Formal synthesis of (±)-trachelanthamidine

Article abstract of DOI:10.3987/COM-05-10541

Base-induced coupling-cyclization stepwise [3+2] annulation of α-sulfonylacetamide with (Z)-2-bromoacrylate yielded the polysubstituted pyroglutamate with three contiguous chiral centers with trans-trans orientation in a one-pot synthesis. The pyrrolizidine skeleton was obtained via the ring-closing metathesis (RCM) method. This facile strategy was used to synthesize (±)-trachelanthamidine.

Full text of DOI:10.3987/COM-05-10541

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Received, 18th August, 2005, Accepted, 26th September, 2005, Published online, 27th September, 2005
FORMAL SYNTHESIS OF (±)-TRACHELANTHAMIDINE
Meng-Yang Chang,*,a Dong-Ciao Wu,b and Nein-Chen Changb
aDepartment of Applied Chemistry, National University of Kaohsiung, Kaohsiung
b
811, Taiwan Department of Chemistry, National Sun Yat-Sen University,
Kaohsiung 804, Taiwan
Abstract — Base-induced coupling-cyclization stepwise [3+2] annulation of
α-sulfonylacetamide with (Z)-2-bromoacrylate yielded the polysubstituted
pyroglutamate with three contiguous chiral centers with trans-trans orientation in
a one-pot synthesis. The pyrrolizidine skeleton was obtained via the ring-closing
metathesis (RCM) method. This facile strategy was used to synthesize
(±)-trachelanthamidine.
INTRODUCTION
Pyrrolizidine alkaloids have long attracted synthetic interest due to their relatively structural features and
wide range of pharmacological activity.1 Diverse and elegant synthetic approaches have been developed
for construction of this core structure, such as 1-hydroxymethylpyrrolizidines.2 In Figure 1,
trachelanthamidine (1, also called laburnine) and isoretronecanol (2) have a common framework and their
only difference is the C1-configuration. Basically, the adopted strategies can be summarized in Lewis
acid promoted tandem [4+2]/[3+2]2h cycloaddition, intramolecular palladium,2a,2i tungsten2c or titanium2f
catalyzed ring closure, intermolecular conjugation of cyclic tertiary amines via organocuprate mediated2b
or photochemically radical initiated2e and chiral material such as glucosamine.2j Here we report a formal
synthesis of (±)-trachelanthamidine (1)2-4 via the stepwise [3+2] annulation5 and ring-closing
metathesis.6-7
Figure 1.
OH
OH
H
N
H
N
1
trachelanthamidine (1)
isoretronecanol (2)

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RESULTS AND DISCUSSION
For the synthesis of pyroglutamate (5) via a stepwise [3+2] annulation reaction,5 (Z)-2-bromoacrylate (3)
and α-sulfonylacetamide (4) were chosen as the starting materials. (Z)-2-Bromoacrylate (3) was given by
ozonolysis of allyl benzyl ether and Wittig olefination of the resulting aldehyde with Ph3P=C(Br)CO2Et
in 86% yield. Allylamine was treated with chloroacetyl chloride and triethylamine to produce
α-chloroacetamide, which was then treated with sodium p-toluenesulfinate salt to give
α-sulfonylacetamide (4) in 85% yield from the two-steps reaction. The one-pot synthesis began with the
reaction of (Z)-2-bromoacrylate (3) with α-sulfonylacetamide (4) (NaH/THF) and proceeded through
stereo- and regioselective annulation with the appropriate carbonyl substrate in a [3+2] mode, resulting in
the overall formation of single pyroglutamate isomer (5) in which the substitutents at C2 and C3 and C3
and C4 are trans to each other.
Scheme 1. Formal synthesis of (±)-trachelanthamidine (1).
OBn
Ts
OBn
OBn
+
Ts
O
EtO2C
(1) LAH, THF (65%)
NaH, THF
(55%)
HO
3
Br
2
N
4
HN
N
(2) Na/Hg, MeOH (80%)
EtO2C
O
O
3
6
4
5
OBn
OH
H
OH
H
1) (COCl)2, DMSO, Et3N
1) Grubbs' 2nd, PhH (81%)
ref. 2e
N
O
7
N
N
2) Ph3P=CH2, THF
(two steps 64%)
2) H2, 10% Pd/C, MeOH (90%)
O
8
1
As shown in Scheme 1, compound (6) was accomplished by reduction of pyroglutamate (5) with lithium
aluminum hydride followed by desulfonation of the resulting alcohol with sodium amalgam. Preparation
of diene (7) was achieved by Swern oxidation of alcohol (6) in dichloromethane followed by Wittig
olefination of the resulting aldehyde with methyltriphenylphosphonium bromide and n-butyllithium in
tetrahydrofuran. To build up the pyrrolizidine skeleton, diene (7) was subjected to ring-closing metathesis
(RCM) reaction employing second generation Grubbs catalyst.6-7 In order to achieve the formal synthesis
of (±)-trachelanthamidine (1), hydrogenation was accomplished by treatment of the resulting compound
with hydrogen on 10% palladium-activated carbon to afford known lactam (8).2e,3i
CONCLUSION
We explored a new synthetic strategy of (±)-trachelanthamidine (1) by an intermolecular stepwise [3+2]
annulation and an intramolecular ring-closing metathesis as the key reactions.

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EXPERIMENTAL
General. Tetrahydrofuran was distilled prior to use from a deep-blue solution of sodium-benzophenone
ketyl. All other reagents were obtained from commercial sources and used without further purification.
Reaction was routinely carried out under an atmosphere of dry nitrogen with magnetic stirring. Extract
was dried with anhydrous magnesium sulfate before concentration in vacuo. Crude product was purified
using column chromatography on silica gel.
Ethyl 1-allyl-3-benzyloxymethyl-4-(4-methylphenylsulfonyl)pyroglutamate (5).
A solution of compound (4) (253 mg, 1.0 mmol) in tetrahydrofuran (5 mL) was carefully added to a
rapidly stirred suspension of sodium hydride (132 mg, 3.3 mmol, 60%) in tetrahydrofuran (30 mL). After
the reaction mixture was stirred at rt for 15 min, a solution of compound (3) (300 mg, 1.01 mmol) in
tetrahydrofuran (30 mL) was added. The reaction mixture was further refluxed for 1 h. The reaction was
quenched with 15% ammonium chloride solution (1 mL) in an ice bath, and concentrated under reduced
pressure. Water (20 mL) was added to the crude product, and the mixture was extracted with ethyl acetate
(3 x 50 mL). The combined organic layers were washed with brine, dried, filtered and evaporated.
Purification on silica gel (hexane/ethyl acetate = 4/1) afforded product (5) (260 mg, 55%) as a viscous oil:
HRMS (ESI, M++1) calcd for C25H30NO6S 472.1794, found 472.1797; 1H NMR (500 MHz, CDCl3) δ
7.80 (d, J = 8.0 Hz, 2H), 7.36-7.25 (m, 7H), 5.60-5.52 (m, 1H), 5.14-5.11 (m, 2H), 4.55 (s, 2H), 4.43 (dd,
J = 4.5, 15.5 Hz, 1H), 4.30-4.17 (m, 2H), 4.09 (d, J = 4.0 Hz, 1H), 3.99 (d, J = 4.0 Hz, 1H), 3.72 (d, J =
4.0 Hz, 2H), 3.65 (dd, J = 8.0, 15.5 Hz, 1H), 3.35-3.32 (m, 1H), 2.45 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 169.85, 164.99, 145.29, 137.23, 134.30, 130.82, 129.55 (2C), 129.43 (2C),
128.43 (2C), 127.91, 127.68 (2C), 119.03, 73.14, 69.85, 67.08, 61.05, 59.05, 45.03, 37.66, 21.69, 14.07;
Anal. Calcd for C25H29NO6S C, 63.67; H, 6.20; N, 2.97; Found C, 63.90; H, 6.34; N, 2.89.
1-Allyl-4-benzyloxymethyl-5-hydroxymethylpyrrolidin-2-one (6).
Lithium aluminum hydride (38 mg, 1.0 mmol) was added to a stirred solution of compound (5) (118 mg,
0.25 mmol) in tetrahydrofuran (10 mL) at ice bath. The mixture was further stirred for 2 h at rt. The
reaction was quenched with 15% ammonium chloride solution (1 mL) and the mixture was concentrated
under reduced pressure. Water (10 mL) was added to the residue, and the mixture was extracted with
ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried, filtered and
evaporated. Purification on silica gel (hexane/ethyl acetate = 2/1) afforded pure alcohol (70 mg, 65%) as a
viscous oil: IR (CHCl3) 3447, 1925, 1690 cm-1; FAB-MS: C23H28NO5S m/z (%) = 91 (100), 136 (87), 154
(93), 430 (M++1, 9); HRMS (ESI, M++1) calcd for C23H28NO5S 430.1688, found 430.1685;1H NMR (500
MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 2H), 7.32-7.22 (m, 7H), 5.66-5.58 (m, 1H), 5.16-5.09 (m, 2H), 4.48
(s, 2H), 4.11 (dd, J = 5.0, 16.0 Hz, 1H), 3.99 (d, J = 5.5 Hz, 1H), 3.71-3.66 (m, 3H), 3.58 (d, J = 4.5 Hz,
2H), 3.54 (dd, J = 4.0, 9.0 Hz, 1H), 3.07-3.03 (m, 1H), 2.85 (br s, 1H), 2.40 (s, 3H); 13C NMR (125 MHz,

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CDCl3) δ 165.10, 145.15, 137.29, 134.41, 131.47, 129.45 (2C), 129.26 (2C), 128.29 (2C), 127.71, 127.52
(2C), 117.90, 72.99, 70.08, 67.29, 61.89, 59.78, 44.13, 35.86, 21.56. 6% Sodium amalgam (Na/Hg, 500
mg) and sodium phosphate (71 mg, 0.5 mmol) were added to a stirred solution of alcohol compound (90
mg, 0.21 mmol) in methanol (5 mL). The mixture was vigorously stirred for 2 h at rt. The residue was
filtered and washed with methanol (2 x 10 mL). The combined organic layers were concentrated under
the reduced pressure to afford the residue. Water (10 mL) was added to the residue, and the mixture was
extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried,
filtered and evaporated. Purification on silica gel (hexane/ethyl acetate = 1/1) produced compound (6) (46
mg, 80%) as a viscous oil: FAB-MS: C16H22NO3 m/z (%) = 91 (51), 107 (37), 137 (100), 154 (100), 219
1
(10), 276 (M++1, 14); HRMS (ESI, M++1) calcd for C16H22NO3 276.1600, found 276.1602; H NMR
(500 MHz, CDCl3) δ 7.36-7.26 (m, 5H), 5.73-5.65 (m, 1H), 5.22-5.15 (m, 2H), 4.52 (dd, J = 11.5, 19.5
Hz, 2H), 4.20 (dd, J = 5.0, 15.5 Hz, 1H), 3.74 (dd, J = 4.0, 12.0 Hz, 1H), 3.64 (d, J = 4.0, 12.0 Hz, 1H),
3.59 (d, J = 7.0 Hz, 1H), 3.51 (dd, J = 3.5, 7.0 Hz, 1H), 3.46 (dd, J = 5.5, 9.5 Hz, 1H), 3.38 (t, J = 8.5 Hz,
1H), 2.63 (dd, J = 9.5, 17.0 Hz, 1H), 2.58-2.52 (m, 1H), 2.45 (br s, 1H), 2.13 (dd, J = 5.0, 17.0 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 174.49, 137.60, 132.62, 128.47 (2C), 127.86, 127.70 (2C), 118.07, 73.24,
71.89, 62.63, 62.33, 43.52, 34.87, 33.70; Anal. Calcd for C16H21NO3 C, 69.79; H, 7.69; N, 5.09; Found C,
69.83; H, 7.54; N, 4.89.
1-Allyl-4-benzyloxymethyl-5-vinylpyrrolidin-2-one (7).
A solution of oxalyl chloride (200 mg, 1.58 mmol) in dichloromethane (10 mL) was mixed with dimethyl
o
o
sulfoxide (200 mg, 2.56 mmol) at –78 C carefully. The solution was warmed to –40 C for 5 min and
o
recooled to –78 C, and then a solution of alcohol (6) (140 mg, 0.51 mmol) in dichloromethane (5 mL)
was added dropwise for 40 min followed by excess triethylamine (800 mg, 7.91 mmol) for 30 min. The
reaction mixture was warmed to rt and poured into 15% ammonium chloride solution (2 mL), and
concentrated under the reduced pressure. The residue was diluted with water (15 mL) and extracted with
ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine and water, dried, filtered
and evaporated to give the crude aldehyde. To a stirred solution of methyltriphenylphosphonium bromide
(714 mg, 2.0 mmol) in tetrahydrofuran (30 mL) was added n-butyllithium (1.0 mL, 1.6 M, 1.6 mmol) at
o
o
–78 C. The orange red colored mixture was stirred at –78 C for 1 h. The crude aldehyde in dry
o
tetrahydrofuran (5 mL) was added to the reaction mixture at –78 C via a syringe and further stirred at
o
–78 C for 2 h. The reaction was quenched with 15% ammonium chloride solution (1 mL) and the
mixture was concentrated. Water (10 mL) was added to the residue, and the mixture was extracted with
ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried, filtered and
evaporated. Purification on silica gel (hexane/ethyl acetate = 2/1) produced compound (7) (88 mg, two
steps 64%) as a viscous oil: IR (CHCl3) 2924, 1684, 1456 cm-1; FAB-MS: C17H22NO2 m/z (%) = 81 (100),

HETEROCYCLES, Vol. 65, No. 12, 2005
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91 (78), 133 (78), 219 (36), 272 (M++1, 21); HRMS (ESI, M++1) calcd for C17H22NO2 272.1650, found
1
272.1648; H NMR (500 MHz, CDCl3) δ 7.37-7.29 (m, 5H), 5.69-5.61 (m, 2H), 5.24-5.10 (m, 4H), 4.52
(s, 2H), 4.28 (ddt, J = 1.5, 5.0, 15.5 Hz, 1H), 3.89 (dd, J = 4.5, 8.5 Hz, 1H), 3.47 (dd, J = 5.5, 9.0 Hz, 1H),
3.42 (dd, J = 5.5, 9.0 Hz, 1H), 3.39 (dd, J = 7.5, 15.5 Hz, 1H), 2.61-2.55 (m, 1H), 2.54-2.27 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 173.72, 137.94, 136.91, 132.22, 128.42 (2C), 127.75, 127.63 (2C), 118.48,
117.80, 73.14, 70.39, 63.21, 43.05, 38.56, 33.31.
1-Hydroxymethylhexahydropyrrolizin-3-one (8).2e,3i
Grubbs’ 2nd catalyst (6 mg, 0.007 mmol) was added to a stirred solution of compound (7) (35 mg, 0.13
mmol) in benzene (30 mL). The reaction mixture was reflux for 36 h. The mixture was concentrated and
the residue was purified by flash column chromatography (hexane/ethyl acetate = 1/1) to yield bicyclic
lactam (25 mg, 81%) as a viscous oil: IR (CHCl3) 2923, 1699, 1457 cm-1; FAB-MS: C15H18NO2 m/z (%)
= 91 (100), 133 (11), 154 (5), 244 (M++1, 13); HRMS (ESI, M++1) calcd for C15H18NO2 244.1337, found
244.1339; 1H NMR (500 MHz, CDCl3) δ 7.38-7.29 (m, 5H), 5.96 (dd, J = 1.5, 6.5 Hz, 1H), 5.86 (dd, J =
1.5, 6.5 Hz, 1H), 4.58 (d, J = 12.5 Hz, 1H), 4.54 (d, J = 12.5 Hz, 1H), 4.44-4.38 (m, 2H), 3.68-3.63 (m,
13
2H), 3.56-3.53 (m, 1H), 2.57-2.50 (m, 2H), 2.41-2.34 (m, 1H); C NMR (125 MHz, CDCl3) δ 176.84,
137.99, 130.57, 128.45 (2C), 128.04, 127.74, 127.47 (2C), 73.21, 71.47, 71.42, 49.87, 44.46, 36.91. 10%
Palladium on activated carbon (10 mg) was added to a stirred solution of bicyclic lactam (24 mg, 0.10
mmol) in methanol (5 mL). Hydrogen was bubbled into the mixture for 10 min, and the reaction mixture
was continued to stir for 3 h at rt under hydrogen atmosphere. The catalyst was filtered through a short
plug of Celite and washing with methanol (2 x 10 mL). The combined organic layers were evaporated to
afford crude products. Purification on silica gel (dichloromethane/methanol = 10/1) produced known
lactam (8) (14 mg, 90%) as a viscous oil: HRMS (ESI, M++1) calcd for C8H14NO2 156.1025, found
1
156.1026; H NMR (500 MHz, CDCl3) δ 3.74-3.63 (m, 3H), 3.53-3.48 (m, 1H), 3.05-3.00(m, 2H),
2.58-2.45 (m, 2H), 2.36-2.30 (m, 1H), 2.13-1.97 (m, 3H), 1.44-1.35 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 173.99, 65.14, 63.91, 44.02, 41.02, 38.11, 31.55, 26.85. Compound (8) was treated with lithium
aluminum hydride in tetrahydrofuran to yield (±)-trachelanthamidine (1). The procedure was shown in
references 2e and 3i.
ACKNOWLEDGEMENTS
The authors would like to thank the National Science Council (NSC 94-2113-M-390-001) of the Republic
of China for financial support.
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