Model support studies toward the total synthesis of the stemona alkaloid stemocurtisine

Article abstract of DOI:10.1016/j.tet.2013.06.099

Herein we report the results of a furan-based approach toward the synthesis of the Stemona alkaloid, stemocurtisine 1 via the linearly fused tricyclic intermediate 3, representing the key A,B,C-ring structural feature of the target molecule. A highly diastereoselective synthesis of compound 3 was achieved starting from 3-furfural 6, in a synthetic sequence that involved; (1) a rapid in situ conversion of an O-mesylate to the corresponding chloride with inversion of configuration from assistance of the neighbouring 3-furanyl group; (2) an intramolecular aza-Wittig reaction to prepare the azepine ring; and (3) a base promoted lactam ring forming step. While methods were established to oxidize the furan ring of 3 to the corresponding γ-hydroxy-α,β-unsaturated lactone we were unable to affect cyclization of the lactam ring hydroxyl group to the γ-position of the lactone to create the cyclic ether feature of the natural product. Model studies were also unsuccessful.

Full text of DOI:10.1016/j.tet.2013.06.099

Tetrahedron 69 (2013) 8042e8050
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Model support studies toward the total synthesis of the stemona
alkaloid stemocurtisine
,
Sudhir R. Shengule 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:
Herein we report the results of a furan-based approach toward the synthesis of the Stemona alkaloid,
stemocurtisine 1 via the linearly fused tricyclic intermediate 3, representing the key A,B,C-ring structural
feature of the target molecule. A highly diastereoselective synthesis of compound 3 was achieved
starting from 3-furfural 6, in a synthetic sequence that involved; (1) a rapid in situ conversion of an
O-mesylate to the corresponding chloride with inversion of configuration from assistance of the
neighbouring 3-furanyl group; (2) an intramolecular aza-Wittig reaction to prepare the azepine ring; and
(3) a base promoted lactam ring forming step. While methods were established to oxidize the furan ring
Received 24 April 2013
Received in revised form 14 June 2013
Accepted 27 June 2013
Available online 4 July 2013
Keywords:
Furan oxidation
Azepine
Lactam
Stemona alkaloid
of 3 to the corresponding
lactam ring hydroxyl group to the
natural product. Model studies were also unsuccessful.
Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.
g
-hydroxy-
a
,b
-unsaturated lactone we were unable to affect cyclization of the
g
-position of the lactone to create the cyclic ether feature of the
1. Introduction
spirotricyclic product 9 and not the desired linearly fused tricyclic
compound 8 (Scheme 2).8
The extracts of roots of the Stemona species of plants have been
used in traditional medicine in SoutheEast Asia, China, and Japan to
treat the symptoms of bronchitis, pertussis, and tuberculosis and
have been used as anti-parasitics on humans and animals.1,2 Some
of the pure alkaloids derived from the extracts of the leaves and
roots of Stemona species have been shown to have significant anti
tussive activity in guinea pig after cough induction3 as well as in-
sect toxicity, antifeedant and repellent activities.4e6 The Stemona
group of alkaloids includes more than 120 different natural prod-
ucts, the majority of which have a common pyrrolo[1,2-a]azepine
nucleus. Stemocurtisine 1 (Scheme 1) was the first Stemona alka-
loid to be isolated with a pyrido[1,2-a]azepine A,B-ring system.7
Our retrosynthetic analysis of 1 (Scheme 1) indicated that the
tricyclic intermediate 3, representing the key A,B,C-ring structural
feature of the target molecule, would be an attractive key in-
termediate toward this endeavour. We envisaged that oxidation of
the furan moiety of 3 could give an intermediate that would allow
for the introduction of the more synthetically challenging ether
bridge between the A and B-rings and result in the tetracyclic
compound 2 (Scheme 1). Our earlier attempts at the synthesis of
a linearly fused tricyclic akin to compound 3 were unsuccessful.
For example, the Sc(OTf)3 catalysed cyclization reaction of the
tethered
furan-4,5-diacetoxypiperid-2-one
7
gave
the
Scheme 1. Retrosynthetic analysis of stemocurtisine 1.
* Corresponding author. E-mail address: spyne@uow.edu.au (S.G. Pyne).
0040-4020/$ e see front matter Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.099

S.R. Shengule et al. / Tetrahedron 69 (2013) 8042e8050
8043
gave the primary amines 15 and 16, which could be separated by
column chromatography providing these compounds in yields of 57
and 14%, respectively. Compounds 15 and 16 were individually
converted, in excellent yields (90e92%) to their respective piper-
idin-2-one derivatives, 17 and 18, by heating a solution of these
compounds in KOH/MeOH. The relative cis and trans 5,6-
configurations of 17 and 18 were based on their respective 1H
NMR coupling constants J5,6. For compound 17, J5,6 was 2.2 Hz,
while that for 18 was 6.6 Hz. These values were consistent with
those of cis (J5,6¼2.7 Hz)15 and trans-5-hydroxy-6-phenylpiperidin-
2-one (J5,6¼6.8 Hz),16 respectively.
Scheme 2. Attempted synthesis of the linearly fused tricyclic compound 8.
2. Results and discussion
To test the feasibility of securing the desired cis-configuration in
our proposed synthesis of 3 we first examined the diaster-
eoselective synthesis of (5R,6R)-6-(3-furyl)-5-hydroxy-piperidin-
2-one 17 (Scheme 3). While the first two synthetic steps were
similar to that reported by Sudalai9 for the synthesis of (5R,6S)-5-
hydroxy-6-phenylpiperidin-2-one from benzaldehyde, rather
than 3-furanal in this synthesis, our synthesis required modifica-
tion of the latter steps because of the presence of the more readily
oxidisable furan ring in Schemes 3 and 4 and our requirement for
lactams with the 6R configuration. The known vinyl alcohol 10,10
prepared by Grignard reaction of vinylmagnesium bromide with
3-furfural 6, was subjected to a JohnsoneClaisen rearrangement9 to
form the methyl ester 11 in 71% yield (Scheme 3). Asymmetric
dihydroxylation11 of the trans alkene of 11 with AD mix-
b gave the
lactone 12 in good yield (78%) and high enantioselectivity (dr >99:1
(from 1H NMR); er >98:2 from Mosher’s ester analysis). The desired
5,6-stereochemistry in the target molecule 17 required converting
the secondary hydroxyl group in 12 into an amino group with
overall retention of configuration. In pursuit of this result we first
attempted to convert the secondary hydroxyl of 12 into the corre-
sponding mesylate using standard conditions (MsCl, Et3N, CH2Cl2,
0 ꢀC).12 All attempts were unsuccessful and only unreacted starting
material was obtained. However we were very delighted to find
that by using the conditions of Tanabe,13 for the mesylation of
secondary alcohols with MsCl and N-methylimidazole (N-MeIm) in
toluene, the alcohol 12 was converted to the secondary chloride 13
with inversion. There is precedence for this type of in situ reaction
of chloride with activated mesylates (e.g., mesylates of benzylic and
allylic alcohols).14 In contrast, the related phenyl analogue of 12
(i.e., 12 in which the 3-furyl group is replaced by a Ph) is readily
converted to its corresponding mesylate, which is relatively stable
under standard conditions.9 The more electron rich 3-furanyl group
in 12 is clearly responsible for this enhanced instability and can
stabilize the expected SN2 and SN1 processes that lead to 12 and its
epimer, respectively. When the diastereomeric mixture of the
chlorides 13 was heated at 80 ꢀC with sodium azide in DMSO the
inverted azides 14 were obtained in 87% overall yield from 12 as
a 4:1 mixture of inseparable diastereomers. The Staudinger re-
action of this azide mixture with triphenylphosphine and water
Scheme 3. Synthesis of cis and trans-6-(3-furyl)-5-hydroxy-piperidin-2-ones 17 and
18.
This chemistry was then further developed to the synthesis of
the more demanding tricyclic system 3 (Scheme 4). The known allyl
alcohol 19,17 synthesized from the reaction of allylmagnesium
bromide and 3-furfural, was converted to the diol 20 in 86% yield by
hydroboration of the terminal alkene with 9-BBN followed by an
oxidative work up with basic H2O2. Diol 20 was then subjected to
the oxidative rearrangement reaction conditions developed by
Walsh18 by treatment with NBS in aqueous THF. This procedure

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S.R. Shengule et al. / Tetrahedron 69 (2013) 8042e8050
Scheme 4. Synthesis of the linearly fused tricyclic compound 3.
provided the desired 2-substituted-3-furfural 21 in 61% yield. The
primary alcohol of 21 was acetylated and the resulting ester 22 was
converted to the allylic alcohol 23 when treated with vinyl-
magnesium bromide in THF. This was then converted to the ester 5
using an analogous JohnsoneClaisen rearrangement procedure to
that as described in Scheme 3. The asymmetric dihydroxylation of 5
its TBS ether 31 in 88% yield (Scheme 5). Oxidation of the furan
ring of 31 with m-CPBA in CH2Cl2 gave the -hydroxy- -un-
saturated lactone 32 as a single diastereoisomer. The configuration
of the newly formed stereogenic center in compound 32 was
confirmed by a single-crystal X-ray crystallographic analysis,
g
a,b
which showed that the tertiary g-hydroxyl group was trans to the
with AD mix-
b
gave the lactone 4 in high yield (89%) and high
two pyrrolidinone substituents (Fig. 1). The reaction of 32 with
TBAF followed by p-TSA gave a separable mixture of the TBS
deprotected compound 33 and dehydrated compound 34 but none
of the desired cyclic ether product 35 was observed. Oxidation of
the furan ring of 30 with NBS in THF gave the diene 34 in 60%
yield. Our attempts to form the cyclic ether 35 from 33 by acid
catalysed reactions (TsOH, toluene, reflux, 16 h or concd H2SO4, rt,
3 h) resulted in the isolation of only 34 in low yields (39 and 35%,
respectively). While related acid catalysed intramolecular ketali-
enantioselectivity (dr >99:1 (from 1H NMR); er >98:2 from
Mosher’s ester analysis). Lactone 4 was subsequently converted
with inversion to chloride 24 (dr 4:1) and then with inversion to
azide 25 (dr 4:1) using analogous chemistry to that described in
Scheme 3. Hydrolysis of the acetate of 25 gave the primary alcohol,
which was converted to the aldehyde 27 upon oxidation with the
DesseMartin periodinane reagent. The azido-aldehyde 27 was then
treated under aza-Wittig reaction conditions19 with triphenyl-
phosphine in anhydrous THF and then the resulting cyclic imine
intermediate was reduced with sodium borohydride. Separation by
column chromatography gave the desired azepine-lactone 28 in
54% yield and its epimer 29 in 14% yield. Compound 28 was then
converted to the long sought after tricyclic compound 3 in 98% by
heating in KOH/MeOH. The relative cis-configuration of 3 is based
on the 1H NMR coupling constant J1,10a of 2.0 Hz (stemocurtisine
numbering).
zation reactions of
g-hydroxy-a,b-unsaturated lactones are
known,21 we suspect that compound 35 did not form because of
its expected high ring strain, made even more unfavourable by the
three sp2 hybridized carbons.2
Oxidation of the furan ring of 3 gave the
saturated lactone 36 in 54% yield as a single diastereomer (Scheme
6). We assigned the trans-configuration to the tertiary -hydroxyl
g-hydroxy-a,b-un-
g
group based on the stereochemical outcome of the oxidation of 31
to 33 (Scheme 5). Compound 36, when subjected to acidic condi-
tions (TsOH, CH2Cl2, rt, 16 h, or BF3$OEt2, rt, 16 h, or anhydrous HCl
in Et2O, CH2Cl2, rt, 3 d) also failed to give the desired ether com-
pound 2, instead, starting material was recovered.
Before examining the oxidation chemistry of 3, and the con-
struction of the ether linkage in target molecule 2 (Scheme 1), we
first studied the oxidation of compound 30, which we had syn-
thesized earlier.20 The hydroxyl group of 30 was first protected as

S.R. Shengule et al. / Tetrahedron 69 (2013) 8042e8050
8045
Scheme 6. Attempted synthesis of the cyclic ether 2.
An attempted oxidation of 37, the OTBS ether derivative of 17,
using m-CPBA failed to proceed and returned only unreacted 37.
The singlet oxygen oxidation21 of 37, however, proceeded in high
yield (91%) and gave the lactone 38 as a single diastereomer
(Scheme 7). Protection of the hydroxyl group of 17 was necessary to
afford a derivative that was soluble in CH2Cl2. Compound 38, when
subjected to BF3$OEt2, CH2Cl2, rt, 3 d led to the formation of TBS
deprotected compound but failed to give any of the desired ether
compound 39 (Scheme 7).
Scheme 5. Attempted synthesis of the cyclic ether 35.
Scheme 7. Attempted synthesis of the cyclic ether 39.
3. Conclusions
In conclusion, we have successfully prepared the linearly fused
tricyclic compound 3, which represents the key A,B,C-ring structural
feature of the Stemona alkaloid, stemocurtisine 1. A highly diaster-
eoselective synthesis of compound 3 was achieved starting from 3-
furfural 6, in a synthetic sequence that involved; (1) a rapid in situ
conversion of an O-mesylate to the corresponding chloride with in-
version of configuration from assistance of the neighbouring 3-
furanyl group; (2) an intramolecular aza-Wittig reaction to prepare
the azepine ring; and (3) a base promoted lactam ring forming step.
While methods were established to oxidize the furan ring of 3 to the
corresponding
g-hydroxy-a,b-unsaturated lactone 36 we were un-
able to affect cyclization of the lactam ring hydroxyl group to the
g-
position of the lactone to create the cyclic ether feature of the natural
product. Model studies were also unsuccessful. This lack of success is
most likely due to the strained nature of the hypothetical cyclic ether
products and the reversible nature of our reaction conditions. We are
currently examining a different strategy that involves less strained
substrates, which have fewer sp2 hybridised carbons and reactions
that are under kinetic control (irreversible reactions).
4. Experimental section
4.1. General procedures
Fig. 1. Molecular structure of compound 32 (C16H25NO5Si) with labelling of selected
atoms, showing the major sites of disordered atoms (Si17 to C23, occupancy 0.84).
Anisotropic displacement ellipsoids show 30% probability levels. Hydrogen atoms are
drawn as circles with small radii (CCDC 924873).
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

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S.R. Shengule et al. / Tetrahedron 69 (2013) 8042e8050
CDCl3 unless otherwise noted. FCC is an abbreviation for flash
column chromatography, which was performed with Merck silica
gel 60 (40e60 mm) and under pressure from compressed air. Petrol
NMR d 177.2, 143.8, 140.6, 123.8, 109.1, 82.7, 69.3, 28.6, 24.0; HRMS
(ESI þve) calculated for C9H11O4 (MþHþ) 183.0657, found 183.0665.
refers to the hydrocarbon fraction of bp 40e60 ꢀC. All the reagents
were purchased from SigmaeAldrich and used for reactions with-
out further purification. Thin layer chromatography (TLC) was
performed with precoated Merck silica gel 60 PF254 aluminium
sheets, the spots were visualized under UV light (254 nm and
366 nm) and further by spraying with an acidified aqueous solution
of ammonium molybdate and cerium(IV) sulphate then heating
until charred. All air-sensitive reactions were carried out in pre-
dried glassware apparatus under a dry nitrogen atmosphere. HRMS
data of all the new compounds was collected using Waters Xevo
and optical rotations for all chiral compounds were measured on
a Jasco P-2000 polarimeter.
4.5. (5R)-5-(Azido(furan-3-yl)methyl)dihydrofuran-2(3H)-one
(14)
To a stirred solution of 12 (300 mg, 1.64 mmol) in toluene
(10 mL) was added triethylamine (0.68 mL, 4.92 mmol), N-meth-
ylimidazole (0.40 mL, 4.92 mmol), and mesyl chloride (0.40 mL,
4.92 mmol). The reaction mixture was stirred at the same tem-
perature for 16 h. Water (5 mL) was added to the reaction mixture
and extracted with ethyl acetate (3ꢁ20 mL). The combined organic
extracts were dried (MgSO4) then evaporated to give the chloro
compound 13, which was used for the next reaction without further
purification. Sodium azide (323 mg, 4.92 mmol) was added to
a stirred solution of 13 in DMSO (5 mL) and the reaction mixture
was heated at 80 ꢀC for 1 h. The reaction mixture was cooled to rt
followed by addition of water (5 mL) and then extracted with
diethyl ether (3ꢁ50 mL). The combined organic extracts were dried
(MgSO4), evaporated and the residue obtained was purified by FCC
over silica gel using a gradient of 0:100e30:70 EtOAc/petrol to give
azide 14 as a colourless liquid (297 mg, 87% for two steps) and as
a mixture of diastereoisomers (4:1). Major isomer: Rf 0.22 (2:3
EtOAc/petrol); IR vmax (cmꢂ1): 2100, 1760, 1250, 1183, 1166, 1122,
4.2. 1-(Furan-3-yl)prop-2-en-1-ol (10)10
A solution of 3-furfual 6 (5.00 g, 52.0 mmol) in diethyl ether
(50 mL) was cooled to 0 ꢀC followed by dropwise addition of
vinylmagnesium bromide (62.5 mL,
1 M solution in THF,
62.5 mmol). The reaction mixture was stirred at the same tem-
perature for 1 h. A saturated solution of NH4Cl (100 mL) was added
and the reaction mixture was warmed to rt. The reaction mixture
further extracted with EtOAc (3ꢁ100 mL) and the combined ex-
tracts were dried (MgSO4) and concentrated to give a thick oil. The
crude residue was further purified by FCC over silica gel using
a gradient of 0:100e15:85 EtOAc/petrol to give 10 as light yellow oil
1031, 996, 919, 870, 753; 1H NMR
(br s, 1H), 4.67e4.63 (m, 1H), 4.52 (d, 1H, J¼4.6 Hz), 2.52e2.46 (m,
2H), 2.26e2.18 (m, 1H), 2.10e2.04 (m, 1H); 13C NMR
176.4, 144.3,
d 7.54 (br s, 1H), 7.44 (s, 1H), 6.47
d
141.5, 119.6, 109.6, 80.7, 60.4, 28.2, 24.6; HRMS (ESI þve) calculated
for C9H10N3O3 (MþHþ) 208.0722, found 208.0732.
(4.19 g, 65%). Rf 0.28 (1:9 diethyl ether/petrol); 1H NMR
d 7.36 (br s,
1H), 7.35 (br s, 1H), 6.36 (br s, 1H), 6.06e5.99 (m, 2H), 5.32 (d, 1H,
J¼17.1 Hz), 5.18 (d, 1H, J¼10.8 Hz), 5.11 (d, 1H, J¼4.6 Hz).
4.6. (R)-5-((R)-Amino(furan-3-yl)methyl)dihydrofuran-2(3H)-
one (15) and (R)-5-((S)-amino(furan-3-yl)methyl)dihy-
drofuran-2(3H)-one (16)
4.3. (E)-Methyl 5-(furan-3-yl)pent-4-enoate (11)
To a stirred solution of 14 (200 mg, 0.96 mmol) in dry THF (5 mL)
was added triphenylphosphine (759 mg, 2.89 mmol) under a N2
atmosphere and the reaction mixture stirred at rt for 1 h. Water
To a stirred solution of 10 (2.00 g, 16.1 mmol) in toluene (50 mL)
was added trimethyl orthoacetate (10 mL, 80.5 mmol), propionic
acid (50 mL) and the reaction mixture was heated at reflux for 16 h.
(500 mL) was added to the reaction flask and the reaction mixture
The reaction mixture was cooled to rt and the solvent was removed
under reduced pressure. The dark brown residue obtained was
purified by FCC over silica gel using a gradient of 0:100e10:90
EtOAc/petrol to give 11 as thick oil (2.05 g, 71%). Rf 0.69 (20:80
EtOAc/petrol); IR vmax (cmꢂ1): 2980, 1733, 1177, 1073, 1023, 964,
was heated at reflux for 3 h. The reaction was cooled to rt and the
solvent was removed under reduced pressure. The residue obtained
was purified by FCC over silica gel using a gradient of 0:100e8:92
MeOH/EtOAc to give first 15 and then 16 as colourless thick liquids
(100 mg, 57% for 15 and 24 mg, 14% for 16). Major isomer: Rf 0.28
870, 775; 1H NMR
d
7.32 (br s, 1H), 7.30 (s, 1H), 6.45 (br s, 1H), 6.25
25
(1:9 MeOH/EtOAc); [
a
]
ꢂ31 (c 2.5, CHCl3); IR vmax (cmꢂ1): 3372,
D
1762, 1501, 1178, 1157, 1014, 911, 831, 795; 1H NMR
d 7.39 (br s, 1H),
(d, 1H, J¼15.8 Hz), 5.88 (dt, 1H, J¼6.3, 15.8), 3.62 (s, 3H), 2.60e2.45
(m, 4H); 13C NMR
d 173.6, 156.0, 143.5, 139.9, 128.1, 120.8, 107.6, 51.7,
7.35 (s, 1H), 6.38 (br s, 1H), 4.84 (dd, 1H, J¼7.3, 14.4 Hz), 3.94 (d, 1H,
34.0, 28.2; HRMS (ESI þve) calculated for C10H13O3 (MþHþ)
J¼6.8 Hz), 2.47e2.40 (m, 2H), 2.12e2.06 (m, 1H), 2.00e1.90 (m, 1H);
13C NMR
d 177.1, 143.8, 140.0, 125.1, 109.2, 82.7, 52.2, 28.8, 24.7;
181.0865, found 181.0858.
HRMS (ESI þve) calculated for C9H12NO3 (MþHþ) 182.0817, found
4.4. (5R)-5-(Furan-3-yl(hydroxy)methyl)dihydrofuran-2(3H)-
one (12)
182.0827. Minor isomer: Rf 0.14 (1:9 MeOH/EtOAc); [a]
25 10 (c 0.6,
D
CHCl3); IR vmax (cmꢂ1): 3372, 1762, 1501, 1178, 1158, 1021, 909, 838,
794; 1H NMR
7.38 (br s, 2H), 6.34 (br s, 1H), 4.64e4.60 (m, 1H),
4.20 (d, 1H, J¼3.6 Hz), 2.48e2.36 (m, 2H), 2.14e2.00 (m, 2H), 1.78
d
To
a stirred solution of AD-mix-b (3.84 g) and meth-
anesulfonamide (260 mg, 2.74 mmol) in water (14 mL) at 0 ꢀC was
added 11 (500 mg, 2.74 mmol dissolved in tert-butanol (14 mL)) and
the reaction mixture was stirred at the same temperature for 16 h.
The reaction mixture was warm to rt and extracted with EtOAc
(3ꢁ50 mL). The combined extracts were dried (MgSO4) then
evaporated to give a thick yellow oil, which purified by FCC over
silica gel using a gradient of 0:100e60:40 EtOAc/petrol to give 12 as
(br s, 2H); 13C NMR
d 177.3,143.8,139.9,124.8,109.2, 83.3, 50.3, 28.7,
22.3; HRMS (ESI þve) calculated for C9H12NO3 (MþHþ) 182.0817,
found 182.0820.
4.7. (5R,6R)-6-(Furan-3-yl)-5-hydroxypiperidin-2-one (17)
Potassium hydroxide (155 mg, 2.76 mmol) was added to a stir-
red solution of 15 (100 mg, 0.55 mmol) in methanol (5 mL) and the
reaction mixture was heated at reflux for 1 h. The reaction mixture
was cooled to rt and the solvent was removed under reduced
pressure. The residue obtained was purified by FCC over silica gel
using a gradient of 0:100e8:92 MeOH/EtOAc to give 17 as a thick
a colourless oil (394 mg, 78%, er >98:2, (S) Mosher ester
d 3.40 (s,
3H, OMe), (R) Mosher ester d 3.54 (s, 3H, OMe)). Rf 0.16 (1:1 EtOAc/
25
petrol); [
a
]
ꢂ34 (c 0.7, CHCl3); IR vmax (cmꢂ1): 3423, 1754, 1185,
D
1156, 1042, 1015, 989, 916, 799, 732, 698; 1H NMR
d 7.46 (br s, 1H),
7.39 (s, 1H), 6.43 (br s, 1H), 4.66e4.60 (m, 2H), 2.64 (d, 1H, J¼4.6 Hz,
OH), 2.52e2.48 (m, 2H), 2.19e2.14 (m, 1H), 2.10e2.04 (m, 1H); 13C
colourless oil (90 mg, 90%). Rf 0.24 (1:9 MeOH/EtOAc); [a]
25 5 (c 2.0,
D

S.R. Shengule et al. / Tetrahedron 69 (2013) 8042e8050
8047
CHCl3); IR vmax (cmꢂ1): 3266, 2922, 1654, 1628, 1387, 1311, 1213,
1158, 1064, 939, 873, 790; 1H NMR
7.44 (br s, 1H), 7.40 (s, 1H), 6.53
0:100e40:60 EtOAc/petrol to give 21 as a colourless liquid (602 mg,
61%). Rf 0.28 (2:3 EtOAc/petrol); IR vmax (cmꢂ1): 3398, 2943, 1670,
d
(br s, 1H, NH), 6.37 (br s, 1H), 4.55 (d, 1H, J¼2.2 Hz), 4.03e4.00 (m,
1655, 1422, 1123, 1090, 1036, 1014, 895, 722; 1H NMR
d 9.93 (s, 1H),
1H), 2.62e2.55 (m, 1H), 2.33e2.27 (m, 1H), 2.08e2.01 (m, 1H),
7.30 (br s, 1H), 6.67 (br s, 1H), 3.63 (t, 2H, J¼5.8 Hz), 3.07 (t, 2H,
1.92e1.87 (m, 1H); 13C NMR
d
172.7, 144.2, 140.6, 123.5, 109.5, 65.7,
J¼7.3 Hz), 1.94 (pent, 2H, J¼6.8 Hz); 13C NMR
d 185.7, 164.9, 142.4,
122.8, 108.5, 61.2, 30.9, 23.3; LRMS (ESI þve) calculated for C8H11O3
54.6, 26.5 (ꢁ2); HRMS (ESI þve) calculated for C9H12NO3 (MþHþ)
182.0817, found 182.0815.
(MþHþ) 155, found 155.
4.8. (5R,6S)-6-(Furan-3-yl)-5-hydroxypiperidin-2-one (18)
Compound 18 (18 mg, 92% as a thick colourless oil) was synthe-
4.12. 3-(3-Formylfuran-2-yl)propyl acetate (22)
To a stirred solutionof 21 (1.80 g,11.7 mmol) in CH2Cl2 (30 mL) was
added DMAP (1.43 g, 11.7 mmol) and acetic anhydride (2.4 mL,
23.4 mmol) and the reaction mixture was stirred at rt for 1 h. The
reaction mixture was diluted with water (5 mL) and then extracted
with CH2Cl2 (3ꢁ50 mL). The combined organic extracts were dried
(MgSO4) then evaporated and the residue obtained was purified by
FCC over silica gel using a gradient of 0:100e20:80 EtOAc/petrol to
give 22 as a thick colourless liquid (2.24 g, 98%). Rf 0.52 (4:1 EtOAc/
petrol); IR vmax (cmꢂ1): 1734, 1677, 1422, 1366, 1235, 1123, 1040, 991,
sized from 16 (20 mg, 0.11 mmol) using the method described above
25
for the synthesis of 17. Rf 0.12 (1:9 MeOH/EtOAc); [
a
]
ꢂ27 (c 0.3,
D
CHCl3); IR vmax (cmꢂ1): 3266, 2922,1654,1638,1387,1308,1213,1158,
1064, 935, 873, 790; 1H NMR
d
7.42 (br s, 2H), 6.38 (br s,1H), 5.91 (br s,
1H, NH) 4.31 (d, 1H, J¼6.6 Hz), 3.86e3.82 (m,1H), 2.62e2.55 (m, 1H),
2.49e2.42 (m, 1H), 2.11e2.05 (m, 1H), 1.92e1.84 (m, 1H); 13C NMR
d
171.6,144.6,140.7,124.8,108.4, 69.6, 56.2, 28.6, 27.1; HRMS (ESI þve)
calculated for C9H12NO3 (MþHþ) 182.0817, found 182.0815.
753;1H NMR
4.06 (t, 2H, J¼6.3 Hz), 3.02 (t, 2H, J¼7.3 Hz), 2.05e2.00 (m, 2H), 2.01 (s,
d
9.90(s,1H), 7.29 (d,1H, J¼1.7Hz), 6.66 (d,1H, J¼1.7Hz),
4.9. 1-(Furan-3-yl)but-3-en-1-ol (19)17
3H); 13C NMR
d 184.8, 171.1, 164.2, 142.5, 122.8, 108.4, 63.2, 27.2, 23.7,
To a stirred solution of 6 (5.00 g, 52.0 mmol) in diethyl ether
(50 mL) at 0 ꢀC was added dropwise allylmagnesium bromide
(63 mL, 1 M solution in THF, 62.5 mmol) over 10 min. The reaction
mixture was stirred at the same temperature for 1 h. A saturated
solution of NH4Cl (100 mL) was added to the reaction mixture and
the reaction mixture further extracted with EtOAc (3ꢁ100 mL). The
combined organic extracts were dried (MgSO4) then evaporated to
give a thick light brown residue. The residue was purified by FCC
over silica gel using a gradient of 0:100e25:100 EtOAc/petrol to
give 19 as a colourless thick liquid (6.39 g, 89%). Rf 0.33 (1:9 diethyl
21.0; LRMS (ESI þve) calculated for C10H12O4Na (MþNaþ) 219, found
219 (100%).
4.13. 3-(3-(1-Hydroxyallyl)furan-2-yl)propyl acetate (23)
Compound 23 (1.11 g, 81% a thick colourless oil) was synthesized
from 22 (1.20 g, 6.12 mmol) using the method described above for
the synthesis of 10 except 1.1 equiv of vinylmagnesium bromide
was used. Rf 0.62 (2:3 EtOAc/petrol); IR vmax (cmꢂ1): 3445, 1734,
1719, 1239, 1038, 985, 919, 740; 1H NMR
d 7.23 (br s, 1H), 6.28 (br s,
ether/petrol); 1H NMR
d
7.38 (br s, 2H), 6.40 (br s, 1H), 5.85e5.73
1H), 6.03e5.96 (m, 1H), 5.27 (d, 1H, J¼17.1 Hz), 5.23 (d, 1H,
(m, 1H), 5.21e5.10 (m, 2H), 4.74e4.67 (m, 1H), 2.54e2.45 (m, 2H),
2.03 (d, 1H, J¼3.8 Hz, OH).
J¼10.2 Hz), 5.09 (d, 1H, J¼4.8 Hz), 4.05e4.01 (m, 2H), 2.72 (t, 2H,
J¼7.3 Hz), 2.00 (s, 3H), 1.96e1.98 (m, 2H); 13C NMR
d 171.4, 151.1,
141.1, 139.7, 121.7, 114.9, 109.4, 67.6, 63.6, 27.5, 22.9, 21.1; HRMS (ESI
4.10. 1-(Furan-3-yl)butane-1,4-diol (20)
þve) calculated for C12H16O4Na (MþNaþ) 247.0946, found 247.0947.
To a stirred solution of 19 (4.50 g, 32.6 mmol) in THF (50 mL) was
added 9-BBN (98 mL, 0.5 M solution in THF, 48.9 mmol) and the
reaction mixture was stirred at rt for 16 h. The reaction mixture was
cooled to 0 ꢀC and 6 M NaOH solution (12 mL) was added to the
reaction mixture followed by dropwise addition of hydrogen per-
oxide (16 mL (30% aqueous solution), 151 mmol) at 0 ꢀC over
30 min. The reaction mixture was warmed to rt and then heated at
reflux for 8 h. The reaction mixture was cooled to rt and extracted
with ethyl acetate (3ꢁ150 mL). The combined organic extracts were
dried (MgSO4) then evaporated and the residue obtained was pu-
rified by FCC over silica gel using a gradient of 50:50e100:0 EtOAc/
petrol to give compound 20 as a thick colourless oil (4.37 g, 86%). Rf
0.36 (80:20 EtOA/petrol); IR vmax (cmꢂ1): 3288, 2924, 1501, 1436,
4.14. (E)-Methyl 5-(2-(3-acetoxypropyl)furan-3-yl)pent-4-
enoate (5)
Compound 5 (737 mg, 59%, as a colourless oil.) was synthesized
from 23 (1.00 g, 4.46 mmol) using the method described above for the
synthesis of 11. Rf 0.68 (80:20 EtOAc/petrol); IR vmax (cmꢂ1): 1734,
1436,1366,1234,1159,1139,1035,1019, 960; 1H NMR
d 7.20 (br s, 1H),
6.38 (br s,1H), 6.18 (d,1H, J¼15.8 Hz), 5.80 (dt,1H, J¼6.6,15.8 Hz), 4.03
(t, 2H, J¼6.3 Hz), 3.66 (s, 3H), 2.69 (t, 2H, J¼7.0 Hz), 2.48e2.42 (m, 4H),
2.03 (s, 3H), 1.95e1.90 (m, 2H); 13C NMR
d 173.6, 171.3, 151.0, 141.3,
127.2, 120.9, 118.8, 108.0, 63.7, 51.8, 34.2, 28.5, 27.4, 22.7, 21.1; HRMS
(ESI þve) calculated for C15H21O5 (MþHþ) 281.1389, found 281.1381.
1151, 1080, 1066, 988, 968, 907, 873, 794, 753; 1H NMR
2H), 6.38 (br s, 1H), 4.66 (dd, 1H, J¼5.3, 7.0 Hz), 3.68e3.61 (m, 2H),
1.85e1.80 (m, 2H), 1.69e1.65 (m, 2H); 13C NMR
143.4, 139.1, 129.3,
d
7.36 (br s,
4.15. 3-(3-((R)-Hydroxy((R)-5-oxotetrahydrofuran-2-yl)
methyl)furan-2-yl)propyl acetate (4)
d
108.7, 67.0, 62.7, 35.2, 29.1; HRMS (ESI þve) calculated for C8H13O3
Compound 4 (448 mg, 89%) was synthesized from 5 (500 mg,
(MþHþ) 157.0786, found 157.0780.
1.78 mmol, as a thick colourless oil, er >98:2 (S) Mosher ester
d 3.48
(s, 3H, OMe), (R) Mosher ester 3.57 (s, 3H, OMe)) using the method
d
4.11. 2-(3-Hydroxypropyl)furan-3-carbaldehyde (21)
described above for the synthesis of 12. Rf 0.23 (3:2 EtOAc/petrol);
25
[a
]
ꢂ24 (c 0.5, CHCl3); IR vmax (cmꢂ1): 3500, 1768, 1729, 1368,
D
To a stirred solution of 20 (1.00 g, 6.41 mmol) in a mixture of
THF:H2O (4:1, 20 mL) was added NBS (1.14 g, 6.41 mmol) in two
portions over 10 min and the reaction mixture was stirred at rt for
4 h. The reaction mixture was diluted with water (5 mL) and then
extracted with EtOAc (3ꢁ100 mL). The combined organic extracts
were dried (MgSO4) then evaporated to give a colourless liquid,
which was purified by FCC over silica gel using a gradient of
1330, 1184, 1155, 1047, 1038, 1015, 982, 898; 1H NMR
d 7.28 (d, 1H,
J¼1.3 Hz), 6.39 (d, 1H, J¼1.3 Hz), 4.62e4.58 (m, 2H), 4.06 (t, 2H,
J¼6.3 Hz, 2H), 2.73 (t, 2H, J¼7.3 Hz), 2.54e2.48 (m, 2H), 2.14e2.11
(m, 1H), 2.01 (s, 3H), 2.01e1.94 (m, 3H); 13C NMR
d 177.0, 171.4,
152.4, 141.7, 117.9, 109.4, 83.0, 69.1, 63.6, 28.6, 27.4, 24.2, 23.1, 21.1;
HRMS (ESI þve) calculated for C14H18O6Na (MþNaþ) 305.1001,
found 305.0999.

8048
S.R. Shengule et al. / Tetrahedron 69 (2013) 8042e8050
4.16. 3-(3-(Azido((R)-5-oxotetrahydrofuran-2-yl)methyl)fu-
ran-2-yl)propyl acetate (25)
was removed under reduced pressure and the residue obtained was
purified by FCC over silica gel using a gradient of 0:100e10:90
MeOH/EtOAc to give 28 (54 mg, 54%) as major isomer and 29 as
minor isomer (14 mg, 14%), both as thick colourless liquids. Major
Compound 25 (315 mg, 69% as a thick colourless oil) was syn-
thesized from 4 (420 mg, 1.48 mmol) as a mixture of di-
astereoisomers (4:1) using the method described above for the
synthesis of 14. Rf 0.56 (3:2 EtOAc/petrol); Major isomer: IR vmax
(cmꢂ1): 2100, 1776, 1734, 1367, 1175, 1160, 1139, 1034, 1020, 989,
isomer (28): Rf 0.31 (5:95 MeOH/EtOAc); [
a]
25 ꢂ20 (c 0.4, CHCl3) IR
D
vmax (cmꢂ1): 2900, 1751, 1437, 1185, 1149, 1060, 1019, 895, 799; 1H
NMR (CD3OD)
d
7.22 (d, 1H, J¼1.9 Hz), 6.30 (d, 1H, J¼1.9 Hz), 4.90 (q,
1H, J¼7.3 Hz), 3.80 (d, 1H, J¼7.3 Hz), 3.30e3.26 (m, 1H), 3.05e3.00
904; 1H NMR
d
7.38 (d, 1H, J¼1.4 Hz), 6.47 (d, 1H, J¼1.4 Hz),
(m,1H), 2.87 (t, 2H, J¼6.3 Hz), 2.62e2.46 (m, 2H), 2.24e2.10 (m, 2H),
4.67e4.62 (m, 1H), 4.52 (d, 1H, J¼5.3 Hz), 4.15e4.09 (m, 2H),
1.86e1.78 (m, 2H); 13C NMR (CD3OD)
d 178.4, 154.0, 141.5, 119.5,
2.79e2.75 (m, 2H), 2.56e2.50 (m, 2H), 2.27e2.20 (m, 1H), 2.08 (s,
111.0, 80.2, 57.8, 46.3, 28.4, 27.1, 26.9, 25.1; HRMS (ESI þve) calcu-
3H), 2.07e2.00 (m, 3H); 13C NMR
d 176.1, 171.0, 153.2, 142.0, 113.8,
lated for C12H16NO3 (MþHþ) 222.1130, found 222.1121. Minor iso-
109.5, 80.8, 63.2, 60.1, 27.9, 27.4, 24.5, 22.8, 20.9; HRMS (ESI þve)
mer (29): Rf 0.18 (5:95 MeOH/EtOAc); [
a
]
25 ꢂ6.0 (c 0.1, CHCl3) IR vmax
D
calculated for C14H17N3O5Na (MþNaþ) 330.1066, found 330.1067.
(cmꢂ1): 2900, 1751, 1185, 1149, 1059, 1037, 895, 799, 721; 1H NMR
(CD3OD)
d
7.20 (d,1H, J¼1.4 Hz), 6.30 (d,1H, J¼1.4 Hz), 4.94e4.86 (m,
4.17. (5R)-5-(Azido(2-(3-hydroxypropyl)furan-3-yl)methyl)di-
hydrofuran-2(3H)-one (26)
1H), 3.92 (d, 1H, J¼4.3 Hz), 3.00e2.88 (m, 3H), 2.84e2.76 (m, 1H),
2.56e2.46 (m, 1H), 2.44e2.28 (m, 2H), 2.20e2.10 (m, 1H), 1.84e1.74
(m, 2H); 13C NMR (CD3OD)
d 177.3, 153.6, 139.7, 119.4, 109.8, 82.2,
To a stirred solution of 25 (300 mg, 0.97 mmol) in methanol
(8 mL) was added KOH (164 mg, 2.93 mmol) and the reaction
mixture was stirred at rt for 1 h. The pH of the reaction mixture was
made acidic by the addition of 2 M HCl in diethyl ether and the
reaction mixture was stirred for 30 min. The reaction mixture was
diluted with water and then extracted with EtOAc (3ꢁ25 mL). The
combined extracts were dried (MgSO4) then evaporated and the
residue obtained was purified by FCC over silica gel using a gradient
of 0:100e30:70 EtOAc/petrol to give 26 as a thick colourless liquid
(186 mg, 72%). Rf 0.52 (7:3 EtOAc/petrol); Major isomer: IR vmax
(cmꢂ1): 3417, 2957, 2099, 1768, 1243, 1220, 1181, 1157, 1043, 1003,
57.2, 47.7, 28.5, 27.8, 26.6, 23.1; HRMS (ESI þve) calculated for
C12H16NO3 (MþHþ) 222.1130, found 222.1120.
4.20. (11R,11aR)-11-Hydroxy-5,6,9,10,11,11a-hexahydrofuro
[3,2-c]pyrido[1,2-a]azepin-8(4H)-one (3)
Compound 3 (39 mg, 98% as thick colourless liquid) was syn-
thesized from 28 (40 mg, 0.18 mmol) using the method described
above for the synthesis of 17. Rf 0.28 (5:95 MeOH/EtOAc); [
a
]
25 ꢂ130
D
(c 0.4, CHCl3); IR vmax (cmꢂ1): 3250,1701,1640,1239,1120,1100, 720;
1H NMR
d
7.30 (br s, 1H), 6.28 (br s, 1H), 4.59 (d, 1H, J¼2.0 Hz), 4.35
920, 877; 1H NMR
d
7.33 (d, 1H, J¼1.4 Hz), 6.41 (d, 1H, J¼1.4 Hz),
(dd, 1H, J¼6.3, 13.7 Hz), 4.19e4.14 (m, 1H), 2.92e2.83 (m, 1H),
2.79e2.66 (m, 3H), 2.41e2.34 (m, 1H), 2.28e2.19 (m, 1H), 2.18e2.10
4.65e4.61 (m, 1H), 4.58 (d, 1H, J¼5.2 Hz), 3.63e3.61 (m, 2H), 2.78 (t,
2H, J¼7.2 Hz), 2.52e2.45 (m, 2H), 2.24e2.12 (m, 1H), 2.08e1.98 (m,
(m,1H),1.97e1.88 (m,1H),1.81e1.72 (m,1H); 13C NMR
d 170.2,153.3,
1H), 1.94e1.82 (m, 2H); 13C NMR
d
176.6, 153.9, 141.8, 113.7, 109.4,
141.6, 115.8, 109.3, 66.7, 62.6, 44.4, 27.1, 25.8, 23.6, 22.9; HRMS (ESI
81.0, 61.1, 60.1, 30.9, 28.0, 24.4, 22.3; HRMS (ESI þve) calculated for
þve) calculated for C12H16NO3 (MþHþ) 222.1130, found 222.1120.
C12H15N3O4Na (MþNaþ) 288.0960, found 288.0962.
4.21. (9S,9aS)-9-((tert-Butyldimethylsilyl)oxy)-4,5,9,9a-tetra-
hydrofuro[2,3-g]indolizin-7(8H)-one (31)
4.18. 3-(3-(Azido((R)-5-oxotetrahydrofuran-2-yl)methyl)fu-
ran-2-yl)propanal (27)
To a stirred solution of 30 (800 mg, 4.14 mmol) in DMF was
added imidazole (564 mg, 8.29 mmol), DMAP (1.00 g, 8.29 mmol)
and TBSCl (1.25 g, 8.29 mmol) and the reaction mixture was stirred
at rt for 2 days. The solvent was removed under reduced pressure
and the residue obtained was dissolved in EtOAc (50 mL) and
washed with water (3ꢁ50 mL). The organic extract was dried
(MgSO4) then evaporated and the residue obtained was purified by
FCC over silica gel using a gradient of 20:80e50:50 EtOAc/petrol to
give 31 as white solid (1.00 g, 85%). Rf 0.42 (1:1 EtOAc/petrol); Mp
To a stirred solution of 26 (150 mg, 0.56 mmol) in dichloro-
methane (10 mL) was added DesseMartin periodinane (360 mg,
0.84 mmol) and the reaction mixturewas stirred at rt for 30 min. The
reaction mixture was added to a beaker containing sodium thio-
sulphate (1.00 g) dissolved in a saturated solution of NaHCO3
(10 mL). The mixture was stirred vigorously for 30 min, then
extracted with CH2Cl2 (3ꢁ25 mL). The combined extracts were dried
(MgSO4) then evaporated and the residue obtained was purified by
FCC over silica gel using a gradient of 0:100e15:85 EtOAc/petrol to
give 27 (130 mg, 87%) as a thick colourless liquid. Rf 0.68 (1:1 EtOAc/
petrol); Major isomer: IR vmax (cmꢂ1): 2100, 1722, 1701, 1246, 1175,
78e80 ꢀC; [
a]
25 122 (c 1.0, CHCl3); IR vmax (cmꢂ1): 2931, 1670, 1428,
D
1252, 1179, 1110, 1081, 1057, 956, 949, 937, 841; 1H NMR
d
7.28 (br s,
1H), 6.19 (br s, 1H), 4.6 (br s, 1H), 4.51e4.49 (m, 1H), 4.48 (dd, 1H,
J¼6.1, 12.9 Hz), 2.93e2.87 (m, 1H), 2.75e2.62 (m, 3H), 2.32 (d, 1H,
J¼16.6 Hz), 0.65 (s, 9H), ꢂ0.02 (s, 3H), ꢂ0.08 (s, 3H); 13C NMR
1159, 1090, 1045, 1004, 918; 1H NMR
d 9.78 (s, 1H), 7.30 (d, 1H,
J¼1.2 Hz), 6.42 (d,1H, J¼1.2 Hz), 4.67 (d,1H, J¼4.8 Hz), 4.64e4.60 (m,
1H), 2.98e2.92 (m, 2H), 2.89e2.84 (m, 2H), 2.54e2.42 (m, 2H),
d
171.2, 149.8, 141.5, 113.7, 108.3, 68.2, 61.0, 42.6, 36.8, 25.5, 23.6,
2.26e2.18 (m, 1H), 2.12e2.04 (m, 2H); 13C NMR
d
200.5, 176.6, 152.4,
17.8, ꢂ4.2, ꢂ4.9; HRMS (ESI þve) calculated for C16H25NO3Si
142.2, 114.4, 109.9, 80.9, 60.1, 42.1, 28.2, 24.5, 18.7; LRMS (ESI þve)
(MþHþ) 308.1682, found 308.1689.
calculated for C12H14N3O4 (MþHþ) 264, found 264 (100%).
4.22. (3aR,9S,9aS)-9-((tert-Butyldimethylsilyl)oxy)-3a-hy-
droxy-4,5,9,9a-tetrahydrofuro[2,3-g]indolizine-2,7(3aH,8H)-
dione (32)
4.19. (R)-5-((R)-5,6,7,8-Tetrahydro-4H-furo[3,2-c]azepin-4-yl)
dihydrofuran-2(3H)-one (28) and (R)-5-((S)-5,6,7,8-tetrahydro-
4H-furo[3,2-c]azepin-4-yl)dihydrofuran-2(3H)-one (29)
To a stirred solution of 31 (1.00 g, 3.25 mmol) in CH2Cl2 (50 mL)
was added m-CPBA (1.69 g, 9.77 mmol) and the reaction mixturewas
stirred at rt for 2 h. The solvent was removed under reduced pres-
sure and the residue obtained was purified by FCC over silica gel
To a stirred solution of 27 (120 mg, 0.45 mmol) in THF (5 mL) was
added triphenylphosphine (478 mg, 1.82 mmol) and the reaction
mixture was stirred under an argon atmosphere for 16 h. Methanol
(18
m
L, 0.45 mmol) and NaBH4 (17 mg, 0.45 mmol) were added to the
using a gradient of 40:60e100:00 EtOAc/petrol to give 32 as a white
25
reaction mixture, which was stirred for another 30 min. The solvent
solid (750 mg, 68%). Rf 0.36 (4:1 EtOAc/petrol); mp 191e193 ꢀC; [
a]
D

S.R. Shengule et al. / Tetrahedron 69 (2013) 8042e8050
8049
ꢂ52 (c 0.4, MeOH); IR vmax (cmꢂ1): 3078, 2932, 1757, 1661, 1464,
above for the synthesis 32. Rf 0.28 (5:95 MeOH/EtOAc); [
a
]
25 ꢂ110
D
1421,1246,1159,1129, 955, 910, 892, 797; 1H NMR
d
6.10 (s,1H), 5.27
(c 0.3, MeOH); IR vmax (cmꢂ1): 3403, 2925, 1739, 1602, 1270, 947,
(br s,1H, OH), 4.78 (dd,1H, J¼6.9,13.4 Hz), 4.52 (d,1H, J¼6.5 Hz), 4.18
(dd, 1H, J¼4.9, 13.4 Hz), 3.04 (t, 1H, J¼12.4 Hz), 2.64 (dd, 1H, J¼7.4,
16.9 Hz), 2.39e2.34 (m, 2H), 1.77e1.73 (m, 1H), 0.87 (s, 9H), 0.11 (s,
649; 1H NMR (CD3OD)
d
6.14 (s, 1H), 4.87 (d, 1H, J¼3.9 Hz),
4.37e4.32 (m, 1H), 4.23e4.18 (m, 1H), 2.57e2.52 (m, 2H), 2.42e2.30
(m, 2H), 2.03e1.90 (m, 3H), 1.70e1.59 (m, 2H); 13C NMR (CD3OD)
3H), 0.10 (s, 3H); 13C NMR
d
171.9,170.5,160.4,115.4,104.4, 66.8, 59.1,
d 170.7, 170.4, 168.0, 118.8, 109.3, 68.1, 62.3, 48.6, 38.5, 27.5, 26.2,
39.7, 37.7, 36.6, 25.9, 18.2, e4.5, e4.7; HRMS (ESI þve) calculated for
22.6; HRMS (ESI þve) calculated for C12H16NO5 (MþHþ) 254.1028,
C16H25NO5Si (MþHþ) 340.1580, found 340.1585.
found 254.1025.
4.23. (3aR,9S,9aS)-3a,9-Dihydroxy-4,5,9,9a-tetrahydrofuro
[2,3-g]indolizine-2,7(3aH,8H)-dione (33) and (9S,9aS)-9-
hydroxy-9,9a-dihydrofuro[2,3-g]indolizine-2,7(5H,8H)-dione
(34)
4.25. (5R,6R)-5-((tert-Butyldimethylsilyl)oxy)-6-(furan-3-yl)
piperidin-2-one (37)
To a stirred solution of 17 (100 mg, 0.55 mmol) in DMF (5 mL)
was added imidazole (113 mg, 1.65 mmol) and TBSCl (249 mg,
1.65 mmol) and the reaction mixture was stirred at rt for 48 h. The
solvent was removed under reduced pressure and the residue was
dissolved in EtOAc (50 mL) and washed with water (3ꢁ50 mL). The
solution was dried (MgSO4) then evaporated and the residue ob-
tained was purified using FCC over silica gel using a gradient of
20:80e80:20 EtOAc/petrol to give 37 as a white solid (130 mg, 80%).
To a stirred solution of 32 (60 mg, 0.17 mmol) in THF (5 mL) was
added TBAF (0.25 mL, 0.25 mmol, 1 M in THF) and the reaction
mixture stirred at the rt for 1 h. TsOH (58 mg, 0.34 mmol) was
added and the reaction mixture was stirred at rt for 30 min. The
solvent was removed under reduced pressure and the residue ob-
tained was purified using FCC over silica gel using a gradient of
0:100e15:85 MeOH/EtOAc to give the diene 34 (7 mg, 19%) and
Rf 0.40 (4:1 EtOAc/petrol); Mp 88e90 ꢀC; [
a
]
25 ꢂ8 (c 0.6, CHCl3); IR
D
vmax (cmꢂ1): 3243, 2933, 2857, 1654, 1618, 1468, 1069, 989, 830,
then the diol 33 (20 mg, 50%), both as colourless thick liquids. 33: Rf
ꢂ18 (c 0.2, MeOH); IR vmax (cmꢂ1):
25
798; 1H NMR
d 7.37 (br s, 1H), 7.36 (s, 1H), 6.36 (br s, 1H), 5.72 (br s,
0.35 (1:9 MeOH/EtOAc); [
a
]
D
3502, 2987, 1730, 1551, 1420, 1200, 1108, 980, 780; 1H NMR (CD3OD)
1H, NH), 4.52 (d, 1H, J¼2.1 Hz), 4.04e4.00 (m, 1H), 2.68e2.61 (m,
2H), 2.37e2.32 (m, 2H), 0.8 (s, 9H), ꢂ0.02 (s, 3H), ꢂ0.22 (s, 3H); 13C
d
6.10 (s, 1H), 4.72e4.66 (m, 1H), 4.57 (d, 1H, J¼2.9 Hz), 4.10 (dd, 1H,
J¼4.9, 13.2 Hz, 1H), 3.07 (t, 1H, J¼12.9 Hz), 2.75 (dd, 1H, J¼5.8,
NMR
d 172.0, 142.2, 140.4, 124.5, 110.3, 67.4, 55.2, 28.0, 26.7, 25.9,
17.1 Hz), 2.34e2.24 (m, 2H), 1.76e1.66 (m, 1H); 13C NMR (CD3OD)
18.2, ꢂ4.22, ꢂ4.90; HRMS (ESI þve) calculated for C15H26NO3Si
(MþHþ) 296.1682, found 296.1686.
d
173.1, 171.1, 161.0, 115.4, 104.4, 65.4, 59.8, 40.7, 36.2, 34.6; HRMS
(ESI þve) calculated for C10H12NO5 (MþHþ) 226.0637, found
226.0637. 34: Rf: 0.38 (1:9 MeOH/EOAc); [a]
25 95 (c 0.2, MeOH); IR
D
vmax (cmꢂ1): 3480, 3068, 2889, 1580, 1391, 1104, 980, 885, 760; 1H
NMR (CD3OD) 6.08 (s, 1H), 6.01e5.99 (m, 1H), 4.97 (d, 1H,
4.26. (5R,6R)-5-((tert-Butyldimethylsilyl)oxy)-6-(2-hydroxy-
5-oxo-2,5-dihydrofuran-3-yl)piperidin-2-one (38)
d
J¼4.4 Hz), 4.79 (t, 1H, J¼4.8 Hz), 4.69 (dd, 1H, J¼5.3, 19.5 Hz), 3.84
To a stirred solution of 37 (80 mg, 0.27 mmol) in CH2Cl2
(d, 1H, J¼19.5 Hz), 2.86 (dd, 1H, J¼4.3, 17.0 Hz), 2.36 (d, 1H,
J¼17.0 Hz); 13C NMR (CD3OD)
d
173.3, 169.3, 149.6, 148.3, 111.4,
(10 mL) was added Hunig’s base (50
mL, 0.27 mmol) and Rose
Bengal (3 mg) and the reaction mixture was cooled to ꢂ78 ꢀC.
Oxygen gas was bubbled through the reaction mixture, which was
exposed to a 500 W flood light and stirred at the same tempera-
ture for 1 h. The reaction mixture was allowed to warm to rt
followed by addition of saturated solution of oxalic acid (2 mL) and
stirred at rt for 30 min. The reaction mixture was extracted with
CH2Cl2 and the combined extracts were dried (MgSO4) then
evaporated and the residue obtained was purified by FCC over
silica gel using a gradient of 0:100e10:90 MeOH/CH2Cl2 to give 38
105.3, 66.0, 60.1, 40.3, 37.7; HRMS (ESI þve) calculated for
C10H10NO4 (MþHþ) 208.0532, found 208.0522.
4.23.1. Synthesis of 34 from 30 using NBS. To a stirred solution of 30
(50 mg, 0.26 mmol) in THF (5 mL) was added NBS (46 mg,
0.26 mmol) and the reaction mixture stirred at rt for 1 h. The sol-
vent was removed under reduced pressure and the residue ob-
tained was purified using FCC over silica gel using a gradient of
0:100e10:90 MeOH/EtOAc to give 34 (32 mg, 60%).
(81 mg, 91%) as a thick oil and as a single diastereomer. Rf 0.25
25
(4:1 EtOAc/petrol); [
a
]
D
ꢂ29 (c 0.3, CHCl3); IR vmax (cmꢂ1): 3232,
4.23.2. Synthesis of 34 from 33 using TsOH. Toa stirredsolutionof 33
(30 mg, 0.13 mmol) in toluene (5 mL) was added TsOH-monohydrate
(23 mg, 0.13 mmol) and the reaction mixture was heated at reflux for
16 h. The solvent was removed under reduced pressure and the res-
idue obtained was purified using FCC over silicagel using a gradient of
0:100e10:90 MeOH/EtOAc to give 34 (11 mg, 39%).
2929, 1759, 1655, 1630, 1471, 1252, 1121, 1084, 945, 852, 806; 1H
NMR d 7.26 (br s, 1H, NH), 6.06 (br s, 2H), 4.49 (br s, 1H), 4.25 (br s,
1H), 2.53 (dt, 1H, J¼7.3, 18.3 Hz), 2.35 (dt, 1H, J¼6.3, 18.3 Hz), 1.89
(br s, 2H), 0.83 (s, 9H), ꢂ0.07 (br s, 6H); 13C NMR
d 172.8, 170.1,
167.0, 120.8, 98.8, 66.3, 54.9, 27.4, 26.6, 25.6, 17.9, ꢂ4.79, ꢂ5.00;
HRMS (ESI þve) calculated for C15H26NO5Si (MþHþ) 328.1580,
found 328.1574.
4.23.3. Synthesis of 34 from 33 using H2SO4. Compound 33 (25 mg,
0.11 mmol) was dissolved in H2SO4 (3 mL) and the reaction mixture
was stirred at rt for 3 h. The reaction mixture was diluted with
water (50 mL) and extracted with EtOAc (3ꢁ25 mL). The combined
organic extracts were dried (MgSO4) and the solvent was removed
under reduced pressure. The residue obtained was purified using
FCC over silica gel using a gradient of 0:100e10:90 MeOH/EtOAc to
give 34 (8 mg, 35%).
4.26.1. X-ray crystallographic data. Atomic coordinates, bond
lengths and angles, and displacement parameters have been de-
posited at the Cambridge Crystallographic Data Centre (CCDC
924873). These data can be obtained free-of-charge via
www.ccdc.cam.ac.uk/data_request/cif,
by
emailing
data_-
request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
þ44 1223 336033.
4.24. (11R,11aR)-3a,11-Dihydroxy-3a,4,5,6,9,10,11,11a-octahy-
drofuro[3,2-c]pyrido[1,2-a]azepine-2,8-dione (36)
Acknowledgements
Compound 36 (14 mg, 82% as thick colourless liquid) was syn-
thesized from 3 (15 mg, 0.06 mmol) using the method described
We thank the Australian Research Council for financial support.

8050
S.R. Shengule et al. / Tetrahedron 69 (2013) 8042e8050
11. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Harting, J.; Jeong,
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