Conception, synthesis, and biological evaluation of original discodermolide analogues

Article abstract of DOI:10.1002/chem.201100675

Due to its intriguing biological activity profile and potential chemotherapeutic application discodermolide (DDM) proved to be an attractive target. Therefore, notable efforts have been carried out directed toward its total synthesis and toward the produc

Full text of DOI:10.1002/chem.201100675

FULL PAPER
DOI: 10.1002/chem.201100675
Conception, Synthesis, and Biological Evaluation of Original Discodermolide
Analogues
Elsa de Lemos,[a] Evangelos Agouridas,[a] Geoffroy Sorin,[a] Antonio Guerreiro,[b]
Alain CommerÅon,[b] Ange Pancrazi,[a] Jean-FranÅois Betzer,*[a]
Marie-Isabelle Lannou,*[a] and Janick Ardisson*[a]
Abstract: Due to its intriguing biologi-
cal activity profile and potential che-
motherapeutic application discodermo-
lide (DDM) proved to be an attractive
target. Therefore, notable efforts have
been carried out directed toward its
total synthesis and toward the produc-
tion and evaluation of synthetic ana-
logues. Recently, we achieved the total
synthesis of DDM. At the present,
guided by the knowledge gained during
our DDM total synthesis and by the re-
quirement of keeping the bioactive
“U” shape conformation, we report the
convergent preparation of five original
analogues. Three types of changes were
realized through modification of the
terminal (Z)-diene moiety, of the
methyl group at the C14-position, and
the lactone region. All analogues were
active in the nanomolar range and two
of them turned out to be equipotent to
DDM.
Keywords: anticancer
cross-coupling discodermolide
nickel · polyketides
agents
·
·
·
Introduction
(+)-Discodermolide (DDM 1) is a polypropionate natural
product originally isolated from the marine sponge Disco-
dermia dissoluta.[1] It was found to be a potent microtubule
stabilizer that binds with remarkable affinity to the taxoid
site on b-tubulin in microtubules.[2] Further studies, however,
revealed clear differences between the two drugs. In vitro,
DDM exhibits greater tubulin polymerization potency than
Taxol, and formed microtubules are much shorter. Addition-
ally, DDM is a poor substrate of the P-glycoprotein pump
and retains antiproliferative potency against b-tubulin
mutant cell lines that are resistant to taxanes and epothilo-
nes.[2j] Interestingly, discodermolide can induce accelerated
cell senescence, which is not a typical characteristic of
Taxol.[3] Of particular relevance are the findings that DDM
and Taxol act synergistically, both in in vitro and in vivo
tumor models, something that is not observed with taxanes
and epothilones.[4]
These exciting activities resulted in a Phase I clinical trial
initiated by Novartis, which was suspended due to pulmona-
ry toxiticy, despite encouraging results.[5] Work towards non-
toxic and active DDM analogues is, however, still ongoing.[6]
(+)-DDM (1) comprises a linear polypropionate back-
bone, punctuated by 13 stereogenic centers, (Z)-olefinic
linkages at C8–C9 and C13–C14, a terminal (Z)-diene sub-
stituent at C21–C24, and a d-lactone. Reported solid-state,
solution, and protein-bound DDM conformations reveal the
unusual result that a common hairpin conformational motif
exists in all three microenvironments.[2a,7] No other flexible
microtubule binding agents exhibit such constancy of confor-
mation. The stability of this strongly preferred form with re-
spect to the central sector of the molecule, is due to steric
factors (i.e. A1,3 and A1,2 strains and syn-pentane interac-
tions) arising from repeated modular segments, composed of
[a] Dr. E. d. Lemos, Dr. E. Agouridas, Dr. G. Sorin, Dr. A. Pancrazi,
Dr. J.-F. Betzer, Dr. M.-I. Lannou, Prof. J. Ardisson
Universitꢀ Paris Descartes, Facultꢀ de Pharmacie
CNRS UMR 8638, 4 avenue de l’Observatoire
75270 Paris Cedex (France)
Fax : (+33)143291403
E-mail: jean-francois.betzer@icsn-gif.fr
marie-isabelle.lannou@parisdescartes.fr
janick.ardisson@parisdescartes.fr
ꢀ
ꢀ
the C(Me) CHX C(Me) fragment and the C8–C9 and
C13–C14 Z double bonds.
[b] Dr. A. Guerreiro, Dr. A. CommerÅon
The natural product was only isolated in low yields, and
no biosynthesis method has been found to produce DDM;
therefore, the material necessary for biological studies must
be generated synthetically. The unique profile of this medici-
nally relevant product has incited a number of efforts direct-
Chemical & Analytical Sciences, Natural Product Chemistry
Sanofi-Aventis, Centre de Recherche de Vitry-Alfortville
13 Quai Jules Guesde, 94403 Vitry-sur-Seine Cedex (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100675.
Chem. Eur. J. 2011, 17, 10123 – 10134
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ed toward the total synthesis of (+)-DDM[8,9,10] and toward
the production of synthetic analogues.[10,11] These studies
have helped to define critical requirements for activity.
Changes in the C15–C24 fragment of DDM were some of
the first modifications investigated. The configuration of the
C16 and C17 stereocentres and the geometry of the C21–
C22 double bond seem crucial for activity. In the C8–C14
region of the molecule, only scarce variations have been re-
ported. This can be attributed to the crucial importance of
the middle part on the spatial orientation of the molecule.
On the contrary, modifying the d-lactone fragment has
yielded most of the analogues that have been generated to
date. Thus, while the carbon backbone is required to set the
overall conformation of the molecule, the diene and lactone
regions provide opportunities to develop analogues with im-
proved potency, pharmacokinetic properties, or simplified
structure.
Recently, we achieved the total synthesis of DDM (1) by
using a straightforward and highly convergent route.[8m,n] As
a result of the modulable character of our approach allow-
ing specific structural modifications, we report here the elab-
oration of five original DDM analogues and their biological
evaluation.
Results and Discussion
The design of the analogues was guided by the chemical
knowledge gained during the total synthesis and by the
strong constraint of keeping the essential “U”-shaped con-
formation of DDM. Therefore, computational conforma-
tional analysis was performed on the focused analogues to
check if the hairpin conformation is still favored.[12]
We envisioned modifying or replacing the terminal C21–
C24 diene, the lactone region, and the methyl group at the
C14-position of DDM. Therefore, we focused on the synthe-
sis of five analogues, 2 (including a C24 gem-di-Me group),
3 and 4 (encompassing a phenyl or a benzyl group at the
C22-position), 5 (substituted by an isopropyl group at C14),
and 6 (in which an aromatic group replaced the d-lactone).
The strategy for the preparation of the five analogues 2–6
patterned after the synthesis of
1 is summarized in
Scheme 1. The same disconnections were made to provide
A, B, and C fragments. The linkage of these subunits will
rely on acetylide addition to Weinreb amide (B–C) and a
Suzuki Pd-catalyzed sp2–sp3 coupling reaction (A–BC).
A central feature of our DDM (1) total synthesis was the
repeated addition of the chiral (R)-crotyltitanium reagent 9
to a (S)-methyl aldehyde 7 to yield homoallylic adducts 10
Scheme 1. DDM analogues: Retrosynthetic analysis.
encompassing
a syn–anti methyl–hydroxy–methyl triad
linked to a (Z)-O-enecarbamate group, with excellent dia-
stereoselectivity (Scheme 2). The enantioenriched (R)-a-
(N,N-diisopropylcarbamoyloxy) crotyltitanium (9) was read-
ily prepared in situ from crotyl diisopropylcarbamate 8, an
equimolar mixture of nBuLi/(ꢀ)-sparteine, and tetra(isopro-
poxy)titanium.[13,14]
Scheme 2. DDM total synthesis: Crotyltitanation of aldehyde 7.
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Discodermolide Analogues
FULL PAPER
Furthermore, reactivity of the (Z)-O-enecarbamate
moiety was critical in the preparation of the C21–C24 termi-
nal (Z)-diene 12 of DDM. The direct vinylation of vinylcar-
bamate 11 was performed through a nickel-catalyzed cross-
coupling reaction in the presence of [Ni
ACHTUNGTERN(NNUG acac)2] with vinyl-
lithium (Scheme 3).[8m–n,15,16]
Scheme 5. Synthetic analysis of DDM analogues: Installation of an iso-
propyl group at the C14-position through dyotropic rearrangement.
Scheme 3. DDM total synthesis: Formation of the terminal (Z)-diene 12.
PMB=p-methoxybenzyl, TBS=tert-butyldimethylsilyl, TES=triethylsil-
yl.
binding site). Therefore, we investigated the simplification
of the DDM backbone with a phenol core to afford ana-
logue 6 while keeping the DDM C7-hydroxyl function.
The synthesis of the DDM analogue 2 bearing a C24 gem-
di-Me group started with the construction of the (Z)-C21–
C24 diene unit (Scheme 6). It was planned by a Ni-mediated
Grignard coupling reaction between the C15–C22 vinylcar-
bamate 11 previously prepared by us during the total syn-
thesis of DDM[8m–n] and 2-methylpropenylmagnesium bro-
mide. The required diene 13 was delivered in very high yield
(94%) and the geometric control was total. This compound
was then smoothly transformed into the corresponding C15–
C24 subunit 18 in two steps. The second key step involved
an sp2–sp3 Suzuki coupling reaction[19] by using B-alkyl orga-
noborane species prepared from alkyl iodide 18 and C1–C14
vinyl iodide 19 already described in our DDM synthesis,[8m–n]
to afford adduct 20 in a nonoptimized 51% yield.
This approach could allow us to modify the (Z)-C21–C24
diene core through an extension of the nickel-catalyzed
cross-coupling reaction from the terminal (Z)-O-enecarba-
mate compound 11. Hence, the elaboration of three original
and more lipophilic DDM analogues was considered, one in-
cluding a (Z)-diene unit with a C24 gem-di-Me group (13)
and two nondiene derivatives with a phenyl or a benzyl core
(14 and 15) (Scheme 4).
Selective cleavage of the C19-TES ether followed by car-
bamate moiety installation and final total deprotection with
concomitant lactonization provided DDM analogue 2.
The elaboration of the nondiene analogue 3 possessing a
phenyl group followed a similar sequence from vinylcarba-
mate 11 (Scheme 7). Thus, the nickel-catalyzed cross-cou-
pling reaction involving phenylmagnesium bromide ensured
the construction of the C15–C24 subunit 21 with high selec-
tivity. Then, sp2–sp3 Suzuki coupling reaction (formation of
22), carbamate function setup, and deprotection delivered
the desired DDM analogue 3.
For the synthesis of the second nondiene analogue 4 bear-
ing a benzyl group, DDQ cleavage of the PMB ether at the
C15-position did not proceed in the presence of the benzyl
function. Therefore, we inverted the order of the first two
steps, DDQ deprotection and Ni-mediated coupling reaction
(Scheme 8). Except for this minor modification, completion
of the synthesis following the established route (Suzuki reac-
tion between alkyl iodide 23 and vinyl iodide 19 to yield 24,
selective carbamate installation, and final deprotection) al-
lowed the preparation of DDM analogue 4.
Scheme 4. Synthetic analysis of DDM analogues: Setup of the analogous
terminal (Z)-dienes through a nickel-catalyzed cross-coupling reaction.
The replacement of the methyl group at the C14-position
by a more sterically demanding isopropyl group was very
original and innovative. Although such a variation has never
been reported so far, we were convinced it could enhance
the specific active conformation of DDM (1). For the build-
ing of the corresponding analogue 5, we studied an improve-
ment of the dyotropic rearrangement developed for our
DDM total synthesis,[8m–n,17] involving an isopropyl cuprate
instead of a methylcuprate, from dihydrofuran 16, to lead to
olefin 17 (Scheme 5).
Replacing the d-lactone fragment by a phenol group sug-
gested great promise even if such already reported ana-
logues were characterized by a slightly lower activity.[11k,18]
However, this loss of activity was not clearly linked to d-lac-
tone modification, since literature compounds were, at the
same time, desoxygenated at the C7-position; structure–ac-
tivity investigations addressing this point showed that the
hydroxyl function at C7 could play a significant role in the
biological activity (possibility of hydrogen bonding in the
The synthesis of the fourth analogue 5, substituted at the
C14-position by an isopropyl group, was then investigated.
DHF (+/ꢀ)-16[8m–n] was subjected to metallate rearrange-
ment under the previously developed optimized laboratory
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J. Ardisson et al.
Scheme 7. Synthesis of DDM analogue 3: a) 14: [NiACTHNUGTRNEUNG(acac)2], Et2O, 0 8C,
phenylmagnesium bromide, 16 h; b) DDQ, CH2Cl2/H2O 95:5, 08C!RT,
3.5 h, 59% over 2 steps; c) I2, PPh3, imid, C6H6/Et2O, 0 8C!RT, 3 h,
86%; d) 21, tBuLi, Et2O, ꢀ788C, 5 min, B-methoxy-9-BBN, THF,
ꢀ788C!RT, then 19, Cs2CO3, [PdCl
2ACHTUGNTREN(UNGN dppf)], AsPh3, DMF, H2O, 16 h,
10%; e) PTSA, MeOH, 08C, 1 h, 69%; f) Cl3CC(O)NCO, CH2Cl2, RT,
15 min, then K2CO3, MeOH, RT, 1.15 h, 58%; g) HCl 4n, THF, RT, 72 h,
91%.
Scheme 6. Synthesis of DDM analogue 2: a) [NiACTHNUTGRNEUNG(acac)2], Et2O, 0 8C, 2-
methylpropenylmagnesium bromide, 16 h, 94%; b) DDQ, CH2Cl2/H2O
95:5, 08C!RT, 3.5 h, 83%; c) I2, PPh3, imid, C6H6/Et2O, 0 8C!RT, 2 h,
61%; d) 18, tBuLi, Et2O, ꢀ788C, 5 min, B-methoxy-9-BBN, THF,
lowed by partial hydrogenation with PtO2 (catalyst of choice
for this congested alkyne) and iodine–tin exchange then
completed the formation of vinyliodide 31. The convergent
coupling of 31 with alkyliodide 32[8m–n] was carried out under
Suzuki conditions.[23] Deprotection of the C1–C24 fragment
33 and carbamate formation at C19 then furnished DDM
analogue 5.
ꢀ788C!RT, then 19, Cs2CO3, [PdCl
2ACHTUGNTREN(UNGN dppf)], AsPh3, DMF, H2O, 16 h,
51%; e) PTSA, MeOH, 08C, 1 h, 70%; f) Cl3CC(O)NCO, CH2Cl2, RT,
15 min, then K2CO3, MeOH, RT, 1.15 h, 78%; g) HCl 4n, THF, RT, 72 h,
47%. acac=acetylacetonate, BBN=borabicycloACHTNUTRGNEUNG[3,3,1]nonane, DDQ=
2,3-dichloro-5,6-dicyano-1,4-benzoquinone, dppf=(diphenylphosphino)-
ferrocene, imid=imidazole, PTSA=p-toluenesulfonic acid.
The synthesis of the simplified DDM analogue 6 bearing
a phenolic group instead of the d-lactone was much faster.
It started with the preparation of amide 35 from commercial
3-hydroxyphenylacetic acid 34 in two steps and 66% yield
(Scheme 11). Subsequent coupling of the C8–C14 alkyne 36
previously prepared in the laboratory,[8m–n] with amide 35 de-
livered adduct 37 after reduction by the (S)-CBS reagent[24]
and protection of the newly generated hydroxy function at
C7. Hydrogenation and iodine–tin exchange then led to vi-
nyliodide 38. Whereas the formation of this vinyliodide 38
proceeded smoothly, significant problems were encountered
during the Suzuki cross-coupling reaction between vinylio-
dide 38 and alkyliodide 32. The required adduct 39 was ob-
tained in a rather low 17% yield, the main isolated product
being the cyclohexene derivative 40, which certainly arose
from an intramolecular Heck coupling reaction.[25]
conditions with a cyano-Gilman isopropylcuprate to lead to
the expected (Z)-alkene (+/ꢀ)-17 in a satisfactory 72%
yield and total diastereoselectivity (Scheme 9). A two-step
sequence, oxidation, and crotyltitanation with the inherently
chiral secondary organometallic reagent (R)-9, delivered the
required homoallylic alcohol 25 as the main product in 41%
yield along with its diastereomer 26 in 25% yield. To con-
firm the configuration of the (S)-C11 secondary hydroxy
center, secondary alcohol 25 was derivatized to give the (R)-
and (S)-a-methoxy-phenylacetic acid (MPA) esters.[20,21]
From vinylcarbamate 25, a-elimination reaction upon a
tBuLi treatment and subsequent C11 alcohol protection fur-
nished alkyne 27.
Coupling of the compound 27 with the amide 28[8m–n] de-
livered the ketone 29 (Scheme 10). Diastereoselective reduc-
tion of this intermediate under CBS conditions[22] led, after
protection of the alcohol at C11, to alkyne 30. Oxidation fol-
The same final three-step sequence (deprotection of the
C1–C24 fragment and carbamate formation at C19) deliv-
ered analogue 6.
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Discodermolide Analogues
FULL PAPER
Scheme 8. Synthesis of DDM analogue 4: a) DDQ, CH2Cl2/H2O 95:5,
08C!RT, 30 min, 60% b) 15: [Ni
ACHTUGNRTEN(NUGN acac)2], Et2O, RT, benzylmagnesium
chloride, 3 h; 73%; c) I2, PPh3, imid, C6H6/Et2O, 0 8C!RT, 2 h, 77%;
d) 23, tBuLi, Et2O, ꢀ788C, 2 min, B-methoxy-9-BBN, THF, ꢀ788C!RT,
then 19, Cs2CO3, [PdCl2ACHTUNGTRENNUNG(dppf)] AsPh3, DMF, H2O, 16 h, 30%; e) PTSA,
MeOH, 08C, 1 h, 80%; f) Cl3CC(O)NCO, CH2Cl2, RT, 15 min, then
K2CO3, MeOH, RT, 1.15 h, 27%; g) HCl 4n, THF, RT, 72 h, 56%.
Scheme 10. Synthesis of analogue 5: a) 27, nBuLi/Et2O, THF, ꢀ408C,
50 min, then 28, ꢀ40!08C, 1 h, 86%; b) (S)-(ꢀ)-2-methyl-CBS-oxaza-
borolidine, BH3.Me2S, THF, ꢀ308C, 2 h, 89%, d.r. 98:2; c) MOMCl,
TBAI, Hunigꢂs base, CH2Cl2, RT, 12 h, 97%; d) HF/Py, Py/THF, RT, 4 h,
87%; e) TEMPO (10 mol%), BAIB, CH2Cl2, RT, 3 h; f) NaClO2,
NaH2PO4, 2-methyl-but-2-ene, tBuOH/H2O, RT, 1 h; g) TMSCHN2,
C6H6/MeOH, RT, 15 min, 65% over 3 steps; h) H2, PtO2 (30 mol%),
AcOEt, RT, 12 h; i) I2, CH2Cl2, 08C, 10 min, 76% over 2 steps; j) 32,
tBuLi, Et2O, ꢀ788C, 5 min, B-methoxy-9-BBN, THF, ꢀ788C!RT, then
31, Cs2CO3, [PdCl2ACTHNURGTNEUNG(dppf)], AsPh3, DMF, H2O, 16 h, 10%; k) PTSA,
MeOH, 08C, 1 h, 72%; l) Cl3CC(O)NCO, CH2Cl2, RT, 15 min, then
K2CO3, MeOH, RT, 1.15 h, 40%; m) HCl 4n, THF, RT, 72 h, 50%.
CBS=Corey-Bakshi-Shibata, Py=pyridine.
comparable to DDM (IC50 (nm) HCT116 and MDA-MB-
231). C24 gem-di-Me analogue 2 and C14-isopropyl ana-
logue 5 were the most potent and both essentially equipo-
tent to DDM (Table 1, entries 1, 2, and 3). They were fol-
lowed in this order by phenolic 6 and C22-Ph 3 analogues
(entries 5 and 6). The C22-benzyl analogue 4 was the least
potent (entry 4).
Scheme 9. Synthesis of alkyne 27: a) tBuLi, iPr2CuLi.LiCN, Et2O/DMS
4:1, 08C!RT, 12 h, then nBu3SnCl, ꢀ308C!RT, 5 h, 72%; b) TEMPO
(10 mol%), BAIB, CH2Cl2, RT, 2 h; c) (R)-9, cyclohexane/pentane 1:7,
ꢀ788C, 3 h, compound 25 41% over 2 steps and compound 26 25% over
2 steps; d) tBuLi, THF, ꢀ408C!ꢀ208C, 20 min, 62%; e) MOMCl,
TBAI, Hunigꢂs base, CH2Cl2, RT, 24 h, 88%. BAIB=[bis-
ACHTUNGTRENNUNG(acetoxy)iodo]benzene, MOM=methoxymethyl, TBAI=tetra-n-buty-
lammonium iodide, Hunigꢂs base=diisopropylethylamine, TEMPO=
The present data reveal that a lipophilic C24 gem-di-Me
group or a sterically demanding C14-isopropyl substituent is
very well-tolerated and confers extremely good biological
activity. This last result suggests the possibility that the C14-
isopropyl substituent may increase the “U” shape bioactive
conformation. The phenolic analogue 6 retains good potency
considering the structure simplification and may be of utility
in the design of straightforward analogues.
2,2,6,6-tetramethyl-1-piperidinyloxy free radical.
Biological evaluation: The five DDM analogues 2, 3, 4, 5,
and 6 were finally screened for cellular activity in compari-
son to DDM (previously synthesized in the laboratory). Cy-
totoxicity asssays were performed on three different cell
lines. All analogues were effective in the nanomolar range
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J. Ardisson et al.
The first requirement was to keep the bioactive U-shaped
conformation of DDM, therefore modeling studies were
achieved before starting the synthesis. Three types of varia-
tion were envisioned depending on our synthetic possibili-
ties: 1) Modifying the diene, which is a lipophilic part of the
compound, with a gem-di-Me group at the C24-position,
phenyl, or benzyl group at C22. 2) Replacing the C14
methyl group by a more sterically demanding alkyl group to
reinforce the U-shaped bioative conformation. 3) Replacing
the d-lactone by a phenol moiety. If the third variation did
efficiently shorten the synthesis of the C1–C7 fragment, the
first two modifications were readily accessible through two
key reactions of our synthesis of DDM. The first one is a
robust and original nickel-catalyzed cross-coupling reaction
between an enecarbamate and the corresponding magnesi-
um derivative and the second is a dyotropic rearrangement
performed on a methyldihydrofuran with the corresponding
isopropylcuprate. Noteworthy, in both cases, the selectivities
were excellent.
Cytotoxicity assays were performed for these five ana-
logues on three different cell lines. All analogues were
active in the nanomolar range, especially the C24-gem-di-
Me and the C14-iPr analogues 2 and 5 both equipotent to
DDM. The phenolic analogue 6 retained a very significant
and encouraging in vitro activity considering the structure
simplification.
Scheme 11. Synthesis of analogue 6: a) TBSCl, imid, DMF, RT, 4 days;
b) HN(CH3)OCH3·HCl, Hunigꢂs base, EDCI·HCl, HOBt, CH2Cl2, RT,
Investigation work towards novel simplified DDM ana-
logues is ongoing in the laboratory.
ACHTUNGTRENNUNG
24 h, 66% over 2 steps; c) 36, nBuLi/Et2O, THF, ꢀ408C, 50 min, then 35,
ꢀ408C->08C, 1 h, 63 %; d) (S)-(ꢀ)-2-Methyl-CBS-oxazaborolidine,
BH3·Me2S, THF, ꢀ308C, 2 h, 81%, d.r. 98:2; e) MOMCl, TBAI, DMAP,
Hunigꢂs base, CH2Cl2, RT, 12 h, 90%; f) H2, PtO2 (30 mol%), AcOEt,
RT, 12 h; g) I2, CH2Cl2, 08C, 10 min, 76% over 2 steps; h) 32, tBuLi,
Et2O, ꢀ788C, 5 min, B-methoxy-9-BBN, THF, ꢀ788C!RT, then 38,
Experimental Section
Cs2CO3, [PdCl2ACHTUNGTRENNUNG(dppf)], AsPh3, DMF, H2O, 16 h, 39 17% and 40 20%;
General: All reactions were carried out in oven or flame-dried glassware
under an argon atmosphere employing standard techniques in handling
air-sensitive materials. All solvents employed were reagent grade. THF
and diethyl ether (Et2O) were freshly distilled from sodium/benzophe-
none under argon immediately prior to use. Dichloromethane, cyclohex-
ane, and pentane were freshly distilled over calcium hydride. All other
reagents were used as supplied. Reactions were magnetically stirred and
monitored by TLC analysis with 0.20 mm SDS 60F254 pre-coated silica
gel plates. Visualization was accomplished with UV light then treatment
with a 10% ethanolic phosphomolybdic acid solution followed with heat-
ing. Flash chromatography was performed with silica gel 60 (particle size
0.040–0.063 mm) supplied by SDS. Yield refers to chromatography and
spectroscopically pure compounds, unless otherwise noted. 1H NMR
spectra were recorded by using an internal deuterium lock at ambient
temperature on a JEOL JNM-ECX 270 or 400 MHz spectrometer. Inter-
nals references of dH =7.26 and 1.96 ppm were used for CDCl3 and
CD3CN, respectively. Data are represented as follows: chemical shift (in
ppm), multiplicity (s=single, d=doublet, t=triplet, q=quartet), integra-
tion, coupling constant (J). 13C NMR spectra were recorded on a Jeol
67.5 or 100.5 MHz spectrometer. Internal references of dC =77.16 and
118.26 ppm were used for CDCl3 and CD3CN, respectively. IR spectra
were recorded on a Nicolet Impact-400 and wavelength (n) is given in
cmꢀ1. Mass spectra were recorded on a GCMS coupling unit with a MSD
5973 spectrometer and a Hewlett–Packard HP-GC 6890 chromatograph.
Ionization was obtained either by electronic impact (EI) or chemical ion-
ization with methane (CI, CH4). Mass spectral data are reported as m/z.
Optical rotations were recorded on a Jasco P-1010 digital polarimeter at
589 nm and reported as follows: [a]2D0, concentration (c in g/100 mL), and
solvent. Elemental analyses were performed on a CHN 240 Perkin–
Elmer instrument by the Service de Microanalyses, Centre d’Etudes
i) 39, PTSA, MeOH, 08C, 1 h, 58%; j) Cl3CC(O)NCO, CH2Cl2, RT,
15 min, then K2CO3, MeOH, RT, 1.15 h, 58%; k) HCl 4n, THF, RT, 24 h,
88%. DMAP=dimethylaminopyridine, EDCI=1-ethyl-3-[3-dimethyla-
mino)propyl]carbodiimide, HOBt=1-hydroxybenzotriazole.
Table 1. Biological evaluation of synthesized analogues 2–6.[a,b]
Entry Compound
IC50 [nm]
IC50 [nm]
IC50 [nm]
HCT116[b] MDA- MB231[b] MDA-A1[b]
1
2
3
4
5
6
DDM (1)
C-24-gem-dimethyl 2 1.3
C-22-phenyl 3
C-22-benzyl 4
C-14-isopropyl 5
phenol 6
5.0
15.6
3.7
110
1009
17.5
66
105.8
155
4494
8709
2200
4836
19
321
2.3
16
[a] Cytotoxicity asssays were based on the determination of the inhibition
of cell growth by measuring the inhibition of the incorporation of
14C-thymidine. [b] Cells lines used: human colon cancer epithelial cell
line HCT116, human breast cancer cell lines MDA-MB-231 (wild type)
and MDA-A1 (anthracycline resistant).
Conclusion
The underlying synthesis blueprint of DDM (1) allowed for
the convergent preparation of five original analogues 2, 3, 4,
5, and 6 of DDM, each of them exhibiting potent cytotoxici-
ty.
10128
www.chemeurj.org
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 10123 – 10134

Discodermolide Analogues
FULL PAPER
Pharmaceutiques, Chatenay-Malabry, F-92296. HRMS were obtained on
a Thermo-Electron MAT-95 spectrometer in the ICMMO, Mass Spec-
trometry Laboratory, Orsay University, F-91 405 Orsay. IUPAC nomen-
clature was used for all compounds.
6.9 Hz, 3H; CH3), 0.89 (d, J=6.9 Hz, 3H; CH3), 0.87 (d, J=6.9 Hz, 3H;
CH3), 0.71 (d, J=6.9 Hz, 3H; CH3), 0.10 (s, 3H; CH3). 0.09 ppm (s, 3H;
CH3); 13C NMR (100.5 MHz, CDCl3): d=174.8 (C), 157.0 (C), 138.7 (C),
136.8 (CH), 136.0 (C), 132.4 (C), 130.6 (CH), 130.1 (2CH), 128.9 (CH),
128.2 (CH), 127.8 (2CH), 125.8 (2CH), 125.1 (CH), 99.5 (CH), 97.7
(CH2), 93.1 (CH2), 86.9 (CH), 82.1 (CH), 79.1 (CH), 77.6 (CH), 77.0
(CH), 66.3 (CH), 56.0 (CH3), 55.2 (CH3), 51.9 (CH3), 41.1 (CH), 39.0,
37.9, 36.1, 35.8, 35.2, 35.1, 34.4, 34.0 (6CH, 2CH2), 26.8 (3CH3), 26.3
(CH3), 23.0 (CH3), 18.4 (CH3), 18.0 (C), 17.6 (CH3), 17.3 (CH3), 16.5
(CH3), 13.8 (CH3), 11.6 (CH3), 10.1 (CH3), 9.3 (CH3), ꢀ3.4 (CH3),
ꢀ3.6 ppm (CH3); IR (film): n˜ =3382, 3315, 3304, 3215, 2983, 2956, 2930,
24-Dimethyl discodermolide 2: p-Toluenesulfonic acid (7 mg,
0.035 mmol, 0.28 equiv) was added to
a solution of compound 20
(130 mg, 0.13 mmol, 1.0 equiv) in MeOH (15 mL) at 08C. After stirring
for 1 h at 08C, triethylamine was added to the reaction mixture
(0.3 equiv) and the solvent was removed under reduced pressure. The
residue was purified by chromatography on silica gel (cyclohexane/
AcOEt,
[2S,4R(1R),5S,6S(2S,3Z,5S,6R,7S,8Z,11S,12R,13S,14S,15S,16Z)]-4-(2-me-
thoxy-carbonyl-1-methyl ethyl-1-yl)-6-{12-(tert-butyldimethylsilyloxy)-
95:5
to
70:30)
to
give
the
expected
alcohol
2901, 2880, 1726, 1090, 1045 cmꢀ1
.
HCl (4n, 6 mL) was added to a solution of the above carbamate (58 mg,
0.06 mmol, 1.0 equiv) in THF (6 mL). The resulting mixture was stirred
72 h at 208C and then solid NaHCO3 was added and the reaction mixture
extracted three times with AcOEt. The organic layers were washed with
water and brine, dried over MgSO4, filtered, and the solvent removed
under reduced pressure. The residue was purified by chromatography on
silica gel (CH2Cl2/MeOH 95:5 to 90:10) to give the title compound,
DDM analogue 2 (18 mg, 47% yield) as an oil. [a]2D0 = +22.0 (c=1.8 in
MeOH); 1H NMR (400.0 MHz, CDCl3): d=6.19 (dd, J=11.2, 11.0 Hz,
1H), 6.03 (d, J=11.2 Hz, 1H), 5.50 (dd, J=11.4, 7.8 Hz, 1H), 5.43 (dd,
J=11.4, 9.6 Hz, 1H), 5.23 (dd, J=11.0, 10.5 Hz, 1H), 5.13 (d, J=10.1 Hz,
1H), 4.78–4.65 (m, 4H), 4.62 (t, J=10.1 Hz, 1H), 3.71 (dd, J=4.1,
3.2 Hz, 1H), 3.29 (dd, J=5.0, 4.6 Hz, 1H), 3.19 (dd , J=5.9, 5.5 Hz, 1H),
2.98 (dqm, J=10.5, 6.9 Hz, 1H), 2.81–2.73 (m, 2H), 2.70 (qd, J=7.3,
4.1 Hz, 1H), 2.72–2.68 (m, 1H), 2.55–2.45 (m, 3H, H-12), 1.99–1.64 (m,
7H), 1.81 (s, 3H; CH3), 1.75 (s, 3H; CH3), 1.64 (s, 3H; CH3), 1.29 (d, J=
7.3 Hz, 3H; CH3), 1.06 (d, J=6.9 Hz, 3H; CH3), 1.01 (d, J=6.9 Hz, 3H;
CH3), 1.00 (d, J=6.9 Hz, 3H; CH3), 096 (2d, J=7.3 Hz, 6H), 0.94 ppm
(d, J=6.4 Hz, 3H; CH3); 13C NMR (100.5 MHz, CDCl3): d=174.8 (C),
158.5 (C), 136.8 (C), 133.9 (CH), 133.7 (CH), 130.9 (CH), 130.4 (CH),
125.9 (C), 121.1 (CH), 118.3 (CH), 79.7 (2CH), 77.3 (CH), 75.8 (CH),
73.1 (CH), 63.2 (CH), 43.9 (CH), 42.0, 38.4, 37.3, 36.7, 36.3, 36.1, 34.3,
34.1 (6CH, 2CH2), 26.3 (2CH3), 23.3 (CH3), 19.8, 18.4, 18.0, 16.0, 15.7,
13.0, 9.2 ppm (7CH3); IR (film): n˜ =3382, 2962, 2929, 2870, 2856, 2360,
2340, 1726, 1682, 1454, 1395, 1032, 668 cmꢀ1; HRMS (ESI): m/z: calcd for
C35H59NO8NaSi: 644.4138 [M+Na]+; found: 644.4142.
5,7,9,11,13,15,19-heptamethyl-14-hydroxy-2,6-bis[(methoxymethyl)oxy]-
icosa-3,8,16,18-tetraen-1-yl}-5-methyl-2-phenyl-1,3-dioxinan (73 mg, 70%
yield). [a]2D0 = +13.9 (c=1.48 in CHCl3); 1H NMR (400.0 MHz, CDCl3):
d=7.48–7.42 (m, 2H), 7.35–7.28 (m, 3H), 6.34 (dd, J=11.5, 11.0 Hz,
1H), 6.07 (d, J=11.5 Hz, 1H), 5.58 (s, 1H), 5.55 (dd, J=11.0, 10.1 Hz,
1H), 5.20 (dd, J=11.0, 10.1 Hz, 1H), 5.18 (dd, J=11.0, 9.6 Hz, 1H), 4.99
(d, J=10.1 Hz, 1H), 4.84 (dd, J=9.6, 9.2 Hz, 1H), 4.71 (d, J=6.9 Hz,
1H), 4.54 (s, 2H), 4.50 (d, J=6.9 Hz, 1H), 4.05 (dd, J=10.1, 3.2 Hz, 1H),
3.82 (dd, J=10.1, 9.6 Hz, 1H), 3.73 (s, 3H; CH3), 3.63 (dd, J=6.4, 2.7 Hz,
1H), 3.33 (s, 6H; 2CH3), 3.35–3.30 (m, 2H), 3.07 (dd, J=5.9, 5.5 Hz,
1H), 2.85–2.75 (m, 3H), 2.55 (dqd, J=10.1, 6.9, 5.9 Hz, 1H), 2.21 (t, J=
12.4 Hz, 1H), 2.00–1.94 (m, 1H), 1.94–1.86 (m, 1H), 1.81 (s, 3H; CH3),
1.76 (s, 3H; CH3), 1.68–1.61 (m, 5H), 1.61 (s, 3H; CH3), 1.22 (d , J=
7.3 Hz, 3H; CH3), 1.01 (d, J=6.9 Hz, 3H; CH3), 0.98 (d, J=6.9 Hz, 3H;
CH3), 0.97 (d, J=6.9 Hz, 3H; CH3), 0.96 (s, 9H; 3CH3) , 0.94 (d , J=
6.9 Hz, 3H; CH3), 0.92 (d, J=6.9 Hz, 3H; CH3), 0.85 (d, J=6.9 Hz, 3H;
CH3), 0.08 (s, 3H; CH3). 0.07 ppm (s, 3H; CH3); 13C NMR (100.5 MHz,
CDCl3): d=174.8 (C), 138.8 (C), 136.9 (CH), 136.8 (C), 132.7 (C), 131.2
(CH), 130.2 (CH), 129.0 (CH), 128.2 (CH), 127.9 (2CH), 126.8 (CH),
125.8 (2CH), 120.0 (CH), 99.6 (CH), 97.8 (CH2), 93.2 (CH2), 86.8 (CH),
82.3 (CH), 79.0 (CH), 77.7 (CH), 75.6 (CH), 66.3 (CH), 56.0 (CH3), 55.2
(CH3), 51.9 (CH3), 41.0 (CH), 39.1 (CH2), 37.9 (CH), 36.8 (CH2), 36.0
(CH), 35.8 (CH), 35.3 (CH), 34.5 (CH), 34.4 (CH3), 27.1 (CH3), 26.3
(CH3), 26.2 (3CH3), 23.3 (CH3), 18.7 (C), 17.5 (CH3), 17.1 (CH3), 16.4
(CH3), 13.1 (CH3), 11.7 (CH3), 9.5 (CH3), 9.3 (CH3), ꢀ3.2 (CH3),
ꢀ3.6 ppm (CH3); IR (film): n˜ =3382, 2969, 2930, 2839, 2857, 1743, 1460,
1453, 1152, 1110, 1092, 1045, 772 cmꢀ1; HRMS (ESI): m/z: calcd for
C52H88O10NaSi: 923.6044 [M+Na]+; found: 923.6045.
22-Phenyl discodermolide 3: p-Toluenesulfonic acid (1.7 mg, 0.009 mmol,
0.28 equiv) was added to a solution of compound 22 (40 mg, 0.032 mmol,
1.0 equiv) in MeOH (4 mL) at 08C. After stirring for 1 h at 08C, triethyl-
amine was added to the reaction mixture (0.3 equiv) and the solvent was
removed under reduced pressure. The residue was purified by chroma-
tography on silica gel (cyclohexane/AcOEt, 95:5 to 60:40) to give the ex-
pected alcohol (20 mg, 69% yield). [a]2D0 = +19.1 (c=0.4 in CHCl3);
1H NMR (400.0 MHz, CDCl3): d=7.48–7.44 (m, 2H), 7.39–7.23 (m, 8H),
6.59 (d, J=11.4 Hz, 1H), 5.61–5.54 (m, 2H), 5.59 (s, 1H), 5.23 (t, J=
10.1 Hz, 1H), 4.99 (d, J=10.1 Hz, 1H), 4.84 (dd, J=10.1, 9.2 Hz, 1H),
4.72 (d, J=6.9 Hz, 1H), 4.56 (s, 2H), 4.50 (d, J=6.9 Hz, 1H), 4.06 (dd,
J=10.1, 3.2 Hz, 1H), 3.82 (dd, J=9.6, 9.2 Hz, 1H), 3.74 (s, 3H; CH3),
3.49 (dd, J=5.0, 3.7 Hz, 1H), 3.35–3.31 (ddd, J=7.8, 3.7, 3.2 Hz, 1H),
3.34 (s, 6H; 2CH3), 3,11 (t , J=5.5 Hz, 1H), 3.02 (dqd, J=7.3, 6.4,
3.7 Hz, 1H), 2.88–2.76 (m, 2H), 2.56 (dqd, J=10.1, 6.9, 5.5 Hz, 1H), 2.13
(t , J=12.4 Hz, 1H), 1.98 (m, 1H), 1.88–1.57 (m, 6H), 1.56 (s, 3H; CH3),
1.22 (d, J=7.3 Hz, 3H; CH3), 1.03 (d, J=6.4 Hz, 3H; CH3), 1.01 (d, J=
6.4 Hz, 3H; CH3), 0.93 (d, J=6.9 Hz, 3H; CH3), 0.90 (d, J=6.9 Hz, 3H;
CH3), 0.90 (s, 9H; 3CH3), 0.87 (d, J=6.9 Hz, 3H; CH3), 0.69 (d, J=
6.9 Hz, 3H; CH3), 0.00 (s, 3H; CH3), ꢀ0.05 ppm (s, 3H; CH3); 13C NMR
(100.5 MHz, CDCl3): d=174.8 (C), 138.8 (C), 137.1 (C), 136.8 (CH),
134.7 (CH), 132.7 (C), 130.8 (CH), 130.2 (CH), 129.0 (CH), 128.6 (2CH),
128.3 (2CH), 128.2 (CH), 127.9 (2CH), 126.9 (CH), 125.8 (2CH), 99.6
(CH), 97.8 (CH2), 93.1 (CH2), 86.8 (CH), 82.2 (CH), 78.7 (CH), 77.7
(CH), 76.7 (CH), 66.3 (CH), 56.0 (CH3), 55.2 (CH3), 51.9 (CH3), 41.0
(CH), 39.1 (CH2), 38.1 (CH), 36.4 (CH2), 35.9 (CH), 35.8 (CH), 35.3
(CH), 34.6 (CH), 34.5 (CH), 26.2 (3CH3), 23.3 (CH3), 18.4 (C), 17.5
(2CH3), 16.4 (CH3), 13.7 (CH3), 11.6 (CH3), 9.4 (CH3), 9.3 (CH3), ꢀ3.3
(CH3), ꢀ3.6 ppm (CH3); IR (film): n˜ =3440, 3377, 2960, 2929, 1461, 1453,
1435, 1151, 1092, 1036 cmꢀ1; HRMS (ESI): m/z calcd for C54H86O10NaSi:
945.5888 [M+Na]+; found: 945.5876.
Trichloroacetylisocyanate (10 mL, 0.085 mmol, 1.05 equiv) was added to a
solution of the above alcohol (73 mg, 0.08 mmol, 1.0 equiv) in CH2Cl2
(6 mL). After stirring for 15 min at 208C, the resulting mixture was con-
centrated in vacuo and the residue taken up in MeOH (8 mL). K2CO3
(61 mg, 0.44 mmol, 5.5 equiv) was added and the resulting solution was
stirred for 1 h 15 min and then concentrated in vacuo and extracted with
AcOEt. The organic layers were washed with water and brine, dried over
MgSO4, filtered, and the solvent removed under reduced pressure. The
residue was purified by chromatography on silica gel (cyclohexane/
AcOEt
90:10
to
50:50)
to
give
the
title
carbamate
[2S,4R(1R),5S,6S(2S,3Z,5S,6R,7S,8Z,11S,12R,13S,14S,15S,16Z)]-4-(2-me-
thoxycarbonyl-1-methyl ethyl-1-yl)-6-{12-(tert-butyldimethylsilyloxy)-14-
(carbamoyloxy)-5,7,9,11,13,15,19-heptamethyl-14-(carbamoyloxy)-2,6-
bis[(methoxymethyl)oxy]- icosa-3,8,16,18-tetraen-1-yl}-5-methyl-2-phenyl-
1,3-dioxinan (59 mg, 78% yield) as a pale oil. [a]2D0 = +30.3 (c=1.18 in
CHCl3); 1H NMR (400.0 MHz, CDCl3)> d=7.49–7.43 (m, 2H; H-Ar),
7.36–7.28 (m, 3H), 6.20 (dd, J=11.4, 11.0 Hz, 1H), 6.04 (d, J=11.4 Hz,
1H), 5.58 (s, 1H), 5.53 (dd, J=11.0, 10.1 Hz, 1H), 5.25 (dd, J=10.5,
10.1 Hz, 1H), 5.22 (dd, J=11.0, 10.1 Hz, 1H), 4.97 (d, J=10.1 Hz, 1H),
4.79–4.70 (m, 1H), 4.83 (dd, J=10.5, 9.6 Hz, 1H), 4.71 (d, J=6.9 Hz,
1H), 4.73–4.70 (m, 1H), 4.54 (s, 2H), 4.50 (d, J=6.9 Hz, 1H), 4.52–4.49
(m, 1H), 4.05 (dd, J=10.1, 3.2 Hz, 1H), 3.82 (dd, J=10.1, 9.2 Hz, 1H),
3.73 (s, 3H; CH3), 3.45 (dd, J=4.6, 4.2 Hz, 1H), 3.33 (s, 6H; 2CH3), 3.06
(dd, J=5.9, 5.5 Hz, 1H), 2.98 (dqm, J=10.1, 6.4 Hz, 1H), 2.85–2.76 (dq,
J=6.9, 3.2 Hz, 1H), 2.85–2.76 (m, 1H), 2.55–2.45 (m, 1H), 2.10–1.82 (m,
6H), 1.82 (s, 3H; CH3), 1.76 (s, 3H; CH3), 1.66 (tq, J=10.1, 6.9 Hz, 1H),
1.57 (s, 3H; CH3), 1.23 (d , J=6.9 Hz, 3H; CH3), 0.99 (d, J=6.9 Hz, 3H;
CH3), 0.98 (d, J=6.9 Hz, 3H; CH3), 0.96 (s, 9H; 3CH3), 0.93 (d, J=
Chem. Eur. J. 2011, 17, 10123 – 10134
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10129

J. Ardisson et al.
Trichloroacetylisocyanate (2.7 mL, 0.023 mmol, 1.05 equiv) was added to
a solution of the preceding alcohol (20 mg, 0.022 mmol, 1.0 equiv) in
CH2Cl2 (1.7 mL). After stirring for 15 min at 208C, the resulting mixture
was concentrated in vacuo and the residue taken up in MeOH (2.2 mL).
K2CO3 (17 mg, 0.12 mmol, 5.5 equiv) was added and the resulting solu-
tion was stirred for 1 h 15 min and then concentrated in vacuo and ex-
tracted with AcOEt. The organic layers were washed with water and
brine, dried over MgSO4, filtered, and the solvent removed under re-
duced pressure. The residue was purified by chromatography on silica gel
(cyclohexane/AcOEt 90:10 to 50:50) to give the title carbamate (12 mg,
58% yield) as a pale oil. [a]2D0 = +33.0 (c=1.2 in CHCl3); 1H NMR
(400.0 MHz, CDCl3): d=7.49–7.44 (m, 2H), 7.37–7.22 (m, 8H), 6.48 (d,
J=11.9 Hz, 1H), 5.62 (dd, J=11.9, 11.0 Hz, 1H), 5.60 (t, J=10.1 Hz,1H),
5.58 (s, 1H), 5.24 (t, J=10.1 Hz, 1H), 4.96 (d, J=10.1 Hz, 1H), 4.84 (dd,
J=10.1, 9.6 Hz, 1H), 4.76 (dd, J=6.4, 5.9 Hz, 1H), 4.72 (d, J=6.9 Hz,
1H), 4.62–4.57 (m, 2H; NH2), 4.56 (s, 2H; CH2), 4.51 (d, J=6.9 Hz, 1H),
4.05 (dd, J=11.7, 3.2 Hz, 1H), 3.83 (t, J=9.2 Hz, 1H), 3.73 (s, 3H; CH3),
3.33 (s, 6H; 2CH3), 3.21–3.13 (m, 2H), 3.08 (dd, J=5.9, 5.5 Hz, 1H),
2.85–2.78 (m, 2H), 2.54 (dqd, J=10.1, 6.4, 5.5 Hz, 1H), 1.98–1.87 (m,
2H), 1.85 (m, 1H), 1.78–1.60 (m, 4H), 1.54 (s, 3H; CH3), 1.22 (d, J=
7.3 Hz, 3H; CH3), 1.11 (d, J=6.9 Hz, 3H; CH3), 1.02 (d, J=6.9 Hz, 3H;
CH3), 0.92 (d, J=6.4 Hz, 3H; CH3), 0.90 (d, J=7.3 Hz, 3H; CH3), 0.88
(d, J=6.4 Hz, 3H; CH3), 0.88 (s, 9H; 3CH3), 0.56 (d, J=6.9 Hz, 3H;
CH3), 0.01 (s, 3H; CH3), ꢀ0.12 ppm (s, 3H; CH3); 13C NMR (100.5 MHz,
CDCl3): d=174.8 (C), 156.9 (C), 138.7 (C), 137.3 (C), 136.6 (CH), 133.5
(CH), 132.5 (C), 130.1 (CH), 129.5 (CH), 129.1 (CH), 128.4 (2CH), 128.3
(2CH), 128.2 (CH), 127.9 (2CH), 126.8 (CH), 125.8 (2CH), 99.6 (CH),
97.9 (CH2), 93.2 (CH2), 87.0 (CH), 82.2 (CH), 79.1 (CH), 77.7 (CH), 77.0
(CH), 66.3 (CH), 56.0 (CH3), 55.2 (CH3), 51.9 (CH3), 41.1 (CH), 39.0
(CH2), 37.9 (CH), 36.0 (CH2), 35.9 (CH), 35.3 (CH), 34.8 (CH), 34.7
(CH), 34.2 (CH), 26.1 (3CH3), 23.0 (CH3), 18.5 (C), 17.7 (CH3), 17.4
(CH3), 16.7 (CH3), 14.1 (CH3), 11.6 (CH3), 9.9 (CH3), 9.4 (CH3),
ꢀ3.5 ppm (2CH3); IR (film): n˜ =3376, 2961, 2930, 1728, 1460, 1147, 1094,
1035, 757 cmꢀ1; HRMS (ESI): m/z: calcd for C55H87NO11NaSi: 988.5946
[M+Na]+; found: 988.5957.
5.59–5.50 (m, 3H), 5.22 (dd, J=10.1, 9.2 Hz, 1H), 5.04 (d, J=9.2 Hz,
1H), 4.84 (dd, J=11.9, 9.2 Hz, 1H), 4.71 (d, J=6.4 Hz, 1H), 4.55 (s, 2H),
4.51 (d, J=6.4 Hz, 1H), 4.40–4.35 (m, 1H), 4.16 (dd, J=5.9, 5.5 Hz, 1H),
4.06 (dd, J=10.1, 3.2 Hz, 1H), 3.83 (m, 1H), 3.74 (s, 3H, CH3), 3.53–3.43
(m, 3H; CH, CH2), 3.33 (s, 6H; 2CH3), 3.09 (dd , J=5.9, 5.5 Hz, 1H),
2.99–2.79 (m, 3H), 2.64–2.54 (m, 1H), 2.18 (dd, J=12.3, 11.9 Hz, 1H),
1.99 (m, 1H), 1.90–1.78 (m, 3H), 1.70–1.60 (m, 2H), 1.60 (s, 3H; CH3),
1.25 (d, J=6.9 Hz, 3H; CH3), 0.97 (d, J=6.4 Hz, 3H; CH3), 0.94 (s;
3CH3), 0.97–0.90 (m, 9H; 3CH3), 0.88 (d , J=6.9 Hz, 3H; CH3), 0.74 (d,
J=6.9 Hz, 3H; CH3), 0.10 (s, 3H; CH3), 0.06 ppm (s, 3H; CH3);
13C NMR (100.5 MHz, CDCl3) d=174.6 (C), 140.9 (C), 138.6 (C), 136.9
(CH), 133.4 (CH), 132.2 (C), 130.2 (CH), 128.7 (CH), 128.2 (2CH), 128.1
(2CH), 128.0 (CH), 127.8 (2CH), 127.7 (2CH), 125.5 (2CH), 99.4 (CH),
97.5 (CH2), 93.0 (CH2), 86.5 (CH), 82.0 (CH), 77.6 (CH), 77.0 (CH), 74.7
(CH), 66.2 (CH), 55.8 (CH3), 55.0 (CH3), 51.7 (CH3), 40.9 (CH), 38.9
(CH2), 38.1 (CH2), 36.8 (CH), 35.7 (CH), 35.2 (CH), 34.3 (CH), 34.0
(CH), 33.8 (CH2), 31.4 (CH), 26.0 (3CH3), 21.7 (CH3), 18.3 (C), 17.8
(CH3), 17.1 (CH3), 16.0 (CH3), 13.2 (CH3), 11.5 (CH3), 9.9 (CH3), 9.1
(CH3), ꢀ3.3 (CH3), ꢀ3.6 ppm (CH3); IR (film): n˜ =3889, 2928, 2897,
2956, 1746, 1690, 1452, 1410, 1154, 1090, 1000, 735, 699 cmꢀ1
.
Trichloroacetylisocyanate (12.5 mL, 0.106 mmol, 1.05 equiv) was added to
a solution of the preceding alcohol (99 mg, 0.10 mmol, 1.0 equiv) in
CH2Cl2 (8 mL). After stirring for 15 min at 208C, the resulting mixture
was concentrated in vacuo and the residue taken up in MeOH (10 mL).
K2CO3 (81 mg, 0.58 mmol, 5.5 equiv) was added and the resulting solu-
tion was stirred for 1 h 15 min and then concentrated in vacuo and ex-
tracted with AcOEt. The organic layers were washed with water and
brine, dried over MgSO4, filtered, and the solvent removed under re-
duced pressure. The residue was purified by chromatography on silica gel
(cyclohexane/AcOEt 90:10 to 50:50) to give the corresponding carbamate
(27 mg, 27% yield) as
a
pale oil. [a]2D0 = +11.3 (c=0.5 in CHCl3);
1H NMR (400.0 MHz, CDCl3): d=7.52–7.45 (m, 2H), 7.35–7.25 (m, 6H),
7.25–7.15 (m, 2H), 6.64 (m, 1H), 6.32 (m, 1H), 5.62 (ddd, J=10.5, 7.8,
7.3 Hz, 1H,), 5.58 (s, 1H), 5.53 (t, J=10.5 Hz, 1H), 5.42 (dd, J=10.5,
10.1 Hz, 1H), 5.21 (dd, J=10.5, 10.1 Hz, 1H), 5.00 (d, J=9.6 Hz, 1H),
4.82 (t, J=10.1 Hz, 1H), 4.75–4.70 (m, 1H), 4.70 (d, J=6.4 Hz, 1H), 4.53
(s, 2H), 4.49 (d, J=6.4 Hz, 1H), 4.05 (dd, J=10.1, 3.2 Hz, 1H), 3.82 (t,
J=9.6 Hz, 1H), 3.73 (s, 3H; CH3), 3.48–3.43 (m, 1H), 3.38–3.30 (m, 2H),
3.32 (s, 6H; 2CH3), 3.07 (t, J=5.5 Hz, 1H), 2.96 (dqd, J=10.1, 6.9,
2.7 Hz, 1H), 2.87–2.75 (qd, J=6.9, 3.2 Hz, 1H), 2.87–2.75 (dqd, J=10.5,
6.9, 5.5 Hz, 1H), 2.54 (dqd, J=9.6, 7.3, 5.5 Hz, 1H), 2.16 (dd, J=12.5,
12.4 Hz, 1H), 2.00–1.80 (m, 4H), 1.79–1.60 (m, 2H), 1.59 (s, 3H; CH3),
1.23 (d, J=6.9 Hz, 3H; CH3), 1.00 (d, J=6.9 Hz, 3H; CH3), 0.99 (d, J=
6.9 Hz, 3H; CH3), 0.96 (d, J=6.9 Hz, 3H; CH3), 0.92 (s, 9H; 3CH3), 0.91
(d, J=7.3 Hz, 3H; CH3), 0.87 (d, J=6.4 Hz, 3H; CH3), 0.73 (d, J=
6.4 Hz, 3H; CH3), 0.11 (s, 3H; CH3), 0.05 ppm (s, 3H; CH3); 13C NMR
(100.5 MHz, CDCl3) d=174.8 (C), 163.5 (C), 157.0 (C), 138.7 (C), 136.8
(CH), 132.3 (CH), 132.1 (C), 130.3 (CH), 128.9 (CH), 128.6 (CH), 128.4
(2CH), 128.3 (2CH), 128.2 (CH), 127.8 (2CH), 125.9 (CH), 125.7 (2CH),
99.6 (CH), 97.7 (CH2), 93.2 (CH2), 86.8 (CH), 82.2 (CH), 78.7 (CH5),
77.7 (CH), 77.3 (CH), 66.3 (CH), 55.9 (CH3), 55.2 (CH3), 51.8 (CH3), 41.1
(CH), 39.0 (CH2), 37.6 (CH), 35.9 (CH), 36.4 (CH), 35.8 (CH), 35.3
(CH2), 34.3 (CH), 34.1 (CH), 33.7 (CH2), 26.1 (3CH3), 23.0 (CH3), 18.4
(C), 17.6 (CH3), 17.3 (CH3), 16.4 (CH3), 13.2 (CH3), 11.6 (CH3), 10.2
(CH3), 9.3 (CH3), ꢀ3.7 (CH3), ꢀ3.3 ppm (CH3); IR (film): n˜ =3354, 2957,
2930, 2889, 2856, 1726, 1600, 1459, 1439, 1375, 1146, 1110, 1093,
HCl (4n, 1.2 mL) was added to a solution of the preceding carbamate
(12 mg, 0.012 mmol, 1.0 equiv) in THF (1.2 mL). The resulting mixture
was stirred 72 h at 208C and then solid NaHCO3 was added and extract-
ed three times with AcOEt. The organic layers were washed with water
and brine, dried over MgSO4, filtered, and the solvent removed under re-
duced pressure. The residue was purified by chromatography on silica gel
(CH2Cl2/MeOH 100:0 to 70:30) to give the title compound 3 (7 mg, 91%
yield). [a]2D0 = +3.2 (c=0.7 in MeOH); 1H NMR (400.0 MHz, CD3CN):
d=7.34–7.25 (m, 4H), 7.25–7.18 (m, 1H), 6.50 (d, J=11.9 Hz, 1H), 5.74
(dd, J=10.5, 10.1 Hz, 1H), 5.64 (dd, J=11.9, 11.4 Hz, 1H), 5.49 (t, J=
10.1 Hz, 1H), 5.15–5.05 (m, 1H), 4.90 (d, J=10.1 Hz, 1H), 4.64 (dd, J=
9.2, 3.2 Hz, 1H), 4.46–4.38 (m, 4H), 3.59 (t, J=4.6 Hz, 1H), 3.56–3.50
(m, 1H), 3.19–3.12 (m, 1H), 3.10–3.08 (m, 1H), 2.71–2.61 (m, 1H), 2.50
(m, 1H), 2.31–2.20 (m, 1H), 1.81–1.40 (m, 10H; 6CH, 2CH2), 1.53 (s,
3H; CH3), 1.14 (d, J=7.3 Hz, 3H; CH3), 1.08 (d, J=6.9 Hz, 3H; CH3),
1.02 (d, J=7.3 Hz, 3H; CH3), 0.98 (d, J=6.9 Hz, 3H; CH3), 0.90 (d, J=
6.4 Hz, 3H; CH3), 0.66 (d, J=6.9 Hz, 3H; CH3), 0.34 ppm (d, J=6.4 Hz,
3H; CH3); 13C NMR (100.5 MHz, CD3CN): d=174.7 (C), 158.4 (C),
138.3 (C), 134.2 (CH), 133.9 (CH), 133.8 (C), 130.9 (CH), 130.3 (CH),
129.4 (CH), 129.3 (5CH), 79.8 (CH), 79.7 (CH), 77.2 (CH), 75.4 (CH),
73.1 (CH), 63.1 (CH), 43.9 (CH), 42.1 (CH2), 38.5 (CH), 37.7 (CH), 36.8
(CH, CH2), 35.8 (CH), 34.2 (CH), 34.1 (CH), 23.6 (CH3), 20.0 (CH3),
18.2 (2CH3), 15.8 (CH3), 15.7 (CH3), 13.0 (CH3), 9.1 ppm (CH3); IR
(film): n˜ =3364, 2961, 2930, 2868, 1706, 1456, 1396, 1387, 1034, 737,
702 cmꢀ1; HRMS (ESI): m/z: calcd for C37H57NO8Na: 666.3982 [M+Na]+;
found: 666.3990.
1032 cmꢀ1
; HRMS (ESI): m/z: calcd for C56H89NO11NaSi: 1002.6103
[M+Na]+; found: 1002.6097.
HCl (4n, 2.7 mL) was added to a solution of preceding carbamate
(27 mg, 0.027 mmol, 1.0 equiv) in THF (2.7 mL). The resulting mixture
was stirred for 72 h at 208C and then solid NaHCO3 was added and ex-
tracted three times with AcOEt. The organic layers were washed with
water and brine, dried over MgSO4, filtered, and the solvent removed
under reduced pressure. The residue was purified by chromatography on
silica gel (CH2Cl2/MeOH 95:5 to 60:40) to give the title 22-benzyl disco-
22-Benzyl discodermolide 4: p-Toluenesulfonic acid (7 mg, 0.037 mmol,
0.28 equiv) was added to a solution of compound 24 (140 mg, 0.13 mmol,
1.0 equiv) in MeOH (15 mL) at 08C. After stirring for 1 h at 08C, trie-
thylamine was added to the reaction mixture (0.3 equiv) and the solvent
was removed under reduced pressure. The residue was purified by chro-
matography on silica gel (cyclohexane/AcOEt, 95:5 to 60:40) to give the
expected alcohol (99 mg, 80% yield). 1H NMR (400.0 MHz, CDCl3): d=
7.50–7.43 (m, 2H), 7.35–7.29 (m, 6H), 7.23–7.17 (m, 2H), 5.59 (s, 1H),
dermolide
4
(10 mg, 56% yield). [a]2D0 = +4.6 (c=1.0 in MeOH);
1H NMR (400.0 MHz, CDCl3): d=7.33–7.14 (m, 5H), 5.66–5.58 (m, 1H),
5.51 (dd, J=11.0, 7.8 Hz, 1H), 5.45–5.34 (m, 2H), 5.16 (d, J=9.6 Hz,
1H), 4.78–4.67 (m, 3H), 4.64–59 (m, 2H), 3.75–3.67 (m, 2H), 3.44 (dd,
10130
www.chemeurj.org
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 10123 – 10134

Discodermolide Analogues
FULL PAPER
J=15.5, 7.8 Hz, 1H), 3.38 (dd, J=15.5, 8.7 Hz, 1H), 3.28 (dd, J=5.9,
3.7 Hz, 1H), 3.19 (dd, J=6.4, 4.6 Hz, 1H), 3.00–2.91 (m, 1H), 2.83–2.75
(m, 1H), 2.74–2.68 (m, 1H), 2.66–2.58 (m, 1H), 2.58–2.45 (m, 1H), 2.03–
1.80 (m, 9H; 5CH, 2CH2), 1.65 (s, 3H; CH3), 1.30 (d, J=7.3 Hz, 3H;
CH3), 1.08 (d, J=6.9 Hz, 3H; CH3), 1.04–0.95 (m, 12H; 4CH3), 0.83 ppm
(d, J=5.5 Hz, 3H; CH3); 13C NMR (100.5 MHz, CD3CN): d=174.7 (C),
157.2 (C), 141.1 (C), 133.0 (CH), 132.9 (CH), 131.5 (C), 130.3 (CH),
128.9 (CH), 128.6 (2CH), 128.4 (2CH), 126.0 (CH), 117.0 (CH), 78.8
(CH), 78.4 (CH), 76.8 (CH), 75.4 (CH), 72.3 (CH), 62.7 (CH), 43.1 (CH)
, 41.4 (CH2), 37.6 (CH), 36.1 (CH), 35.6 (CH), 35.5 (CH, CH2), 33.6,
(CH2), 33.4 (CH), 32.7 (CH), 22.5 (CH3), 18.6 (CH3), 17.4 (CH3), 16.4
(CH3), 14.8 (CH3), 14.3 (CH3), 12.1 (CH3), 8.4 ppm (CH3); IR (film): n˜ =
3384, 2984, 2932, 2877, 2859, 1712, 1698, 1454, 1390, 1387, 1285, 1100,
1031, 739, 700 cmꢀ1; HRMS (ESI): m/z: calcd for C38H59O8NaN: 680.4138
[M+Na]+; found: 680.4133.
13C NMR (100.5 MHz, CDCl3): d=174.8 (C), 157.1 (C), 141.7 (C), 138.7
(CH), 137.7 (C), 133.5 (CH), 132.0 (CH), 129.8 (CH), 128.7 (CH), 128.3
(CH), 128.2 (CH), 127.9 (2CH), 125.8 (2CH), 117.9 (CH2), 99.7 (CH),
97.7 (CH2), 93.1 (CH2), 86.8 (CH), 82.2 (CH), 78.8 (CH), 77.7 (CH), 77.0
(CH), 66.3 (CH), 56.0 (CH3), 55.2 (CH3), 51.9 (CH3), 41.2, 39.0, 37.9,
35.9, 35.8, 35.4, 34.4, 33.6, 31.6 (9CH, 2CH2, C-2, C-4, C-6, C-10, C-12,
C-15, C-16, C-18, C-20, CHACHTUNTRGNEUN(G CH3)2), 26.2 (3CH3), 18.5 (C), 22.6 (CH3),
21.9 (CH3), 17.5 (CH3), 17.1 (CH3), 15.9 (CH3), 13.7 (CH3), 11.7 (CH3),
9.4 (CH3), 9.3 (7CH3), ꢀ3.3 (CH3), ꢀ3.8 ppm (CH3); IR (film): n˜ =3440,
3355, 2998, 2933, 1730, 1721, 1460, 1450, 1409, 1395, 1094, 1034 cmꢀ1
;
HRMS (ESI): m/z: calcd for C54H93O11NNaSi: 982.6415 [M+Na]+; found:
982.6437.
HCl (4n, 0.9 mL) was added to a solution of preceding carbamate (8 mg,
0.008 mmol, 1.0 equiv) in THF (0.9 mL). The resulting mixture was
stirred for 72 h at 208C and then solid NaHCO3 was added and the mix-
ture extracted three times with AcOEt. The organic layers were washed
with water and brine, dried over MgSO4, filtered, and the solvent re-
moved under reduced pressure. The residue was purified by chromatog-
raphy on silica gel (CH2Cl2/MeOH 95:5 to 70:30) to give 14-isopropyl
discodermolide 5 (2 mg, 50% yield). 1H NMR (400.0 MHz, CDCl3): d=
6.64 (ddd, J=17.4, 10.5, 10.1 Hz, 1H), 6.05 (dd, J=11.0, 10.5 Hz, 1H),
5.55 (dd, J=11.0, 7.8 Hz, 1H), 5.45 (dd, J=12.4, 11.0 Hz, 1H), 5.37 (dd,
J=11.0, 10.1 Hz, 1H), 5.25 (d, J=17.4 Hz, 1H), 5.20 (d, J=10.1 Hz, 1H),
5.14 (d, J=10.5 Hz, 1H), 4.80–4.76 (m, 1H), 4.72 (dd, J=6.9, 4.1 Hz,
1H), 4.70–4.59 (m, 4H), 3.80–3.72 (m, 2H), 3.30 (t, J=5.0 Hz, 1H), 3.21
(dd, J=7.3, 4.6 Hz, 1H), 3.06–2.98 (m, 1H), 2.88–2.80 (m, 1H), 2.75–2.62
(m, 2H), 2.16 (hept, J=7.8 Hz, 1H), 2.00–1.85 (m, 9H; 5CH, 2CH2),
1.33 (d, J=7.3 Hz, 3H; CH3), 1.09 (d, J=6.9 Hz, 3H; CH3), 1.06 (d, J=
7.3 Hz, 3H; CH3), 1.05 (d, J=6.0 Hz, 3H; CH3), 1.03 (d, J=6.9 Hz, 3H;
CH3), 1.01 (d, J=6.9 Hz, 6H; 2CH3), 0.96 (d, J=6.4 Hz, 3H; CH3),
0.85 ppm (d, J=6.0 Hz, 3H; CH3); HRMS (ESI): m/z: calcd for
C35H59O8NNa: 644.4138 [M+Na]+; found: 644.4133.
14-Isopropyl discodermolide 5: p-Toluenesulfonic acid (2 mg,
0.008 mmol, 0.28 equiv) was added to a solution of compound 33 (30 mg,
0.029 mmol, 1.0 equiv) in MeOH (4 mL) at 08C. After stirring for 1 h at
08C, triethylamine was added to the reaction mixture (0.3 equiv) and the
solvent removed under reduced pressure. The residue was purified by
chromatography on silica gel (cyclohexane/AcOEt 95:5 to 70:30) to give
expected alcohol (19 mg, 72% yield). [a]2D0 = +8.4 (c=0.38 in CHCl3);
1H NMR (400.0 MHz, CDCl3): d=7.50–7.42 (m, 2H), 7.38–7.27 (m, 3H),
6.63 (ddd, J=16.9, 11.0, 10.5 Hz, 1H), 6.16 (dd, J=11.0, 10.5 Hz, 1H),
5.59 (s, 1H), 5.53 (dd, J=10.5, 10.1 Hz, 1H), 5.33 (t, J=10.5 Hz, 1H),
5.27–5.23 (m, 1H), 5.20 (d, J=16.9 Hz, 1H), 5.16 (d, J=10.5 Hz, 1H),
5.05 (d, J=9.6 Hz, 1H), 4.85 (dd, J=10.1, 9.6 Hz, 1H), 4.72 (d, J=
6.9 Hz, 1H), 4.50 (s, 2H; CH2), 4.49 (d, J=6.9 Hz, 1H), 4.06 (dd, J=10.1,
2.7 Hz, 1H), 3.84 (dd, J=10.1, 9.2 Hz, 1H), 3.73 (s, 3H; CH3), 3.62 (dd,
J=5.9, 3.2 Hz, 1H), 3.35–3.32 (m, 1H), 3.34 (s, 3H; CH3), 3.31 (s, 3H;
CH3), 3.08 (t , J=5.5 Hz, 1H), 2.87–2.78 (m, 3H), 2.65–2.53 (m, 1H),
2.19–2.06 (m, 2H), 1.95 (dd, J=14.2, 12.4 Hz, 1H), 1.90–1.79 (m, 2H),
1.72–1.60 (m, 3H), 1.44 (s, 1H), 1.23 (d, J=6.9 Hz, 3H; CH3), 1.02–0.87
(m, 12H; 6CH3), 0.93 (s, 9H; 3CH3), 0.88 (d, J=6.9 Hz, 3H; CH3), 0.75
(d, J=6.9 Hz, 3H; CH3), 0.10 ppm (s, 6H; 2CH3); 13C NMR (100.5 MHz,
CDCl3): d=175.1 (C), 142.5 (C), 139.0 (C), 138.0 (CH), 134.9 (CH),
132.3 (CH), 131.4 (CH), 129.0 (CH), 128.5 (CH), 128.2 (2CH), 126.1
(2CH), 127.2 (CH), 118.8 (CH2), 99.9 (CH), 98.0 (CH2), 93.4 (CH2), 87.0
(CH), 82.5 (CH), 79.2 (CH), 77.6 (CH), 76.3 (CH), 66.5 (CH), 56.3
(CH3), 55.5 (CH3), 52.2 (CH3), 41.1 (CH), 39.3 (CH2), 38.3 (CH), 36.5
(CH), 35.6 (CH2), 35.5 (CH), 35.1 (CH), 34.4 (CH), 33.9 (CH), 32.3
(CH), 26.5 (3CH3), 18.5 (C), 22.9 (CH3), 22.4 (CH3), 18.7 (CH3), 17.5
(CH3), 16.1 (CH3), 13.9 (CH3), 11.9 (CH3), 9.7 (CH3), 9.5 (CH3), ꢀ2.9
(CH3), ꢀ3.4 ppm (CH3); IR (film): n˜ =3055, 2956, 2931, 2909, 1742, 1736,
Phenol discodermolide 6: Compound 39 (16 mg, 0.017 mmol, 1.0 equiv)
was diluted in MeOH (2 mL) at 08C and p-toluenesulfonic acid (0.9 mg,
0.0047 mmol, 0.28 equiv) was added. After stirring for 1 h at 08C, trie-
thylamine was added to the reaction mixture (0.3 equiv) and the solvent
removed under reduced pressure. The residue was purified by chroma-
tography on silica gel (cyclohexane/Et2O 95:5 to 60:40) to give the ex-
pected alcohol (8 mg, 58% yield). [a]2D0 = +20.8 (c=0.8 in CHCl3);
1H NMR (400.0 MHz, CDCl3): d=7.13 (t, J=7.8 Hz, 1H), 6.84 (d, J=
7.8 Hz, 1H), 6.76 (s, 1H), 6.68 (d, J=7.8 Hz, 1H), 6.66 (ddd, J=16.5,
11.0, 10.5 Hz, 1H), 6.13 (t, J=11.0 Hz, 1H), 5.49 (dd, J=10.5, 10.1 Hz,
1H), 5.33 (dd, J=11.0, 10.1 Hz, 1H), 5.25 (d, J=16.5 Hz, 1H), 5.24 (t,
J=10.5 Hz, 1H), 5.16 (d, J=10.5 Hz, 1H), 4.89 (d, J=10.1 Hz, 1H), 4.61
(s, 2H), 4.59 (d, J=6.4 Hz, 1H), 4.61–4.55 (m, 1H), 4.36 (d, J=6.4 Hz,
1H), 3.62 (dd, J=5.5, 3.2 Hz, 1H), 3.40 (s, 3H; CH3), 3.33 (ddd, J=8.7,
3.2, 2.7 Hz, 1H), 3.16 (d, J=8.7 Hz, 1H), 3.02 (s, 3H; CH3), 2.93 (dd, J=
6.4, 5.0 Hz, 1H), 2.85–2.76 (m, 3H), 2.75 (dd, J=7.8, 5.0 Hz, 1H), 2.58–
2.52 (m, 1H), 2.21 (dd, J=12.4, 11.9 Hz, 1H), 1.95–1.85 (m, 1H), 1.82–
1.75 (m, 2H), 1.60 (s, 3H; CH3), 0.98 (s, 18H; 6CH3), 0.99–0.92 (m;
4CH3), 0.74 (d, J=6.9 Hz; CH3), 0.18 (s, 6H; 2CH3), 0.09 ppm (s, 6H;
2CH3); 13C NMR (100.5 MHz, CDCl3): d=155.3 (C), 140.2 (C), 137.0
(CH), 134,7 (CH), 132.4 (CH), 132.0 (CH), 131.0 (C), 130.4 (CH), 128.9
(CH), 128.7 (CH), 122.7 (CH), 121.7 (CH), 118.5 (CH2), 117.7 (CH), 97.7
(CH2), 93.0 (CH2), 87.0 (CH), 78.9 (CH), 76.2 (CH), 71.9 (CH), 55.9
(CH3), 54.9 (CH3), 42.0 (CH2), 37.9 (CH), 36.5 (CH2), 36.3 (CH), 35.6
(CH), 34.6 (CH), 34.4 (CH), 26.6 (3CH3), 26.2 (3CH3), 23.3 (CH3), 18.4
(2C), 18.1 (CH3), 17.1 (CH3), 16.9 (CH3), 13.4 (CH3), 9.4 (CH3), ꢀ3.2
(2CH3), ꢀ3.7 (CH3), ꢀ4.4 ppm (CH3); IR (film): n˜ =3373, 2957, 2929,
1460, 1453, 1433, 1377, 1146, 1093, 1013, 836, 772 cmꢀ1
.
Trichloroacetylisocyanate (2.6 mL, 0.022 mmol, 1.05 equiv) was added to
a solution of preceding alcohol (19 mg, 0.021 mmol, 1.0 equiv) in CH2Cl2
(1.7 mL). After stirring for 15 min at 208C, the resulting mixture was con-
centrated in vacuo and the residue taken up in MeOH (2.1 mL). K2CO3
(16 mg, 0.45 mmol, 5.5 equiv) was added and the resulting solution was
stirred for 1 h 15 min and then concentrated in vacuo and extracted with
AcOEt. The organic layers were washed with water and brine, dried over
MgSO4, filtered, and the solvent removed under reduced pressure. The
residue was purified by chromatography on silica gel (cyclohexane/
AcOEt 90:10 to 50:50) to give the title carbamate (8 mg, 40% yield) as a
1
pale oil. [a]2D0 = +20.7 (c=0.80 in CHCl3); H NMR (400.0 MHz, CDCl3):
d=7.50–7.42 (m, 2H), 7.37–7.27 (m, 3H), 6.60 (ddd, J=16.5, 11.0,
10.5 Hz, 1H), 6.04 (t, J=11.0 Hz, 1H), 5.58 (s, 1H), 5.53 (t, J=10.5 Hz,
1H, H-9, m, 1H), 5.39 (dd, J=11.0, 10.5 Hz, 1H), 5.25–5.11 (m, 4H),
5.03 (d, J=10.1 Hz, 1H), 4.85 (dd, J=10.1, 8.7 Hz, 1H), 4.71 (d, J=
6.4 Hz, 1H), 4.71–4.67 (m, 1H), 4.51 (s, 2H; CH2), 4.50 (d, J=6.4 Hz,
1H), 4.05 (dd, J=11.0, 2.7 Hz, 1H), 3.84 (dd, J=10.1, 9.6 Hz, 1H), 3.73
(s, 3H; CH3), 3.43 (dd, J=4.6, 4.1 Hz, 1H), 3.32 (s, 3H; CH3), 3.30 (s,
3H; CH3), 3.05 (t, J=5.5 Hz, 1H), 3.03–2.96 (m, 1H), 2.87–2.78 (m, 2H),
2.58 (dqd, J=10.1, 6.9, 5.5 Hz, 1H), 2.12 (hept, J=6.4 Hz), 2.03–1.67 (m,
7H; 2CH2, 3CH), 1.23 (d, J=7.3 Hz, 3H; CH3), 1.00 (d, J=6.9 Hz, 3H;
CH3), 0.99 (d, J=6.9 Hz, 3H; CH3), 0.96–0.90 (m, 9H; 3CH3), 0.93 (s,
9H; 3CH3), 0.89 (d, J=6.9 Hz, 3H; CH3), 0.88 (d, J=6.9 Hz, 3H; CH3),
0.73 (d, J=6.9 Hz, 3H; CH3), 0.11 (s, 3H; CH3), 0.08 ppm (s, 3H; CH3);
2857, 1148, 1096, 1031, 1004, 838 cmꢀ1
.
Trichloroacetylisocyanate (2.3 mL, 0.019 mmol, 1.05 equiv) was added to
a solution of preceding alcohol (15 mg, 0.018 mmol, 1.0 equiv) in CH2Cl2
(1.4 mL). After stirring for 15 min at 208C, the resulting mixture was con-
centrated in vacuo and the residue was taken up in MeOH (1.8 mL).
K2CO3 (14 mg, 0.10 mmol, 5.5 equiv) was added and the resulting solu-
tion was stirred for 1 h 15 min and then concentrated in vacuo and ex-
tracted with AcOEt. The organic layers were washed with water and
brine, dried over MgSO4, filtered, and the solvents were removed under
Chem. Eur. J. 2011, 17, 10123 – 10134
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10131

J. Ardisson et al.
reduced pressure. The residue was purified by chromatography on silica
gel (cyclohexane/AcOEt 90:10 to 50:50) to give the title carbamate
(9 mg, 58% yield). [a]D20 = +31.7 (c=0.9 in CHCl3); 1H NMR
(400.0 MHz, CDCl3): d=7.15 (t, J=7.8 Hz, 1H), 6.84 (d, J=7.8 Hz, 1H),
6.73 (s, 1H), 6.72 (d, J=7.8 Hz, 1H), 6.60 (ddd, J=16.5, 11.0, 10.1 Hz,
1H), 6.03 (dd, J=11.0, 10.5 Hz, 1H), 5.48 (dd, J=10.5, 10.1 Hz, 1H),
5.34 (dd, J=10.5, 10.1 Hz, 1H), 5.25–5.22 (m, 1H), 5.22 (d, J=16.5 Hz,
1H), 5.19 (dd, J=10.5, 10.1 Hz, 1H), 5.13 (d, J=10.1 Hz, 1H), 4.73 (d,
J=6.9 Hz, 1H), 4.73–4.64 (m, 1H), 4.64 (d, J=6.9 Hz, 1H), 4.62 (d, J=
6.9 Hz, 1H), 4.62–4.53 (m, 3H; 1CH, 1CH2), 4.45 (d, J=6.9 Hz, 1H),
3.46 (s, 3H; CH3), 3.48 (dd, J=6.4, 3.2 Hz, 1H), 3.18 (s, 3H; CH3), 2.92–
2.87 (m, 2H), 2.81–2.73 (m, 2H), 2.69 (dd, J=13.7, 5.9 Hz, 1H), 2.54
(dqm, J=10.1, 6.9 Hz, 1H), 2.18 (t, J=12.4 Hz, 1H), 2.01–1.87 (m, 2H),
1.70–1.66 (m, 1H), 1.58 (s, 3H; CH3), 0.99 (d, J=6.9 Hz; CH3), 0.98 (d,
J=6.9 Hz; CH3), 0.93 (d, J=6.9 Hz; CH3), 0.92 (s, 18H; 6CH3), 0.89 (d,
J=6.9 Hz; CH3), 0.71 (d, J=6.9 Hz; CH3), 0.08 (s, 6H; 2CH3), 0.07 ppm
(s, 6H; 2CH3); 13C NMR (100.5 MHz, CDCl3) d=157.3 (C), 156.0 (C),
139.9 (C), 137.0 (CH), 134.0 (CH), 132.5 (CH), 132.1 (C), 130.5 (CH),
130.1 (CH), 129.6 (CH), 128.7 (CH), 122.1 (CH), 117.9 (CH2), 116.2
(CH), 113.7 (CH), 97.3 (CH2), 93.0 (CH2), 87.2 (CH), 78.9 (CH), 77.3
(CH), 71.3 (CH), 56.0 (CH3), 55.2 (CH3), 41.7 (CH2), 37.8 (CH), 37.3
(CH2), 35.5 (CH), 34.9 (CH), 34.4 (CH), 34.3 (CH), 26.2 (6CH3), 22.7
(CH3), 18.5 (2C), 17.8 (CH3), 17.3 (CH3), 17.1 (CH3), 12.7 (CH3), 10.1
(CH3), ꢀ3.2 (2CH3), ꢀ3.3 (CH3), ꢀ3.4 ppm (CH3); IR (film): n˜ =3353,
2960, 2930, 2885, 1720, 1711, 1455, 1096, 1031 cmꢀ1. HRMS (ESI): m/z:
calcd for C48H85O8NNaSi2: 882.5711 [M+Na]+; found: 566.3447.
of untreated cells comprising C 20 mL of dilution medium containing 1%
of the product of ethanol. (GI%=(RꢀB)ꢃ100/C%). The IC50 values are
calculated by using the equation 205, XLFit software (IDBS company,
UK) by nonlinear regression analysis with the Marquardt algorithm.[26]
Acknowledgements
We thank Sanofi-Aventis for fellowships for E.d.L. and A.A.
[1] a) S. P. Gunasekera, R. E. Longley, R. A. Isbrucker, J. Nat. Prod.
2002, 65, 1830–1837; b) S. P. Gunasekera, M. Gunasekera, R. E.
Longley, G. K. Schulte, J. Org. Chem. 1990, 55, 4912–4915; Correc-
tion: S. P. Gunasekera, M. Gunasekera, R. E. Longley, G. K. Schulte,
J. Org. Chem. 1991, 56, 1346; c) S. P. Gunasekera, G. K. Paul, R. E.
Longley, R. A. Isbruker, S. A. Pomponi, J. Nat. Prod. 2002, 65,
1643–1648.
[2] a) A. Canales, R. Matesanz, N. M. Gardner, J. M. Andreu, I. Pater-
son, J. F. Diaz, J. Jimenez-Barbero, Chem. Eur. J. 2008, 14, 7557–
7569; b) V. M. Sꢄnchez-Pedregal, K. Kubicek, J. Meiler, I. Lyothier,
I. Paterson, T. Carlomagno, Angew. Chem. 2006, 118, 7548–7554;
Angew. Chem. Int. Ed. 2006, 45, 7388–7394; c) S. Xia, C. S. Kenesky,
P. V. Rucker, A. B. Smith III, G. A. Orr, S. B. Horwitz, Biochemistry
2006, 45, 11762–11775; d) R. M. Bluey, I. Barasoain, E. Jackson, A.
Meyer, P. Giannakakou, I. Paterson, S. Mooberry, J. M. Andreu, J. F.
Diaz, Chem. Biol. 2005, 12, 1269–1279; e) S. Honore, K. Kamath, D.
Braguer, L. Wilson, C. Briand, M. A. Jordan, Mol. Cancer Ther.
2003, 2, 1303–1311; f) L. He, G. A. Orr, S. B. Horwitz, Drug Discov-
ery Today 2001, 6, 1153–1164; g) L. He, H. Y. Chia-Ping, S. B. Hor-
witz, Mol. Cancer Ther. 2001, 1, 3–10; h) L. A. Martello, M. J. La-
Marche, L. He, T. J. Beauchamp, A. B. Smith III, S. B. Horwitz,
Chem. Biol. 2001, 8, 843–855; i) M. Kalesse, ChemBioChem 2000, 1,
171–175; j) R. J. Kowalski, P. Giannakakou, S. P. Gunasekera, R. E.
Longley, B. W. Day, E. Hamel, Mol. Pharmacol. 1997, 52, 613–622;
k) E. ter Haar, R. J. Kowalski, E. Hamel, C. M. Lin, R. E. Longley,
S. P. Gunasekera, H. S. Rosenkranz, B. W. Day, Biochemistry 1996,
35, 243–250; l) R. Balachandran, E. ter Haar, M. J. Welsh, S. G.
Grant, B. W. Day, Anti-Cancer Drugs 1998, 9, 67–76.
Preceding carbamate (9 mg, 0.010 mmol, 1.0 equiv) was dissolved in
MeOH (1 mL). HCl (4n, 1 mL) was added and the resulting mixture was
stirred for 24 h at 208C and then solid NaHCO3 was added. The reaction
mixture was extracted three times with AcOEt. The organic layers were
washed with water and brine, dried over MgSO4, filtered, and the solvent
removed under reduced pressure. The residue was purified by chroma-
tography on silica gel (CH2Cl2/MeOH 95:5 to 80:20) to give phenol dis-
codermolide
6
(5 mg, 88% yield). [a]2D0 = +7.54 (c=0.5 in CHCl3);
1H NMR (400.0 MHz, CDCl3): d=7.16 (t, J=8.2 Hz, 1H), 6.77–6.70 (m,
3H), 6.61 (ddd, J=16.9, 10.5, 10.1 Hz, 1H), 6.04 (dd, J=11.0, 10.5 Hz,
1H), 5.52 (d, J=8.2 Hz, 1H), 5.33 (dd, J=11.0, 9.6 Hz, 1H), 5.23 (d, J=
16.9 Hz, 1H), 5.21 (d, J=8.2 Hz, 1H), 5.13 (d, J=10.1 Hz, 1H), 5.08 (d,
J=10.1 Hz, 1H), 4.72 (dd, J=9.2, 3.2 Hz, 1H), 4.70–4.62 (m, 3H; 1CH,
1CH2), 3.40 (dd, J=9.2, 2.7 Hz, 1H), 3.36 (dd, J=5.5, 2.7 Hz, 1H), 3.14
(t, J=5.9 Hz, 1H), 3.01–2.97 (m, 1H), 2.82–2.63 (m, 2H), 2.56–2.48 (m,
1H), 2.20–2.10 (m, 2H), 2.00–1.90 (m, 2H), 1.66 (s, 3H; CH3), 1.07–0.88
(m; 4CH3), 0.71 ppm (d, J=5.5 Hz; CH3); 13C NMR (100.5 MHz,
CDCl3): d=157.4 (C), 139.4 (C), 135.3 (C), 133.8 (CH), 133.4 (C), 132.2
(CH), 131.8 (CH), 130.1 (CH), 129.7 (CH), 129.4 (CH), 129.3 (CH),
121.3 (CH), 118.0 (CH2), 115.8 (CH), 114.1 (CH), 79.5 (CH), 77.6 (CH),
76.2 (CH), 68.6 (CH), 44.0 (CH2)„ 42.9 (CH), 37.1 (CH2), 36.5 (CH), 36.2
(CH), 34.7 (CH), 32.0 (CH), 23.0 (CH3), 18.9 (CH3), 17.4 (CH3), 17.1
(CH3), 12.1 (CH3), 9.3 ppm (CH3); IR (film): n˜ =3360, 2350, 2341, 1620,
[3] L. E. Klein, B. S. Freeze, A. B. Smith III, S. B. Horwitz, Cell Cycle
2005, 4, 501–507.
[4] a) M. Khrapunovich-Baine, V. Menon, P. Verdier-Pinard, A. B.
Smith III; R. H. Angeletti, A. Fiser, S. B. Horwitz, H. Xiao, Bio-
chemistry 2009, 48, 11664–11677; R. H. Angeletti, A. Fiser, S. B.
Horwitz, H. Xiao, Biochemistry 2009, 48, 11664–11677; b) G. S.
Huang, L. Lopez-Barcons, B. S. Freeze, A. B. Smith III, G. L. Gold-
berg, S. B. Horwitz, H. M. McDaid, Clin. Cancer Res. 2006, 12, 298–
304; c) L. A. Martello, H. M. McDaid, D. L. Regl, C.-P. H. Yang, D.
Meng, T. R. R. Pettus, M. D. Kaufman, H. Arimoto, S. J. Danishef-
sky, A. B. Smith III, S. B. Horwitz, Clin. Cancer Res. 2000, 6, 1978–
1987.
[5] A. Mita, C. Lockhart, T. L. Chen, K. Bocinski, J. Curtright, W.
Cooper, L. Hammond, M. Rothenberg, E. Rowinsky, S. Sharma, J.
Clin. Oncol. 2004, 22, 133S–133S (14S—ASCO Annual Meeting
Proceedings, Post-Meeting Edition), abstract 2025.
[6] For instance: a) I. Paterson, G. J. Naylor, N. M. Gardner, E.
Guzman, A. E. Wright, Chem. Asian J. 2011, 6, 459–473; b) I. Pater-
son, G. J. Naylor, T. Fujita, E. Guzman, A. E. Wright, Chem.
Commun. 2010, 46, 261–263; c) K. Prantz, J. Mulzer, Chem. Eur. J.
2010, 16, 485–506; d) Y. Fan, E. M. Schreiber, B. W. Day, J. Nat.
Prod. 2009, 72, 1748–1754; e) X. Mollat du Jourdain, M. Noshi, P. L.
Fuchs, Org. Lett. 2009, 11, 543–545; f) H. Cao, K. A. Parker, Org.
Lett. 2008, 10, 1353–1356.
1434, 1396, 668 cmꢀ1
; HRMS (ESI): m/z: calcd for C35H59O8NNa:
566.3457 [M+Na]+; found: 566.3447.
Antiproliferative activity of discodermolide analogues 2–6: The antiproli-
ferative activity of discodermolide analogues 2–6 was determined by
measuring the inhibition of cell proliferation of HCT116, MDA-A1, and
MDA-MB-231 cells.
The cells were seeded in cell culture medium at a concentration of 10,000
cells per well in 0.17 mL of medium, and 20 mL of test product at various
concentrations and 10 mL of thymidine [methyl-14C] (100 mCimLꢀ1—spe-
cific activity 47.90 mCimmolꢀ1, NEN Technologies, Reference batch
technologies NEC568 3550–001) were added; then the cells were incubat-
ed at 378C and 5% CO2. Medium used for growing HCT116 cells:
DMEM 2 mm l-glutamine, 200 IUmLꢀ1 penicillin, 200 mgmLꢀ1 strepto-
mycin, and 10% (VVꢀ1) fetal calf serum (Life Technologies).
After 96 h, the incorporation of 14C-thymidine was counted in a liquid
scintillation counter 1450 Microbeta Wallac Trilux. R results are ex-
pressed in cpm (counts per minute) and converted to percentage of
growth inhibition GI% by first subtracting the average number of cpm
of wells without B cells and then dividing by the number of cpm of wells
[7] a) A. S. Jogalekar, F. H. Kriel, Q. Shi, B. Cornett, D. Cicero, J. P.
Snyder, J. Med. Chem. 2010, 53, 155–165, and references therein;
b) L. B. Salum, L. C. Dias, A. D. Andricopulo, QSAR Comb. Sci.
10132
www.chemeurj.org
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Chem. Eur. J. 2011, 17, 10123 – 10134

Discodermolide Analogues
FULL PAPER
2009, 28, 325–337; c) A. B. Smith, M. LaMarche, M. Falcone-Hind-
ley, Org. Lett. 2001, 3, 695–698.
C. Madiraju, B. W. Day, D. P. Curran, Bioorg. Med. Chem. 2003, 11,
3335–3357; k) M. A. Burlingame, S. J. Shaw, K. F. Sundermann, D.
Zhang, J. Petryka, E. Mendoza, F. Liu, D. C. Myles, M. J. LaMarche,
T. Hirose, B. S. Freeze, A. B. Smith III, Bioorg. Med. Chem. Lett.
2004, 14, 2335–2338; l) A. B. Smith III, B. S. Freeze, M. J. LaMar-
che, T. Hirose, I. Brouard, M. Xian, K. F. Sundermann, S. J. Shaw,
M. A. Burlingame, S. B. Horwitz, D. C. Myles, Org. Lett. 2005, 7,
315–318; m) A. B. Smith III, B. S. Freeze, M. J. LaMarche, T.
Hirose, I. Brouard, P. V. Rucker, M. Xian, K. F. Sundermann, S. J.
Shaw, M. A. Burlingame, S. B. Horwitz, D. C. Myles, Org. Lett. 2005,
7, 311–314; n) S. J. Shaw, K. F. Sundermann, M. A. Burlingame,
D. C. Myles, B. S. Freeze, M. Xian, I. Brouard, A. B. Smith III, J.
Am. Chem. Soc. 2005, 127, 6532–6533; o) A. B. Smith III, B. S.
Freeze, M. J. LaMarche, J. Sager, K. W. Kinzler, B. Vogelstein,
Bioorg. Med. Chem. Lett. 2005, 15, 3623–3626; p) S. J. Shaw, H. G.
Menzella, D. C. Myles, M. Xian, A. B. Smith III, Org. Biomol.
Chem. 2007, 5, 2753–2755.
[8] DDM total synthesis: a) J. B. Nerenberg, D. T. Hung, P. K. Somers,
S. L. Schreiber, J. Am. Chem. Soc. 1993, 115, 12621–12622; b) D. T.
Hung, J. B. Nerenberg, S. L. Schreiber, J. Am. Chem. Soc. 1996, 118,
11054–11080; c) A. B. Smith III, Y. Qiu, D. R. Jones, K. Kobayashi,
J. Am. Chem. Soc. 1995, 117, 12011–12012; d) A. B. Smith III, T. J.
Beauchamp, M. J. LaMarche, M. D. Kaufman, Y. Qiu, H. Arimoto,
D. R. Jones, K. Kobayashi, J. Am. Chem. Soc. 2000, 122, 8654–8664,
and references therein; e) S. S. Harried, G. Yang, M. A. Strawn,
D. C. Myles, J. Org. Chem. 1997, 62, 6098–6099; f) S. S. Harried,
C. P. Lee, G. Yang, T. I. H. Lee, D. C Myles, J. Org. Chem. 2003, 68,
6646–6660; g) J. A. Marshall, Z.-H. Lu, B. A. Johns, J. Org. Chem.
1998, 63, 817–823; h) J. A. Marshall, B. A. Johns, J. Org. Chem.
1998, 63, 7885–7892; i) I. Paterson, G. J. Florence, K. Gerlach, J. P.
Scott, Angew. Chem. 2000, 112, 385–388; Angew. Chem. Int. Ed.
2000, 39, 377–380; j) I. Paterson, G. J. Florence, Eur. J. Org. Chem.
2003, 2193–2208; k) I. Paterson, I. Lyothier, J. Org. Chem. 2005, 70,
5494–5507, and references therein; l) A. Arefolov, J. S. Panek, J.
Am. Chem. Soc. 2005, 127, 5596–5603, and references therein;
m) E. de Lemos, F. H. Porꢀe, A. CommerÅon, J.-F. Betzer, A. Pan-
crazi, J. Ardisson, Angew. Chem. 2007, 119, 1949–1953; Angew.
Chem. Int. Ed. 2007, 46, 1917–1921; n) E. de Lemos, F. H. Porꢀe, A.
Bourin, J. Barbion, E. Agouridas, M.-I. Lannou, A. CommerÅon, J.-
F. Betzer, A. Pancrazi, J. Ardisson, Chem. Eur. J. 2008, 14, 11092–
11112.
[12] It has been shown by stochastic conformational analysis (Monte
Carlo method, Spartan’04 Win. Software, MMF94aq force field)
from RX diffraction DDM structure, that the “U”-shaped conform-
ers of the three following analogues were the lowest in energy (see
the Supporting Information).
[13] a) D. Hoppe, Angew. Chem. 1984, 96, 930–946; Angew. Chem. Int.
Ed. Engl. 1984, 23, 932–948; b) D. Hoppe, O. Zschage, Angew.
Chem. 1989, 101, 67–69; Angew. Chem. Int. Ed. Engl. 1989, 28, 69–
71; c) O. Zschage, D. Hoppe, Tetrahedron 1992, 48, 8389–8392;
[9] For a preparative scale synthesis
of DDM, see: a) S. J. Mickel, D.
Niederer,
R.
Daeffler,
A.
Osmani, E. Kuesters, E. Schmid,
K. Schaer, R. Gamboni, W. Chen,
E. Loeser, F. R. Kinder, Jr., K.
Konigsberger, K. Prasad, T. M.
ˇ
Ramsey, O. Repic, R.-M. Wang,
G. Florence, I. Lyothier, I. Pater-
son, Org. Process Res. Dev. 2004,
8, 122–130, and the four prece-
dent papers; b) S. J. Mickel, R.
Daeffler, W. Prikoszovich, Org.
Process Res. Dev. 2005, 9, 113–
120; c) O. Loiseleur, G. Koch, J.
Cercus, F. Schꢅrch, Org. Process
Res. Dev. 2005, 9, 259–271.
[10] For recent reviews on DDM syn-
thesis and DDM analogue design,
synthesis, and biological activity,
d) D. Hoppe, T. Hense, Angew. Chem. 1997, 109, 2376–2410;
Angew. Chem. Int. Ed. Engl. 1997, 36, 2282–2316.
see: a) S. J. Shaw, Mini-Rev. Med.
Chem. 2008, 8, 276–284, and references therein; b) A. B. Smith III,
B. S. Freeze, Tetrahedron 2008, 64, 261–298, and references therein;
c) G. J. Florence, N. M. Gardner, I. Paterson, Nat. Prod. Rep. 2008,
25, 342–375, and references therein d) I. Paterson, G. J. Florence,
Top. Curr. Chem. 2009, 275-278, 73–119, and references therein.
[11] Design and synthesis of DDM analogues (highlights): a) D. T. Hung,
J. B. Nerenberg, S. L. Schreiber, Chem. Biol. 1994, 1, 67–71; b) I. Pa-
terson, K. R. Gibson, R. M. Oballa, Tetrahedron Lett. 1996, 37,
8585–8588; c) I. Paterson, G. J. Florence, K. Gerlach, J. P. Scott, N.
Sereinig, J. Am. Chem. Soc. 2001, 123, 9535–9544; d) F. R., Kind-
er, Jr., K. W. Bair, W. C. Chen, G. Florence, C. Francavilla, P. Geng,
S. Gunasekera, Q. Guo, P. T. Lassota, R. E. Longley, M. G. Palermo,
I. Paterson, S. Pomponi, T. M. Ramsey, L. Rogers, M. Sabio, N. Ser-
einig, E. Sorensen, R. M. Wang, A. Wright, Presented at American
Association for Cancer Research 93rd Annual meeting, San Francis-
co, 2002. Poster 3650; e) F. R. Kinder, WO 2002012220, 2002;
f) F. R. Kinder, Jr., P. K. Paka, E. M. Loeser WO 2002098843, 2002;
g) F. R. Kinder, Jr., K. W. Bair, T. M. Ramsey, M. L. Sabio WO
2003014102, 2003; h) S. P. Gunasekera, S. J. Mickel, R. Daeffler, D.
Niederer, A. E. Wright, P. Linley, T. Pitts, J. Nat. Prod. 2004, 67,
749–756; i) D. P. Curran, T. Furukawa, Org. Lett. 2002, 4, 2233–
2235; j) J. M. Minguez, S. Y. Kim, K. A. Giulano, R. Balachandran,
[14] a) V. Fargeas, P. Le Mꢀnez, I. Berque, J. Ardisson, A. Pancrazi, Tet-
rahedron 1996, 52, 6613–6634; b) I. Berque, P. Le Mꢀnez, P. Razon,
C. Anies, A. Pancrazi, J. Ardisson, A. Neuman, T. Prangꢀ, J.-D.
Brion, Synlett 1998, 1132–1134; c) I. Berque, P. Le Mꢀnez, P. Razon,
A. Pancrazi, J. Ardisson, J.-D. Brion, Synlett 1998, 1135–1137; d) I.
Berque, P. Le Mꢀnez, P. Razon, J. Mahuteau, J.-P. Fꢀrꢀzou, A. Pan-
crazi, J. Ardisson, J.-D. Brion, J. Org. Chem. 1999, 64, 373–381.
[15] F.-H. Porꢀe, A. Clavel, J.-F. Betzer, A. Pancrazi, J. Ardisson, Tetra-
hedron Lett. 2003, 44, 7553–7556.
[16] Noteworthy, in this particular case, the vinylation reaction of 11
with vinylmagnesium bromide gave highly variable but mostly low
yields. The reaction with solely vinyllithium species without magne-
sium salt (produced from tetravinyltin and MeLi) allowed the for-
mation of the desired product 12 in a reproducible high yield.
[17] a) P. Kocienski, S. Wadman, K. Cooper, J. Am. Chem. Soc. 1989,
111, 2363–2365; b) P. Kocienski, C. Barber, Pure Appl. Chem. 1990,
62, 1933–1940; c) P. Kocienski in Organic Synthesis via Organome-
tallics Proceeding of the Fourth Symposium in Aachen, 1992; E.
Enders, H.-J. Eds; Verlag Wiesbaden: Germany, 1992.
[18] 7-Hydroxyphenol analogue 6 was briefly presented only once: W.
Chen, K. W. Blair, P. T. Lassota, T. M. Ramsey, E. Sorensen, R. M.
Chem. Eur. J. 2011, 17, 10123 – 10134
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10133

J. Ardisson et al.
Wang, F. R. Kinder, Jr., Abstracts of Papers, 224th Meeting of the
American Chemical Society, Boston, 2002, Abstracts ORGN 790.
[19] J. A. Marshall, G. M. Schaaf, J. Org. Chem. 2003, 68, 7428–7432.
[20] a) B. M. Trost, J. L. Belletire, S. Godleski, P. G. McDougal, J. M. Bal-
kovec, J. J. Baldwin, M. E. Christy, G. S. Ponticello, S. L. Varga, J. P.
Springer, J. Org. Chem. 1986, 51, 2370–2374; b) J. M. Seco, E.
QuiÇoꢄ, R. Riguera, Chem. Rev. 2004, 104, 17–117.
[24] The C7 centre of configuration of the alcohol precursor of 37 was
confirmed through derivatization to the corresponding (R)- and (S)-
[21] The assignment of the configuration of the (S)-C12 methyl centre of
compound 25 was determined in analogy with the corresponding se-
quence developed for DDM synthesis.
[22] a) E. J. Corey, R. K. Bakshi, S. Shibata, J. Am. Chem. Soc. 1987, 109,
5551–5553; b) E. J. Corey, C. J. Helal, Angew. Chem. 1998, 110,
2092–2118; Angew. Chem. Int. Ed. 1998, 37, 1986–2012; c) B. M.
Trost, J. L. Gunzner, O. Dirat, Y. H. Rhee, J. Am. Chem. Soc. 2002,
124, 10396–10415.
[23] In this case, the Suzuki cross-coupling reaction gave a highly disap-
pointing low yield (10%). We suspected that the isopropyl group
could have deleterious effects for steric reasons. Therefore, we in-
vestigated this reaction between model substrates; however, under
the same conditions; the desired product was obtained in 61%
yield.
a-methoxy-phenylacetic acid (MPA) ester (see the Experimental
Section).[20]
[25] The formation of the cyclohexene 40 through an intramolecular cou-
pling reaction proves the fold of the C8–C14 core.
[26] D. W. Marquardt, J. Soc. Ind. Appl. Math. 1963, 11, 431–441.
Received: March 3, 2011
Published online: July 26, 2011
10134
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Chem. Eur. J. 2011, 17, 10123 – 10134