Total synthesis of gambierol: Subunit coupling and completion

Article abstract of DOI:10.1002/chem.200500994

The preceding manuscript detailed our synthesis of the gambierol A-C and F-H ring precursors. Reported herein is a description of the coupling of the two precursors and the conversion of the coupled material into gambierol. Coupling of the subunits involv

Full text of DOI:10.1002/chem.200500994

FULL PAPER
DOI: 10.1002/chem.200500994
Total Synthesis of Gambierol: Subunit Coupling and Completion
Henry W. B. Johnson, Utpal Majumder, and Jon D. Rainier*[a]
Abstract: The preceding manuscript
detailed our synthesis of the gambierol
A–C and F–H ring precursors.Report-
ed herein is a description of the cou-
pling of the two precursors and the
conversion of the coupled material into
gambierol.Coupling of the subunits in-
volved ester formation, enol ether
RCM, and mixed thioketal formation
and reduction.By employing this strat-
egy we were able to bring highly ad-
vanced subunits into the coupling and,
as a result, we were able to minimize
the number of post-coupling transfor-
mations required to complete gambier-
ol.At the completion of the synthesis,
we generated 7.5 mg (1.5% overall
yield) of (À)-gambierol in 44 steps
(longest linear sequence).
Keywords: gambierol · glycosides ·
metathesis
· natural products ·
total synthesis
Introduction
corporation of the H-ring side chain would result in the syn-
thesis of gambierol.
As mentioned in the preceding manuscript, gambierol is a
member of the marine ladder toxin family and was isolated
by Yasumoto and co-workers from cultured Gambierdiscus
toxicus (GI-1 strain).[1,2] As it is not available in any signifi-
cant quantities from the natural source,[3] synthesis is proba-
bly the most effective method to uncover its biological prop-
erties and the only way to carry out SAR work.[4] When we
became interested in the chemical synthesis of gambierol we
had two criteria that we considered: First, any approach to
its synthesis needed to be efficient enough to enable us to
carry out structure activity work to gain better insight into
gambierolꢀs biological target(s).Equally critical to us was
that the approach employ novel coupling chemistry that
once developed might prove to be beneficial for future work
in the ladder toxin/polyether area.With this in mind, we
opted to pursue an approach that would utilize enol ether–
olefin ring-closing metathesis (RCM) chemistry in subunit
coupling that would result in the generation of the D-ring.[5]
If successful, this would set the stage for well-precedented
ketal reduction chemistry to the E-ring.[6] Subsequently, in-
Results and Discussion
From our perspective, the strategy outlined above was ad-
vantageous in that: a) esterification would be employed to
couple the two subunits (i.e., 4 + 5 ! 3); b) the enol
ether–olefin RCM chemistry would be used to generate the
presumably easier to form six-membered D-ring (3 ! 2); c)
the more difficult seven-membered E-ring would come from
a cyclization and ketal reduction sequence (2 ! 1); d) in
principle, the H-ring olefin would be compatible with this
strategy and thus reduce the number of post-coupling trans-
formations.The preceding manuscript detailed our synthesis
of the gambierol A–C and F–H ring precursors
(Scheme 1).[7] Reported herein is a description of the cou-
pling of the two precursors and the conversion of the cou-
pled material into gambierol.
Subunit coupling—1st Generation strategy: Our efforts to
couple the A–C and F–H precursors began with the genera-
tion of 8 from the esterification of 7 with 6.A two-step enol
ether–olefin RCM reaction using the Grubbs II catalyst to
effect ring-closure was used to generate dihydropyran 10
(Scheme 2).[8] Oxidation of the cyclic enol ether by using di-
methyl dioxirane (DMDO) and directed reduction using
DIBAL-H provided the corresponding secondary alcohol as
a 3:1 mixture of diastereomers.[8] Of note is that the use of
hydroboration, oxidation on 10 resulted in the competitive
[a] H.W.B.Johnson, Dr.U.Majumder, Prof.J.D.Rainier
University of Utah, Department of Chemistry
315 South 1400 East, Salt Lake City, Utah 84112 (USA)
Fax : (+1)801-581-8433
E-mail: rainier@chem.utah.edu
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2006, 12, 1747 – 1753
ꢁ 2006 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
1747

With 11 in hand, it remained to form the E-ring.Unfortu-
nately, all attempts to affect the cyclization of 11 were un-
successful [Eq.(1)].Included were attempts to generate the
corresponding mixed thioketal through the use of EtSH and
various acids and the generation of the cyclic ether directly
through the use of BiBr3 and Et3SiH or TMSOTf and
Ph2MeSiH.[11,12] Based upon the lack of olefinic protons in
1
the H NMR spectra of recovered samples we believe that
the H-ring olefin was undergoing competitive decomposition
under the reaction conditions.
Scheme 1.
reduction of the H-ring olefin.[9] That the reaction gave a
mixture of C(17) diastereomers favoring the undesired a-
isomer was not a problem; we took advantage of the ther-
modynamic stability of the desired C(17) b-stereochemistry
by oxidizing the C(16) alcohol and equilibrating the C(17)
stereocenter to give 11.[10] Equilibration resulted in a 4:1
mixture of isomers that could be separated and recycled.
In an attempt to avoid the olefin decomposition problem,
À
we examined the corresponding C(28) C(29) saturated sub-
strate.Although somewhat less than ideal in that the use of
this substrate would require that the olefin be introduced
post-coupling, at the very least these experiments would
enable us to determine the overall feasibility of the ap-
proach.With this in mind, coupling, metathesis, and oxida-
tion/reduction was carried out as described previously to
give 15 [Eq.(2)]. [13] Subjecting 15 to a variety of conditions
to generate the corresponding O,S-ketal all failed.[14] The
main products were either the acyclic dithiane 16 or decom-
position when attempts were made to push the reaction.
Clearly the use of the C(21) tertiary alcohol as a nucleophile
to generate gambierolꢀs E-ring was problematic in our
hands.
Scheme 2.a) DCC, DMAP, CH 2Cl2, RT (90%); b) TiCl4, TMEDA, THF,
CH2Cl2, Zn, PbCl2, CH2Br2; c)
9 (20 mol%) (75%, two steps); d)
From the efforts described above, it was clear that an al-
ternate coupling protocol was needed.Because of our con-
tinued belief that it could become a highly efficient means
of generating polycyclic ethers, we opted to continue to
DMDO (acetone free), CH2Cl2, À658C to RT; DIBAl-H, À658C (80%,
3:1 a/b mixture); e) TPAP, NMO (80%); f) DBU, PhH, 808C (100%,
b/a 4:1); TMEDA: tetramethylethylenediamine, TPAP: tetrapropylam-
monium perruthenate.
1748
www.chemeurj.org
ꢁ 2006 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
Chem. Eur. J. 2006, 12, 1747 – 1753

Natural Products
FULL PAPER
pursue an enol ether–olefin RCM strategy (Scheme 3).
However, instead of employing metathesis to generate the
“easier” D-ring, we would use it to generate the seven-mem-
bered E-ring.Subsequently, a ketal cyclization and reduction
sequence would be employed to generate the D-ring.
idation of the resulting primary alcohol.For reasons that
will become clear (see below), we utilized both the terminal
and the internal olefin containing substrates 26 and 27, re-
spectively, as precursors to the E-ring.Subsequent to olefin
formation, hydrolysis of the C(21) tertiary TMS ether also
resulted in the hydrolysis of the C(32) TBS ether.Reincor-
poration of the TBS ether gave coupling precursors 30 and
31.
Scheme 3.
Scheme 5.a) DDQ, H 2O, CH2Cl2 (98%); b) TPAP, NMO; c) PPh3PCH2;
d) Ph3PCHCH3; e) CSA, MeOH; f) TBSCl, NEt3, DMAP, CH2Cl2;
DDQ: 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
To examine this approach, our syntheses of both the A–C
and F–H subunits required modification.The generation of
the A–C substrate 23 was carried out from 21 according to
the sequence of reactions illustrated in Scheme 4.Exchange
of the C(1) benzyl ether for a TBDPS ether and selective
acid catalyzed hydrolysis of the primary TIPS ether in the
presence of the secondary TIPS ether and primary TBDPS
ether gave 22 after bis-TES ether formation.Selective hy-
drolysis of the primary TES ether and oxidation provided
coupling precursor 23.
With the precursors in hand, we examined their unifica-
tion [Table 1, Eq.(3)].Not surprising based upon our earlier
work that attempted to use it to generate an E-ring ketal,
esterification of the C(21) tertiary alcohols 30 and 31 with
acids 23 or 32[15] proved challenging.After considerable ex-
perimentation,[16] we found that the Yamaguchi protocol
worked the best in our hands.[17] Important was that we
employ elevated temperatures and, because the intermedi-
ate anhydride was not stable for indefinite periods of time,
that the formation of the anhydride be monitored by
1H NMR.[18] When this protocol was followed, the coupled
products 33 and 34 could be generated in ꢀ90% yield
(Table 1, entries 8 and 9).
We were now prepared to examine the metathesis chemis-
try to the E-ring.To this goal, our attempts to generate the
acyclic enol ether corresponding to ester 33 were completely
ineffective.Instead, we isolated a very small amount of
cyclic enol ether 37 along with a mixture of products all
lacking the terminal olefin [Eq.(4)].
Scheme 4.a) LiDBB, THF, À78 to À408C (80%); b) TBDPSCl, NEt3,
DMAP, CH2Cl2, À788C (95%); c) CSA, CH2Cl2, RT (92%); d) TESCl,
NEt3, DMAP, CH2Cl2 (100%); e) AcOH, H2O/MeOH (97%); f) TPAP,
NMO, CH2Cl2 (97%); g) NaClO2, 2-methyl-2-butene, NaHPO4, H2O,
tBuOH (95%); LiDBB: lithium 4,4’-di-tert-butylbiphenylide, CSA: cam-
phorsulfonic acid.
The gambierol F–H precursors 30 and 31 were construct-
ed according to the sequence illustrated in Scheme 5.Oxida-
tive hydrolysis of the PMB group was followed by TPAP ox-
Chem. Eur. J. 2006, 12, 1747 – 1753
ꢁ 2006 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
www.chemeurj.org
1749

J.D.Rainier et al.
Table 1.Subunit coupling of gambierol A–C precursors 32 and 23 with F–H precursors 30 and 31.
nal olefin 33.Based upon the
poor conversions
observed
when 33 was independently
subjected to the reaction condi-
tions [Eq.(4)], we believe that
the reasons for the low and cap-
ricious conversions in the reac-
tion was related to the instabili-
ty of terminal olefin 33 to the
reaction conditions; it was
being siphoned out of the meta-
thesis pathway by undergoing a
competitive non-productive de-
composition.To overcome this
and to improve the overall effi-
ciency of this process, we pro-
posed to employ a Ti alkylidene
(R ¼
6
H) rather than a methyli-
Entry
Alcohol
Acid
Conditions
R
R’
R’’
Ester
Yield [%]
dene (R=H).Reaction of an
alkylidene in the “undesired di-
rection” would simply result in
the re-generation of the rela-
tively stable substituted olefin
(i.e., 34).Ultimately the alkyli-
dene would react to give 38 and
cyclic product 37 after its de-
composition to 39 and cycliza-
tion.From a practical perspec-
tive, critical to this proposal
was that the Takai–Utimoto
protocol has been shown to be
1
2
3
4
5
6
7
8
9
30
30
30
30
30
30
30
30
31
32
32
32
32
32
32
32
32
23
DCC, DMAP
(COCl)2; NaH
(COCl)2; Zn
35
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
b-PMB
b-PMB
b-PMB
b-PMB
b-PMB
b-PMB
b-PMB
b-PMB
a-TIPS
H
H
H
H
H
H
H
H
33
33
33
33
33
33
33
33
34
0
0
0
0
A,[a] 12 h
B,[a] 0.5 h
B,[a] 4 h
30–60
35
0
B,[a] 1.3 h
B,[a] 1.3 h
92[b]
90[b]
TBDPS
CH3
[a] Condition A: 36 (6 equiv), NEt3 (7.5 equiv), DMAP (7.5 equiv), CH2Cl2 (À20 to À58C); condition B: 36
(6 equiv), NEt3 (7.5 equiv), DMAP (7.5 equiv), CH2Cl2 (408C).[b] Progress of anhydride formation was moni-
tored by H NMR.
1
In light of the steric environment about the ester in 33, it
was not surprising that acyclic enol ether formation was
problematic.[19,20] We decided to simultaneously increase the
stability of the olefin and our chances of generating the acy-
clic enol ether by utilizing internal alkene substrate 34.In-
terestingly however, when 34 was subjected to the Takai–
Utimoto protocol preferential decomposition of the olefin
was again observed.The only identifiable products from this
transformation were cyclic enol ether 37 and terminal olefin
33.
amenable to the generation of a variety of alkylidenes
through the use of different dibromoalkanes in its in situ
preparation.[23]
We were very pleased when this hypothesis proved to be
accurate.By subjecting a-TIPS substrate 34 to the Takai–
Utimoto ethylidene reagent that was generated from dibro-
moethane instead of dibromomethane we isolated 43 in
60% yield.Interesting is that this reaction also led to a sub-
stantial quantity of acyclic enol ether 44 [Eq.(6)].
At this stage, we decided to attempt to optimize the for-
mation of cyclic enol ether 37 by taking advantage of the
propensity for the reaction of the presumed Ti methylidene
from the Takai–Utimoto reagent with the olefin.[21,22] Mech-
anistically, the interaction of the Ti methylidene with the
alkene in 34 produces one of two intermediate titanacyclo-
butanes (Scheme 6).The intermediate that leads to cyclic
enol ether 37 has Ti oriented at the more hindered, “inter-
nal” position of the alkene (i.e., 38).The alternative “unde-
sired” orientation proceeds through titanocyclobutane 40
having Ti proximal to the methyl group and leads to termi-
Acyclic enol ether 44 could be converted into cyclic sub-
strate 43 when subjected to the 2nd generation Grubbs cata-
lyst but only when ethylene was added to the reaction.It
1750
www.chemeurj.org
ꢁ 2006 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
Chem. Eur. J. 2006, 12, 1747 – 1753

Natural Products
FULL PAPER
was important that 44 be converted into the corresponding
terminal olefin prior to it undergoing cyclization.[24] Elevat-
ed reaction temperatures were required to avoid the genera-
tion of dihydropyran 45 from isomerization of the olefin
and cyclization.With the ability to transform 44 into 43, our
overall yield for the conversion of ester 34 into heptacycle
43 increased to a respectable 80% (Table 2).
(Scheme 7).The isomers were separated and the minor
isomer (e.g. 50) was recycled to a 4:1 mixture of isomers by
using imidazole and heat.Other bases (DBU) were much
less effective in this reaction.[10] Following its formation,
ketone 49 was treated with CSA to remove the C(13) TES
group.As was seen previously in our synthesis of the F–H
coupling precursor (see Scheme 6), it was fortuitous that
these conditions also removed
the C(32) TBS group.Gambier-
olꢀs octacyclic core was com-
Table 2.Conversion of acyclic enol ether 44 into heptacycle 43.
pleted by subjecting the hy-
droxy ketone from 49 to Zn-
(OTf)2 and EtSH.In contrast to
our attempts to generate the E-
ring, this reaction generated a
single O,S-ketal diastereomer
without any degradation of the
H-ring olefin.Undoubtedly, the
more facile cyclization to form
the D-ring is responsible for
this result.Reduction of the
O,S-ketal by using Ph3SnH then
gave the gambierol octacycle in
97% yield.
Entry
Conditions
Yield [%] (43)
1
2
3
4
5
9 (20 mol%), PhH, RT to 808C
9 (20 mol%), PhCH3, 1108C
46 (20 mol%), hexanes, 608C
9 (20 mol%), PhH, 808C, ethylene (1 atm); N2 purge, 9 (20 mol%), 408C
9 (20 mol%), PhH, 808C, ethylene (1 atm); N2 purge, 9 (20 mol%), 808C
0 (60% recovered 44)
0 (60% 45)
0 (80% recovered 44)
30 (40% 45)
65 (20% 45)
D-Ring: With the E-ring finally in hand, we turned our at-
tention to the reductive cyclization chemistry to the D-ring.
To this goal, selective oxidation of the cyclic enol ether with
DMDO followed by reduction of the intermediate epoxide
with DIBAL-H gave secondary alcohol 48 as a 10:1 mixture
of diastereomers [Eq.(8)]. We did not anticipate the facial
selectivity in the dioxirane reaction as it is from the side of
the C(21) angular methyl group.This phenomenon seems to
be a general feature of fused oxepenes having a-substitution
as evidenced by our results with the gambierol H-ring and
with bicyclic models from tribenzyl-d-glucal.[25,26]
Scheme 6.
It remained to attach the skipped triene side chain and
remove the remaining protecting groups.To this end, we
borrowed heavily from the work of Yamamoto and
Sasaki.[2,27] Oxidation of the primary alcohol was followed
by the conversion of the resulting aldehyde into the corre-
Oxidation of the secondary alcohol using TPAP gave ke-
tones 49 and 50 as a 10:1 mixture of diastereomers
Chem. Eur. J. 2006, 12, 1747 – 1753
ꢁ 2006 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
www.chemeurj.org
1751

J.D.Rainier et al.
To conclude, this manuscript has described our total syn-
thesis of the marine ladder toxin gambierol.This work has
described a new subunit coupling strategy to polycyclic
ethers.Critical to the success was the use of a titanium eth-
ylidene in an olefin metathesis, carbonyl–olefination cycliza-
tion reaction.Current investigations include the exploration
of the biological properties of synthetic gambierol and ana-
logues as well as the application of this coupling strategy to
other marine polycyclic ethers.
Acknowledgements
We are grateful to the National Institutes of Health, General Medical
Sciences (GM56677) for support of this work.We would like to thank
Dr.Charles Mayne for help with NMR experiments and Dr.Elliot M.
Rachlin for help in obtaining mass spectra.
Scheme 7.a) TPAP, NMO (93%); b) imidazole, CH 2Cl2, 408C (100%,
b/a 4:1); c) CSA, MeOH (90%); d) Zn(OTf)2, EtSH (86%); e) Ph3SnH,
AIBN (97%).
[1] a) M.Satake, M.Murata, T.Yasumoto, J. Am. Chem. Soc. 1993, 115,
361; b) A.Morohashi, M.Satake, T.Yasumoto,
1998, 39, 97.
Tetrahedron Lett.
[2] a) H.Fuwa, N.Kainuma, K.Tachibana, M.Sasaki,
J. Am. Chem.
sponding diiodoalkene using a modified Corey–Fuchs addi-
tion reaction (Scheme 8).[28] Stereoselective reduction using
Zn(Cu) couple,[29] global deprotection using SiF4,[30] and
Stille coupling of the resulting triol with dienyl stannane
53[27] provided (À)-gambierol.The spectroscopic and physi-
cal data for synthetic gambierol was identical to that report-
ed previously.Impressive in this work is that only 12 post-
coupling transformations were required to complete the syn-
thesis from A–C and F–H subunits 23 and 31, respectively.
Overall, our synthesis involved 44 steps (longest linear se-
quence from d-glucal, 69 total steps) and resulted in a 1.5%
overall yield of gambierol.[31] Using the chemistry described
we were able to generate 7.5 mg of gambierol that we are
currently using in ion channel binding studies.
Soc. 2002, 124, 14983; b) I.Kadota, H.Takamura, K.Sata, A.Ohno,
K.Matsuda, M.Satake, Y.Yamamoto, J. Am. Chem. Soc. 2003, 125,
11893.
[3] In Yasumotoꢀs original isolation, 1100 L of fermentation broth re-
sulted in 1.2 mg of gambierol.
[4] Some SAR work has already been carried out, see a) E.Ito, Suzuki-
F.Toyota, K.Tashimori, H.Fuwa, K.Tachibana, M.Sataki, M.
Sasaki, Toxicon 2003, 42, 733; b) H.Fuwa, K.Kainuma, K.Tachiba-
na, C.Tsukano, M.Satake, M.Sasaki, Chem. Eur. J. 2004, 10, 4894;
c) H.Fuwa, H.Kainuma, M.Satake, M.Sasaki,
Bioorg. Med. Chem.
Lett. 2003, 13, 2519.
[5] a) O.Fujimura, GC. .Fu, RH. .Grubbs,
4029; b) J.S. Clark, J.G. Kettle,
J. Org. Chem. 1994, 59,
Tetrahedron Lett. 1997, 38, 123;
c) M.H.D.Postema, J. Org. Chem. 1999, 64, 1770; d) J.S.Clark, O.
Hamelin, Angew. Chem. 2000, 112, 380; Angew. Chem. Int. Ed.
2000, 39, 372; e) A.K. Chatterjee, J.P. Morgan, M. Scholl, R.H.
Grubbs, J. Am. Chem. Soc. 2000, 122, 3783; f) J.D. Rainier, J.M.
Cox, S.P.Allwein, Tetrahedron Lett. 2001, 42, 179.
[6] a) K.C. Nicolaou, C.V.C. Prasad, C-.K. Hwang, M.E. Duggan,
C.A. Veale, J. Am. Chem. Soc. 1989, 111, 5321; b) K.C. Nicolaou,
C.K.Hwang, D.A.Nugiel, J. Am. Chem. Soc. 1989, 111, 4136.
[7] U.Majumder, J.M.Cox, H.W.B.Johnson, J.D.Rainier,
Chem. Eur.
J. 2006, 12, 1736.
[8] For other examples of this reduction see: a) J.M.Cox, J.D.Rainier,
Org. Lett. 2001, 3, 2919; b) U. Majumder, J.M. Cox, J.D. Rainier,
Org. Lett. 2003, 5, 913; c) K.Fujiwara, D.Awakura, M.Tsunashima,
A.Nakamura, T.Honma, A.Murai,
d) ref.[7].
J. Org. Chem. 1999, 64, 2616;
[9] K.Tsushima, K.Araki, A.Murai, Chem. Lett. 1989, 1313.
[10] K.C.Nicolaou, K.R.Reddy, G.Skokotas, F.Sato, X-.Y.Xiao, C-.K.
Hwang, J. Am. Chem. Soc. 1993, 115, 3558.
[11] For an example of the successful use of BiBr3, Et3SiH, see P.A.
Evans, J.Cui, S.J.Gharpure, R.J.Hinkle,
J. Am. Chem. Soc. 2003,
125, 11456.
[12] For an example of the successful use of Et3SiH, TMSOTf see K.
Suzuki, T.Nakata, Org. Lett. 2002, 4, 3943.
[13] See Supporting Information for the generation of 15.
[14] We were also unsuccessful in our attempts to convert hydroxy
ketone 15 directly into the octacycle using BiBr3, Et3SiH or
TMSOTf, Et3SiH.
Scheme 8.a) TPAP, NMO (100%); b) CHI 3, KOtBu, PPh3 (94%); c) Zn/
Cu couple; d) SiF4 (95%); e) [Pd2(dba)3], P(furyl)3, CuI, DMSO, 53
(85%).
[15] Generated in an analogous fashion to 23, see Supporting Informa-
tion.
[16] I.Shiina, M.Kubota, R.Ibuka, J. Org. Chem. 2004, 69, 1822.
1752
www.chemeurj.org
ꢁ 2006 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
Chem. Eur. J. 2006, 12, 1747 – 1753

Natural Products
FULL PAPER
[17] J.Inanaga, K.Hirata, H.Saeki, T.Katsuki, M.Yamaguchi,
Bull.
[24] Following the generation of the terminal alkene, ethylene had to be
purged from the reaction flask with nitrogen in order to induce cyc-
lization.
[25] S.P.Allwein, J.M.Cox, B.E.Howard, H.W.B.Johnson, J.D.Raini-
er, Tetrahedron 2002, 58, 1997.
[26] DFT calculations on model bicyclic oxepenes predict the same sense
of facial selectivity as that observed experimentally.A.Orendt,
S.W.Roberts, J.D.Rainier, unpublished results.
Chem. Soc. Jpn. 1979, 52, 1989.
[18] If the reaction was allowed to proceed for prolonged periods of
time we observed significant decomposition of the anhydride.
[19] In substrates containing olefinic esters, we have found the steric en-
vironment about the ester to be important in determining the
amount of acyclic versus cyclic enol ether product, see U.Majumd-
er, J.D.Rainier, Tetrahedron Lett. 2005, 46, 7209.
[20] Attempts to generate either the acyclic or cyclic enol ethers using
other alkylidene reagents (Tebbe, Petasis, Takeda) were unsuccess-
ful.
[27] I.Kadota, A.Ohno, Y.Matsukawa, Y.Yamamoto,
Tetrahedron Lett.
1998, 39, 6373.
[28] P.Michel, A.Rassat, Tetrahedron Lett. 1999, 40, 8579.
[21] The Tebbe reagent has been used to carry out related cyclizations:
[29] I.Kadota, H.Ueno, A.Ohno, Y.Yamamoto,
44, 8645.
Tetrahedron Lett. 2003,
a) J.R. Stille, R.H. Grubbs,
b) J.R. Stille, B.D. Santarsiero, R.H. Grubbs,
55, 843; c) K.C.Nicolaou, M.H.D.Postema, C.F.Claiborne,
J. Am. Chem. Soc. 1986, 108, 855;
J. Org. Chem. 1990,
J. Am.
[30] E.J.Corey, K.Y.Yi, Tetrahedron Lett. 1992, 33, 2289.
[31] In comparison, Sasakiꢀs synthesis involved 71 steps (longest linear
sequence, 107 total steps) and 0.57% overall yield while Yamamo-
toꢀs synthesis required 66 steps (longest linear sequence, 102 total
steps) and 1.2% overall yield. Both syntheses involved 24 post-cou-
pling steps.
Chem. Soc. 1996, 118, 1565; d) K.C. Nicolaou, M.H.D. Postema,
E.W.Yue, A.Nadin, J. Am. Chem. Soc. 1996, 118, 10335.
[22] For a related transformation that utilizes the Takeda protocol, see:
H.Uehara, T.Oishi, M.Inoue, M.Shoji, Y.Nagumo, M.Kosaka, J-.
Y.Le Brazidec, M.Hirama, Tetrahedron 2002, 58, 6493.
[23] T.Okazoe, K.Takai, K.Oshima, K.Utimoto,
J. Org. Chem. 1987,
Received: August 15, 2005
52, 4410.
Published online: December 6, 2005
Chem. Eur. J. 2006, 12, 1747 – 1753
ꢁ 2006 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
www.chemeurj.org
1753