A concise total synthesis of amphidinolide T2

Article abstract of DOI:10.1002/chem.201001794

RCM+AD=T2: In the presence of the C16-methylene group, regioselective ring-closing metathesis (RCM) formed the (12E)-endocyclic double bond, which underwent Os-catalyzed asymmetric dihydroxylation (AD) to give the desired 12,13-diol intermediate required

Full text of DOI:10.1002/chem.201001794

DOI: 10.1002/chem.201001794
A Concise Total Synthesis of Amphidinolide T2
Huoming Li,[a] Jinlong Wu,[a] Jialu Luo,[a] and Wei-Min Dai*[a, b]
Dedicated to the memory of Professor Xian Huang
Amphidinolides T1–T5 (1–5 in Scheme 1) are 19-mem-
termined, including an X-ray crystal structural analysis of
1.[2c] Cytotoxicity was reported for 1–4 with IC50 values of
7.0–18 and 10–35 mgmLÀ1 against murine lymphoma L1210
and human epidermoid carcinoma KB cells, respectively.[2b]
These amphidinolide T congeners commonly possess an “a-
hydroxy ketone” subunit at C12 and C13 and are distin-
guishable from each other by the relative position and abso-
lute configuration of the C12/C13 hydroxy and the C14
methyl groups (except for the side chain of 2). The close
structural relationship is illustrated by the base-promoted
epimerization of 4 into 5.[2c] Total synthesis of amphidinolide
bered ring macrolides isolated from symbiotic marine dino-
flagellate Amphidinium sp.[1,2] and their structures were de-
T1 and T3–T5 has been accomplished by several leading
[8]
laboratories,[3–7] along with synthesis of the C1 C12 and
À
[5c]
À
the C13 C22 (for 2) fragments.
As the continuation of
our total synthesis of amphidinolide X and Y,[9] we report
herein the total synthesis of amphidinolide T2 (2) from frag-
ments 6 and 7[5b,8b] by using a key sequence of ring-closing
metathesis (RCM)[10] and asymmetric dihydroxylation
(AD)[11] to assemble the C12/C13 “a-hydroxy ketone” subu-
nit (Scheme 1).[12]
Three ring-formation methods have been used in the total
synthesis of amphidinolide T1 and T3–T5.[13] Besides the
classical macrolactonization,[4,6,7] Fꢀrstner et al. assembled
the 19-membered ring between C4 and C5 by RCM–hydro-
genation.[3] Alternatively, Jamison et al. utilized the Ni-cata-
lyzed reductive macrolactonization of the seco alkynyl alde-
Scheme 1. Structures of amphidinolide T1–T5 (1–5) and the fragments 6
and 7 for total synthesis of amphidinolide T2 (2) by RCM and AD.
TBDPS=tert-butyldiphenylsilyl.
3
3
À
hyde to form the C12 C13 sp –sp bond with concomitant
installation of the masked “a-hydroxy ketone” subunit.[5]
For our synthesis, given in Scheme 2, we should achieve
1) regio- and diastereoselective RCM between C12 and C13
[a] Dr. H. Li, Dr. J. Wu, Dr. J. Luo, Prof. Dr. W.-M. Dai
Laboratory of Asymmetric Catalysis and Synthesis
Department of Chemistry, Zhejiang University
Hangzhou 310027 (P.R. China)
Fax : (+86)571-87953128
E-mail: chdai@zju.edu.cn
chdai@ust.hk
[b] Prof. Dr. W.-M. Dai
Department of Chemistry
The Hong Kong University of Science and Technology
Clear Water Bay, Kowloon, Hong Kong SAR (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001794.
Scheme 2. Proposed formation of (E)-8 by RCM and conversion into 2.
11530
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2010, 16, 11530 – 11534

COMMUNICATION
in the presence of the C16 methylene group; 2) regio- and
diastereoselective dihydroxylation of the endocyclic C12=
C13 double bond in (E)-8 in the presence of the C16 exocy-
clic methylene group; and 3) regioselective oxidation of the
C13 hydroxy group in the 12,13-diol. We envisaged that the
relatively low reactivity of the 1,1-disubstituted double bond
in RCM[14] might provide the basis for our required regiose-
lectivity in the ring formation. In contrast, selective dihy-
droxylation of 1,2-disubstituted alkenes over 1,1-disubstitut-
ed counterparts is very rare.[11b] We expected that the sub-
stituents and ring conformation may be helpful for “shield-
ing” the C16 methylene group during AD after inspecting
the crystal structure of 1.[2c]
Scheme 3 shows the synthesis of the diene alcohol 6. The
chiral iodide 9 was obtained from methyl (S)-lactate in 92%
overall yield through protection of the hydroxy group as the
TBDPS ether, reduction of the ester moiety by BH3·SMe2,
and conversion of the hydroxy group into the iodide in the
presence of I2, PPh3, and imidazole. It was then transformed
into the aldehyde 11 in 72% overall yield in four steps:
1) alkylation of methyl acetoacetate with 9; 2) enantioselec-
tive hydrogenation of the b-ketone ester;[15] 3) TES ether
formation; and 4) controlled DIBAL-H reduction of the
ester moiety. On the other hand, the chiral iodide 10 was
prepared by a modified procedure from methyl (R)-(À)-3-
hydroxy-2-methylpropionate (Roche ester) in 76% overall
yield by tosylation, partial ester reduction, Wittig-type meth-
ylenation, and iodide replacement of the tosylate. Addition
of the alkyllithium prepared from 10 with the aldehyde 11
gave, after DMP oxidation, the ketone 12. The latter was
treated with the Nystedꢂs reagent 13[16] to directly afford the
diene alcohol 6 (76%) as the major product along with the
TES ether 14 (16%), suggesting that the TES ether 14 un-
derwent partial cleavage under the Lewis acidic conditions.
Upon exposure to TFA/H2O/THF (1:4:100, RT, 2.5 h), the
TES ether 14 was converted into the alcohol 6 in 90% yield.
We obtained the acid fragment 7 through a nine-step se-
quence by using the SmI2-mediated enantioselective reduc-
tive coupling of the (1S,2R)-N-methylephedrine-derived
crotonate with aldehydes to secure the cis stereochemistry
at C7/C8 on the tetrahydrofuran ring.[8b] As shown in
Scheme 4, the alcohol 6 and the acid 7 were condensed to
give the seco ester, which was then treated with Grubbs
second-generation initiator Ib (5 mol%) in CH2Cl2 at reflux
for 4 h, affording the macrolactones (E)-8 (63%) and (Z)-8
(23%) (entry 2, Table 1). We were pleased to achieving high
regioselectivity in the RCM reaction without affecting the
C16 methylene group. To improve the E/Z ratio, the RCM
reaction was carried out in different solvents. A remarkable
solvent effect was found; by using Ib only the seco ester was
Scheme 3. Synthesis of the alcohol fragment 6. a) 4-Toluenesulfonyl chlo-
ride (TsCl), 4-dimethylaminopyridine (DMAP), Et3N, CH2Cl2, RT, 12 h,
98%; b) i) diisobutylaluminum hydride (DIBAL-H), PhMe, À908C, 1 h;
ii) nBuLi, MeP+Ph3BrÀ, THF, 08C, 0.5 h, 83% (2 steps); c) LiI, Et2O,
reflux, 4 h, 94%; d) TBDPSCl, imidazole, THF, RT, 2 h, 99%;
e) i) BH3·SMe2, THF, reflux, 2 h; ii) I2/PPh3/imidazole (4:2:4), THF,
reflux, 1 h, 93% (2 steps); f) methyl acetoacetate, NaH, nBuLi, THF/hex-
amethylphosphoric triamide (HMPA) (3:1), 08C; 9, RT, 4 h, 59% (82%
based on reacted starting material (brsm)); g) [RuBr2{(R)-BINAP}]
(BINAP=2,2’-bis(diphenylphosphino)-1,1’-binaphthyl), MeOH, 608C,
6 h, 90%; h) triethylsilyl trifluoromethanesulfonate (TESOTf), 2,6-luti-
dine, CH2Cl2, 08C, 0.5 h, 99%; i) DIBAL-H, CH2Cl2, À788C, 1 h, 99%;
j) 10, tBuLi, pentane/Et2O (3:2), À788C, 0.5 h and À208C, 0.5 h, then 11,
À788C, 2 h, 70% (82% brsm); k) Dess–Martin periodinane (DMP),
NaHCO3, RT, 2 h, 87%; l) 13, TiCl4, THF, reflux, 0.5 h, 76% 6, 16% 14;
m) trifluoroacetic acid (TFA)/H2O/THF (1:4:100), RT, 2.5 h, 90%.
Scheme 4. Synthesis of macrolactones (E)-8 and (Z)-8 by RCM. a) 1-(3-
Dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride
(EDCI),
DMAP, RT, 16 h, 91%; b) 5 mol% Ib, CH2Cl2, reflux, 4 h, 63% (E)-8,
23% (Z)-8. Mes=2,4,6-trimethylphenyl.
Chem. Eur. J. 2010, 16, 11530 – 11534
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11531

W.-M. Dai et al.
Table 1. Results of RCM of the seco ester and attempted isomerization
of (Z)-8.
Substrate
Reaction conditions[a]
Products
AHCTUNGTRENNUNG
(Yield [%])[b]
[d]
1
2
3
4
5
6
7
8
seco ester Ia, 15 h[c]
seco ester Ib, 4 h
seco ester IIa, 5 h
seco ester IIb, 10 h
seco ester III, 10 h
–
(E)-8 (63), (Z)-8 (23)
[e]
–
(E)-8 (60), (Z)-8[f] (21)
(E)-8 (60), (Z)-8[g] (20)
(Z)-8
(Z)-8
(Z)-8
Ib, CH2Cl2, 1008C, 0.5 h, MW (E)-8[e] (trace)
[e]
IIa, 1 d
I2 (cat.), 1 d
–
–
[e]
[a] With 5 mol% of the indicated initiator and in CH2Cl2 at reflux unless
otherwise stated, MW = microwave. [b] Isolated yields. [c] 10 mol% of
Ia. [d] 60% of the seco ester was recovered. [e] Recovery of the starting
materials. [f] 10% of the seco ester was recovered. [g] 11% of the seco
ester was recovered.
recovered in hexane after heating at reflux for 8 h, whereas
an inseparable mixture of unidentified byproducts was ob-
tained in toluene at 808C for 4.5 h[17] (data not shown in
Table 1).
The indenylidene ruthenium complexes IIa[18] and IIb[9c]
were reported for the formation of macrocyclic di- and tri-
substituted E-double bonds possessing a-substituents. We
examined the first-generation initiators Ia and IIa for the
RCM reaction, but they failed to form any product with re-
covery of the seco ester (entries 1 and 3, Table 1). In con-
trast, the second-generation indenylidene-derived initiator
IIb and Hoveyda–Grubbs second-generation initiator III
could promote the RCM reaction, but they were less effi-
cient than Ib, giving similar ratios for (E)-8 and (Z)-8 (en-
tries 4 and 5 vs. entry 2, Table 1). These results imply that
the highly reactive complex Ib is the best for assembling the
19-membered ring of amphidinolide T congeners.[3] We then
turned our attention to isomerization of the isolated (Z)-8,
but we found that no reaction took place in the presence of
the ruthenium complexes Ib and IIa, and I2, respectively, in
CH2Cl2 at reflux for one day or at 1008C for 0.5 h along
with microwave irradiation[19] (entries 6–8, Table 1). These
negative results suggest that the RCM reaction in Scheme 4
might be kinetically controlled and the product (Z)-8, once
formed, could not enter into the reverse-reaction pathway.[20]
Nevertheless, the diastereoselectivity (E/Zꢀ73:27) of our
RCM reaction catalyzed by Ib is comparable to the results
(E/Z=67:33–86:14) reported for the RCM reactions be-
tween C4 and C5 in the total synthesis of other amphidino-
lide T congeners.[3]
The next challenging task en route to our target was the
installation of the a-hydroxy ketone unit at C12 and C13 in
the correct absolute configuration (Scheme 5). Our prelimi-
nary results showed that no dihydroxylation of (E)-8 oc-
curred with commercial AD-mix-b alone. When the combi-
nation of K2OsO2(OH)2 and NMO was used, a complex re-
action mixture was obtained, implying that a chiral ligand is
essential for selective dihydroxylation (entry 1, Table 2). By
using the modified AD-mix-b at room temperature for 8 h,
compound (E)-8 was converted into the desired diol 15a
(48%) and the fully oxidized tetraols 15c (45%) along with
Scheme 5. Total synthesis of 2. a) 2.5 mol% K2OsO2(OH)4, 10 mol%
(DHQD)2AQN ((DHQD)2AQN =hydroquinidine (anthraquinone-1,4-
diyl) diether), K2CO3, K3Fe(CN)6, MeSO2NH2, tBuOH/H2O (1:1), 08C,
7 h, 59% 15a, 13% 15b, 5% 15c (9% of (E)-8 was recovered); b) tert-
butyldimethylsilyl trifluoromethanesulfonate (TBSOTf), 2,6-lutidine,
CH2Cl2, À788C, 1 h, 77%; c) DMP, NaHCO3, RT, 3 h, 95%; d) HF·pyri-
dine, MeCN, RT, 16 h, 91%; e) 5 mol% K2OsO2(OH)4, 10 mol%
(DHQ)2PHAL ((DHQ)2PHAL=hydroquinine 1,4-phthalazinediyl dieth-
er), AD-mix-a, MeSO2NH2, tBuOH/H2O (1:1), 08C, 7 h, 30% 15d (as a
50:50 inseparable mixture of two diastereomers), 15% 15e, 15% 15c.
6% of the diastereomeric diol 15b (entry 2, Table 2). When
the same AD was performed at 08C, formation of the tet-
raol 15c was reduced to 18% yield with an increased yield
of the minor diol 15b (18%), while the yield of the desired
diol 15a remained similar (entry 3, Table 2). These results
might be explained by the following considerations: 1) AD
of the C12=C13 endocyclic double bond in (E)-8 is faster
than the C16 exocyclic counterpart and the diastereoselec-
tivity (the ratio of 15a:15b) might be temperature insensi-
tive because the isolated yield for 15a was nearly the same;
and 2) further dihydroxylation of the C16 methylene group
is much easier for 15b than 15a and the reaction rate is tem-
perature dependent, resulting in higher conversion of 15b at
11532
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 11530 – 11534

Amphidinolide T2
COMMUNICATION
Table 2. Some results of dihydroxylation of (E)-8 and (Z)-8.[a]
With the diol 15a in hand, it was smoothly transformed
into the target macrolide 2 (Scheme 5). When 15a was sub-
jected to silylation, only the C12 TBS ether 16 was obtained
in 77% yield as the result of steric hindrance around the
C13 hydroxy group in 15a and 16. Finally, DMP oxidation
of 16 followed by global desilylation gave 2 in 87% overall
Substrate
Chiral ligand
Products (Yield [%])[b]
[c]
1
2
3
4
5
6
(E)-8
(E)-8
(E)-8
(E)-8
(E)-8
(Z)-8
–
A
complex mixture
(DHQD)2PHAL[d,e]
15a (48), 15b (6), 15c (45)
15a (51), 15b (18), 15c (18)
15a (44), 15b (8), 15c (18)
15a (59), 15b (13), 15c[i] (5)
15d (30), 15e (15), 15c (15)
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
1
yield. The H and 13C NMR spectroscopy data of our syn-
ACHTUNGTRENNUNG
thetic 2, with [a]2D7 = À28.6 (c = 0.50, CHCl3), are identical
[a] Carried out in tBuOH/H2O (1:1) in the presence of K2OsO2(OH)4
(5 mol%), the chiral ligand (10 mol%), MeSO2NH2 (1 equiv), and other
additives as stated. [b] Isolated yields. [c] K2OsO2(OH)4 (15 mol%) and
4-methyl morpholine N-oxide (NMO) (3 equiv) in acetone/H2O (5:1) at
RT for 4 h. [d] AD-mix-b was added. [e] RT, 8 h. [f] 08C, 7 h.
[g] MeSO2NH2 (1 equiv), K2CO3 (3 equiv), and K3Fe(CN)6 (3 equiv) were
added. [h] 2.5 mol% of K2OsO2(OH)4 was used. [i] 9% of (E)-8 was re-
covered. [j] AD-mix-a was added.
to those of the natural macrolide.[2b]
In conclusion, we have accomplished the first total synthe-
sis of 2 in 8.0% overall yield from methyl (S)-lactate
through a 16-step sequence, highlighting installation of the
C12/C13 “a-hydroxy ketone” subunit by RCM and AD in a
regio- and stereoselective manner. Our approach is flexible
and might be applicable to the total synthesis of other am-
phidinolide T congeners. Selective dihydroxylation of the
endocyclic (E)-1,2-disubstituted double bond over the exo-
cyclic methylene in (E)-8 is interesting and suggests steric
hindrance among the substrate and the bulky oxidant as the
major factor for the selectivity.[11b]
room temperature. If the above argument is correct, the dia-
stereoselectivity for AD of (E)-8 using the chiral ligand
(DHQD)2PHAL should not be higher than 74:26 and the
major diol 15a might be formed from a chirality-matched
process.[21]
To improve diastereoselectivity, we tried AD of (E)-8
using (DHQD)2AQN, which is considered as a generally
preferred chiral ligand for AD of aliphatic mono-, 1,1-di-,
1,2-(E)-di-, tris-, and cyclic 1,2-(Z)-disubstituted alkenes.[11a]
The extended anthraquinone-1,4-diyl ring in (DHQD)2AQN
is much more bulky than the 1,4-phthalazinediyl skeleton in
(DHQD)2PHAL. We were not sure whether the increasing
steric demand of the ligand backbone could suppress the un-
desired dihydroxylation of the C12=C13 double bond in
(E)-8 from the direction near to the C14 methyl group or
the ligand could favorably promote dihydroxylation of the
C16 methylene group in 15b, leading to better kinetic reso-
lution among the diols 15a and 15b.[21] Fortunately, we
found that the ratio of 15a/15b could be enhanced to 85:15
with a similar isolated yield of the tetraol 15c although the
lower total mass recovery (70%) was not understood
(entry 4 vs. entry 3, Table 2). By reducing the amount of Os
Acknowledgements
The Laboratory of Asymmetric Catalysis and Synthesis is established
under the Cheung Kong Scholars Program of The Ministry of Education
of China. This work is supported in part by The National Natural Science
Foundation of China (grant no. 20772107), Zhejiang University, and Zhe-
jiang University Education Foundation.
Keywords: dihydroxylation · macrocycles · metathesis ·
regioselectivity · total synthesis
[1] For reviews, see: a) J. Kobayashi, M. Tsuda, Nat. Prod. Rep. 2004,
21, 77–93; b) J. Kobayashi, T. Kubota, J. Nat. Prod. 2007, 70, 451–
460; c) J. Kobayashi, J. Antibiot. 2008, 61, 271–284.
[2] a) M. Tsuda, T. Endo, J. Kobayashi, J. Org. Chem. 2000, 65, 1349–
1352; b) J. Kobayashi, T. Kubota, T. Endo, M. Tsuda, J. Org. Chem.
2001, 66, 134–142; c) T. Kubota, T. Endo, M. Tsuda, M. Shiro, J. Ko-
bayashi, Tetrahedron 2001, 57, 6175–6179.
[3] a) A. Fꢀrstner, C. Aꢃssa, R. Riveiros, J. Ragot, Angew. Chem. 2002,
114, 4958–4960; Angew. Chem. Int. Ed. 2002, 41, 4763–4766; b) C.
Aꢃssa, R. Riveiros, J. Ragot, A. Fꢀrstner, J. Am. Chem. Soc. 2003,
125, 15512–15520.
[4] A. K. Ghosh, C. Liu, J. Am. Chem. Soc. 2003, 125, 2374–2375.
[5] a) E. A. Colby, K. C. OꢂBrien, T. F. Jamison, J. Am. Chem. Soc.
2004, 126, 998–999; b) E. A. Colby, K. C. OꢂBrien, T. F. Jamison, J.
Am. Chem. Soc. 2005, 127, 4297–4307; c) K. C. OꢂBrien, E. A.
Colby, T. F. Jamison, Tetrahedron 2005, 61, 6243–6248.
[6] L.-S. Deng, X.-P. Huang, G. Zhao, J. Org. Chem. 2006, 71, 4625–
4635.
[7] J. S. Yadav, C. S. Reddy, Org. Lett. 2009, 11, 1705–1708.
[8] a) C. Abbineni, P. K. Sasmal, K. Mukkanti, J. Iqbal, Tetrahedron
Lett. 2007, 48, 4259–4262; b) J. Luo, H. Li, J. Wu, X. Xing, W.-M.
Dai, Tetrahedron 2009, 65, 6828–6833.
[9] a) Y. Chen, J. Jin, J. Wu, W.-M. Dai, Synlett 2006, 1177–1180; b) J.
Jin, Y. Chen, J. Wu, W.-M. Dai, Org. Lett. 2007, 9, 2585–2588;
c) W.-M. Dai, Y. Chen, J. Jin, J. Wu, J. Lou, Q. He, Synlett 2008,
1737–1741.
[10] For selective reviews on RCM, see: a) R. H. Grubbs, S. Chang, Tet-
rahedron 1998, 54, 4413–4450; b) A. Fꢀrstner, Angew. Chem. 2000,
to 2.5 mol% with an Os/ACTHNUTRGNE(UGN DHQD)2AQN ratio of 1:4, the tet-
raol 15c was significantly diminished to 5%, while the diols
15a and 15b were isolated in 59 and 13% yields, respective-
ly (entry 5, Table 2). The improved ratio of 15a/15b using
(DHQD)2AQN supports the above-mentioned chirality-
matched dihydroxylation of (E)-8 using the hydroquinidine-
derived ligands.[21]
We attempted selective AD of (Z)-8 using the hydroqui-
nine-derived ligand, (DHQ)2PHAL, but the result was infe-
rior: the diol 15d was obtained as a 50:50 mixture of two in-
separable diastereomers in 30% combined yield, implying a
nonstereoselective dihydroxylation of the C12=C13 endocy-
clic double bond in (Z)-8 (entry 6, Table 2). Isolation of the
diol 15e (15% yield) suggests that the C12=C13 double
bond in 15e is difficult to undergo further dihydroxylation
presumably due to a change in the ring conformation. Im-
provement on selective AD of (Z)-8 should await for future
investigation.
Chem. Eur. J. 2010, 16, 11530 – 11534
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11533

W.-M. Dai et al.
112, 3140–3172; Angew. Chem. Int. Ed. 2000, 39, 3012–3043;
c) T. M. Trnka, R. H. Grubbs, Acc. Chem. Res. 2001, 34, 18–29;
d) R. R. Schrock, A. H. Hoveyda, Angew. Chem. 2003, 115, 4740–
4782; Angew. Chem. Int. Ed. 2003, 42, 4592–4633; e) A. Deiters,
S. F. Martin, Chem. Rev. 2004, 104, 2199–2238; f) R. H. Grubbs, Tet-
rahedron 2004, 60, 7117–7140; g) K. C. Nicolaou, P. G. Bulger, D.
Sarlah, Angew. Chem. 2005, 117, 4564–4601; Angew. Chem. Int. Ed.
2005, 44, 4490–4527; h) A. Gradillas, J. Pꢄrez-Castells, Angew.
Chem. 2006, 118, 6232–6247; Angew. Chem. Int. Ed. 2006, 45, 6086–
6101; i) Y. Schrodi, R. L. Pederson, Aldrichimica Acta 2007, 40, 45–
52; j) A. H. Hoveyda, A. R. Zhugralin, Nature 2007, 450, 243–251.
Also see: Handbook of Metathesis, Vols. 1–3 (Ed.: R. H. Grubbs),
Wiley-VCH, Weinheim, 2003.
D. J. Dixon, S. V. Ley, Angew. Chem. 2005, 117, 586–590; Angew.
Chem. Int. Ed. 2005, 44, 580–584.
[13] E. A. Colby, T. F. Jamison, Org. Biomol. Chem. 2005, 3, 2675–2684.
[14] M. Ulman, R. H. Grubbs, Organometallics 1998, 17, 2484–2489.
[15] J. P. GenÞt, V. Ratovelomanana-Vidal, M. C. CaÇo de Andrade, X.
Pfister, P. Guerreiro, J. Y. Lenoir, Tetrahedron Lett. 1995, 36, 4801–
4804.
[16] S. Matsubara, M. Sugihara, K. Utimoto, Synlett 1998, 313–315.
[17] a) L. Sun, G. Feng, Y, Guan, Y. Liu, J. Wu, W.-M. Dai, Synlett
2009, 2361–2365; b) K. F. W. Hekking, D. C. J. Waalboer, M. A. H.
Moelands, F. L. van Delft, F. P. J. T. Rutjes, Adv. Synth. Catal. 2008,
350, 95–106.
ˇ
[18] J. Pospꢅsil, C. Mꢀller, A. Fꢀrstner, Chem. Eur. J. 2009, 15, 5956–
[11] For recent reviews on AD, see: a) A. B. Zaitsev, H. Adolfsson, Syn-
thesis 2006, 1725–1756; b) A. FranÅais, O. Bedel, A. Haudrechy, Tet-
rahedron 2008, 64, 2495–2524.
5968.
[19] N. Q. Vu, C. L. L. Chai, K. P. Lim, S. C. Chia, A. Chen, Tetrahedron
2007, 63, 7053–7058.
[12] For examples involving 5–7-membered rings, see: a) K. B. Lindsay,
S. G. Pyne, J. Org. Chem. 2002, 67, 7774–7780; b) O. Bedel, A. Hau-
drechy, Y. Langlois, Eur. J. Org. Chem. 2004, 3813–3819; c) S. V.
Ley, A. Antonello, E. P. Balskus, D. T. Booth, S. B. Christensen, E.
Cleator, H. Gold, K. Hçgenauer, U. Hꢀnger, R. M. Myers, S. F.
Loiver, O. Simic, M. D. Smith, H. Søhoel, A. J. A. Woolford, Proc.
Natl. Acad. Sci. USA 2004, 101, 12073–12078; for an example of
large ring systems, see: d) G. L. Nattrass, E. Dꢅez, M. M. McLachlan,
[20] a) A. Fꢀrstner, K. Radkowski, C. Wirtz, R. Goddard, C. W. Leh-
mann, R. Mynott, J. Am. Chem. Soc. 2002, 124, 7061–7069; b) Y.
Matsuya, S. Takayanagi, H. Nemoto, Chem. Eur. J. 2008, 14, 5275–
5281.
[21] A discussion on AD of (E)-8 and (Z)-8 can be found in the Support-
ing Information.
Received: June 24, 2010
Published online: August 27, 2010
11534
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 11530 – 11534