Alternative synthetic path to (-)-adalinine via a SmI2-promoted fragmentation of a 3-oxopyrrolidine derivative

Article abstract of DOI:10.1016/j.tetlet.2009.05.114

A novel and stereocontrolled synthetic path to a coccinellid alkaloid, (-)-adalinine, was established by employing the reductive carbon-nitrogen bond cleavage reaction and subsequent recyclization of a 3-oxopyrrolidine derivative with samarium diiodide, a

Full text of DOI:10.1016/j.tetlet.2009.05.114

Tetrahedron Letters 50 (2009) 4654–4657
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Alternative synthetic path to (À)-adalinine via a SmI2-promoted
fragmentation of a 3-oxopyrrolidine derivative
*
Toshio Honda , Chihiro Hisa
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41, Shinagawa, Tokyo 142-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and stereocontrolled synthetic path to a coccinellid alkaloid, (À)-adalinine, was established by
employing the reductive carbon–nitrogen bond cleavage reaction and subsequent recyclization of a
3-oxopyrrolidine derivative with samarium diiodide, as key steps, where water was found to be the best
proton source.
Received 7 May 2009
Revised 28 May 2009
Accepted 29 May 2009
Available online 6 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Adalinine
Coccinellid alkaloid
Fragmentation
Samarium diiodide
C–N bond cleavage
(À)-Adalinine 1 was isolated from secretion of the European
two-spotted ladybird beetle, Adalia bipunctata, as a minor piperi-
dine alkaloid having a chiral quaternary carbon center, together
with a major alkaloid, (À)-adaline 2 (Fig. 1).1 This alkaloid 1 has
also been proposed to be biosynthetically derived from adaline 2
via a retro-Mannich reaction.1
First, the fragmentation of 3 was carried out by using SmI2
(5.0 equiv) in THF–HMPA at 0 °C for 15 h; however, only decompo-
sition of the starting material was observed (entry 6). We note in
advance that proton sources play an important role in this frag-
mentation reaction. We therefore decided to find the best proton
source in THF solution by screening, and the results obtained are
summarized in Table 1. In the presence of MeOH as the proton do-
nor in THF–HMPA, the reaction of 3 with SmI2 (5.0 equiv) at 0 °C
for 5 min gave the secondary alcohols 5 as an inseparable diaste-
reoisomeric mixture in 85% yield in a ratio of ca. 1:1 (entry 1). As
can be seen in Table 1, almost all of the proton sources, such as
In 2000, we established
(À)-adalinine, in which a SmI2-promoted regioselective carbon–
nitrogen bond cleavage reaction of the -amino ester derived from
a novel synthetic procedure for
a
pyroglutamic acid followed by recyclization of the fragmentation
product providing the corresponding d-lactam was involved as
the key reactions (Fig. 2).2
During the course of our studies directed toward the total syn-
thesis of bioactive alkaloids employing cyclic amino acids as start-
ing materials,3 we became interested in developing an alternative
method for the stereoselective synthesis of (À)-adalinine.4
We thought that the most straightforward way to achieve this
goal was carbon–nitrogen bond cleavage of a 3-oxopyrrolidine
derivative having a butyric acid moiety at the 5-position and sub-
sequent cyclization of the resulting primary amine with the ester
function, based on the consideration of its retrosynthetic route de-
picted in Figure 3.
O
O
NH
O
N
H
1
2
. (−) - adaline
. (−) - adalinine
Figure 1. Structures of (À)-adalinine and (À)-adaline.
Prior to the synthesis of (À)-adalinine, we attempted to find
optimal reaction conditions for a SmI2-promoted fragmentation
reaction employing a readily accessible 3-oxopyrrolidine deriva-
tive 3 having a quaternary carbon center at the 5-position.5
SmI2
THF-HMPA
R1
R2
R1
R2
R1
R2
CO2Me
NH2
CO2Me proton source
N
H
N
H
O
* Corresponding author. Tel.: +81 3 5498 5791; fax: +81 3 3787 0036.
E-mail address: honda@hoshi.ac.jp (T. Honda).
Figure 2. SmI2-promoted fragmentation of a-amino ester.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.114

T. Honda, C. Hisa / Tetrahedron Letters 50 (2009) 4654–4657
4655
O
O
O
cyclization
SmI2
C5H11
C5H11
N
H
CO2R
O
N
H
H2N
CO2R
(-) - adalinine
1) alkylation
2) elongation
of side chain
1) deprotection P1O
2) oxidation
P1O
C5H11
N
N
CO2R
CO2R
P2
P2
P1, P2 = protecting groups
R = alkyl
Figure 3. Retrosynthetic analysis of (À)-adalinine.
Table 1
Screening of proton sources for Sml2-promoted fragmentation
O
O
HO
SmI2 (5.0 equiv)
THF
C5H11
C5H11
OMOM
C5H11
OMOM
+
N
OMOM
N
Bn
Bn
BnHN
3
4
5
Entry
Additive (equiv)
Time
Temperature
Products (yield)
1
2
3
4
5
6
7
8
9
HMPA (5.0) + MeOH (2.5)
DMEA (10)
MeOH (2.5)
NiI2 (0.05)
Nil2 (0.05) + MeOH (2.5)
HMPA (5.0)
HMPA (5.0) + tert-BuOH (2.5)
tert-BuOH (2.5)
tert-BuOH (2.5)
H2O (2.5)
5 min
10 min
2 h
6 h
4 h
15 h
6 h
15 h
2 h
0 °C
0 °C
0 °C
0 °C–rt
0 °C
0 °C
0 °C
0 °C
Reflux
5 (85%)
5 (75%)
4 (trace), 5 (50%)
5 (25%), 3 (58%)
5 (43%)
Decompose
5 (68%)
5 (10%)
5 (60%)
4 (50%)
10
2 h
0 °C
70% yield from 10. Subsequent oxidation of 11 in two steps via the
corresponding aldehyde provided an acid, which was further trans-
formed to the ester 128 in 39% yield from 11.
N,N-dimethylethanolamine (DMEA), NiI2, tert-BuOH, and the com-
bination of those proton sources, were also found to be ineffective
for this fragmentation (entries 2, 4, 5, and 7–9).
The desired precursor thus obtained was subjected to SmI2-
mediated reductive carbon–nitrogen bond cleavage reaction
exploiting water as the proton donor by two routes (Scheme 2).
First, the N-Boc group of ester 12 was removed by treatment
with ZnBr2 to give the amine 13, which on heating in toluene fur-
nished the lactam 149 in 86% yield from 12. Treatment of 14 with
5.0 equiv of SmI2 in THF in the presence of 2.5 equiv of water at
0 °C for 3 h, however, afforded the reduction product 15 as the ma-
jor product in 61% yield as a mixture of diastereoisomers, together
with 22% of the recovered starting material. On the other hand, a
reductive carbon–nitrogen bond cleavage reaction of the amine
13 with 5.0 equiv of SmI2 in THF in the presence of 2.5 equiv of
water at 0 °C for 30 min generated two products, which, without
separation, were heated at reflux in toluene to give (À)-adalinine
in 16% yield from 12 and the bicyclic compound 15 in 38% yield
from 12.10 The spectroscopic data for the synthesized compound
1 including its specific optical rotation were identical to those re-
When MeOH (2.5 equiv) was employed as the proton source in
THF solution, the desired product 4 was obtained in a trace amount
(<3%) (entry 3). Unfortunately, the yield of 4 could not be improved
under various reaction conditions attempted by the use of MeOH.
We were pleased to find that the choice of water as a proton source
afforded the desired carbon–nitrogen bond cleavage product 4 in
moderate yield (entry 10). Although its pivotal role is still unclear
at present, it has been shown that the use of water as the proton
donor sometimes had a profound impact on various factors, such
as the reaction rate, mechanism, and stereoselectivity of SmI2-
mediated one-electron transfer reactions.6
Given these considerations, we started to prepare a key precur-
sor for a SmI2-promoted carbon–nitrogen bond cleavage reaction
as follows (Scheme 1).
The known ester 67 readily accessible from (4R)-hydroxy-
L-pro-
line was alkylated with n-amyl iodide in the presence of LiHMDS as
the base in THF to give a mixture of diastereomers, which, without
separation, was reduced with DIBAL to give primary alcohols 7 and
8 in 56% and 28% yields, respectively. Oxidation of the major alco-
hol 6 followed by Wittig reaction of the resulting aldehyde with
the phosphonium salt 9 afforded the olefin 10 in 80% yield from
7. After treatment of 10 with TBAF, the resulting olefin was hydro-
genated over platinum oxide to furnish the saturated alcohol 11 in
ported in the literature,4d
[
a]
À24.2 (c 1.50, CH2Cl2), {lit.4d
[a]
D
D
À28.3 (c 1.6, CH2Cl2)}.
The poor yield of the fragmentation product in this reaction
compared to that in a similar reaction for a-amino esters as shown
in Figure 2 was rationalized by assuming that the formation of
samarium-involved five-membered chelation intermediate, which

4656
T. Honda, C. Hisa / Tetrahedron Letters 50 (2009) 4654–4657
1) LiHMDS, Amyl iodide
TBSO
TBSO
TBSO
THF, -20 °C
2) DIBAL, THF, 0 °C
C5H11
OH
OH
CO2Me
N
Boc
+
C5H11
N
Boc
N
Boc
84% from 6
(7:8 = 2:1)
6
7
8
1) SO3-Py, DMSO
DIPEA, CH2Cl2, 0 °C
HO
TBSO
1) TBAF, THF, rt
overnight
C5H11
C5H11
+
2) PtO2, H2, EtOH
rt, overnight
N
N
(CH2)4OH
OTBS
2) Ph3P
OTBS
Boc
Boc
-
Br
9
10
11
n - BuLi, THF, 0 °C
1) PCC, CH2Cl2, rt
2) Pinnick Oxid. rt
O
C5H11
(CH2)3CO2Me
3) MeI, K2CO3
DMF, rt
N
Boc
12
Scheme 1. Preparation of the key precursor 12.
HO
O
O
SmI2, H2O
THF, 0 °C
C5H11
C5H11
toluene, reflux
C5H11
N
N
N
(CH2)3CO2Me
Boc
O
O
14
15
ZnBr2
CH2Cl2
rt
12
13
: R = Boc
: R = H
SmI2, H2O
THF, 0 °C
O
O
toluene
reflux
HO
C5H11
(CH2)3CO2Me
C5H11
+
15
+
O
N
H
C5H11
N
H
H2N
(CH2)3CO2Me
(−) - adalinine: 1
Scheme 2. Synthesis of (À)-adalinine.
might facilitate the fragmentation reaction, seemed to have diffi-
culties due to steric strain observed for a 3-oxopyrrolidine deriva-
tive compared to a-amino esters (Fig. 4).
In summary, we were able to establish an alternative stereose-
lective chiral synthesis of (À)-adalinine 1 by employing reductive
carbon–nitrogen bond cleavage reaction of a 3-oxopyrrolidine
derivative as a key reaction. In this synthesis, we assumed that
the formation of samarium-involved chelation intermediate plays
an important role for the desired fragmentation. It is also notewor-
thy that water was found to be the best proton source in this reac-
tion. This methodology seems to be applicable to various types of
3-oxopyrrolidine and 3-oxopiperidine derivatives, and its applica-
tion is now under investigation in our laboratory.
R2
Acknowledgments
SmI2
R2
OR3
N
OR3
R1
I
N
R1
This research was supported financially in part by a grant for
the Open Research Center Project and a Grant-in-Aid from the Min-
istry of Education, Culture, Sports, Science and Technology of
Japan.
O
O
Sm
I
O
O
SmI2
R3
R2
R3
R2
References and notes
N
N
R1
R1
Sm
1. Lognay, G.; Hemptinne, J. L.; Chan, F. Y.; Gasper, CH.; Marlier, M.; Braekman, J.
C.; Daloze, D.; Pasteels, J. M. J. Nat. Prod. 1996, 59, 510.
2. Honda, T.; Kimura, M. Org. Lett. 2000, 2, 3925.
Figure 4. Assumed chelation intermediates.

T. Honda, C. Hisa / Tetrahedron Letters 50 (2009) 4654–4657
4657
3. (a) Katoh, M.; Matsune, R.; Nagase, H.; Honda, T. Tetrahedron Lett. 2004, 45,
6221; (b) Honda, T.; Takahashi, R.; Namiki, H. J. Org. Chem. 2005, 70, 499; (c)
Katoh, M.; Mizutani, H.; Honda, T. Tetrahedron Lett. 2005, 46, 5161; (d) Katoh,
M.; Hisa, C.; Honda, T. Tetrahedron Lett. 2007, 48, 4692.
28.37, 23.5, 23.3, 22.5, 19.4, 13.9; MS (EI) (m/z): 355 (M+); HRMS m/z calcd for
C19H33NO5 (M+): 355.2344, found: 355.2358.
9. Selected data for 9: colorless solid. Mp 50–52 °C; [
a
]
D À131.1 (c 1.04, CHCl3); IR
(thin film): 2955, 2933, 2860, 1763, 1644, 1456, 1409, 1181, 1149 cmÀ1
;
1H
4. For the synthesis of racemic adalinine, see: (a) Broeders, F.; Braekman, J. C.;
Daloze, D. Bull. Soc. Chim. Belg. 1997, 106, 377; (b) Yamazaki, N.; Ito, T.;
Kibayashi, C. Synlett 1999, 37; (c) Wardrop, D. J.; Landrie, C. L.; Ortiz, J. A. Synlett
2003, 1352; For the synthesis of (À)-adalinine, see: (d) Yamazaki, N.; Ito, T.;
NMR (CDCl3) d 4.34 (d, J = 20.0 Hz, 1H), 3.67 (d, J = 20.0 Hz, 1H), 2.75 (dt, J = 4.4,
18.6 Hz, 1H), 2.67 (d, J = 17.5 Hz, 1H), 2.64 (dd, J = 8.9, 18.7 Hz, 1H), 2.47 (d,
J = 17.6 Hz, 1H), 2.24 (dt, J = 3.4, 13.6 Hz, 1H), 1.89–1.96 (m, 2H), 1.68–1.77 (m,
2H), 1.53–1.60 (m, 1H), 1.14–1.37 (m, 6H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR
(CDCl3) d 208.3, 171.1, 64.2, 51.5, 30.4, 37.5, 31.8, 31.5, 30.4, 24.0, 22.4, 16.5,
13.9; MS (EI) (m/z): 223 (M+); HRMS m/z calcd for C13H21NO2 (M+): 223.1572,
found: 223.1557. Anal Calcd for C13H21NO2: C, 69.92; H, 9.48; N, 6.27. Found: C,
69.79; H, 9.30; N, 6.18.
Kibayashi, C. Tetrahedron Lett. 1999, 40, 739; For
a recent review of the
coccinellied alkaloids, see: (e) King, A. G.; Meinwald, J. Chem. Rev. 1996, 96,
1105.
5. Compound
3
was
prepared
from
methyl
N-benzyl-(4R)-tert-
butyldimethylsilyloxyprolinate by alkylation with amyl iodide in the
presence of LiHMDS and subsequent LiAlH4 reduction.
10. Typical experimental procedure for a SmI2-promoted fragmentation reaction: To a
stirred solution of 12 (200.0 mg, 0.56 mmol) in CH2Cl2 (6.00 mL) was added
ZnBr2 (254 mg, 1.12 mmol) at room temperature, and the resulting mixture
was stirred overnight. After removal of the insoluble materials by filtration, the
filtrate was treated with aqueous NaHCO3, and extracted with CHCl3. The
extract was concentrated, and the residue was dissolved in THF (6.0 mL). To
this solution were added SmI2 (0.2 M in THF, 14.0 mL, 2.8 mmol) and H2O
6. (a) Hasegawa, E.; Ishiyama, K.; Fujita, T.; Kato, T.; Abe, T. J. Org. Chem. 1997, 62,
2396; (b) Keck, G. E.; Wager, C. A.; Sell, T.; Wager, T. T. J. Org. Chem. 1999, 64,
2172; (c) Dahlën, A.; Hilmersson, G. Chem. Eur. J. 2003, 9, 1123; (d) Chopade, P.
R.; Prasad, E.; Flowers, R. A. J. Am. Chem. Soc. 2004, 126, 44; (e) Farran, H.;
Shmaryahu Hoz, S. J. Org. Chem. 2009, 74, 2075; (f) Ankner, T.; Hilmersson, G.
Org. Lett. 2009, 11, 1865.
(25 lL, 1.4 mmol) at 0 °C, and the whole mixture was stirred for a further
7. Enders, D.; Kirchhoff, J. H.; Koebberling, J.; Peiffer, T. H. Org. Lett. 2001, 3, 1241.
30 min at the same temperature. The mixture was treated with aqueous
NaHCO3 and Et2O, and the whole mixture was filtered through a pad of Celite
to remove insoluble materials. The filtrate was extracted with Et2O, and the
ethereal solution was dried over Na2SO4. Evaporation of the solvent gave a
residue, which was dissolved in toluene. After heating the toluene solution at
reflux for 10 min, the solvent was removed to leave a residue, which was
purified by column chromatography on silica gel to afford (À)-adalinine 1 and
alcohols 15.
8. Selected data for 8: colorless oil. [
2930, 2860, 1763, 1740, 1703, 1455, 1439, 1393, 1367, 1256, 1170, 1138, 1107,
994, 873 cmÀ1 1H NMR (CDCl3) d 3.89 (s, 1H), 3.82 (s, 1H), 3.67 (s, 3H), 2.70–
a]D À4.32 (c 1.02, CHCl3); IR (thin film): 2956,
;
2.47 (m, 2H), 2.27–2.43 (m, 2H), 2.17–2.26 (m, 1H), 2.05 (br s, 1H), 1.56–1.89
(m, 4H), 1.48 (d, J = 19.5 Hz, 9H), 1.08–1.37 (m, 8H), 0.84–0.92 (m, 3H); 13C
NMR (CDCl3) d 210.3, 209.5, 173.7, 173.4, 154.2, 153.1, 80.7, 79.8, 64.8, 64.3,
56.6, 56.5, 51.5, 48.0, 47.2, 39.7, 39.2, 38.3, 37.8, 33.9, 33.8, 32.0, 31.8, 28.44,