A new synthetic method for an indolizidine skeleton by C-N bond formation via a π-allylpalladium complex

Article abstract of DOI:10.1248/cpb.52.1082

Pd(0)-catalyzed intramolecular cyclic reaction via a π-allylpalladium complex provided an indolizidine skeleton in satisfactory high and reproducible yields by using allylic compound having an acetoxyl group as a leaving group. These results must be available for syntheses of various functional indolizidine alkaloids.

Full text of DOI:10.1248/cpb.52.1082

1082
Chem. Pharm. Bull. 52(9) 1082—1085 (2004)
Vol. 52, No. 9
A New Synthetic Method for an Indolizidine Skeleton by C–N Bond
p
Formation via a -Allylpalladium Complex
Yaeko YAMADA,*,a Wakako TAKAHASHI,a Yoshihisa ASADA,a Junko HOLIUCHI,a Kazuyoshi TAKEDA,b
a
and Yoshihiro HARIGAYA
a School of Pharmaceutical Sciences, Kitasato University; 5–9–1 Shirokane, Minato-ku, Tokyo 108–8641, Japan: and
b Ebara Research Co., LTD; 4–2–1, Honfujisawa, Fujisawa 251–8502, Japan.
Received March 15, 2004; accepted June 12, 2004; published online June 16, 2004
Pd(0)-catalyzed intramolecular cyclic reaction via a p-allylpalladium complex provided an indolizidine
skeleton in satisfactory high and reproducible yields by using allylic compound having an acetoxyl group as a
leaving group. These results must be available for syntheses of various functional indolizidine alkaloids.
Key words p-allylpalladium complex; indolizidine; Pd(0); C–N bond formation
group is to raise the reactivity of palladium-catalyzed cyclic
reaction and the other is if cyclization occurs to give 5, vinyl
group of the side chain will serve to convert 5 to a biologi-
cally active compound.
In initial studies when employing Boc, Cbz, Moz as an
amino-protected group, acetyl group was removed at the
same time in the process of the elimination of these amino-
protective group due to acid conditions in the reaction. Fi-
nally, the Aloc (allyloxycarbonyl) group proved to be suitable
for an amino-protected groups because it is easily removed
under mild neutral conditions by using a Pd(0) reagent. The
synthetic procedure of a precursor 4 is shown as follows
(Chart 1).
L-Proline methyl ester hydrochloride 1 was protected with
the Aloc group by treatment with Aloc-chloride in pyri-
dine–CH2Cl2 at 0 °C to afford N-Aloc derivative 2, quantita-
tively. Grignard reaction of methyl ester 2 using three equiva-
lents of vinyl magnesium bromide in THF at 0 °C, followed
by acetylation with acetyl chloride at room temperature af-
forded bisallylic compound 3 in 67% yield from 2.
Two kinds of reaction conditions (A, B) were adopted for
removal of the Aloc group. Compound 3 reacted with
Pd(Ph3P)4 in the presence of dimedone in THF at room tem-
perature to give amine 4 in 75% yield, and also with
In recent years, p-allylpalladium complexes have found
wide application in the field of synthetic organic chemistry1)
since the report by Smidt in 1959.2) Especially, allylic alkyla-
tion via a p-allylpalladium complex is an important
reaction.3) This reaction is known to involve the processes of
oxidative addition of Pd(0) to allylic compounds which have
appropriate leaving groups to make a p-allylpalladium com-
plex and subsequent reaction with such nucleophiles as car-
bon, nitrogen, oxygen to make C–C, C–N, C–O bond forma-
tion. Among them, amines have been known to be the most
reactive nucleophiles to a p-allylpalladium complex to make
both intra- and intermolecular C–N bond formation readily.4)
Several intramolecular C–N bond formations via p-allyl-
palladium complex have been applied to the synthesis of
alkaloids such as inandenin-12-one,5) perhydrohistrionico-
toxin.6,7) We are interested in application of p-allylpalladium
complex in the synthesis of alkaloids having nitrogen in the
bridge head such as pyrrolizidine and indolizidine. However,
little study has been reported on the synthesis of condensed-
ring compounds such as pyrrolizidine, indolizidine via a p-
allylpalladium complex except only a few reports.5,8,9) In
1989, Trost reported the synthesis of all-pumiliotoxin 339B8)
by constructing an indolizidine skeleton via intramolecular
C–N bond formation of an allyllic compound having epoxide
as a leaving group. However, construction of pyrrolizidine
and indolizidine skeleton by palladium-catalyzed intramolec-
ular C–N bond formation of allylic compound having other
leaving group than epoxide group have not yet been reported.
Generally, allylic acetate and allylic carbonate which have
each acetoxyl and methoxycarbonyloxyl group as a leaving
group, respectively have been well used as allylic compounds
up to date in palladium-catalyzed cyclic reaction. In this
paper we wish to communicate our results in the application
of a p-allylpalladium complex to construct an indolizidine
skeleton which has nitrogen at the brige-head using acetoxyl
group as a leaving group.
Initially, we selected a pyrrolizidine skeleton as a target for
a condensed-ring compound having nitrogen at the bridge-
head. Our strategy for the synthesis of the pyrrolizidine
skeleton via a p-allylpalladium complex involves the synthe-
sis of a key compound 4 from a L-proline derivative, follow-
ing the palladium-catalyzed cyclic reaction.
Chart 1
One of the reason for using allylacetate 4 having bisallyl
* To whom correspondence should be addressed. e-mail: konday@pharm.kitasato-u.ac.jp
© 2004 Pharmaceutical Society of Japan

September 2004
1083
Chart 3
serve as an important precursor to synthesize naturally occur-
ing alkaloids such as the Ipalpidine13) group (Chart 3). We
are now going to transformation of 15 to Ipalpidine by fol-
lowing strategy.
Selective oxidation of vinyl group of side chain, followed
by appropriate reduction would produce methyl group, then
Heck reaction of phenyl iodide with an inner olefin of the
ring would give Ipalpidine.
Chart 2
The reason why the Pd(0)-catalyzed cyclic reaction did not
occur in precursor 3 and it occurred successfully in precursor
12 is considered that the strain of the five-membered ring
having bridge-head nitrogen is presumed more large than that
of six-membered ring.
This cyclic reaction will be utilized for syntheses of vari-
ous functional indolizidine alkaloids and other condensed-
ring compound having nitrogen at the bridge-head. We are
now examining the scope and limitations of this reaction. In
conclusion, Pd(0)-catalyzed cyclic reaction using allylic
compound 12, having an acetoxyl group as a leaving group
provided an indolizidine skeleton in satisfactory high and re-
producible yields. These results will serve to build up various
indolizidine skeletons and other condensed-ring compounds
having nitrogen at the bridge-head such as quinolizidine.
Pd(OAc)2 in the presence of 3,3ꢀ,3ꢁ-phosphinidynetris(ben-
zenesulfonic acid)trisodium salt (TPPTS), HNEt2 in
CH3CN–H2O to give amine 4 in 96% yield.
Unfortunately, C–N bond formation to produce 5 did not
occur with substrate 4 using Pd(0) in spite of our many ef-
forts varying the catalyst such as Pd(Ph3P)4, Pd2(dba)3, vary-
ing the base such as NEt3, NaH, DBU and varying the sol-
vent such as CH3CN, DMF, THF to give mostly starting ma-
terial 4 only in all cases. Pd(0) catalyzed cyclic reaction from
3 to 5 directly did not occur using Pd(Ph3P)4, dimedone in
THF even under violent condition at 70 °C.
Then we turned our attention to construction of an in-
dolizidine skeleton. The precursor 12 for Pd(0)-catalyzed
cyclic reaction to an indolizidine skeleton was synthesized as
described in Chart 2. L-Proline was protected with the Aloc Experimental
1H- and 13C-NMR were recorded on Varian VXR-300, XL-400 spectrom-
group in a similar way to give 7, quantitatively. The
Arndt–Eistert reaction10,11) was employed to obtain benzyl N-
Aloc-pyrrolidine-2-acetate 10. N-Aloc proline 7 was con-
verted to acyl chloride 8 by oxalyl chloride in DMF–CH2Cl2
at 0 °C to room temperature, followed by formation of dia-
zoketone 9 using TMSCHN2 in THF–CH3CN at 0 °C and
then the crude substance 9 was heated at 185 °C in collidine
in the presence of benzyl alcohol to afford benzyl acetate 10
in 59% yield from 7. Alkaline hydrolysis of ester 10 by treat-
ment with K2CO3 in MeOH–H2O, followed by esterification
with TMSCHN2 in benzene–MeOH at room temperature af-
forded methyl ester 11 in 65% yield from 10. Grignard reac-
tion of 11 by using three equivalents of vinyl magnesium
eters. IR spectra were recorded with a JASCO FT/IR Spectrometer for win-
dows. Mass spectra were obtained on a JEOL-JMX-DX 300 mass spectrom-
eter (low-resolution mass spectrometry) and JEOL-JMS-AX505 HA mass
spectrometer (high-resolution mass spectrometry). Routine monitoring of re-
action was carried out using Merck 60 GF254 silica gel, glass-supported
plates (TLC). Flash column chromatography was done on silica gel 60
PF254 (Merck).
(2S)-N-Allyloxycarbonyl-L-proline Methyl Ester (2) Pyridine
(4.68 ml, 57.8 mmol), allyloxycarbonyl (Aloc) chloride (3.68 ml, 34.7 mmol)
were added to a solution of proline methyl ester hydrochloride (3.83 g,
23.1 mmol) in CH2Cl2 (96 ml), stirred for 20 min at 0 °C and stirred further
for 20 min at room temperature. A reaction mixture was diluted with CHCl3
(100 ml), washed with saturated NaHCO3 solution (40 mlꢃ2), saturated
NaCl solution (10 mlꢃ2) and organic layer was dried over Na2SO4, concen-
trated in vacuo. The residue was purified by flash column chromatography
(silica gel, n-hexane : AcOEtꢄ1 : 1) to give 2 (4.92 g, 100%) as colorless oil.
Rfꢄ0.90 (CHCl3 : MeOHꢄ10 : 1); [a]D22 ꢂ54.34° (cꢄ0.99, CHCl3); IR
12)
bromide in the presence of anhydrous CeCl3 in THF at
0 °C, followed by acetylation gave a bisallylic compound 12
as a main product in 39% yield. When Grignard reaction was
carried out in the absence of CeCl3, 12 was obtained in 24%
yield, accompanied with isomer 13 which resulted from con-
1
(CHCl3) nmax cmꢂ1: 1650 (vinyl), 1690 (–NCOO–), 1740 (–COOCH3); H-
NMR (400 MHz) d: 1.90 (2H, m, 4-H2), 2.00 (1H, m, 3-Ha), 2.20 (1H, m, 3-
Hb), 3.48 (1H, m, 5-Ha), 3.57 (1H, m, 5-Hb), 3.69, 3.71 (total 3H, each s,
COOCH3), 4.34 (1H, ddd, Jꢄ15.0, 10.0, 4.0 Hz, 2-H), 4.55 (2H, m,
jugate addition of a second molecule of vinyl group to the –OCH2–), 5.14, 5.18 (total 1H, each dd, Jꢄ11.0, 2.0 Hz, ꢄCH2-cis), 5.23,
5.29 (total 1H, each dd, Jꢄ18.0, 2.0 Hz, ꢄCH2-trans), 5.88 (1H, m, –CHꢄ);
initially formed vinyl ketone 14 (Chart 2).
Then, transformation of the indolizidine precursor 12 by
Pd(0)-catalyzed cyclic reaction was performed. Attempts for
13C-NMR (100.6 MHz) d: 23.44, 24.26 (each t, 4-C), 29.83, 30.86 (each t, 3-
C), 46.28, 46.79 (each t, 5-C), 52.07, 52.13 (each q, COOCH3), 58.74, 59.05
(each d, 2-C), 65.71, 65.87 (each t, –OCH2), 116.90, 117.21 (each t, ꢄCH2),
removal of the Aloc group of 12 caused, fortunately, C–N
bond formation at the same time as described belows. p-Al-
lylpalladium cyclization of 12 using Pd(Ph3P)4 in the pres-
ence of dimedone in THF at ꢂ20 °C to 0 °C afforded suc-
cessfully indolizidine derivative 15 as a single product in
62% yield. The base 15 was derived to HCl salts by treat-
ment with 0.1 N HCl in 75% yield. The indolizidine 15 will
132.73, 132.88 (each d, –CHꢄ), 154.09, 154.64 (each s, NCOO), 173.05,
173.20 (each s, COOCH3); HR-FAB-MS m/z: 214.1082 [MꢅH]ꢅ, Calcd for
C10H16O4N: 214.1079.
(2S)-N-Allyloxycarbonyl-2-(1-acetyloxy-1-vinyl-2-propenyl) Pyrroli-
dine (3) Vinyl magnesium bromide solution (1 M, in THF) (4.31 ml,
4.31 mmol) was dropped to a solution of 2 (437 mg, 2.05 mmol) at 0 °C,
stirred for 1 h under argon and vinyl magnesium bromide solution (1 M, in
THF) (1.00 ml, 1.00 mmol) was further added and stirred 1 h at 0 °C. After

1084
Vol. 52, No. 9
that, acetyl chloride (0.36 ml, 5.13 mmol) was added to the reaction mixture
and stirred for 45 min at room temperature. THF was evaporated in vacuo
and neutralized with saturated NH4Cl solution, extracted with AcOEt
(100 mlꢃ3). The organic layer was washed with saturated NaCl (20 mlꢃ3),
dried over Na2SO4, concentrated in vacuo to afford crude substance
(642 mg) as orange oil, which was purified by flash column chromatography
(silica gel, n-hexane : AcOEtꢄ10 : 1—7 : 1—5 : 1) to afford 3 (383 mg, 67%)
as light yellow oil. Rfꢄ0.18 (n-hexane : AcOEtꢄ5 : 1); [a]D24 ꢂ38.8°
(cꢄ0.98, CHCl3); IR (CHCl3) nmax cmꢂ1: 1735 (OCOCH3), 1690 (NCOO);
1H-NMR (400 MHz, pyridine-d5, 80.0 °C) d: 1.63—1.71 (1H, m, 4-Hb),
1.83—1.95 (3H, m, 3-H, 4-Ha), 2.08 (3H, s, OCOCH3), 3.35 (1H, ddd,
Jꢄ11.0, 8.0, 6.0 Hz, 5-Hb), 3.38 (1H, ddd, Jꢄ11.0, 8.0, 6.0 Hz, 5-Ha), 4.72
(1H, ddt, Jꢄ13.5, 5.0, 1.5 Hz, –OCHa–), 4.78 (1H, ddt, Jꢄ13.5, 5.0, 1.5 Hz,
–OCHb–), 5.01 (1H, dd, Jꢄ6.0, 5.0 Hz, 2-H), 5.22 (1H, dq, Jꢄ10.5, 1.5 Hz,
ꢄCH2-cis), 5.31 (2H, dd, Jꢄ11.0, 1.5 Hz, 3ꢀ,3ꢁ-H2-cis), 5.40 (2H, dq,
Jꢄ17.5, 1.5 Hz, ꢄCH2-trans), 5.40 (2H, dq, Jꢄ17.5, 1.5 Hz, 3ꢀ,3ꢁ-H2-trans),
6.07 (1H, ddt, Jꢄ17.5, 10.5, 5.0 Hz, –CHꢄ), 6.32 (1H, dd, Jꢄ17.5, 11.0 Hz,
2ꢀ-H), 6.45 (1H, dd, Jꢄ17.5, 11.0 Hz, 2ꢁ-H); HR-FAB-MS m/z: 302.1357
[MꢅNa]ꢅ, Calcd for C15H21O4NNa: 302.1368.
ꢄCH2), 132.55, 132.62 (each d, –CHꢄ), 154.33, 156.75 (each s, NCOO),
176.04, 177.87 (s, COOH); HR-FAB-MS m/z: 200.0920 [MꢅH]ꢅ, Calcd for
C9H14O4N: 200.0923.
Benzyl (2S)-N-Allyloxycarbonylpyrrolidine-2-acetate (10) Oxalyl
chloride (4.8 ml, 56 mmol), DMF (2 drops) were dropped to a solution of 7
(9.4 g, 47 mmol) in CH2Cl2 (78 ml) at 0 °C and stirred for 15 min and stirred
further for 1 h at room temperature. A reaction mixture was concentrated in
vacuo to afford acyl chloride 8. Trimethylsilyl diazomethane (TMSCHN2)
(2 M solution in hexane) (52 ml, 103 mmol) was added to a solution of 8 in
CH3CN (98 ml)–THF (98 ml) at 0 °C under argon and stirred for 2 h. The re-
action mixture was evaporated in vacuo to afford diazo compound 9. Com-
pound 9 was dissolved in a solution of benzyl alcohol (20 ml) and 2,4,6-col-
lidine (20 ml) and stirred at 185 °C for 7 min. The reaction mixture was di-
luted with benzene (500 ml), washed with 10% citric acid (100 mlꢃ5), H2O
(100 mlꢃ2), saturated NaCl (100 mlꢃ2), dried over Na2SO4, concentrated in
vacuo to afford light yellow oil (28 g), which was purified by flash column
chromatography (silica gel, benzene : CHCl3 : etherꢄ2 : 2 : 1) to afford
10 (8.4 g, 59%) as light green oil. Rfꢄ0.45 (benzene : CHCl3 : etherꢄ
2 : 2 : 1); [a]D22 ꢂ38.89° (cꢄ0.54, CHCl3); IR (CHCl3) nmax cmꢂ1: 1720
1
(2S)-2-(1-Acetyloxy-1-vinyl-2-propenyl) Pyrrolidine (4) by Method A
Tetrakis (triphenylphosphine) palladium (0) [Pd(Ph3P)4] (31.7 mg,
0.03 mmol), dimedone (293 mg, 2.09 mmol) were added to a solution of 3 in
THF (5.0 ml) at room temperature under argon and stirred for 2 h. Pd(Ph3P)4
(31.7 mg, 0.03 mmol) was further added and stirred for 1.5 h. Pd(Ph3P)4
(9.5 mg, 0.008 mmol) was further added and stirred for 30 min. The reaction
mixture was concentrated in vacuo, diluted with ether (30 ml) and filtered.
The filtrate was extracted with citric acid (20 mlꢃ4), the water layer was ad-
justed to pHꢄ10 with NaHCO3 and extracted by ether (100 mlꢃ4). Ether
layer was dried over Na2SO4, concentrated in vacuo to afford the residue
(56.9 mg) as light yellow oil, which was purified by preparative TLC (silica
gel, CHCl3 : MeOHꢄ10 : 1) to give 4 (40.1 mg, 75%) as orange oil. Rfꢄ0.15
(benzene : acetoneꢄ10 : 1); [a]D24 ꢂ62.3° (cꢄ1.39, CHCl3); IR (CHCl3) nmax
cmꢂ1: 1735 (OCOCH3); 1H-NMR (400 MHz) d: 1.70 (1H, m, 4-Ha), 1.90
(1H, m, 4-Hb), 2.00 (2H, m, 3-H2), 2.10 (3H, s, OCOCH3), 3.35 (1H, dt,
Jꢄ11.0, 8.0 Hz, 5-Ha), 3.56 (1H, ddd, Jꢄ11.0, 8.0, 5.0 Hz, 5-Hb), 4.19 (1H,
dd, Jꢄ9.0, 6.0 Hz, 2-H), 5.19, 5.22 (total 2H, each dd, Jꢄ11.0, 2.0 Hz, 3ꢀ,3ꢁ-
H2-cis), 5.46, 5.49 (total 2H, each dd, Jꢄ17.0, 2.0 Hz, 3ꢀ,3ꢁ-H2-trans), 5.93,
5.95 (total 2H, each dd, Jꢄ17.0, 11.0 Hz, 2ꢀ,2ꢁ-H), 6.78 (1H, s, NH); 13C-
NMR (100.6 MHz) d: 23.10 (q, OCOCH3), 24.27 (t, 4-C), 28.30 (t, 3-C),
49.69 (t, 5-C), 67.42 (d, 2-C), 78.83 (s, 1ꢀ-C), 115.33 (t, 3ꢀ-C), 116.09 (t, 3ꢁ-
C), 137.29 (d, 2ꢀ-C), 140.15 (d, 2ꢁ-C), 172.57 (s, OCOCH3); HR-FAB-MS
m/z: 218.1153 [MꢅNa]ꢅ, Calcd for C11H17O2 NNa: 218.1157.
(COOCH2Ph), 1680 (NCOO), 1600 (vinyl), 1500—1470 (arom); H-NMR
(400 MHz): d: 1.70—1.80 (1H, m, 3-Ha), 1.81—1.87 (2H, m, 4-H2), 2.07
(total 1H, ddd, Jꢄ15.0, 12.0, 8.0 Hz, 3-Hb), 2.40 (1H, dd, Jꢄ15.0, 9.0 Hz,
1ꢀ-Ha), 2.87, 3.02 (total 1H, each dd, Jꢄ15.0, 3.5 Hz, 1ꢀ-Hb), 3.40 (2H, m,
Jꢄ6.0 Hz, 5-H2), 4.23, 4.25 (total 1H, dm, Jꢄ8.0 Hz, 2-H), 4.58 (2H, t,
Jꢄ6.0 Hz, –OCH2), 5.10, 5.13 (total 2H, each d, Jꢄ12.0 Hz, benzyl–CH2–),
5.19 (1H, d, Jꢄ11.0 Hz, ꢄCH2-cis), 5.29 (1H, dq, Jꢄ17.0, 2.0 Hz, ꢄCH2-
trans), 5.92 (1H, ddt, Jꢄ17.0, 11.0, 6.0 Hz, –CHꢄ), 7.35 (5H, s, arom); 13C-
NMR (100.6 MHz): d: 22.76, 23.58 (each t, 4-C), 30.58, 31.37 (each t, 3-C),
38.32, 39.32 (each t, 1ꢀ-H), 46.37, 46.72 (each t, 5-C), 53.99, 54.55 (each d,
2-C), 65.59, 65.75 (each t, –OCH2), 66.26 (t, benzyl–CH2), 117.16, 117.28
(each t, ꢄCH2), 127.22, 127.36, 128.20, 128.54, 128.71 (each d,
COOCH2Ph), 133.00, 133.17 (each d, –CHꢄ), 135.90 (s, COOCH2Ph–1ꢀ-
C), 154.55 (s, NCOO), 171.10, 171.24 (each s, COOCH2Ph); HR-FAB-MS
m/z: 304.1551 [MꢅH]ꢅ, Calcd for C7H22O4N: 304.1549.
Methyl (2S)-N-Allyloxycarbonylpyrrolidine-2-acetate (11) A solution
of 10 (902 mg, 2.98 mmol) in MeOH (36 ml) was dropped to a solution of
K2CO3 (1.44 g, 10.4 mmol) in H2O (1.8 ml) and stirred at 65 °C for 4 h.
K2CO3 (0.41 g, 2.98 mmol) was further added and stirred for 18 h. The reac-
tion mixture was acidified with 10% HCl, diluted with H2O (30 ml), ex-
tracted by AcOEt (100 mlꢃ3). The organic layer was washed with H2O
(30 ml), dried over Na2SO4, concentrated in vacuo to afford crude carboxylic
acid. TMSCHN2 (2 M solution in hexane) (1.93 ml, 3.87 mmol) was dropped
to a solution of the carboxylic acid in MeOH (6.0 ml)–benzene (24 ml) and
stirred for 30 min at room temperature. The reaction mixture was concen-
trated in vacuo to afford yellow oil (735 mg), which was purified by flash
column chromatography (silica gel, benzene : CHCl3 : etherꢄ20 : 20 : 1) to
afford yellow oil 11 (442 mg, 65% from 10). Rfꢄ0.30 (benzene :
(2S)-2-(1-Acetyloxy-1-vinyl-2-propenyl) Pyrrolidine (4) by Method B
HNEt2 (0.49 ml, 4.69 mmol), Pd(OAc)2 (9.6 mg, 0.04 mmol), TPPTS
(48.5 mg, 0.09 mmol) were added to a solution of 3 (595 mg, 2.13 mmol) in
CH3CN : H2Oꢄ10 : 1 (0.6 ml) under argon at room temperature and stirred
for 30 min. The reaction mixture was evaporated in vacuo, diluted by CHCl3
(200 ml), washed with saturated NaCl (10 mlꢃ2). Water layer was extracted CHCl3 : etherꢄ2 : 2 : 1); [a]D22 ꢂ43.20° (cꢄ0.50, CHCl3); IR (CHCl3) nmax
with CHCl3 (200 ml). Combined CHCl3 solution was dried over Na2SO4, cmꢂ1
:
1720 (–COOCH3), 1680 (–NCOO–), 1600 (vinyl); 1H-NMR
evaporated in vacuo to afford 4 (400 mg, 96%) as light yellow oil, which was (400 MHz) d: 1.70—1.80 (1H, m, 3-Ha), 1.80—1.90 (2H, m, 4-H2), 2.07
(total 1H, ddd, Jꢄ16.0, 12.0, 8.5 Hz, 3-Hb), 2.34 (1H, dd, Jꢄ15.0, 8.5 Hz,
1ꢀ-Ha), 2.82, 2.96 (total 1H, each dd, Jꢄ15.0, 3.5 Hz, 1ꢀ-Hb), 3.40 (2H, m,
5-H2), 3.66 (3H, s, COOCH3), 4.19, 4.24 (total 1H, dm, Jꢄ8.5 Hz, 2-H),
4.58 (2H, t, Jꢄ5.0 Hz, –OCH2), 5.19 (1H, dd, Jꢄ10.0, 1.0 Hz, ꢄCH2-cis),
5.29 (1H, dd, Jꢄ17.0, 1.0 Hz, ꢄCH2-trans), 5.93 (1H, ddt, Jꢄ17.0, 10.0,
5.0 Hz, –CHꢄ); 13C-NMR (100.6 MHz) d: 22.72, 23.55 (each t, 4-C), 30.58,
31.35 (each t, 3-C), 38.14, 39.05 (each t, 1ꢀ-H), 46.37, 46.72 (each t, 5-C),
51.54 (q, 3ꢀ-C), 53.96, 54.52 (each d, 2-C), 65.57, 65.75 (each t, –OCH2),
117.13, 117.28 (each t, ꢄCH2), 133.03, 133.16 (each d, –CHꢄ), 154.55 (s,
NCOO), 171.85 (each s, COOCH3); HR-FAB-MS m/z: 228.1236 [MꢅH]ꢅ,
Calcd for C11H18O4N: 228.1236.
(2S)-N-Allyloxycarbonyl-2-(2-acetyloxy-2-vinyl-3-butenyl)pyrrolidine
(12) Anhydrous CeCl3 (264 mg, 1.1 mmol) prepared by the literature pro-
cedure12) was suspended in THF (0.5 ml) and stirred for 2 h under argon at
room temperature, then a solution of 11 (83 mg, 0.365 mmol) in THF (1 ml)
was added and stirred for 1 h at room temperature. Vinyl magnesium bro-
mide (0.97 ml, 1 M solution in hexane, 1.1 mmol) was dropped at 0 °C and
stirred for 30 min. Acetyl chloride (0.062 ml, 0.88 mmol), dimethylamino-
pyridine (5 mg) was added at 0 °C, then stirred for 30 min at room tempera-
ture. Saturated NH4Cl (20 ml) was added to quench Grignard reagent com-
pletely, extracted with ether (100 mlꢃ2). The organic layer was washed with
saturated NaCl (10 mlꢃ3), dried over Na2SO4, concentrated in vacuo. The
resulted residue was purified by flash column chromatography (Silica gel,
used next reaction without purification. Compound 4 was identified to 4
obtained by above procedure by comparison of 1H-NMR, Rfꢄ0.23
benzene : acetoneꢄ10 : 1.
(2S)-N-Allyloxycarbonyl-L-proline (7) A solution of allyloxycarbonyl
chloride (Aloc-Cl) (3.57 ml, 33.7 mmol) in ether (40 ml) was dropped to a
solution of L-proline (5.97 g, 51.8 mmol), NaHCO3 (11.3 g, 135 mmol) in
H2O (118 ml) under argon, and stirred for 1.5 h at room temperature. Then, a
solution of NaHCO3 (5.66 g, 67.4 mmol) in H2O (59 ml) and Aloc-Cl
(3.57 ml, 33.7 mmol) in ether (40 ml) were added again and stirred for 16 h.
The reaction mixture was diluted with ether (160 ml) and partitioned to
aqueous and organic layers. Aqueous layer was acidified with concentrated
HCl, extracted with AcOEt (200 mlꢃ3). AcOEt layer was washed with satu-
rated NaCl solution (40 mlꢃ2), dried over Na2SO4, evaporated in vacuo to
afford 7 as colorless oil, quantitatively. Rfꢄ0.63 (t-BuOH : AcOH : H2Oꢄ
4 : 1 : 5); [a]D22 ꢂ95.58° (cꢄ0.95, CHCl3); IR (CHCl3) nmax cmꢂ1: 1750
(–COOH), 1690 (–NCOO–), 1600 (vinyl), 1H-NMR (400 MHz) d: 1.85—
2.30 (4H, m, 3, 4-H2), 3.47 (1H, m, 5-Ha), 3.57 (1H, m, 5-Hb), 4.36, 4.40
(total 1H, each dd, Jꢄ8.0, 4.0 Hz, 2-H), 4.58, 4.62 (total 2H, each d,
Jꢄ5.0 Hz, –OCH2), 5.16, 5.22 (total 1H, each dd, Jꢄ10.5, 1.5 Hz, ꢄCH2-
cis), 5.31 (1H, dd, Jꢄ18.0, 1.5 Hz, ꢄCH2-trans), 5.84—5.98 (1H, m,
–CHꢄ), 8.04 (1H, br, –COOH); 13C-NMR (100.6 MHz) d: 23.41, 24.27
(each t, 4-C), 29.26, 30.88 (each t, 3-C), 46.57, 46.85 (each t, 5-C), 58.56,
59.23 (each d, 2-C), 66.02, 66.45 (each t, –OCH2), 117.22, 117.72 (each t,

September 2004
1085
15 (13.3 mg) was dissolved in AcOEt (10 ml) and extracted with 0.1 N HCl
(2 mlꢃ2), the HCl layer was concentrated in vacuo to afford colorless pow-
hexane : AcOEtꢄ8 : 1) to afford 12 (42.2 mg, 39.4%) as colorless oil.
Rfꢄ0.58 (n-hexane : AcOEtꢄ1 : 1); [a]D22 ꢂ14.12° (cꢄ0.85, CHCl3); IR
der (12.4 mg, 75%). [a]D23 ꢅ43.75° (cꢄ0.16, CHCl3); H-NMR (400 MHz)
1
1
(CHCl3) nmax cmꢂ1: 1740 (–OCOOCH3), 1680 (NCOO), 1640 (vinyl); H-
d: 2.10 (1H, m, 2-Ha), 2.24 (2H, m, 1-H), 2.40 (1H, m, 2-Hb), 2.74 (1H, m,
8-Ha), 2.80 (1H, m, 3-Ha), 2.90 (1H, m, 8-Hb), 3.14 (1H, m, 8a-H), 3.42,
3.44, 3.57 (total 1H, each d, Jꢄ15.5 Hz, 5-Ha), 3.97 (1H, m, 3-Hb), 4.16
(1H, d, Jꢄ15.5 Hz, 5-Hb), 5.16 (1H, d, Jꢄ10.5 Hz, 2ꢀ-H-cis), 5.24 (1H, d,
Jꢄ17.5 Hz, 2ꢀ-H-trans), 5.67 (1H, br s, 6-H), 6.40 (1H, dd, Jꢄ17.5, 10.5 Hz,
1ꢀ-H), 12.5 (1H, br s, HCl); 13C-NMR (100.6 MHz) d: 20.46, 20.63 (each t,
2-C), 27.36 (t, 8-C), 28.59 (t, 1-C), 50.30 (t, 5-C), 52.91 (t, 3-C), 62.65 (d,
8a-C), 114.67, 114.69 (each t, 2ꢀ-C), 117.82 (d, 6-C), 135.94 (s, 7-C),
136.35 (d, 1ꢀ-C), HR-FAB-MS m/z: 150.1290 [MꢂHClꢅH]ꢅ, Calcd for
C10H16N: 150.1283.
NMR (300 MHz) d: 1.84 (2H, m, 4-H2), 1.92 (2H, m, 3-H2), 1.98 (1H, m, 4-
Hb), 2.26 (1H, m, 1ꢀ-Ha), 2.67 (2H, t, Jꢄ6.5 Hz, 4ꢀ-H2), 2.82 (1H, d,
Jꢄ15.0 Hz, 1ꢀ-Hb), 3.40 (2H, br d, Jꢄ5.0 Hz, 5-H2), 3.81 (3H, s,
–OCOOCH3), 3.99 (1H, br t, Jꢄ7.0 Hz, 2-H), 4.57 (total 2H, d, Jꢄ5.0 Hz,
–OCH2), 4.98 (1H, d, Jꢄ10.5 Hz, 6ꢀ-H-cis), 5.03 (1H, dd, Jꢄ17.0, 1.0 Hz,
3ꢀ-H), 5.07 (1H, d, Jꢄ17.0 Hz, 6ꢀ-H-trans), 5.19 (1H, dd, Jꢄ10.5, 1.0 Hz,
ꢄCH2-cis), 5.29 (1H, dd, Jꢄ17.0, 10.5 Hz, ꢄCH2-trans), 5.75 (1H, ddt,
Jꢄ17.0, 10.5, 5.0 Hz, 5ꢀ-H), 5.93 (1H, ddt, Jꢄ17.0, 10.5, 6.5 Hz, –CHꢄ);
13C-NMR (75 MHz) d: 22.77, 23.64 (each t, 4-C), 29.44, 29.67 (each t, 4ꢀ-
H), 30.03, 30.12 (each t, 3-C), 36.99, 38.09 (each t, 1ꢀ-C), 46.36, 46.63
(each t, 5-C), 55.10, 55.15 (q, OCOOCH3), 55.96 (d, 2-C), 65.46, 65.68
(each t, –OCH2), 115.42 (d, 3ꢀ-H), 116.85 (t, ꢄCH2), 117.04 (t, 6ꢀ-H),
133.14, 133.26 (each d, –CHꢄ), 135.36, 135.40 (each d, 5ꢀ-C), 146.69,
146.74 (each s, 2ꢀ-C), 153.26 (s, NCOO), 154.57 (s, OCOOCH3); HR-FAB-
MS m/z: 318.1322 [MꢅNa]ꢅ, Calcd for C15H21O5NNa: 318.1317.
References
1) Tsuji J., “Palladium Reagents and Catalysts,” Chap. 4, John Wiley and
Sons, Tokyo, 1995, pp. 290—339.
2) Smidt J., Hafner W., Angew. Chem., 71, 284 (1959).
3) Tsuji J., Tetrahedron, 42, 4361—4401 (1986).
4) Tsuji J., Shimizu I., Minami I., Ohashi Y., Sugiura T., Takahashi K., J.
Org. Chem., 50, 1523—1529 (1985).
5) Andriamialisoa R. Z., Langlois N., Langlois Y., Heterocycles, 14,
1457—1460 (1980).
6) Godleski S. A., Meinhart J. D., Miller D. J., Tetrahedron Lett., 22,
2247—2550 (1981).
7) Godleski S. A., Heacock D. J., Meinhart J. D., Wallendael S. V., J. Org.
Chem., 48, 2101—2103 (1983).
8) Trost B. M., Scanlan T. S., J. Am. Chem. Soc., 111, 4988—4990
(1989).
9) Stien D., Anderson G. T., Chase C. E., Koh Y. H., Weinreb S. M., J.
Am. Chem. Soc., 121, 9574—9579 (1999).
10) Aoyama T., Shioiri T., Tetrahedron Lett., 21, 4461—4462 (1980).
11) Aoyama T., Shioiri T., Chem. Pharm. Bull., 29, 3249—3255 (1981).
12) Imamoto T., Takiyama N., Nakamura K., Hatajima T., Kamiya Y., J.
Am. Chem. Soc., 111, 4392—4398 (1989).
(8aS)-6,7-Dehydro-7-vinylindolizidine
(15) Pd(Ph3P)4
(13.5 mg,
11.7 mmol), dimedone (65.6 mg, 0.47 mmol) were added to a solution of 12
(38 mg, 0.13 mmol) in THF (1.4 ml) at ꢂ20 °C under argon and stirred for
4 h. Pd(Ph3P)4 (13.5 mg, 11.7 mmol) was further added and stirred for 1 h.
After that the mixture was stirred at 0 °C for 14 h. The reaction mixture was
concentrated in vacuo, diluted with ether (20 ml), filtered through celite pad,
concentrated in vacuo to give crude substance, which was purified by flash
column chromatography (Silica gel, benzene : hexaneꢄ10 : 1–CHCl3 :
MeOHꢄ50 : 1—30 : 1) to afford 15 (12.3 mg, 63.7%) as red oil. Rfꢄ0.18
(CHCl3 : MeOHꢄ10 : 1); [a]D23 ꢅ20.00° (cꢄ0.06, CHCl3); 1H-NMR
(400 MHz) d: 1.54 (2H, m, 1-H2), 1.88 (2H, m, 2-H2), 2.02 (1H, m, 8-Ha),
2.16 (1H, m, 3-Ha), 2.22 (1H, m, 8a-H), 2.48 (1H, dt, Jꢄ16.0, 3.0 Hz, 8-
Hb), 2.86 (1H, d, Jꢄ17.0 Hz, 5-Ha), 3.22 (1H, td, Jꢄ9.0, 2.0 Hz, 3-Hb),
3.61 (1H, ddd, Jꢄ17.0, 5.0, 2.0 Hz, 5-Hb), 4.96 (1H, d, Jꢄ10.0 Hz, 2ꢀ-H-
cis), 5.11 (1H, d, Jꢄ17.0 Hz, 2ꢀ-H-trans), 5.72 (1H, td, Jꢄ2.0, 1.0 Hz, 6-H),
6.42 (1H, dd, Jꢄ17.0, 10.0 Hz, 1ꢀ-H) 13C-NMR (100.6 MHz) d: 21.43 (t, 2-
C), 30.80 (t, 1-C), 31.02 (t, 8-C), 52.57 (t, 5-C), 54.17 (t, 3-C), 59.83 (d, 8a-
C), 110.92 (t, 2ꢀ-C), 126.47 (d, 6-C), 135.00 (s, 7-C), 138.60 (d, 1ꢀ-C); HR-
EI-MS m/z: 149.1205 [M]ꢅ, Calcd for C10H15N: 149.1204.
13) Ikhiri K., Koulodo D. D. D., Garba M., Mamane S., Ahond A., Poupat
C., Potier P., J. Nat. Prod., 50, 152—156 (1987).
(8aS)-6,7-Dehydro-7-vinylindolizidine HCl salt (15·HCl). Compound