3, 137.2;
HRMS calcd for: C18H28NO4 (MH)þ: 322.2013, found: 322.2019.
4.1.5. (S)-1-Benzyl-5-((4S,40R,5S)-2,2,20,20-tetramethyl-4,40-bi(1,3-
dioxolan)-5-yl)pyrrolidin-2-one (9). The
g-hydroxylamino ester 4
(1.66 g, 3.92 mmol) was dissolved in a mixture of AcOH/THF/H2O
(60/30/30 mL). Zinc dust (5.1 g, 78.4 mmol) was added and the
reaction mixture was stirred at 50 ꢀC for 1.5 h, monitoring by TLC.
Water (200 mL) was added after reaction was complete and the
mixture was treated with K2CO3 until basic (pH>10). The solution
was extracted with EtOAc (4ꢂ100 mL), and the combined organic
extracts were washed with brine (100 mL), dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. The residue was
dissolved in MeOH (60 mL), K2CO3 was added and the mixture was
stirred at room temperature for 10 h. At this point, water was added
and solution was extracted with EtOAc (4ꢂ60 mL). The combined
organic extracts were dried over Na2SO4, filtered and concentrated
under reduced pressure. The crude product was purified by column
chromatography (silica gel: 50 g, 80% EtOAc/hexanes, then EtOAc)
4.1.8. (1R)-1-((4R,5S)-5-(1-Benzylpyrrolidin-2-yl)-2,2-dimethyl-1,3-
dioxolan-4-yl)-2-(tert-butyldimethylsilyloxy)ethanol (12). Substrate
11 (0.21 g, 0.654 mmol) was dissolved in CH2Cl2 (15 mL) and im-
idazole (0.133 g, 1.635 mmol) was added, followed by TBDMSCl
(0.117 g, 0.785 mmol) and the reaction mixture was stirred at room
temperature for 19 h, monitoring by TLC. The solvent was removed
and the crude mixture was purified by column chromatography
(silica gel: 25 g, 20% EtOAc/hexanes) giving 12 as a colorless oil
25
(0.28 g, 99%), Rf (50%, hexanes/EtOAc) 0.58; [
a
]
ꢁ9.4 (c 0.32,
D

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J. Rehak et al. / Tetrahedron 67 (2011) 5762e5769
5767
CHCl3); nmax (KBr) 3027, 2985, 2937, 2875, 2788, 1494, 1454, 1380,
1371 cmꢁ1
dH (300 MHz, CDCl3) 0.10 (s, 3H), 0.11 (s, 3H), 0.93 (s,
1H), 3.61 (dd, J¼5.7, 10.7 Hz, 1H), 3.72 (dd, J¼4.0, 8.1 Hz, 1H), 3.86
(dd, J¼7.3, 10.7 Hz, 1H), 4.14 (t, J¼3.6 Hz, 1H); dC (150 MHz, CD3OD)
25.8, 31.1, 55.8, 62.2, 69.2, 71.3, 75.0, 79.2; HRMS calcd for:
C8H16NO3 (MH)þ: 174.1125, found: 174.1129.
;
9H), 1.33 (s, 3H), 1.42 (s, 3H), 1.71e1.89 (m, 2H), 1.93e2.09 (m, 2H),
2.48 (td, J¼6.9, 13.9 Hz, 1H), 2.76 (ddd, J¼6.6, 7.7, 14.3 Hz, 1H), 3.23
(q, J¼7.0 Hz, 1H), 3.42 (d, J¼12.6 Hz, 1H), 3.71e3.78 (m, 2H, H-1),
3.92e3.97 (m, 1H), 4.05e4.11 (m, 2H), 4.15 (dd, J¼5.4, 9.1 Hz, 1H),
7.23e7.38 (m, 5H); dC (75 MHz, CDCl3) ꢁ5.3, ꢁ5.2, 18.5, 21.6, 25.5,
25.6, 28.2, 26.0, 51.1, 59.9, 63.9, 65.1, 69.5, 76.9, 77.9, 107.9, 127.3,
128.4, 129.5, 137.7; HRMS calcd for: C24H42NO4Si (MH)þ: 436.2883,
found: 436.2887.
4.1.12. tert-Butyl 2-((4S,40R,5S)-2,2,20,20-tetramethyl-4,40-bi(1,3-
dioxolan)-5-yl)pyrrolidine-1-carboxylate (15). Substrate 10 (0.5 g,
1.38 mmol) was dissolved in a mixture of (EtOH/EtOAc, 10:10 mL),
Boc2O (0.321 g, 1.66 mmol) and 20% PdOH/C (0.05 g, 0.07 mmol)
were added and the reaction mixture was stirred under a hydrogen
atmosphere (balloon) at room temperature for 22 h. The PdOH/C
was removed by filtration and the solution was concentrated under
reduced pressure. The crude mixture was purified by column
4.1.9. (3aR,4S,8aS,8bS)-5-Benzyl-4-((tert-butyldimethylsilyloxy)
methyl)-2,2-dimethyloctahydro-[1,3]dioxolo[4,5-a]pyrrolizin-5-ium
chloride (13). Pyrrolidine 12 (0.28 g, 0.64 mmol) was dissolved in
pyridine (12 mL) and solution was cooled to ꢁ20 ꢀC, whereupon
MsCl (0.247 mL, 3.2 mmol) was added by microsyringe. The re-
action was allowed to warm to room temperature, and was stirred
for 15 h, when a solution of CuSO4 (50 mL, 1 M in water) was added.
The mixture was extracted with EtOAc (5ꢂ50 mL) and the com-
bined organic extracts were dried over Na2SO4, filtered, and con-
centrated under reduced pressure. The brown solid residue was
chromatography (silica gel: 50 g, 10% EtOAc/hexanes) to give 15 as
25
a colorless oil (0.51 g, 99%), Rf (10% EtOAc/hexanes) 0.58; [a]
D
ꢁ38.9 (c 0.213, CHCl3); nmax (KBr) 2983, 2935, 2879, 1697, 1479,
1456, 1393 cmꢁ1
dH (300 MHz, CDCl3) 1.30 (s, 3H), 1.34 (s, 3H), 1.38
;
(s, 3H), 1.41 (s, 3H), 1.45 (s, 9H), 1.71e1.82 (m, 1H), 1.87e2.04 (m,
3H), 3.30e3.40 (m, 2H), 3.81e3.92 (m, 1H), 4.01e4.14 (m, 3H),
4.25e4.35 (br s, 1H), 4.53e4.76 (m, 1H); dC (75 MHz, CDCl3) 24.3,
24.6, 25.5, 26.2, 26.5, 26.8, 28.5, 46.1, 56.3, 68.5, 73.6, 78.1, 79.1, 79.3,
109.5, 109.7, 154.3; HRMS calcd for: C19H33NO6Na (MNa)þ:
394.2206, found: 394.2201.
used in the next step without further purification (0.31 g), mp
25
219e221 ꢀC; [
a]
ꢁ65.4 (c 0.055, CHCl3); nmax (KBr) 3424, 2988,
D
2956, 2925, 2890, 2854, 1496, 1471 cmꢁ1
;
dH (300 MHz, CDCl3) 0.19
(s, 3H), 0.20 (s, 3H), 0.96 (s, 9H), 1.37 (s, 3H), 1.62 (s, 3H), 1.37e1.61
(m, 1H), 2.01e2.16 (m, 1H), 2.36e2.53 (m, 1H), 2.87e3.01 (m, 1H),
3.55 (td, J¼8.4, 11.6 Hz, 1H), 4.15 (ddd, J¼5.6, 7.7 12,6 Hz, 1H),
4.27e4.35 (m, 3H), 6.58 (d, J¼12.6 Hz, 1H), 4.90 (d, J¼12.6 Hz, 1H),
5.08 (q, J¼6.5 Hz, 1H), 5.16 (d, J¼6.5 Hz, 1H), 5.71 (t, J¼5.2 Hz, 1H),
7.47e7.55 (m, 5H); dC (75 MHz, CDCl3) ꢁ5.6, ꢁ5.1, 18.0, 22.2, 23.2,
25.3, 25.8, 26.4, 57.5, 58.7, 61.8, 74.2, 75.4, 80.1, 80.8, 112.1, 127.1,
129.6, 130.8, 133.4; HRMS calcd for: C24H40NO3Si (MꢁCl)þ:
418.2777, found: 418.2781.
4.1.13. tert-Butyl 2-((4S,5R)-5-((R)-1,2-dihydroxyethyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)pyrrolidine-1-carboxylatea (16). Method
A: Substrate 15 (0.52 g, 1.37 mmol) was dissolved in acetonitrile
(20 mL), Zn(NO3)2$6H2O (4.05 g, 13.7 mmol) was added and the
mixture was stirred at room temperature for 1 day, whereupon
a solution of K2CO3 (100 mL, 1 M in water) was added. The mixture
was extracted with EtOAc (3ꢂ100 mL) and the combined organic
extracts were washed with brine (100 mL), dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel: 50 g, 33% EtOAc/
hexanes) to provide starting material 15 (0.172 g 33%) and car-
boxylate 16 (0.227 g, 50%).
Method B: Water (0.017 mL, 1.05 mmol) and InCl3 (0.134 g,
0.704 mmol) were added to a solution of substrate 15 (0.121 g,
0.352 mmol) in acetonitrile (10 mL) at room temperature and the
reaction mixture was stirred for 1 day, monitoring by TLC. When
the bis-deprotected product was detected, then the reaction was
quenched with a solution of K2CO3 (50 mL, 1 M in water). The
mixture was extracted with EtOAc (3ꢂ40 mL) and the combined
organic extracts were washed with brine (40 mL), dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel: 25 g,
4.1.10. (3aR,4S,8aS,8bS)-4-((tert-Butyldimethylsilyloxy)methyl)-2,2-
dimethylhexahydro-3aH-[1,3]dioxolo[4,5-a]pyrrolizine (14). Crude
13 (0.30 g) was transferred to a thick walled tube as a solution in
CH2Cl2. the solvent was removed under reduced pressure. Toluene
(30 mL) was used to dissolve solid residue, Et3N (3 mL) and KI
(0.104 g, 0.64 mmol) were added and tube was sealed and heated to
165 ꢀC for 5 h. After this time, solvent was removed under reduced
pressure. The residue was purified by column chromatography
(silica gel: 25 g, EtOAc), giving the pyrrolizidine 14 as a yellow oil
25
(0.166 g, 79% after two steps), Rf (80% EtOAc/hexanes) 0.19; [a]
D
þ29.7 (c 0.209, CHCl3); nmax (KBr) 2954, 2928, 2856, 1471, 1463,
1379, 1369 cmꢁ1
dH (300 MHz, CDCl3) 0.06 (s, 6H), 0.88 (s, 9H), 1.28
;
(s, 3H), 1.32e1.39 (m, 1H), 1.51 (s, 3H), 1.63e1.74 (m, 1H), 1.81e1.95
(m, 2H), 2.73 (dd, J¼5.7, 11.9 Hz, 1H), 2.88e3.00 (m, 2H), 3.44 (t,
J¼8.5 Hz,1H), 3.67 (dd, J¼5.7, 9.9 Hz,1H), 3.93 (dd, J¼7.1, 9.9 Hz,1H),
4.50 (d, J¼5.9 Hz, 1H), 4.74 (dd, J¼5.0, 5.7 Hz, 1H); dC (75 MHz,
CDCl3) ꢁ5.4, 5.3, 18.3, 24.2, 24.7, 26.5, 25.9, 28.2, 53.2, 62.9, 68.6,
72.2, 81.6, 83.1, 111.0; HRMS calcd for: C17H34NO3Si (MH)þ:
328.2308, found: 328.2302.
33% EtOAc/hexanes) to furnish 16 as a colorless oil (0.096 g, 83%), Rf
25
(EtOAc) 0.36; [
a]
ꢁ41.2 (c 0.25, CHCl3); nmax (KBr) 3400, 2978,
D
2934, 2878, 1691, 1663, 1393, 1365 cmꢁ1
;
dH (300 MHz, CDCl3) 1.31
(s, 3H), 1.42 (s, 3H), 1.43 (s, 9H), 1.70e1.79 (m, 1H), 1.84e2.08 (m,
3H), 3.25e3.45 (m, 2H), 3.65 (dd, J¼5.1, 10.5 Hz, 1H), 3.71 (ddd,
J¼5.1, 8.4, 8.8 Hz, 1H), 3.80 (dd, J¼2.6, 10.4 Hz, 1H), 4.12e4.21 (m,
1H), 4.29e4.33 (m, 1H) 4.45e4.52 (br s, 1H); dC (75 MHz, CDCl3)
24.5, 24.7, 26.6, 27.2, 28.5, 46.7, 56.1, 64.9, 69.6, 77.0, 78.8, 79.8,
107.9, 155.2; HRMS calcd for: C16H29NO6Na (MNa)þ: 354.1893,
found: 354.1896.
4.1.11. (1S,2R,3S,7aS)-3-(Hydroxymethyl)hexahydro-1H-pyrrolizine-
1,2-diol (2). Pyrrolizidine 14 (0.166 g, 0.507 mmol) was dissolved in
MeOH (10 mL), HCl (3 mL, 3.04 mmol, 3.6% in water) was added and
the reaction mixture was stirred at room temperature for 2 days.
The solvent was removed under reduced pressure and the crude
residue was purified by column chromatography (AmberliteÓ (IRA-
4.1.14. tert-Butyl 2-((4S,5R)-5-((R)-2-(tert-butyldimethylsilyloxy)-1-
hydroxyethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)pyrrolidine-1-
carboxylate (17). Diol 16 (0.168 g, 0.507 mmol) was dissolved in
DMF (5 mL) and imidazole (0.09 g, 1.32 mmol) was added followed
by TBDMSCl (0.091 g, 0.61 mmol) and the reaction mixture was
stirred at room temperature for 5 h. Water (100 mL) was then
added and the mixture was extracted with EtOAc (4ꢂ50 mL). The
combined organic layers were washed with brine (50 mL), dried
over Na2SO4, filtered, and concentrated under reduced pressure.
401 Serva): 25 g, MeOH). The target pyrrolizine 2 was isolated as
25
a yellow solid (0.087 g, 99%), mp 169e171 ꢀC; [
a
]
þ32.0 (c 0.2,
D
MeOH); nmax (KBr) 3354, 3041, 2914, 2871, 2544, 1456, 1360,
1321 cmꢁ1
;
dH (600 MHz, CD3OD) 1.71e1.77 (m, 2H), 1.78e1.84 (m,
1H), 1.89e1.95 (m, 1H), 2.66e2.69 (m, 1H), 2.77 (ddd, J¼3.3, 5.7,
7.3 Hz, 1H), 2.86 (ddd, J¼5.6, 7.8, 10.9 Hz, 1H), 3.39 (dt, J¼3.8, 7.9 Hz,

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J. Rehak et al. / Tetrahedron 67 (2011) 5762e5769
5768
The crude mixture was purified by column chromatography (silica
gel: 25 g, 33% EtOAc/hexanes) giving 17 as a colorless oil (0.205 g,
in water) was added and the mixture extracted with dichloro-
methane (3ꢂ50 mL). The combined organic extracts were dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The crude brown oil was dissolved in MeOH (15 mL), HCl (2 mL,
1 M) was added and the mixture was stirred at room temperature
for 2 h. The solvent was removed by rotatory evaporator and the
crude solid was purified by column chromatography (AmberliteÓ
91%), Rf (50% EtOAc/hexanes) 0.62; [
a]
25 ꢁ48.2 (c 0.19, CHCl3); nmax
D
(KBr) 3411, 2928, 2856, 1694, 1671, 1471, 1456, 1391, 1365 cmꢁ1
; dH
(600 MHz, CDCl3) 0.07 (s, 6H), 0.89 (s, 9H), 1.30 (s, 3H), 1.43 (s, 3H),
1.44 (s, 9H),1.72e1.77 (m,1H),1.85e1.92 (m,1H),1.95e2.04 (m, 2H),
2.40e2.70 (br s, 1H), 3.22e3.41 (m, 2H), 3.61e3.64 (m, 1H),
3.66e3.72 (m, 1H), 3.78 (dd, J¼2.7, 9.7 Hz, 1H), 3.98e4.21 (m, 1H),
4.28e4.48 (m, 1H), 4.54e4.76 (m, 1H); dC (150 MHz, CDCl3) ꢁ5.5,
ꢁ5.4, 18.3, 24.5, 25.0, 25.6, 25.8, 26.2, 28.5, 46.6, 56.5, 64.3, 69.3,
75.4, 78.3, 79.1, 108.1, 154.9; HRMS calcd for: C22H43NO6SiNa
(MNa)þ: 468.2752, found: 468.2752.
(IRA-401 Serva): 25 g, MeOH). The target indolizidine 20 was iso-
25
lated as a pale brown solid (0.067 g, 71%), mp 155e157 ꢀC; [
a]
D
þ14.3 (c 0.51, MeOH); nmax (KBr) 3372, 3038, 2916, 2871, 2544,
1456, 1361 cmꢁ1
dH (600 MHz, CDCl3) 1.46e1.54 (m, 1H), 1.64e1.71
;
(m, 1H), 1.71e1.81 (m, 1H), 1.95e2.01 (m, 1H), 2.16 (q, J¼8.9 Hz, 1H),
2.23 (dt, J¼6.3, 10.0 Hz, 1H), 2.46 (dd, J¼1.4, 11.5 Hz, 1H), 2.83 (dd,
J¼1.7, 11.5 Hz, 1H), 2.97 (dt, J¼2.5, 8.8 Hz, 1H), 3.59 (dd, J¼2.5,
10.0 Hz,1H), 3.77e3.81 (m, 2H); dC (150 MHz, CDCl3) 21.7, 29.1, 54.0,
54.9, 63.7, 71.7, 72.8, 73.1; HRMS calcd for: C8H16NO3 (MH)þ:
174.1125, found: 174.1124.
4.1.15. tert-Butyl 2-((4S,5S)-5-((R)-2-(tert-butyldimethylsilyloxy)-1-
(methylsulfonyloxy)ethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)pyrroli-
dine-1-carboxylate (18). MsCl (0.1 mL, 1.35 mmol) and DMAP
(3.3 mg, 0.0269 mmol) were added to a solution of substrate 17
(0.12 g, 0.269 mmol) in pyridine (5 mL). The reaction mixture was
stirred at room temperature for 15 h, whereupon a solution of
CuSO4 (50 mL, 1 M in water) was added. The mixture was extracted
with EtOAc (5ꢂ50 mL) and the combined organic extracts were
dried over Na2SO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by column chromatography (silica
4.1.18. (Z)-1-Phenyl-N-(((3aS,4S,8aR)-2,2,6,6-tetramethyltetrahydro-
[1,3]dioxolo[4,5-e][1,3]dioxepin-4-yl)methylene)methanamine oxide
(21). Compound 8 (2.01 g, 5.5 mmol) was dissolved in acetone
(100 mL), water (2 mL), HgO (2.38 g, 11 mmol) and HgCl2 (2.99 g,
11 mmol) were added and the resultant slurry was stirred at reflux
for 3 h. The mixture was then cooled to room temperature, solids
were removed by filtration through pad of CeliteÒ and the solvent
was removed under reduced pressure. The residue was dissolved in
CHCl3 (50 mL) and the white precipitate formed was removed by
filtration through a pad of CeliteÒ. The filtrate was washed with
aqueous KI (2ꢂ50 mL, 1 M) and brine (50 mL), the organic extracts
were dried with Na2SO4, filtered, and evaporated under reduced
pressure. The residual yellow oil was dissolved in dichloromethane
(55 mL), anhydrous MgSO4 (3.3 g, 27.5 mmol) and N-benzylhy-
droxylamine (0.68 g, 5.5 mmol) were added and the reaction mix-
ture was stirred at room temperature for 14 h monitoring by TLC. On
completionof the reaction, the MgSO4 was removed byfiltration and
the solvent was removed under reduced pressure. The residue was
purified by column chromatography (silica gel: 50 g, 75% EtOAc/
hexanes) and nitrone 21 was obtained as a colorless solid (1.12 g,
gel: 25 g, 33% EtOAc/hexanes) to provide 18 as a colorless oil
25
(0.131 g, 93%), Rf (20% EtOAc/hexanes) 0.43; [
a]
ꢁ26.4 (c 0.265,
D
CHCl3); nmax (KBr) 2954, 2932, 2884, 2858, 1684, 1390, 1361 cmꢁ1
;
dH (300 MHz, CDCl3) ꢁ0.02 (s, 3H), 0.08 (s, 3H), 0.89 (s, 9H), 1.32 (s,
3H), 1.45 (s, 3H), 1.42 (s, 9H), 1.74e1.84 (m, 1H), 1.89e2.04 (m, 3H),
3.11e3.16 (m, 1H), 3.19 (s, 3H), 3.35e3.42 (m, 1H), 3.87 (dd, J¼4.0,
12.0 Hz, 1H), 4.05e4.14 (m, 2H), 4.45e4.50 (m, 1H), 4.61e4.73 (m,
1H), 4.76e4.84 (m, 1H); dC (75 MHz, CDCl3) ꢁ5.6, 5.5, 18.2, 24.4,
25.0, 25.7, 26.0, 26.3, 28.5, 39.3, 46.6, 56.6, 62.3, 72.9, 77.6, 79.2,
80.7, 108.2, 155.0; HRMS calcd for: C23H45NO8SSiNa (MNa)þ:
546.2527, found: 546.2529.
4.1.16. (S)-tert-Butyl
2-((4S,5S)-2,2-dimethyl-5-((S)-oxiran-2-yl)-
1,3-dioxolan-4-yl)pyrrolidine-1-carboxylate (19). TBAF$3H2O was
added to a solution of 18 (0.193 g, 0.368 mmol) in THF (15 mL) and
the reaction mixture was stirred at room temperature for 2 h. A
solution of K2CO3 (50 mL, 1 M in water) was added and the mixture
was extracted with EtOAc (3ꢂ50 mL), the combined organic layers
dried over Na2SO4, filtered, and concentrated under reduced pres-
sure. The residue was dissolved in MeOH (10 mL), a solution of
K2CO3 (5 mL,1 M in water) was added and the reaction mixture was
stirred at room temperature for 14 h monitoring by TLC (EtOAc). A
solution of K2CO3 (50 mL,1 M in water) was added on completion of
reaction, the mixture was extracted with EtOAc (5ꢂ40 mL) and the
combined organic extracts were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel: 25 g, 66% EtOAc/hexanes then
EtOAc) and 19 was isolated as colorless crystals (0.095 g, 82%) mp
60%), mp 150e152 ꢀC; Rf (50% EtOAc/hexanes) 0.19; [
a
]
25 ꢁ60.2 (c
D
0.201, CHCl3); nmax (KBr) 3030, 2993, 2932, 1576, 1498, 1462,
1445 cmꢁ1
; dH (600 MHz, CDCl3) 1.34 (s, 3H),1.49 (s, 3H),1.51 (s, 6H),
3.93 (dd, J¼5.2, 10.2 Hz, 1H), 3.98 (dd, J¼1.5, 5.4 Hz, 2H), 4.09e4.11
(m, 1H), 4.91 (d, J¼7.8 Hz, 1H), 4.96 (d, J¼7.8 Hz, 1H), 5.20 (dd, J¼7.8,
10.1 Hz, 1H), 6.74 (d, J¼7.8 Hz, 1H), 7.35e7.41 (m, 5H); dC (150 MHz,
CDCl3) 23.3, 25.6, 25.8, 26.2, 58.3, 62.9, 70.2, 76.1, 77.5, 102.0, 109.0,
128.7,128.8,128.9,132.7,135.8; Anal. Calcd for: C18H25NO5: C, 64.46;
H, 7.51; N, 4.18; Found: C, 64.69; H, 7.84; N, 4.22.
4.1.19. Methyl 4-(benzyl(hydroxy)amino)-4-((3aS,4S,8aR)-2,2,6,6-
tetramethyltetrahydro-[1,3]dioxolo[4,5-e][1,3]dioxepin-4-yl)buta-
noate (22). A stirred and carefully deoxygenated solution of the
nitrone 21 (0.335 g,1 mmol) in dry THF (10 mL) was cooled to ꢁ82 ꢀC
under a nitrogen atmosphere. Methyl acrylate and water were
degassed by refluxing under a stream of nitrogen for 20 min, then
methyl acrylate (0.126 mL,1.4 mmol), water (0.144 mL, 8 mmol) and
a solution of SmI2 (30 mL, 0.1 M in THF) were then added. The
temperature was kept at ꢁ82 ꢀC until the reaction was judged to be
complete by TLC analysis, whereupon a solution of Na2S2O3 (50 mL)
was added. The mixture was extracted with EtOAc (4ꢂ50 mL) and
the combined organic extracts were washed with brine (50 mL),
dried over Na2SO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by silica gel column chromatography
(silica gel: 25 g, 33% EtOAc/hexanes) furnishing 22 as a colorless oil
(0.376 g, 88%, dr: >95:5), mp 86e87 ꢀC; Rf (50% hexanes/EtOAc) 0.6;
109e110 ꢀC; Rf (EtOAc) 0.62; [
a
]
25 ꢁ54.3 (c 0.21, CHCl3); nmax (KBr)
D
2987, 2942, 2869, 1683, 1475, 1458, 1393, 1379, 1370 cmꢁ1
; dH
(300 MHz, CDCl3) 1.33 (s, 3H),1.46 (s, 9H),1.52 (s, 3H),1.73e1.94 (m,
2H), 2.02e2.15 (m, 2H), 2.68e2.76 (br s, 1H), 2.85 (t, J¼4.2 Hz, 1H),
3.02e3.13 (m, 1H), 3.24e3.33 (m, 1H), 3.44 (ddd, J¼3.2, 8.3, 11.1 Hz,
1H), 3.87 (t, J¼7.0 Hz, 1H), 3.95e4.07 (m, 1H), 4.68 (d, J¼7.6 Hz, 1H);
dC (75 MHz, CDCl3) 24.4, 24.9, 26.0, 26.6, 28.5, 43.6, 46.7, 50.2, 57.5,
77.8, 78.7, 79.4, 108.9, 155.0; HRMS calcd for: C16H27NO5 (MNa)þ:
336.1781, found: 336.1785.
4.1.17. (6S, 7R,8S,8aS)-Octahydroindolizine-6, 7, 8-triol
(20). Substrate 19 (0.17 g, 0.542 mmol) was dissolved in dichloro-
methane (10 mL), TMSI (0.37 mL, 2.71 mmol) was added and the
mixture was stirred at room temperature for 4 h monitoring by TLC
(EtOAc). On completion of reaction a solution of K2CO3 (50 mL, 1 M
[a
]
D ꢁ38.5 (c 0.195, CHCl3); nmax (KBr) 3448, 2991, 2951, 2945, 2481,
1713,1452,1438 cmꢁ1
;
dH (600 MHz, CDCl3) 1.34 (s, 3H),1.36 (s, 3H),

ꢀ
J. Rehak et al. / Tetrahedron 67 (2011) 5762e5769
5769
6. (a) Yoda, H.; Asai, F.; Takabe, K. Synlett 2000, 1001e1003; (b) Izquierdo, I.; Plaza,
M.-T.; Robles, R.; Franco, F. Tetrahedron: Asymmetry 2001, 12, 2481e2487; (c)
Izquierdo, I.; Plaza, M.-T.; Franco, F. Tetrahedron: Asymmetry 2004, 15,
1465e1469; (d) Calveras, J.; Casas, J.; Parella, T.; Joglar, J.; Clapes, P. Adv. Synth.
Catal. 2007, 349, 1661e1666; (e) Affolter, O.; Baro, A.; Frey, W.; Laschat, S. Tet-
rahedron 2009, 65, 6626e6634.
7. (a) Frederickson, M. Tetrahedron 1997, 53, 403e425; (b) Gothelf, K. V.;
Jørgensen, K. A. Chem. Rev. 1998, 98, 863e910; (c) Merino, P.; Franco, S.; Mer-
chan, F. L.; Romero, P.; Tejero, T.; Uriel, T. S. Tetrahedron: Asymmetry 2003, 14,
3731e3743; (d) Osborn, H. M. I.; Gemmel, N.; Harwood, L. M. J. Chem. Soc.,
Perkin Trans. 1 2002, 2419e2438; (e) Koumbis, A. E.; Gallos, J. K. Curr. Org. Chem.
2003, 7, 585e628; (f) Pellissier, H. Tetrahedron 2007, 63, 3235e3285.
1.47 (s, 3H), 1.56 (s, 3H), 1.75e1.84 (br s, 1H), 2.27e2.35 (m, 1H),
2.47e2.51 (m, 2H), 2.86e2.92 (br s, 1H), 3.58 (s, 3H), 3.83 (d,
J¼13.2 Hz, 1H), 3.89e3.94 (m, 1H), 3.95e3.96 (m, 2H), 4.04 (d,
J¼13.2 Hz, 1H), 4.14e4.17 (m, 1H), 4.28 (d, J¼9.4 Hz, 1H), 4.97e5.04
(br s, 1H), 7.24e7.42 (m, 5H); dC (150 MHz, CDCl3) 20.9, 24.2, 25.4,
25.6, 28.2, 32.5, 51.6, 58.6, 60.9, 66.9, 68.2, 76.6, 77.3, 102.1, 108.2,
128.4,128.5,128.7,134.4,175.4; Anal. Calcd for: C22H33NO7: C, 62.39;
H, 7.85; N, 3.31; Found: C, 62.70; H, 7.91; N, 3.11.
ꢂ
ꢀ
ꢀ
ꢀ
ꢁ
ꢀ
ꢁ
ꢀ
€
4.1.20. 1-Benzyl-5-((3aS,4S,8aR)-2,2,6,6-tetramethyltetrahydro-[1,3]
8. (a) Kuban, J.; Blanarikova, I.; Fisera, L.; Jaroskova, L.; Fengler-Veith, M.; Jager, V.;
ꢁ ꢁ
ꢀ
Kozísek, J.; Humpa, O.; Pronayova, N.; Langer, V. Tetrahedron 1999, 55,
9501e9514; (b) Fischer, R.; Druckova, A.; Fisera, L.; Rybar, A.; Hametner, C.;
Cyranski, M. K. Synlett 2002, 1113e1117; (c) Kuban, J.; Kolarovic, A.; Fisera, L.;
Jager, V.; Humpa, O.; Pronayova, N.; Ertl, P. Synlett 2001, 1862e1865; (d) Kuban,
J.; Kolarovic, A.; Fisera, L.; Jager, V.; Humpa, O.; Pronayova, N. Synlett 2001,
1866e1868; (e) Blanarikova-Hlobilova, I.; Kopanicakova, Z.; Fisera, L.; Cyranski,
M. K.; Salanski, P.; Jurczak, J.; Pronayova, N. Tetrahedron 2003, 59, 3333e3339;
(f) Fischer, R.; Druckova, A.; Fisera, L.; Hametner, C. ARKIVOC 2002, viii, 80e90;
dioxolo[4,5-e][1,3]dioxepin-4-yl)pyrrolidin-2-one
(0.123 g, 0.462 mmol) and water (0.5 mL) were added to a solution
of -hydroxylamino ester 22 (0.1 g, 0.231 mmol) in acetonitrile
(23). Mo(CO)6
ꢀ
ꢁ
ꢀ
ꢀ
ꢀ
ꢁ
ꢁ
g
€
ꢀ
ꢀ
ꢀ
ꢁ
ꢁ
€
ꢀ
ꢀ
(5 mL) and the mixture was stirred at reflux for 3 h monitoring by
TLC. Aqueous K2CO3 (40 mL, 1 M) was added, the mixture was
extracted with EtOAc (4ꢂ40 mL) and the combined organic layers
were washed with brine (40 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel: 50 g, 20% EtOAc/hexanes then
ꢀ
ꢀ
ꢀ
ꢁꢀ
ꢀ
ꢁ
ꢀ
ꢀ
ꢀ
ꢀ
ꢁ
ꢁ
ꢁ
ꢀ
ꢀ
(g) Dugovic, B.; Fisera, L.; Cyranski, M. K.; Hametner, C.; Pronayova, N.; Obranec,
M. Helv. Chim. Acta 2005, 88, 1432e1443.
ꢀ
9. (a) Masson, G.; Cividino, P.; Py, S.; Vallee, Y. Angew. Chem., Int. Ed. 2003, 42,
2265e2268; (b) Riber, D.; Skrydstrup, T. Org. Lett. 2003, 5, 229e231; (c) Jo-
hannesen, S. A.; Albu, S.; Hazell, R. G.; Skrydstrup, T. Chem. Commun. 2004,
1962e1963; (d) Cividino, P.; Py, S.; Delair, P.; Greene, A. E. J. Org. Chem. 2007, 72,
EtOAc) and 23 was isolated as colorless crystals (0.052 g, 60%), mp
25
141e144 ꢀC; Rf (80% EtOAc/hexanes) 0.27; [
a]
þ13.4 (c 0.209,
D
ꢀ
485e493; (e) Masson, G.; Py, S.; Vallee, Y. Angew. Chem., Int. Ed. 2002, 41,
CHCl3); nmax (KBr) 2987, 2891, 2862, 2821, 1681, 1676, 1496, 1462,
1772e1775; (f) Chavarot, M.; Rivard, M.; Rose-Munch, F.; Rose, E.; Py, S. Chem.
Commun. 2004, 2330e2331; (g) Racine, E.; Py, S. Org. Biomol. Chem. 2009, 7,
3385e3387; (h) Zhong, Y.-W.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2004, 6,
3953e3956.
1445 cmꢁ1
;
dH (600 MHz, CDCl3) 1.29 (s, 3H), 1.31 (s, 3H), 1.34 (s,
3H), 1.48 (s, 3H), 1.85e1.93 (m, 1H), 2.06e2.11 (m, 1H), 2.29 (ddd,
J¼1.5, 10.1, 16.6 Hz, 1H), 2.56 (td, J¼9.8, 19.6 Hz, 1H), 3.73 (d,
J¼9.8 Hz, 1H), 3.76 (d, J¼14.9 Hz, 1H), 3.84 (dd, J¼5.6, 10.0 Hz, 1H),
3.96e3.99 (m, 3H), 4.15 (td, J¼1.5, 5.6 Hz, 1H), 5.22 (d, J¼14.9 Hz,
1H), 7.22e7.32 (m, 5H); dC (150 MHz, CDCl3) 18.7, 23.8, 25.0, 25.5,
28.5, 30.8, 43.9, 56.5, 58.3, 68.3, 75.5, 76.6, 101.8, 108.5, 127.6, 128.0,
128.6, 136.4, 175.8; Anal. Calcd for: C21H29NO5: C, 67.18; H, 7.79; N,
3.73; Found: C, 67.37; H, 8.12; N, 3.67.
ꢀ
10. (a) Masson, G.; Zeghida, W.; Cividino, P.; Py, S.; Vallee, Y. Synlett 2003,
1527e1529; (b) Masson, G.; Philouze, C.; Py, S. Org. Biomol. Chem. 2005, 3,
2067e2069; (c) Desvergnes, S.; Desvergnes, V.; Martin, O. R.; Itoh, K.; Liu, H.;
Py, S. Bioorg. Med. Chem. 2007, 15, 6443e6449.
ꢀ
ꢁ
ꢁ ꢁ
ꢀ
ꢁ
ꢀ
ꢀꢁ
11. (a) Rehak, J.; Fisera, L.; Kozísek, J.; Perasínova, L.; Steiner, B.; Koos, M. ARKIVOC
ꢁ
ꢁ ꢁ
ꢁ
ꢀ
2008, viii, 18e27; (b) Rehak, J.; Fisera, L.; Podolan, G.; Kozísek, J.; Perasínova, L.
Synlett 2008, 1260e1264; (c) Rehak, J.; Fisera, L.; Pronayova, N. ARKIVOC 2009,
vi, 146e157.
ꢀ
ꢁ
ꢀ
ꢀ
12. Zinner, H. Chem. Ber. 1950, 83, 275e277.
13. Aslani-Shotorbani, G.; Buchanan, J. G.; Edgar, A. R.; Shahidi, P. K. Carbohydr. Res.
1985, 136, 37e52.
Acknowledgements
14. Kumar, V.; Dev, S. Tetrahedron 1987, 43, 5933e5948.
15. Yadar, J. S.; Chandrasekhar, S.; Sasmal, P. K. Tetrahedron Lett. 1997, 38,
8765e8768.
The authors are grateful to the Slovak Grant Agency (No. 1/0236/
09, No. 1/0115/10 and No. 1/0679/11).
ꢀ
16. Dondoni, A.; Franco, S.; Junquera, F.; Merchan, F.; Merino, P.; Tejero, T. Synth.
Commun. 1994, 18, 2537e2550.
17. Vijayasaradhi, S.; Singh, J.; Singh, A. I. Synlett 2000, 110e112.
18. Pfrengle, F.; Dekaris, V.; Schefzig, L.; Zimmer, R.; Reissig, H.-U. Synlett 2008,
2965e2968.
References and notes
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24. Crystallograhic Data (excluding structure factors) for the structures in this
paper have been deposited with the Cambridge Crystallographic Data Center
and allocated the deposition numbers CCDC 800 702 and CCDC 800 703. Copies
of the data can be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1E2, UK, (fax: þ44 (0) 1223 336033 or email: deposit@
ccdc.cam.ac.uk).
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