Thermodynamic equilibration in Pd(0)-catalyzed interconversion of highly constrained [2.1.2] bicyclic lactones: its mechanistic investigation

Article abstract of DOI:10.1016/j.tetlet.2010.03.016

Mechanistic study on the stereoselective construction of [2.1.2] bicyclic lactone skeleton via Pd(0)-catalyzed intramolecular allylic alkylation was described. The observed excellent stereoselectivity is likely due to Pd(0)-catalyzed equilibration of highly strained [2.1.2] bicyclic lactone framework via π-σ-π isomerization of π-allylpalladium complex. An efficient synthetic route to allylic carbonate as a requisite cyclization precursor has also been developed by employing a sequence of ring-closing metathesis, followed by epoxidation/desilylation of the resulting substituted oxasilepene intermediate.

Full text of DOI:10.1016/j.tetlet.2010.03.016

Tetrahedron Letters 51 (2010) 2697–2699
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Thermodynamic equilibration in Pd(0)-catalyzed interconversion of highly
constrained [2.1.2] bicyclic lactones: its mechanistic investigation
Young Taek Han a, Seung-Mann Paek a, Sujin Lee a, Jong-Wha Jung a, Jae-Kyung Jung b, Seung-Yong Seo c,
Jeeyeon Lee a, Young-Ger Suh a,
*
a College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
b College of Pharmacy, Chungbuk National University, Cheongju 361-763, Republic of Korea
c College of Pharmacy, Woosuk University, Wanju, 565-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Mechanistic study on the stereoselective construction of [2.1.2] bicyclic lactone skeleton via Pd(0)-cata-
lyzed intramolecular allylic alkylation was described. The observed excellent stereoselectivity is likely
Received 3 February 2010
Revised 2 March 2010
Accepted 8 March 2010
Available online 12 March 2010
due to Pd(0)-catalyzed equilibration of highly strained [2.1.2] bicyclic lactone framework via
p-r-p isom-
erization of -allylpalladium complex. An efficient synthetic route to allylic carbonate as a requisite cycli-
p
zation precursor has also been developed by employing a sequence of ring-closing metathesis, followed
by epoxidation/desilylation of the resulting substituted oxasilepene intermediate.
Ó 2010 Elsevier Ltd. All rights reserved.
Recently, we have reported highly stereoselective construction
of unique bicyclic lactones via intramolecular Pd(0)-catalyzed
allylic alkylation.1,2 The [2.1.2] or [2.2.1] bicyclic lactones could
be utilized as excellent equivalents of contra thermodynamic tri-
cis-substituted cyclopentanes, which have importantly been
utilized for total syntheses of bioactive natural products.2,3 These
applications implied high utility of the bicyclic lactone architec-
tures (Fig. 1).
observed in conversion of 7 as a diastereomeric mixture to the
corresponding bicyclic lactone 8 (Eq. 1).4 We could solve the prob-
lem by cyclization of the diastereomerically pure allylic carbonate
73c,4 or the highly diastereoselective route of 1 to 2, followed by
desulfonylation and subsequent cross metathesis of bicyclic
lactone 3 with siloxyheptene.3d In spite of the development of
successful route, the observed diastereoselectivity was quite disap-
pointing because the rapid
p-r-p isomerization of p-allylpalla-
On the way of our synthetic studies toward (+)-brefeldin A,
however, unexpectedly poor diastereoselectivity (dr 2:1) was
dium complex was anticipated for the exclusive formation of the
desired bicyclic lactone 8.
OH
O
H
H
R
dr 20:1
HO
O
Pd(dppe)2
O
PhO2S
O
OR
CH2Cl2
reflux
80%
O
O
2 R=SO2Ph
3 R=H
(+)-Brefeldin A
and its lactam analog
Na-Hg
1 R=CO2Et
O
H
R
OR
Pd(0)
O
O
dr 20:1
O
O
PhO2S
4
CH2Cl2
reflux
88%
CO2H
O
H
HO
H
5 R=SO2Ph
6 R=H
R=CO2Et
Na-Hg
Bacillariolide lll
Figure 1. Stereoselective synthesis and applications of bicyclic lactones.
* Corresponding author. Tel.: +82 2 880 7875; fax: +82 2 888 0649.
E-mail address: ygsuh@snu.ac.kr (Y.-G. Suh).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.016

2698
Y. T. Han et al. / Tetrahedron Letters 51 (2010) 2697–2699
H
H
SO2Ph
7
H
O
O
H
EtO2CO
7
2
O
SO2Ph
H
PhO2S
O
2
2
O
8
O
+
10
2 major
PdL2
1
Pd(0)
π−σ−π
or
isomerization
H
8
7
PhO2S
H
H
O
SO2Ph
1
O
O
OCO2Et
7
8
SO2Ph
2
O
O
H
9
O
H
+
PdL2
11
2' minor
Figure 2. Plausible pathway for the highly diastereoselective cyclization.
SO2Ph
7
OTBS
PhO2S
MeO2C
13
PhO2S
O
dr 2:1
OTBS
O
O
Pd(dppe)2
2
PhO2S
7
2
( )3
O
O
OR
CH2Cl2
reflux, 75%
Si
O
OCO2Et
O
12 R=H
9 R=CO2Et
O
( )3
8
7
F
ð1Þ
Thus, investigation on the origin of diastereoselectivity was
PhO2S
MeO2C
TsO
15
O
Si
OH
focused on isomerization of -allylpalladium complex
p-r
-p
p
because the diastereoselectivity seems to be complicated by the
disubstituted olefinic system3c rather than the stereochemistry at
C7. In particular, we were interested in reversibility of the C2–C7
single bond formation in the highly constrained bicyclic system
such as 2 on the basis of Pd(0)-catalyzed C–C bond cleavage/forma-
tion sequence,5 which would reinforce high diastereoselectivity of
the cyclization process for [2.1.2] bicyclic lactone 2 through C2–C7
cleavage of the thermodynamically less favorable product 20 fol-
14
Scheme 2. Retrosynthesis for the monosubstituted allylic carbonate 9.
Accordingly, the exclusive formation of 2 as a thermodynamically
favored product was also expected regardless of the stereochemis-
try of the secondary alcohol at C7 of 9 (Fig. 2).
Thus, an efficient synthesis of allylic carbonate 9 possessing ter-
minal olefin was planned as outlined in Scheme 2.8 It was envisioned
that allylic alcohol 12 could be conveniently synthesized through a
sequence of desilylation and ring opening9 of epoxide 13, followed
by subsequent lactone formation. It was also anticipated that the
unstable epoxide 13 could be prepared via ring-closing metathesis
of diene 1410 followed by epoxidation of the resulting olefin. Diene
14 would be readily prepared from the known homoallylic alcohol
1511 by allylsilylation and alkylation of benzenesulfonylacetate.
As shown in Scheme 3, the alcohol 15 was silylated and the
resulting tosylate 16 was subjected to enolate alkylation
conditions of NaH in DMF to afford silyl ether 14 in a yield of
lowed by p-r-p
isomerization (Fig. 2).1,6,7
Basedonthehypothesis, weexaminedPd(0)-catalyzedequilibra-
tion7 between 2 and 20. At first, chromatographically separable
diastereomers 2 and 20 were prepared by stereoselective cyclization
of precursor 1,1 and interconversion between the major diastereo-
mer 2 and the minor diastereomer 20 was carried out (Scheme 1).
Upon treatment of the minor product 20 with Pd(dppe)2 in refluxing
CH2Cl2 for 2 h, the major product 2 was obtained exclusively (ca.
20:1) as expected. It was obvious that combination of the highly
strained bicyclic framework and the relatively less hindered termi-
nal olefin was responsible for the reversible C(sp3)–C(sp3) bond
cleavage/formation in the presence of Pd(0) catalyst5 (Scheme 1).
It is noteworthy that the thermodynamic equilibration of C–C single
bond cleavage/formation in bicyclic systems such as 20 has not been
reported yet, although a few examples of C–C single bond cleavage
under similar conditions were reported for cyclopropane, cyclobu-
tane, or sterically encumbered quaternary carbon skeleton to the
best of our knowledge.5
PhO2S
TsO
17
MeO2C
b
a
TsO
O
Si
OH
16
15
MesN
NMes
PhO2S
Ph
18
Cl
Cl
PhO2S
Ru
Confirming the interconversion of the [2.1.2] bicyclic lactones 2
and 20, we turned our attention to thermodynamic equilibration of
the Pd(0)-catalyzed allylic alkylation of allylic carbonate 9 as a dia-
stereomeric mixture. It was anticipated that the presence of a less
hindered terminal olefin in the cyclization precursor 9 would not
complicate the Pd(0)-catalyzed equilibration between 2 and 20.
MeO2C
19
O
PCy3
Si
MeO2C
14
O
Si
c
PhO2S
MeO2C
O
PhO2S
e
d
O
O
OH
Si
O
12
13
PhO2S
SO2Ph
7
f
SO2Ph
7
8
SO2Ph
Pd(dppe)2
O
H
O
O
2
7
+
2
2
O
OCO2Et
8
CH2Cl2
reflux
O
O
9
O
H
O
H
2 major8
2' minor
2' minor
Scheme 3. Reagents and conditions (a) allyldimethylsilyl chloride, imidazole, DMF,
0 °C to rt, 91%; (b) 17, NaH, DMF, 0 °C to 80 °C, 72 h, 82%; (c) 1 mol % 18, CH2Cl2,
40 °C, 20 min, 95%; (d) mCPBA, NaHCO3, CH2Cl2, ꢀ40 °C, 72 h; (e) TBAF, THF, 0 °C,
5 h, 99%; (f) ClCO2Et, pyridine, CH2Cl2, 0 °C to rt, 6 h, 94%.
2 : 2' > 20 : 1
(2h, 80%)
Scheme 1. Pd(0)-catalyzed equilibration of 2 and 20.

Y. T. Han et al. / Tetrahedron Letters 51 (2010) 2697–2699
2699
3. (a) Suh, Y.-G.; Jung, J.-K.; Suh, B.-C.; Lee, Y.-C.; Kim, S.-A. Tetrahedron Lett. 1998,
39, 5377; (b) Suh, Y.-G.; Seo, S.-Y.; Jung, J.-K.; Park, O.-H.; Jeon, R.-O.
Tetrahedron Lett. 2001, 42, 1691; (c) Suh, Y.-G.; Jung, J.-K.; Seo, S.-Y.; Min, K.-
H.; Shin, D.-Y.; Lee, Y.-S.; Kim, S.-H.; Park, H.-J. J. Org. Chem. 2002, 67, 4127; (d)
Seo, S.-Y.; Jung, J.-K.; Paek, S.-M.; Lee, Y.-S.; Kim, S.-H.; Suh, Y.-G. Tetrahedron
Lett. 2006, 47, 6527; (e) Paek, S.-M.; Seo, S.-Y.; Min, K.-H.; Shin, D.-M.; Chung,
Y.-K.; Suh, Y.-G. Heterocycles 2007, 71, 1059.
SO2Ph
H
PhO2S
SO2Ph
H
a
O
O
O
+
O
OCO2Et
O
O
9
2
2'
> 19 : 1
4. Ph. D. Thesis of J.-K. Jung, Seoul National University, 1999.
Scheme 4. Reagents and conditions: (a) 5 mol % Pd(dppe)2, CH2Cl2, 40 °C, 2 h, 80%.
5. For examples of C–C single bond cleavage and formation in the presence of
Pd(0), see: (a) Burgess, K. Tetrahedron Lett. 1985, 26, 3049; (b) Burgess, K. J. Org.
Chem. 1987, 52, 2046; (c) Nilsson, Y. I. M.; Andersson, P. G.; Backvall, J. E. J. Am.
Chem. Soc. 1993, 115, 6609; (d) Bricout, H.; Carpentier, J. F.; Mortreux, A.
Tetrahedron Lett. 1997, 38, 1053; (e) Nishimura, T.; Matsumura, S.; Maeda, Y.;
Uemura, S. Tetrahedron Lett. 2002, 43, 3037; (f) Matsumura, S.; Maeda, Y.;
Nishimura, T.; Uemura, S. J. Am. Chem. Soc. 2003, 125, 8862; (g) Nishimura, T.;
Nishiguchi, Y.; Maeda, Y.; Uemura, S. J. Org. Chem. 2004, 69, 5342; (h) Ohmura,
T.; Taniguchi, H.; Kondo, Y.; Suginome, M. J. Am. Chem. Soc. 2007, 129, 3518; (i)
Yang, Y.; Huang, X. Synlett 2008, 1366; (j) Matsuda, T.; Shigeno, M.; Murakami,
M. Org. Lett. 2008, 10, 5219; (k) Jiang, M.; Shi, M. Organometallics 2009, 28,
5600.
75% for two steps. Diene 14 was treated with Grubbs’ 2nd genera-
tion catalyst 1812 to provide oxasilepene 19 in a yield of 95%. For-
tunately, dimeric or olefin-isomerized byproduct was not
observed. Epoxidation of oxasilepene 19 with mCPBA afforded
the unstable epoxide 13, which was directly treated with TBAF to
give the requisite allylic alcohol 12 in 2:1 diastereomeric ratio in
nearly quantitative yield for two steps.13 The diastereomeric mix-
ture 12 was converted to the corresponding carbonate 9 by stan-
dard ethoxycarbonylation.3 Finally, we were able to secure the
desired cyclization precursor 9 in more than 10 g scale via an im-
proved sequence of RCM, epoxidation, and then desilylation (65%
from 15).14
6. For the
p-r-p isomerization of p-allyl-palladium complex, see Hayashi, T.;
Yamamoto, A.; Hagihara, T. J. Org. Chem. 1986, 51, 723 and references therein.
7. Ibuka et al. reported that thermodynamic equilibration in the presence of Pd
could change the stereochemical outcome. Ibuka, T.; Mimura, N.; Aoyama, H.;
Akaji, M.; Hono, H.; Miwa, Y.; Taga, T.; Nakai, K.; Tamamura, H.; Fujii, N.;
Yamamoto, Y. J. Org. Chem. 1997, 62, 999.
With allylic carbonate 9 possessing terminal olefin in hand, the
key Pd(0)-catalyzed cyclization was carried out as shown in
Scheme 4.15 Upon Pd(dppe)2 treatment of 9 in CH2Cl2 at reflux con-
dition, di-cis-substituted [2.1.2] bicyclic lactone 2 was obtained in
more than 19:1 ratio, which was determined by isolation of each
isomers. The result was in accordance with the cyclization result
of our previous cyclization precursor 1. This also supports Pd(0)-
catalyzed thermodynamic equilibration of the highly strained
[2.1.2] bicyclic lactone systems via sequential C–C bond cleavage,
isomerization, and recyclization. The diastereoselectivity of this
cyclization seems independent of the stereochemistry at allylic po-
sition of the allylic carbonate precursors unless the terminal ole-
finic carbon is substituted.
8. Olefin cleavage of 1, followed by vinyl Grignard addition did not afford the
allylic alcohol 9 effectively. The difficulty is likely due to the presence of labile
b-acetoxy moiety. Substituted alkynyl addition to the corresponding aldehyde
provided the propargylic alcohol in a moderate yield (30–40%, for two steps).
9. Kiely, A. F.; Jernelius, J. A.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2002,
124, 2868.
10. For recent reviews concerning olefin cross metathesis reactions, see: Connon, S.
J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900. and references therein.
11. Jana, G.; Viso, A.; Diaz, Y.; Castillon, S. Eur. J. Org. Chem. 2003, 209.
12. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
13. Diastereomeric ratio at C7 was determined after desulfonylation of carbonate 9
using 6% Na–Hg, B(OH)3 in MeOH.
14. Synthesis of 9: To a solution of 19 (70 mg, 0.19 mmol) in CH2Cl2 (2 mL), NaHCO3
(48 mg, 0.57 mmol) was added and the reaction mixture was cooled to ꢀ40 °C.
A solution of mCPBA (70 mg, 0.29 mmol) in CH2Cl2 (2 mL) was added and the
reaction mixture was stirred for 3 days at the same temperature. After addition
of aqueous NaHSO3, the mixture was extracted with EtOAc twice. The
combined organic layer was dried over MgSO4, filtered, and concentrated in
vacuo. The residue was dissolved in THF (1 mL), and TBAF (1 mL, 1.0 M solution
in THF) was added at 0 °C. After stirring for 5 h, the reaction was quenched
with H2O and the reaction mixture was extracted with EtOAc twice. The
combined organic layer was dried over MgSO4, filtered, and concentrated. The
residue was purified by chromatography on silica gel with a mixture of EtOAc
and n-hexane (2:1) to afford 56 mg (99%) of allylic alcohol 12 for two steps as
colorless oil. The allylic alcohol 12 was dissolved in CH2Cl2 (5 mL) and treated
with pyridine (0.2 mL) and ClCO2Et (0.1 mL) at 0 °C. The reaction was quenched
with H2O and the reaction mixture was extracted with EtOAc twice. The
combined organic layer was dried over MgSO4, filtered, and concentrated. The
residue was purified by column chromatography on silica gel with a mixture of
EtOAc and n-hexane (1:3) to afford 64 mg (94%) of allylic carbonate 9 as a
colorless oil. 1H NMR (CDCl3, 300 MHz, mixture of four diastereomers) d 7.93–
7.85 (m, 2H), 7.69–7.63 (m, 1H), 7.57–7.51 (m, 2H), 5.80–5.68 (m, 1H), 5.37–
5.16 (m, 3H), 4.82 and 4.58 (m, 1H) 4.18–4.10 (m, 2H), 4.08 and 4.00 (m, 1H),
3.10 and 2.79 (m, 1H), 2.55 and 2.30 (m, 1H), 2.08–1.92 (m, 1H), 1.28–1.16 (m,
4H) ppm.; 13C NMR (CDCl3, 125 MHz, mixture of four diastereomers) d 170.7,
167.1, 166.9, 153.7, 136.4, 136.2, 134.7, 134.4, 134.3, 134.1, 133.9, 129.1, 129.0,
128.9, 128.7, 127.5, 118.9, 118.6, 117.7, 77.1, 76.3, 76.0, 74.9, 74.7, 74.5, 74.2,
74.1, 64.4, 64.3, 63.8, 634, 63.3, 60.0, 39.7, 39.3, 39.1, 29.8, 29.6, 28.9, 28.7, 20.7,
In summary, mechanistic aspect of highly stereoselective con-
struction of the synthetically useful [2.1.2] bicyclic lactone system
via Pd(0)-catalyzed intramolecular allylic alkylation was investi-
gated. The excellent diastereoselectivity of the favorable [2.1.2]
bicyclic lactone isomer is attributed to Pd(0)-catalyzed thermody-
namic equilibration of each isomer via
p-r-p isomerization of
p-allyl palladium complexes, which formed from either allylic
carbonate or energetically less favorable [2.1.2] bicyclic lactone
isomer. It is also noteworthy that Pd(0)-catalyzed cleavage of
C–C single bond was observed for the synthetically useful and
unique [2.1.2] bicyclic lactone system. We expect that mechanistic
insight and evidences for thermodynamic equilibration could pro-
vide highly versatile synthetic applications.
Acknowledgments
This research work was supported by the Center for Bioactive
Molecular hybrids, Yonsei University, and in part by the Research
Institute of Pharmaceutical Science, Seoul National University.
13.8 ppm; FT-IR (KBr) v
max(cmꢀ1) 2984, 1778, 1744, 1448, 1372, 1324; LRMS
(FAB) m/z 369 (M+H+); HRMS (FAB) calcd for C17H21O7S 369.1008 (M+H+)
found 369.1014.
15. Pd(0)-assisted alkylation of allylic carbonate 9: To
a solution of allylic
carbonate 9 (480 mg, 1.6 mmol) in CH2Cl2 (20 mL), a solution of Pd(dppe)2
(73 mg, 5 mol %) in CH2Cl2 (5 mL) was added at 40 °C. After 2 h reflux, the
reaction mixture was cooled to room temperature, diluted with Et2O, and
filtered by silica gel. The mixture was concentrated and the residue was
purified by column chromatography on silica gel with a mixture of EtOAc and
n-hexane (2:1) to afford 340 mg (76%) of the major adduct 2 and 17 mg (4%) of
the minor adduct 20.
References and notes
1. Suh, Y.-G.; Jung, J.-K.; Kim, S.-A.; Shin, D.-Y.; Min, K.-H. Tetrahedron Lett. 1997,
38, 3911.
2. Seo, S.-Y.; Jung, J.-K.; Paek, S.-M.; Lee, Y.-S.; Kim, S.-H.; Lee, K.-O.; Suh, Y.-G. Org.
Lett. 2004, 6, 429.