Sequential deprotectionecyclisation reaction: Stereoselective synthesis of azabicyclic β-enamino ester derivatives and (-) indolizidine 209D

Article abstract of DOI:10.1016/j.tet.2012.11.029

This paper describes a new strategy for the stereoselective synthesis of pyrrolizidine and indolizidine based enamino esters and their acyl derivatives from L-proline. The key reaction in this process involves deprotection followed by ring closure of cyclic N-Boc amino-β-ketoesters. Also, the synthesis of 5R,9R- (-)-indolizidine 209D has been accomplished using this protocol.

Full text of DOI:10.1016/j.tet.2012.11.029

Tetrahedron 69 (2013) 527e536
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Sequential deprotectionecyclisation reaction: stereoselective synthesis
of azabicyclic
b
-enamino ester derivatives and (ꢀ) indolizidine 209D
Thanasekaran Ponpandian a b, Shanmugam Muthusubramanian a
,
,
*
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, India
b Orchid Chemicals and Pharmaceuticals Ltd, Department of Medicinal Chemistry, R&D Centre, Chennai 600119, India
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 10 October 2012
Accepted 7 November 2012
Available online 12 November 2012
This paper describes a new strategy for the stereoselective synthesis of pyrrolizidine and indolizidine
based enamino esters and their acyl derivatives from
deprotection followed by ring closure of cyclic N-Boc amino-
(ꢀ)-indolizidine 209D has been accomplished using this protocol.
Ó 2012 Elsevier Ltd. All rights reserved.
L-proline. The key reaction in this process involves
b
-ketoesters. Also, the synthesis of 5R,9R-
Keywords:
b
-Enamino esters
Knoevenagel type adducts
Pyrrolizidine
Deprotective cyclisation
Indolizidine 209D
1. Introduction
alkyl amines.7d,9 Recently, Lee and co-workers reported the one pot
synthesis of exo-cyclic enamino esters from nitrile derivatives via
Blaise reaction intermediate.9c In a review recently published by
Heterocyclic b-enamino esters have widespread applications in
organic synthesis because of their versatile reactivity both as nu-
cleophiles and electrophiles.1 They also act as valuable in-
termediates in the total synthesis of natural products.2 Eschenmoser
coupling reaction3 was the well established method for the prepa-
Murthy et al., they presented the synthesis and application of b-
enamino carbonyl compounds.9d As pyrrolizidine and indolizidine
alkaloids have a wide and varied distribution in nature and display
a broad range of interesting biological activities, novel strategies for
the synthesis of these azabicyclic skeletons continue to receive
considerable attention.10
ration of heterocyclic b-enamino esters and their acyl derivatives
(Knoevenagel type adducts). This reaction, which serves as the key
step in the synthesis of various natural products,4 has some limi-
tationsdformation of a mixture of geometrical isomers, long re-
action times, moderate yields and isolation of by-products.5
Recently, Varga and co-workers6 reported the synthesis of indoli-
Pyrrolizidine b-enamino ester 5 (Fig. 1) has been used for the
total synthesis of Symchiral11 and indolizidine
b
-enamino ester 6
O
O
zidine b-enamino ester 2 (Fig. 1) as a mixture of E and Z isomers in
O
n
O
O
3:1 ratio using Eschenmoser coupling reaction. So several meth-
odologies have been developed for the synthesis of pyrrolidine and
piperidine based enamino esters and their acyl derivatives.7 Hart
et al. developed an efficient methodology for the preparation of
Knoevenagel type adducts 3 (Fig. 1) from (methylthio)alkylideni-
minium salts and active methylene compounds,7a,8 though the ge-
ometry around the double bond has not been elaborated. Lhommet
and co-workers reported the synthesis of pyrrolidine and piperidine
n
n
N
N
R
R'
O
N
R
R' = CN, COOEt,
COCH3 or Tosyl;
n = 1 or 2
n = 0 (1)
n = 1 (2)
n = 1 or 2
(4)
(3)
O
R
R
O
N
N
N
O
based b-enamino esters 4 (Fig.1) from u-halogeno-b-keto esters and
R
O
O
R = alkyl, aryl, OEt,
heteroaryl
O
O
(6)
(5)
(7)
* Corresponding author. Tel.: þ91 452 2458246; fax: þ91 452 2459845; e-mail
address: muthumanian2001@yahoo.com (S. Muthusubramanian).
Fig. 1. Vinylogous urethanes and related Knoevenagel type adducts.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.029

528
T. Ponpandian, S. Muthusubramanian / Tetrahedron 69 (2013) 527e536
(Fig. 1) has been employed in the synthesis of Dendrobatid alka-
loids, such as Gephyrotoxin and Dihydrogephyrotoxin.2c In this
article, we wish to report a convenient and efficient method for the
obtained compounds treated with ethyl acetoacetate dianions13 in
THF at 0 ꢁC. However no reaction took place even at 60 ꢁC with
different solvents. In the case of nosylate derivative (13), a com-
plex reaction mixture was observed even at 0 ꢁC in THF. The
tosylate 12 was then converted into halides 14 and 15 by refluxing
with LiBr in acetone and LiI in THF, respectively. The halide de-
rivatives 14 and 15 also failed to give 8 with ethyl acetoacetate
stereoselective synthesis of pyrrolizidine and indolizidine based b-
enamino esters (1 & 2) and Knoevenagel type adducts (7) (Fig. 1)
from readily available starting materials. The application of this
protocol to synthesise indolizidine alkaloids has also been
explored.
dianions. Thus the direct synthesis of b-keto ester 8 by CeC bond
formation between ethyl acetoacetate dianions and electrophilic
reagents 11e15 could not be achieved under the reported reaction
conditions.
2. Results and discussion
The synthesis of 8 was then tried from a Nazarov type reagent,
a derivative of the ethyl 3-oxo-4-pentenoate. Incidentally, various
methods are available for the synthesis of Nazarov’s reagents,14
which act as useful intermediates for the synthesis of various nat-
ural products.15 WittigeHornereEmmons reaction has been chosen
in the present study for the synthesis of Nazarov type reagent. From
Retrosynthetic analyses of azabicyclic enamino esters are illus-
trated in Scheme 1. We envisioned that the chiral enamino ester
could be constructed from the chiral
obtained from commercially available
designed to obtain -keto ester 8, the intermediate precursor of the
desired -enamino ester. Method A: regioselective alkylation of
b
-keto ester 8, which could be
L-proline. Three routes were
b
b
the known N-Boc-(S)-prolinal 16, prepared from
-proline,12 8 was
L
dimetalated ethyl acetoacetate with a chiral pyrrolidine derivative;
Method B: hydrogenation of a Nazarov-type reagent, which could
obtained as depicted in Scheme 3. The phosphonate reagent 17
(ethyl 4-(diethylphosphono)acetoacetate) was prepared in quanti-
tative yield from commercially available diethyl phosphite and
ethyl 4-chloroacetoacetate in the presence of sodium hydride.14f
be prepared by WittigeHornereEmmons reaction between
g-
phosphorylated ethyl acetoacetate and a chiral carboxaldehyde;
Method C: from propionic acid derivatives.
H
O
O
LG
PG
(LG = Leaving group)
+
N
O
(Method A)
H
O
O
O
H
H
OH
O
O
H
OEt
EtO
N
OEt
OEt
H
P
+
N
H
O
N
PG
N
PG
O
O
O
8
(Method B)
Enamino esters
(L-Proline)
OH
H
O
N
PG
(Method C)
Scheme 1. Retrosynthetic analyses for enamino ester construction.
The cyclisation of 8 can be achieved by a protocol involving
sequential N-deprotection followed by acid mediated condensation
The HornereWadswortheEmmons reaction between N-Boc-(S)-
prolinal 16 and the reagent 17 with sodium hydride proceeded
between the nucleophilic amine and the keto group of the
ester.
b
-keto
smoothly to furnish g,d-unsaturated b-keto ester 18 in 96% yield.
The H NMR spectrum of 18 reveals the presence of keto and enol
forms in nearly 3:1 ratio.
The reduction of the double bond was readily achieved by hy-
drogenation of 18 in ethanol (Pd/C, H2 (40 psi), 2 h), affording 8 in
quantitativeyield. The enantiomeric purityof product 8, determined
by chiral HPLC analysis, was found to be 16% ee (ratio 58:42%). The
1
The essential intermediate 8 was attempted from N-Boc-
proline as shown in Scheme 2. According to a known procedure,12
the reduction of N-Boc- -proline (9) was carried out without
racemisation to get N-Boc- -prolinol 10. The hydroxy group of 10
was then converted into sulfonate esters 11/12/13 and the
L-
L
L
OEt
O
O
H
OH
H
H
X
OH
O
H
O
BDMS
THF
OEt
O
N
N
N
N
(i) NaH
Boc
Boc
Boc
Boc
(ii) n-BuLi
8
X = OMs (11)
OTs (12)
0 oC to 60 oC
10
9
THF or DME or
ONs (13)
dioxane
Br
I
(14)
(15)
Scheme 2. Alkylation of dimetalated ethyl acetoacetate.

T. Ponpandian, S. Muthusubramanian / Tetrahedron 69 (2013) 527e536
529
OEt
O
OEt
N
Boc
O
EtO P
H
H
O
Base
THF, 0 oC
96%
O
O
OEt
10% Pd/C
EtOH, 2h
99%
O
+
N
Boc
N
O
O
OEt
Boc
OEt
8
N
16
17
Boc
OH
O
18
(3:1 ratio)
Scheme 3. Synthesis of b-keto ester intermediate 8 through Nazarov reagent.
epimerisation could have occurred during the condensation stage.
Other strong bases, such as t-BuOK and n-BuLi also led to 8 in 20% ee
and 15% ee, respectively. WittigeHornereEmmons reaction of
enantiopure aldehyde normally affords the corresponding olefin
without affecting the chiral purity,16 the observed epimerisation
may be due the dianionic ylide (17a) used in this condensation
reaction (Scheme 4).
The observed optical rotation of the
b
-enamino ester 1 is ½a D25
ꢂ
ꢀ100.8 (c 0.5, CH2Cl2). The stereochemistry around the double
bond was assigned as E on the basis of 1H NMR data. The chemical
shift value of the olefinic hydrogen of 1 is 4.44 ppm in CDCl3. The
reported chemical shift value of the pyrrolizidine enamino ester is
4.42 ppm for E isomer.11
Selective C-acylation and aroylation of 1,3-dicarbonyl com-
pounds with acid chloride using anhydrous magnesium chloride18
19
or SmCl3 are known. Acetylation of 8 under these conditions
O
P
O
O
P
O
Base (2 equ)
THF, 0 o
O
O
followed by subsequent deprotection and cyclisation may lead to
either 21 or 22 (Scheme 6). Anticipating this to happen, acetylation
of 8 was carried out with acetyl chloride in the presence of anhy-
drous magnesium chloride and pyridine in methylene dichloride
and afforded 20 in 98% yield. 20 underwent deprotective cyclisation
with trifluoroacetic acid providing the corresponding iminium ion
22a, which on neutralisation afforded the pyrrolizidine core 22
beside considerable amount of ethyl acetoacetate and pyrrolizin-3-
one 23. The anticipated azepine skeleton 21 has not been formed at
all, pathway B being preferred to A.
Aromatic acid chlorides were also employed for acylation and
thus the treatment of 8 with benzoyl chloride under the same
condition yielded 39% of 24, 22% of 25 and 23% of 23 (Scheme 7).
However, when the reaction mixture (iminium ion 24a) was neu-
tralized with aqueous Et3N (5% solution) instead of aqueous
NaHCO3, it is found that the formation of the by-products was
marginally reduced giving 24 in 60% yield, whereas when the re-
O
O
C
O
O
O
O
17a
Scheme 4. Generation of dianionic phosphonate 17a.
Enantiopure 8 was obtained starting from the alkanoic acid 19.
Thus, 19 prepared from
-proline,17 was allowed to react with 1,10-
L
carbonyl diimidazole (CDI) in THF to yield the imidazolide, which
was treated in situ with ethyl potassium malonate and anhydrous
MgCl2 affording 84% of 8 with an enantiomeric excess of 99%. The
deprotective cyclisation of 8 using Brønsted acid (TFA, HCl or TfOH)
or Lewis acid (BF3$OEt2) in dichloromethane led to the formation of
iminium ion 1a and this, on neutralisation with aqueous bi-
carbonate, afforded the pyrrolizidine
b-enamino ester 1 in 98% yield
(Scheme 5). No epimerisation was observed in this step (>99% ee).
OEt
O
H
OH
H
OH
O
H
H
Ethyl pot. malonate
CDI, Anhy.MgCl2
60 oC, 84%
BF3.OEt2
or H+
5 steps
Ref 17
O
N
+
O
O
O
N
H
N
N
Boc
Boc
19
8
1a
iminum ion
O
H
N
Aq.NaHCO3
O
work-up
98%
1
Scheme 5. Synthesis of pyrrolizidine b-enamino ester 1.
The deprotective cyclisation of 8 was characterised by the ab-
sence of active eCH2e proton signal at 3.58 ppm and the presence
of sharp singlet at 4.44 ppm in 1, which corresponds to the ]CH
proton. The formation of product was further supported by the
appearance of eCH]CHe signals at 78.8 and 169.5 ppm, which is
reliable for -enamino esters.
action mixture was stirred with a mixture of water and ethyl ace-
tate (1:1) for about 30 min, 24 was isolated as the exclusive product
(95%). It is clear that when aqueous basic solution was employed for
neutralisation of the iminium ion, apart from the formation of 24,
the nucleophilic attack of water on 24a is also competing yielding
23 and 25. But when a mixture of watereethyl acetate was
d
d
d
b

530
T. Ponpandian, S. Muthusubramanian / Tetrahedron 69 (2013) 527e536
O
O
O
21a
O
O
O
O
Aq.NaHCO3
O
H
+
N
A
H
A
H
O
N
OEt
H
Acetyl chloride
Anhy.MgCl2
O
21
N
Boc
OEt
O
O
TFA
B
Pyridine
MDC
98%
H
H
H
N
Boc
O
O
O
8
+
+
OEt
N
N
+
Aq.NaHCO3
work-up
B
N
20
O
O
O
24%
25%
23
O
O
40%
22a
22
Scheme 6. Acetylation followed by deprotective cyclisation of 8.
H
O
H
O
O
O
Cl
Anhy. MgCl2
Pyridine
MDC
+
H
OEt
N
Aq.NaHCO3
N
OEt
+
+
+
8
N
O
O
O
then TFA
25
O
23
23%
Ph
24
EtO
39%
22%
24a
Scheme 7. Benzoylation followed by deprotective cyclisation of 8.
employed, the iminium ion 24a just got neutralised through the
ketoeenol tautomerism and a nucleophilic attack by water mole-
cule on the electron deficient azomethine carbon was not favoured.
The enantiomeric purity of product 24 was determined by chiral
HPLC analysis, the enantiomeric excess being>99%. The observed
are shown in Fig. 2. Even the introduction of strong electron
withdrawing substituents, such as nitro, formyl and trifluoromethyl
groups at different positions of the aryl ring in order to achieve the
azepine skeleton 21a (cyclisation through path A) was not suc-
cessful and in all cases the corresponding pyrrolizidines were ob-
tained (26e30). Other aromatic and heteroaromatic acid chlorides
have also been successfully tested in this reaction (31e35). In all the
cases, only the E isomers were obtained as demonstrated by single
crystal X-ray crystallographic study of 2820 (Fig. 3).
optical rotation of the
CH2Cl2). The mechanism of formation of 23, 24 and 25 from 8 is
shown in Scheme 8.
b
-enamino ester 24 is ½a D25
ꢀ63.7 (c 0.46,
ꢂ
Using the optimised reaction conditions, various aroyl chlorides
were treated with 8 (obtained from method B) and the corre-
sponding pyrrolizidine based Knoevenagel type adducts prepared
The reaction between
b-keto ester 8 (obtained from method C)
and chloroacetyl chloride in anhydrous MgCl2/pyridine/MDC
H
H
H
O
H
..
+
HO
N
N
N
O
O
+
O
PhCOCl
TFA
OH
N
Boc
Boc
O
O
O
O
OH
O
MgCl2, py
O
O
O
8
O
CF3COO
O
+
H
H
H
H
OH
+
H
+
H
..
OH2
O
24
+
N
O
H2O
..
N
O
N
(from path II)
O-
O
N
A
q
H
u
O
o
OEt
u
25
O
O
s
O
O
..
O
H3O+
b
H
a
O
N
23
s
e
I
O
+N
O
OH
+
..
2
OH2
O
c
A
O
II
O
H
H
H2O
O
H
O
t
H
O
E
/
+
O
2
O
+N
HO
26a
N
N
H
OEt
H
OEt
O
O
+
24
Scheme 8. Proposed mechanism for the formation of 23, 24 and 25.

T. Ponpandian, S. Muthusubramanian / Tetrahedron 69 (2013) 527e536
531
O
R
OEt
O
MgCl2, py
O
N
N
Boc
+
MDC
then TFA
O
R
Cl
O
O
O
O
O
O
O
O
O
N
O
N
O
N
N
O
O2N
O
O
NO2
NO2
22 (85%)
27 (83%)
28 (80%)
26 (87%)
O
O
O
O
O
O
O
O
N
O
N
N
N
O
O
O
O
CF3
O
Cl
H
29 (72%)
31 (90%)
30 (78%)
32 (91%)
Cl
O
O
O
O
O
N
N
N
O
O
O
O
O
33 (94%)
34 (87%)
35 (89%)
Fig. 2. Synthesis of pyrrolizidine based Knoevenagel type adducts (22, 26e35).
medium yielded 82% of the furanone intermediate 36 after 5 h
through the sequential C-acylation and O-alkylation. The depro-
tection of 36 was carried out with trifluoroacetic acid and the
subsequent cyclisation at 50 ꢁC afforded 71% of the tricyclic system
with an azepine skeleton, 37 (Scheme 9). When the reaction be-
tween 3-chloropropionyl chloride and 8 was attempted, the pyr-
anone intermediate 38 failed to give the cyclisation compound 40
even after 10 h reflux in MDC or EtOH (Scheme 9).
Fig. 3. ORTEP diagram of 28 (CCDC number 880531).

532
T. Ponpandian, S. Muthusubramanian / Tetrahedron 69 (2013) 527e536
H
H
H
H
O
O
O
MgCl2
O
MDC, 50 oC
10 min
TFA, MDC
30 min
N
+
N
N
H
Cl
N
O
Cl
O
pyridine, MDC
5h
Boc
O
Boc
O
O
O
71%
EtO
OEt
EtO
82%
O
O
O
8
36
37
H
H
H
MDC, 50 oC, 10h
O
O
H
O
O
O
MgCl2
O
TFA, MDC
30 min
96%
+
N
N
H
N
O
Cl
Cl
pyridine, MDC
or
N
Boc
Boc
EtOH, 90 oC, 10h
20h
75%
EtO
O
EtO
39
O
O
OEt
O
8
38
Scheme 9. Synthesis of azepine skeleton from 8.
40
To demonstrate the synthetic utility of this approach, we ach-
ratio 3:1.6 Diastereoselective hydrogenation of the
b-enamino ester
ieved the enantioselective synthesis of (5R,9R)-(ꢀ) indolizidine
209D. (ꢀ)Indolizidine 209D acts as a noncompetitive blocker of
neuromuscular transmission.21 Wittig reaction between N-Boc-(S)
prolinal and (2-carboxyethyl)-triphenylphosphonium bromide
4122 in the presence of sodium hydride or t-BuOK in DMSO at
various temperature (between 0 ꢁC and 60 ꢁC) did not yield the
product 42. However in presence of LiHMDS in THF at 0 ꢁC the
reaction yielded 42 as a mixture of E and Z isomers. The mixture of
the geometrical isomers was then hydrogenated with Pd/C and
H2 (40 psi) to afford 43 in 69% from 16. 43 on reaction with 1,10-
carbonyl diimidazole (CDI) in THF afforded the corresponding
imidazolide, which on in situ treatment with ethyl potassium
2 was achieved by PtO2/H2 and the observed optical rotation of 44
a 25
(½ ꢂD ꢀ52.2 (c 1.4, CH2Cl2)) matched with that available in the
litrature.23 According to the known procedure,23 the 5-substituted
indolizidine 44 was converted into indolizidine alkaloid 45, (5R,
9R)-(ꢀ) indolizidine 209D, whose physical and spectral data24
match with the reported one. The observed optical rotation ½a D25
ꢂ
ꢀ77.8 (c 0.4, CH2Cl2) is also in consistent with the previously re-
ported [reported ½a D25
ꢂ
ꢀ77.1 (c 0.34, CH2Cl2),24b
½
a 2D5
ꢂ
ꢀ89.6 (c 1.88,
CH2Cl2)24c].
3. Conclusion
malonate and anhydrous MgCl2 yielded the
b-keto ester. The
An efficient route to pyrrolizidine and indolizidine based
subsequent deprotective cyclisation by boron trifluouride etherate
vinylogous urethanes and Knoevenagel type adducts has been ac-
yielded indolizidine
(Scheme 10).
b-enamino ester 2 in 92% from 43
complished from readily available L-proline. This methodology, an
alternative to Eschenmoser reaction, provides the (E)-isomer as the
sole product. The synthetic utility of this protocol has demonstrated
by the stereoselective synthesis of 5R, 9R-(ꢀ)-indolizidine 209D.
We have also developed a practical route for the synthesis of nat-
urally occurring pyrrolizidine, indolizidine and azepine skeletons
This transformation leads to the E isomer of 2 alone and the
geometry of the double bond has been confirmed by the compar-
ison of the spectral data with those available in the literature.6 This
way of getting 2 seems to be stereoselective as the reported method
of preparing 2 leads to a diastereomeric mixture of E and Z in the
from L-proline.
O
O
O
OH
H
H
O
OH
H
Ph
P
H
Br
Ph
10% Pd/C
MeOH
69% from 16
LiHMDS
THF, 0 o
+
OH
C
N
N
Ph
N
Boc
Boc
Boc
41
43
42
16
O
O
H
H
OEt
H2, PtO2
EtOH
95%
O
BF3.OEt2, MDC
O
Ethyl pot. malonate
CDI, Anhy.MgCl2
H
N
N
Aq.NaHCO3 work-up
O
O
N
92% from 43
60 o
C
Boc
44
2
H
N
CuI/n-BuLi
ether, -30 o
H
H
N
LiAlH4, THF
rt, 0.5h
Tosyl chloride
Et3N, DCM, rt
C
H
N
1h
OH
OTs
96%
3h
92%
95%
44a
45
5R, 9R(-) Indolizidine 209D
44b
Scheme 10. Synthesis of 5R, 9R-(ꢀ) indolizidine 209D.

T. Ponpandian, S. Muthusubramanian / Tetrahedron 69 (2013) 527e536
533
4. Experimental section
4.1. General
(2ꢃ20 mL), the combined organic layer was washed water, dried
over anhydrous Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography (5% ethyl acetate/hexanes) to
obtain the desired 8 (2.4 g, 92%) as colourless oil (enantiopurity is
>99%). [Found: C, 61.37; H, 8.70; N, 4.48. C16H27NO5 requires C,
61.32; H, 8.68; N, 4.47%]; Rf (100% DCM) 0.35; IR (KBr) 2976, 2934,
1H NMR spectra were recorded on 400 or 300 MHz and 13C NMR
spectra were recorded on 100 or 75 MHz in DMSO-d6 or CDCl3 using
300 MHz or 400 MHz spectrometer. Chemical shifts are reported in
1744, 1716, 1690, 1478, 1454, 1395, 1367 cmꢀ1
DMSO-d6)
;
1H NMR (400 MHz,
d
(parts per million) relative to TMS. Electrospray ionization (ESI)
d
1.18 (3H, t, J¼7.1 Hz, CH3), 1.39 (9H, s, Boc-H), 1.50e1.55
mass spectra were obtained on Agilent mass spectrometer. Infrared
spectra were recorded on a Shimadzu FT-IR instrument (KBr pellet)
and the band positions are reported in reciprocal of centimetres
(cmꢀ1). Melting points were determined on a melting point appa-
ratus (Inlab Pvt Ltd, India) equipped with a thermometer and were
uncorrected. Elemental analyses were performed on a PerkineElmer
2400 Series II Elemental CHNS analyzer. The single crystal X-ray
diffraction was done on a Bruker Axs Kappa Apexll CCD diffractom-
eter, SAIF in Indian Institute of Technology Madras. Silica gel-G plates
(Merck) were used for TLC; here UV and/or KMnO4 were used as
revealing agents. All reactions were carried out in a nitrogen atmo-
sphere. Solvents and reagents were dried and purified prior to use:
tetrahydrofuran and ether (distilled from sodium/benzophenone);
dichloromethane (distilled from CaH2). All the reagents and solvents
were purchased from commercial sources and the compounds 11,25a
12,25b 14,25c 15,25a were prepared by literature procedure.
(2H, m, CH2), 1.76e1.84 (4H, m, CH2), 2.48e2.53 (2H, m, CH2),
3.22e3.24 (2H, m, CH2), 3.58 (2H, s, CH2), 3.62e3.65 (1H, m, CH),
4.08 (2H, q, J¼7.1 Hz, OCH2); 13C NMR (100 MHz, DMSO-d6)
d 14.0,
22.6, 23.6, 28.1, 29.3, 30.3, 46.5, 48.8, 56.3, 60.4, 78.2, 153.9, 167.3,
203.1; ESI-m/z calcd for [C16H27NO5þH]þ 314.2, found 314.1.
4.1.4. Synthesis of (E)-ethyl 2-((S)-tetrahydro-1H-pyrrolizin-3(6H)-
ylidene) acetate (1). A solution of 8 (0.5 g, 1.6 mmol) in dry MDC
(20 mL) was cooled to 5 ꢁC and dry HCl gas was purged for 5 min.
The resulting mixture was stirred at 5 ꢁC for 30 min, poured into
saturated NaHCO3 solution (50 mL) and extracted with dichloro-
methane (2ꢃ60 mL). The combined organic layer was washed with
water (3ꢃ70 mL), brine solution (1ꢃ50 mL), dried over anhydrous
Na2SO4 and concentrated in vacuo. The residue was purified by
column chromatography (10% ethyl acetate/hexanes) to obtain the
desired 1 (0.305 g, 98%) as light-yellow oil. [Found: C, 67.71; H, 8.81;
N, 7.73. C11H17NO2 requires C, 67.66; H, 8.78; N, 7.17%]; Rf (100%
4.1.1. Synthesis of (S)-tert-butyl 2-((E)-4-(ethoxycarbonyl)-3-oxobut-
1-enyl)pyrrolidine-1-carboxylate (18) (mixture of ketoeenol form). To
a slurry of sodium hydride (0.42 g, 17.4 mmol) (60% dispersion in
mineral oil) in dry THF (20 mL) cooled to 5 ꢁC wasadded phosphonate
1714f (3.1 g, 11.6 mmol) in dry THF (10 mL) dropwise over a period of
1 h under nitrogen atmosphere and stirred for 0.5 h. Then N-Boc-(S)-
prolinal 16 (2.3 g,11.6 mmol) in dry THF (10 mL) was added dropwise
over a period of 0.5 h and stirred at 5 ꢁC for 1 h. The reaction mixture
waspoured intowater(200 mL) and acidified (pH¼5)with dil HCl (2%
aqueous solution) and extracted with ethyl acetate (2ꢃ200 mL). The
combined organic layer was washed with water (3ꢃ200 mL), brine
solution (1ꢃ100 mL), dried over anhydrous Na2SO4 and concentrated
to give 18 (3.45 g, 96%) as yellow oil. Rf (5% MeOH/DCM) 0.52; Keto
DCM) 0.43; ½a 2D5
ꢀ100.8 (c 0.5, CH2Cl2); IR (KBr) 2931, 2857, 1685,
ꢂ
1598, 1448 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
1.23 (3H, t, J¼7.1 Hz,
CH3), 1.23e1.26 (1H, m, CH2), 1.51e1.57 (1H, m, CH2), 2.02e2.12 (1H,
m, CH2), 2.13e2.23 (3H, m, CH2), 2.96e3.06 (2H, m, CH2), 3.06e3.16
(1H, m, CH2), 3.76 (1H, dd, J¼17.2, 8.8 Hz, CH2), 3.85e3.90 (1H, m,
CH), 4.08 (2H, q, J¼7.1 Hz, OCH2), 4.44 (1H, s, ]CH); 13C NMR
(100 MHz, CDCl3) d 14.9, 28.5, 29.7, 32.0, 36.2, 44.0, 58.4, 66.2, 78.8,
163.8, 169.5; ESI-m/z calcd for [C11H17NO2þH]þ 196.1, found 196.1.
4.1.5. General procedure for the synthesis of Knoevenagel adducts 22,
24, 26e35. To the stirring suspension of anhydrous MgCl2
(1.6 mmol) in dry MDC (20 mL) at 5 ꢁC, 8 (1.6 mmol) was added in
dry MDC (5 mL) followed by the addition of pyridine (3.2 mmol)
over a period of 20 min. After the mixture was stirred for 30 more
min at 5 ꢁC, acid chloride (1.7 mmol) in MDC (2 mL) was added. The
resulting mixture was stirred for 15 min at 5 ꢁC and then at room
temperature for 5 h. The resulting suspension was acidified
(pH¼3) with dil HCl (2% solution) and washed with water
(2ꢃ10 mL). To the organic layer was added TFA (2 mL) and stirred
at room temperature for 1 h. The reaction mixture was added into
water (150 mL) & ethyl acetate (150 mL) mixture and stirred at
room temperature for 30 min. The organic layer was washed with
water (3ꢃ150 mL), brine solution (1ꢃ100 mL), dried over anhy-
drous Na2SO4 and concentrated in vacuo. The residue was purified
by column chromatography with MDC/MeOH (99/1) as eluent to
give the product.
form: 1H NMR (400 MHz, DMSO-d6)
d
1.18 (3H, t, J¼7.1 Hz, CH3), 1.34
(9H, s, Boc-H), 1.75e1.77 (3H, m, CH2), 2.05e2.07 (1H, m, CH2),
3.26e3.29 (2H, m, CH2), 3.75 (2H, s, CH2), 4.09 (2H, q, J¼7.1 Hz, OCH2),
4.31e4.33 (1H, m, CH), 5.94e5.97 (1H, m, ]CH), 6.82 (1H, dd, J¼15.8,
5.9 Hz, ]CH). Enol form: 1H NMR (400 MHz, DMSO-d6)
d 1.23 (3H, t,
J¼7.1 Hz, CH3), 1.40 (9H, s, Boc-H), 1.77e1.79 (3H, m, CH2), 2.07e2.09
(1H, m, CH2), 3.27e3.29 (2H, m, CH2), 4.18 (2H, q, J¼7.1 Hz, OCH2),
4.39e4.41 (1H, m, CH), 5.25 (1H, s, ]CH), 6.20e6.23 (1H, m, ]CH),
6.44e6.47 (1H, m, ]CH); (one enolic OH proton was not seen in 1H
NMR) ESI-m/z calcd for [C16H25NO5þH]þ 312.2, found 312.1.
4.1.2. Synthesis of tert-butyl 2-(4-(ethoxycarbonyl)-3-oxobutyl)pyr-
rolidine-1-carboxylate (8) (mixture of enantiomers). A suspension of
18 (3.3 g, 10.6 mmol) and 10% PdeC (0.33 g, 10 wt %) in anhydrous
ethanol (100 mL) was stirred under hydrogen atmosphere (40 psi) at
room temperature for 2 h. The catalyst was filtered off and the filtrate
was concentrated to give pure 8 (3.3 g, 99%) as colourless oil (58:42
ratio of enantiomers) (enantiomeric puritydseeSupplementary data).
4.1.6. (E)-Ethyl 2-(tetrahydro-1H-pyrrolizin-3(6H)-ylidene)-3-oxobu-
tanoate (22). Colourless oil; [found: C, 65.85; H, 8.09; N, 5.91.
C
13H19NO3 requires C, 65.80; H, 8.07; N, 5.90%]; Rf (2% MeOH/DCM)
0.34; IR (KBr) 2973, 2927, 1688, 1633, 1531, 1455 cmꢀ1 1H NMR
(400 MHz, CDCl3)
;
d
1.32 (3H, t, J¼7.2 Hz, CH3), 1.42e1.44 (1H, m, CH2),
4.1.3. Synthesis of (S)-tert-butyl 2-(4-(ethoxycarbonyl)-3-oxobutyl)
pyrrolidine-1-carboxylate (8) (single enantiomer). To a suspension
of carbonyl diimidazole (1.5 g, 9.1 mmol) in dry THF (15 mL) was
added a solution of 19 (2 g, 8.2 mmol) in dry THF (15 mL) and stirred
at room temperature for 2 h. To this reaction mixture, ethyl po-
tassium malonate (0.73 g, 4.3 mmol) and anhydrous MgCl2 (1.5 g,
9.1 mmol) were added. The resulting mixture was stirred at 60 ꢁC
for 2 h, poured into water (10 mL) and acidified with 5% aqueous
HCl to pH 2e3. The mixture was extracted with dichloromethane
1.56e1.66 (1H, m, CH2), 2.06e2.20 (4H, m, CH2), 2.28 (3H, s, CH3),
2.70e2.77 (1H, m, CH2), 2.92e3.01 (1H, m, CH2), 3.36e3.41 (1H, m,
CH2), 4.09e4.17 (2H, m, CH2 & CH), 4.18e4.24 (2H, m, OCH2); 13C NMR
(75 MHz, CDCl3)
d 14.2, 26.7, 27.2, 30.7, 30.9, 38.2, 47.8, 59.7, 68.9,
99.99, 166.6, 169.3, 195.4; ESI-m/z calcd for [C13H19NO3þH]þ 238.1,
found 238.1.
4.1.7. (E)-Ethyl 2-((S)-tetrahydro-1H-pyrrolizin-3(6H)-ylidene)-3-
oxo-3-phenylpropanoate (24). Colourless semi-solid; [found: C,

534
T. Ponpandian, S. Muthusubramanian / Tetrahedron 69 (2013) 527e536
72.26; H, 7.09; N, 4.69. C18H21NO3 requires C, 72.22; H, 7.07; N,
128.5, 129.6, 137.5, 148.4, 167.5, 169.0, 192.2, 192.5; ESI-m/z calcd for
[C19H21NO4þH]þ 328.1, found 328.1.
4.68%]; Rf (2% MeOH/DCM) 0.43; ½a D25
ꢂ
ꢀ63.7 (c 0.46, CH2Cl2); IR
(KBr) 2925, 1683, 1626, 1598, 1578, 1538, 1449 cmꢀ1
;
1H NMR
(400 MHz, CDCl3)
d
0.70 (3H, t, J¼7.2 Hz, CH3), 1.43 (1H, td, J¼10.0,
4.1.12. (E)-Ethyl 3-(4-(trifluoromethyl)phenyl)-2-(tetrahydro-1H-pyr-
rolizin-3(6H)-ylidene)-3-oxopropanoate (30). Pale-yellow semi-
solid; [found: C, 62.16; H, 5.50; N, 3.82. C19H20F3NO3 requires C,
62.12; H, 5.49; N, 3.81%]; Rf (2% MeOH/DCM) 0.41; IR (KBr) 2929,
1.6 Hz, CH2), 1.63e1.73 (1H, m, CH2), 2.09e2.19 (2H, m, CH2),
2.19e2.26 (2H, m, CH2), 2.58e2.62 (1H, m, CH2), 2.97e3.06 (1H, m,
CH2), 3.28e3.32 (1H, m, CH2), 3.78e3.84 (2H, m, OCH2), 4.12e4.16
(1H, m, CH), 4.29 (1H, ddd, J¼18.0, 9.6, 1.1 Hz, CH2), 7.34e7.38 (2H,
m, AreH), 7.40e7.44 (1H, m, AreH), 7.74 (2H, dd, J¼8.4, 1.4 Hz,
1681, 1623, 1599, 1575, 1534 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 0.70
(3H, t, J¼7.1 Hz, CH3),1.45e1.50 (1H, m, CH2),1.69e1.77 (1H, m, CH2),
2.14e2.29 (4H, m, CH2), 2.56e2.63 (1H, m, CH2), 2.99e3.08 (1H, m,
CH2), 3.33e3.36 (1H, m, CH2), 3.81 (2H, q, J¼7.1 Hz, OCH2), 4.17e4.19
(1H, m, CH), 4.31 (1H, dd, J¼18.1, 9.6 Hz, CH2), 7.62 (2H, d, J¼8.0 Hz,
AreH), 7.80 (2H, d, J¼8.0 Hz, AreH); 13C NMR (100 MHz, CDCl3)
AreH); 13C NMR (100 MHz, CDCl3)
d 13.7, 27.5, 27.9, 31.6, 37.9, 47.9,
59.4, 69.5, 97.5, 128.0, 128.3, 131.0, 142.7, 166.1, 169.3, 194.2; ESI-m/z
calcd for [C18H21NO3þH]þ 300.1, found 300.1.
4.1.8. (E)-Ethyl 2-(tetrahydro-1H-pyrrolizin-3(6H)-ylidene)-3-(4-
nitrophenyl)-3-oxopropanoate (26). Yellow semi-solid; [found: C,
62.82; H, 5.86; N, 8.15. C18H20N2O5 requires C, 62.78; H, 5.85; N,
8.13%]; Rf (2% MeOH/DCM) 0.37; IR (KBr) 2921, 1687, 1629, 1591,
d 13.6, 27.3, 27.8, 31.6, 38.1, 48.2, 59.6, 69.8, 97.0, 125.0, 125.5, 128.3,
132.2,146.2,167.2,169.0,192.3; ESI-m/z calcd for [C19H20F3NO3þH]þ
368.1, found 368.1.
1584, 1529, 1502 cmꢀ1; 1H NMR (400 MHz, DMSO-d6)
d
0.70 (3H, t,
4.1.13. (E)-Ethyl
3(6H)-ylidene)-3-oxopropanoate
3-(3-chlorophenyl)-3-(tetrahydro-1H-pyrrolizin-
(31). Colourless semi-solid;
J¼7.2 Hz, CH3), 1.48e1.53 (1H, m, CH2), 1.68e1.74 (1H, m, CH2),
2.11e2.30 (4H, m, CH2), 2.59e2.64 (1H, m, CH2), 3.00e3.09 (1H, m,
CH2), 3.18e3.22 (1H, m, CH2), 3.77 (2H, q, J¼7.2 Hz, OCH2),
4.16e4.22 (2H, m, CH2 & CH), 7.82 (2H, d, J¼8.7 Hz, AreH), 8.31 (2H,
[found: C, 64.81; H, 6.05; N, 4.21. C18H20ClNO3 requires C, 64.77; H,
6.04; N, 4.20%]; Rf (2% MeOH/DCM) 0.42; IR (KBr) 2927, 1686, 1621,
1594, 1571, 1536,1449 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 0.76 (3H, t,
d, J¼8.7 Hz, AreH); 13C NMR (100 MHz, CDCl3)
d
13.5, 27.0, 27.5,
J¼7.2 Hz, CH3), 1.40e1.49 (1H, m, CH2), 1.64e1.75 (1H, m, CH2),
2.12e2.25 (4H, m, CH2), 2.55e2.62 (1H, m, CH2), 2.97e3.07 (1H, m,
CH2), 3.28e3.34 (1H, m, CH2), 3.78e3.93 (2H, m, OCH2), 4.11e4.20
(1H, m, CH), 4.28 (1H, dd, J¼18.0, 9.5 Hz, CH2), 7.30 (1H, t, J¼7.8 Hz,
AreH), 7.38e7.41 (1H, m, AreH), 7.59e7.62 (1H, m, AreH), 7.71 (1H, t,
31.2, 38.1, 48.1, 59.4, 69.8, 96.8, 123.1, 128.5, 148.6, *167.6, 168.5,
190.8; ESI-m/z calcd for [C18H20N2O5þH]þ 345.1, found 345.1.
4.1.9. (E)-Ethyl 2-(tetrahydro-1H-pyrrolizin-3(6H)-ylidene)-3-(3-
nitrophenyl)-3-oxopropanoate (27). Yellow semi-solid; [found: C,
62.83; H, 5.86; N, 8.14. C18H20N2O5 requires 62.78; H, 5.85; N,
8.13%]; Rf (2% MeOH/DCM) 0.37; IR (KBr) 2922, 1688, 1628, 1592,
J¼1.7 Hz, AreH); 13C NMR (100 MHz, CDCl3)
d 13.8, 27.4, 27.9, 31.6,
38.1, 48.1, 59.5, 69.7, 96.8,126.3,128.3,129.3,130.8,134.1,144.6,166.8,
168.9,192.3; ESI-m/z calcd for [C18H20ClNO3þH]þ 334.1, found 334.1.
1585, 1524, 1506 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 0.75 (3H, t,
J¼7.2 Hz, CH3), 1.47e1.52 (1H, m, CH2), 1.71e1.76 (1H, m, CH2),
2.15e2.29 (4H, m, CH2), 2.57e2.61 (1H, m, CH2), 3.01e3.09 (1H, m,
CH2), 3.32e3.35 (1H, m, CH2), 3.85 (2H, m, OCH2), 4.19e4.21 (1H, m,
CH), 4.32 (1H, dd, J¼18.2, 9.4 Hz, CH2), 7.55 (1H, t, J¼8.2 Hz, AreH),
8.03 (1H, dd, J¼8.2, 1.3 Hz, AreH), 8.27 (1H, dd, J¼8.2, 1.3 Hz, AreH),
4.1.14. (E)-Ethyl
3-(2-chlorophenyl)-3-(tetrahydro-1H-pyrrolizin-
3(6H)-ylidene)-3-oxopropanoate (32). White solid; mp 81e82 ꢁC;
[found: C, 64.82; H, 6.06; N, 4.21. C18H20ClNO3 requires C, 64.77; H,
6.04; N, 4.20%]; Rf (2% MeOH/DCM) 0.41; IR (KBr) 2929, 1687, 1623,
1591, 1573, 1534 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 0.71 (3H, t,
8.53 (1H, t, J¼1.3 Hz, AreH); 13C NMR (100 MHz, DMSO-d6)
d
13.5,
J¼7.2 Hz, CH3), 1.50e1.55 (1H, m, CH2), 1.71e1.76 (1H, m, CH2),
2.16e2.29 (4H, m, CH2), 2.87e2.90 (1H, m, CH2), 3.03e3.07 (1H, m,
CH2), 3.53e3.57 (1H, m, CH2), 3.77 (2H, q, J¼7.2 Hz, OCH2),
4.20e4.24 (1H, M, CH), 4.34 (1H, dd, J¼18.4, 8.7 Hz, CH2), 7.22e7.25
(2H, m, AreH), 7.31e7.38 (2H, m, AreH); 13C NMR (100 MHz, CDCl3)
26.5, 27.2, 30.6, 37.8, 47.7, 58.6, 69.5, 95.3, 121.8, 125.0, 129.8, 133.8,
144.0, 147.4, 166.8, 167.5, 189.2; ESI-m/z calcd for [C18H20N2O5þH]þ
345.1, found 345.1.
4.1.10. (E)-Ethyl 2-(tetrahydro-1H-pyrrolizin-3(6H)-ylidene)-3-(2-
nitrophenyl)-3-oxopropanoate (28). Yellow solid; mp 107e108 ꢁC;
[found: C, 62.82; H, 5.86; N, 8.15. C18H20N2O5 requires C, 62.78; H,
5.85; N, 8.13%]; Rf (2% MeOH/DCM) 0.37; IR (KBr) 2925, 1689, 1631,
d 13.2, 26.7, 27.2, 31.1, 38.4, 48.3, 59.4, 69.8, 99.4, 126.1, 128.3, 129.2,
129.4, 130.7, 143.5, 168.5, 168.6, 189.6; ESI-m/z calcd for
[C18H20ClNO3þH]þ 334.1, found 334.1. HRMS calculated for
C18H21ClNO3 (MþþNa) 356.1029, found 356.1042.
1596, 1588, 1520, 1509 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 0.71 (3H,
t, J¼7.2 Hz, CH3), 1.51e1.54 (1H, m, CH2), 1.69e1.79 (1H, m, CH2),
2.16e2.31 (4H, m, CH2), 3.08e3.20 (2H, m, CH2), 3.67e3.81 (3H, m,
CH2 & OCH2), 4.25e4.33 (2H, m, CH & CH2), 7.25 (1H, d, J¼7.8 Hz,
AreH), 7.43 (1H, t, J¼7.8 Hz, AreH), 7.58 (1H, t, J¼7.8 Hz, AreH),
4.1.15. (E)-Ethyl 2-(tetrahydro-1H-pyrrolizin-3(6H)-ylidene)-3-oxo-
m-tolylpropanoate (33). Yellow semi-solid; [found: C, 72.87; H, 7.42;
N, 4.48. C19H23NO3 requires C, 72.82; H, 7.40; N, 4.47%]; Rf (2% MeOH/
DCM) 0.45; ½a 2D5
ꢂ
ꢀ11.9 (c 0.4, CH2Cl2); IR (KBr) 2931,1690,1627,1594,
8.02 (1H, d, J¼7.8 Hz, AreH); 13C NMR (100 MHz, CDCl3)
d
13.4, 26.5,
1570, 1531, 1449 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
0.73 (3H, t,
27.0, 30.8, 39.3, 48.5, 59.3, 70.0, 97.7, 123.7, 127.6, 128.1, 133.1, 141.4,
146.2, 167.8, 170.1, 187.3; ESI-m/z calcd for [C18H20N2O5þH]þ 345.1,
found 345.1.
J¼7.2 Hz, CH3), 1.40e1.45 (1H, m, CH2), 1.65e1.73 (1H, m, CH2),
2.08e2.15 (3H, m, CH2), 2.17e2.26 (1H, m, CH2), 2.37 (3H, s, CH3),
2.59e2.62 (1H, m, CH2), 2.97e3.06 (1H, m, CH2), 3.28e3.31 (1H, m,
CH2), 3.76e3.90 (2H, m, OCH2), 4.12e4.15 (1H, m, CH), 4.26 (1H, dd,
J¼18.3, 8.7 Hz, CH2), 7.24e7.27 (2H, m, AreH), 7.55 (1H, m, AreH), 7.58
4.1.11. (E)-Ethyl
3-(4-formylphenyl)-2-(tetrahydro-1H-pyrrolizin-
3(6H)-ylidene)-3-oxopropanoate (29). Pale-yellow sticky; [found: C,
69.75; H, 6.49; N, 4.29. C19H21NO4 requires C, 69.71; H, 6.47; N,
4.28%]; Rf (2% MeOH/DCM) 0.39; IR (KBr) 2925, 1705, 1686, 1621,
(1H, s, AreH); 13C NMR (100 MHz, CDCl3)
d 13.7, 21.4, 27.7, 28.0, 31.6,
37.8, 47.9, 59.3, 69.4, 97.2, 125.7, 127.9, 128.9, 131.8, 137.7, 142.6, 165.8,
169.3, 194.4; ESI-m/z calcd for [C19H23NO3þH]þ 314.1, found 314.1.
1595, 1572, 1531 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 0.69 (3H, t,
J¼7.0 Hz, CH3), 1.43e1.50 (1H, m, CH2), 1.69e1.75 (1H, m, CH2),
2.15e2.29 (4H, m, CH2), 2.59e2.66 (1H, m, CH2), 3.01e3.06 (1H, m,
CH2), 3.35e3.38 (1H, m, CH2), 3.76e3.86 (2H, m, OCH2), 4.18e4.24
(1H, m, CH), 4.30 (1H, dd, J¼18.3, 9.2 Hz, CH2), 7.83 (2H, d, J¼8.2 Hz,
AreH), 7.88 (2H, d, J¼8.2 Hz, AreH), 10.06 (1H, s, CHO); 13C NMR
4.1.16. (E)-Ethyl 3-(furan-2-yl)-2-(tetrahydro-1H-pyrrolizin-3(6H)-
ylidene)-3-oxopropanoate (34). Brown solid; mp 74e75 ꢁC; [found:
C, 66.47; H, 6.64; N, 4.85. C16H19NO4 requires C, 66.42; H, 6.62; N,
4.84%]; Rf (2% MeOH/DCM) 0.40; IR (KBr) 2919, 1685, 1624, 1598,
1574, 1531 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
0.97 (3H, t, J¼7.1 Hz,
(100 MHz, CDCl3)
d 13.7, 27.3, 27.8, 31.6, 38.2, 48.3, 59.6, 69.9, 97.2,
CH3), 1.38e1.43 (1H, m, CH2), 1.62e1.68 (1H, m, CH2), 2.08e2.21

T. Ponpandian, S. Muthusubramanian / Tetrahedron 69 (2013) 527e536
535
(4H, m, CH2), 2.63e2.66 (1H, m, CH2), 2.96e3.01 (1H, m, CH2),
3.31e3.34 (1H, m, CH2), 3.94e4.07 (2H, m, OCH2), 4.08e4.14 (1H, m,
CH), 4.23 (1H, dd, J¼17.9, 9.3 Hz, CH2), 6.46 (1H, dd, J¼3.4, 0.6 Hz,
AreH), 6.98 (1H, d, J¼3.4 Hz, AreH), 7.46 (1H, d, J¼0.6 Hz, AreH);
H), 1.58 (2H, br, CH2), 1.76 (2H, br, CH2), 1.88 (2H, br, CH2), 2.33 (2H,
br, CH2), 2.53 (2H, br, COCH2), 3.19e3.24 (2H, m, CH2), 3.67 (1H, br,
CH), 4.14 (2H, q, J¼6.7 Hz, OCH2), 4.51 (2H, t, J¼6.3 Hz, OCH2); 13C
NMR (100 MHz, DMSO-d6)
d 14.0, 22.5, 23.4, 28.1, 29.3, 30.0, 34.9,
13C NMR (100 MHz, CDCl3)
d
14.1, 27.3, 27.7, 31.3, 37.5, 47.7, 59.4,
46.0, 46.2, 56.2, 60.6, 67.9, 78.5, 112.6, 165.2, 176.9, 187.7; ESI-m/z
69.3, 96.2, 111.7, 114.7, 144.2, 155.6, 165.1, 168.7, 180.8; ESI-m/z calcd
calcd for [C19H29NO6þH]þ 368.2, found 368.1.
for [C16H19NO4þH]þ 290.1, found 290.1.
4.1.22. Ethyl 5,6-dihydro-4-oxo-2-(2-((S)-pyrrolidin-2-yl)ethyl)-4H-
pyran-3-carboxylate (39). Colourless sticky; [found: C, 62.95; H,
7.94; N, 5.25. C14H21NO4 C, 62.90; H, 7.92; N, 5.24%]; Rf (10% MeOH/
4.1.17. Diethyl 2-(tetrahydro-1H-pyrrolizin-3(6H)-ylidene) malonate
(35). Colourless oil; [found: C, 62.94; H, 7.94; N, 5.25. C14H21NO4
requires C, 62.90; H, 7.92; N, 5.24%]; Rf (2% MeOH/DCM) 0.33; IR
DCM) 0.19; 1H NMR (400 MHz, DMSO-d6)
d
1.20 (3H, t, J¼7.1 Hz,
(KBr) 2929, 1675, 1631, 1585, 1571, 1555 cmꢀ1
;
1H NMR (400 MHz,
CH3),1.30e1.40 (1H, m, CH2),1.50e1.60 (1H, m, CH2),1.98e2.50 (4H,
m, CH2), 2.59e2.72 (3H, m, COCH2 & CH2), 2.80e2.89 (1H, m, CH2),
3.10e3.14 (1H, m, CH2), 3.58e3.64 (2H, m, OCH2), 3.92 (1H, dd,
J¼17.5, 9.2 Hz, CH2), 4.02e4.11 (3H, m, OCH2 & CH), 4.36 (1H, br, D2O
CDCl3)
d
1.28 (6H, t, J¼7.1 Hz, CH3), 1.2e1.38 (1H, m, CH2), 1.54e1.60
(1H, m, CH2), 2.02e2.19 (4H, m, CH2), 2.91e3.02 (2H, m, CH2), 3.33
(1H, td, J¼11.4, 3.0 Hz, CH2), 3.95e4.02 (2H, m, CH & CH2), 4.12e4.24
(4H, m, OCH2); 13C NMR (100 MHz, CDCl3)
d
14.5, 27.6, 28.1, 31.3,
exchangeable, NH); 13H NMR (100 MHz, DMSO-d6)
d 14.2, 26.4, 27.0,
37.7, 46.3, 59.9, 68.7, 90.1, 163.5, 168.2; ESI-m/z calcd for
30.3, 37.8, 45.5, 47.3, 58.2, 59.1, 68.6, 99.1,165.1,168.4,195.2; ESI-m/z
[C14H21NO4þH]þ 268.1, found 268.1.
calcd for [C14H21NO4þH]þ 268.1, found 268.1.
4.1.18. General procedure for the synthesis 36, 37, 38 and 39. To the
stirring suspension of anhydrous MgCl2 (1.6 mmol) in dry MDC
(20mL)at5ꢁC, 8(1.6 mmol) wasaddedindryMDC (5 mL)followed by
the addition of pyridine (3.2 mmol) over a period of 20 min. After the
mixturewasstirredfor30moreminat5ꢁC,chloroacetylchlorideor3-
chloropropionyl chloride (1.7 mmol) in MDC (2 mL) was added. The
resulting mixture was stirred for 15 min at 5 ꢁC and then at room
temperature for 5e20 h. The resulting suspension was acidified
(pH¼3) with dil HCl (2% solution) and washed with water (2ꢃ10 mL)
and concentrated invacuo. The crude product was purified bycolumn
chromatography using MDC/MeOH as eluent to give pure 36 or 38. To
the Boc compound 36or 38 in MDC (10 mL) was added TFA (2 mL) and
theobtainedsolutionstirredatroomtemperaturefor1h.Thereaction
mixture was added into water and basified (pH¼9) with aqueous
NaHCO3. The resulting mixture was extracted with DCM (2ꢃ150 mL),
thecombinedorganiclayerwaswashedwithwater(2ꢃ100 mL), brine
solution (1ꢃ100 mL), dried over anhydrous Na2SO4 and concentrated
invacuoat50ꢁC.Theresiduewaspurifiedbycolumnchromatography
with MDC/MeOH (99/1) as eluent to give 37 or 39.
4.1.23. Synthesis of 4-((R)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)
butanoic acid (43). To a suspension of (2-carboxyethyl)triphenyl-
phosphonium bromide 41 (18.8 g, 45 mmol) in dry THF (120 mL) at
ꢀ10 ꢁC, under nitrogen atmosphere, was added LiHMDS (12.5 g,
75 mmol). The mixture was stirred for 45 min, and a solution of N-
Boc-S-prolinal 16 (3 g, 15 mmol) in dry THF (50 mL) was added over
a period of 30 min. The resulting mixture was stirred at 0 ꢁC for 1 h
and then quenched by the addition of 5% aqueous HCl. To the re-
sultant mixture, ethyl acetate (300 mL) was added, the organic layer
was separated and washed with saturated NaHCO3 solution
(2ꢃ150 mL). The combined washings were acidified (pH¼2) with dil
HCl (5% aqueous solution) and extracted with ethyl acetate
(2ꢃ200 mL). The organic layer was washed with water (1ꢃ150 mL),
brine solution (1ꢃ100 mL), dried over anhydrous Na2SO4 and con-
centratedtogivecrude42(3.1g)asyellowoil. Crude42(3g,12mmol)
in ethanol (150 mL) was stirred at room temperature with 10% PdeC
(0.3 g) in hydrogen atmosphere (40 psi) for 2 h. The catalyst was
filtered off, washed with ethanol (20 mL) and the combined filtrate
and washing was concentrated. The residue was purified by column
chromatography (1% MeOH/DCM) to yield 43 (2.7 g, 69% from 16) as
a colourless sticky product. [Found: C, 60.72; H, 9.03; N, 5.45.
4.1.19. (S)-tert-Butyl 2-(2-(3-(ethoxycarbonyl)-4,5-dihydro-4-oxofu-
ran-2-yl)ethyl)pyrrolidine-1-carboxylate (36). Colourless sticky;
[found: C, 61.22; H, 7.72; N, 3.97. C18H27NO6 requires C, 61.17; H, 7.70;
N, 3.96%]; Rf (2% MeOH/DCM) 0.28; 1H NMR (400 MHz, DMSO-d6)
C
13H23NO4 C, 60.68; H, 9.01; N, 5.44%]; Rf (2% MeOH/DCM) 0.29; 1H
NMR (400 MHz, DMSO-d6) 1.12e1.15 (1H, m, CH2), 1.38 (9H, s, Boc-
d
H),1.43e1.53 (2H, m, CH2),1.54e1.68 (2H, m, CH2),1.70e1.85 (3H, m,
CH2), 2.21 (2H, t, J¼7.2 Hz, CH2), 3.17e3.32 (2H, m, CH2), 3.62 (1H, m,
CH), 12.01 (1H, s, D2O exchangeable, COOH); 13C NMR (100 MHz,
d
1.23 (3H, t, J¼7.0 Hz, CH3), 1.38 (9H, s, Boc-H), 1.69e1.78 (4H, m,
CH2), 1.94 (2H, br, CH2), 2.94 (1H, br, CH2), 3.21e3.28 (3H, m, CH2),
3.73 (1H, br, CH), 4.17 (2H, q, J¼7.0 Hz, OCH2), 4.78 (2H, s, CH2); 13
C
DMSO-d6) d 19.8, 22.7, 28.2, 30.2, 30.5, 35.3, 46.6, 56.4, 78.1, 153.8,
NMR (100 MHz, DMSO-d6)
d
14.2, 22.6, 28.1, 29.8, 29.9, 30.5, 46.3,
176.8; ESI-m/z calcd for [C13H23NO4eH]þ 256.1, found 256.1.
56.2, 59.6, 76.0, 78.3, 108.1, 153.5, 161.7, 195.7, 200.0; ESI-m/z calcd
for [C18H27NO6þH]þ 354.2, found 354.1.
4.1.24. Synthesis of (E)-ethyl 2-((R)-hexahydroindolizin-5(1H)-yli-
dene) acetate (2).6 To a suspension of carbonyl diimidazole (0.69 g,
4.3 mmol) in dry THF (5 mL) was added a solution of 43 (1 g,
3.9 mmol) in dry THF (5 mL) and stirred at room temperature for
2 h. To this reaction mixture, ethyl potassium malonate (0.73 g,
4.3 mmol) and anhydrous MgCl2 (0.41 g, 4.3 mmol) were added.
The resulting mixture was stirred at 60 ꢁC for 2 h, poured into water
(10 mL) and acidified with 5% aqueous HCl to pH 2e3. The mixture
was extracted with dichloromethane (2ꢃ20 mL), the combined
organic layer was washed water, dried over anhydrous Na2SO4 and
then cooled to 5 ꢁC, and BF3$OEt2 (1.5 mL, 11.7 mmol) was added,
stirred for 1 h. The mixture was then poured into saturated NaHCO3
solution (20 mL) and extracted with ethyl acetate (2ꢃ60 mL). The
combined organic layer was washed with water (3ꢃ60 mL), brine
solution (1ꢃ60 mL), dried over anhydrous Na2SO4 and concentrated
in vacuo. The residue was purified by column chromatography with
hexane/ethyl acetate (90/10) as eluent to obtain the desired 2
4.1.20. (8aS)-6,7,8,8a,9,10-Hexahydro-4H-furo[2,3-e]pyrrolo[1,2-a]
azepine-3,4(2H)-dione (37). White solid; mp 147e149 ꢁC; [found: C,
63.81; H, 6.34; N, 6.78. C11H13NO3 requires C, 63.76; H, 6.32; N,
6.76%]; Rf (5% MeOH/DCM) 0.21; IR (KBr) 1729, 1658, 1563, 1472,
1353, 1329, 1300 cmꢀ1 1H NMR (400 MHz, DMSO-d6)
; d 1.41e1.53
(1H, m, CH2), 1.62e1.73 (1H, m, CH2), 2.08e2.27 (4H, m, CH2),
2.98e3.08 (1H, m, CH2), 3.47 (1H, br, CH2), 4.11 (2H, br, CH & CH2),
4.32 (3H, br, OCH2 & CH2); 13C NMR (100 MHz, DMSO-d6)
d 26.4,
27.2, 29.7, 37.8, 49.0, 70.5, 70.8, 87.3, 167.2, 173.0, 192.0; ESI-m/z
calcd for [C11H13NO3þH]þ 208.1, found 208.1.
4.1.21. (S)-tert-Butyl 2-(2-(3-(ethoxycarbonyl)-5,6-dihydro-4-oxo-
4H-pyran-2-yl)ethyl)pyrrolidine-1-carboxylate
(38). Colourless
sticky; [found: C, 62.16; H, 7.98; N, 3.82. C19H29NO6 requires C,
62.11; H, 7.96; N, 3.81%]; Rf (2% MeOH/DCM) 0.29; 1H NMR
(400 MHz, DMSO-d6)
d
1.22 (3H, t, J¼6.7 Hz, CH3), 1.35 (9H, s, Boc-
(0.75 g, 92%) as light-yellow oil. 1H NMR (400 MHz, CDCl3)
d 1.25

536
T. Ponpandian, S. Muthusubramanian / Tetrahedron 69 (2013) 527e536
(3H, t, J¼7.1 Hz, CH3), 1.28e1.31 (1H, m, CH2), 1.36e1.43 (1H, m,
CH2), 1.51e1.62 (1H, m, CH2), 1.79e1.91 (2H, m, CH2), 1.98e2.10 (3H,
m, CH2), 2.92 (1H, ddd, J¼14.7, 10.9, 7.1 Hz, CH2), 3.22e3.29 (4H, m,
CH & CH2), 4.09 (2H, q, J¼7.2 Hz, OCH2), 4.37 (1H, br, ]CH); 13C
References and notes
1. (a) Greenhill, J. V. Chem. Soc. Rev. 1977, 6, 277; (b) Leu, P.; Greenhill, J. V. Adv.
Heterocycl. Chem. 1996, 67, 207; (c) Stanovnik, B.; Svete, J. Chem. Rev. 2004, 104,
2433; (d) Cheng, Y.; Huang, Z. T.; Wang, M. X. Curr. Org. Chem. 2004, 8, 325.
2. For example: (a) Michael, J. P.; Koning, C. B.; Gravestock, D.; Hosken, G. D.;
Howard, A. S.; Jungmann, C. M.; Krause, R. W. M.; Parsons, A. S.; Pelly, S. C.;
Stanbury, T. V. Pure Appl. Chem. 1999, 71, 979; (b) Munchhof, M. J.; Meyers, A. I. J.
Am. Chem. Soc. 1995, 117, 5399; (c) Hart, D. J.; Kanai, K. J. Am. Chem. Soc. 1983,
105, 1255; (d) Pinnick, H. W.; Chang, Y. H. J. Org. Chem. 1978, 43, 4662; (e) Cook,
G. R.; Beholz, L. G.; Stille, J. R. Tetrahedron Lett. 1994, 35, 1699; (f) Hernandez, A.;
Marcos, M.; Rapoport, H. J. Org. Chem. 1995, 60, 2683; (g) Michael, J. P.;
Gravestock, D. Eur. J. Org. Chem. 1998, 865.
3. (a) Roth, M.; Dubs, P.; Gotschi, E.; Eschenmoser, A. Helv. Chim. Acta 1971, 54,
710; (b) Shiosaki, K. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon: Oxford, 1991; Vol. 2, pp 865e892; (c) Hussaini, S. R.; Moloney,
M. G. Org. Biomol. Chem. 2006, 4, 2600; (d) Michael, J. P.; Koning, C. B.; Hosken,
G. D.; Stanbury, T. V. Tetrahedron 2001, 57, 9635.
4. (a) Tanino, H.; Nakata, T.; Kaneko, T.; Kishi, Y. J. Am. Chem. Soc. 1977, 99, 2818;
(b) Meerholz, C. A.; Gerrans, G. C.; Howard, A. C. Tetrahedron Lett. 1980, 21, 1373;
(c) Brown, F. R.; Ireland, R. E. J. Org. Chem. 1980, 45, 1868; (d) Yoneda, F.; Chu, G.
N.; Ibuka, T. J. Chem. Soc., Chem. Commun. 1984, 597; (e) Gardette, D.; Gramain,
J. C.; Celerier, J. P.; Haviari, G.; Fargeau-Bellassoued, M. C.; Bellec, C.; Blot, J.;
David, O.; Lhommet, G. J. Org. Chem. 1999, 64, 3122; (f) Neto, B. A. D.; Lapis, A. A.
M.; Bernd, A. B.; Russowsky, D. Tetrahedron 2009, 65, 2484.
5. (a) Petersen, J. S.; Fels, G.; Rapoport, H. J. Am. Chem. Soc. 1984, 106, 4539; (b)
Marchand, P.; Bellec, C.; FargeauBellassoued, M. C.; Nezry, C.; Lhommet, G.
Heterocycles 1996, 43, 63; (c) Russowsky, D.; Neto, B. A. D. Tetrahedron Lett.
2004, 45, 1437.
6. Varga, T. R.; Nemes, P.; Mucsi, Z.; Scheiber, P. Tetrahedron Lett. 2007, 48, 1159.
7. (a) Gugelchuk, M. M.; Hart, D. J.; Tsai, Y. M. J. Org. Chem. 1981, 46, 3671; (b)
Michael, J. P.; Hosken, G. D.; Howard, A. S. Tetrahedron 1988, 44, 3025; (c)
Lambert, P. H.; Vaultier, M.; Carrie, R. J. Org. Chem. 1985, 50, 5352; (d) David, O.;
Bellassoued, M. C. F.; Lhommet, G. Tetrahedron Lett. 2002, 43, 3471; (e) Wilson,
C. A.; Bryson, T. A. J. Org. Chem. 1975, 40, 800; (f) Elliott, M. C.; Wordingham, S. V.
Synthesis 2006, 7, 1162.
8. For example: (a) Cheng, Y.; Zhao, M.; Wang, M. X.; Wang, L. B.; Huang, Z. T.
Synth. Commun. 1995, 25, 1339; (b) Michael, J. P.; Koning, C. B.; Malefetse, T. J.;
Yillah, I. Org. Biomol. Chem. 2004, 2, 3510; (c) Fujita, R.; Watanabe, N.;
Tomisawa, H. Chem. Pharm. Bull. 2002, 50, 225; (d) Maruoka, H.; Okabe, F.;
Yamagata, K. J. Heterocycl. Chem. 2008, 15, 1503; (e) Fujita, R.; Hoshino, M.;
Nishiuchi, Y.; Tomisawa, H. Yakugaku Zasshi 2006, 126, 109.
9. (a) Calvet, S.; David, O.; Bacque, C. V.; Bellassoued, M. C. F.; Lhommet, G. Tet-
rahedron 2003, 59, 6333; (b) Vitale, S. C.; Bacque, C. V.; Bellassoued, M. C. F.;
Lhommet, G. J. Org. Chem. 2006, 71, 2071; (c) Kim, J. H.; Shin, H.; Lee, S. J. Org.
Chem. 2012, 77, 1560; (d) Govindh, B.; Diwakar, B. S.; Murthy, Y. L. N. Org.
Commun. 2012, 5, 105.
10. (a) Robins, D. J. Nat. Prod. Rep. 1989, 6, 221; (b) Robins, D. J. Nat. Prod. Rep. 1993,
10, 487; (c) Robins, D. J. Nat. Prod. Rep. 1994, 11, 613; (d) Michael, J. P. Nat. Prod.
Rep. 1997, 14, 619; (e) Liddell, J. R. Nat. Prod. Rep. 1997, 14, 653.
NMR (100 MHz, CDCl3)
d 14.9, 20.2, 22.7, 26.1, 29.3, 33.3, 47.9, 58.1,
59.1, 81.2, 160.8, 169.1. ESI-m/z calcd for [C12H19NO2þH]þ 210.1,
found 210.1. This could be the E form as assigned earlier,6 though
there are small variation in the 1H NMR data.
4.1.25. Synthesis of ethyl 2-((5S, 8aR)-octahydroindolizin-5-yl)ace-
tate (44).6 A mixture of 2 (1 g, 4.8 mmol) and PtO2 (0.1 g) in an-
hydrous ethanol (100 mL) was stirred under hydrogen atmosphere
(70 psi) at room temperature for 4 h. The catalyst was filtered off,
the filtrate was concentrated to give pure 44 (0.95 g, 95%) as a light-
yellow oil. ½a 2D5
ꢂ
ꢀ52.2 (c 1.4, CH2Cl2) [reported ½a D25
ꢀ51.3 (c 1.34,
ꢂ
CH2Cl2)23]; 1H NMR (400 MHz, DMSO-d6)
d 1.24e1.26 (1H, m, CH2),
1.28 (3H, t, J¼7.2 Hz, CH3), 1.30e1.32 (2H, m, CH2), 1.40e1.47 (1H, m,
CH2), 1.66e1.93 (7H, m, CH2), 2.06e2.08 (1H, m, CH2), 2.29 (1H, m,
CH2), 2.48 (1H, m, CH2), 2.70 (1H, dd, J¼14.8, 4.9 Hz, CH2), 3.15 (1H,
td, J¼7.8, 2.1 Hz, CH2), 4.14 (2H, q, J¼7.2 Hz, OCH2); ESI-m/z calcd for
[C12H21NO2þH]þ 212.2, found 212.1.
4.1.26. Synthesis of 2-((5S,8aR)-octahydroindolizin-5-yl)ethanol
(44a). The title compound was prepared according to the known
literature procedure.23 Colourless oil. 1H NMR (400 MHz, CDCl3)
d
1.06e1.10 (2H, m, CH2), 1.18e1.24 (2H, m, CH2), 1.40e1.42 (1H, m,
CH2), 1.54e1.62 (3H, m, CH2), 1.67e1.78 (5H, m, CH2), 1.86e1.89 (1H,
m, CH2), 1.97e1.99 (1H, m, CH), 3.08e3.11 (1H, m, CH), 3.33e3.46
(2H, m, CH2), 4.35 (1H, br, D2O exchangeable, OH).
4.1.27. Synthesis of 2-((5S,8aR)-octahydroindolizin-5-yl)ethyl 4-
methylbenzenesulfonate (44b). The title compound was prepared
according to the known literature procedure.23 Light-yellow sticky.
1H NMR (400 MHz, CDCl3)
d 0.97e1.01 (2H, m, CH2), 1.05e1.12 (1H,
m, CH2), 1.12e1.24 (1H, m, CH2), 1.39e1.42 (1H, m, CH2), 1.50e1.85
(8H, m, CH2), 1.88e1.91 (2H, m, CH2 & CH), 2.42 (3H, s, CH3),
2.89e2.91 (1H, m, CH), 4.05e4.09 (2H, t, CH2), 7.49 (2H, d, J¼8.2 Hz,
AreH), 7.79 (2H, d, J¼8.2 Hz, AreH).
11. Smith, D. C.; Fuchs, P. L. J. Org. Chem. 1995, 60, 2692.
4.1.28. Physical and spectroscopic data for (5R, 8aR)-5-hexyl-octa-
12. Reed, P. E.; Katzenellenbogen, J. Z. J. Org. Chem. 1991, 56, 2624.
13. Kaiser, E. M.; Petty, J. D.; Knutson, P. L. A. Synthesis 1977, 509.
14. (a) Stork, G.; Guthikonda, R. N. Tetrahedron Lett. 1972, 13, 2755; (b) Pichat, L.;
Beaucourt, J. P. Synthesis 1973, 537; (c) Trost, B. M.; Kunz, R. A. J. Org. Chem. 1974,
39, 2648; (d) van den Goorbergh, J. A. M.; van der Gen, A. Tetrahedron Lett. 1980,
21, 3621; (e) Pellicciari, R.; Fringuelli, R.; Ceccherelli, P.; Sisani, E. J. Chem. Soc.,
Chem. Commun. 1979, 959; (f) Bodalski, R.; Pietrusiewicz, K. M.; Monkiewicz, J.;
Koszuk, J. Tetrahedron Lett. 1980, 21, 2287; (g) Ley, S. V.; Woodward, P. R. Tet-
rahedron Lett. 1987, 28, 345; (h) Moorhoff, C. M.; Schneider, D. F. Tetrahedron
Lett. 1987, 28, 559.
hydroindolizine (45).24 The title compound was prepared according
to the known literature procedure.23 yellow oil; ½a D25
ꢂ
ꢀ77.8 (c 0.4,
CH2Cl2) [reported ½a D25
ꢂ
ꢀ77.1 (c 0.34, CH2Cl2),24b
½ ꢂ
a 2D5
ꢀ89.6 (c 1.88,
CH2Cl2)24c]; 1H NMR (400 MHz, DMSO-d6)
d
0.87 (3H, t, J¼7.1 Hz,
CH3), 1.00e1.07 (2H, m, CH2), 1.13e1.24 (11H, m, CH2), 1.50e1.61
(4H, m, CH2), 1.68e1.78 (3H, m, CH2), 1.85 (3H, t, J¼8.5 Hz, CH2),
3.08 (1H, td, J¼8.2, 2.8 Hz, CH); 13C NMR (100 MHz, CDCl3)
d 14.3,
15. Kaur, T. Synlett 2006, 2853.
20.6, 22.8, 24.9, 26.03, 29.9, 30.7, 31.05, 31.2, 32.04, 34.8, 51.7, 64.1,
16. For example: (a) Marcus, J.; van Meurs, P. J.; van den Nieuwendijk, A. M. C. H.;
Porchet, M.; Brussee, J.; van der Gen, A. Tetrahedron 2000, 56, 2491; (b)
Stockman, R. A.; McDermott, P. J.; Newton, A. F.; Magnus, P. Synlett 2010, 559;
(c) Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873.
65.2; ESI-m/z calcd for [C14H27NþH]þ 210.2, found 210.1.
17. Poon, C. Y.; Chiu, P. Tetrahedron Lett. 2004, 45, 2985.
18. Rathke, M. W.; Cowan, P. J. J. Org. Chem. 1985, 50, 2622.
19. Shen, Q.; Huang, W.; Wang, J.; Zhou, X. Org. Lett. 2007, 9, 4491.
20. CCDC number 880531.
Acknowledgements
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Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2012.11.029.