Synthesis of psudoheliotridane via formal [3+2] annulation and ring-closing metathesis

Article abstract of DOI:10.1016/j.tet.2004.04.074

Base-induced coupling/cyclization stepwise [3+2] annulation of α-sulfonylacetamide with (Z)-2-bromoacrylates yielded polysubstituted pyroglutamates 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 psudoheliotridane.

Full text of DOI:10.1016/j.tet.2004.04.074

Tetrahedron 60 (2004) 5545–5550
Synthesis of psudoheliotridane via formal [312] annulation and
ring-closing metathesisq;qq
b
b
b
b
,
Meng-Yang Chang,a Ru-Ting Hsu, Tze-Wei Tseng, Pei-Pei Sun and Nein-Chen Chang
,
*
*
aDepartment of Applied Chemistry, National University of Kaohsiung, No. 700, Kaohsiung University Road, Kaohsiung 811, Taiwan, ROC
bDepartment of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, ROC
Received 9 April 2004; revised 28 April 2004; accepted 30 April 2004
Abstract—Base-induced coupling/cyclization stepwise [3þ2] annulation of a-sulfonylacetamide with (Z)-2-bromoacrylates yielded
polysubstituted pyroglutamates 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 psudoheliotridane.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Recently, we introduced a new and general methodology for
the syntheses of pyroglutamates via [3þ2] annulation
reactions between different a-sulfonylacetamide derivatives
and various ethyl (Z)-2-bromo-2-propenoates.1 – 4 To
demonstrate the synthetic utility of our methodology and
continuing our investigation on the application of this
methodology to the synthesis of alkaloids, the synthesis of
pyrrolizidine alkaloids psudoheliotridane (1a) was investi-
gated.5 Pyrrolizidines and related compounds have attracted
considerable attention due to their chemical and pharmaco-
logical properties (Fig. 1).
2.1. Retrosynthetic approach to psudoheliotridane
Our approach to psudoheliotridane (1a) was shown in
Scheme 1. We envisioned that the pyrrolizidine skeleton
could be achieved via the facile intermolecular [3þ2]
annulation to pyroglutamate skeleton followed by intramo-
lecular ring-closing metathesis (RCM) with Grubbs’
catalyst.
2.2. Synthesis of psudoheliotridane
Allylamine was treated with chloroacetyl chloride and
triethylamine to produce a-chloroacetamide, which was
then treated with p-toluenesulfinic acid sodium salt; the two-
step reaction gave a-sulfonylacetamide 3 in 85% yield.
Treatment of acetaldehyde with Ph3P¼C(Br)CO2Et gave
ethyl (Z)-2-bromo-2-butenoate 4 in 98% yield.6 Compounds
3 and 4 were the reasonable starting materials for the
synthesis of pyroglutamate skeleton.
The [3þ2] reaction of 3 with 4 (NaH/THF)1 proceeded
smoothly, the cyclized pyroglutamate 5 was obtained as a
single isomer in 52% yield in which the substitutents at C2
and C3 and C3 and C4 are trans to each other (Scheme 2).
The reaction mechanism for the outstanding stereo-
selectivity of the annulation reaction has been reported by
us.1–4 The structure of 5 was determined by single-crystal
X-ray analysis.7 With the requisite pyroglutamate 5 in hand,
we then examined the reduction of 5. When 5 was treated
with lithium aluminum hydride, 6a and 6b were yielded in
the ratio of 7:1 with 86% overall yield. However, reaction of
5 with alane reagent [LiAlH4/AlCl3], only 6b was produced.
Under a milder condition, the reduction of 5 with sodium
borohydride gave the desired 6a as the sole product in 90%
Figure 1. Structure of psudoheliotridane (1a) and heliotridane (1b).
q CDRI Communication No. 6414.
qq Supplementary data associated with this article can be found in the
online version, at doi: 10.1016/j.tet.2004.02.074
Keywords: Stepwise [3þ2] annulation; Ring-closing metathesis;
Psudoheliotridane.
*
Corresponding authors. Tel.: þ886-7-5919464; fax: þ886-7-5919348
(M.-Y.); tel.: þ886-7-5252000x3913; fax: þ886-7-5253913 (N.-C.);
e-mail addresses: mychang@nuk.edu.tw; ncchang@mail.nsysu.edu.tw
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.074

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M.-Y. Chang et al. / Tetrahedron 60 (2004) 5545–5550
Scheme 1.
Scheme 2.
yield. Preparation of diene 2 was achieved by Swern
oxidation of alcohol 6a followed by Wittig olefination of the
resulting aldehyde with methyl triphenylphosphonium
iodide. Diene 2 is a reasonable intermediate for the
synthesis of psudoheliotridane (1a) (Diagram 1).
hydrates, heterocycles and alkaloids.8,9 In our case, the
pivotal issues were the ring strain in the [3.3.0] bicyclic
product and the amino group in the pyrrolidine ring that
could potentially chelate the metal center of the Grubbs’
metathesis catalyst and thus form unproductive complex.
When 2 was subjected to a RCM reaction employing first
generation Grubbs’ catalyst A [Cl2(PCy3)2Ru¼CHPh], the
expected bicyclic lactam 7 was generated in low yield
(Fig. 2).
Figure 2. Commercially available Grubbs catalyst A and B.
During the ring closure process, bis(olefin)-pyroglutamate 2
was affected by catalyst A, isomerization of double bond
occurred and enamine-olefin 7a was the major product
under a number of conditions (prolonged reaction time,
elevated temperature, different solvents). This result was
rather surprising because catalyst A has been shown tolerant
a variety of functional groups, although there have been
scattered reports of double bond migration problems
with this catalyst.8,9 The ring strain existed in the desired
Diagram 1. X-ray crystallography of 5.
To build up the pyrrolizidine skeleton, diene 2 was
subjected to RCM reaction. Ring-closing metathesis
(RCM) has been established as a powerful method for the
elaboration of medium-sized rings, including carbo-

M.-Y. Chang et al. / Tetrahedron 60 (2004) 5545–5550
5547
5,5-fused product 7 might retard the normally facile
cyclization.8
5.12 (m, 2H), 4.00 (s, 2H), 3.86–3.83 (m, 2H), 2.41 (s, 3H);
13C NMR (75 MHz, CDCl3) d 160.60, 145.64, 135.29,
133.10, 130.05 (2£), 128.18 (2£), 117.00, 62.06, 42.34,
21.66. Anal. Calcd for C12H15NO3S: C, 56.90; H, 5.97; N,
5.53. Found: C, 56.72; H, 6.04; N, 5.58.
We next turn our attention to examine the second generation
Grubbs’ catalyst B, which has higher thermal stability and
lower sensitivity to double bond migration. Using similar
reaction conditions, compound 7 was obtained as the major
product in 65% yield. Finally, desulfonation of 7 was
accomplished by treatment of 7 with 6% sodium amalgam
(Na/Hg) to give compound 8. To accomplish the synthesis
of psudoheliotridane (la), hydrogenation of double bond in 8
was conducted with 10% palladium on carbon.
4.1.2. Ethyl 2-bromo-2-buteoate (4).6 A solution of
acetaldehyde (1.32 g, 30.0 mmol) in DCM (10 mL) was
added to a rapidly stirred solution of Ph3P¼C(Br)CO2Et
(13.2 g, 3.1 mmol) in DCM (40 mL), then stirred at rt for
7 h. The resulting mixture was concentrated under reduced
pressure. Water (20 mL) was added to the residue, and
extracted with ethyl acetate (3£50 mL). The combined
organic layers were washed with brine, dried, filtered and
evaporated. Purification of the crude product by column
chromatography on silica gel with hexane/ethyl acetate
3. Conclusion
(40/1–20/1) produced
4
(585 mg, 98%). 1H NMR
We explored one-pot reaction, using facile intermolecular
cycloaddition strategy, to form the pyroglutamate skeleton.
Efficient intramolecular ring-closing metathesis (RCM),
using the second Grubbs’ catalyst B, generated pyrrolizidine
skeleton. This consecutive cyclization strategy is syntheti-
cally useful for constructing pyrrolizidine alkaloids. The
formal synthesis of psudoheliotridane (la) was accom-
plished. We are currently studying the scope of this process
as well as additional applications of this approach to the
synthesis of various pyrrolizidines and indolizidines.
(300 MHz, CDCl3) d 7.37 (q, J¼6.0 Hz, 1H), 4.27 (q,
J¼6.0 Hz, 2H), 1.94 (d, J¼6.0 Hz, 3H), 1.32 (t, J¼6.0 Hz,
3H).
4.1.3. Ethyl 1-allyl-3-methyl-4-(4-methylphenylsul-
fonyl)pyroglutamate (5). A solution of 3 (253 mg,
1.0 mmol) in THF (30 mL) was carefully added to a rapidly
stirred suspension of sodium hydride (1.24 g, 3.1 mmol,
60%) in THF (30 mL). After the reaction mixture was
stirred at rt for 15 min, a solution of 4 (212 mg, 1.1 mmol) in
THF (30 mL) was added. The resulting mixture was stirred
for 6 h at refluxed temperature, quenched with saturated
ammonium chloride solution (2 mL) in an ice bath, and
concentrated under reduced pressure. Water (20 mL) was
added to the crude product, and extracted with ethyl acetate
(3£50 mL). The combined organic layers were washed with
brine, dried, filtered and evaporated. Purification of the
crude product by column chromatography on silica gel with
hexane/ethyl acetate (4/1–2/1–1/1) produced 5 (190 mg,
52%): mp 101–103 8C; FAB-MS: C18H23NO5S m/z
(%)¼136 (100), 154 (28), 210 (10), 366 (Mþþ1, 45);
HRMS (FAB, Mþþ1) Calcd for C18H24NO5S 366.1375,
4. Experimental
4.1. General
Dichloromethane (DCM) and tetrahydrofuran (THF) were
distilled prior to use. All other reagents and solvents were
obtained from commercial sources and used without further
purification. Reactions were routinely carried out under an
atmosphere of dry nitrogen with magnetic stirring. Products
in organic solvents were dried with anhydrous magnesium
sulfate before concentration in vacuo. All reported melting
temperatures are uncorrected.
1
found 366.1373; H NMR (500 MHz, CDCl3) d 7.82 (d,
J¼8.0 Hz, 2H), 7.35 (d, J¼8.0 Hz, 2H), 5.65–5.57 (m, 1H),
5.20–5.12 (m, 2H), 4.42 (dd, J¼5.0, 15.0 Hz, 1H), 4.31–
4.18 (m, 2H), 3.70 (d, J¼4.5 Hz, 1H), 3.62 (dd, J¼8.0,
15.0 Hz, 1H), 3.60 (d, J¼5.5 Hz, 1H), 3.21–3.14 (m, 1H),
2.44 (s, 3H), 1.42 (d, J¼7.5 Hz, 3H), 1.32 (t, J¼7.5 Hz, 3H);
13C NMR (125 MHz, CDCl3) d 169.46, 164.94, 145.29,
134.37, 130.78, 129.54 (2£), 129.42 (2£) 119.72, 71.72,
63.69, 61.79, 44.92, 32.59, 21.67, 20.79, 14.07. Anal. Calcd
for C18H23NO5S: C, 59.16; H, 6.34; N, 3.83. Found: C,
59.41; H, 6.24; N, 3.80.
4.1.1. 1-Allyl-2-(4-methylphenylsulfonyl)acetamide (3).
Chloroacetyl chloride (1.2 g, 10.6 mmol) in THF (20 mL)
was added to a solution of allylamine (0.57 g, 10.0 mmol)
and triethylamine (1.06 g, 10.5 mmol) in THF (30 mL) in an
ice bath for 30 min, then stirred at rt for 4 h. The mixture
was concentrated under reduced pressure. Water (30 mL)
was added to the crude product and extracted with ethyl
acetate (3£50 mL). The combined organic layers were
washed with brine (2£20 mL), dried, filtered and evapor-
ated. Without purification, the crude product with p-toluene-
sulfinic acid sodium salt (3.2 g, 16.5 mmol) was refluxed in
dioxane (70 mL) and water (70 mL) for 15 h. The mixture
was concentrated under reduced pressure and the residue
was extracted with ethyl acetate (3£100 mL). The combined
organic layers were washed with brine (2£20 mL), dried,
filtered and evaporated. Recrystallization on hexane
(60 mL) and ethyl acetate (30 mL) yielded 3 (2.15 g,
85%): mp 136–137 8C (hexane/ethyl acetate); EI-MS:
C12H15NO3S m/z (%)¼98 (100), 253 (Mþ, 1); HRMS (EI,
Mþ) Calcd for C12H15NO3S 253.0773, found 253.0770; 1H
NMR (300 MHz, CDCl3) d 7.75 (d, J¼8.1 Hz, 2H), 7.33 (d,
J¼8.1 Hz, 2H), 6.90 (br s, 1H), 5.82–5.73 (m, 1H), 5.24–
Single-crystal X-ray diagram:7 crystal of 5 was grown by
slow diffusion of ethyl acetate into a solution of 5 in DCM to
yield colorless prism. The compound crystallizes in the
orthorhombic crystal system, space group. Pca2(1),
˚
˚
˚
a¼9.8102(11) A, b¼10.3120(12) A, c¼18.686(2) A,
3
V¼1890.3(4) A , Z¼4, dCalcd¼1.284 mg/m3, absorption
˚
coefficient 0.198 mm21, F(000)¼776, 2u range (1.97–
26.048).
4.1.4. 1-Allyl-5-hydroxymethyl-4-methyl-3-(4-methyl-
phenylsulfonyl)pyrrolidin-2-one (6a) and 1-allyl-3-
methyl-4-(4-methylphenylsulfonyl)prolinol (6b). For

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M.-Y. Chang et al. / Tetrahedron 60 (2004) 5545–5550
NaBH4 condition: a solution of 5 (310 mg, 0.85 mmol) in
ethanol (10 mL) was stirred at rt, and sodium borohydride
(150 mg, 4.0 mmol) and lithium chloride (170 mg,
4.0 mmol) was added. The mixture was stirred for 12 h at
rt. Saturated sodium bicarbonate solution (1 mL) was added
to the mixture and the mixture was concentrated under
reduced pressure. Water (1 mL) was added to the
residue, and the mixture was extracted with DCM
(3£10 mL). The combined organic layers were washed
with brine, dried, filtered and evaporated. Purification of
the crude product by column chromatography on silica gel
with hexane/ethyl acetate (2/1–1/1) produced 6a (247 mg,
90%).
C16H23NO3S: C, 62.11; H, 7.49; N, 4.53. Found: C, 61.91;
H, 7.32; N, 4.55.
4.1.5. 1-Allyl-4-methyl-3-(4-methylphenylsulfonyl)-5-
vinyl-pyrrolidin-2-one (2). A solution of oxalyl chloride
(0.14 mL, 1.56 mmol) in DCM (10 mL) at 278 8C, and
dimethyl sulfoxide (0.19 mL, 2.67 mmol) were added
carefully. The solution was warmed to 240 8C for 5 min
and recooled to 278 8C, and then a solution of alcohol 6a
(160 mg, 0.5 mmol) in DCM (5 mL) was added dropwise
for 40 min followed by excess triethylamine (4 mL) for
30 min. The reaction mixture was warmed to rt and poured
into saturated aqueous ammonium chloride solution (2 mL),
and concentrated. The residue was diluted with water
(15 mL) and extracted with ethyl acetate (3£30 mL). The
organic layer was washed with brine and water, dried,
filtered and evaporated to give the crude aldehyde product:
FAB-MS: C17H21NO3S m/z (%)¼136 (100), 154 (41), 219
(11), 320 (Mþ21, 63), 322 (Mþþ1, 20); HRMS (FAB,
Mþþ1) Calcd for C16H20NO4S 322.1113, found 322.1111;
1H NMR (300 MHz, CDCl3) d 9.57 (d, J¼3.0 Hz, 1H), 7.78
(d, J¼9.0 Hz, 2H), 7.35 (d, J¼9.0 Hz, 2H), 5.74–5.66 (m,
1H), 5.25–5.15 (m, 2H), 4.20–4.05 (m, 1H), 3.93–3.83 (m,
1H), 3.58 (d, J¼3.0 Hz, 1H), 3.50–3.40 (m, 1H), 3.06–2.93
(m, 1H), 2.43 (s, 3H), 1.35 (d, J¼6.0 Hz, 3H). To a stirred
solution of methyl triphenylphosphonium iodide (808 mg,
2.0 mmol) in THF (50 mL) was added n-butyllithium
(1.0 mL, 1.6 M, 1.6 mmol) and hexamethylphosphoric
triamide (HMPA, 0.4 mL) at 278 8C. The orange red
colored mixture was stirred at 278 8C for 1 h. The resulting
aldehyde product was added to the reaction mixture at
278 8C via a syringe and further stirred at 278 8C for 2 h.
The reaction was quenched with aqueous saturated
ammonium chloride (10 mL) and the mixture was extracted
with diethyl ether (3£50 mL) and the combined organic
layers were washed with brine, dried, filtered and evapor-
ated. Purification on silica gel (hexane/ethyl acetate¼2/1)
produced compound 2 (114 mg, 72%): gum; FAB-MS:
C17H21NO3S m/z (%)¼136 (36), 219 (13), 320 (Mþþ1,
100); HRMS (FAB, Mþþ1) Calcd for C17H22NO3S
For LAH condition: a solution of 5 (310 mg, 0.85 mmol) in
THF (20 mL) was added to a rapidly stirred suspension of
lithium aluminum hydride (76 mg, 2.0 mmol) and the
resulting reaction mixture was stirred for 2 h, then quenched
with saturated ammonium chloride solution (1 mL) and
extracted with ethyl acetate (3£20 mL). The organic layers
were washed with brine, dried, filtered and evaporated.
Purification of the crude product by column chromato-
graphy on silica gel with hexane/ethyl acetate (2/1–1/1)
produced 6a (206 mg, 75%) and 6b (29 mg, 11%).
For alane condition: a solution of 5 (310 mg, 0.85 mmol in
THF (10 mL) was added to a solution of lithium aluminum
hydride (57 mg, 1.5 mmol) and aluminum chloride
(214 mg, 1.6 mmol) in THF (10 mL) via syringe at 0 8C.
The mixture was refluxed for 2 h at rt, quenched with
saturated ammonium chloride solution (1 mL) under cool-
ing, and concentrated. The residue was diluted with water
(15 mL) and extracted with ethyl acetate (3£30 mL). The
organic layer was washed with brine and water, dried,
filtered and concentrated to produce crude compound.
Purification on silica gel (hexane/ethyl acetate¼1/1–1/2)
produced 6b.
For 6a: gum; FAB-MS: C16H21NO4S m/z (%)¼136 (71),
154 (63), 324 (Mþþ1, 100); HRMS (FAB, Mþþ1) Calcd
for C16H22NO4S 324.1269, found 324.1270; 1H NMR
(500 MHz, CDCl3) d 7.84 (d, J¼8.5 Hz, 2H), 7.37 (d,
J¼8.5 Hz, 2H), 5.75–5.67 (m, 1H), 5.22–5.18 (m, 2H),
4.12 (dd, J¼5.5, 15.5 Hz, 1H), 3.84–3.73 (m, 3H), 3.62 (d,
J¼6.0 Hz, 1H), 3.23 (q, J¼4.5 Hz, 1H), 2.97–2.90 (m, 1H),
2.45 (s, 3H), 2.18 (br s, 1H), 1.33 (d, J¼7.0 Hz, 3H); 13C
NMR (125 MHz, CDCl3) d 165.34, 145.32, 134.60, 131.91,
129.58 (2£), 129.47 (2£), 118.36, 72.29, 64.62, 61.85,
44.32, 30.16, 21.72, 20.70. Anal. Calcd for C16H21NO4S: C,
59.42; H, 6.54; N, 4.33. Found: C, 59.66; H, 6.32; N, 4.40.
1
320.1322, found 320.1320; H NMR (500 MHz, CDCl3) d
7.86 (d, J¼8.0 Hz, 2H), 7.36 (d, J¼8.0 Hz, 2H), 5.69–5.55
(m, 2H), 5.33–5.28 (m, 2H), 5.18–5.05 (m, 2H), 4.13 (dd,
J¼4.5, 15.0 Hz, 1H), 3.64 (d, J¼8.0 Hz, 1H), 3.49–3.43 (m,
2H), 2.75–2.68 (m, 1H), 2.44 (s, 3H), 1.33 (d, J¼6.5 Hz,
3H); 13C NMR (125 MHz, CDCl3) d 164.90, 145.11,
136.05, 134.98, 131.11, 129.54 (2£), 129.48 (2x), 120.70,
118.47, 71.60, 66.85, 43.64, 34.61, 21.69, 18.53. Anal.
Calcd for C17H21NO3S: C, 63.92; H, 6.63; N, 4.39. Found:
C, 63.68; H, 6.57; N, 4.47.
For 6b: gum; FAB-MS: C16H23NO3S m/z (%)¼122 (100),
154 (59), 278 (32), 310 (Mþþ1, 99); HRMS (FAB, Mþþ1)
Calcd for C16H24NO3S 310.1477, found 310.1476; 1H NMR
(500 MHz, CDCl3) d 7.80 (d, J¼8.0 Hz, 2H), 7.37 (d,
J¼8.0 Hz, 2H), 5.79–5.71 (m, 1H), 5.21–5.14 (m, 2H),
3.69 (dd, J¼3.0, 11.5 Hz, 1H), 3.60 (dd, J¼3.0, 11.5 Hz,
1H), 3.42 (d, J¼11.5 Hz, 1H), 3.37 (dd, J¼4.5, 13.5 Hz,
1H), 3.20–3.16 (m, 1H), 2.72–2.60 (m, 3H), 2.48–2.44 (m,
1H), 2.46 (s, 3H), 2.17 (br s, 1H), 1.00 (d, J¼7.0 Hz, 3H);
13C NMR (125 MHz, CDCl3) d 144.93, 134.68, 133.88,
129.80 (2£), 129.15 (2£), 118.21, 71.98, 68.21, 57.56,
55.18, 52.95, 35.91, 21.66, 18.04. Anal. Calcd for
4.1.6. 1-Methyl-2-(4-methylphenylsulfonyl)-1,2,5,7a-
tetrahydro-pyrrolizin-3-one (7) and 4-methyl-1-pro-
penyl-3-(4-methylphenylsulfonyl)-5-vinyl-pyrrolidin-2-
one (7a). 1st or 2nd Grubbs’ catalyst (0.01 mmol) was
added to a solution of 2 (32 mg, 0.1 mmol) in 1,2-
dichloroethane (3 mL) and the reaction mixture was
refluxed under nitrogen atmosphere for 36 h. The mixture
was concentrated and purified by flash column chromato-
graphy (hexane/ethyl acetate¼2/1–1/1) to yield 7 and 7a.
For Grubb’s 1st generation catalyst, the yield: 7 (2 mg, 7%)
and 7a (23 mg, 72%); For Grubb’s 2nd generation catalyst,
the yield: 7 (21 mg, 66%) and 7a (3 mg, 9%).

M.-Y. Chang et al. / Tetrahedron 60 (2004) 5545–5550
5549
For 7: gum; FAB-MS: C15H17NO3S m/z (%)¼136 (100),
154 (94), 242 (3), 292 (Mþþ1, 78); HRMS (FAB, Mþþ1)
Calcd for C15H18NO3S 292.1008, found 292.1007; 1H NMR
(200 MHz, CDCl3) d 7.88 (d, J¼8.0 Hz, 2H), 7.34 (d,
J¼8.0 Hz, 2H), 5.94–5.88 (m, 2H), 4.37–4.32 (m, 1H),
4.13–4.11 (m, 1H), 3.98 (d, J¼11.5 Hz, 1H), 3.67–3.62 (m,
1H), 2,82–2.77 (m, 1H), 2.45 (s, 3H), 1.47 (d, J¼6.5 Hz,
3H); 13C NMR (50 MHz, CDCl3) d 167.55, 145.01, 135.28,
129.84 (2£), 129.71 (2£), 120.11, 111.72, 72.95, 71.26,
50.58, 40.50, 21.69, 17.92.
Council (NSC-93-2113-M-390-002) of the Republic of
China for financial support.
References and notes
1. Sun, P. P.; Chang, M. Y.; Chiang, M. Y.; Chang, N. C. Org.
Lett. 2003, 5, 1761.
2. Chang, M. Y.; Sun, P. P.; Chen, S. T.; Chang, N. C. Tetrahedron
Lett. 2003, 44, 5271.
For 7a: mp 113–114 8C; EI-MS: C17H21NO3S m/z (%)¼69
(77), 91 (100), 164 (78), 319 (Mþ, 2); HRMS (EI, Mþ)
Calcd for C17H21NO3S 319.1237, found 319.1236; 1H NMR
(500 MHz, CDCl3) d 7.83 (d, J¼8.5 Hz, 2H), 7.35 (d,
J¼8.5 Hz, 2H), 6.59 (dd, J¼1.5, 14.5 Hz, 1H), 5.79–5.72
(m, 1H), 5.30–5.23 (m, 3H), 3.74 (dd, J¼4.6, 8.5 Hz, 1H),
3.64 (d, J¼6.0 Hz, 1H), 2.75–2.69 (m, 1H), 2.44 (s, 3H),
1.64 (dd, J¼1.5, 7.0 Hz, 3H), 1.32 (d, J¼7.0 Hz, 3H); 13C
NMR (125 MHz, CDCl3) d 162.99, 145.21, 137.62, 134.70,
129.53 (2x), 129.42 (2x), 123.26, 118.07, 111.83, 72.04,
66.58, 34.83, 21.65, 19.61, 15.50. Anal. Calcd for
C17H21NO3S: C, 63.92; H, 6.63; N, 4.39. Found: C, 63.76;
H, 6.54; N, 4.44.
3. Chang, M. Y.; Sun, P. P.; Chen, S. T.; Chang, N. C.
Heterocycles 2003, 60, 1865.
4. Chang, M. Y.; Chen, C. Y.; Tasi, M. R.; Tzeng, T. W.; Chang,
N. C. Synthesis 2004, 840.
5. For syntheses of heliotridane and pseudoheliotridane, see:
(a) Ashweek, N. J.; Coldham, I.; Snowden, D. J.; Vennall, G. P.
Chem. Eur. J. 2002, 8, 195. (b) Kim, S.-H.; Kim, S.-I.; Lai, S.;
Cha, J. K. J. Org. Chem. 1999, 64, 6771. (c) Coldham, I.;
Hufton, R.; Snowden, D. J. J. Am. Chem. Soc. 1996, 118, 5322.
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4.1.7. 1-Methyl-1,2,5,7a-tetrahydro-pyrrolizin-3-one (8).
6% Sodium amalgam (Na/Hg, 0.5 g) and sodium phosphate
(71 mg, 0.5 mmol) were added to a stirred solution of 7
(30 mg, 0.1 mmol) in methanol (5 mL), and vigorously
stirred for 2 h at rt. The residue was filtered and washed with
methanol (2£10 mL) and the combined organic layers
were washed with brine, dried, filtered and evaporated.
Purification on silica gel (hexane/ethyl acetate¼1/1–1/2)
produced 8 (12 mg, 86%): oil; HRMS (EI, Mþ) Calcd for
1
C8H11NO 137.0841, found 137.0841; H NMR (200 MHz,
CDCl3) d 5.92–5.83 (m, 2H), 4.41–4.32 (m, 1H), 4.22–
4.14 (m, 1H), 3.70–3.61 (m, 1H), 2.32–2.15 (m, 2H),
1.82–1.72 (m, 1H), 1.22 (d, J¼7.5 Hz, 3H).
4.1.8. 1-Methyl-hexahydro-pyrrolizin-3-one (9).5e,g,m,p
10% Palladium on activated carbon (10 mg) was added to
the solution of 8 (7 mg, 0.05 mmol) in methanol (10 mL).
Then hydrogen was bubbled into the mixture for 10 min,
and the reaction mixture was continued to stir for 3 h at rt.
The catalyst was filtered through a short plug of Celite and
washing with methanol (2£5 mL). The combined organic
layers were evaporated. Purification on silica gel (hexane/
6. Kakimoto, M.; Kai, M.; Kondo, K. Chem. Lett. 1982, 525.
7. CCDC 221916 contains the supplementary crystallographic
data for this paper. This data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: þ44-
1223-336033; e-mail: deposit@ccdc.cam.ac.uk).
1
ethyl acetate¼1/1–1/2) produced 9 (6 mg, 85%). The H
NMR data was in accordance with the reported in the
literature.
8. For related examples of RCM, see: (a) Huwe, C. M.; Blechert,
S. Tetrahedron Lett. 1995, 36, 1621. (b) Arisawa, M.;
Takezawa, E.; Nishida, A.; Mori, M.; Nakagawa, M. Synlett
1997, 1179. (c) Overkleeft, H. S.; Bruggeman, P.; Pandit, U. K.
Tetrahedron Lett. 1998, 39, 3869. (d) Arisawa, M.; Takahashi,
M.; Takezawa, E.; Yamaguchi, T.; Torisawa, Y.; Nishida, A.;
Nakagawa, M. Chem. Pharm. Bull. 2000, 48, 1593.
(e) Rambaud, L.; Compain, P.; Martin, O. R. Tetrahedron:
Asymmetry 2001, 12, 1807. (f) Martin, R.; Alcon, M.; Pericas,
M. A.; Riera, A. J. Org. Chem. 2002, 67, 6896.
5. Supplementary Material
Experimental procedures and photocopies of 1H-NMR
(CDCl3) spectral data for 2, 5, 6a, 6b, 7, 7a, 8 were
supported.
Acknowledgements
9. For reviews of RCM, see: (a) Grubbs, R. H.; Miller, S. J.; Fu,
G. C. Acc. Chem. Res. 1995, 28, 446. (b) Schmalz, H. G. Angew.
The authors would like to thank the National Science

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Chem., Int. Ed. Engl. 1995, 34, 1833. (c) Schuster, M.; Blechert,
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