Synthesis of (-)-trachelanthamidine using a single electron transfer reaction in 1,4-dimethylpiperazine

Article abstract of DOI:10.1016/j.tet.2008.06.005

Synthesis of (-)-trachelanthamidine, one of the pyrrolizidine alkaloids, has been achieved by using a single electron transfer reaction of 2-(2-acetoxyethenyl)-N-(trichloroacetyl)pyrrolidine in boiling 1,4-dimethylpiperazine as the key step.

Full text of DOI:10.1016/j.tet.2008.06.005

Tetrahedron 64 (2008) 7771–7773
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Synthesis of (ꢀ)-trachelanthamidine using a single electron transfer
reaction in 1,4-dimethylpiperazine
*
Hiroyuki Ishibashi , Masamichi Sasaki, Tsuyoshi Taniguchi
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 May 2008
Received in revised form 2 June 2008
Accepted 3 June 2008
Available online 6 June 2008
Synthesis of (ꢀ)-trachelanthamidine, one of the pyrrolizidine alkaloids, has been achieved by using
a single electron transfer reaction of 2-(2-acetoxyethenyl)-N-(trichloroacetyl)pyrrolidine in boiling 1,4-
dimethylpiperazine as the key step.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
We previously reported that N-allylic trichloroacetamides 1
underwent radical cyclization in boiling 1,4-dimethylpiperazine to
give five-membered lactams 3 in good yields.1 This cyclization can
be explained as proceeding via a single electron transfer (SET) re-
action from the nitrogen atom of 1,4-dimethylpiperazine used as
a solvent to the substrates 1 followed by an elimination of chloride
anion to give radical 2 (Scheme 1). This method is highly promising
for the following reasons: (1) the reaction is completed in a very
short time (usually within 15 min), (2) 1,4-dimethylpiperazine used
as a solvent can be easily removed by an evaporator, and (3)
a combination of a radical initiator such as azobis(isobutyronitrile)
(AIBN) and a hydrogen atom source such as Bu3SnH is not required
for this radical cyclization.
2.1. Attempt to cyclize N-trichloroacetyl derivative 9 in
boiling 1,4-dimethylpiperazine
We initiated our investigation by examining the cyclization of
trichloroacetamide 9. Synthesis of 9 was begun by Julia olefination
between aldehyde 5, prepared by Swern oxidation of 4, and
benzyloxy sulfone 64 to give alkene 7. N-Deprotection of compound
7 followed by N-trichloroacetylation of the resultant 8 gave 9. 1
a-
H
NMR spectra of 9 showed it to be a mixture of E and Z isomers in
a ratio of ca. 1:2 (Scheme 2).
O
O
S
OBn
S
N
H
6
H
N
H
OBn
Cl
Cl
CHO
Boc
Me
Swern
LiHMDS
•
OH
Boc
1,4-dimethylpiperazine
reflux
CCl2
CCl3
O
N
THF, 0 °C
61%
N
Boc
7
N
R
3
O
N
R
O
N
R
1
5
4
H
N
CCl3COCl
H
N
TMSOTf
2
OBn
OBn
CCl3
2,6-lutidine
Et3N
Scheme 1. Radical cyclization of 1 in 1,4-dimethylpiperazine to give 3.
CH2Cl2, 0 °C
92%
CH2Cl2, 0 °C
95%
H
O
9
8
We applied this method to the synthesis of (ꢀ)-trachel-
OBn
anthamidine (14),2 one of the pyrrolizidine alkaloids,3 from
L-pro-
H
N
1,4-dimethylpiperazine
reflux
Cl
Cl
linol [(S)-(þ)-2-pyrrolidinemethanol]. We report herein the results
of work in this area.
O
Scheme 2. Preparation and attempted radical cyclization of 9.
Heating of compound 9 in boiling 1,4-dimethylpiperazine,
however, gave no cyclization product after 72 h of heating. This
result is particularly surprising in view of the previous result that
* Corresponding author. Tel.: þ81 76 234 4474; fax: þ81 76 234 4476.
E-mail address: isibasi@p.kanazawa-u.ac.jp (H. Ishibashi).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.005

7772
H. Ishibashi et al. / Tetrahedron 64 (2008) 7771–7773
compound 1 gave cyclization product 3 in good yield. We then
turned our attention to compound 11.
Kagaku Co., Ltd., spherical, neutral, 63–210
mm) or on alumina 90
(Merck, neutral, 63–200 m) under pressure.
m
4.2. 2-(2-Benzyloxyethenyl)-N-(tert-butoxycarbonyl)-
pyrrolidine (7)
2.2. Synthesis of (L)-trachelanthamidine using a single
electron transfer reaction of N-trichloroacetyl derivative 11 in
boiling 1,4-dimethylpiperazine
To a mixture of 5 (966 mg, 5.00 mmol), prepared by Swern ox-
idation of 4,9 and
a-benzyloxy sulfone 6 (1.74 g, 5.46 mmol) in THF
Compound 11 having an acetoxy alkene was easily prepared by
acid hydrolysis of compound 9 followed by treatment of the
resulting aldehyde 10 with acetic anhydride.5 1H NMR spectra of 11
showed it to be a mixture of E and Z isomers in a ratio of ca. 1:1
(Scheme 3).
(50 mL) was added a 1.05 M solution of LiHMDS in THF (10.4 mL,
10.9 mmol) at 0 ꢁC over a period of 5 min, and the mixture was
stirred at room temperature for 30 min. The reaction mixture was
poured into a saturated aqueous solution of NH4Cl and extracted
with AcOEt. The organic phase was washed with brine, dried
(MgSO4), and concentrated. The residue was chromatographed on
Ac2O, KOAc
Et3N
H
N
H
N
OAc
CCl3
1% HCl
CHO
CCl3
silica gel (hexane/AcOEt, 19:1) to give 7 (918 mg, 61%, E/Z¼1:2) as
9
24
120 °C
59%
THF,rt
96%
a pale yellow oil. [
a
]
þ17.2 (c 0.39, CHCl3); IR (CHCl3)
n 1660,
D
1680 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d 1.43 (9H, s), 1.66–2.13 (4H,
O
10
O
11
m), 3.37 (2H, br s), 4.19, 4.44 (total 1H, both br s), 4.70–4.85 (1H, m),
4.72, 4.77 (total 2H, both s), 5.99, 6.45 (total 1H, both br s), 7.30–7.38
OAc
H2, Pd/C
NaOAc
H
1
(5H, m); 13C NMR (125 MHz, CDCl3)
d 28.51, 28.52, 52.6, 71.2, 73.8,
7
6
Cl
1,4-dimethylpiperazine
8
2
3
O
78.8, 78.9, 127.3, 127.5, 127.8, 127.9, 128.4, 128.5, 137.0, 147.7; HRMS
calcd for C18H25NO3: 303.1835, found: 303.1823.
reflux
52%
N
Cl
EtOH, rt
quant.
4
5
12
4.3. 2-(2-Benzyloxyethenyl)pyrrolidine (8)
OAc
H
OH
H
LiAlH4
Toa solutionof 7(300 mg, 0.989 mmol) and2,6-lutidine (318 mg,
2.97 mmol) in CH2Cl2 (10 mL) was added trimethylsilyl tri-
fluoromethanesulfonate (242 mg, 1.09 mmol) at 0 ꢁC, and the mix-
ture was stirred at the same temperature for 10 min. The reaction
mixture was diluted with water and extracted with CH2Cl2. The or-
ganic phase was washed with brine, dried (Na2SO4), and concen-
trated. The residue was chromatographed on silica gel (CHCl3/
THF,reflux
N
N
86%
O
13
14
Scheme 3. Synthesis of (ꢀ)-trachelanthamidine (14) using radical cyclization of 11.
We were delighted to find that compound 11 gave the desired
cyclization product 12 in 52% yield by heating in 1,4-dimethylpi-
perazine for 15 min. 1H NMR spectra of 12 showed it to be a single
stereoisomer.
Dichlorine atoms of compound 12 were removed by catalytic
hydrogenolysis, quantitatively. Finally, reduction of both the ace-
toxy group and the carbonyl group of lactam 13 by LiAlH4 furnished
MeOH/Et3N, 20:1:1) to give 8 (184 mg, 92%, E/Z¼1:2) as a paleyellow
25
oil. [a
]
ꢀ7.4 (c 0.39, CHCl3); IR (CHCl3)
n
1655, 1665 cmꢀ1; 1H NMR
D
(500 MHz, CDCl3) d 1.32–1.46, 1.70–1.85, 1.87–1.98 (total 5H, all m),
2.82–2.88 (1H, m), 3.00–3.06 (1H, m), 3.44 (1/3H, q, J¼7.9 Hz), 4.00
(2/3H, d, J¼7.9 Hz), 4.74 (2/3H, dd, J¼7.9, 6.7 Hz), 4.72 (1/3ꢂ2H, s),
4.79 (2/3ꢂ2H, s), 4.91 (1/3H, dd, J¼12.2, 7.9 Hz), 6.04 (2/3H, d,
J¼6.7 Hz), 6.50 (1/3H, d, 12.2 Hz), 7.28–7.38 (5H, m); 13C NMR
(ꢀ)-trachelanthamidine (14) in 86% yield: [
a
]
D
ꢀ13.2 (c 0.72,
(125 MHz, CDCl3)
d 25.2, 25.3, 32.6, 33.1, 46.2, 53.3, 57.6, 71.1, 73.8,
EtOH),6 lit.7 [
a
]
D ꢀ13.8 (c 1.28, EtOH), lit.8 [
D ꢀ13.5 (c 2.0, EtOH).
a
]
107.6,110.8,127.3,127.6,127.9,128.4,136.9,137.4,145.3,146.9; HRMS
calcd for C13H17NO: 203.1310, found: 203.1308.
3. Conclusion
4.4. 2-(2-Benzyloxyethenyl)-N-(trichloroacetyl)pyrrolidine (9)
We have achieved a short synthesis of (ꢀ)-trachelanthamidine
(14) from -prolinol by using single electron transfer (SET) reaction of
L
To a solution of 8 (1.34 g, 6.59 mmol) and triethylamine (1.00 g,
9.89 mmol) in CH2Cl2 (65 mL) was added trichloroacetyl chloride
(1.44 g, 7.91 mmol) at 0 ꢁC, and the mixture was stirred at the same
temperaturefor10 min. Thereactionmixturewasdilutedwithwater
and extracted with CH2Cl2. The organic phase was washed with
brine, dried (Na2SO4), and concentrated. The residue was chroma-
compound 11 in boiling 1,4-dimethylpiperazine. It is still obscure why
no radical cyclization product can be obtained by reaction of tri-
chloroacetyl derivative 9 in boiling 1,4-dimethylpiperazine. The ben-
zyloxy group in 9 is apparently more electron rich than is an acetoxy
group in 11. It can therefore be presumed that the electron density of
the alkenic bond plays an important role in effecting the single elec-
tron transfer (SET) reaction in 1,4-dimethylpiperazine. Elucidation of
the mechanism of this SET reaction must await further experiments.
tographed on silica gel (hexane/AcOEt,13:1) to give 9 (2.19 mg, 95%)
25
as a pale yellow oil. [
a
]
D
þ2.7 (c 0.8, CHCl3); IR (CHCl3)
n ;
1665 cmꢀ1
d 1.71–2.20 (4H, m), 3.78–3.83 (1H, m),
1H NMR (500 MHz, CDCl3)
3.98–4.03 (1H, m), 4.44 (2/3H, t, J¼7.3 Hz), 4.64 (1/3H, br s), 4.74 (1/
3Hꢂ2H, s), 4.76–4.78 (1/3H, m), 4.84 (2/3ꢂ2H, AB q, J¼12.2 Hz), 5.00
(2/3H, dd, J¼13.4, 7.3 Hz), 6.10 (2/3H, d, J¼6.7 Hz), 6.67 (1/3H, d,
4. Experimental
4.1. General
J¼12.8 Hz), 7.30–7.38 (5H, m); 13C NMR (125 MHz, CDCl3)
d 25.1, 25.7,
31.2, 31.4, 49.0, 49.5, 56.8, 59.6, 71.5, 74.1, 94.0, 102.9, 107.1, 127.3,
127.6, 127.85, 127.90, 128.4, 136.7, 137.3, 145.7, 149.9, 158.2, 158.3;
HRMS calcd for C15H16Cl3NO2: 347.0247, found: 347.0241.
Infrared (IR) spectra were recorded on a Shimadzu FTIR-8100
spectrophotometer for solutions in CHCl3. 1H NMR and 13C NMR
spectra were measured on a JEOL EX 500 (500 MHz) or a JEOL JNM-
EX 270 (270 MHz) spectrometer. Chemical shifts (
d
) quoted are
4.5. 2-N-(Trichloroacetyl)pyrrolidineacetaldehyde (10)
relative to tetramethylsilane. High-resolution mass spectra (HRMS)
were obtained with a JEOL JMS-SX-102A mass spectrometer. Col-
umn chromatography was carried out on silica gel 60N (Kanto
To a solution of 9 (450 mg,1.29 mmol) in THF (26 mL) was added
1% HCl (30 mL) at 0 ꢁC and the mixture was stirred at room

H. Ishibashi et al. / Tetrahedron 64 (2008) 7771–7773
7773
temperature for 36 h. The mixture was basified by adding a satu-
rated aqueous solution of NaHCO3 and the mixture was extracted
with CH2Cl2. The organic phase was washed with brine, dried
(Na2SO4), and concentrated. The residue was chromatographed on
filtrate was concentrated. The residue was chromatographed on
silica gel (hexane/AcOEt, 1:3) to give 13 (12.6 mg, 100%) as a color-
25
less oil. [
a]
ꢀ27.3 (c 0.39, CHCl3); IR (CHCl3)
n
1680, 1740 cmꢀ1; 1H
D
NMR (500 MHz, CDCl3) d 1.39–1.50 (1H, m), 2.02–2.19 (3H, m), 2.08
silica gel (hexane/AcOEt, 5:1) to give 10 (321 mg, 96%) as a pale
(3H, s), 2.41–2.51 (1H, m), 2,54–2.58 (2H, m), 3.06 (1H, ddd, J¼12.2,
9.1, 3.7 Hz), 3.56 (1H, dt, J¼10.6, 7.9 Hz), 3.66–3.70 (1H, m), 4.11 (1H,
dd, J¼11.0, 7.3 Hz), 4.20 (1H, dd, J¼11.0, 5.5 Hz); 13C NMR (67.8 MHz,
25
yellow oil. [
a
]
D
ꢀ31.5 (c 2.1, CHCl3); IR (CHCl3)
n ;
1665, 1725 cmꢀ1
1H NMR (500 MHz, CDCl3)
d 1.67–1.74 (1H, m), 1.90–2.08 (2H, m),
2.21–2.28 (1H, m), 2.64 (1H, ddd, J¼17.1, 7.9, 1.2 Hz), 3.08 (1H, ddd,
CDCl3) d 20.8, 26.8, 31.4, 38.3, 41.1, 41.2, 65.0, 65.3, 170.7, 173.0;
J¼17.1, 4.3, 1.8 Hz), 3.78–3.82 (1H, m), 4.06–4.10 (1H, m), 4.51–4.56
HRMS calcd for C10H15NO3: 197.1052, found: 197.1049.
(1H, m), 9.79 (1H, s); 13C NMR (125 MHz, CDCl3)
d 25.3, 30.1, 47.0,
49.8, 56.3, 93.4, 159.1, 199.5; HRMS calcd for C8H10Cl3NO2:
256.9778, found: 256.9772.
4.9. (1R,8S)-1-Pyrrolizidinemethanol (trachelanthamidine)
(14)
4.6. 2-(2-Acetoxyethenyl)-N-(trichloroacetyl)pyrrolidine (11)
To a solution of 13 (90.0 mg, 0.46 mmol) in THF (5 mL) was
added lithium aluminum hydride (70 mg, 1.83 mmol) at 0 ꢁC and
the mixture was heated at reflux for 3 h. After cooling to room
temperature, water (0.07 mL), 10% NaOH (0.1 mL), and water
(0.21 mL) were added successively, and the mixture was further
stirred for 30 min. The mixture was filtered through Celite and the
filtrate was concentrated. The residue was chromatographed on
alumina (CH22C5l2/MeOH, 5:1) to give 14 (55.0 mg, 86%) as a pale
A mixture of 10 (40.0 mg, 0.155 mmol), triethylamine (31.0 mg,
0.309 mmol), potassium acetate (1.5 mg, 0.0155 mmol), and acetic
anhydride (324 mg, 3.17 mmol) was heated at 120 ꢁC for 1 h. After
cooling to room temperature, the reaction mixture was diluted
with water and extracted with CH2Cl2. The organic phase was
washed with brine, dried (Na2SO4), and concentrated. The residue
was chromatographed on silica gel (hexane/AcOEt, 8:1) to give 11
yellow oil. [
a
]
D
ꢀ13.2 (c 0.72, CHCl3), lit.7 [
D ꢀ13.8 (c 1.28, EtOH),
a]
(27.6 mg, 59%) as a colorless oil. IR (CHCl3)
NMR (270 MHz, CDCl3) 1.72–1.83 (1H, m), 1.95–2.23 (3H, m), 2.11,
n ;
1660, 1755 cmꢀ1 1H
lit.8 [
a
]
D ꢀ13.5 (c 2.0, EtOH); 1H NMR (270 MHz, CDCl3)
d 1.50–2.05
d
(7H, m), 2.48–2.64 (2H, m), 2.95 (1H, dt, J¼10.5, 6.3 Hz), 3.13 (1H,
2.19 (total 3Hꢂ1/2, s), 3.81–3.90 (1H, m), 3.99–4.09 (1H, m), 4.69–
4.73(1/2H, m), 4.82 (1/2H, dd, J¼7.9, 6.7 Hz), 5.03–5.07 (1/2H, m),
5.38 (1/2H, dd, J¼12.2, 7.3 Hz), 7.15 (1/2H, d, J¼6.7 Hz), 7.35 (1/2H, d,
ddd, J¼10.1, 7.1, 3.5 Hz), 3.22 (1H, dd, J¼13.2, 6.3 Hz), 3.59 (2H, d,
6.3 Hz), 4.05–4.25 (1H, br); 13C NMR (67.8 MHz, CDCl3)
d 25.6, 29.9,
31.9, 48.3, 54.4, 54.7, 64.9. 67.6; HRMS calcd for C8H15NO: 141.1154,
found: 141.1154.
J¼12.2 Hz); 13C NMR (125 MHz, CDCl3)
d 20.6, 20.7, 25.1, 25.7, 30.5,
31.1, 49.4, 49.6, 56.3, 58.6, 93.7, 112.5,112.9, 134.9,138.1, 158.6, 167.4,
167.7; HRMS calcd for C10H12Cl3NO3: 298.9883, found: 298.9884.
Acknowledgements
4.7. (1R,8S)-1-Acetoxymethyl-2,2-dichloropyrrolizidin-
3-one (12)
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,
and Technology of Japan.
A solution of 11 (42.5 mg, 0.14 mmol) in N,N’-dimethylpiper-
azine (2 mL) was heated at reflux for 15 min. After cooling to room
temperature, the reaction mixture was diluted with water and
extracted with CH2Cl2. The organic phase was washed with brine,
dried (MgSO4), and concentrated. The residue was chromato-
References and notes
1. Ishibashi, H.; Haruki, S.; Uchiyama, M.; Tamura, O.; Matsuo, J. Tetrahedron Lett.
2006, 47, 6263–6266.
graphed on silica gel (hexane/AcOEt, 5:1) to give 12 (19.5 mg, 52%)
25
as a pale yellow oil. [
a
]
ꢀ34.6 (c 0.72, CHCl3); IR (CHCl3)
n
2. For recent synthesis of (ꢀ)-trachelanthamidine, see: (a) Craig, D.; Hyland, C. J. T.;
Ward, S. E. Synlett 2006, 2142–2144; (b) Chang, M.-Y.; Wu, D.-C.; Chang, N.-C.
Heterocycles 2005, 65, 2965–2971; (c) Kim, S.-H.; Kim, S.-I.; Lai, S.; Cha, J. K. J. Org.
Chem. 1999, 64, 6771–6775; (d) Konno, H.; Kishi, M.; Hiroya, K.; Ogasawara, K.
Heterocycles 1998, 49, 33–37; (e) Knight, D. W.; Share, A. C.; Gallagher, P. T.
J. Chem. Soc., Perkin Trans. 1 1997, 2089–2097; (f) Ishibashi, H.; Uemura, N.;
Nakatani, H.; Okazaki, M.; Sato, T.; Nakamura, N.; Ikeda, M. J. Org. Chem. 1993, 58,
2360–2368.
3. For reviews on the synthesis of pyrrolizidine alkaloids, see: (a) Liddell, J. R. Nat.
Prod. Rep. 2000, 17, 455–462; (b) Ikeda, M.; Sato, T.; Ishibashi, H. Heterocycles
1988, 27, 1465–1487.
4. Surprenant, S.; Chan, W. Y.; Berthelette, C. Org. Lett. 2003, 5, 4851–4854.
5. Simmons, D. P.; Reichlin, D.; Skuy, D. Helv. Chim. Acta 1988, 71, 1000–1004.
6. A partial racemization might occur in Swern oxidation of alcohol 4 to give al-
dehyde 5.
D
1725 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d 1.50–1.58 (1H, m), 2.10–
2.25 (3H, m), 2.11 (3H, s), 2.77 (1H, dd, J¼13.7, 7.8 Hz), 3.26–3.30
(1H, m), 3.55–3.61 (1H, m), 3.67 (1H, dd, J¼14.6, 8.9 Hz), 4.49–4.57
(2H, m); 13C NMR (125 MHz, CDCl3)
d 20.7, 26.5, 30.4, 41.9, 58.1,
61.41, 61.45, 86.8, 164.5, 170.5; HRMS calcd for C10H13Cl2NO3:
265.0273, found: 265.0256.
4.8. (1R,8S)-1-(Acetoxymethyl)pyrrolizidin-3-one (13)
A solution of 12 (17.0 mg, 0.064 mmol) in EtOH (2 mL) was
vigorously stirred under H2 atmosphere at room temperature in the
presence of 10% Pd/C (2 mg) and NaOAc (13 mg, 0.16 mmol) for 4
days. The reaction mixture was filtered through Celite and the
7. Tsuda, Y.; Marion, L. Can. J. Chem. 1963, 41, 1919–1923.
8. Robins, D. J.; Sakdarat, S. J. Chem. Soc., Perkin Trans. 1 1981, 909–913.
9. Reed, P. E.; Katzenellenbogen, J. A. J. Org. Chem. 1991, 56, 2624–2634.