Further studies on enantioselective synthesis of (+)-anatoxin-a using enyne metathesis: unexpected inversion of chirality via a skeletal rearrangement of 9-azabicyclo[4.2.1]nonene derivative

Article abstract of DOI:10.1016/j.tet.2006.05.088

The formal total synthesis of (+)-anatoxin-a was accomplished using enyne metathesis as a key step. It is very interesting that (+)-anatoxin-a was synthesized from (S)-pyroglutamic acid via an unusual inversion of chirality, which is rationalized in terms

Full text of DOI:10.1016/j.tet.2006.05.088

Tetrahedron 62 (2006) 10518–10527
Further studies on enantioselective synthesis of (D)-anatoxin-a
using enyne metathesis: unexpected inversion of chirality via
a skeletal rearrangement of 9-azabicyclo[4.2.1]nonene derivative
b,
Tomohiro Tomita,a Yoichi Kita,a Tsuyoshi Kitamura,a Yoshihiro Satoa, and Miwako Mori
*
*
aGraduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
bHealth Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan
Received 17 January 2006; revised 2 May 2006; accepted 22 May 2006
Available online 10 August 2006
Abstract—The formal total synthesis of (+)-anatoxin-a was accomplished using enyne metathesis as a key step. It is very interesting that
(+)-anatoxin-a was synthesized from (S)-pyroglutamic acid via an unusual inversion of chirality, which is rationalized in terms of a skeletal
rearrangement of 9-azabicyclo[4.2.1]nonene derivative at the stage of oxymercuration of the diene.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
azabicyclo[4.2.1]nonene skeleton, via ring-closing enyne
metathesis.5 Anatoxin-a, which was isolated from the blue-
green freshwater algae Anabaena flos-aquae, is one of the
most powerful agonists of the nicotinic acetylcholine re-
ceptor6 and has an azabicyclo[4.2.1]nonene skeleton bearing
a,b-unsaturated ketone. Because of the unique structure and
biological activity of anatoxin-a, many groups have synthe-
sized anatoxin-a by various interesting methods.7 The struc-
ture of anatoxin-a prompted us to attempt its synthesis using
enyne metathesis as a key step. Our retrosynthetic analysis
is shown in Scheme 2.
Metathesis reaction is now one of the most promising strat-
egies for the construction of various functionalized rings
contained in natural products and biologically active sub-
stances.1,2 Among the various types of metathesis reaction,
enyne metathesis3 has the following unique and useful prop-
erties for organic synthesis: (1) the terminal alkylidene
moiety of alkene in the substrate 1 formally migrates on the
alkyne carbon to produce the cyclized product 2 containing
1,3-diene, which should serve for further functionalization
on the ring (Scheme 1) and (2) enyne metathesis is com-
pletely atom economical compared to the corresponding
diene metathesis.
O
O
TsN
HN
TsN
1
R1
6
R1
R2
Enyne Metathesis
(+)-anatoxin-a
(-)-3 ((-)-N-Ts-anatoxin-a)
(1R,6R)-4
Ph
R2
Ru
R
R
1
2
2
OR1
R2O
5
O
N
N
H
CO2H
N
3
Ts
Scheme 1.
(R)-(+)-pyroglutamic acid
(R)-6
(2R,5R)-5
Recently, we have shown the efficiency of enyne metathesis
for the construction of various ring-sized cyclic compounds
and the synthesis of natural products and related compounds
via ring-closing enyne metathesis and also for the syn-
thesis of 1,3-diene derivatives from alkyne and ethylene via
intermolecular enyne metathesis.4 In that context, we had
interest in the synthesis of anatoxin-a, which has a strained
Scheme 2. Retrosynthetic analysis of (+)-anatoxin-a.
The synthesis of (+)-anatoxin-a from (ꢀ)-N-Ts-anatoxin-
a ((ꢀ)-3) has been reported in the literature,8 and (ꢀ)-3
would be synthesized from (1R,6R)-4 through oxidation of
the 1,3-diene moiety. The compound (1R,6R)-4 having
a strained azabicyclo[4.2.1]nonene ring system would be
constructed by metathesis of enyne (2R,5R)-5 in the cis-
substituents on the pyrrolidine ring. In the synthesis of
* Corresponding authors. Tel./fax: +89 11 706 4982; e-mail: biyo@pharm.
hokudai.ac.jp
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.088

T. Tomita et al. / Tetrahedron 62 (2006) 10518–10527
10519
(2R,5R)-5, a p-toluenesulfonyl group as a protecting group
on nitrogen was chosen because it was expected that H
to its enantiomer, (R)-(+)-pyroglutamic acid. In this case,
(2S,5S)-5 would be synthesized as the substrate for enyne
metathesis, which should lead to the synthesis of (ꢀ)-ana-
toxin-a, the antipode of the naturally occurring form. The
synthesis of (2S,5S)-5 was carried out as shown in Scheme 4.
1
and 13C NMR spectral data in the case of an amide protect-
ing group would be complicated because of the existence of
rotation isomers of the amide carbonyl group. To synthesize
the substrate (2R,5R)-5 for enyne metathesis, hydrogenation
of imine (R)-6 should be suitable, and the compound (R)-6
could be derived from (R)-(+)-pyroglutamic acid. We de-
scribe herein the synthesis of (+)-anatoxin-a using enyne
metathesis as a key step.9–11 Furthermore, during the course
of our investigation, we encountered an unexpected inver-
sion of chirality by a skeletal rearrangement of 9-azabi-
cyclo[4.2.1]nonene derivative, which is also described.
BnO(CH2)3Br, Mg
O
O
THF
N
CH2OSi
N
H
CO2H
Boc
11
(S)-(-)-pyroglutamic acid
t
Si=Si BuPh2
NHBoc
OSi
50% CF3CO2H
OSi
BnO
CH2Cl2
BnO
N
O
12: 86%
(S)-6a: 92%
2. Model study for conversion of 1,3-diene to
a,b-unsaturated ketone
1. Dess–Martin
Oxidation
1. PtO2, H2
OSi
HO
N
2. CH3PPh3Br
2. TsCl, Et
3N
Ts
3. Pd(OH)2, H2
tBuOK
In the above-mentioned retrosynthetic analysis (Scheme 2),
conversion of the 1,3-diene moiety in the cyclized product 4
is a very important process. Thus, the oxidation condition of
the diene moiety was examined. As a model compound, aze-
pine derivative 9 having a diene moiety was used (Scheme 3).
We have already reported that metathesis of enyne having
a terminal alkene and alkyne proceeded smoothly under
ethylene gas using first-generation ruthenium–carbene com-
plex 8a12 and that compound 9 was obtained from 7 in good
yield.4e
13: 84% (3 steps)
1. TBAF
2. Dess–Martin
OSi
Oxidation
N
H
H
N
Ts
Ts
3. CBr4, PPh3
4. BuLi
NOE
14: 97% (2 steps)
(2S,5S)-5: 65% from 14
Scheme 4. Synthesis of a substrate.
Conversion of (ꢀ)-pyroglutamic acid into 11 by a known
method15 followed by treatment of 11 with Grignard reagent
smoothly proceeded with opening of the pyrrolidine ring to
give ketone 12.16 Deprotection of the tert-butoxycarbonyl
group with CF3CO2H gave cyclized imine (S)-6a.16 Hydro-
genation of (S)-6a using PtO2 followed by protection of
nitrogen with the tosyl group and then deprotection of
the benzyl group gave pyrrolidine derivative 13. Dess–
Martin oxidation followed by Wittig reaction afforded
alkene 14, which was converted into enyne (2S,5S)-5 by
the usual method. The stereochemistry of the substituents on
(2S,5S)-5 was confirmed by an NOE experiment to be cis.
Next, the construction of a 9-azabicyclo[4.2.1]nonene struc-
ture using enyne metathesis was investigated, and the results
are summarized in Table 1.
Cy3P
Ph
Cl
Ru
Cl
Cy3P
8a
PdCl2, CuCl
O
O2, DMF-H2O
H2C=CH2
67%
N
N
N
Ts
Ts
Ts
7
9
10
(recovery of 9: 79%)
1. Hg(OAc)2
then NaBH4
10: 67%
2. Dess–Martin
Oxidation
Scheme 3. Conversion of diene into a,b-unsaturated ketone.
First, oxidation of 9 with PdCl2 and CuCl in aqueous DMF
was carried out under oxygen.13 However, the reaction mix-
ture changed to yellow color and the starting material was re-
covered in 79% yield after 24 h, presumably indicating that
the diene moiety in 9 strongly coordinated to the palladium
complex and the oxidation of 1,3-diene moiety did not pro-
ceed. Next, oxymercuration of 9 followed by treatment with
NaBH4 was carried out and then the resultant alcohol was
subjected to Dess–Martin oxidation14 to give desired 10 in
67% yield from 9.
We have already reported that the use of ethylene gas is
effective for enyne metathesis of the substrate having a termi-
nal alkyne.4e,17 Thus, enyne metathesis of 5 was initially car-
ried out using 5 mol % of 8a in CH2Cl2 under ethylene gas,
but the expected product 4a was obtained in only 15% yield
along with the starting material 5 and diene 16 in 25% and
13% yields, respectively (run 1). The diene 16 would be
produced via an intermolecular metathesis reaction between
the alkyne moiety in 5 and ethylene.4c,4f,4m,4p,4t,18 Next, the
second-generation Ru–carbene complex 8b19 was used and
the reaction was carried out in CH2Cl2 upon heating under
ethylene gas (run 2). However, the desired compound 4a
was obtained in only 7% yield along with 16 in 61% yield.
When the reaction of 5 using 8c20 was carried out in
CH2Cl2 at room temperature under ethylene gas, the yield
of the desired product was slightly improved to 28%. How-
ever, no other identified product was obtained in this reaction
(run 3). Next, we tried enyne metathesis of 15, which was
easily synthesized from 5 by protection of the terminal
3. Synthesis of anatoxin-a from (S)-(L)-pyroglutamic
acid
Having achieved the conversion of diene 9 into a,b-unsatu-
rated ketone 10, we next investigated the synthesis of
anatoxin-a as an optically active form. Initially, we chose
(S)-(ꢀ)-pyroglutamic acid as the starting material because
this material is readily available and is inexpensive compared

10520
T. Tomita et al. / Tetrahedron 62 (2006) 10518–10527
Table 1. Enyne metathesis of (2S,5S)-5 and (2S,5S)-15
spectral data unambiguously agreed with those reported in
the literature.8 However, we were surprised that the [a]D
value of our synthetic N-tosylanatoxin-a showed a sign
opposite to that of (+)-N-tosylanatoxin-a in the literature,
although the absolute value was in agreement with that in
the literature. This means that (ꢀ)-N-tosylanatoxin-a was
synthesized from (S)-(ꢀ)-pyroglutamic acid along with an
unexpected inversion of chirality during the synthesis. Since
conversion of (ꢀ)-N-tosylanatoxin-a to (+)-anatoxin-a had
been already reported,8 the formal total synthesis of (+)-ana-
toxin-a was achieved.23
TsN
6
Ph
Ru
1
N
N
CH2Cl2
Ts
Ts
R
R
16
(2S,5S)-5: R=H
BuLi, TMSCl (1S,6S)-4a: R=H
95%
(1S,6S)-4b: R=TMS
(2S,5S)-15: R=TMS
MesN
NMes
Cl
MesN
Cl
NMes
Ph
Cy3P
Cl
Ph
Cl
Ru
O
Ru
Ru
Cy3P
8a
Cl
Cl
Cy3P
Ph
8b
8c
4. Consideration of the inversion of chirality during
the synthesis
Runa Substrate
Ru
Temp Time Product (%) SM recov.
(%)
catalystb
(h)
We succeeded in the formal total synthesis of (+)-anatoxin-
a from (S)-(ꢀ)-pyroglutamic acid using enyne metathesis as
a key step. However, there remained the important question
of when the inversion of chirality takes place during the syn-
thesis. In order to answer this question, we first tried to con-
firm the absolute configuration of an intermediate before the
metathesis reaction (Scheme 6). Hydrogenation of (S)-6a,
which was derived from (S)-(ꢀ)-pyroglutamic acid as shown
in Scheme 4, gave pyrrolidine derivative 17 in good yield.
The compound 17 was successfully converted to the corre-
sponding (S)-camphor sulfonamide 18, which was easily
crystallized.
4
16
1
2
3
(2S,5S)-5
8a
8b
8c
rt
24.5 15
13
61
—
25
—
—
Reflux
rt
2
4
7
28
4
5
6
(2S,5S)-15 8b
8c
8b
Reflux
rt
Reflux
3.5 27
3.5 27
2.5 85
—
—
—
65
—
—
a
Reactions for runs 1–3 were carried out under an atmosphere of ethylene,
and reactions for runs 4–6 were carried out under an atmosphere of Ar.
Run 1: 5 mol % of Ru–carbene complex was used; runs 2–5: 10 mol % of
Ru–carbene complex was used; run 6: 20 mol % of Ru–carbene complex
was used.
b
PtO2, H2
alkyne moiety with the silyl group.4p When enyne metathe-
sis of 15 was carried out in CH2Cl2 using 10 mol % of 8b un-
der argon upon heating, the desilylated product 4a instead of
the expected product 4b was obtained in 27% yield along
with the starting material 15 in 65% yield (run 4). The reac-
tion of 15 using Ru–carbene complex 8c in CH2Cl2 at room
temperature also gave the desilylated product 4a in 27%
yield, in which case, however, the starting material was com-
pletely consumed (run 5). Thus, enyne metathesis of 15 was
carried out in CH2Cl2 using 20 mol % of 8b under argon
upon heating (run 6). As a result, the reaction was completed
in 2.5 h and the cyclized product 4a was obtained in 85%
yield. In these reactions, desilylation occurred during the
metathesis reaction,21 although the reason is not clear.
OSi BuPh2
t
t
OSi BuPh2
BnO
BnO
N
H
N
17: 93%
(S)-6a
1. (S)-camphor sulfonyl
chloride, DMAP, Et3N
BnO
OH
2
5
N
S
O
2. TBAF, THF
O
O
18: 95% (2 steps)
Scheme 6. Confirmation of the absolute configuration of 6a.
The absolute configuration of 18 was unequivocally deter-
mined by X-ray analysis as shown in Figure 1,24 which
means that the compound 17 maintained the chirality de-
rived from (S)-(ꢀ)-pyroglutamic acid.
Next, we investigated the final stage for the synthesis of
anatoxin-a from the enyne metathesis product (1S,6S)-4a
(Scheme 5).
1. Hg(OAc)2
then NaBH4
42% (4a; 32%)
O
TsN
TsN
O
TsN
2. Dess-Martin
Oxidation
86%
(+)-N-Ts-anatoxin-a (-)-N-Ts-anatoxin-a
(1S,6S)-4a
(+)-3
(-)-3
not obtained
actually obtained
lit.8 [α]D25 +14.7 (c 1.40, CHCl3) [α]D25 -15.0 (c 0.65, CHCl3)
Scheme 5. Synthesis of N-tosylanatoxin-a.
Oxymercuration of (1S,6S)-4a followed by treatment with
NaBH4 afforded alcohol in 42% yield, and the starting
material 4a was recovered in 32% yield.22 Dess–Martin
oxidation of the alcohol afforded N-tosylanatoxin-a, whose
Figure 1. X-ray structure of compound 18.

T. Tomita et al. / Tetrahedron 62 (2006) 10518–10527
10521
CbzN
enyne metathesis
CO2H
O
cat. 8b
N
H
N
Cbz
(R)-(+)-pyroglutamic acid
(2R,5R)-19a
(1R,6R)-20a
O
1. NaIO4, THF, H2O
2. TMSI, MeCN
OH
OH
HN
1. OsO4, Et3N
2. NaHCO3 aq.
CbzN
3. HCl, MeOH
21
(+)-anatoxin-a
Scheme 7. Martin’s total synthesis of (+)-anatoxin-a.
Ts
N
Since it is unlikely that the inversion of chirality with
respect to both chiral centers at C2 and C5 positions takes
place during the conversion of 17 to the metathesis substrate
5 (cf. Scheme 4), we presume that the compound 5 also
maintains the chirality derived from (S)-(ꢀ)-pyroglutamic
acid and that the inversion of chirality takes place at a later
stage.
TsN
TsN
6
Hg(OAc)2
+
1
1
1
3
3
H
O
H
(AcO)2Hg
AcOHg
TsN
(1S,6S)-4a
23
24
Ts
N
Ts
N
The total synthesis of (+)-anatoxin-a via enyne metathesis
was reported by Martin at almost the same time as our re-
port.10 In Martin’s synthesis, (1R,6R)-20a was constructed
by enyne metathesis of (2R,5R)-19a, which was derived
from (R)-(+)-pyroglutamic acid. Conversion of (1R,6R)-
20a to (+)-anatoxin-a was achieved with the maintenance
of chirality through osmylation of the alkene followed by
cleavage of the corresponding diol (Scheme 7).
HO
NaBH4
OH
OH
AcOHg
Dess-Martin
Oxidation
26
25
O
TsN
1
TsN
+
Martin’s synthesis is very similar to our synthesis, although
the substrate of enyne metathesis as well as the procedure for
conversion of the diene moiety to a,b-unsaturated ketone is
different. Thus, we investigated the conversion of (2S,5S)-5
to N-Ts-anatoxin-a (3) according to Martin’s procedure
(Scheme 8).
3
(-)-N-Ts-anatoxin-a
(-)-3
AcOHg
ent-24
Scheme 9. Plausible mechanism for inversion of chirality.
The diene moiety in (1S,6S)-4a would coordinate to
Hg(OAc)2 complex to produce olefin–Hg complex 23. Mi-
gration of the nitrogen atom from the C1-position to the
C3-position along with cleavage of the N–C1 bond would
take place in the complex 23 to give 24. Spontaneous nucleo-
philic attack of H2O on the allyl cation moiety in 24 would
take place to give 25, which was converted to the alcohol 26
by reduction with NaBH4. It is noteworthy that the alcohol
26 has a (1R,6R)-configuration, which could be converted
to (ꢀ)-N-Ts-anatoxin-a by Dess–Martin oxidation. If ent-
24 was produced along with 24 from the olefin–Hg complex
23, or if 24 was in equilibrium with ent-24, racemization
should occur in both cases to give 26 as a racemic mixture.
The fact that (1R,6R)-26 was obtained from (1S,6S)-4a with
a high optical purity strongly suggests that the migration of
the nitrogen atom from the C1-position to the C3-position
in 23 took place in a stereospecific manner without the for-
mation of ent-24 and also that equilibrium between 24 and
ent-24 may not exist.
NaHMDS
MeOTf
N
N
Ts
Ts
(2S,5S)-5
(2S,5S)-19b: 82%
TsN
TsN
1. OsO4, Et3N
2. NaHSO3 aq.
8b
CH2Cl2
3. NaIO4, THF
H2O
O
22: 78%
(+)-N-Ts-anatoxin-a
(+)-3
[α]D20 +12.8 (c 0.44, CHCl3)
Scheme 8. Conversion of (2S,5S)-5 to N-Ts-anatoxin-a according to
Martin’s procedure.
As a result, (+)-N-Ts-anatoxin-a was obtained without the
inversion of chirality originating from the substrate. This re-
sult strongly suggests that enyne metathesis proceeds with
the maintenance of chirality regardless of the substrate and
that the inversion of chirality in our synthesis takes place
at the stage of conversion of the diene moiety to a,b-unsatu-
rated ketone using oxymercuration reaction. One plausible
mechanism for the inversion of chirality during the oxymer-
curation reaction is shown in Scheme 9.
5. Conclusion
In summary, we have accomplished the formal total synthe-
sis of (+)-anatoxin-a using enyne metathesis as a key step.

10522
T. Tomita et al. / Tetrahedron 62 (2006) 10518–10527
The remarkable features of our synthesis are as follows: (1)
a highly strained azabicyclo[4.2.1]nonene skeleton was con-
structed by ring-closing enyne metathesis of a pyrrolidine
derivative and (2) the synthesis of (+)-anatoxin-a was
achieved from (S)-pyroglutamic acid via an unusual inver-
sion of chirality, which is rationalized in terms of a skeletal
rearrangement of 9-azabicyclo[4.2.1]nonene derivative at
the stage of oxymercuration of the diene.
(m, 2H); 13C NMR (100 MHz, CDCl3) d 197.0 (C), 144.8
(CH), 142.9 (C), 140.9 (C), 136.1 (C), 129.4 (CHꢂ2),
127.0 (CHꢂ2), 49.5 (CH2), 43.9 (CH2), 27.1 (CH2), 25.8
(CH2), 25.6 (CH2), 21.8 (CH3); LRMS (EI) m/z 293 (M+),
155, 138, 109, 96; HRMS (EI) calcd for C15H19O3NS
(M+) 293.1083, found 293.1085.
6.1.2. (2S)-8-Benzyloxy-1-(tert-butyldiphenylsilyloxy)-
2-(tert-butyloxycarbonyl)-amino-octan-5-one(12).Asolu-
tion of 1-benzyloxy-3-bromo-propane (1.90 g, 8.3 mmol) in
THF (7 mL) was added dropwise to a suspension of Mg
(229 mg, 9.94 mmol) in THF (5 mL), and the mixture was
stirred at room temperature for 30 min. To a THF solution
of the Grignard reagent was added a solution of 1115
(2.25 g, 4.5 mmol) in THF (16 mL) at 0 ꢁC, and the mixture
was stirred at room temperature for 1.7 h. The reaction mix-
ture was quenched by adding satd NH4Cl aq at 0 ꢁC, and the
aqueous layer was extracted with AcOEt. The organic layer
was washed with brine and dried over Na2SO4. After re-
moval of the solvent, the residue was purified by column
chromatography on silica gel (hexane/AcOEt ¼ 3:1) to
give 12 (2.77 g, 86%) as a colorless oil. IR (neat) n 3364,
1714, 739, 701 cmꢀ1; 1H NMR (270 MHz, CDCl3) d 7.62–
7.65 (m, 4H), 7.29–7.43 (m, 11H), 4.64 (d, J¼8.9 Hz, 1H),
4.47 (s, 2H), 3.55–3.64 (m, 3H), 3.44–3.49 (m, 2H), 2.40–
2.52 (m, 4H), 1.86–1.92 (m, 2H), 1.76–1.83 (m, 2H), 1.43
(s, 9H), 1.07 (s, 9H); LRMS (EI) m/z 603 (M++1), 546,
306, 278, 91; HRMS (EI) calcd for C36H50O5NSi (M++H)
604.3459, found 604.3450. [a]2D1 ꢀ13.0 (c 1.03, CHCl3).
6. Experimental
6.1. General
All manipulations were carried out under an atmosphere of
argon unless otherwise mentioned. Ethylene gas was puri-
fied by passage through the aqueous CuCl solution (2.0 g
of CuCl in 180 mL of saturated NH4Cl aqueous solution)
and concentrated H2SO4 and then KOH tubes. Ruthenium
complexes 8a and 8b were purchased from Strem Chemi-
cals, Inc. Ruthenium complex 8c was prepared according
to the literature procedure.19 All other solvents and reagents
were purified when necessary using standard procedure.
6.1.1. 3-Acetyl-2,5,6,7-tetrahydro-1-p-toluenesulfonyl-
1H-azepine (10). To a solution of 9 (20 mg, 74 mmol) in
H2O/THF (1/1, 0.9 mL) was added Hg(OAc)2 (36 mg,
112 mmol) at 0 ꢁC, and the mixture was stirred at room
temperature for 1.5 h. To the mixture were added MeOH
(0.9 mL), 3 M NaOH aq (0.5 mL), and NaBH4 (19 mg,
0.50 mmol), and the mixture was stirred at room temperature
for 16 h. The mixture was extracted with Et2O, and the or-
ganic layer was washed with brine, dried over Na2SO4. After
removal of the solvent, the residue was purified by column
chromatography on silica gel (hexane/AcOEt ¼ 2:1) to
give the alcohol (15 mg, 71%) as a colorless oil. IR (neat)
6.1.3. (S)-5-(3-(Benzyloxy)propyl)-2-(tert-butyldiphenyl-
silyloxymethyl)-3,4-dihydro-2H-pyrrole ((S)-6a). To a
solution of 12 (51 mg, 0.08 mmol) in CH2Cl2 (0.2 mL)
was added trifluoroacetic acid (0.2 mL), and the mixture
was stirred at room temperature for 2.5 h. To the mixture
was added 3 M NaOH aq, and the aqueous layer was ex-
tracted with Et2O. The organic layer was washed with brine
and dried over Na2SO4. After removal of the solvent, the res-
idue was purified by column chromatography on silica gel
(hexane/AcOEt ¼ 1:1) to give (S)-6a (38 mg, 92%) as a col-
orless oil. IR (neat) n 1646, 1112, 737, 701 cmꢀ1; 1H NMR
(270 MHz, CDCl3) d 7.22–7.69 (m, 15H), 4.47 (s, 2H), 4.15
(m, 1H), 3.87 (dd, J¼3.5, 10.0 Hz, 1H), 3.73 (dd, J¼5.1,
10.0 Hz, 1H), 3.52 (t, J¼6.2 Hz, 2H), 2.40–2.64 (m, 4H),
1.79–1.97 (m, 4H), 1.03 (s, 9H); LRMS (EI) m/z 485
(M+), 394, 336, 278; HRMS (EI) calcd for C31H39O2NSi
(M+) 604.3459, found 604.3450. [a]2D2 +41.5 (c 1.01,
CHCl3).
n 3482, 2925, 2853 cmꢀ1 1H NMR (270 MHz, CDCl3)
;
d 7.70 (d, J¼8.1 Hz, 2H), 7.30 (d, J¼8.1 Hz, 2H), 5.79
(dd, J¼5.5, 5.7 Hz, 1H), 4.29 (dd, J¼12.9, 12.9 Hz, 1H),
3.91 (d, J¼16.4 Hz, 1H), 3.76 (d, J¼16.4 Hz, 1H), 3.51
(dd, J¼12.7, 12.7 Hz, 1H), 3.33 (dd, J¼11.7, 12.7 Hz,
1H), 2.42 (s, 3H), 2.23 (m, 2H), 1.94 (br, 1H), 1.81 (m,
2H), 1.26 (s, 3H); 13C NMR (100 MHz, CDCl3) d 143.0
(C), 142.1 (C), 136.1 (C), 129.5 (CHꢂ2), 127.7 (CHꢂ2),
127.0 (CH), 71.9 (CH), 50.4 (CH2), 45.2 (CH2), 26.8
(CH2), 26.4 (CH2), 21.9 (CH3), 21.5 (CH3); LRMS (EI)
m/z 295 (M+), 277, 250, 224, 184, 155, 122, 91; HRMS
(EI) calcd for C15H21NSO3 (M+) 295.1244, found 295.1242.
To a solution of the alcohol (11 mg, 0.037 mmol) in CH2Cl2
(1 mL) was added Dess–Martin periodinane (47 mg,
0.11 mmol) at 0 ꢁC, and the mixture was stirred at room
temperature for 2 h. To the mixture were added satd
NaHCO3 aq and satd Na2S2O3 aq, and the aqueous layer
was extracted with AcOEt. The organic layer was washed
with brine and dried over Na2SO4. After removal of the sol-
vent, the residue was purified by column chromatography on
silica gel (hexane/AcOEt ¼ 1:1) to give 10 (10 mg, 95%) as
a colorless oil. IR (neat) n 3204, 2925, 1665, 1340, 1228,
6.1.4. 3-((2S,5R)-2-(tert-Butyldiphenylsilyloxymethyl)-
1-p-toluenesulfonylpyrrolidin-5-yl)-propan-1-ol (13). A
solution of (S)-6a (118 mg, 0.24 mmol) and PtO2 (6 mg,
0.02 mmol) in EtOH (1 mL) was stirred at room temperature
under an atmosphere of hydrogen (1 atm) for 1 h. The
mixture was filtered through a pad of Celite, and the filtrate
was concentrated. The residue was purified by column chro-
matography on silica gel (AcOEt only) to give the corre-
sponding pyrrolidine (i.e., the compound 17 in Scheme 6)
(109 mg, 92%) as a colorless oil. IR (neat) n 3346, 1472,
1
1
1159, 1093 cmꢀ1; H NMR (270 MHz, CDCl3) d 7.68 (d,
739, 701 cmꢀ1; H NMR (270 MHz, CDCl3) d 7.26–7.67
J¼8.1 Hz, 2H), 7.29 (d, J¼8.1 Hz, 2H), 6.95 (dd, J¼5.5,
5.9 Hz, 1H), 4.12 (s, 2H), 3.44 (t, J¼6.3 Hz, 2H), 2.47 (dt,
J¼5.5, 5.9 Hz, 2H), 2.42 (s, 3H), 2.28 (s, 3H), 1.84–1.94
(m, 15H), 4.50 (s, 2H), 3.71 (dd, J¼4.6, 10.0 Hz, 1H),
3.61 (dd, J¼4.9, 10.0 Hz, 1H), 3.49 (t, J¼5.4 Hz, 2H),
3.07–3.12 (m, 2H), 2.93 (br, 1H), 1.32–1.95 (m, 8H), 1.06

T. Tomita et al. / Tetrahedron 62 (2006) 10518–10527
10523
(s, 9H); LRMS (EI) m/z 603 (M+), 546, 306, 278, 91; HRMS
(EI) calcd for C31H42O2NSi (M+ꢀ1) 488.2985, found
488.3009. [a]2D3 +2.0 (c 1.00, CHCl3).
(400 MHz, CDCl3) d 9.76 (s, 1H), 7.66–7.69 (m, 4H), 7.57
(d, J¼8.4 Hz, 2H), 7.38–7.47 (m, 6H), 7.27 (d, J¼8.4 Hz,
2H), 3.94 (dd, J¼3.8, 10.0 Hz, 1H), 3.56–3.71 (m, 3H),
2.72–2.78 (m, 1H), 2.45–2.51 (m, 1H), 2.42 (s, 3H), 1.92–
1.98 (m, 1H), 1.76–1.85 (m, 2H), 1.60–1.64 (m, 1H),
1.40–1.43 (m, 1H), 1.19–1.31 (m, 1H), 1.19 (s, 9H); 13C
NMR (100 MHz, CDCl3) d 201.7 (C), 143.2 (C), 135.4
(CHꢂ2), 134.1 (C), 133.2 (C), 133.1 (C), 129.5 (CHꢂ4),
129.4 (CHꢂ4), 127.5 (CHꢂ2), 127.4 (CHꢂ2), 66.6 (CH2),
62.4 (CH), 60.7 (CH), 40.4 (CH2), 30.2 (CH2), 28.2 (CH2),
27.1 (CH2, CH3), 21.7 (CH3ꢂ3), 19.5 (C); LRMS (EI) m/z
(M+ꢀt-Bu) 492, 414, 336, 280, 259, 155, 91; HRMS (EI)
calcd for C27H30O4NSSi (M+ꢀt-Bu) 492.1654, found
492.1665. [a]2D7 ꢀ40.2 (c 0.97, CHCl3).
To a solution of the pyrrolidine (2.25 g, 4.5 mmol) in
CH2Cl2 (9 mL) were added Et3N (2.0 mL, 15 mmol), p-tol-
uenesulfonyl chloride (940 mg, 4.9 mmol), and DMAP
(16 mg, 0.13 mmol), and the mixture was stirred at room
temperature for 14 h. To the mixture was added 10% HCl
aq, and the aqueous layer was extracted with AcOEt. The or-
ganic layer was washed with brine and dried over Na2SO4.
After removal of the solvent, the residue was purified by
column chromatography on silica gel (hexane/AcOEt ¼ 4:1)
to give the tosylamide (2.76 g, 96%) as a colorless oil. IR
(neat) n 2931, 2857, 2360, 1738, 1598, 1347, 1162,
1
1112 cmꢀ1; H NMR (400 MHz, CDCl3) d 7.64–7.68 (m,
To a solution of Ph3P+CH3Brꢀ (3.83 g, 10.7 mmol) in THF
t
4H), 7.58 (d, J¼7.9 Hz, 2H), 7.22–7.44 (m, 13H), 4.47 (s,
2H), 3.94 (d, J¼5.9 Hz, 1H), 3.39–3.62 (m, 5H), 2.41 (s,
3H), 1.82–1.91 (m, 2H), 1.42–1.65 (m, 6H), 1.06 (s, 9H);
13C NMR (100 MHz, CDCl3) d 142.8 (C), 138.3 (C), 135.3
(CHꢂ2), 134.4 (C), 133.2 (C), 133.0 (C), 129.4 (CHꢂ4),
129.2 (CHꢂ4), 127.9 (CHꢂ2), 127.4 (CHꢂ2), 127.2
(CHꢂ2), 127.1 (CHꢂ3), 72.5 (CH2), 69.9 (CH2), 66.3
(CH2), 61.8 (CH), 61.5 (CH), 60.0 (CH2), 33.0 (CH2), 29.3
(CH2), 26.7 (CH3), 26.2 (CH2), 21.2 (CH3ꢂ2), 19.0 (C),
14.0 (CH3); LRMS (EI) m/z 584 (M+ꢀt-Bu), 486, 372, 280,
155, 91; HRMS (EI) calcd for C34H38O4NSSi (M+ꢀt-Bu)
584.2296, found 584.2291. [a]2D7 ꢀ15.3 (c 0.96, CHCl3).
(27 mL) was added BuOK (1.09 g, 9.8 mmol) at 0 ꢁC, and
the mixture was stirred at room temperature for 20 min. To
the solution was added a solution of the aldehyde (2.68 g,
4.9 mmol) in CH2Cl2 (22 mL) at ꢀ78 ꢁC, and the mixture
was allowed to warm to 0 ꢁC and stirred at 0 ꢁC for 14 h.
To the mixture was added satd NH4Cl aq, and the aqueous
layer was extracted with AcOEt. The organic layer was
washed with brine and dried over Na2SO4. After removal
of the solvent, the residue was purified by column chromato-
graphy on silica gel (hexane/AcOEt ¼ 3:1) to give 14
(2.61 g, 98%) as a colorless oil. IR (neat) n 3070, 2958,
2930, 2857, 1736, 1639, 1598, 1348, 1162 cmꢀ1; 1H NMR
(400 MHz, CDCl3) d 7.67 (d, J¼7.0 Hz, 4H), 7.60 (d,
J¼8.4 Hz, 2H), 7.38–7.46 (m, 6H), 7.26 (d, J¼8.4 Hz,
2H), 5.78 (ddt, J¼6.3, 10.2, 17.2 Hz, 1H), 5.00 (dd, J¼0.9,
17.2 Hz, 1H), 4.94 (dd, J¼0.9, 10.2 Hz, 1H), 3.94 (dd,
J¼2.4, 5.9 Hz, 1H), 3.49–3.67 (m, 3H), 2.42 (s, 3H), 1.87–
2.08 (m, 4H), 1.18–1.51 (m, 4H), 1.07 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 142.9 (C), 137.7 (CH), 135.3
(CHꢂ2), 134.5 (C), 133.3 (C), 133.1 (C), 129.4 (CHꢂ2),
129.3 (CHꢂ4), 127.5 (CHꢂ4), 127.3 (CHꢂ2), 114.5
(CH2), 66.5 (CH3), 62.0 (CH), 61.5 (CH), 35.8 (CH2), 30.5
(CH2), 29.6 (CH2), 27.1 (CH2), 27.0 (CH2), 21.7 (CH3ꢂ3),
19.4 (C); LRMS (EI) m/z 546 (M+), 490, 414, 334, 292,
278, 252, 199, 155, 91; HRMS (EI) calcd for C32H41O3NSSi
(M+) 547.2569, found 547.2576. [a]2D3 ꢀ25.2 (c 1.07,
CHCl3).
A solution of the tosylamide (238 mg, 0.37 mmol) and
Pd(OH)2/C (20 wt %, 55 mg, 0.08 mmol) in EtOH (4 mL)
was stirred at room temperature under an atmosphere of hy-
drogen (1 atm) for 62 h. The mixture was filtered through
a pad of Celite, and the filtrate was concentrated. The residue
was purified by column chromatography on silica gel
(AcOEt only) to give 13 (195 mg, 95%) as a colorless oil.
1
IR (neat) n 3420, 2931, 2858, 1345, 1161 cmꢀ1; H NMR
(400 MHz, CDCl3) d 7.65–7.68 (m, 4H), 7.60 (d,
J¼8.4 Hz, 2H), 7.37–7.47 (m, 6H), 7.27 (d, J¼8.4 Hz,
2H), 3.94 (d, J¼5.9 Hz, 1H), 3.59–3.64 (m, 6H), 2.42 (s,
3H), 1.80–1.93 (m, 2H), 1.37–1.63 (m, 7H), 1.06 (s, 9H);
13C NMR (100 MHz, CDCl3) d 142.9 (C), 135.2 (CHꢂ4),
135.1 (CHꢂ4), 134.1 (C), 133.0 (C), 132.9 (C), 129.3
(CH), 129.2 (CH), 127.3 (CH), 127.2 (CH), 127.1 (CH),
127.0 (CH), 66.4 (CH2), 62.3 (CH2), 61.9 (CH), 61.6
(CH), 32.8 (CH2), 29.5 (CH2), 27.0 (CH2), 26.9 (CH3),
21.5 (CH3), 21.4 (CH3), 21.4 (CH3), 21.3 (CH3), 19.2 (C);
LRMS (EI) m/z 550 (M+ꢀ1), 494, 416, 338, 320, 155, 91;
HRMS (EI) calcd for C31H40O4NSSi (M+ꢀ1) 584.2296,
found 584.2291. [a]2D7 ꢀ26.6 (c 1.42, CHCl3).
6.1.6. (2S,5S)-5-(But-3-enyl)-2-ethynyl-1-p-toluenesulfo-
nylpyrrolidine ((2S,5S)-5). To a solution of 14 (112 mg,
4.5 mmol) in THF (2 mL) was added TBAF (1.0 M THF
solution, 0.3 mL, 0.3 mmol), and the mixture was stirred at
room temperature for 1.5 h. To the mixture was added H2O,
and the aqueous layer was extracted with Et2O. The organic
layer was washed with brine and dried over Na2SO4. After
removal of the solvent, the residue was purified by column
chromatography on silica gel (hexane/AcOEt ¼ 1:1) to give
the alcohol (62 mg, 98%) as a colorless oil. IR (neat) n 3510,
6.1.5. (2S,5S)-2-(tert-Butyldiphenylsilyloxymethyl)-
5-(but-3-enyl)-1-p-toluenesulfonylpyrrolidine (14). To a
solution of 13 (385 mg, 0.7 mmol) in CH2Cl2 (7 mL) was
added Dess–Martin periodinane (442 mg, 1.0 mmol) at
0 ꢁC, and the mixture was stirred at room temperature for
2 h. To the mixture were added satd NaHCO3 aq and satd
Na2S2O3 aq, and the aqueous layer was extracted with
AcOEt. The organic layer was washed with brine and dried
over Na2SO4. After removal of the solvent, the residue was
purified by column chromatography on silica gel (hexane/
AcOEt ¼ 4:1) to give the aldehyde (380 mg, 99%) as a color-
less oil. IR (neat) n 2931, 2858, 1732, 1346, 1161; 1H NMR
2954, 2874, 1736, 1640, 1598, 1343 cmꢀ1 1H NMR
;
(400 MHz, CDCl3) d 7.72 (d, J¼8.1 Hz, 2H), 7.33 (d,
J¼8.1 Hz, 2H), 5.84 (ddt, J¼6.8, 10.3, 17.0 Hz, 1H), 5.06
(dd, J¼1.8, 17.0 Hz, 1H), 4.99 (dd, J¼1.8, 10.3 Hz, 1H),
3.60–3.71 (m, 4H), 2.86 (br, 1H), 2.44 (s, 3H), 2.10–2.16
(m, 2H), 1.91–1.98 (m, 1H), 1.49–1.70 (m, 4H), 1.34–1.42
(m, 1H); 13C NMR (100 MHz, CDCl3) d 143.4 (C), 137.5
(CH), 133.9 (C), 129.5 (CHꢂ2), 127.3 (CHꢂ2), 114.7
(CH2), 66.0 (CH3), 63.0 (CH), 62.1 (CH), 35.7 (CH2), 30.5

10524
T. Tomita et al. / Tetrahedron 62 (2006) 10518–10527
(CH2), 29.4 (CH2), 27.3 (CH2), 21.7 (CH2); LRMS (EI) m/z
309 (M+), 278, 254, 224, 155, 122, 91; HRMS (EI) calcd for
C16H23O3NS (M+) 303.1396, found 309.1398. [a]2D1 +51.1
(c 1.33, CHCl3).
(400 MHz, CDCl3) d 7.75 (d, J¼8.2 Hz, 2H), 7.30 (d,
J¼8.2 Hz, 2H), 5.80 (ddt, J¼6.5, 10.0, 17.0 Hz, 1H), 5.03
(dd, J¼1.8, 17.0 Hz, 1H), 4.97 (dd, J¼1.8, 10.0 Hz, 1H),
4.41–4.47 (m, 1H), 3.73–3.76 (m, 1H), 2.34 (s, 3H), 2.12
(d, J¼2.4 Hz, 1H), 2.00–2.14 (m, 3H), 1.89–1.96 (m, 1H),
1.60–1.81 (m, 4H); 13C NMR (100 MHz, CDCl3) d 143.2
(C), 137.6 (CH), 135.4 (C), 129.4 (CHꢂ2), 127.2 (CHꢂ2),
114.7 (CH2), 83.5 (CH), 71.5 (C), 61.1 (CH), 51.4 (CH),
35.5 (CH2), 32.8 (CH2), 30.5 (CH2), 30.2 (CH2), 21.7
(CH3); LRMS (EI) m/z 303 (M+), 274, 262, 248, 222, 155,
148, 91, 77, 65; HRMS (EI) calcd for C17H21O2NS (M+)
303.1284, found 303.1293. [a]2D6 ꢀ41.9 (c 0.82, CHCl3).
To a solution of the alcohol (1.42 g, 4.6 mmol) in CH2Cl2
(46 mL) was added Dess–Martin periodinane (2.34 g,
5.5 mmol) at 0 ꢁC, and the mixture was stirred at room tem-
perature for 1.5 h. To the mixture were added satd NaHCO3
aq and satd Na2S2O3 aq, and the aqueous layer was extracted
with AcOEt. The organic layer was washed with brine and
dried over Na2SO4. After removal of the solvent, the residue
was purified by column chromatography on silica gel
(hexane/AcOEt ¼ 3:1) to give the aldehyde (1.20 g, 86%)
as a colorless oil. IR (neat) n 2924, 1734, 1639, 1598,
6.1.7. (2S,5S)-5-(But-3-enyl)-2-(2-(trimethylsilyl)-
ethynyl)-1-p-toluenesulfonylpyrrolidine ((2S,5S)-15). To
a solution of (2S,5S)-5 (36 mg, 0.12 mmol) in THF (1 mL)
was added BuLi (2.6 M hexane solution, 0.07 mL,
0.18 mmol) at ꢀ78 ꢁC, and the mixture was stirred at the
same temperature for 45 min. To the solution was added tri-
methylsilyl chloride (0.05 mL, 0.35 mmol) at ꢀ78 ꢁC, and
the mixture was stirred at the same temperature for 1 h. To
the mixture was added H2O, and the aqueous layer was
extracted with AcOEt. The organic layer was washed with
brine and dried over Na2SO4. After removal of the solvent,
the residue was purified by column chromatography on silica
gel (hexane/AcOEt ¼ 5:1) to give (2S,5S)-15 (42 mg, 95%)
as a viscous oil. IR (neat) n 2923, 1642, 1599, 1344,
1
1348, 1161 cmꢀ1; H NMR (400 MHz, CDCl3) d 9.63 (d,
J¼1.9 Hz, 1H), 7.71 (d, J¼8.2 Hz, 2H), 7.34 (d, J¼8.2 Hz,
2H), 5.83 (ddt, J¼6.2, 10.2, 16.8 Hz, 1H), 5.06 (dd, J¼1.7,
16.8 Hz, 1H), 5.01 (dd, J¼1.7, 10.2 Hz, 1H), 3.87 (dd,
J¼1.9, 7.9 Hz, 1H), 3.67–3.71 (m, 1H), 2.44 (s, 3H), 1.97–
2.17 (m, 4H), 1.69–1.75 (m, 1H), 1.52–1.62 (m, 3H); 13C
NMR (100 MHz, CDCl3) d 199.7 (C), 143.9 (C), 137.3
(C), 129.7 (CHꢂ3), 127.5 (CHꢂ2), 115.1 (CH2), 67.8
(CH), 61.4 (CH), 35.4 (CH2), 30.4 (CH2), 30.1 (CH2), 25.7
(CH2), 21.8 (CH3); LRMS (EI) m/z 307 (M+), 278, 252,
224, 155, 91; HRMS (EI) calcd for C16H21O3NS (M+)
307.1242, found 307.1242. [a]2D2 ꢀ50.6 (c 1.22, CHCl3).
1
1155 cmꢀ1; H NMR (400 MHz, CDCl3) d 7.76 (d, J¼
To a solution of CBr4 (5.16 g, 16 mmol) in CH2Cl2 (19 mL)
were added PPh3 (8.16 g, 31 mmol) and a solution of the
aldehyde (1.20 g, 3.9 mmol) in CH2Cl2 (59 mL) at 0 ꢁC,
and the mixture was stirred at the same temperature for
1.5 h. To the mixture was added H2O, and the aqueous layer
was extracted with AcOEt. The organic layer was washed
with brine and dried over Na2SO4. After removal of the sol-
vent, the residue was purified by column chromatography on
silica gel (hexane/AcOEt ¼ 3:1) to give the corresponding
dibromide (1.74 g, 96%) as a colorless oil. IR (neat)
7.6 Hz, 2H), 7.27 (d, J¼7.6 Hz, 2H), 5.77 (ddt, J¼6.5,
11.1, 17.2 Hz, 1H), 4.97 (dd, J¼11.1, 17.2 Hz, 2H), 4.55
(dd, J¼2.3, 7.3 Hz, 1H), 3.79–3.86 (m, 1H), 2.42 (s, 3H),
2.04–2.10 (m, 2H), 1.58–1.99 (m, 6H), 0.12 (s, 9H); 13C
NMR (100 MHz, CDCl3) d 143.0 (C), 137.8 (CH), 136.5
(C), 129.3 (CHꢂ2), 127.2 (CHꢂ2), 114.5 (CH2), 105.2 (C),
88.0 (C), 60.9 (CH), 52.1 (CH), 35.1 (CH2), 33.2 (CH2),
30.6 (CH2), 30.1 (CH2), 21.7 (CH3), 0.1 (CH3ꢂ3); LRMS
(EI) m/z 375 (M+), 360, 320, 220, 155, 91; HRMS (EI) calcd
for C20H29O2NSSi (M+) 375.1681, found 375.1688.
n 2924, 1734, 1640, 1598, 1348, 1161 cmꢀ1 1H NMR
;
(400 MHz, CDCl3) d 7.74 (d, J¼8.2 Hz, 2H), 7.33 (d,
J¼8.2 Hz, 2H), 6.46 (d, J¼7.9 Hz, 1H), 5.84 (ddt, J¼6.7,
10.3, 17.0 Hz, 1H), 5.06 (dd, J¼1.8, 17.0 Hz, 1H), 5.01
(dd, J¼1.8, 10.3 Hz, 1H), 4.13 (dt, J¼7.8, 7.8 Hz, 1H),
3.73–3.76 (m, 1H), 2.44 (s, 3H), 2.09–2.15 (m, 2H), 1.90–
1.97 (m, 2H), 1.50–1.69 (m, 4H); 13C NMR (100 MHz,
CDCl3) d 143.4 (C), 139.9 (CH), 137.4 (CH), 134.2 (C),
129.5 (CHꢂ2), 127.5 (CHꢂ2), 114.8 (CH2), 89.3 (C), 62.9
(CH), 61.4 (CH), 35.8 (CH2), 30.6 (CH2), 30.2 (CH2),
29.4 (CH2), 21.7 (CH3); LRMS (EI) m/z 463 (M+), 408,
384, 308, 278, 252, 155, 91; HRMS (EI) calcd for
C17H21O2NSBr2 (M+) 460.9680, found 460.9659. [a]2D2
ꢀ76.6 (c 1.03, CHCl3).
6.1.8. Typical procedure for enyne metathesis of (2S,5S)-
15 using Ru–carbene complex 8b (Table 1, run 6). A solu-
tion of (2S,5S)-15 (13 mg, 0.034 mmol) and Ru–carbene
complex 8b (6 mg, 0.007 mmol) in degassed CH2Cl2
(0.7 mL) was heated under reflux for 2.5 h. Upon cooling
to room temperature, an excess amount of ethyl vinyl ether
was added to the mixture in order to stop the metathesis re-
action, and the mixture was stirred at room temperature for
1 h. After the mixture was concentrated, the residue was
purified by column chromatography on silica gel (hexane/
AcOEt¼8:1) to give (1S,6S)-4a (9 mg, 85%) as a viscous oil.
IR (neat) n 2925, 2852, 1732, 1633, 1598, 1337, 1161 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 7.73 (d, J¼8.5 Hz, 2H), 7.27
(d, J¼8.5 Hz, 2H), 6.21 (dd, J¼10.9, 17.7 Hz, 1H), 5.67 (dd,
J¼5.8, 6.2 Hz, 1H), 5.14 (d, J¼17.7 Hz, 1H), 4.98 (d,
J¼10.9 Hz, 1H), 4.90 (d, J¼8.1 Hz, 1H), 4.41–4.44 (m,
1H), 2.42 (s, 3H), 2.16–2.29 (m, 2H), 2.00–2.08 (m, 2H),
1.72–1.85 (m, 2H), 1.56–1.69 (m, 2H); 13C NMR
(100 MHz, CDCl3) d 143.2 (C), 142.8 (C), 138.1 (CH),
137.5 (C), 131.9 (CH), 129.4 (CHꢂ2), 126.8 (CHꢂ2),
111.0 (CH2), 58.7 (CH), 57.6 (CH), 34.2 (CH2), 31.8
(CH2), 30.9 (CH2), 29.9 (CH2), 21.7 (CH3); LRMS (EI)
m/z 303 (M+), 155, 148, 121, 91; HRMS (EI) calcd for
To a solution of the dibromide (129 mg, 0.3 mmol) in THF
(3 mL) was added BuLi (1.55 M hexane solution, 0.6 mL,
0.9 mmol) at ꢀ78 ꢁC, and the mixture was stirred at the
same temperature for 1 h. To the mixture was added H2O,
and the aqueous layer was extracted with Et2O. The organic
layer was washed with brine and dried over Na2SO4. After
removal of the solvent, the residue was purified by column
chromatography on silica gel (hexane/AcOEt ¼ 3:1) to
give (2S,5S)-5 (68 mg, 80%) as a viscous oil. IR (neat)
n 3250, 2928, 1641, 1598, 1348, 1159 cmꢀ1 1H NMR
;

T. Tomita et al. / Tetrahedron 62 (2006) 10518–10527
10525
C17H21O2NS (M+) 303.1294, found 303.1293. [a]2D2 ꢀ5.2 (c
added 10% HCl aq, and the aqueous layer was extracted with
AcOEt. The organic layer was washed with brine and dried
over Na2SO4. After removal of the solvent, the residue was
purified by column chromatography on silica gel (hexane/
AcOEt ¼ 4:1) to give the camphorsulfonamide (432 mg,
93%) as a colorless oil. IR (neat) n 2957, 2859, 1745,
1.03, CHCl3).
6.1.9. Spectral data of (2S,5S)-5-(but-3-enyl)-2-(1,3-buta-
dien-2-yl)-1-p-toluenesulfonylpyrrolidine (16). IR (neat) n
2924, 2849, 1725, 1638, 1600, 1346, 1160 cmꢀ1; 1H NMR
(270 MHz, CDCl3) d 7.69 (d, J¼8.1 Hz, 2H), 7.27 (d, J¼
8.1 Hz, 2H), 6.34 (dd, J¼11.1, 17.8 Hz, 1H), 5.85 (ddt, J¼
6.3, 12.3, 16.6 Hz, 1H), 5.46 (s, 1H), 4.98–5.19 (m, 5H),
4.42–4.47 (m, 1H), 3.59–3.68 (m, 1H), 2.41 (s, 3H), 1.94
(m, 4H), 1.53 (m, 4H); LRMS (EI) m/z 331 (M+), 276,
248, 176, 155, 91; HRMS (EI) calcd for C19H25O2NS (M+)
331.1602, found 331.1606. [a]2D0 ꢀ16.9 (c 0.15, CHCl3).
1345, 1150 cmꢀ1 1H NMR (270 MHz, CDCl3) d 7.63–
;
7.68 (m, 4H), 7.23–7.43 (m, 6H), 4.45 (s, 2H), 3.82–3.73
(m, 1H), 3.58 (dd, J¼7.3, 9.2 Hz, 1H), 3.41 (ddd, J¼6.6,
9.2, 15.8 Hz, 2H), 3.23 (d, J¼14.4 Hz, 1H), 2.61 (d,
J¼14.4 Hz, 1H), 2.48–2.59 (m, 1H), 2.37 (dt, J¼4.0,
18.5 Hz, 1H), 1.79–2.10 (m, 7H), 1.26–1.69 (m, 6H), 1.13
(s, 3H), 1.06 (s, 9H); 13C NMR (100 MHz, CDCl3) d 215.0
(C), 138.3 (C), 135.3 (CHꢂ4), 133.1 (C), 133.0 (C), 129.4
(CHꢂ4), 128.1 (CHꢂ2), 127.5 (CHꢂ2), 127.4 (CHꢂ2),
127.2 (CH), 72.8 (CH2), 70.1 (CH2), 66.3 (CH2), 62.0
(CH), 61.7 (CH), 58.3 (C), 47.7 (C), 44.3 (CH2), 43.0
(CH), 42.7 (CH2), 33.4 (CH2), 30.3 (CH2), 27.3 (CH2),
27.0 (CH2, CH3ꢂ3), 26.6 (CH2), 25.5 (CH2), 20.0
(CH3ꢂ2), 19.4 (C); LRMS (EI) m/z 701 (M+), 686, 644,
432, 218, 91; HRMS (EI) calcd for C41H55O5NSSi (M+)
701.3556, found 701.3570. [a]2D0 +6.1 (c 1.34, CHCl3).
6.1.10. Synthesis of (L)-N-Ts-anatoxin-a ((L)-3) from
(1S,6S)-4a. To a solution of Hg(OAc)2 (12 mg, 38 mmol)
in H2O (0.4 mL) was added a solution of (1S,6S)-4a
(6 mg, 19 mmol) in THF (0.4 mL) at 0 ꢁC, and the mixture
was stirred at room temperature for 2.5 h. To the mixture
was added MeOH (0.8 mL), 3 M NaOH aq (0.8 mL), and
NaBH4 (5 mg, 0.13 mmol) at 0 ꢁC, and the mixture was
stirred at room temperature for 37 h. To the mixture was
added H2O, and the aqueous layer was extracted with
Et2O. The organic layer was washed with brine and dried
over Na2SO4. After removal of the solvent, the residue was
purified by column chromatography on silica gel (hexane/
AcOEt ¼ 5:1) to give the alcohol (3 mg, 42%) as a colorless
oil along with the starting (1S,6S)-4a (2 mg, 32%). IR (neat)
n 3511, 2966, 2928, 1735, 1598, 1338, 1160 cmꢀ1; 1H NMR
(400 MHz, CDCl3) d 7.75 (d, J¼8.4 Hz, 2H), 7.28 (d,
J¼8.4 Hz, 2H), 5.62 (dd, J¼5.7, 5.8 Hz, 1H), 4.53 (d,
J¼9.2 Hz, 1H), 4.44–4.45 (m, 1H), 4.30 (q, J¼6.4 Hz,
1H), 2.42 (s, 3H), 2.25–2.31 (m, 1H), 1.86–1.95 (m, 3H),
1.49–1.75 (m, 4H), 1.35 (d, J¼6.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 150.7 (C), 142.9 (C), 137.2 (C),
130.8 (Cꢂ2), 129.5 (CHꢂ2), 126.9 (CHꢂ2), 124.4 (CH),
72.2 (CH), 60.1 (CH), 57.6 (CH), 33.1 (CH2ꢂ2), 28.9
(CH2), 23.4 (CH2), 22.1 (CH3), 21.7 (CH3); LRMS (EI)
m/z 321 (M+), 303, 166, 155, 91; HRMS (EI) calcd for
C17H23O3NS (M+) 321.1406, found 321.1398. [a]2D3 ꢀ39.0
(c 0.73, CHCl3).
To a solution of the camphorsulfonamide (432 mg,
0.62 mmol) in THF (7 mL) was added TBAF (1.0 M THF
solution, 1.0 mL, 1 mmol) at 0 ꢁC, and the mixture was
stirred at room temperature for 4 h. To the mixture was
added H2O, and the aqueous layer was extracted with
Et2O. The organic layer was washed with brine and dried
over Na2SO4. After removal of the solvent, the residue was
purified by column chromatography on silica gel (hexane/
AcOEt ¼ 4:1) to give 18 (271 mg, 95%) as a colorless solid,
which was recrystallized from ether to give a colorless plate
(mp 107–109 ꢁC) for X-ray analysis.24
1
IR (neat) n 3482, 2956, 2882, 1744, 1340, 1149 cmꢀ1; H
NMR (400 MHz, CDCl3) d 7.28–7.36 (m, 5H), 4.49 (s,
2H), 3.84–3.91 (m, 1H), 3.77–3.83 (m, 2H), 3.55–3.69 (m,
2H), 3.49 (dd, J¼6.1, 6.5 Hz, 2H), 3.29 (d, J¼4.2 Hz, 1H),
2.84 (d, J¼4.2 Hz, 1H), 2.50–2.56 (m, 1H), 2.35–2.41 (m,
1H), 1.51–2.11 (m, 14H), 1.15 (s, 3H), 0.90 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 214.9 (C), 138.2 (C), 128.1
(CHꢂ2), 127.4 (CHꢂ2), 127.3 (CH), 72.9 (CH2), 70.0
(CH2), 66.2 (CH2), 63.1 (CH), 62.2 (CH), 58.3 (C), 47.8
(C), 44.0 (CH2), 43.0 (CH), 42.6 (CH2), 33.3 (CH2), 30.2
(CH2), 27.5 (CH2), 27.0 (CH2), 26.6 (CH2), 25.6 (CH2),
20.3 (CH3), 20.0 (CH3); LRMS (EI) m/z 464 (M+), 446,
432, 248, 218, 91; HRMS (EI) calcd for C25H37O5NS (M+)
463.2404, found 463.2392. [a]2D0 +34.1 (c 0.73, CHCl3).
To a solution of the alcohol (7 mg, 0.02 mmol) in CH2Cl2
(0.5 mL) was added Dess–Martin periodinane (20 mg,
0.05 mmol) at 0 ꢁC, and the mixture was stirred at room tem-
perature for 1.5 h. To the mixture were added satd NaHCO3
aq and satd Na2S2O3 aq, and the aqueous layer was extracted
with AcOEt. The organic layer was washed with brine and
dried over Na2SO4. After removal of the solvent, the residue
was purified by column chromatography on silica gel
(hexane/AcOEt ¼ 1:1) to give (ꢀ)-N-Ts-anatoxin-a ((ꢀ)-
3) (6 mg, 86%) as a colorless solid, whose spectral data
were identical with those previously reported.8 [a]D25
ꢀ15.0 (c 0.65, CHCl3).
6.1.12. (2S,5S)-5-(But-3-enyl)-2-(prop-1-ynyl)-1-p-tolue-
nesulfonylpyrrolidine ((2S,5S)-19b). To a solution of
(2S,5S)-5 (101 mg, 0.33 mmol) in THF (1.6 mL) was added
NaHMDS (1.0 M THF solution, 1.0 mL, 1 mmol) at ꢀ78 ꢁC,
and the mixture was stirred at the same temperature for
5 min. To the mixture was added methyl trifluoromethane-
sulfonate (0.2 mL, 1.7 mmol) at ꢀ78 ꢁC, the mixture was
stirred at the same temperature for 2 h. To the mixture was
added satd NaHCO3 aq, and the aqueous layer was extracted
with Et2O. The organic layer was washed with brine and
dried over Na2SO4. After removal of the solvent, the residue
was purified by column chromatography on silica gel
(hexane/AcOEt ¼ 3:1) to give (2S,5S)-19b (87 mg, 82%)
6.1.11. (2S,5R)-5-(3-Benzyloxypropyl)-2-(hydroxy-
methyl)-1-((1S)-10-camphorsulfonyl)-pyrrolidine (18).
To a solution of 17 (323 mg, 0.66 mmol), which is an inter-
mediate for the synthesis of 13 from (S)-6a (see, Section
6.1.4), in CH3CN (3 mL) were added Et3N (0.2 mL,
1.6 mmol), (1S)-10-camphorsulfonyl chloride (327 mg,
2.0 mmol), and DMAP (162 mg, 1.3 mmol), and the mixture
was stirred at room temperature for 24 h. To the mixture was

10526
T. Tomita et al. / Tetrahedron 62 (2006) 10518–10527
2. For reviews of olefin metathesis, see: (a) Grubbs, R. H.; Miller,
S. J. Acc. Chem. Res. 1995, 28, 446; (b) Schuster, M.; Blechert,
S. Angew. Chem., Int. Ed. 1997, 36, 2036; (c) Schmalz, H.-G.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1833; (d) Grubbs,
R. H.; Chang, S. Tetrahedron 1998, 54, 4413; (e) Armstrong,
S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371; (f) Phillips,
as a colorless oil. IR (neat) n 2925, 2852, 1732, 1633, 1598,
1
1337, 1161 cmꢀ1; H NMR (400 MHz, CDCl3) d 7.73 (d,
J¼8.0 Hz, 2H), 7.29 (d, J¼8.0 Hz, 2H), 5.82 (ddt, J¼6.2,
10.3, 16.4 Hz, 1H), 5.03 (d, J¼16.4 Hz, 1H), 4.97 (d,
J¼10.3 Hz, 1H), 4.41 (m, 1H), 3.66–3.77 (m, 1H), 2.41 (s,
3H), 2.00–2.12 (m, 3H), 1.55–1.94 (m, 1H). [a]2D1 ꢀ61.4
(c 0.94, CHCl3).
€
A. J.; Abell, A. D. Aldrichim. Acta 1999, 32, 75; (g) Furstner,
A. Angew. Chem., Int. Ed. 2000, 39, 3013; (h) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18; (i) Schrock,
R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42,
4592; (j) Connnon, S. J.; Blechert, S. Angew. Chem., Int. Ed.
2003, 42, 1900; (k) Connon, S. J.; Blechert, S. Top.
Organomet. Chem. 2004, 7, 93; (l) Schmidt, B.; Hermanns, J.
Top. Organomet. Chem. 2004, 7, 223; For a recent review of
synthetic utilization of metathesis reactions, see: (m)
Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int.
Ed. 2005, 44, 4490.
6.1.13. (1S,6S)-2-(2-Propen-2-yl)-9-p-toluenesulfonyl-9-
azabicyclo[4.2.1]nona-2ene (22). A solution of (2S,5S)-
19b (87 mg, 0.3 mmol) and Ru–carbene complex 8c
(23 mg, 0.03 mmol) in degassed CH2Cl2 (3 mL) was stirred
at room temperature for 29 h. To the mixture was added
DMSO (0.1 mL), and the mixture was stirred at room
temperature for 23 h. After removal of the solvent, the resi-
due was purified by column chromatography on silica gel
(hexane/AcOEt ¼ 3:1) to give 22 (68 mg, 78%) as a color-
1
less oil. H NMR (270 MHz, CDCl3) d 7.72 (d, J¼8.3 Hz,
3. For reviews of enyne metathesis, see: (a) Mori, M. Top.
Organomet. Chem. 1998, 1, 133; (b) Mori, M. In Handbook
of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH Verlag GmbH
& Co. KGaA: Weinheim, 2003; Vol. 2, p 176; (c) Poulsen,
C. S.; Madsen, R. Synthesis 2003, 1; (d) Diver, S. T.;
Giessert, A. J. Chem. Rev. 2004, 104, 1317.
2H), 7.27 (d, J¼8.3 Hz, 2H), 5.77 (dd, J¼5.9, 6.6 Hz, 1H),
4.93–5.04 (m, 3H), 4.39–4.40 (m, 1H), 2.44–2.53 (m, 1H),
2.41 (s, 3H), 2.14–2.27 (m, 1H), 2.00–2.10 (m, 1H), 1.88
(s, 3H), 1.52–1.83 (m, 5H); LRMS m/z 317 (M+), 302,
261, 162, 155, 91; HRMS calcd for C18H23O2NS (M+)
317.1452, found 317.1449. [a]2D1 ꢀ12.4 (c 1.03, CHCl3).
4. For reports from our laboratory, see: (a) Kinoshita, A.; Mori, M.
Synlett 1994, 1020; (b) Kinoshita, A.; Mori, M. J. Org. Chem.
1996, 61, 8356; (c) Kinoshita, A.; Mori, M. Heterocycles 1997,
46, 287; (d) Kinoshita, A.; Sakakibara, N.; Mori, M. J. Am.
Chem. Soc. 1997, 119, 12388; (e) Mori, M.; Sakakibara, N.;
Kinoshita, A. J. Org. Chem. 1998, 63, 6082; (f) Kinoshita,
A.; Sakakibara, N.; Mori, M. Tetrahedron 1999, 55, 8155; (g)
Mori, M.; Kitamura, T.; Sakakibara, N.; Sato, Y. Org. Lett.
2000, 2, 543; (h) Mori, M.; Kitamura, T.; Sato, Y. Synthesis
2001, 654; (i) Kitamura, T.; Mori, M. Org. Lett. 2001, 3,
1161; (j) Mori, M.; Kuzuba, Y.; Kitamura, T.; Sato, Y. Org.
Lett. 2002, 4, 3855; (k) Kitamura, T.; Sato, Y.; Mori, M.
Chem. Commun. 2001, 1258; (l) Kitamura, T.; Sato, Y.; Mori,
M. Adv. Synth. Catal. 2002, 344, 678; (m) Mori, M.;
Tonogaki, K.; Nishiguchi, N. J. Org. Chem. 2002, 67, 224;
(n) Saito, N.; Sato, Y.; Mori, M. Org. Lett. 2002, 4, 803; (o)
Mori, M.; Kuzuba, Y.; Kitamura, T.; Sato, Y. Org. Lett. 2002,
4, 3855; (p) Tonogaki, K.; Mori, M. Tetrahedron Lett. 2002,
43, 2235; (q) Kitamura, T.; Kuzuba, Y.; Sato, Y.; Wakamatsu,
H.; Fujita, R.; Mori, M. Tetrahedron 2004, 60, 7375; (r)
Kitamura, T.; Sato, Y.; Mori, M. Tetrahedron 2004, 60, 9649;
(s) Mori, M.; Wakamatsu, H.; Tonogaki, K.; Fujita, R.;
Kitamura, T.; Sato, Y. J. Org. Chem. 2005, 70, 1066; (t)
Mori, M.; Tonogaki, K.; Kinoshita, A. Org. Synth. 2005, 81, 1.
5. For a review of the construction of oxygen- and nitrogen-con-
taining heterocycles by ring-closing metathesis, see: Deiters,
A.; Martin, S. F. Chem. Rev. 2004, 104, 2199.
6. (a) Devlin, J. P.; Edwards, O. E.; Gorham, P. R.; Hunter, N. R.;
Pike, R. K.; Stavric, B. Can. J. Chem. 1977, 55, 1367; (b)
Carmichael, W. W.; Biggs, D. F.; Gorham, P. R. Science
1975, 187, 542.
7. For a recent review on synthetic approach to anatoxin-a, see:
(a) Mansell, H. L. Tetrahedron 1996, 52, 6025 and references
cited therein; For recent reports on the synthesis of (+)- and/
or (ꢀ)-anatoxin-a, see: (b) Hjelmgaard, T.; Søtofte, I.;
Tanner, D. J. Org. Chem. 2005, 70, 5688; (c) Muniz, M. N.;
Kanazawa, A.; Greene, A. E. Synlett 2005, 1328; (d) Wegge,
T.; Schwarz, S.; Seitz, G. Tetrahedron: Asymmetry 2000, 11,
1405; (e) Trost, B. M.; Oslob, J. D. J. Am. Chem. Soc. 1999,
121, 3057; (f) Aggarwal, V. K.; Humphries, P. S.; Fenwick, A.
6.1.14. (D)-N-Ts-anatoxin-a ((D)-3). To a solution of OsO4
(47 mg, 0.15 mmol) in THF (2 mL) was added Et3N
(0.04 mL, 0.3 mmol), and the mixture was stirred at room
temperature for 5 min. To the mixture was added a solution
of 22 (47 mg, 0.15 mmol) in THF (1.2 mL) at ꢀ78 ꢁC, the
mixture was stirred at room temperature for 64 h. To the
mixture was added satd NaHSO3 aq (2.6 mL), and the mix-
ture was heated under reflux for 2.5 h. The mixture was ex-
tracted with AcOEt, and the organic layer was washed with
brine and dried over Na2SO4. After removal of the solvent,
the residue was purified by column chromatography on silica
gel (hexane/AcOEt ¼ 3:1) to give the diol (31 mg, 59%) as
a colorless oil. 1H NMR (400 MHz, CDCl3) d 7.73 (d,
J¼8.2 Hz, 2H), 7.29 (d, J¼8.2 Hz, 2H), 5.69 (dd, J¼7.0,
7.0 Hz, 1H), 4.73 (d, J¼9.4 Hz, 1H), 4.43 (dd, J¼3.5,
3.8 Hz, 1H), 3.72 (d, J¼11.1 Hz, 1H), 3.58 (d, J¼11.1 Hz,
1H), 2.75 (br, 1H), 2.55 (br, 1H), 2.42 (s, 3H), 2.23–2.39
(m, 2H), 1.91–2.05 (m, 2H), 1.49–1.79 (m, 4H), 1.36 (s,
3H). [a]2D1 ꢀ62.8 (c 1.23, CHCl3).
To a solution of the diol (31 mg, 0.09 mmol) in H2O/THF
(1/1, 1.7 mL) was added NaIO4 (58 mg, 0.27 mmol), and
the mixture was stirred at room temperature for 1.5 h. To
the mixture was added H2O, and the aqueous layer was ex-
tracted with Et2O. The organic layer was washed with brine
and dried over Na2SO4. After removal of the solvent, the res-
idue was purified by column chromatography on silica gel
(hexane/AcOEt ¼ 3:1) to give N-Ts-anatoxin-a 3 (24 mg,
85%) as a colorless solid, whose spectral data were identical
to those previously obtained. And the [a]D value of the
synthetic N-Ts-anatoxin-a ([a]2D0 +12.8 (c 0.44, CHCl3))
was identical to that previously reported.7e
References and notes
1. (a) Grubbs, R. H. Handbook of Metathesis; Wiley-VCH:
Weinheim, 2003; (b) F€urstner, A. Topics in Organometallic
Chemistry; Springer: Berlin, Heidelberg, 1998; Vol. 1.

T. Tomita et al. / Tetrahedron 62 (2006) 10518–10527
10527
Angew. Chem., Int. Ed. 1999, 38, 1985; For recent reports on
the synthesis of (ꢃ)-anatoxin-a, see: (g) Parsons, P. J.; Camp,
N. P.; Edwards, N.; Sumoreeah, L. R. Tetrahedron 2000, 56,
309; (h) Oh, C.-Y.; Kim, K.-S.; Ham, W.-H. Tetrahedron Lett.
1998, 39, 2133; (i) Parsons, P. J.; Camp, N. P.; Underwood,
J. M.; Harvey, D. M. Tetrahedron 1996, 52, 11637.
8. Somfai, P.; Ahman, J. Tetrahedron Lett. 1992, 33, 3791.
9. For a preliminary communication of a part of this work, see:
Mori, M.; Tomita, T.; Kita, Y.; Kitamura, T. Tetrahedron Lett.
2004, 45, 4397.
10. At almost the same time as publication of our synthesis of
(+)-anatoxin-a (Ref. 9), Martin et al. reported the synthesis
of (+)-anatoxin-a from (R)-(+)-pyroglutamic acid in which
enyne metathesis was used for construction of a 9-azabicy-
clo[4.2.1]nonene skeleton. See: (a) Brenneman, J. B.; Martin,
S. F. Org. Lett. 2004, 6, 1329; (b) Brenneman, J. B.;
Machauer, R.; Martin, S. F. Tetrahedron 2004, 60, 7301.
11. The synthesis of (ꢀ)-ferruginine, which has a structure similar
to that of anatoxin-a, was recently reported, in which a 7-aza-
bicyclo[3.2.1]octane skeleton was constructed from pyrro-
lidine derivative using an enyne metathesis. See: Aggarwal,
V. K.; Astle, C. J.; Rogers-Evans, M. Org. Lett. 2004, 6,
1469.
15. Pickering, L.; Malhi, B. S.; Coe, P. L.; Walker, R. T.
Nucleosides Nucleotides 1994, 13, 1493.
16. Giovannini, A.; Savoia, D.; Umani-Ronchi, A. J. Org. Chem.
1989, 54, 228.
17. For a lead reference to the discussion on the role of ethylene gas
in enyne metathesis, see: Lloyd-Jones, G. C.; Margue, R. G.;
de Varies, J. G. Angew. Chem., Int. Ed. 2005, 44, 7442.
18. For other examples of intermolecular metathesis of alkyne and
ethylene, see: (a) Smulik, J. A.; Diver, S. T. J. Org. Chem. 2000,
65, 1788; (b) Smulik, J. A.; Diver, S. T. Org. Lett. 2000, 2,
2271; (c) Smulik, J. A.; Giessert, A. J.; Diver, S. T.
Tetrahedron Lett. 2002, 43, 209.
19. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953.
20. Wakamatsu, H.; Blechert, S. Angew. Chem., Int. Ed. 2002, 41,
2403.
21. In the metathesis of enyne having a silyl group on the alkyne,
desilylation did not usually occur. See Ref. 4p.
22. The optical purity of the recovered 4a was completely same to
that of the starting material 4a of the oxymercuration reaction.
23. In our preliminary communication,9 the structure of the syn-
thetic (+)-N-Ts-anatoxin-a was incorrectly drawn as that of
the antipode (i.e., (ꢀ)-N-Ts-anatoxin-a) because of the confu-
sion arising from the unexpected inversion of chirality.
24. Crystallographic data for the structure of 18 have been depos-
ited with the Cambridge Crystallographic Data Centre as sup-
plementary publication number CCDC 295170. Copies of
the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44
1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
12. Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039.
13. (a) Tsuji, J.; Kaito, M.; Yamada, T.; Mandai, T. Bull. Chem.
Soc. Jpn. 1978, 51, 1915; (b) Tsuji, J. Synthesis 1984, 369;
(c) Tsuji, J.; Nagashima, H.; Nemoto, H. Org. Synth. 1984,
62, 9.
14. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.