Strategy for the assembly of chiral bicyclic lactams: A concise synthetic route to (-)-coniceine

Article abstract of DOI:10.1055/s-2008-1067204

A concise asymmetric synthesis of chiral bicyclic lactams combining a highly stereoselective 1,2-addition on SAMP hydrazones with a ring closure metathesis has been achieved. The synthetic utility of this approach has been emphasized by the total synthesis of (-)-coniceine in high enantiomeric excess. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067204

PAPER
2771
Strategy for the Assembly of Chiral Bicyclic Lactams: A Concise Synthetic
Route to (–)-Coniceine
Synthesisof (–
t
)-Coni
é
c
eine phane Lebrun,a,b Axel Couture,*a,b Eric Deniau,a,b Pierre Grandclaudona,b
a
Université des Sciences et Technologies de Lille 1, LCOP, Bâtiment C3(2), 59655 Villeneuve d'Ascq, France
CNRS, UMR 8009 ‘Chimie Organique et Macromoléculaire’, 59655 Villeneuve d’Ascq, France
Fax +33(3)20336309; E-mail: axel.couture@univ-lille1.fr
b
Received 23 April 2008
also developed, such as the concomitant reduction/cy-
clization sequence applied to proline and biocatalytically
enantioenriched piperidine derived esters 95i and 10,5j re-
spectively (path f) and the annulation of the polyenic com-
pounds, 11,5k 12,5l and 135m relying on the ring-closing
metathesis (RCM) reaction as the ultimate step (path g).
Abstract: A concise asymmetric synthesis of chiral bicyclic lac-
tams combining a highly stereoselective 1,2-addition on SAMP hy-
drazones with a ring closure metathesis has been achieved. The
synthetic utility of this approach has been emphasized by the total
synthesis of (–)-coniceine in high enantiomeric excess.
Key words: alkaloids, lactams, metathesis, ring closure, stereo-
selectivity
O
S
n( )
Tol
*
N
( )q
In the past decade, a whole range of biologically active in-
dolizidine and quinolizidine alkaloids have been isolated
from the skin secretions of neotropical amphibians1 and
these lipophilic skin alkaloids have caught the attention of
the medical world due to their potential biological activi-
ties.2 d-Coniceine (1a) is a very representative member of
this class of bicyclic compounds having a nitrogen-atom
ring juncture.3 However, it is not considered as a true al-
kaloid (i.e., not naturally occurring), but has been shown
to derive from the poison hemlock alkaloid coniine by
chemical transformation. Despite the fact that d-coniceine
is the structurally simplest indolizidine alkaloid, it has at-
tracted great attention from the synthetic chemists since
its elaboration serves as a testing ground for new synthetic
methodology and provides foundation for extension to
more complex and functionalized systems. Consequently,
this has resulted in several successful approaches to the
compound in both racemic4 and optically active forms.5,6
The asymmetric syntheses of this indolizidine alkaloid
that have appeared in print can be cursorily classified into
two main categories. The first one hinges upon the reduc-
tion of the carbonyl function of the fused chiral six and
five-membered lactams 2 and 3, and the main synthetic
approaches to these lactamic systems are portrayed in
Scheme 1. Thus, compound 2 was obtained by reduction
of the chiral sulfinylenamide 45a,b (path a) and by an asym-
metric Heck reaction of an iodoalkenyl unsaturated pip-
eridone 55c,d (path b). The five-membered analogue 3 was
obtained by reduction of the tosyl group of diastereopure
65e (path c), by chemical manipulation of N-a or -g-hy-
droxyalkylated lactams 75f,g (path d) and by a double re-
duction/cyclization sequence applied to the chiral
enaminone 85h (path e). Convergent strategies leading in-
differently to the parent compounds 2 and 3 have been
X
N
O
4
( )p
Y
O
11 X = H2, Y = O, p = 0, q = 1
12 X = H2, Y = O, p = 1, q = 0
13 X = O, Y = H2, p = 0, q = 1
(a)
N
I
5
(g)
(b)
O
CO2Me
H
N
Ts
( )n
(f)
O
m( )
N
( )n
*
(c)
( )p
*
N
Z
2 m = 2, n = 1
3 m = 1, n = 2
6
9 n = 1, p = 1
10 n = 2, p = 0
(e)
(d)
O
H
O
N
OH
*
( )2
EtO2C
N
H
7
8
N
*
1a
( )p
O
(k)
O
(h)
OH
( )3
*
N
H
( )m
n( )
(i)
14
(j)
N
Br
( )2
Ph
OH
( )m
MsO
*
N
( )n
*
18 m = p = 1, n = 2
19 m = 2, n = p = 1
N
Boc
PG
15
16 PG = Boc, m = 1, n = 4
17 PG = Cbz, m = 2, n = 3
SYNTHESIS 2008, No. 17, pp 2771–2775
x
x.
x
x
.
2
0
0
8
Advanced online publication: 24.07.2008
DOI: 10.1055/s-2008-1067204; Art ID: Z09308SS
Scheme 1 Synthetic approaches to indolizidine
© Georg Thieme Verlag Stuttgart · New York

2772
S. Lebrun et al.
PAPER
MeO
The second conceptual approach to 1a disclosed in
Scheme 1 is based upon the preliminary elaboration of a
pyrrolidine or piperidine derivative equipped with an ap-
propriate functionality to secure the subsequent assembly
of the bicyclic framework.6 In this context the final cre-
ation of the newly formed heterocycle was usually en-
sured by an intramolecular N-alkylation reaction
involving an halide deriving from the amino alcohol 146a
(path h), an alkenyl halide 15 obtained by asymmetric
deprotonation of a protected pyrrolidine6b (path i), and fi-
nally structurally different mesylates 166c and 176d (path
j). The fused alkaloid was also accessed by an intramolec-
ular reductive aminocyclization involving deprotected
amino acetals 186e and 196f (path k).
OMe
23
N
NH2
N
O
N
CH2Cl2, MgSO4
BnO
BnO
( )n
( )n
H
H
22a n = 1
22b n = 2
21a n = 1 (85%)
21b n = 2 (88%)
1.
Li
PCy3
Cl
Ph
MeO
O
Ru
–78 °C then r.t.
Cl
PCy3
2.
COCl
CH2Cl2
reflux, 5 h
N
N
–78 °C then r.t.
Since pyrrolidine and piperidine are salient and ubiqui-
tous structural features of a wide array of natural products,
most of the synthetic approaches disclosed in Scheme 1
rely on the development of functionalized precursors de-
riving from the natural chiral pool (e.g., proline, serine,
pyroglutamic acid, pyroglutaminol, and phenylglycinol).
Consequently synthetic routes involving tailor-made ste-
reocontroling agents (e.g., oxazolidine, chiral sulfinyl
group, biocatalytically generated amino alcohols) are
rather scant.
BnO
( )n
20a n = 1 (49%)
20b n = 2 (55%)
MeO
O
MeO
N
1. H2, Pd/C (5%)
EtOH , r.t. , 12 h
2. TsCl, Et3N
r.t. , 5 h
O
N
N
N
TsO
BnO
We wish to report in this paper a concise and conceptually
different asymmetric synthetic approach to the represen-
tative alkaloid d-coniceine (1a), which hinges upon the in-
stallation of the mandatory stereogenic centre and the
assembly of the piperidine template at the very early stage
of the synthesis. This approach combines a ring-closing
metathesis with the highly diastereoselective nucleophilic
1,2-addition of an allyllithiated species on a chiral SAMP
hydrazone preequipped with a suitably substituted ap-
pendage liable to secure the ultimate formation of the
fused model.
( )n
( )n
24a n = 1 (83%)
24b n = 2 (78%)
25a n = 1 (77%)
25b n = 2 (72%)
O
NaH, THF, 20 °C
then reflux, 2 h
MMPP, MeOH
r.t., 24 h
HN
TsO
( )n
26a n = 1 (79%)
26b n = 2 (75%)
The first facet of the synthesis depicted in Scheme 2 was
the elaboration of the diolefinic hydrazide 20a. The syn-
thesis started with the preparation of hydrazone 21a,
which was readily accessible by simply mixing the pro-
tected hydroxycarboxaldehyde 22a with the enantiomeri-
cally pure hydrazine, (S)-(–)-1-amino-2-(methoxy-
methyl)pyrrolidine (SAMP, 23). Owing to the efficiency
and to the high level of diastereoselection observed upon
reaction of SAMP hydrazones with organometallic
reagents7 the assembly of the diolefinic hydrazide 20a
was performed as a single one-pot reaction. Thus chiral
hydrazone 21a was submitted to addition reaction with
allyllithium8 and the lithium hydrazide salt was intercept-
ed with acryloyl chloride to afford the requisite dienehy-
drazide 20a. This polyenic compound, candidate for the
planned RCM reaction was obtained essentially as a sin-
gle diastereomer detectable by NMR spectroscopy (de ≥
95% after chromatographic treatment) then confirming
the remarkable stereoselectivity associated with the dias-
tereofacial 1,2-addition process7 allowing the introduc-
tion of the absolute stereochemistry early in the sequence.
This bis-olefin 20a was then subjected to a ring-closure
metathesis which ranks high in the hierarchy of synthetic
O
LiAlH4, THF
reflux, 3 h
N
N
( )n
( )n
2a n = 1 (86%)
2b n = 2 (80%)
(–)-coniceine (1a) n = 1 (91%)
1b n = 2 (85%)
Scheme 2
tactics for the elaboration of nitrogen containing ring sys-
tems.9 Gratifyingly this technique delivered a very satis-
factory yield of the virtually diastereochemically pure
cyclic enehydrazide (S,S)-24a.
Interestingly, the double bond of 24a can be regarded as a
chemical handle for alternative functionalizations and
henceforth 24a represents a potentially useful synthetic
intermediate for the synthesis of piperidine alkaloids and
functionalized related congeners. Catalytic hydrogenation
of the olefinic double bond of 24a was accomplished with
the concomitant release of the benzyl protection of the hy-
droxyalkyl appendage and conversion into the tosylate
(R,S)-25a could be efficiently achieved in the sequel (77%
Synthesis 2008, No. 17, 2771–2775 © Thieme Stuttgart · New York

PAPER
Synthesis of (–)-Coniceine
2773
umn chromatography (EtOAc–PE, 30:70) to afford hydrazone 21a
(29.6 g, 85%) or 21b (32.1 g, 88%) as a colorless oil.
over two steps). Treatment of (R,S)-25a with magnesium
monoperoxyphthalate (MMPP)10 triggered off the forma-
tion of the NH-free piperidone (R)-26a with the release of
the chiral appendage. This operation delivered very satis-
factory yield of the virtually enantiopure 6-alkylpiperidin-
2-one (R)-26a and set up the system for cyclization. The
subsequent deprotonation/annulation sequence proceeded
uneventfully to afford the fused lactam 2a with an excel-
lent yield. The absolute configuration as well as the enan-
tiopurity of (R)-2a was determined by comparing the sign
and optical rotation value with that of an authentic sample
assembled by a conceptually different synthetic route.5k
Interestingly the viability and versatility of the process
was emphasized by the synthesis of the homologue of the
series, that is, the octahydroquinolizinone (S)-2b11
(Scheme 2). This compound was obtained by the same re-
action sequence applied to the cyclic enehydrazide (S)-
24b readily assembled from the protected hydroxycarbox-
aldehyde 22b, via 21b and 20b. Compound (S)-2b was
obtained in high yield and excellent enantioselectivity by
this process. Finally reduction of 2a with lithium alumi-
num hydride5e in diethyl ether at 25 °C for two hours pro-
vided 85% yield of (R)-1a. The absolute configuration
was confirmed to be R and enantiopurity of our synthetic
(R)-(–)-coniceine [(R)-1a] was clearly established from
the optical rotation and spectroscopic data that matched
with those reported for the natural product.12 Incidentally
reduction of chiral bicyclic lactam 2b gave access to the
optically inactive quinolizidine (1b) in high yield.4e
(S)-4-Benzyloxybutylidene-2-methoxymethylpyrrolidin-1-yl-
amine [(S)-(21a)]
[a]D25 –84.0 (c 3.80, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.79–1.88 (m, 6 H), 2.22–2.29 (m,
2 H), 2.58–2.66 (m, 1 H), 3.26–3.57 (m, 9 H), 4.46 (s, OCH2Ph, 2
H), 6.61 (t, J = 5.6 Hz, 1 H, CH=N), 7.19–7.32 (m, 5 Harom).
13C NMR (75 MHz, CDCl3): d = 22.1, 26.7, 27.8, 29.8, 50.2, 59.1,
63.4, 69.7, 72.8, 74.7, 127.4, 127.5, 128.3, 138.0, 138.6.
Anal. Calcd for C17H26N2O2: C, 70.31; H, 9.02; N, 9.65. Found: C,
70.06; H, 9.24; N, 9.41.
(S)-5-Benzyloxypentylidene-2-methoxymethylpyrrolidin-1-yl-
amine [(S)-(21b)]
[a]D25 –81.3 (c 2.10, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.53–1.96 (m, 8 H), 2.19–2.24 (m,
2 H), 2.65–2.73 (m, 1 H), 3.36–3.59 (m, 9 H), 4.49 (s, 2 H,
OCH2Ph), 6.63 (t, J = 5.5 Hz, 1 H, CH=N), 7.21–7.35 (m, 5 Harom).
13C NMR (75 MHz, CDCl3): d = 22.1, 24.5, 26.6, 29.3, 32.9, 50.4,
59.2, 63.5, 70.2, 72.8, 74.8, 127.5, 127.6, 128.3, 138.6, 138.8.
Anal. Calcd for C18H28N2O2: C, 71.02; H, 9.27; N, 9.20. Found: C,
70.83; H, 9.50; N, 8.98.
Dienehydrazides 20a,b; General Procedure
PhLi (1.8 M in dibutyl ether, 2.22 mL, 4 mmol) was added dropwise
to a solution of allyltriphenyltin (1.56 g, 4 mmol) in Et2O (15 mL).
After stirring at r.t. for 30 min, the suspension was cooled at –78 °C
and a solution of hydrazone (S)-21a or (S)-21b (4 mmol) in Et2O (5
mL) was added dropwise by syringe. The mixture was stirred at
–78 °C for 30 min, then allowed to warm to r.t., and stirred for an
additional 12 h. The mixture was then recooled to –78 °C and acry-
loyl chloride (6 mmol, 545 mg) was added dropwise. After stirring
at this temperature for 30 min, the mixture was allowed to warm to
r.t. over 3 h. H2O (15 mL) was added dropwise, the mixture was fil-
tered, and extracted with CH2Cl2 (3 × 30 mL). The combined organ-
ic extracts were dried (MgSO4), the solvent was removed under
vacuum, and the product purified by flash column chromatography
(EtOAc–PE, 30:70) to afford dienehydrazide 20a (0.38 g, 49%) or
20b (0.44 g, 55%) as a yellow oil.
In summary a simple procedure has been devised for the
assembly of chiral piperidones with a functionalized ap-
pendage at C2 in high enantiopurity. Additionally, a route
to bicyclic lactams has been achieved and the synthetic
utility of these compounds has been further enhanced by
the total synthesis of (–)-coniceine (1a).
Melting points were determined on a Reichert-Thermopan appara-
tus and are uncorrected. 1H and 13C NMR spectra were recorded on
a Bruker AM 300 spectrometer. Optical rotations were measured on
a Perkin-Elmer P 241 polarimeter. Elemental analyses were ob-
tained using a Carlo-Erba CHNS-11110 equipment. The silica gel
used for flash column chromatography was Merck Kieselgel of
0.040–0.063 mm particle size. Petroleum ether (PE, boiling range,
40–60 °C), EtOAc, acetone, and MeOH were used as eluents. Dry
glassware was obtained by oven-drying and assembled under argon.
Argon was used as the inert atmosphere and was passed through a
drying tube to remove moisture. The glassware was equipped with
rubber septa and reagent transfer was performed by syringe tech-
niques. THF and Et2O were distilled from sodium benzophenone
ketyl immediately before use. MeOH and EtOH were distilled from
Mg turnings and CH2Cl2 from CaH2, before storage on 4 Å molec-
ular sieves. The aldehydes 22a13 and 22b14 were prepared according
to reported procedures.
(S,S)-N-[1-(3-Benzyloxypropyl)but-3-enyl]-N-(2-methoxymeth-
ylpyrrolidin-1-yl)acrylamide [(S,S)-(20a)]
[a]D25 –13.1 (c 1.66, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.51–1.89 (m, 7 H), 2.12–2.18 (m,
1 H), 2.63–2.85 (m, 3 H), 3.06–3.31 (m, 8 H), 3.48 (t, J = 6.5 Hz, 2
HSAMP), 4.49 (s, 2 H, OCH2Ph), 4.96–5.13 (m, 2 Hvinyl), 5.55 (dd,
J = 2.2, 10.4 Hz, 1 Hvinyl), 5.68–5.81 (m, 1 Hvinyl), 6.28 (dd, J = 2.2,
17.2 Hz, 1 Hvinyl), 7.06 (dd, J = 10.4, 17.2 Hz, 1 Hvinyl), 7.25–7.36
(m, 5 Harom).
13C NMR (75 MHz, CDCl3): d = 21.2, 26.3, 27.7, 30.3, 37.1, 51.9,
56.6, 58.5, 58.9, 70.3, 72.9, 73.7, 117.1, 126.2, 127.5, 127.6, 128.3,
129.3, 136.0, 137.2, 169.3.
Anal. Calcd for C23H34N2O3: C, 71.47; H, 8.87; N, 7.25. Found: C,
71.33; H, 9.01; N, 7.09.
Hydrazones 21a,b; General Procedure
(S,S)-N-(1-Allyl-5-benzyloxypentyl)-N-(2-methoxymethylpyr-
rolidin-1-yl)acrylamide [(S,S)-(20b)]
(S)-1-Amino-2-methoxymethylpyrrolidine (SAMP, 15.6 g, 0.12
mol) and MgSO4 (500 mg) were added to a solution of the aldehyde
22a or 22b (0.1 mol) in CH2Cl2 (60 mL) and the mixture was stirred
at r.t. for 12 h. MgSO4 was filtered off and the solvent was evapo-
rated under vacuum. The crude residue was purified by flash col-
[a]D25 –18.3 (c 1.22, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.33–1.48 (m, 2 H), 1.55–1.94 (m,
7 H), 2.15–2.28 (m, 1 H), 2.58–2.94 (m, 3 H), 3.02–3.33 (m, 8 H),
3.47 (t, J = 6.7 Hz, 2 HSAMP), 4.49 (s, 2 H, OCH2Ph), 4.94–5.09 (m,
Synthesis 2008, No. 17, 2771–2775 © Thieme Stuttgart · New York

2774
S. Lebrun et al.
PAPER
2 Hvinyl), 5.56 (dd, J = 2.2, 10.4 Hz, 1 Hvinyl), 5.65–5.82 (m, 1 Hvinyl),
6.28 (dd, J = 2.3, 17.3 Hz, 1 Hvinyl), 7.07 (dd, J = 10.4, 17.3 Hz, 1
(R,S)-Toluene-4-sulfonic Acid 3-[1-(2-Methoxymethyl)pyrroli-
din-1-yl]-6-oxopiperidin-2-yl]propyl Ester [(R,S)-25a]
[a]D25 –10.3 (c 0.58, CHCl3).
Hvinyl), 7.25–7.32 (m, 5 Harom).
13C NMR (75 MHz, CDCl3): d = 21.3, 24.3, 26.5, 29.7, 33.4, 37.1,
51.9, 56.8, 58.5, 59.0, 70.3, 72.9, 73.7, 117.0, 126.2, 127.5, 127.6,
128.3, 129.3, 136.1, 138.5, 169.2.
1H NMR (300 MHz, CDCl3): d = 1.31–1.69 (m, 7 H), 1.75–2.03 (m,
5 H), 2.27 (t, J = 6.2 Hz, 2 H, CH2CO), 2.42 (s, 3 H, CH3), 2.88–
2.96 (m, 1 H), 3.17–3.25 (m, 5 H), 3.42–3.50 (m, 2 H), 3.74–3.81
(m, 1 H), 3.92–4.05 (m, 2 H), 7.32 (d, J = 8.1 Hz, 2 Harom), 7.75 (d,
J = 8.1 Hz, 2 Harom).
13C NMR (75 MHz, CDCl3): d = 17.5, 21.6, 23.0, 25.6, 27.2, 27.4,
29.1, 34.0, 53.1, 58.7, 59.7, 62.1, 70.5, 76.7, 127.8, 129.9, 133.0,
144.8, 169.0.
Anal. Calcd for C24H36N2O3: C, 71.96; H, 9.06; N, 6.99. Found: C,
72.22; H, 9.01; N, 6.78.
Enehydrazides 24a,b; General Procedure
A solution of the dienehydrazide 20a or 20b (1 mmol) and the first-
generation Grubbs catalyst (0.05 mmol, 5 mol%) in anhyd CH2Cl2
(10 mL) was stirred at r.t. for 24 h under argon. The mixture was
concentrated and the resulting residue was purified by column chro-
matography (EtOAc–PE, 50:50) to give the enehydrazide 24a (0.30
g, 83%) or 24b (0.29 g, 78%) as a yellow oil.
Anal. Calcd for C21H32N2O5S: C, 59.41; H, 7.60; N, 6.60. Found: C,
59.25; H, 7.88; N, 6.50.
(S,S)-Toluene-4-sulfonic Acid 4-[1-(2-Methoxymethyl)pyrroli-
din-1-yl]-6-oxopiperidin-2-yl]butyl Ester [(S,S)-25b]
[a]D25 –8.7 (c 0.80, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.18–1.42 (m, 5 H), 1.53–2.02 (m,
9 H), 2.25 (t, J = 6.1 Hz, 2 H, CH2CO), 2.43 (s, 3 H, CH3), 2.94–
3.01 (m, 1 H), 3.20–3.28 (m, 5 H), 3.37–3.49 (m, 2 H), 3.73–3.83
(m, 1 H), 4.00 (t, J = 6.3 Hz, 2 H, CH2OTs), 7.31 (d, J = 8.0 Hz, 2
Harom), 7.74 (d, J = 8.0 Hz, 2 Harom).
(S,S)-6-(3-Benzyloxypropyl)-1-(2-methoxymethylpyrrolidin-1-
yl)-5,6-dihydro-1H-pyridin-2-one [(S,S)-24a]
[a]D25 –24.2 (c 0.62, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.42–1.83 (m, 6 H), 1.96–2.05 (m,
2 H), 2.24 (ddd, J = 1.9, 5.8, 17.9 Hz, 1 H, CH2C=), 2.66 (ddt,
J = 2.7, 7.3, 17.9 Hz, 1 H, CH2C=), 3.10–3.19 (m, 1 H), 3.27–3.34
(m, 5 H), 3.45 (t, J = 6.4 Hz, 2 HSAMP), 3.61–3.69 (m, 2 H), 3.73–
3.81 (m, 1 H), 4.46 (s, 2 H, OCH2Ph), 5.77 (dd, J = 2.6, 9.7 Hz, 1 H,
CH=), 6.27–6.34 (m, 1 H, CH=), 7.23–7.35 (m, 5 Harom).
13C NMR (75 MHz, CDCl3): d = 17.2, 21.9, 23.0, 26.9, 27.4, 28.8,
32.2, 32.4, 34.0, 53.1, 58.7, 59.7, 62.5, 70.4, 76.7, 127.8, 129.8,
133.0, 144.8, 169.0.
13C NMR (75 MHz, CDCl3): d = 26.5, 26.8, 27.3, 28.0, 29.0, 52.8,
58.9, 60.5, 61.8, 70.2, 72.9, 76.4, 126.1, 127.5, 127.6, 128.3, 136.8,
138.4, 162.7.
Anal. Calcd for C22H34N2O5S: C, 60.25; H, 7.81; N, 6.39. Found: C,
60.17; H, 8.09; N, 6.62.
Piperidin-2-ones (R)-26a and (S)-26b; General Procedure
Magnesium monoperoxyphtalate (MMPP·6H2O 3.75 mmol, 1.86 g)
was added to a solution of hydrazide 25a or 25b (1.5 mmol) in
MeOH (20 mL). The mixture was stirred at r.t. until no starting ma-
terial remained (TLC monitoring; silica gel Merck GF 254; EtOAc).
The mixture was then poured into CH2Cl2 (40 mL) and the organic
layer was washed with aq sat. NaHCO3 (40 mL). The aqueous layer
was separated and extracted with CH2Cl2 (3 × 30 mL). The com-
bined organic extracts were washed successively with H2O (10
mL), brine (10 mL), and dried (MgSO4). Evaporation of the solvent
furnished an oily product, which was purified by flash column chro-
matography using EtOAc as eluent to afford 26a (0.37 g, 79%) or
26b (0.36 g, 75%).
Anal. Calcd for C21H30N2O3: C, 70.36; H, 8.44; N, 7.81. Found: C,
70.27; H, 8.67; N, 8.06.
(S,S)-6-(3-Benzyloxybutyl)-1-(2-methoxymethylpyrrolidin-1-
yl)-5,6-dihydro-1H-pyridin-2-one [(S,S)-24b]
[a]D25 –29.3 (c 0.50, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.34–1.87 (m, 8 H), 1.95–2.04 (m,
2 H), 2.26 (ddd, J = 1.9, 6.0, 18.0 Hz, 1 H, CH2C=), 2.67 (ddt,
J = 2.8, 7.5, 18.0 Hz, 1 H, CH2C=), 3.11–3.19 (m, 1 H), 3.32–3.38
(m, 5 H), 3.46 (t, J = 6.3 Hz, 2 HSAMP), 3.60–3.69 (m, 2 H), 3.74–
3.85 (m, 1 H), 4.49 (s, 2 H, OCH2Ph), 5.78 (dd, J = 2.6, 9.8 Hz, 1 H,
CH=), 6.28–6.35 (m, 1 H, CH=), 7.23–7.34 (m, 5 Harom).
13C NMR (75 MHz, CDCl3): d = 22.9, 23.1, 27.2, 27.9, 29.8, 32.0,
52.8, 58.9, 60.6, 61.9, 70.1, 72.9, 76.3, 126.1, 127.5, 127.6, 128.3,
136.8, 138.5, 162.7.
(R)-Toluene-4-sulfonic Acid 3-(6-Oxopiperidin-2-yl)propyl
Ester [(R)-26a]
White solid; mp 73–74 °C; [a]D25 –13.6 (c 0.48, CHCl3).
Anal. Calcd for C22H32N2O3: C, 70.94; H, 8.66; N, 7.52. Found: C,
70.71; H, 8.95; N, 7.40.
1H NMR (300 MHz, CDCl3): d = 1.33–1.48 (m, 2 H), 1.53–1.65 (m,
4 H), 1.74–1.88 (m, 2 H), 2.12–2.35 (m, 2 H), 2.44 (s, 3 H, CH3),
3.25–3.31 (m, 1 H), 4.01 (t, J = 6.2 Hz, 2 H, CH2OTs), 6.88 (br s, 1
H, NH), 7.33 (d, J = 8.2 Hz, 2 Harom), 7.76 (d, J = 8.2 Hz, 2 Harom).
13C NMR (75 MHz, CDCl3): d = 19.8, 21.6, 24.7, 27.8, 31.2, 32.6,
52.3, 70.1, 127.9, 129.9, 132.8, 144.9, 172.9.
Hydrazides (R,S)-25a and (S,S)-25b; General Procedure
A solution of enehydrazide 24a or 24b (1.5 mmol) in EtOH (20 mL)
was stirred with activated Pd/C (10%, 15 mg) at r.t. under an atmo-
sphere of H2 for 12 h at which time TLC indicated complete con-
sumption of starting material. The mixture was filtered on a pad of
Celite that was further eluted with EtOH (40 mL), and then CH2Cl2
(40 mL). The filtrate was concentrated under vacuum and the result-
ing product was dissolved in anhyd CH2Cl2 (10 mL). The mixture
was cooled to 0 °C and TsCl (1.1 equiv, 1.65 mmol) was added, fol-
lowed by Et3N (1.5 equiv, 2.25 mmol). The mixture was warmed to
r.t. and stirred for 5 h, at which time H2O (10 mL) was added. The
layers were separated and the aqueous layer was extracted with
CH2Cl2 (3 × 20 mL). The combined organic fractions were dried
(MgSO4), filtered, and evaporated to give a crude product, which
was purified by flash column chromatography on silica gel using
EtOAc as eluent to afford hydrazides 25a (0.49 g, 77%) or 25b
(0.47 g, 72%) as a colorless oil.
Anal. Calcd for C15H21NO4S: C, 57.86; H, 6.80; N, 4.50. Found: C,
57.74; H, 6.75; N, 4.43.
(S)-Toluene-4-sulfonic Acid 4-(6-Oxopiperidin-2-yl)butyl Ester
[(S)-26b]
Oil; [a]D25 +8.8 (c 0.34, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.22–1.51 (m, 5 H), 1.58–1.69 (m,
3 H), 1.81–1.88 (m, 2 H), 2.19–2.33 (m, 2 H), 2.43 (s, 3 H, CH3),
3.21–3.32 (m, 1 H), 3.99 (t, J = 6.3 Hz, 2 H, CH2OTs), 6.63 (br s, 1
H, NH), 7.33 (d, J = 8.1 Hz, 2 Harom), 7.76 (d, J = 8.1 Hz, 2 Harom).
13C NMR (75 MHz, CDCl3): d = 19.6, 21.2, 21.6, 28.0, 28.7, 31.3,
36.1, 52.8, 70.2, 127.9, 129.9, 132.5, 144.8, 172.6.
Synthesis 2008, No. 17, 2771–2775 © Thieme Stuttgart · New York

PAPER
Synthesis of (–)-Coniceine
2775
Anal. Calcd for C16H23NO4S: C, 59.05; H, 7.12; N, 4.30. Found: C,
59.22; H, 6.92; N, 4.15.
(5) (a) Hua, D. H.; Bharathi, S. N.; Takusagawa, F.; Tsujimoto,
T.; Panangadan, J. A. K.; Hung, M. H.; Bravo, A. A.;
Erpelding, A. M. J. Org. Chem. 1989, 54, 5659. (b) Hua, D.
H.; Bharathi, S. N.; Panangadan, J. A. K.; Tsujimoto, A.
J. Org. Chem. 1991, 56, 6998. (c) Sato, Y.; Nukui, S.;
Sodeoka, M.; Shibasaki, M. Tetrahedron 1994, 50, 371.
(d) Nukui, S.; Sodeoka, M.; Shibasaki, M. Tetrahedron Lett.
1993, 34, 4965. (e) Costa, A.; Nájera, C.; Sansano, J. M.
Tetrahedron: Asymmetry 2001, 12, 2205. (f) Yoda, H.;
Katoh, H.; Ujihara, Y.; Takabe, K. Tetrahedron Lett. 2001,
42, 2509. (g) Arai, Y.; Kontani, T.; Koizumi, T. Chem. Lett.
1991, 2135. (h) Waldmann, H.; Braun, M. J. Org. Chem.
1992, 57, 4444. (i) Davies, S. B.; McKervey, M. A.
Tetrahedron Lett. 1999, 40, 1229. (j) Sánchez-Sancho, F.;
Herradón, B. Tetrahedron: Asymmetry 1998, 9, 1951.
(k) Park, S. H.; Kang, H. J.; Ko, S.; Park, S.; Chang, S.
Tetrahedron: Asymmetry 2001, 12, 2621. (l) Arisawa, M.;
Takahashi, M.; Takezawa, E.; Yamaguchi, T.; Torisawa, Y.;
Nishida, A.; Nakagawa, M. Chem. Pharm. Bull. 2000, 48,
1593. (m) Michael, D.; Groaning, M. D.; Meyers, A. I.
Chem. Commun. 2000, 1027.
Bicyclic Lactams (R)-2a and (S)-2b; General Procedure
Pentane-prewashed NaH (0.88 mmol, 1.1 equiv, 60% dispersion in
oil) was suspended in anhyd THF (15 mL) and a solution of the to-
sylate 26a or 26b (0.8 mmol) in anhyd THF (3 mL) was added drop-
wise by syringe at –20 °C. The mixture was stirred at r.t. for 30 min
and then refluxed for 2 h. The mixture was cooled in an ice-water
bath and sat. aq NH4Cl (5 mL) was carefully added. The organic
layer was separated and the aqueous layer was extracted with
CH2Cl2 (2 × 20 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated. The crude residue was puri-
fied by column chromatography (acetone–PE, 50:50) to give (R)-
hexahydroindolizin-5-one [(R)-2a];5k yield: 86 mg (86%); [a]D
25
–6.3 (c 0.30, CH2Cl2) {Lit.5k [a]D25 –6.6 (c 0.4, CH2Cl2)} or (S)-oc-
25
tahydroquinolizin-4-one [(S)-2b];11 yield: 89 mg (80%); [a]D
+10.2 (c 0.91, CHCl3).
Bicyclic Lactams (R)-Coniceine (1a) and Quinolizidine (1b);
General Procedure
A solution of lactam 2a or 2b (0.5 mmol) in THF (2 mL) was added
slowly at 0 °C under argon to a suspension of LiAlH4 (0.75 mmol,
1.5 equiv) in anhyd THF (5 mL). The resulting mixture was stirred
under reflux for 3 h. After careful hydrolysis with sat. aq NH4Cl (5
mL), CH2Cl2 (15 mL) was added and the organic layer was separat-
ed. The aqueous layer was extracted with CH2Cl2 (2 × 15 mL). The
combined organic layers were dried (Na2SO4), filtered, and concen-
trated. The crude residue was purified by column chromatography
(EtOAc–MeOH, 50:50) to give (R)-coniceine [(R)-1a];12 yield: 50
(6) (a) Hjelmgaard, T.; Gardette, D.; Tanner, D.; Aitken, D. J.
Tetrahedron: Asymmetry 2007, 18, 671. (b) Dieter, R. K.;
Chen, N.; Watson, R. T. Tetrahedron 2005, 61, 3221.
(c) Sibi, M. P.; Christensen, J. W. J. Org. Chem. 1999, 64,
6434. (d) Takahata, H.; Kubota, M.; Takahashi, S.; Momose,
T. Tetrahedron: Asymmetry 1996, 7, 3047. (e) Andrés, J.
M.; Herráiz-Sierra, I.; Pedrosa, R.; Pérez-Encabo, A. Eur. J.
Org. Chem. 2000, 1719. (f) Michael, J.; Munchhof, M. J.;
Meyers, A. I. J. Org. Chem. 1995, 60, 7084.
25
23
mg (91%); [a]D –9.8 (c 1.10, EtOH) {Lit.12 [a]D –10.2 (c 1.76,
(7) Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D.
Tetrahedron 2002, 58, 2253.
EtOH)} or quinolizidine (1b);4e yield: 53 mg (85%).
(8) Tamaru, Y.; Harada, T.; Nishi, S.; Yoshida, Z. Tetrahedron
Lett. 1982, 23, 2383.
References
(9) (a) Pandit, U. K.; Overkleeft, H. S.; Borer, B. C.; Bieräugel,
H. Eur. J. Org. Chem. 1999, 959. (b) Felpin, F.-X.;
Lebreton, J. Eur. J. Org. Chem. 2003, 3693. (c) Dieters, A.;
Martin, S. F. Chem. Rev. 2004, 104, 2199. (d) Lebrun, S.;
Couture, A.; Deniau, E.; Grandclaudon, P. Org. Lett. 2007,
9, 2473.
(10) (a) Fernández, R.; Ferrete, A.; Lassaletta, J. M.; Llera, J. M.;
Monge, A. Angew. Chem. Int. Ed. 2000, 39, 2893.
(b) Fernández, R.; Ferrete, A.; Lassaletta, J. M.; Llera, J. M.;
Martín-Zamora, E. Angew. Chem. Int. Ed. 2002, 41, 831.
(c) Fernández, R.; Ferrete, A.; Llera, J. M.; Magriz, A.;
Martín-Zamora, E.; Díez, E.; Lassaletta, J. M. Chem. Eur. J.
2004, 10, 737.
(1) For reviews on indolizidine alkaloids, see: (a) Franklin, A.
S.; Overman, L. E. Chem. Rev. 1996, 96, 502. (b) Michael,
J. P. Nat. Prod. Rep. 1999, 16, 675. (c) Michael, J. P. Nat.
Prod. Rep. 2005, 22, 603.
(2) (a) Brooke, P.; Harris, D. J.; Longmore, R. B. J. Agric. Food
Chem. 1996, 44, 2129. (b) Daly, J. W. Alkaloids: Chemical
and Biological Perspectives, Vol. 10; Pelletier, S. W., Ed.;
Pergamon: Oxford, 1996, 155–299.
(3) Roberts, M. F.; Brown, R. T. Phytochemistry 1981, 20, 447.
(4) For some recent examples, see: (a) Burnett, D. A.; Choi,
J.-K.; Hart, D. J.; Tsai, Y.-M. J. Am. Chem. Soc. 1984, 106,
8201. (b) Pearson, W. H.; Lin, K.-C. Tetrahedron Lett. 1990,
31, 7571. (c) Martin-Lopez, M. J.; Bermejo-Gonzales, F.
Tetrahedron Lett. 1994, 35, 4235. (d) Jung, M. E.; Choi, Y.
M. J. Org. Chem. 1991, 56, 6729. (e) D’hooghe, M.; De
Kimpe, R. Tetrahedron 2003, 59, 3099.
(11) Lim, S. H.; Ma, S.; Beak, P. J. Org. Chem. 2001, 66, 9056.
(12) Ringdahl, B.; Pinder, A. R.; Pereira, W. E.; Oppenheimer, N.
J.; Craig, J. C. J. Chem. Soc., Perkin Trans. 1 1984, 1.
(13) Crimmins, M. T.; DeBaillie, A. C. J. Am. Chem. Soc. 2006,
128, 4936.
(14) Pihko, P. M.; Aho, J. E. Org. Lett. 2004, 6, 3849.
Synthesis 2008, No. 17, 2771–2775 © Thieme Stuttgart · New York