Total synthesis of the potent antitumor macrolides pladienolide B and D

Article abstract of DOI:10.1002/anie.200604997

Getting cross: The total syntheses of two pladienolides (see picture), which have prominent antitumor activity based on a unique mechanism of action, have been accomplished, and their absolute configurations were verified. The 12-membered aliphatic macrolide structure was formed by ring-closing metathesis, and the side-chain moiety was coupled to the macrolide by Julia-Kocienski olefination or cross-metathesis. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200604997

Communications
DOI: 10.1002/anie.200604997
Total Synthesis
Total Synthesis of the Potent Antitumor Macrolides Pladienolide B
and D**
Regina M. Kanada, Daisuke Itoh, Mitsuo Nagai, Jun Niijima, Naoki Asai, Yoshiharu Mizui,
Shinya Abe, and Yoshihiko Kotake*
In 2004 Sakai et al. reported the identification of seven
12-membered macrolides (pladienolides A–G),from Strepto-
myces platensis Mer-11107 by way of a cell-based assay that
evaluated the suppression of hypoxia-induced gene expres-
sion controlled by the human VEGF promoter.[1] The most
potent pladienolides (B (2) and D (3)) have IC50 values in the
low nanomolar range (Scheme 1). They also inhibit the
those of anticancer drugs currently in clinical use.[2] Pladie-
nolides B and D also cause in vivo tumor regression in several
human cancer xenograft models.[2] These results encouraged
us to search for novel antitumor agents based on these unique
lead compounds. After intensive studies,we discovered E7107
(4),a urethane derivative of pladienolide D that possesses
enhanced in vivo potency and better physicochemical proper-
ties.[3] Intravenous treatment of several tumor xenograft
models with E7107 for five consecutive days has led to
complete remission as well as tumor shrinkage in a variety of
tumor xenografts.[4] In light of these promising preclinical
data,E7107 will soon enter clinical trials.
The absolute structure of pladienolide B was recently
elucidated by Asai et al.[5] To verify this structure,and that of
pladienolide D,and to facilitate the discovery of novel
analogues with advantageous pharmaceutical profiles we
have executed the first total syntheses of pladienolides B
and D. Our syntheses confirm the absolute structures of the
compounds and provide a strategy for the preparation of
novel synthetic analogues based on the efficient application of
olefin metathesis technology.
Scheme 1. Pladienolides A, B, and D as well as E7107.
Our retrosynthetic analysis is shown in Scheme 2. We
wanted to install the stereogenic centers in a reagent-
controlled fashion so that we could synthesize other stereo-
isomers simply by changing the stereochemistry of the
growth of a variety of cancer cell lines in vitro with low
nanomolar IC50 values. COMPARE analysis with panel
screening of 39 human cancer cell lines indicated that the
compounds have a unique mode of antitumor action unlike
À
reagents. The C14 C15 double bond was disconnected to
afford a side-chain moiety and a macrolide unit; this strategy
gave us efficient access to structural variants of each moiety.
Our knowledge of the reactivity of the hydroxy groups of
pladienolide A (1) led us to believe that the C7 hydroxy group
could be acetylated regioselectively. We expected to be able
to obtain the macrolide moiety by an esterification reaction
and a subsequent ring-closing olefin metathesis (RCM)
between a C1–C8 unit and a C9–C14 unit.[6] To our knowl-
edge,there have been only a few reported uses of RCM for
the construction of an aliphatic (not containing phenyl
moieties as ring members) 12-membered macrolide structure,
but there is no precedent for sterically hindered and highly
functionalized ones.[7] We expected to be able to prepare the
side-chain moiety by means of a Julia–Kocienski olefination[8]
and the asymmetric epoxidation developed by Shi and co-
workers[9] from a C15–C18 unit and a C19–C23 unit.
Our syntheses commenced with the construction of the
macrolide moiety (Scheme 3). Aldehyde 5,prepared from
nerol by protection with a PMB group and regioselective
ozonolysis,[10] was subjected to the SmII-mediated asymmetric
Reformatsky reaction described by Fukuzawa et al. using
bromoacetyloxazolidinone 6 as a chiral auxiliary to afford b-
hydroxyamide 7 with good diastereoselectivity (82% de).[11]
[*] Dr. R. M. Kanada,[+] Dr. D. Itoh,[+] Dr. Y. Mizui, Dr. Y. Kotake
Discovery Research Laboratories II
Eisai Co., Ltd.
5-1-3 Tokodai, Tsukuba, Ibaraki, 300-2635 (Japan)
Fax: (+81)29-847-4012
E-mail: y-kotake@hhc.eisai.co.jp
Dr. M. Nagai, J. Niijima, S. Abe
Tsukuba Chemical Research
API Research Laboratories
Eisai Co., Ltd. (Japan)
Dr. N. Asai
Structural Analysis Section
Analytical Research Laboratories
Eisai Co., Ltd. (Japan)
[+] These authors contributed equally to this work.
[**] We are grateful to Dr. T. Tsuchida (Mercian Corp.) for supplying the
natural products. We thank T. Uehara, M. Gotoda, S. Naito, and M.
Gomibuchi for performing compound analyses; A. Okuda for
purifying compounds by HPLC; as well as T. Sakai and Dr. Y. Fukuda
for their help. We thank Dr. T. Owa, Dr. D. Rossignol, and Dr. R.
Lebedev for proof-reading the manuscript.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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hydroxy group,and methylation,ester
8 was obtained in
good yield (85%).[12] A second asymmetric reaction,the
asymmetric dihydroxylation of 8,proceeded in 76% de,but
the resulting isomers could not be separated.[12] Protection of
the diastereomeric mixture of syn-diols with a benzylidene
acetal group and subsequent removal of the terminal PMB
group afforded primary alcohol 9 as a crystalline solid.
Recrystallization afforded 9 as a single diastereomer.[13]
Sequential oxidation,Wittig olefination,and hydrolysis gave
the desired C1–C8 unit 10 in 64% yield (Scheme 3).
Synthesis of the C9–C14 unit began with construction of
the C10 and C11 stereogenic centers by an anti-aldol reaction
developed by Paterson et al. by using aldehyde 11 and lactate-
derived chiral ketone 12 (Scheme 4).[14] This reaction pro-
Scheme 2. Retrosynthetic analysis of pladienolides. PG=protecting
group.
Scheme 4. Synthesis of C9–C14 unit 14 and macrolide moiety 17:
a) 12, Cy2BCl, Me2NEt, diethyl ether, À788C to À268C, recrystalliza-
tion, 81% (>99% de); b) TBSOTf, 2,6-lutidine, CH2Cl2, À788C, quant.;
c) LiBH4, THF, À788C to RT; d) NaIO4, THF/H2O (4:1), RT; e) methyl-
triphenylphosphonium iodide, nBuLi, THF, À158C, 73% (3 steps);
f) 1n HCl, MeCN, RT, 99%; g) 10, 2,4,6-trichlorobenzoyl chloride,
Et3N, THF, 08C to RT, then 14, DMAP, toluene, RT, 93%; h) 2nd-
generation Hoveyda–Grubbs catalyst, BHT, toluene, reflux, 46%;
i) DDQ, CH2Cl2/pH 7 buffer (10:1), RT, 80%; j) DMP, CH2Cl2, R T,
quant.; Bz=benzoyl, Cy=cyclohexyl, Tf=trifluoromethanesulfonyl,
DMAP=4-dimethylaminopyridine, 2nd generation Hoveyda–Grubbs
catalyst=[1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichlo-
ro[O-isopropoxyphenylmethylidene]ruthenium, BHT=2,6-di-tert-butyl-
4-methylphenol.
Scheme 3. Synthesis of C1–C8 unit 10: a) Sm0, CH2I2, 6, THF, À788C
to RT, 90% (>98% de); b) LiOH, H2O2, THF/H2O (4:1), RT; c) TMS
diazomethane, THF/MeOH (10:1), RT; d) TBSCl, imidazole, DMF, RT,
85% (3 steps); e) AD-mix-a, methanesulfonamide, tBuOH/H2O (1:1),
08C, 92% (76% de); f) benzaldehyde dimethyl acetal, PPTS, CH2Cl2,
RT, 98%; g) DDQ, CH2Cl2/H2O (10:1), 08C, recrystallization, 65%;
h) DMP, CH2Cl2, RT; i) methyltriphenylphosphonium iodide, nBuLi,
THF, À158C to RT, 78% (2 steps); j) LiOH, THF/MeOH/H2O (2:2:1),
RT, 82%. PMB=p-methoxybenzyl, de=diastereomeric excess,
TMS=trimethylsilyl, TBS=tert-butyldimethylsilyl, PPTS=pyridinium
p-toluenesulfonate, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone,
DMP=Dess–Martin periodinane.
ceeded with excellent diastereoselectivity (98% de),and the
desired anti-aldol product 13 was obtained in pure form after
recrystallization and protection with a TBS group. An
additional four steps,including oxidative cleavage of the a-
benzoyloxy ketone,gave desired C9–C14 unit
14. An
esterification reaction between C1–C8 unit 10 and C9–C14
unit 14 by means of the method described by Yamaguchi and
co-workers afforded bis-terminal olefin 15.[15]
We next investigated the key RCM reaction to construct
the macrolide moiety. By screening various reaction con-
Separation of the diastereomers by column chromatography
on silica gel gave the desired b-hydroxyamide 7 in > 98% de.
After removal of the chiral auxiliary,protection of the
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ditions (catalysts,solvents,additives,reaction temperatures,
etc.)[16,17] we determined that the use of the second-generation
Hoveyda–Grubbs catalyst in refluxing toluene afforded the
best results: the desired macrolide 16 was obtained in 46%
yield.[16d] Steric hindrance was clearly responsible for the low
À
yield. A substantial amount of isomerized product with a C7
C8 olefin was also formed.[18] Removal of the PMB group and
subsequent oxidation with DMP gave macrolide 17 for
coupling with the side-chain moiety. The macrolide 16 was
obtained as a crystalline solid,and its three-dimensional
structure,including the absolute configuration,was confirmed
by X-ray crystallographic analysis.
Next,we synthesized the side-chain moiety of pladieno-
lide B (Scheme 5). Aldehyde 19 was obtained from the known
hydroxy amide 18.[19] Aldehyde 19 was treated with the C15–
C18 unit (sulfone 20),which was prepared in six steps from
methyl (R)-3-hydroxy isobutyrate according to a standard
procedure,[20] to give trans-olefin 21 exclusively. After
removal of the Bn group,the resulting alcohol was converted
into sulfone 22 with concurrent removal of the TES group
during the oxidation step. The unprotected hydroxy group
was found to increase the yield and diastereoselectivity of the
asymmetric epoxidation described by Shi and co-workers,[21]
and afforded desired epoxide 23 in good yield as a single
diastereomer after recrystallization.[9] The structure and
stereochemistry of 23 were confirmed by X-ray crystallo-
graphic analysis. The hydroxy group of 23 was protected as
the DEIPS ether to provide side-chain fragment 24.
With the macrolide and the side-chain fragments in hand,
we investigated their coupling to construct the entire carbon
framework of pladienolide B. Julia–Kocienski olefination
between aldehyde 17 and sulfone 24 smoothly afforded the
desired E,E-diene 25 exclusively. We expected to be able to
remove all the protecting groups from 25 in a single step
under acidic conditions to afford tetraol 1 (pladienolide A),
but the benzylidene group proved resistant under the acidic
conditions tested; the two silyl groups were removed before
the benzylidene group,and the resulting hydroxy group at the
C21-position opened the neighboring epoxide to form a
tetrahydrofuran ring. Therefore,the two silyl groups were
converted into acid-stable dichloroacetyl groups to provide
27. Note that when an acetyl group was used instead of the
dichloroacetyl group,the carbonyl unit of the acetyl moiety
on the C21-hydroxy group also attacked the epoxide by
means of a neighboring effect,and two diols were obtained. [22]
Therefore,the dichloroacetyl group,in which the carbonyl
oxygen atom is relatively electron-deficient,was the best
choice in this case. The benzylidene group was removed by
treatment with PPTS in MeOH over 46 h to afford 6,7-diol 28.
Methanolysis of 28 gave pladienolide A (1). The final
regioselective acetylation proceeded as expected,and pladie-
nolide B (2) was obtained in good yield. The spectral data and
optical rotation data of 1 and 2 were in agreement with the
data available for natural pladienolides A and B,respec-
tively.[23]
Scheme 5. Synthesis of side-chain moiety 24 and completion of the
total syntheses of pladienolides A and B: a) N,O-dimethylhydroxyl-
amine hydrochloride, Me3Al, CH2Cl2, À788C, quant.; b) TESOTf, 2,6-
lutidine, CH2Cl2, 08C, 99%; c) DIBAL, toluene, À788C, 89%; d) 20,
KHMDS, THF, À788C, 68%; e) Li0, 4,4’-di-tert-butyl-biphenyl, THF,
À788C, 77%; f) 5-mercapto-1-phenyltetrazole, Ph3P, DIAD, THF, RT,
91%; g) MoO7(NH4)6·4H2O, H2O2, EtOH, RT, 81%; h) 1,2:4,5-di-O-
isopropylidene-d-erythro-2,3-hexodiuro-2,6-pyranose, oxone, K2CO3,
MeCN/0.05m Na2B4O7·10H2O in 0.4 mm Na2EDTA (pH 9; 3:2), 08C,
recrystallization, 71% (>99% de); i) DEIPSCl, imidazole, DMF, RT,
quant.; j) 17, KHMDS, THF, À788C, 64%; k) TBAF, THF, RT, quant.;
l) dichloroacetic anhydride, Et3N, DMAP, CH2Cl2, 08C, quant.;
m) PPTS, MeOH, RT, 64%; n) K2CO3, MeOH, RT, 96%; o) acetic
anhydride, Et3N, DMAP, CH2Cl2, 08C, 82%. TES=triethylsilyl,
DIBAL=diisobutylaluminum hydride, KHMDS=potassium hexa-
methyldisilazide, Bn=benzyl, DIAD=diisopropyl azodicarboxylate,
EDTA=ethylenediaminetetraacetic acid, DEIPS=diethylisopropylsilyl,
TBAF=tetrabutylammonium fluoride.
pladienolide D has the same stereochemistry as pladienoli-
de B at the other nine stereogenic carbon centers. However,
because C16 is quaternary, J-based configuration analysis of
pladienolide D cannot be used to elucidate the stereochem-
istry at that position. To address this issue,we carried out a
chemical degradation and derivatization study on pladieno-
lide D (Scheme 6). The side-chain fragment bearing the C16
We next approached the total synthesis of pladienolide D.
Pladienolides B and D differ only at C16,where a hydroxy
group is present in pladienolide D but not in pladienolide B.
1
Similarities in the H and 13C NMR spectra suggested that
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Scheme 6. Chemical degradation of pladienolide D and derivatization
of alcohol 29 to benzylidene acetal 31: a) TESCl, Et3N, DMAP, CH2Cl2,
RT, 82%; b) O3, dimethylsulfide, CH2Cl2/MeOH (1:1), À788C, then
NaBH4, 08C, 38%; c) TBAF, THF, RT, 89%; d) tBuOK, MeOH, RT,
73%; e) p-bromobenzaldehyde dimethyl acetal, CSA, CH2Cl2, R T,
31a=54%, 31b=28%. CSA=camphorsulfonic acid.
stereogenic center (29) was prepared from natural pladieno-
lide D (3) by protection with a TES group,careful ozonolysis,
and reduction with NaBH4.[24] Fragment 29 was deprotected
with TBAF and then transformed to tetrahydrofuran 30 by
treatment with potassium tert-butoxide. The 1,3-diol moiety
of 30 was converted into the corresponding benzylidene
acetal to afford 31 as a mixture of diastereomers (a:b 2:1),
which were easily separated by column chromatography on
silica gel. Compounds 31a and 31b were studied by extensive
NMR analysis,and NOESY correlations observed for 31a
and 31b supported the assignment of the stereochemistry of
C16 as R,as shown in Scheme 1. [25]
By using the information obtained for the stereochemistry
of pladienolide D,we started its total synthesis. We originally
envisioned the use of a Julia–Kocienski olefination for
coupling the macrolide and the side chain,as for pladieno-
lide B. However,model reactions demonstrated that protec-
tion of the tertiary alcohol at C16 with TES,MOM,ethoxy
ethyl,or SEM groups obstructed the Julia–Kocienski olefi-
nation. Therefore,olefin cross-metathesis (CM) seemed to be
a better alternative to establish a quaternary carbon atom
adjacent to the diene moiety in the side chain.[26] The CM
reaction between the macrolide moiety bearing a terminal
diene (32) and various tertiary allylic alcohols afforded
products in good yield with the C16 quaternary carbon
atom. Therefore,we used this key reaction in our synthesis.
The total synthesis of pladienolide D is shown in
Scheme 7. Compound 32 was conveniently prepared from
aldehyde 17: sequential Tebbe olefination,[27] removal of the
TBS and benzylidene acetal groups,and regioselective
acetylation gave desired diene 32 in 54% overall yield from
17. The side chain with a tertiary allyl alcohol moiety was
prepared from known alcohol 33.[28] Sulfone 34 was prepared
in excellent yield from alcohol 33 by a Mitsunobu reaction[29]
and subsequent oxidation.[30] Sulfone 34 was then allowed to
react with aldehyde 19 to give skipped diene ester 35 in 97%
yield and high E selectivity (E:Z 17:1).[8] Reduction of ester
35 with DIBAL gave the corresponding allyl alcohol,which
Scheme 7. Total synthesis of pladienolide D: a) Tebbe reagent, pyri-
dine, toluene/THF (7:1), RT, 75%; b) PPTS, MeOH, RT, 77%; c) acetic
anhydride, Et3N, DMAP, CH2Cl2, RT, 93%; d) 5-mercapto-1-phenyltetra-
zole, Ph3P, DIAD, THF, RT, quant.; e) MoO7(NH4)6·4H2O, H2O2,
EtOH, RT, quant.; f) KHMDS, 19, DME/THF, À608C, 97%; g) DIBAL,
toluene, À788C, 74%; h) Ti(OiPr)4, (À)-DET, tBuOOH, 4-Š MS,
À308C, CH2Cl2, 91% (90% de); i) TsCl, Et3N, DMAP, CH2Cl2, R T,
quant.; j) 1n HCl, THF, RT, quant.; k) 1,2:4,5-di-O-isopropylidene-d-
erythro-2,3-hexodiuro-2,6-pyranose, oxone, K2CO3, MeCN/aqueous
Na2EDTA (4”10À4 m; 3:2), 08C, 87% (81% de), then recrystallization,
52% (>99% de); l) KI, acetone-DMF, (5:1), reflux; m) Zn, CuI, EtOH/
H2O (2:3), sonication, RT (99% in 2 steps); n) 39/32=2/1, 2nd
generation Grubbs catalyst (5 mol%), CH2Cl2, reflux, 64%. Tebbe
reagent=[m-chloro-m-methylene[bis(cyclopentadienyl)titanium]di-
methylaluminum], DME=1,2-dimethoxyethane, DET=diethyl tartrate,
Ts =p-toluenesulfonyl, 2nd-generation Grubbs catalyst=benzylidene-
[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(tricyclo-
hexylphosphine)ruthenium.
was subjected to Sharpless asymmetric epoxidation[31] to
afford epoxide 36 in good yield and diasteroselectivity (91%,
90% de). Tosylation of the primary hydroxy group and
removal of the TES group under weakly acidic conditions
provided alcohol 37. Asymmetric epoxidation of 37 by the
method developed by Shi and co-workers afforded diepoxide
38 (81% de),which was purified by recrystallization to give
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[4] M. Iwata et al.,see the Supporting Information.
[5] N. Asai,Y. Kotake,N. Fukuda,J. Niijima,T. Uehara,T. Sakai,
Antibiot.,submitted.
optically pure 38. Iodination and subsequent cleavage of the
epoxide in 38 with a zinc/copper couple[32] gave desired
tertiary allyl alcohol 39 in 99% yield. Finally,olefin cross-
metathesis between 32 and 39 afforded pladienolide D (3) in
64% yield and excellent stereoselectivity.[26] The E selectivity
was consistent with a literature report indicating that a CM
reaction between an unprotected tertiary allylic alcohol and
an a-olefin gives the trans olefin selectively.[26,33] In addition,
Hoye and Zhao have reported that a free allylic hydroxy
group has an activating effect on ring-closing metathesis
(RCM).[34] Hence,the same effect may be a good driving force
in our synthesis. It should also be noted that few examples of
CM reactions between olefins bearing a quaternary carbon
atom and an a-olefin during the synthesis of a natural product
have been reported to the best of our knowledge.
J.
[6] For recent reviews of ring-closing metathesis,see a) S.-Y. Han,S.
Chang in Handbook of Metathesis, Vol. 2 (Ed.: R. H. Grubbs),
Wiley-VCH,Weinheim, 2003,pp. 5 – 127; b) R. H. Grubbs,S.
Chang, Tetrahedron 1998, 54,4413 – 4450; c) S. K. Armstrong, J.
Chem. Soc. Perkin Trans. 1 1998,371 – 388; d) A. Fꢀrstner,
Angew. Chem. 2000, 112,3140 – 3172; Angew. Chem. Int. Ed.
2000, 39,3012 – 3043; e) L. Yet, Chem. Rev. 2000, 100,2963 –
3007; f) T. M. Trnka,R. H. Grubbs, Acc. Chem. Res. 2001, 34,
18 – 29; g) J. Prunet, Angew. Chem. 2003, 115,2932 – 2936;
Angew. Chem. Int. Ed. 2003, 42,2826 – 2830; h) R. R. Schrock,
A. H. Hoveyda, Angew. Chem. 2003, 115,4740 – 4782; Angew.
Chem. Int. Ed. 2003, 42,4592 – 4633; i) A. Deiters,S. F. Martin,
Chem. Rev. 2004, 104,2199 – 2238; j) R. H. Grubbs, Tetrahedron
2004, 60,7117 – 7140; k) K. C. Nicolaou,P. G. Bluger,D. Sarlah,
Angew. Chem. 2005, 117,4564 – 4601; Angew. Chem. Int. Ed.
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[7] For previous examples of the use of RCM for construction of 12-
membered aliphatic macrolides,see a) A. Fꢀrstner,K. Lange-
mann, Synthesis 1997,792 – 803; b) A. Fꢀrstner,T. Mꢀller, J. Am.
Chem. Soc. 1999, 121,7814 – 7821; c) S. Sasmal,A. Geyer,M. E.
Maier, J. Org. Chem. 2002, 67,6260 – 6263; d) M. D. Ronsheim,
C. K. Zercher, J. Org. Chem. 2002, 67,1878 – 1885; e) X. Wang,
J. A. Porco,Jr., Angew. Chem. 2005, 117,3127 – 3131; Angew.
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M. Sharma,S. Khadem,D. M. Leek,P. Arya, J. Comb. Chem.
2006, 8,715 – 734.
The spectral data and optical rotation data of 3 were
virtually identical to those of the natural product. We also
compared the antitumor activity of synthetic pladienolides B
and D with the activity of the natural products. The
IC50 values of synthetic and natural pladienolides B and D
against WiDr colon cancer cell growth inhibition were
essentially identical: 0.90 nm and 7.5 nm for the synthetic
products and 0.86 nm and 5.9 nm for the natural ones,
respectively.
In conclusion,we have achieved the first total synthesis of
pladienolides B (2) and D (3),through longest linear sequen-
ces of 22 and 19 steps,respectively,in overall yields of 2.1%
and 2.2%,respectively. These syntheses confirmed the
absolute stereochemistry of pladienolides B and D. Note
that our synthetic approaches involve the first example of
ring-closing metathesis for the construction of a sterically
hindered aliphatic 12-membered macrolide structure and also
exhibit an effective application of cross-metathesis to the
synthesis of natural products. The exploitation of cross-
metathesis at the culmination of our total synthesis is quite
efficient and versatile because the fragments can be assem-
bled without protecting groups to directly provide the final
target in sufficient yield. We believe that this synthetic effort
provides a practical route to novel pladienolide analogues
that could not be obtained from natural resources.
[8] P. R. Blakemore,W. J. Cole,P. J. Kocienski,A. Morley, Synlett
1998,26 – 28.
[9] a) Z.-X. Wang,Y. Tu,M. Frohn,J.-R. Zhang,Y. Shi,
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[10] P. A. Grieco,Y. Masaki,D. Boxler, J. Am. Chem. Soc. 1975, 97,
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[11] S. Fukuzawa,H. Matsuzawa,S. Yoshimitsu, J. Org. Chem. 2000,
65,1702 – 1706.
[12] The stereochemistries of the newly introduced hydroxy groups
were checked by means of the modified Mosherꢂs method.
1
[13] No other diastereomers were detected by H NMR spectrosco-
py.
[14] I. Paterson,D. Wallac,C. J. Cowden, Synthesis 1998,639 – 652.
[15] J. Inanaga,K. Hirata,H. Saeki,T. Katsuki,M. Yamaguchi, Bull.
Chem. Soc. Jpn. 1979, 52,1989 – 1993.
Received: December 11,2006
Revised: March 1,2007
[16] For the metathesis catalysts we investigated,see a) P. Schwab,
R. H. Grubbs,J. W. Ziller, J. Am. Chem. Soc. 1996, 118,100 –
110; b) M. Scholl,S. Ding,C. W. Lee,R. H. Grubbs, Org. Lett.
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Published online: April 17,2007
Keywords: antitumor agents · metathesis · natural products ·
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total synthesis
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