Highly diastereoselective N-acyliminium ion cyclization reactions of a tethered furan

Article abstract of DOI:10.1016/j.tet.2012.10.014

The acid catalysed cyclization reactions of tethered furan-4,5- dihydroxypyrrolid-2-ones and furan-4,5-diacetoxypyrrolid-2-ones, via their corresponding N-acyliminium ion intermediates, have been studied. In the case of the tethered furan-3,4-dihydroxypyrrolid-2-one 16, having a two carbon tether, the linearly fused tricyclic compound 18 was formed with high cis selectivity (cis/trans=84:16) when BF₃·OEt₂ was used as a catalyst. However, when the cyclization reaction was carried out on the related tethered furan-4,5-diacetoxypyrrolid-2-one 17, the linearly fused tricyclic compound 20 was formed as a single diastereoisomer with trans selectivity. In contrast, the attempted cyclization of the tethered furan-4,5-dihydroxypyrrolid- 2-one 26, having a one carbon tether, did not result in formation of the corresponding linearly fused tricyclic system, instead it formed the dimer 29 as a single diastereoisomer. Cyclization reactions of the related tethered furan-4,5-diacetoxypyrrolid-2-one 27 also failed to give the corresponding linearly fused tricyclic system or macrocycle.

Full text of DOI:10.1016/j.tet.2012.10.014

Tetrahedron 68 (2012) 10280e10285
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Tetrahedron
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Highly diastereoselective N-acyliminium ion cyclization reactions
of a tethered furan
,
Sudhir R. Shengule a, Gregory Ryder a, Anthony C. Willis b, Stephen G. Pyne a
*
a School of Chemistry, University of Wollongong, Wollongong, New South Wales 2522, Australia
b Research School of Chemistry, Australian National University, Canberra, ACT 0200, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 August 2012
Received in revised form 12 September 2012
Accepted 2 October 2012
Available online 12 October 2012
The acid catalysed cyclization reactions of tethered furanꢀ4,5-dihydroxypyrrolid-2-ones and furane4,5-
diacetoxypyrrolid-2-ones, via their corresponding N-acyliminium ion intermediates, have been studied.
In the case of the tethered furane3,4-dihydroxypyrrolid-2-one 16, having a two carbon tether, the lin-
early fused tricyclic compound 18 was formed with high cis selectivity (cis/trans¼84:16) when BF3$OEt2
was used as a catalyst. However, when the cyclization reaction was carried out on the related tethered
furane4,5-diacetoxypyrrolid-2-one 17, the linearly fused tricyclic compound 20 was formed as a single
diastereoisomer with trans selectivity. In contrast, the attempted cyclization of the tethered furane4,5-
dihydroxypyrrolid-2-one 26, having a one carbon tether, did not result in formation of the corresponding
linearly fused tricyclic system, instead it formed the dimer 29 as a single diastereoisomer. Cyclization
reactions of the related tethered furane4,5-diacetoxypyrrolid-2-one 27 also failed to give the corre-
sponding linearly fused tricyclic system or macrocycle.
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
1. Introduction
As a part of our study towards the total synthesis of stemo-
curtisine 11 (Fig. 1), we aimed to synthesize linearly fused cis tri-
cyclic systems
3 via N-acyliminium ion cyclization of the
intermediate formed from the acyclic aminal 22 (Scheme 1). Com-
pound 3 could be used as a model compound to study the oxidation
reactions of the furan moiety of 3 and the formation of the cyclic
ether linkage found in stemocurtisine 1.
Scheme 1.
In our previous studies towards the synthesis of linearly fused
tricyclic systems we attempted the N-acyliminium ion cyclization
reactions of 43 (Scheme 2). The attempted acid-catalysed cycliza-
tion reaction of 4a resulted in formation of the dimer 5 as a single
distereoisomer while a similar reaction on the diactetate 4b
resulted in the macrocycle 6 as a single isomer. Further the reaction
was carried out on intermediate 4c (n¼1 or 2) by blocking the C-5
furan nucleophilic site by Br substitution. This resulted in the for-
mation of the spirocyclic compounds 7 and 8 as single di-
astereomers. Unfortunately these reactions failed to give the
requisite 6-7-5 (A, B, C ring) skeleton of stemocurtisine (1) by
favouring six-membered ring formation over formation of the de-
sired azepine ring.
There are no reports on the synthesis of 5-7-5 or 6-7-5 linearly
fused ring structures without substitution at the C-5 position of the
furan ring but there are a few reports on the synthesis of a 5-6-5 or
6-6-5 tricyclic system via N-acyliminium ion cyclization reactions
of furan.4 Tannis, for example, reported the synthesis of linearly
fused tricyclic systems 10e11 by N-acyliminium ion cyclization
reactions of the tethered furan intermediate 95 (Scheme 3). Based
Fig. 1. The structure of stemocurtisine 1.
* Corresponding author. E-mail address: spyne@uow.edu.au (S.G. Pyne).
0040-4020/$ e see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.014

S.R. Shengule et al. / Tetrahedron 68 (2012) 10280e10285
10281
16 was carried out using acetic anhydride and pyridine giving the
diacetate 17 in excellent yield (94%).
Scheme 4. Reagents and conditions: (a) nitromethane, (i) NaOH, (ii) HCl, 0 ꢁCert, 1 h,
93%; (b) LiAlH4, Et2O, reflux, 16 h; (c) (S)-malic acid, xylene, 180 ꢁC, 16 h, 59% (two
steps); (d) NaBH4, EtOH, ꢀ40 ꢁC to ꢀ10 ꢁC, 1 h, 69%; (e) Ac2O, pyridine, DMAP, rt, 2 h,
94%.
In our previous work on N-acyliminium ion cyclization reactions
of tethered furans we found that TFA was the best acid for these
reactions.3 Diol 16 was thus subjected to these cyclization reaction
conditions by treatment with 3 equiv of TFA in CH2Cl2 at rt. TLC
analysis indicated completion of the reaction in 10 min (Scheme 5).
Further, 1H NMR spectroscopic analysis of the crude reaction mix-
ture showed formation of two cyclised products in the di-
astereoisomeric ratio of 78:22. The mixture was separated by
column chromatography to give 18 and 19 in yields of 69% and 19%,
respectively. The 2D NMR spectroscopic data and single X-ray
crystallographic data (Fig. 2) of 18 confirmed that the major di-
astereomer was the cis-isomer 18 and thus the minor isomer was
the trans-isomer 19. Diacetate 17 when subjected to identical re-
action conditions gave the tricyclic 20 as a single diastereomer in
90% yield. To confirm the stereochemistry of the newly formed
compound the acetate group of 20 was saponified using KOH giving
alcohol 19, which was identical in all aspects to the compound
Scheme 2.
on these successful results we decided to investigate this reaction
for the synthesis of the linearly fused cis tricyclic systems 3 (n¼1 or
2), which could be used as a model compound in the development
of a synthesis of stemocurtisine 1.
Scheme 3.
2. Results and discussion
Nitroalkene 13 was prepared from commercially available 2-
furfural by a nitro-aldol condensation reaction with nitrometh-
ane6 (Scheme 4). Compound 13 was further reduced using lithium
aluminium hydride to give furfurylamine 14.7 Compound 15 was
synthesized from the reaction of amine 14 and L-malic acid, using
a procedure that we reported earlier.3 The C-1 carbonyl group was
selectively reduced using sodium borohydride giving the diol 16 as
a single diastereisomer.8 The appearance of the H-1 proton of diol
16 in the 1H NMR spectrum as a singlet identified the trans ste-
reochemical relationship between H-1 and H-2.8 Acetylation of diol
Scheme 5. Reagents and conditions: (a) TFA, CH2Cl2, rt, 10 min, 86% for 18 and 19 and
90% for 20; (b) KOH, MeOH, rt, 16 h, 97%.

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S.R. Shengule et al. / Tetrahedron 68 (2012) 10280e10285
Fig. 2. Molecular structure of 18 (C10H11NO3) with labelling of selected atoms.
formed as the minor isomer when the reaction was carried out on
16 (Scheme 5). These findings are synthetically useful since from
the one precursor 16 we can readily access either the cis- or trans-
isomer 18 and 19, respectively, depending upon the nature of the C-
4 pyrrolidinone substituent. The high cis selectivity observed for
the formation of 18 could be attributed to the intramolecular hy-
drogen bonding in the cyclization intermediate 21 (Scheme 6).9
Whereas, formation of 20 as a single diastereoisomer could be
explained by the formation of the acetoxonium ion intermediate 23
directing the nucleophilic attack of the furan ring from the opposite
side of the participating C-3 acetoxy group.
For compound 16, we screened other cyclization reaction con-
ditions by using different protic acids/Lewis acids, solvents and
temperatures (Table 1). When the reaction was carried out with the
Lewis acid Sc(OTf)3 it formed the products 18 and 19 in a combined
yield of 69% yield with poor distereoselectivity (58:42, entry 1). The
use of BF3$OEt2 in dichloromethane at rt formed products with high
selectivity (18/19¼84:16) but the reaction did not proceed at
ꢀ40 ꢁC (entries 2e4). We also attempted a cyclization using
Scheme 6. Proposed mechanism for the formation of cis 18 and trans 21
diastereoisomers.
BF3$OEt2 in toluene but the reaction did not proceed because of the
insolubility of the starting material. The use of lithium tetra-
fluoroborate gave a mixture of 18 and 19 in a ratio of 65:35 (entry
5). The reaction did not proceed at all when carried out with lith-
ium triflate and aluminium chloride (entries 6 and 7). The use of
diethylaluminium chloride formed the products 18 and 19 in very
poor yield and with moderate selectivity (entry 8). The use of p-
toluenesulfonic acid or camphorsulfonic acid in MeCN did not help
improve the selectivity (entries 9 and 11). When the reaction was
carried out with TFA in water, no cyclization was observed after
Table 1
Acid (A)/Lewis acid (LA) catalysed cyclization reactions of 16 to give products 18 and 19
Entry
A/LA
Temp (ꢁC)
Solvent
Time
Yielda (%)
Ratiob (dr) (18/19)
1
2
3
4
5
6
7
8
Sc(OTf)3
BF3$OEt2
BF3$OEt2
BF3$OEt2
LiBF4
Li(OTf)3
AlCl3
Et2AlCl
p-TSA
TFA
CSA
p-TSA
HCl/Et2O
rt
rt
rt
MeCN
MeCN
CH2Cl2
CH2Cl2
MeCN
MeCN
CHCl3
MeCN
MeCN
H2O
1 h
69
75
82
85
67
NR
NR
30
74
NR
81
78
80
58:42
66:34
84:16
84:16
65:35
d
10 min
10 min
1 h
1 h
16 h
ꢀ40 ꢁC to rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
2 h
3 h
d
75:25
58:42
d
9
10 min
16 h
30 min
30 min
30 min
10
11
12
13
MeCN
CH2Cl2
CH2Cl2
59:41
47:53
48:52
a
Combined yield of 18 and 19.
b
Diastereomeric ratio calculated using 1H NMR spectroscopy.

S.R. Shengule et al. / Tetrahedron 68 (2012) 10280e10285
10283
stirring the reaction mixture overnight (entry 10). Reactions were
also carried out with p-toluenesulfonic acid and HCl/Et2O in CH2Cl2
to give a mixture of 18 and 19 in almost 1:1 ratios (entries 12
and 13).
After successfully synthesizing the cis and trans linearly fused
tricyclic skeleton 5-6-5 (18 or 19) we further investigated if the
same conditions could be used to synthesize an analogous 5-5-5
tricyclic ring structure. The potential precursors 26 and 27 were
synthesized from commercially available furfurylamine in a similar
way to the synthesis of 16 and 17 (Scheme 7). In this case when diol
26 was treated with 1 equiv of TFA in CH2Cl2 it formed the dimer 29
as a single diastereoisomer in 60% yield (Scheme 8). This result is
similar to our previous results obtained for the attempted cycliza-
tion reaction of 4a (Scheme 2).3 The 1H NMR coupling constant J1,2
of 5.2 Hz suggested that the rings were cis-fused.8 To avoid the
intermolecular cyclization process the diol was protected as its
diacetate derivative 27. Attempted cyclization of 27 under acidic
conditions followed by column chromatography resulted only in
formation of the alcohol 28, which could have formed by the re-
action of the intermediate N-acyliminium ion with water on silica
gel (Scheme 8). The MS analysis of the reaction mixture did indicate
formation of a trace amount of a macrocyclic product similar to the
one observed (6) in the cyclization reaction of 4b (Scheme 2).
Further, we prepared precursor 30 by bromination of 27 using NBS.
Compound 30 was then subjected to the cyclization reaction con-
ditions by treatment with 3 equiv of TFA in CH2Cl2 for 16 h. The 1H
NMR spectroscopic and MS analysis of the reaction product showed
the formation of the corresponding C-5 alcohol and none of the
desired cyclised product.
Scheme 8. Reagents and conditions: (a) TFA (1 equiv), CH2Cl2, rt, 2 h, 60%; (b) TFA
(3 equiv), CH2Cl2, rt, 16 h; (c) BF3$OEt2, MeCN, rt, 16 h; (d) NBS, DMF, 0 ꢁC, 1 h, 68%.
stereochemistry. We propose that the cis adduct formation could be
because of intramolecular hydrogen bonding between the hydroxyl
group and electron rich furan ring, whereas trans adduct formation
could be due to the presence of an acetoxonium ion intermediate
(23). Attempted cyclization of 26 to form the analogues 5-5-5 ring
structure failed and instead formed the dimer 29 as a single di-
astereoisomer. The cyclization reaction of 27 and 30 also failed to
give the desired cyclised products. Clearly cyclization to form the
more strained 5-5-5 linearly fused system (3, n¼0, Scheme 1) is
much less favourable.
4. Experimental
4.1. General
All IR spectra were run as neat samples. All NMR spectra were
run at 500 MHz (1H NMR) or 125 MHz (13C NMR) in solution of
CDCl3 unless otherwise noted. FCC is an abbreviation for flash
column chromatography. Petrol refers to the hydrocarbon fraction
of bp 40e60 ꢁC. All the reagents were purchased from Sigma-
eAldrich and used for reactions without further purification. HRMS
data of all the new compounds were collected using Waters Xevo
and optical rotations for all chiral compounds were measured on
Jasco P-2000 polarimeter.
Scheme 7. Reagents and conditions: (a) (S)-malic acid, xylene, 180 ꢁC, 18 h, 83%; (b)
NaBH4, EtOH, ꢀ30 ꢁC to ꢀ4 ꢁC, 1 h, 42%; (c) Ac2O, pyridine, DMAP, rt, 1 h, 72%.
4.1.1. (E)-2-(2-Nitrovinyl)furan
(13).6 Nitromethane
(7.00 mL,
130 mmol), 2-furfural (5.00 g, 52.0 mmol) and methanol (10.1 mL,
0.25 mol) were added to a round bottomed flask and the reaction
mixture cooled to 0 ꢁC. Aqueous 1 M NaOH (130 mL, 130.2 mmol)
was added via an addition funnel for 5 min then an ice/water
mixture (25 mL) was added and the mixture was stirred at 0 ꢁC for
15 min. The mixture was then slowly added to aqueous 8 M HCl
(50 mL) and allowed to stir until the reaction was confirmed to be
complete by TLC analysis. The mixture was extracted with CH2Cl2
(3ꢂ150 mL) and combined extracts were washed with brine, dried
(MgSO4), filtered and concentrated to give a brown residue. The
product was purified by FCC over silica gel using a gradient of
0:100e15:85 EtOAc/petrol to afford 13 as a yellow solid (6.73 g,
3. Conclusions
We have investigated the protic acid/Lewis acid-catalysed re-
actions of tethered furane3,4-dihydroxypyrrolid-2-ones and
furane3,4-diacetoxypyrrolid-2-ones, via their corresponding N-
acyliminium ion intermediates. In the case of the tethered
furane3,4-dihydroxypyrrolid-2-one 16 the reaction formed the
tricyclic linearly fused system 18 with high cis selectivity. The re-
action was further screened using various acids/Lewis acids. The
use of BF3$OEt2 in dichloromethane gave the best results with high
selectivity for formation of the cis adduct (cis/trans¼84:16). When
the reaction was carried out on the diacetate 17 it formed the trans
93%); mp 68e70 ꢁC (lit. 74 ꢁC);6 1H NMR
7), 7.59 (br s, 1H, H-2), 7.53 (d, 1H, J 13.4 Hz, H-6), 6.89 (d, 1H, J
d 7.77 (d, 1H, J 13.4 Hz, H-
adduct 20 as
a
single diastereoisomer with opposite

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S.R. Shengule et al. / Tetrahedron 68 (2012) 10280e10285
3.2 Hz, H-4), 6.57 (dd, 1H, J 1.4, 3.2 Hz, H-3). The NMR spectral data
H-30), 5.93 (s, 1H, H-5), 5.03 (d, 1H, J 6.3 Hz, H-4), 3.78e3.84 (m, 1H,
CHHN), 3.27e3.33 (m,1H, CHHN), 2.81e2.96 (m, 3H, H-3a and CH2),
2.30 (d, 1H, J 18.0 Hz, H-3b), 2.05 (s, 3H, OAc), 2.02 (s, 3H, OAc); 13C
agreed with those reported in the literature.6
4.1.2. (S)-1-(2-(Furan-2-yl)ethyl)-3-hydroxypyrrolidine-2,5-dione
(15). To a stirred solution of lithium aluminium hydride (3.00 g,
81.0 mmol) in Et2O (30 mL) at 0 ꢁC was added a solution of 13
(3.00 g, 27.0 mmol) in Et2O (50 mL) over 10 min. The reaction
mixture was slowly warmed to reflux temperature and then heated
at reflux with stirring overnight. The reaction mixture was then
cooled to 0 ꢁC and quenched by the dropwise addition of water
(5 mL) followed by addition of 10% aqueous NaOH solution (5 mL).
The reaction mixture was diluted with Et2O (100 mL) and filtered
through Celite. The residue was washed with Et2O (50 mL). The
filterate was dried (MgSO4) and the solvent was removed under
reduced pressure. The crude amine 14 was used in next step
without any further purification. Compound 14 was added to
NMR d
173.2 (C-2), 170.1 (Ac), 169.8 (Ac), 152.2 (C-20), 141.7 (C-50),
110.4 (C-40), 106.7 (C-30), 86.8 (C-5), 71.0 (C-4), 39.7 (CH2 N), 35.9
(C-3), 26.6 (CH2), 21.0 (Ac), 20.9 (Ac); HRMS (ESI þve) calculated for
C14H18NO6 (MþHþ) 296.1134, found 296.1126.
4.1.5. (9S,9aS)-9-Hydroxy-4,5,9,9a-tetrahydrofuro[2,3-g]indolizin-
7(8H)-one (18) and (9S,9aR)-9-hydroxy-4,5,9,9a-tetrahydrofuro[2,3-
g]indolizin-7(8H)-one (19). To a stirred solution of 16 (200 mg,
0.94 mmol) in CH2Cl2 (5 mL) was added TFA (0.210 mL, 2.84 mmol)
and the reaction mixture was stirred at rt for 10 min. The solvent
was removed under reduced pressure and the residue was purified
by FCC over silica gel using a gradient of 0:100e8:92 MeOH/EtOAc
first to elute 19 (35 mg, 19%) as a thick colourless oil and then 18
(123 mg, 69%) as a white solid.
a mixture of L-malic acid (3.61 g, 27.0 mmol) and xylene (100 mL)
and the reaction mixture was heated at 180 ꢁC for 16 h in a flask
having a DeaneStark water trap. The solvent was then removed
under reduced pressure and the residue was purified by FCC over
silica gel using a gradient of 10:90e50:50 EtOAc/petrol to give 15 as
Major isomer (18): Rf: 0.23 (5:95 MeOH/EtOAc); mp: 192e195 ꢁC;
[a]
25 192.4 (c 2, MeOH); IR vmax (cmꢀ1): 3240,1655,1648,1279,1173,
D
1133, 1106, 1052, 733; 1H NMR
d 7.39 (br s, 1H, H-10), 6.30 (d, 1H, J
1.6 Hz, H-9), 4.70e4.74 (m, 1H, H-8a), 4.51 (t, 1H, J 4.4 Hz, H-1), 4.46
(dd, 1H, J 6.1, 12.9 Hz, H-5a), 2.90e3.00 (m, 1H, H-5b), 2.68e2.78 (m,
a light yellow solid (3.33 g, 59% for the two steps); Rf: 0.57 (60:40
EtOAc/petrol); mp 55e60 ꢁC; [
a
]
ꢀ20.7 (c 3.5, CHCl3); IR vmax
3H, H-6 and H-2a), 2.48 (d,1H, J 17.0 Hz, H-2b); 13C NMR
d 171.8 (C-3),
25
D
(cmꢀ1): 3388, 1684, 1439, 1410, 1154, 1141, 1003, 744; 1H NMR
d
7.29
151.1 (C-7), 142.9 (C-10), 112.1 (C-8), 107.2 (C-9), 66.9 (C-1), 60.5 (C-
(br s, 1H, H-50), 6.24 (br s, 1H, H-40), 6.03 (d, 1H, J 2.4 Hz, H-30), 4.58
(dd, 1H, J 4.8, 8.3 Hz, H-3), 3.77 (t, 2H, J 6.8 Hz, CH2N), 3.02 (dd, 1H, J
8.3, 18.0 Hz, H-4a), 2.94 (t, 2H, J 6.8 Hz, CH2), 2.62 (dd, 1H, J 4.8,
8a), 41.5 (C-2), 36.5 (C-5), 23.5 (C-6); HRMS (ESI þve) calculated for
C10H12NO3 (MþHþ) 194.0817, found 194.0809.
25
Minor isomer (19): Rf: 0.36 (5:95 MeOH/EtOAc); [
a
]
ꢀ94.7 (c
D
18.0 Hz, H-4b); 13C NMR
d
178.4 (C-2), 174.0 (C-5), 151.6 (C-20), 142.0
2.5, MeOH); IR vmax (cmꢀ1): 3347, 1662, 1654, 1225, 1091, 1031, 893,
(C-50), 110.5 (C-40), 107.0 (C-30), 67.0 (C-3), 37.7 (CH2N), 37.2 (C-4),
26.1 (CH2); HRMS (ESI þve) calculated for C10H12NO4 (MþHþ)
210.0766, found 210.0775.
734, 600; 1H NMR
d
7.29 (br s, 1H, H-10), 6.40 (d, 1H, J 1.7 Hz, H-9),
4.42e4.46 (m, 2H, H-8a and H-5a), 4.18 (dd, 1H, J 1.4, 6.0 Hz, H-1),
3.50 (br s,1H, OH), 2.90e2.97 (m,1H, H-5b), 2.67e2.75 (m, 2H, H-2a
and H-6a), 2.58 (dd, 1H, J 4.9, 16.0 Hz, H-6a), 2.52 (dd, 1H, J 0.9,
4.1.3. (4S,5R)-1-(2-(Furan-2-yl)ethyl)-4,5-dihydroxypyrrolidin-2-
one (16). A solution of 15 (1.20 g, 5.74 mmol) in ethanol (20 mL) was
cooled toꢀ40 ꢁC followed by the addition of NaBH4 (1.00 g,
28.7 mmol). The reaction mixture was warmed to ꢀ10 ꢁC over 1 h.
The reaction was quenched by the addition of a saturated aqueous
solution of NaHCO3 (5 mL). The reaction mixture was extracted with
EtOAc(3ꢂ50 mL)andthecombinedextractsweredried(MgSO4)and
the solvent was removed under reduced pressure. The crude residue
was purified by FCC over silica gel using a gradient of 0:100e15:85
MeOH/EtOAc to give 16 as a thick colourless oil (835 mg, 69%) and as
16.6 Hz, H-2b); 13C NMR
d 171.5 (C-3),148.2 (C-7),142.3 (C-10),117.0
(C-8), 107.3 (C-9), 72.1 (C-1), 62.0 (C-8a), 41.1 (C-2), 36.3 (C-5), 23.3
(C-6); HRMS (ESI þve) calculated for C10H12NO3 (MþHþ) 194.0817,
found 194.0809.
4.1.6. (9S,9aR)-7-Oxo-4,5,7,8,9,9a-hexahydrofuro[2,3-g]indolizin-9-
yl acetate (20). The title compound was synthesized from 17
(0.080 g, 0.270 mmol) using the method described for the synthesis
of 18 and 19. In this reaction compound 20 was formed as a single
diastereoisomer (57 mg, 90%, thick colourless oil); Rf: 0.42 (60:40
a single diastereomer; Rf: 0.33 (5:95 MeOH/EtOAc); [
a
]
25 33.4 (c 1.0,
EtOAc/petrol); [
a
]
D
25 ꢀ83.5 (c 1.7, CHCl3); IR vmax (cmꢀ1): 1739, 1689,
D
MeOH); IR vmax (cmꢀ1): 3323,1662,1653,1457,1254,1147,1060, 983,
1684, 1419, 1363, 1225, 1036, 888, 736, 701; 1H NMR
d
7.27 (s, 1H, H-
706, 679; 1H NMR (CD3OD)
d
7.34 (br s,1H, H-50), 6.26 (t,1H, J 1.8 Hz,
10), 6.29 (s, 1H, H-9), 5.06e5.11 (m, 1H, H-1), 4.55 (br s, 1H, H-8a),
4.48 (dd, 1H, J 6.6, 13.2 Hz, 1H, H-5a), 2.93e3.00 (m, 1H, H-5b),
2.74e2.86 (m, 2H, H-2a and H-6a), 2.48e2.60 (m, 2H, H-2b and H-
H-40), 6.09 (d,1H, J 1.8 Hz, H-30), 4.80 (br s,1H, H-5), 4.02 (dd,1H, J 0.9,
5.5 Hz, H-4), 3.63e3.68 (m, 1H, CHHN), 3.37e3.43 (m, 1H, CHHN),
2.83e2.91 (m, 2H, CH2), 2.75 (dd,1H, J 6.5,17.4 Hz, H-3a), 2.12 (d,1H, J
6b), 2.10 (s, 3H, OAc); 13C NMR
d 171.2 (C-3),170.6 (OAc), 148.8 (C-7),
17.4 Hz, H-3b); 13C NMR (CD3OD)
d
174.3 (C-2),152.7 (C-20),141.5 (C-
142.3 (C-10), 116.3 (C-8), 107.5 (C-9), 72.0 (C-1), 60.9 (C-8a), 37.7 (C-
2), 36.9 (C-5), 23.0 (C-6), 21.2 (OAc); HRMS (ESI þve) calculated for
C12H14NO4 (MþHþ) 236.0923, found 236.0930.
50), 110.1 (C-40), 106.1 (C-30), 90.0 (C-5), 71.4 (C-4), 38.7 (CH2N), 38.1
(C-3), 26.0 (CH2); HRMS (ESI þve) calculated for C10H14NO4 (MþHþ)
212.0923, found 212.0933.
4.1.7. (9S,9aR)-9-Hydroxy-4,5,9,9a-tetrahydrofuro[2,3-g]indolizin-
7(8H)-one (19). To a stirred solution of 20 (50 mg, 0.21 mmol) in
methanol (5 mL) was added KOH (60 mg, 1.06 mmol) and the re-
action mixture was stirred at rt overnight. The solvent was removed
under reduced pressure and the residue was purified by FCC over
silica gel using a gradient of 0:100e8:92 MeOH/EtOAc to give the
title compound (40 mg, 97%, thick colourless oil), which was
spectroscopically identical to compound 19 prepared from 16.
4.1.4. (2R,3S)-1-(2-(Furan-2-yl)ethyl)-5-oxopyrrolidine-2,3-diyl di-
acetate (17). To a stirred solution of 16 (600 mg, 2.84 mmol) in
pyridine (10 mL) was added acetic anhydride (0.870 mL,
8.53 mmol) and DMAP (35 mg, 0.28 mmol). The reaction mixture
was stirred at rt for 16 h. The solvent was removed under reduced
pressure and the residue was dissolved in EtOAc (20 mL) and
washed with a saturated aqueous solution of CuSO4 (3ꢂ10 mL). The
combined organic layer was dried (MgSO4) and the residue was
purified using FCC over silica gel using a gradient of 0:100e25:75
EtOAc/petrol to give 17 as a thick colourless oil (789 mg, 94%); Rf:
4.1.8. (S)-1-(Furan-2-ylmethyl)-3-hydroxypyrrolidine-2,5-dione
(25). The title compound was synthesized from furfurylamine
(3.62 g, 37.0 mmol) using the method described for the synthesis of
15 (6.08 g, 83%, pale yellow solid); Rf: 0.52 (70:30 EtOAc/petrol); mp
0.66 (60:40 EtOAc/petrol); [
1739, 1714, 1424, 1419, 1369, 1216, 1145, 1042, 1012, 962, 731; 1H
NMR
7.28 (br s, 1H, H-50), 6.24 (br s, 1H, H-40), 6.04 (d, 1H, J 2.6 Hz,
a]
25 61.6 (c 1.7, CHCl3); IR vmax (cmꢀ1):
D
d
73e78 ꢁC; [
a
]
D
25 ꢀ68 (c 1.6, CHCl3); IR vmax (cmꢀ1): 3380, 1693,1429,

S.R. Shengule et al. / Tetrahedron 68 (2012) 10280e10285
10285
1394, 1326, 1242, 1153, 1085, 1007, 927, 757, 704, 635; 1H NMR
(CD3OD)
7.38 (br s, 1H, H-50), 6.32 (br s, 1H, H-40), 6.30 (br s, 1H, H-
was further purified by FCC over silica gel using a gradient of
20:80e50:50 EtOAc/petrol to give 30 as a thick colourless liquid
d
25
30), 4.82 (br s, 1H, OH), 4.64 (s, 2H, CH2), 4.61e4.56 (m, 1H, H-3),
3.07 (dd, 1H, J 8.5, 18.4 Hz, H-4a), 2.51 (dd, 1H, J 3.8, 18.4 Hz, H-4b);
13C NMR (CD3OD) 177.9 (C-2), 174.7 (C-5), 149.2 (C-20), 142.4 (C-50),
110.3 (C-40), 108.4 (C-30), 66.8 (C-3), 37.5 (C-4), 34.6 (CH2). HRMS
(ESI þve) calculated for C9H10NO4 (MþHþ) 196.0610, found
196.0602.
(260 mg, 68%); Rf: 0.78 (60:40 EtOAc/petrol); [
a
]
18.9 (c 1.6,
D
CHCl3); IR vmax (cmꢀ1): 1738, 1716, 1437, 1410, 1369, 1220, 1209,
1159,1122,1042, 956, 899; 1H NMR 6.27 (d,1H, J 2.9 Hz, H-40), 6.22
d
(d, 1H, J 2.9 Hz, H-30), 6.09 (s, 1H, H-5), 5.09 (d, 1H, J 6.3 Hz, H-4),
4.56 (d, 1H, J 15.6 Hz, CH2), 4.37 (d, 1H, J 15.6 Hz, CH2), 2.92 (dd,1H, J
6.3, 18.0 Hz, H-3a), 2.38 (d, 1H, J 18.0 Hz, H-3b), 2.05 (s, 6H, 2ꢂOAc);
13C NMR
d
172.9 (C-2), 170.0 (OAc), 169.9 (OAc), 151.4 (C-20), 121.9
4.1.9. (4S,5R)-1-(Furan-2-ylmethyl)-4,5-dihydroxypyrrolidin-2-one
(26). The title compound was synthesized from 25 (1.00 g,
5.03 mmol) using the method described for the synthesis of 16
(C-50), 112.3 (C-40), 111.9 (C-30), 86.4 (C-5), 71.1 (C-4), 38.2 (CH2),
35.8 (C-3), 21.0 (OAc), 20.9 (OAc); HRMS (ESI þve) calculated for
79
C13
H
BrNO6 (MþHþ) was 360.0083, found 360.0094.
15
(440 mg, 42% as a colourless solid); Rf: 0.68 (10:90 MeOH/EtOAc);
25
mp 93e98 ꢁC; [
a]
52 (c 0.7, MeOH); IR vmax (cmꢀ1): 3191, 1655,
D
4.2. X-ray crystallographic study
1463, 1441, 1396, 1350, 1308, 1261, 1229, 1149, 1055, 1012, 934, 895,
816, 740, 693, 628. 1H NMR (CD3OD) 7.40 (br s, 1H, H-50), 6.32 (m,
d
4.2.1. Crystal data. Compound 18. C10H11NO3, M¼193.20, T¼200 K,
orthorhombic, space group P212121, Z¼4, a¼5.6003(2), b¼7.3077(3),
1H, H-40), 6.28 (m, 1H, H-30), 4.83 (br s, 1H, H-5), 4.74 (d, 1H, J
16.2 Hz, CHHN), 4.16 (d, 1H, J 16.2 Hz, CHHN), 4.04 (d, 1H, J 6.2 Hz,
H-4). 2.80 (dd, 1H, J 6.2, 17.6 Hz, H-3a), 2.16 (d, 1H, J 17.6 Hz, H-3b).
3
c¼22.0455(8) A, V¼902.22(6) A , Dx¼1.422 g/cm3, 13,966 re-
ꢀ
ꢀ
flections measured (2
q
¼5e55ꢁ) merged to 1233 unique data,
13
C NMR 174.1 (C-2), 150.0 (C-20), 142.5 (C-50), 110.1 (C-40), 108.0 (C-
R¼0.026 [for 1157 data with I>2 (I)], Rw¼0.068 [all data], S¼1.00.
s
30), 89.2 (C-5), 71.2 (C-4), 38.1 (C-3), 35.9 (CH2); HRMS (ESI þve)
calculated for C9H12NO4 (MþHþ) 198.0766, found 198.0760.
4.2.2. Structure determination. Images were measured on a Nonius
KappaCCD diffractometer (Mo radiation, graphite mono-
K
a
4.1.10. (2R,3S)-1-(Furan-2-ylmethyl)-5-oxopyrrolidine-2,3-diyl diac-
etate (27). The title compound was synthesized from 26 (180 mg,
0.91 mmol) using the method described for the synthesis of 17
ꢀ
chromator,
l
¼0.71073 A) and data extracted using the DENZO
package.10 Structure solution was by direct methods (SIR92).11 The
structure was refined using the CRYSTALS program package.12
Atomic coordinates, bond lengths and angles and displacement
parameters have been deposited at the Cambridge Crystallographic
Data Centre (CCDC no. 895472). These data can be obtained free-of-
charge via www.ccdc.cam.ac.uk/data_requerst/cif, by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: þ44 1223 336033.
(185 mg, 72%, colourless oil); Rf: 0.78 (60:40 EtOAc/petrol); [a]
25 47
D
(c 1.6, CHCl3); IR vmax (cmꢀ1): 2361,1715,1439,1415,1367,1212,1163,
1147,1074,1042,1010, 963, 924, 899, 885, 861, 833, 757, 741, 685, 657,
637, 628.1H NMR (CD3OD) 7.44 (br s,1H, H-50), 6.36 (br s,1H, H-40),
d
6.30 (br s,1H, H-30), 6.10 (s,1H, H-5), 5.11 (d,1H, J 5.8 Hz, H-4), 4.61 (d,
1H, J 15.6 Hz, CHHN), 4.40 (d,1H, J 15.6 Hz, CHHN), 3.02 (dd,1H, J 6.4,
18.1, H-3a), 2.38 (d, 1H, J 18.1, H-3b), 2.02 (s, 3H, OAc), 2.01, (s, 3H,
OAc); 13C NMR (CD3OD)
d 174.0 (C-2),170.2 (OAc),170.2 (OAc),149.6
(C-20), 142.8 (C-50), 110.3 (C-40), 108.6 (C-30), 86.7 (C-5), 71.1 (C-4),
37.5 (C-3), 35.3 (CH2), 19.5 (OAc), 19.4 (OAc); HRMS (ESI þve) cal-
culated for C13H15NO4 (MþHþ) 282.0978, found 282.0982.
Acknowledgements
We thank the Australian Research Council and the University of
Wollongong for financial support.
4.1.11. (3aS,7aS)-1,5-Bis(furan-2-ylmethyl)octahydro-[1,4]dioxino
[2,3-b:5,6-b0]dipyrrole-2,6-dione (29). Cyclisation of the compound
26 (100 mg, 0.500 mmol) was attempted using TFA (39
mL,
References and notes
0.50 mmol) and CH2Cl2 (5 mL) stirred at rt for 2 h. The solvent was
removed under reduced pressure and the residue was purified
using FCC on a silica gel, eluted with a gradient of 20:80e70:30
EtOAc/petrol to give 29 as thick colourless liquid (55 mg, 60%); Rf:
1. Mungkornasawakul, P.; Pyne, S. G.; Jatisatienr, A.; Supyen, D.; Lie, W.; Ung, A. T.;
Skelton, B. W.; White, A. H. J. Nat. Prod. 2003, 66, 980e982.
2. For review on N-acyliminium ions see: (a) Speckamp, W. N.; Hiemstra, H.
Tetrahedron 1985, 41, 4367e4416; (b) Speckamp, W. N.; Moolenaar, M. J. Tet-
rahedron 2000, 56, 3817e3856; (c) Maryanoff, B. E.; Zhang, H.; Cohen, J. H.;
Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004, 104, 1431e1628; (d) Yazici, A.;
Pyne, S. G. Synthesis 2009, 339e368; (e) Yazici, A.; Pyne, S. G. Synthesis 2009,
513e541; (f) Martinez-Estibalez, U.; Gomez-SanJuan, A.; Garcia-Calvo, O.;
Aranzamendi, E.; Lete, E.; Sotomayor, N. Eur. J. Org. Chem. 2011, 20e21.
3. Shengule, S. R.; Willis, A.; Pyne, S. G. Tetrahedron 2012, 68, 1207e1215.
4. (a) Gao, S.; Tu, Y. Q.; Hu, X.; Wang, S.; Hua, R.; Jiang, Y.; Zhao, Y.; Fan, X.; Zhang,
S. Org. Lett. 2006, 8, 2373e2376; (b) Grigg, R.; Sridharan, V.; Sykes, D. A. Tet-
rahedron 2008, 64, 8952e8962; (c) Rose, M. D.; Cassidy, M. P.; Rashatasakhon,
P.; Padwa, A. J. Org. Chem. 2007, 72, 538e549; (d) Lee, H. I.; Cassidy, M. P.;
Rashatasakhon, P.; Padwa, A. Org. Lett. 2003, 72, 5067e5070.
0.53 (60:40 EtOAc/petrol); [
2365, 1697, 1506, 1448, 1382, 1271, 1238, 1189, 1169, 1146, 1061,
1075, 1047, 1010, 956, 734, 686, 668, 634, 625; 1H NMR
7.34 (br s,
a]
25 67.3 (c 2.0, CHCl3); IR vmax (cmꢀ1):
D
d
2H, 2ꢂH-50), 6.32e6.30 (m, 2H, 2ꢂH-40), 6.28 (d, 2H, J 3.0 Hz, 2ꢂH-
30), 4.92 (d, 2H, J 15.0 Hz, 2ꢂCHHN), 4.77 (d, 2H, J 5.2 Hz, 2ꢂH-5),
4.20e4.14 (m, 2H, 2ꢂH-4), 4.11 (d, 2H, J 15.0 Hz, 2ꢂCHHN), 2.82 (dd,
2H, J 8.4, 18.0 Hz, 2ꢂH-3a), 2.65 (dd, 2H, J 4.4, 18.0 Hz, 2ꢂH-3b); 13C
NMR
d
171.8 (2ꢂC-2), 149.4 (2ꢂC-20), 142.9 (2ꢂC-50), 110.7 (2ꢂC-40),
109.3 (2ꢂC-30), 83.0 (2ꢂC-5), 66.5 (2ꢂC-4), 36.9 (2ꢂC-3), 36.1
(2ꢂCH2); HRMS (ESI þve) calculated for C18H19N2O6 (MþHþ) was
359.1243, found 359.1233.
5. Tannis, S. P.; Deaton, M. V.; Dixon, L. A.; McMills, M. C.; Raggon, J. W.; Collins,
M. A. J. Org. Chem. 1998, 63, 6914e6928.
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Chem. 2011, 9, 8171e8177.
8. Morgan, I. R.; Yazici, A.; Pyne, S. G. Tetrahedron 2008, 64, 1409e1419.
9. Mauriello, F.; Armandi, M.; Bonelli, B.; Onida, B.; Garrone, E. J. Phys. Chem. C
2010, 114, 18233e18239.
10. Otwinowski, Z.; Minor, W. In Methods in Enzymology; Carter, C. W., Jr., Sweet, R.
M., Eds.; Macromolecular Crystallography, Part A; Academic: New York, NY,
1997; Vol. 276, pp 307e326.
11. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Burla, M. C.; Polidori,
G.; Camalli, M. J. Appl. Crystallogr. 1994, 27, 435.
4.1.12. 1.12(2R,3S)-1-((5-Bromofuran-2-yl)methyl)-5-oxopyrrolidine-
2,3-diyl diacetate (30). To
a stirred solution of 27 (0.30 g,
1.06 mmol) in DMF (5 mL) was added NBS (0.188 g, 1.06 mmol) at
0 ꢁC and the reaction mixture was stirred at the same temperature
for 1 h. A saturated aqueous solution of NaHCO3 (3 mL) was added
to the reaction mixture and further extracted with EtOAc
(3ꢂ25 mL). The combined organic layer was dried (MgSO4) and the
solvent was removed under reduced pressure. The residue obtained
12. Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, K.; Watkin, D. J. J. Appl.
Crystallogr. 2003, 36, 1487.