Molecular editing and biological evaluation of amphidinolide X and Y

Article abstract of DOI:10.1002/chem.200802069

Deliberate deviations from the previously described total syntheses of amphidinolide X (1) and Y (2) allowed a collection of seven designed analogues of these extremely scarce marine natural products to be obtained. These fully synthetic "natural product-

Full text of DOI:10.1002/chem.200802069

DOI: 10.1002/chem.200802069
Molecular Editing and Biological Evaluation of Amphidinolide X and Y
Alois Fꢀrstner,*[a] Egmont Kattnig,[a] Gerhard Kelter,[b] and Heinz-Herbert Fiebig[b]
Abstract: Deliberate deviations from
the previously described total syntheses
of amphidinolide X (1) and Y (2) al-
lowed a collection of seven designed
analogues of these extremely scarce
marine natural products to be ob-
tained. These fully synthetic “natural
product-like” compounds enabled first
insights into the previously unknown
structure–activity relationships govern-
ing this series. Although the average
cytotoxicity is moderate, it was found
that certain bladder, colon and prostate
cancer cell lines are fairly sensitive,
and that the best synthetic analogues
are more active than the natural prod-
ucts themselves. The syntheses rely on
the 9-MeO-9-BBN variant of the
Suzuki coupling for the formation of
the carbon frameworks, as well as on
Yamaguchi lactonization reactions for
the cyclization of the macrocyclic rings.
Keywords: anticancer
agents
·
cross-coupling · macrolides · natural
products
·
structure–activity
relationships
Introduction
X[9,10] and Y[10] series. These campaigns served as a stringent
testing ground for the methodology developed in this labo-
ratory;[11–13] as the largely catalysis-based routes are inher-
ently flexible, however, they might also qualify as basis for a
synthesis-driven editing of the molecular framework of the
individual targets as part of a more ambitious program at
the chemistry/biology interface. The accompanying paper in
this issue describes, among other things, such a “diverted
total synthesis”[14] project modelled around amphidinolide V
as one of the rarest members of this class.[8] Outlined below
is a similar investigation on the sister compounds amphidi-
nolide X and Y, which again focused on the preparation of
such structural variants that cannot (or at least not easily)
be obtain by functionalization or derivatization of the natu-
ral products themselves. This “molecular editing” exercise
led to a collection of de-novo analogues with deep-seated
structural modifications, that allowed us to obtain first in-
sights into structure–activity relationships determining the
cytotoxicity profile of this series.
Marine dinoflagellates of the Amphidinium sp. represent an
exceptionally rich source of bioactive secondary metabolites
of mixed polyketide origin.[1] To date, more than thirty dif-
ferent “amphidinolides”, grouped together into sub-families
ranging from A–Y, have been extracted from culture broths
of such algae. These macrolides are distinguished by a set of
rather unusual structural features and exhibit good to out-
standing levels of cytotoxicity, even though they were tested
only against a very small number of cancer cell lines. This is
mainly due to the low isolation yields which limit the supply
of material available from the natural sources and therefore
constitute a serious handicap for a more detailed biological
evaluation.[1]
Challenged by the diverse molecular architectures of the
amphidinolides and inspired by their potential biological sig-
nificance, the synthetic community has paid considerable at-
tention to this family of natural products.[2,3] Our group has
contributed to this venture, upon describing total syntheses
of members of the amphidinolide B,[4] G,[4,5] H,[4,5] T,[6] V,[7,8]
Results and Discussion
Design aspects: Amphidinolide X (1) was described by Ko-
bayashi and co-workers as the first naturally occurring mac-
rodiolide consisting of a diacid and a diol unit rather than of
two hydroxy-acid segments.[15] It is closely related to amphi-
dinolide Y (2),[16] since an oxidative cleavage of the hemike-
tal form of 2 contracts its odd-numbered lactone to the 16-
membered macrodiolide core displayed by 1 (Scheme 1).[16]
[a] Prof. A. Fꢀrstner, Dr. E. Kattnig
Max-Planck-Institut fꢀr Kohlenforschung
45470 Mꢀlheim/Ruhr (Germany)
Fax : (+49)208-306-2994
E-mail: fuerstner@mpi-muelheim.mpg.de
[b] Dr. G. Kelter, Prof. H.-H. Fiebig
Oncotest GmbH, Am Flughafen 12–14
79108 Freiburg (Germany)
4030
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FULL PAPER
Both compounds are extremely rare (0.001 and 0.0007%, re-
spectively, of the wet weight of the algae) and were de-
scribed as moderately cytotoxic agents against murine lym-
phoma L1210 cells (IC50 =0.6 mgmLꢀ1 and 0.8 mgmLꢀ1) and
human epidermoid carcinoma KB cells (IC50 =7.5 mgmLꢀ1
and 8.0 mgmLꢀ1).[15,16]
the quarternary stereocenter by a branched, yet achiral
entity should be advantageous in preparative terms but may
not compromise the activity profile, compounds 4 and 9, re-
spectively, were considered attractive analogues to be
chased (Figure 1).
Scheme 1. Structures of and chemical relationship between amphidino-
lide X (1) and Y (2).
Our total syntheses dismantled 1 and 2 such that building
block A representing the common tetrahydrofuran ring
could be used en route to both targets (Scheme 2).[9,10,17]
This fragment was successfully coupled to either vinyliodide
B or the more sophisticated segment C by means of the 9-
MeO-9-BBN variant of the Suzuki reaction.[18,19] The result-
ing compounds were then elaborated by productive Yama-
guchi lactonization reactions[20–22] into the macrocyclic natu-
ral products.
Figure 1. Envisaged analogues of amphidinolide X and Y for biological
testing. Structural changes relative to the parent compounds are high-
lighted in red. It is of note that the tertiary center C-19 in 1 corresponds
to C-18 in 2.
The synthetically challenging tertiary ether motif in A was
set in high optical purity by recourse to a relay strategy
based on iron-catalyzed opening of a propargyl epoxide pre-
cursor, as previously described by our group.[23,24] This
method also allowed for the preparation of the C-19 epimer
of amphidinolide X (3).[10] Since the formal replacement of
Along the same lines, it was envisaged to formally eradi-
cate the chiral centers at C-4 and/or C-11 on the macrocyclic
frame (amphidinolide X numbering), which display no more
but a methyl branch. It is a priori difficult to predict which
consequences such modifications may entail for the chemi-
cal stability as well as the biological activity of the resulting
compounds. A previous “diverted total synthesis” project
pursued by our group had revealed a significant correlation
between a seemingly innocent methyl substituent decorating
the core of latrunculin B with the actin-binding capacity of
this macrolide.[25] In this particular case, the fully synthetic
nor-analogue turned out to be significantly more potent
than the natural product itself; therefore, analogues 5–7
modelled around amphidinolide X were considered poten-
tially interesting targets. Finally, it seemed necessary to ad-
dress the role of the enoate moiety in 1, which may serve as
a Michael acceptor for biological nucleophiles. In order to
probe this possible role, it was planned to replace the a,b-
unsaturated ester of 1 by a saturated entity as shown in
compound 8 (Figure 1).
Preparation of the building blocks: With the tableau of de-
Scheme 2. Basic disconnections of the previous total syntheses of 1 and 2.
sirable analogues defined, efficient routes to the building
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4031

A. Fꢀrstner et al.
Table 1. Reduction of ketone 14 with different metal hydrides.
blocks required for their assembly had to be devised. To this
end, ethyl glyoxalate 10 was subjected to a copper-catalyzed
carbonyl-ene reaction with isobutene, which furnished gram
quantities of alcohol 12 with 92% enantiomeric excess
(Scheme 3).[26] The subsequent protection as a 3,4-dimethoxy-
benzyl (DMB) ether, however, was problematic, resulting in
substantial loss in optical purity upon treatment of 12 with
DMB-trichloroacetimidate under either mildly acidic condi-
tions or by Finkelstein reaction. Only when the alkylation
was performed in THF at ꢀ208C using strictly equimolar
amounts of KH as the base and DMB-Br/TBAI as the alky-
lating agent could product 13 be obtained in appreciable
yield and acceptable 83% ee. In contrast, the subsequent
chain extension by a Claisen condensation occurred without
incident using the lithium enolate derived from tert-butyl
acetate as the nucleophile.
Entry
Reagents and conditions
anti/syn
Yield [%][a]
1
2
3
4
5
6
7
8
Zn
(BH4)2, Et2O, ꢀ788C
1:4
1:3.5
1:5
1:1.1
1.6:1
1.5:1
1:6
58 (85)
55 (79)
21 (60)
40
78
83
LiAlH4, Et2O, ꢀ788C
K-selectride, THF, ꢀ788C
CBS[b]
KBH4, MeOH, ꢀ788C
NaBH4, MeOH, ꢀ788C
NaBH4, d-tartaric acid, THF, ꢀ208C
NaBH4, l-tartaric acid, THF, ꢀ208C
65 (72)
65 (77)
7:1
[a] Isolated yields (yield based on recovered starting material). [b] BH3-
AHCTUNRTGEG(NNNU SMe2), (S)-3,3-diphenyl-1-methylpyrrolidino-[1,2-c]-1,3,2-oxazaborole,
toluene, ꢀ158C, cf. ref. [29].
uct with respectable selectivity (entry 8).[30] The control ex-
periments shown in entries 6 and 7 make clear that this re-
duction is ligand-controlled, as the use of NaBH4 alone re-
sulted in a very modest diastereomeric ratio, whereas the
use of d-tartaric acid as the additive inverted the stereo-
chemical course. Routine flash chromatography furnished
anti-15 in optically pure form, as it allowed to remove all
diastereomers derived from the competing syn reduction or
from the antipodal substrate, given the fact that 13 and
hence also 14 had only been 83% optically pure.
Iodo-etherification of anti-15 effectively set the tertiary
ether (Scheme 3).[31] The subsequent reduction of the neo-
pentylic iodide in 16 was swiftly accomplished with NaBH4
in the presence of catalytic amounts of InCl3 in MeCN,[32]
whereas conventional radical dehalogenation conditions
were unsatisfactory. Reduction of the remaining ester in 17
followed by conversion of the resulting primary alcohol 18
into iodide 19 completed the synthesis of the required build-
ing block.
The vinyliodide fragment 27 lacking the C-11 methyl
branch (amphidinolide X numbering) was obtained by alky-
lation of 2-methyl-1,3-dithiane 20 with (S)-21 (>99% ee)[33]
followed by opening of the epoxide in 22 with propynyl lith-
ium in the presence of BF3ACTHNUTRGNEUNG
(OEt2) (Scheme 4).[34,35] Treat-
ment of 23 with ethyleneglycol and iodine in MeCN gently
swapped the thioketal for the corresponding 1,3-dioxolane
24,[36,37] which served as the substrate for a subsequent hy-
drozirconation/iodination[38] sequence once the free hydroxy
group had been protected as PMB-ether. For a regioselec-
tive hydrozirconation of a non-symmetrical alkyne to occur,
it is believed that thermodynamic conditions need to be op-
erative.[38,39] The acetal ring in 25, however, turned out to be
sensitive toward the Lewis-acidic Schwartz reagent, thus
leading to rather poor yields of the desired product 26 if the
mixture was allowed to stir for extended periods of time
and/or at higher temperatures (ꢁ408C). However, a work-
able compromise between selectivity (d.r. ꢁ 96:4) and pro-
ductivity (60%) was reached when 25 was treated with
[Cp2Zr(H)Cl] in THF at +358C for 140 min, followed by ad-
dition of iodine to the reaction mixture at ꢀ788C. Cleavage
of the -OPMB group with DDQ[40] afforded the desired
building block 27 to be incorporated into the amphidinolide
congeners 6 and 7 (Scheme 4). At this stage, the minor re-
gioisomeric vinyl iodide formed in the hydrozirconation/io-
Scheme 3. a) Isobutene, complex 11 (10 mol%), CH2Cl2, 08C, 90%
(92% ee); b) DMBBr, KH, (nBu)4NI, THF, ꢀ40 ! ꢀ208C, 62% (83%
ee); c) tBuOC(O)CH3, LiHMDS, THF, ꢀ788C, 96%; d) see Table 1; e)
I2, NaHCO3, Et2O/MeCN, 08C, 89% (dr 2.2:1); f) NaBH4, InCl3
(15 mol%), MeCN, 88%; g) Dibal-H, CH2Cl2, ꢀ158C ! 08C, 85%; h)
I2, PPh3, imidazole, Et2O/MeCN, 89%; DMBBr=3,4-dimethoxybenzyl
bromide; LiHMDS=lithium hexamethyldisilazide.
A chelate-controlled reduction of the resulting product 14
was thought to produce the required anti-configured diol
15.[27,28] Surprisingly, however, the use of either Zn
ACTHNUGTRNEUGN(BH4)2,
LiAlH4 or K-Selectride invariably afforded syn-15 as the
major isomer, likely because of the competing influence of
the ester carbonyl group which seems to outperform the
guidance exerted by the -ODMB ether (Table 1). Attempted
CBS-reduction of 14 was plagued by low yields and found
virtually unselective.[29] Gratifyingly, NaBH4 modified with
L-tartaric acid in THF at ꢀ208C provided the desired prod-
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Amphidinolide X and Y
FULL PAPER
Scheme 4. a) i) nBuLi, THF, ii) epoxide 21, ꢀ408C ! RT, 86%; b) prop-
ynyl lithium, BF
G
I2, MeCN, 08C, 64%; d) PMBCl, NaH, (nBu)4NI, DMF, 81%; e) i)
[Cp2Zr(H)Cl], THF, 358C; ii) I2, ꢀ788C, 60% (d.r. 94:6); f) DDQ,
CH2Cl2, phosphate buffer (pH 7), 91%; PMB=p-methoxybenzyl;
DDQ=2,3-dichloro-5,6-dicyano-p-benzoquinone.
dination step could be conveniently removed by flash chro-
matography.
Acids 29 and 31 required for the preparation of the envis-
aged analogues were readily obtained by hydrogenation of
the known compound 28 or by cross-metathesis of 30 with
methyl acrylate, respectively.[41,42] They were attached in
high yields to segments 27 or 32[10] by intermolecular Yama-
guchi esterification reactions as shown in Scheme 5.
A fully synthetic analogue of amphidinolide Y: The modi-
fied tetrahydrofuran 19 was coupled with segment 37[10] pre-
viously used in the total synthesis of 2 upon metal-halogen
exchange with tBuLi and trapping of the resulting organo-
lithium reagent with 9-MeO-9-BBN; a subsequent alkyl-
Suzuki reaction reliably transferred the functionalized alkyl
residue from the resulting borate 38 to the organopalladium
Scheme 5. a) H2 (1 atm), Pd/C (10% w/w), MeOH, 94%; b) 29, 2,4,6-tri-
chlorobenzoyl chloride, Et3N, toluene, then DMAP cat., 92%; c) methyl
acrylate, second generation Hoveyda–Grubbs catalyst (2 mol%), CH2Cl2,
69%; d) 31, 2,4,6-trichlorobenzoyl chloride, Et3N, toluene, then DMAP
cat., 86%; e) 28, 2,4,6-trichlorobenzoyl chloride, Et3N, toluene, then
DMAP cat., 91%; f) 31, 2,4,6-trichlorobenzoyl chloride, Et3N, toluene,
then DMAP cat., 85%.
complex
(Scheme 6).[18,19,43]
The crude product 39 was
immediately subjected to
derived
from
37
and
[(dppf)PdCl2]
cleavage of the -ODMB ether
with DDQ[40] to give 40 in
45% unoptimized yield over
both steps. Saponification of
the methyl ester and conver-
sion of the resulting acid into
the corresponding triethylam-
monium salt 41 set the stage
for the Yamaguchi macrolacto-
nization[20–22,44] and final depro-
tection with the aid of dilute
HOAc. Because of the sensi-
tivity of the seco-acid and the
ring closed product 42 in
which the glycoside was still in
place, these last steps were
best performed without rigor-
ous purification of the inter-
mediates. Overall, this se-
quence provided compound 9
as a first fully synthetic conge-
Scheme 6. a) tBuLi, Et2O/THF, then 9-MeO-9-BBN, ꢀ788C ! RT; b) [(dppf)PdCl2]·CH2Cl2 (5 mol%), AsPh3
(10 mol%), K3PO4, aq. DMF; c) DDQ, CH2Cl2, phosphate buffer (pH 7), 08C, 45% (over steps a)–c)); d)
LiOH, MeOH/THF/H2O 4:1:1, then Et3N; e) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, then DMAP cat., tol-
uene; f) HOAc/THF/H2O 4:1:1, 43% (over three steps).
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4033

A. Fꢀrstner et al.
ner of amphidinolide Y, which—in analogy to the natural
product[10,16]—exists as a mixture of the hydroxyketone- and
the 6(9)-hemiketal form in CDCl3 solution (4.8:1)
(Scheme 6).
of the enone moiety of 1 (Scheme 8). No significant changes
to the experimental protocols were necessary in either case,
thus attesting to the robustness of the chosen approach.
Even though the extension of this synthesis plan to ana-
logues 6 and 7 was equally successful, it turned out that
these compounds, deprived of the methyl group at C-11, are
considerably more fragile in chemical terms (Scheme 7 and
8). Whereas the Suzuki cross-coupling reactions and the
cleavage of the acetals were accomplished with ease, the
seco-acid derivatives 54 and 49, respectively, were found un-
usually labile and had to be handled with great care. As
they tend to degrade the aldol subunit on their own back-
bones much faster than their relatives bearing a C-11 methyl
group, they were immediately converted into the corre-
sponding macrolactones. The yields obtained in the Yama-
guchi reactions, however, were considerably lower than in
the previous cases, again reflecting the stability issues men-
tioned above. Nevertheless, sufficient amounts of the target-
ed compounds could be secured for biological testing.
Analogues of the amphidinolide X series: In line with the
results outlined above, the simplified tetrahydrofuran seg-
ment 19 could also be combined with vinyl iodide 43[10] by
recourse to the 9-MeO-9-BBN variant of the Suzuki cou-
pling.[18,19] From there on, it sufficed to follow the blueprint
of our previous total synthesis of amphidinolide
X
(Scheme 7).[9,10] Specifically, the selective cleavage of the
methyl ester in 44 was effected with LiI in hot pyridine,[45]
which left the sterically more encumbered ester group un-
touched. Although the aldol entity in 45 unmasked by acid
catalyzed cleavage of the acetal ring turned out to be rather
sensitive, it was possible to cleave the -ODMP ether with
DDQ in buffered medium in high yield.[40] The macrocyclic
ring of 4 was then closed by Yamaguchi lactonization of the
resulting seco-acid 46 (Scheme 7).[20–22]
The same sequence of reactions also provided access to
congener 5, which solely lacks the methyl branch at C-4, as
well as to product 8 incorporating a saturated ester in lieu
Assessment of the cytotoxicity profile: Amphidinolide X (1)
and Y (2) were described as moderately active but roughly
equipotent against murine lymphoma L1210 and human epi-
dermoid carcinoma KB cells.[15,16] A more detailed inspec-
tion of their activity and selectivity profile, however, is miss-
ing. To this end, both compounds together with the synthetic
analogues described above were assayed against a panel of
human cancer cell lines. Relevant results of this investiga-
tion are compiled in Table 2.
Whereas our data confirm a moderate average cytotoxici-
ty, it was surprising to find that 1 was considerably more
active than 2. Although this result contrast the literature re-
ports,[15,16] it is internally calibrated because the amphidino-
lide Y analogue 9 was also by and large inactive, whereas
congeners 4–8 reflect the level of activity as well as the se-
lectivity profile characteristic of their parent compound am-
phidinolide X. The best results were recorded for analogue
5 lacking the C-4 methyl branch, which is slightly more
active than the natural product itself. Compound 8 incorpo-
rating a saturated diacid segment comes next in terms of po-
tency, which shows that the enone part of 1 is not an essen-
tial structural motif. In contrast, however, removal of the
methyl group at C-11 as well as formal replacement of the
chiral tertiary ether at C-18 by a seemingly closely related
gem-dimethyl group results in diminished potency. Equally
consistent throughout the series is the fact that the urothe-
lial bladder carcinoma BXF 1218 L was found most sensitive
to treatment with the drugs, followed by the colorectal carci-
noma cell line HT29 and the prostate cancer cell line
PC3M.
Scheme 7. a) tBuLi, Et2O/THF, then 9-MeO-9-BBN, ꢀ788C ! RT; b)
[(dppf)PdCl2]·CH2Cl2 (5 mol%), AsPh3 (10 mol%), K3PO4, aq. DMF,
68%; c) LiI, pyridine, reflux; d) aq. HOAc, 58% (over both steps); e)
DDQ, CH2Cl2, phosphate buffer (pH 7), 81%; f) 2,4,6-trichlorobenzoyl
chloride, Et3N, THF, then DMAP cat., toluene, 56%; g) iodide 36,
[(dppf)PdCl2]·CH2Cl2 (5 mol%), AsPh3 (10 mol%), K3PO4, aq. DMF,
67%; h) LiI, pyridine, reflux; i) aq. HOAc, THF, 658C, 56% (over both
steps); j) DDQ, CH2Cl2, phosphate buffer (pH 7), 82%; k) 2,4,6-trichloro-
benzoyl chloride, Et3N, THF, then DMAP cat., toluene, 16%.
Conclusion
Whereas the chemical derivatization of natural products has
a long history as an exploratory tool for medicinal chemis-
try, this approach is very often not applicable to bioactive
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Amphidinolide X and Y
FULL PAPER
undertaking may be rewarded
by the fact that deliberate de-
viations from a successful syn-
thesis plan can bring analogues
with deep seated structural
“point mutations” into reach
that are not available other-
wise. The synthesis campaign
described above illustrates this
notion. Specifically, a set of
seven designed analogues of
the macrolides amphidinolide
X and Y has been prepared
which exhibit such modifica-
tions in every segment of the
macrocyclic frames of the
parent compounds. The fact
that these de novo syntheses
were possible within a reasona-
ble timeframe bears testimony
to the inherent flexibility and
chemical robustness of the un-
derlying blueprint. Moreover,
the acquired compound collec-
tion of fully synthetic “natural
product-like” derivatives al-
lowed first insights into the
previously
completely
un-
known SAR of these marine
natural products. Although the
average cytotoxicity against a
panel of human cancer cell
lines is moderate, it was found
that certain bladder-, colon-
and prostate cancer cell lines
are reasonably sensitive. More-
over, the best analogues, which
are either deprived of the
methyl substituent at C-4 or in-
Scheme 8. a) tBuLi, Et2O/THF, then 9-MeO-9-BBN, ꢀ788C ! RT; b) 35, [(dppf)PdCl2]·CH2Cl2 (5 mol%),
AsPh3 (10 mol%), K3PO4, aq. DMF, 79%; c) LiI, pyridine, reflux; d) aq. HOAc, THF, 658C, 54% (over both
steps); e) DDQ, CH2Cl2, phosphate buffer (pH 7), 71%; f) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, then
DMAP cat., toluene, 32%; g) 34, [(dppf)PdCl2]·CH2Cl2 (5 mol%), AsPh3 (10 mol%), K3PO4, aq. DMF, 63%;
h) LiI, pyridine, reflux; i) aq. HOAc, THF, 658C, 52% (over both steps); j) DDQ, CH2Cl2, phosphate buffer
(pH 7), 81%; k) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, then DMAP cat., toluene, 58%; l) 33,
[(dppf)PdCl2]·CH2Cl2 (5 mol%), AsPh3 (10 mol%), K3PO4, aq. DMF, 73%; m) LiI, pyridine, reflux; n) aq.
HOAc, THF, 658C, 68% (over both steps); o) DDQ, CH2Cl2, phosphate buffer (pH 7), 71%; p) 2,4,6-trichloro-
benzoyl chloride, Et3N, THF, then DMAP cat., toluene, 59%.
corporate
a saturated ester
rather than an enone into the
secondary metabolites of marine origin, simply because they
are too scarce. In these cases, total synthesis has to fill the
gap. Even though this may require considerable efforts, the
macrodiolide skeleton, are somewhat more active than the
natural product amphidinolide X itself.
Table 2. Antitumor activity of amphidinolide X and Y and their analogues against selected human tumor cell lines.
Cell line
Type
IC50 [mgmLꢀ1
]
1
2
4
5
6
7
8
9
BXF 1218L
HT29
bladder
colorectal
gastric
lung
breast
melanoma
prostate
prostate
ovarian
uterus
3.51
5.15
>10
7.89
7.33
5.95
6.40
>10
>10
9.47
>10
4.70
8.11
9.34
>10
>10
>10
>10
>10
>10
>10
3.21
3.70
7.68
8.58
>10
6.90
7.57
9.28
>10
>10
7.82
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
4.29
>10
>10
>10
>10
>10
>10
6.60
6.90
5.48
6.31
>10
10.00
5.75
7.46
>10
9.12
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
GXF 251L
LXFA 629L
MAXF 401NL
MEXF 462NL
PC3M
22RV1
OVCAR3
UXF 1138L
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A. Fꢀrstner et al.
tert-Butyl (4R)-4-((3,4-dimethoxybenzyl)oxy)-6-methyl-3-oxo-6-hepten-
oate (14): A solution of tert-butyl acetate (1.9 mL, 14 mmol) in THF
Experimental Section
(7.0 mL) was added over 15 min to
a solution of LiHMDS (2.4 g,
General: All reactions were carried out under Ar. The solvents used
were purified by distillation over the drying agents indicated and were
transferred under Argon: THF, Et2O (Mg/anthracene), CHCl3 (P4O10),
CH2Cl2, MeCN, Et3N, pyridine (CaH2), DMF (Desmodur, dibutyltin di-
laurate), MeOH (Mg), hexanes, cyclohexane, toluene, benzene (Na/K).
Flash chromatography: Merck silica gel 60 (230–400 mesh). NMR: Spec-
tra were recorded on a DPX 300, AV 400 or DMX 600 spectrometer
(Bruker) in the solvents indicated; chemical shifts (d) are given in ppm
relative to TMS, coupling constants (J) in Hz. The solvent signals were
used as references and the chemical shifts converted to the TMS scale
(CDCl3: dC =77.1 ppm, dH =7.26 ppm; CD2Cl2: dC =54.0 ppm, dH =
5.32 ppm; C6D6: dC =128.1, dH =7.16 ppm); IR (film): Nicolet FT-7199
14 mmol) in THF (38 mL) at ꢀ788C. The mixture was stirred for 30 min
at this temperature before a solution of compound 13 (1.50 g, 4.7 mmol)
in THF (7.0 mL) was introduced. After stirring for 4 h at ꢀ788C, the re-
action was quenched at that temperature with aq. sat. NH4Cl (20 mL)
and the mixture allowed to reach ambient temperature. The aqueous
layer was repeatedly extracted with methyl tert-butyl ether, the combined
organic phases were dried over Na2SO4, filtered, and evaporated, and the
residue was purified by flash chromatography (hexanes/ethyl acetate
10:1) to provide compound 14 as a colorless oil (1.70 g, 96%). Keto–enol
tautomer ratio in CDCl3: 5.6:1 (NMR). [a]2D0 =41.6 (c=1.12, CHCl3);
ketone form: 1H NMR (400 MHz, CDCl3): d=6.77–6.74 (m, 1H), 6.71–
6.65 (m, 2H), 4.70–4.69 (m, 1H), 4.65–4.64 (m, 1H), 4.41 (d, J=11.3 Hz,
1H), 4.26 (d, J=11.3 Hz, 1H), 3.87 (dd, J=7.8, 5.3 Hz, 1H), 3.73 (s, 3H),
3.72 (s, 3H), 3.38 (d, J=15.8 Hz, 1H), 3.29 (d, J=15.8 Hz, 1H), 2.33–2.20
(m, 2H), 1.56 (s, 3H), 1.30 ppm (s, 9H); 13C NMR (100 MHz, CDCl3):
d=205.4, 166.4, 149.0, 148.9, 140.8, 129.7, 120.6, 114.0, 111.3, 110.9, 82.8,
81.9, 72.6, 55.9, 55.8, 46.0, 40.1, 28.0, 22.5 ppm; enol form: 1H NMR
(400 MHz, CDCl3): d=12.00 (brs, 1H), 5.05 (s, 1H), 6.77–6.65 (m, 3H),
4.66 (s, 1H), 4.63 (s, 1H), 4.45 (d, J=11.7 Hz, 1H), 4.18 (d, J=11.7 Hz,
1H), 3.92–3.86 (m, 1H), 3.73 (s, 3H), 3.72 (s, 3H), 2.33–2.20 (m, 2H),
1.53 (s, 3H), 1.36 ppm (s, 9H); IR (film): n˜ =3076, 1742, 1717, 1593, 1517,
1368, 1264, 1159, 895 cmꢀ1; MS (EI): m/z (%): 378 (4) [M+], 238 (5), 167
(9), 156 (9), 151 (100); HRMS (ESI): m/z: calcd for C21H30O6Na [M+
+Na]: 401.1934, found: 401.1931; elemental analysis calcd (%) for
C21H30O6: C 66.65, H 7.99; found: C 66.57, H 8.08.
spectrometer, wavenumbers in cmꢀ1
. MS (EI): Finnigan MAT 8200
(70 eV), (ESI) Finnigan MAT 95, accurate mass determination: Finnigan
MAT 95, Bruker APEX III FT-ICR-MS (7 T magnet). Melting points:
Bꢀchi melting point apparatus (corrected). Elemental analyses: H.
Kolbe, Mꢀlheim/Ruhr. Unless stated otherwise, all commercially avail-
able compounds (Lancaster, Fluka, Aldrich) were used as received.
Preparation of the building blocks
Ethyl (2R)-2-hydroxy-4-methyl-4-pentenoate (12): A mixture of (S,S)-bis-
(phenyloxazoline) (290 mg, 0.87 mmol) and CuACTHNURGTNEUNG(OTf)2 (320 mg,
0.87 mmol) in CH2Cl2 (26 mL) was stirred for 4 h at ambient temperature
before it was cooled to ꢀ788C and transferred to a mixture of isobuty-
lene in CH2Cl2 (1.1m, 6.7 mL, 7.3 mmol) and freshly distilled ethyl glyox-
alate in toluene (ethyl glyoxalate/toluene 1.5:1, 3.6 mL, 22 mmol) at 08C.
The resulting green-blue solution was stirred for 18 h at 08C, before it
was concentrated to a small volume and directly loaded onto a silica
column. Eluation with pentanes/diethyl ether 3:1 gave alcohol 12 as a
colorless oil (1.0 g, 90%). The enantiomeric excess (ee 92%) was deter-
mined by GC by comparison with the racemate (25 m Lipodex G 399,
2208C, 0.5 bar H2). [a]D20 =9.3 (c=5.57, Et2O); 1H NMR (400 MHz,
CDCl3): d=4.89 (d, J=1.4 Hz, 1H), 4.82 (d, J=0.8 Hz, 1H), 4.32 (dd,
J=8.3, 4.2 Hz, 1H), 4.25 (q, J=7.2 Hz, 2H), 2.68 (brs, 1H), 2.53 (dd, J=
14.2, 4.2 Hz, 1H), 2.37 (dd, J=14.2, 8.3 Hz, 1H), 1.79 (s, 3H), 1.30 ppm
(t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=174.7, 140.9, 114.0,
69.1, 61.7, 42.7, 22.5, 14.2 ppm; IR (film): n˜ =3476, 3077, 1736, 1649,
1205, 1100, 893 cmꢀ1; MS (EI): m/z (%): 158 (14) [M+], 140 (68), 125 (6),
112 (49), 97 (10), 95 (12), 85 (62), 42 (75), 67 (17), 57 (77), 41 (73), 29
(100); HRMS (EI): m/z: calcd for C8H14O3 [M+]: 158.0943, found:
158.0942.
tert-Butyl (3S,4R)-4-((3,4-dimethoxybenzyl)oxy)-3-hydroxy-6-methyl-6-
heptenoate (anti-15): NaBH4 (720 mg, 19 mmol) was added in portions
to a solution of l-(+)-tartaric acid (2.9 g, 19 mmol) in THF (35 mL) and
the resulting suspension was stirred for 4 h at reflux temperature before
it was cooled to ꢀ208C. A solution of compound 14 (1.2 g, 3.2 mmol) in
THF (25 mL) was added over 30 min and stirring continued for 20 h at
this temperature. The reaction was then quenched with aq. sat. NH4Cl
(40 mL), the mixture diluted with ethyl acetate (40 mL) and allowed to
reach ambient temperature. The aqueous layer was repeatedly extracted
with ethyl acetate and the combined organic phases were dried over
Na2SO4, filtered, and evaporated. The residue was purified by flash chro-
matography (hexanes/ethyl acetate 5:1) to give a mixture of the anti-con-
figured alcohol and its syn-configured isomer (anti/syn 7:1, 780 mg, 65%)
as well as a second fraction of reisolated starting material 14 (190 mg,
16%). The isomers can be separated by flash chromatography (hexanes/
ethyl acetate 8:1) to provide anti-15 (600 mg, 50%) and syn-15 (70 mg,
6%) in pure form each. The enantiomeric excess of anti-15 (ee >99%)
and syn-15 (ee 98%) was determined by HPLC by comparison with the
Ethyl (2R)-2-((3,4-dimethoxybenzyl)oxy)-4-methyl-4-pentenoate (13):
KH (330 mg, 8.3 mmol) was added in portions to a solution of 12 (1.30 g,
8.3 mmol), 3,4-dimethoxybenzyl bromide (3.8 g, 17 mmol), and tetra-n-
butylammonium iodide (610 mg, 1.7 mmol) in THF (100 mL) at ꢀ408C.
The reaction mixture was warmed to ꢀ208C over the course of 2 h and
stirred for another 3 h at this temperature. The reaction was quenched
with aq. sat. NaHCO3 (40 mL), the mixture diluted with methyl tert-butyl
ether (50 mL) and allowed to reach ambient temperature. The aqueous
layer was repeatedly extracted with methyl tert-butyl ether and the com-
bined organic phases were dried over Na2SO4, filtered, and evaporated.
The residue was purified by flash chromatography (hexanes/ethyl acetate
15:1) to give compound 13 as a colorless oil (1.60 g, 62%). The enantio-
meric excess (ee 83%) was determined by HPLC by comparison with the
racemate (250 mm Chiralpak AS-H, 1 4.6 mm, n-heptane/2-propanol
98:2, 0.5 mLminꢀ1, 2.4 MPa, 298 K, UV, 220 nm). [a]2D0 =53.6 (c=1.37,
racemates (250 mm Chiralpak AD,
1 4.6 mm, n-heptane/2-propanol
90:10, 0.5 mLminꢀ1, 1.7 MPa, 298 K, UV, 220 nm). anti-15: [a]2D0 =ꢀ31.4
(c=1.03, CHCl3); 1H NMR (400 MHz, CDCl3): d=6.91 (d, J=1.8 Hz,
1H), 6.86 (dd, J=8.1, 1.8 Hz, 1H), 6.81 (d, J=8.1 Hz, 1H), 4.83 (s, 2H),
4.56 (s, 2H), 4.09–4.04 (m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.62 (dt, J=
7.7, 4.7 Hz, 1H), 3.11 (brs, 1H), 2.50 (d, J=4.5 Hz, 1H), 2.49 (d, J=
8.0 Hz, 1H), 2.34 (dd, J=14.2, 7.6 Hz, 1H), 2.24 (dd, J=14.2, 4.8, 1H),
1.76 (s, 3H), 1.45 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=172.4,
148.9, 148.6, 142.5, 131.0, 120.3, 113.2, 111.3, 110.8, 81.2, 79.3, 72.4, 70.0,
55.9, 55.8, 39.1, 37.7, 28.1, 22.8 ppm; IR (film): n˜ =3530, 3074, 1726, 1517,
1368, 1264, 1156, 889 cmꢀ1; MS (EI): m/z (%): 380 (3) [M+], 323 (7), 235
(3), 205 (7), 167 (20), 151 (100), 57 (11); HRMS (EI): m/z: calcd for
C21H32O6 [M+]: 380.2199, found: 380.2201; elemental analysis calcd (%)
for C21H32O6: C 66.29, H 8.48; found: C 66.19, H 8.42.
1
Et2O); H NMR (400 MHz, CDCl3): d=6.92 (d, J=1.8 Hz, 1H), 6.85 (dd,
J=8.1, 1.8 Hz, 1H), 6.81, (d, J=8.1 Hz, 1H), 4.82–4.81 (m, 1H), 4.79–
4.78 (m, 1H), 4.64 (d, J=11.5 Hz, 1H), 4.37 (d, J=11.5 Hz, 1H), 4.20
(dq, J=7.1, 1.3 Hz, 2H), 4.06 (dd, J=7.7, 5.7 Hz, 1H), 3.87 (s, 3H), 3.87
(s, 3H), 2.47 (m, 2H), 1.72 (s, 3H), 1.28 ppm (t, J=7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=172.5, 149.0, 148.7, 141.0, 130.0, 120.6,
113.5, 111.3, 110.8, 76.7, 72.1, 60.8, 55.9, 55.8, 41.2, 22.5, 14.3 ppm; IR
(film): n˜ =3076, 1746, 1500, 1265, 1109, 893 cmꢀ1; MS (EI): m/z (%): 308
(21) [M+], 208 (5), 167 (38), 151 (100); HRMS (ESI): m/z: calcd for
C17H24O5Na [M++Na]: 331.1516, found: 331.1515; elemental analysis
calcd (%) for C17H24O5: C 66.21, H 7.84; found: C 66.15, H 7.80.
syn-15 (ee 98%): [a]2D0 =1.6 (c=2.9, MeOH);1H NMR (400 MHz,
CDCl3): d=6.90 (d, J=1.6 Hz, 1H), 6.86 (dd, J=8.1, 1.6 Hz, 1H), 6.82
(d, J=8.1 Hz, 1H), 4.84 (s, 2H), 4.59 (d, J=11.3 Hz, 1H), 4.47 (d, J=
11.3 Hz, 1H), 4.06–4.02 (m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.52 (dt, J=
6.5, 3.5 Hz, 1H), 2.75 (brs, 1H), 2.48 (d, J=8.3 Hz, 1H), 2.45 (d, J=
4.8 Hz, 1H), 2.40 (dd, J=13.7, 6.1 Hz, 1H), 2.30 (dd, J=13.9, 6.8 Hz,
1H), 1.76 (s, 3H), 1.44 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=
171.7, 149.0, 148.7, 142.3, 130.8, 120.5, 113.4, 111.4, 110.9, 81.0, 78.3, 72.1,
68.9, 55.9, 55.8, 39.4, 38.4, 28.1, 22.8 ppm.
4036
www.chemeurj.org
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 4030 – 4043

Amphidinolide X and Y
FULL PAPER
tert-Butyl ((2S,3R,5RS)-3-((3,4-dimethoxybenzyl)oxy)-5-(iodomethyl)-5-
methyltetrahydro-2-furanyl)acetate (16): A solution of iodine (700 mg,
2.8 mmol) in Et2O was added over 25 min to a mixture containing anti-15
(520 mg, 1.4 mmol) and NaHCO3 (460 mg, 5.5 mmol) in MeCN (10 mL)
at 08C. After reaching ambient temperature, the mixture was stirred for
15 min before the reaction was quenched with a mixture of Na2S2O3
(5 mL) and aq. sat. NaHCO3 (5 mL). The aqueous layer was repeatedly
extracted with methyl tert-butyl ether, the combined organic phases were
dried over Na2SO4, filtered and evaporated, and the residue was purified
by flash chromatography (hexanes/ethyl acetate 8:1) to give product 16
as a mixture of diastereoisomers (d.r. 2.2:1, 620 mg, 89%). Major isomer:
1H NMR (400 MHz, CDCl3): d=6.90–6.82 (m, 3H), 4.49–4.38 (m, 3H),
4.02–3.96 (m, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.55 (d, J=9.7 Hz, 1H),
3.39 (d, J=9.7 Hz, 1H), 2.49–2.37 (m, 4H), 1.44 ppm (s, 12H); 13C NMR
(100 MHz, CDCl3): d=169.8, 149.0, 148.6, 130.4, 120.2, 111.1, 110.9, 83.3,
83.0, 81.0, 80.5, 71.5, 55.914, 40.9, 40.5, 28.1, 27.6, 17.0 ppm. Minor
isomer: 1H NMR (400 MHz, CDCl3): d=6.90–6.82 (m, 3H), 4.49–4.38
(m, 3H), 4.02–3.96 (m, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.26 (s, 1H), 3.25
(s, 1H), 2.22 (dd, J=13.5, 7.0 Hz, 1H), 2.01–1.94 (m, 3H), 1.59 (s, 3H),
1.44 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=169.8, 149.0, 148.6,
130.4, 120.2, 111.1, 110.9, 83.0, 81.8, 80.8, 80.8, 71.6, 55.8, 42.5, 40.5, 28.1,
310.1783; elemental analysis calcd (%) for C17H26O5: C 65.78, H 8.44;
found: C 65.70, H 8.38.
AHCTUNGTRENGN(UN 4R,5S)-4-((3,4-Dimethoxybenzyl)oxy)-5-(2-iodoethyl)-2,2-dimethyl-tetra-
hydrofuran (19): PPh3 (130 mg, 0.49 mmol) and imidazole (44 mg,
0.65 mmol) were added to a solution of 18 (100 mg, 0.25 mmol) in Et2O/
MeCN 1:1 (2.8 mL) at 08C. After stirring for 5 min, a solution of iodine
(125 mg, 0.49 mmol) in Et2O (1.4 mL) was added dropwise and the re-
sulting mixture was stirred for 1 h. The reaction was quenched with aq.
sat. NH4Cl (3.0 mL), the aqueous layer was repeatedly extracted with
methyl tert-butyl ether, and the combined extracts were dried over
Na2SO4, filtered and evaporated. The residue was purified by flash chro-
matography (hexanes/ethyl acetate 12:1) to give iodide 19 as a colorless
oil (122 mg, 89%). [a]2D0 =ꢀ43.0 (c=1.04, CHCl3); 1H NMR (400 MHz,
CD2Cl2): d=6.86–6.82 (m, 3H), 4.44 (d, J=11.4 Hz, 1H), 4.36 (d, J=
11.4 Hz, 1H), 3.94 (dt, J=8.4, 4.4 Hz, 1H), 3.83 (s, 3H), 3.82 (s, 3H),
3.79 (dt, J=7.0, 4.5 Hz, 1H), 3.28–3.17 (m, 2H), 2.13–2.04 (m, 1H), 1.88
(dd, J=13.1, 4.2 Hz, 1H), 2.00–1.92 (m, 2H), 1.31 (s, 3H), 1.22 (s, 3H);
13C NMR (100 MHz, CD2Cl2): d=149.8, 149.4, 131.4, 120.7, 112.0, 111.8,
84.2, 83.0, 81.2, 72.0, 56.4, 56.3, 44.7, 39.9, 30.3, 28.6, 2.9; IR (film): n˜ =
2967, 2930, 1593, 1516, 1464, 1264, 1158 cmꢀ1; MS (EI): m/z (%): 420 (27)
[M+], 235 (2), 166 (3), 151 (100); HRMS (ESI): m/z: calcd for
C17H25O4INa [M++Na]: 443.0690, found: 443.0685; elemental analysis
calcd (%) for C17H25O4I: C 48.58, H 6.00; found: C 48.60, H 6.08.
26.2, 18.4; IR (film): n˜ =2975, 2933, 1727, 1517, 1367, 1264, 1158 cmꢀ1
;
MS (EI): m/z (%): 506 (8) [M+], 449 (24), 283 (13), 265 (6), 223 (8), 205
(8), 167 (78), 151 (100), 57 (9); HRMS (EI): m/z: calcd for C21H31O6I
[M+]: 506.1165, found: 506.1165; elemental analysis calcd (%) for
C21H31O6I: C 49.81, H 6.17; found: C 49.54, H 6.31.
(2S)-2-((2-Methyl-1,3-dithian-2-yl)methyl)oxirane (22):
A solution of
nBuLi (1.6m in hexanes, 13 mL, 21 mmol) was added over 5 min to a so-
lution of 2-methyl-1,3-dithiane (2.8 g, 21 mmol) in THF (35 mL) at 08C
(exothermic!). Once the addition was complete, the solution was stirred
for 3 min at ambient temperature before its was cooled to ꢀ408C and
treated with a solution of (S)-21 (1.9 g, 21 mmol) in THF (10 mL). After
20 min at ꢀ408C and 4 h at ambient temperature, the reaction was
quenched with aq. sat. NH4Cl (50 mL), the aqueous layer was repeatedly
extracted with methyl tert-butyl ether, the combined extracts were dried
over Na2SO4, filtered, and evaporated, and the residue was purified by
flash chromatography (hexanes/ethyl acetate 6:1) to afford epoxide 22 as
tert-Butyl ((2S,3R)-3-((3,4-dimethoxybenzyl)oxy)-5,5-dimethyltetrahydro-
2-furanyl)acetate (17): NaBH4 (50 mg, 1.3 mmol) was added to a suspen-
sion of InCl3 (17 mg, 0.08 mmol) in MeCN (1.0 mL) at ꢀ408C. The mix-
ture was stirred for 5 min before it was allowed to reach ambient temper-
ature. After 5 min, a solution of 16 (270 mg, 0.53 mmol) in MeCN
(4.2 mL) was introduced and stirring continued for 1 h. The reaction was
quenched with water (2.0 mL), the aqueous layer was repeatedly extract-
ed with methyl tert-butyl ether and the combined organic phases were
dried over Na2SO4, filtered and evaporated. The residue was purified by
flash chromatography (hexanes/ethyl acetate 8:1) to provide compound
17 as a colorless oil (180 mg, 88%). [a]2D0 =ꢀ22.8 (c=1.45, CHCl3);
1H NMR (400 MHz, CDCl3): d=6.88 (d, J=1.6 Hz, 1H), 6.86 (dd, J=
8.1, 1.8 Hz, 1H), 6.81 (d, J=8.1 Hz, 1H), 4.44 (s, 2H), 4.32 (dt, J=6.3,
4.2 Hz, 1H), 3.97 (dt, J=6.9, 3.9 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H),
2.50–2.40 (m, 2H), 1.96 (dd, J=13.1, 6.8 Hz, 1H), 1.89 (dd, J=13.1,
3.8 Hz, 1H), 1.43 (s, 9H), 1.35 (s, 3H), 1.26 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=170.2, 149.0, 148.6, 130.9, 120.1, 111.0, 110.9, 83.5,
80.9, 80.6, 79.5, 71.5, 55.9, 55.8, 44.0, 40.7, 30.0, 28.4, 28.1 ppm; IR (film):
n˜ =2972, 2934, 1729, 1517, 1367, 1263, 1158 cmꢀ1; MS (EI): m/z (%): 380
(8) [M+], 324 (16), 235 (6), 167 (67), 151 (100), 57 (16); HRMS (EI):
m/z: calcd for C21H32O6 [M+]: 380.2199, found: 380.2197; elemental anal-
ysis calcd (%) for C21H32O6: C 66.29, H 8.48; found: C 66.20, H 8.56.
a colorless oil (3.4 g, 86%). [a]2D0 =ꢀ6.4 (c=4.2, CH2Cl2) [lit.:[36] [a]D22
=
ꢀ4.9 (c=4.7, CH2Cl2)]; 1H NMR (400 MHz, CDCl3): d=3.20–3.16 (m,
1H), 2.95–2.79 (m, 5H), 2.52 (dd, J=5.0, 2.7 Hz, 1H), 2.23 (dd, J=14.7,
4.8 Hz, 1H), 2.10 (dd, J=14.7, 6.3 Hz, 1H), 2.06–1.87 (m, 2H), 1.71 ppm
(s, 3H); 13C NMR (100 MHz, CDCl3): d=48.7, 47.4, 46.3, 44.0, 28.1, 26.3,
26.2, 24.6 ppm; IR (film): n˜ =3045, 2920, 1446, 1422, 1277, 1258,
864 cmꢀ1; MS (EI): m/z (%): 190 (41) [M+], 133 (100); HRMS (EI): m/z:
calcd for C8H14OS2 [M+]: 190.0486, found: 190.0488.
(2R)-1-(2-Methyl-1,3-dithian-2-yl)-4-hexyn-2-ol (23): An excess of pro-
pyne was condensed into THF (120 mL) at ꢀ788C and treated dropwise
with a solution of nBuLi (1.6m in hexanes, 13 mL, 21 mmol). After stir-
ring for 30 min, BF3·OEt2 (2.7 mL, 21 mmol) was introduced and stirring
continued for 20 min at ꢀ788C before a solution of epoxide 22 (3.1 g,
16 mmol) in THF (25 mL) was slowly added. The mixture was stirred for
1 h at ꢀ788C before the reaction was quenched with aq. sat. NH4Cl
(50 mL). The aqueous layer was repeatedly extracted with methyl tert-
butyl ether, the combined organic phases were dried over Na2SO4, fil-
tered, and evaporated, and the residue was purified by flash chromatog-
raphy (hexanes/ethyl acetate 10:1) to afford alcohol 23 as a colorless oil
(3.4 g, 91%). The enantiomeric excess (ee 98%) was determined by GC
by comparison with the racemate. [a]2D0 =ꢀ76.4 (c=1.29, CHCl3);
1H NMR (400 MHz, CDCl3): d=4.04–3.99 (m, 1H), 3.26 (brs, 1H), 3.03–
2.92 (m, 2H), 2.79–2.73 (m, 2H), 2.40–2.26 (m, 3H), 2.12 (dd, J=15.0,
1.8 Hz, 1H), 2.07–1.99 (m, 1H), 1.92–1.82 (m, 1H), 1.78 (t, J=2.6 Hz,
3H), 1.64 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=78.1, 75.2, 67.9,
47.6, 46.3, 28.4, 28.0, 26.7, 26.5, 24.6, 3.5 ppm; IR (film): n˜ =3439, 2916,
2231, 1439, 1423, 1276, 1102, 867 cmꢀ1; MS (EI): m/z (%): 230 (24) [M+],
177 (7), 156 (53), 133 (100), 53 (25); HRMS (EI): m/z: calcd for
C11H18OS2 [M+]: 230.0799, found: 230.0798; elemental analysis calcd (%)
for C11H18OS2: C 57.35, H 7.87; found: C 57.42, H 7.81.
2-((2S,3R)-3-((3,4-Dimethoxybenzyl)oxy)-5,5-dimethyltetrahydro-2-furan-
yl)ethanol (18):
A solution of Dibal-H (1.0m in hexanes, 1.8 mL,
1.8 mmol) was added over 20 min to a solution of ester 17 (135 mg,
0.36 mmol) in CH2Cl2 (2.7 mL) at ꢀ158C and the resulting mixture was
stirred for 2 h at this temperature and for 4 h at 08C. The reaction was
quenched with aq. potassium/sodium tartrate (1m, 2.7 mL) and stirring
was continued until a clean phase separation was reached. The aqueous
layer was repeatedly extracted with methyl tert-butyl ether, the combined
organic phases were dried over Na2SO4, filtered and evaporated, and the
residue was purified by flash chromatography (hexanes/ethyl acetate 1:1)
to give alcohol 18 as a colorless oil (94 mg, 85%). [a]2D0 =ꢀ50.2 (c=1.0,
CHCl3); 1H NMR (400 MHz, CDCl3): d=6.87–6.81 (m, 3H), 4.47 (d, J=
11.3 Hz, 1H), 4.39 (d, J=11.3 Hz, 1H), 4.11–4.06 (m, 1H), 3.88 (s, 3H),
3.87 (s, 3H), 3.88–3.83 (m, 1H), 3.77–3.74 (m, 2H), 2.26 (brs, 1H), 2.01
(dd, J=12.9, 7.4 Hz, 1H), 1.87 (dd, J=12.9, 4.9 Hz, 1H), 1.90–1.72 (m,
2H), 1.34 (s, 3H), 1.27 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
149.0, 148.7, 130.4, 120.2, 111.1, 111.0, 83.7, 82.5, 80.9, 71.8, 61.3, 55.9,
55.8, 44.0, 36.3, 30.0, 28.3 ppm; IR (film): n˜ =3442, 2967, 1593, 1517,
1465, 1265, 1158 cmꢀ1; MS (EI): m/z (%): 310 (19) [M+], 235 (3), 167 (5),
151 (100); HRMS (EI): m/z: calcd for C17H26O5 [M+]: 310.1780, found:
(2R)-1-(2-Methyl-1,3-dioxolan-2-yl)-4-hexyn-2-ol (24): Iodine (2.4 g,
9.6 mmol) was added in portions to a solution of dithiane 23 (740 mg,
3.2 mmol) and ethylene glycol (1.0 mL, 18 mmol) in MeCN (15 mL) at
08C. After stirring for 10 min, the reaction was quenched by pouring the
Chem. Eur. J. 2009, 15, 4030 – 4043
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4037

A. Fꢀrstner et al.
cold solution into a mixture of vigorously stirred aq. sat. NaHCO3 and
aq. sat. Na2S2O3 1:1 (50 mL). The aqueous layer was repeatedly extracted
with methyl tert-butyl ether, the combined organic phases were dried
over Na2SO4, filtered, and evaporated, and the residue was purified by
flash chromatography (hexanes/ethyl acetate 8:1) to afford compound 24
as a colorless oil (380 mg, 64%). [a]2D0 =ꢀ8.8 (c=1.2, CHCl3); 1H NMR
(400 MHz, CD2Cl2): d=4.00–3.89 (m, 5H), 3.44 (d, J=1.3 Hz, 1H), 2.35–
2.15 (m, 2H), 1.99 (dd, J=14.6, 2.0 Hz, 1H), 1.82–1.74 (m, 1H), 1.77 (t,
J=2.6 Hz, 3H), 1.35 ppm (s, 3H); 13C NMR (100 MHz, CD2Cl2): d=
110.7, 77.9, 76.1, 67.6, 65.3, 64.9, 44.5, 27.9, 24.5, 3.7 ppm; IR (film): n˜ =
3512, 2920, 2234, 1219, 1106, 1054, 949, 820 cmꢀ1; MS (EI): m/z (%): 169
(4) [M+ꢀMe], 131 (7), 87 (100), 53 (4); HRMS (CI): m/z: calcd for
C10H17O3 [M++H]: 185.1178, found: 185.1180; elemental analysis calcd
(%) for C10H16O3: C 65.19, H 8.75; found: C 65.07, H 8.64.
1H), 4.02–3.89 (m, 5H), 3.46 (brs, 1H), 2.38 (d, J=1.4 Hz, 3H), 2.22–
2.10 (m, 2H), 1.81 (dd, J=14.6, 2.3 Hz, 1H), 1.74 (dd, J=14.6, 9.4 Hz,
1H), 1.33 ppm (s, 3H); 13C NMR (100 MHz, CD2Cl2): d=138.2, 110.7,
95.8, 67.6, 65.3, 64.9, 44.9, 38.8, 28.2, 24.5 ppm; IR (film): n˜ =3518, 2982,
2885, 1636, 1377, 1053, 818 cmꢀ1; MS (EI): m/z (%): 312 (0.2) [M+], 297
(3), 181 (1), 131 (10), 87 (100); HRMS (ESI): m/z: calcd for C10H17O3INa
[M++Na]: 335.0117, found: 335.0115; elemental analysis calcd (%) for
C10H17O3I: C 38.48, H 5.49; found: C 38.39, H 5.43.
(3R)-6-Methoxy-3-methyl-6-oxohexanoic acid (29): Pd on charcoal (10%
w/w, 6 mg) was added to a solution of 28 (61 mg, 0.35 mmol) in MeOH
(3.5 mL). H2 was bubbled through the suspension for 5 min before the
mixture was stirred for 4 h under a H2 atmosphere (ꢂ1 atm). For work
up, the mixture was filtered through a pad of silica which was rinsed with
ethyl acetate, and the filtrates were evaporated to give product 29 as a
colorless oil (58 mg, 94%). [a]2D0 =4.7 (c=1.2, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=9.17 (brs, 1H), 3.66 (s, 3H), 2.40–2.27 (m, 3H),
2.16 (dd, J=15.1, 7.7 Hz, 1H), 2.01–1.92 (m, 1H), 1.77–1.68 (m, 1H),
1.57–1.48 (m, 1H), 0.96 (d, J=6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=178.8, 174.1, 51.6, 41.7, 31.6, 31.4, 29.7, 19.3; IR (film): n˜ =3010, 2957,
2933, 1732, 1707 cmꢀ1; MS (EI): m/z (%): 175 (0.2) [M++H], 143 (35),
128 (54), 115 (81), 101 (6), 96 (20), 87 (36), 83 (47), 74 (63), 69 (49), 59
(48), 55 (100); HRMS (CI): m/z: calcd for C8H15O4 [M++H]: 175.0970,
found: 175.0968; elemental analysis calcd (%) for C8H14O4: C 55.16, H
8.15; found: C 55.16, H 8.10.
2-((2R)-2-((4-Methoxybenzyl)oxy)-4-hexynyl)-2-methyl-1,3-dioxolane
(25): NaH (39 mg, 1.6 mmol) was added to a solution of 24 (250 mg,
1.4 mmol) in DMF (9.0 mL) at 08C. The mixture was stirred for 10 min
at 08C and for 30 min at ambient temperature before p-methoxybenzyl
chloride (240 mL, 1.6 mmol) and tetra-n-butylammonium iodide (50 mg,
0.14 mmol) were introduced. After stirring for 14 h, the reaction was
quenched with aq. sat. NaHCO3 (20 mL), the aqueous layer was repeat-
edly extracted with methyl tert-butyl ether, the extracts were washed with
water, dried over Na2SO4, filtered and evaporated, and the residue was
purified by flash chromatography (hexanes/ethyl acetate 12:1
+ 1%
Et3N) to afford product 25 as a colorless oil (330 mg, 81%). [a]2D0 =ꢀ26.6
(c=1.24, CHCl3). 1H NMR (400 MHz, CDCl3): d=7.29 (d, J=8.7 Hz,
2H), 6.86 (d, J=8.7 Hz, 2H), 4.55 (d, J=11.1 Hz, 1H), 4.46 (d, J=
11.1 Hz, 1H), 3.97–3.89 (m, 4H), 3.80 (s, 3H), 3.70–3.64 (m, 1H), 2.44–
2.40 (m, 2H), 2.01–1.99 (m, 2H), 1.79 (t, J=2.5 Hz, 3H), 1.37 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=159.1, 130.7, 129.4, 113.7, 109.1,
77.1, 75.9, 74.3, 70.8, 64.4, 64.4, 55.3, 42.8, 25.0, 24.5, 3.6 ppm; IR (film):
n˜ =2984, 2920, 2233, 1514, 1253, 1053, 820 cmꢀ1; MS (EI): m/z (%): 304
(0.6) [M+], 202 (6), 121 (100), 87 (22); HRMS (ESI): m/z: calcd for
C18H24O4Na [M++Na]: 327.1567, found: 327.1563.
(4E)-6-Methoxy-6-oxo-4-hexenoic acid (31): Second generation Grubbs-
Hoveyda catalyst (62 mg, 0.10 mmol)[42] was added to a solution of 4-pen-
tenoic acid 30 (500 mg, 5.0 mmol) and methyl acrylate (2.3 mL,
25.0 mmol) in CH2Cl2 (50 mL). The solution was stirred for 16 h at ambi-
ent temperature before it was filtered through a pad of silica which was
rinsed with hexanes/ethyl acetate (2:1). The combined filtrates were con-
centrated and the residue was purified by flash chromatography (hex-
anes/ethyl acetate 4:1 ! 2:1) to afford acid 31 as a white solid (540 mg,
69%). M.p. 39–408C; 1H NMR (400 MHz, CDCl3): d=9.51 (brs, 1H),
6.98–6.91 (m, 1H), 5.86 (d, J=15.6 Hz, 1H), 3.71 (s, 3H), 2.52–2.51 ppm
(m, 4H); 13C NMR (100 MHz, CDCl3): d=178.0, 166.8, 146.6, 121.9, 51.5,
32.1, 26.8 ppm; IR (film): n˜ =3007, 2956, 2626, 1713, 1700, 1660, 1319,
1157 cmꢀ1; MS (EI): m/z (%): 158 (0.2) [M+], 140 (34), 127 (32), 113
(18), 108 (100), 99 (29), 81 (75), 45 (22); HRMS (CI): m/z: calcd for
C7H11O4 [M++H]: 159.0657, found: 159.0655.
2-((2R,4E)-2-((4-Ethylbenzyl)oxy)-5-iodo-4-hexenyl)-2-methyl-1,3-dioxo-
lane (26):
A
mixture containing 25 (140 mg, 0.45 mmol) and
[Cp2Zr(H)Cl] (290 mg, 1.1 mmol) in THF (4.8 mL) was stirred in the
dark for 140 min at 30–358C before it was cooled to ꢀ788C. A solution
of iodine (290 mg, 1.1 mmol) in THF (2.0 mL) was slowly added and stir-
ring continued for 5 min at this temperature before the mixture was
poured into aq. sat. NaHCO3 (10 mL). Extraction with methyl tert-butyl
ether (10 mL), washing of the organic layer with aq. sat. Na2S2O3 and
brine, drying over Na2SO4, filtration and evaporation of the solvent af-
forded a residue which was purified by flash chromatography (hexanes/
ethyl acetate 15:1 + 2% Et3N) to give product 26 as a pale yellow oil
(mixture of regioisomers, d.r. 96:4, 117 mg, 60%). [a]2D0 =ꢀ2.7 (c=3.30,
CHCl3). Major isomer: 1H NMR (400 MHz, CDCl3): d=7.26 (d, J=
8.7 Hz, 2H), 6.88 (d, J=8.7 Hz, 2H), 6.22 (dt, J=7.4, 1.5 Hz, 1H), 4.47
(d, J=11.1 Hz, 1H), 4.42 (d, J=11.1 Hz, 1H), 3.98–3.85 (m, 4H), 3.80 (s,
3H), 3.62–3.56 (m, 1H), 2.38–2.23 (m, 2H), 2.36 (d, J=1.6 Hz, 3H), 1.99
(dd, J=14.7, 5.6 Hz, 1H), 1.78 (dd, J=14.7, 5.4 Hz, 1H), 1.35 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=159.1, 137.6, 130.6, 129.4, 113.8,
109.0, 95.2, 74.3, 70.6, 64.5, 64.4, 55.3, 43.1, 36.2, 27.8, 24.5 ppm; IR
(film): n˜ =2957, 2876, 1514, 1249, 1039, 820 cmꢀ1; MS (EI): m/z (%): 417
(0.3) [M+ꢀMe], 305 (4), 121 (100), 87 (25); HRMS (ESI): m/z: calcd for
C18H25O4INa [M++Na]: 455.0690, found: 455.0691; elemental analysis
calcd (%) for C18H25O4I: C 50.01, H 5.83; found: C 49.86, H 5.72.
Compound 34: Et3N (60 mL, 0.43 mmol) and 2,4,6-trichlorobenzoyl chlo-
ride (25 mL, 0.16 mmol) were successively added to a solution of acid 31
(25 mg, 0.16 mmol) in toluene (1.3 mL) and the resulting mixture was
stirred for 1 h at ambient temperature. A solution of alcohol 32 (47 mg,
0.14 mmol) in toluene (1.3 mL) was introduced, followed by DMAP
(18 mg, 0.14 mmol), and stirring was continued for 1 h. The mixture was
filtered through a pad of Celite, which was carefully rinsed with toluene.
The combined filtrates were concentrated and the residue was purified
by flash chromatography (hexanes/ethyl acetate 10:1 + 1% Et3N) to
give ester 34 as
a
colorless oil (58 mg, 86%). [a]2D0 =5.9 (c=0.95,
CH3OH); 1H NMR (300 MHz, CD2Cl2): d=6.94 (dt, J=15.7, 6.4 Hz,
1H), 6.05 (dd, J=10.0, 1.5 Hz, 1H), 5.86 (dt, J=15.7, 1.5 Hz, 1H), 5.08–
5.03 (m, 1H), 3.93–3.82 (m, 4H), 3.69 (s, 3H), 2.72–2.60 (m, 1H), 2.56–
2.41 (m, 4H), 2.40 (d, J=1.5 Hz, 3H), 1.89 (dd, J=14.9, 8.0 Hz, 1H),
1.77 (dd, J=14.9, 3.3 Hz, 1H), 1.27 (s, 3H), 0.94 ppm (d, J=6.9 Hz, 3H);
13C NMR (75 MHz, CD2Cl2): d=172.2, 167.1, 147.7, 142.3, 122.2, 109.2,
95.9, 73.0, 65.1, 65.0, 51.8, 41.2, 40.4, 33.2, 28.4, 27.8, 24.5, 16.6 ppm; IR
(film): n˜ =2976, 1726, 1659, 1267, 1152 cmꢀ1; MS (EI): m/z (%): 451 (0.5)
[M+ꢀMe], 293 (5), 185 (7), 113 (11), 109 (7), 87 (100); HRMS (ESI):
m/z: calcd for C18H27O6INa [M++Na]: 489.0745, found: 489.0749; ele-
mental analysis calcd (%) for C18H27O6I: C 46.36, H 5.84; found: C 46.28,
H 5.76.
2-((2R,4E)-2-((4-Ethylbenzyl)oxy)-5-iodo-4-hexenyl)-2-methyl-1,3-dioxo-
lane (27): DDQ (210 mg, 0.92 mmol) was added in portions to a vigo-
rously stirred solution of compound 26 (265 mg, 0.61 mmol) in CH2Cl2
(6.1 mL) and aq. phosphate buffer solution (pH 7, 6.1 mL) at 08C. The
mixture was stirred for 14 h at ambient temperature, diluted with CH2Cl2
(12 mL) and the reaction quenched with aq. sat. NaHCO3 (12 mL). The
aqueous layer was repeatedly extracted with CH2Cl2, the combined ex-
tracts were dried over Na2SO4, filtered and evaporated, and the residue
was purified by flash chromatography (hexanes/ethyl acetate 12:1 + 1%
Et3N) to give alcohol 27 as a colorless oil (174 mg, 91%). [a]2D0 =4.1 (c=
3.0, CHCl3); 1H NMR (400 MHz, CD2Cl2): d=6.24 (tq, J=7.5, 1.5 Hz,
Compound 33: Prepared analogously from acid 29 (19 mg, 0.11 mmol)
and alcohol 32 (30 mg, 92 mmol) as a colorless oil (41 mg, 92%). [a]D20
=
ꢀ1.4 (c=0.9, CH2Cl2); 1H NMR (400 MHz, C6D6): d=6.25 (dd, J=9.9,
1.5 Hz, 1H), 5.30–5.26 (m, 1H), 3.61–3.44 (m, 4H), 3.36 (s, 3H), 2.51
(ddd, J=9.9, 6.9, 4.3 Hz, 1H), 2.20 (d, J=1.5 Hz, 3H), 2.14–2.09 (m,
3H), 2.00–1.94 (m, 3H), 1.76 (dd, J=14.9, 3.3 Hz, 1H), 1.71–1.62 (m,
1H), 1.48–1.39 (m, 1H), 1.27 (s, 3H), 0.84 (d, J=6.4 Hz, 3H), 0.82 ppm
4038
www.chemeurj.org
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 4030 – 4043

Amphidinolide X and Y
FULL PAPER
(d, J=6.9 Hz, 3H); 13C NMR (100 MHz, C6D6): d=173.2, 171.8, 142.3,
109.0, 95.6, 72.2, 64.6, 64.6, 51.0, 41.7, 41.3, 40.2, 31.8 (2C), 30.0, 28.0,
24.5, 19.5, 16.4 ppm; IR (film): n˜ =2960, 2879, 1732, 1258, 1154,
1041 cmꢀ1; MS (EI): m/z (%): 482 (0.2) [M+], 380 (0.3), 293 (9), 201 (4),
157 (47), 125 (37), 97 (6), 87 (100); HRMS (ESI): m/z: calcd for
C19H31O6INa [M++Na]: 505.1058, found: 505.1059.
1.82 (m, 2H), 1.75 (dd, J=15.0, 2.7 Hz, 1H), 1.63 (d, J=1.2 Hz, 3H),
1.65–1.55 (m, 2H), 1.30 (s, 3H), 1.26 (s, 3H), 1.24 (s, 3H), 1.11 (d, J=
6.8 Hz, 3H), 0.88 ppm (d, J=6.9 Hz, 3H); 13C NMR (100 MHz, CD2Cl2):
d=171.7, 167.4, 153.0, 149.7, 149.3, 137.2, 131.7, 125.8, 120.6, 120.3, 112.0,
111.8, 109.5, 84.8, 83.0, 80.6, 74.0, 71.9, 65.0, 64.9, 56.4, 56.3, 51.8, 44.8,
41.2, 40.6, 37.4, 36.5, 34.1, 33.5, 30.4, 28.5, 24.5, 19.4, 16.9, 16.7 ppm; IR
(film): n˜ =2967, 2933, 1727, 1657, 1517, 1453, 1266, 1158 cmꢀ1; MS (EI):
m/z (%): 646 (4) [M+], 474 (5), 151 (100); HRMS (ESI): m/z: calcd for
C36H54O10Na [M++Na]: 669.3609, found: 669.3611.
Compound 35: Prepared analogously from acid 28 (43 mg, 0.25 mmol)
and alcohol 27 (65 mg, 0.21 mmol) as a colorless oil (88 mg, 91%). [a]D20
=
ꢀ0.24 (c=3.6, CH2Cl2); 1H NMR (400 MHz, CD2Cl2): d=6.90 (dd, J=
15.7, 7.1 Hz, 1H), 6.13 (tq, J=7.5, 1.4 Hz, 1H), 5.83 (dd, J=15.7, 1.4 Hz,
1H), 5.14–5.08 (m, 1H), 3.92–3.85 (m, 4H), 3.70 (s, 3H), 2.88–2.77 (m,
1H), 2.39 (dd, J=15.4, 6.8 Hz, 1H), 2.37 (d, J=1.5 Hz, 3H), 2.29 (dd, J=
15.4, 7.3 Hz, 1H), 2.33–2.30 (m, 2H), 1.96 (dd, J=14.8, 7.3 Hz, 1H), 1.82
(dd, J=14.8, 4.4 Hz, 1H), 1.29 (s, 3H), 1.12 ppm (d, J=6.8 Hz, 3H);
13C NMR (100 MHz, CD2Cl2): d=171.4, 167.3, 152.7, 136.7, 120.5, 109.0,
96.8, 69.9, 65.1, 65.0, 51.9, 42.6, 41.1, 36.4, 33.5, 28.2, 24.6, 19.5 ppm; IR
(film): n˜ =2955, 1725, 1656, 1272, 1153, 1053 cmꢀ1; MS (EI): m/z (%): 451
(0.8) [M+ꢀMe], 364 (2), 294 (4), 279 (9), 210 (5), 155 (1), 123 (6), 87
(100); HRMS (ESI): m/z: calcd for C18H27O6INa [M++Na]: 489.0745,
found: 489.0747; elemental analysis calcd (%) for C18H27O6I: C 46.36, H
5.84; found: C 46.30, H 5.78.
Compound 47: Prepared analogously from alkyl iodide 19 (53 mg,
0.13 mmol) and vinyl iodide 36 (57 mg, 0.13 mmol) as a colorless oil
1
(52 mg, 67%). [a]2D0 =ꢀ35.3 (c=0.9, CH2Cl2); H NMR (400 MHz, C6D6):
d=6.96 (dt, J=15.7, 6.4 Hz, 1H), 6.92 (d, J=1.8 Hz, 1H), 6.89 (dd, J=
8.0, 1.9 Hz, 1H), 6.67 (d, J=8.0 Hz, 1H), 5.81 (dt, J=15.7, 1.5 Hz, 1H),
5.48–5.42 (m, 1H), 5.32 (dt, J=7.2, 1.0 Hz, 1H), 4.40 (d, J=11.6 Hz,
1H), 4.32 (d, J=4.32 Hz, 1H), 4.16 (dt, J=7.6, 4.9 Hz, 1H), 3.74 (dt, J=
7.2, 4.2 Hz, 1H), 3.62–3.48 (m, 4H), 3.53 (s, 3H), 3.45 (s, 3H), 3.41 (s,
3H), 2.34–2.11 (m, 8H), 2.05 (dd, J=14.8, 8.0 Hz, 1H), 1.89 (dd, J=14.8,
3.4 Hz, 1H), 1.82 (dd, J=12.9, 3.9 Hz, 1H), 1.78–1.68 ppm (m, 3H), 1.58
(s, 3H), 1.41 (s, 3H), 1.31 (s, 3H), 1.25 (s, 3H); 13C NMR (100 MHz,
C6D6): d=171.3, 166.4, 150.4, 150.0, 147.3, 138.3, 131.7, 122.1, 120.4,
119.7, 112.5, 112.3, 109.1, 84.7, 82.7, 80.1, 71.7, 70.7, 64.6 (2C), 55.8, 55.8,
50.9, 44.8, 42.9, 36.5, 34.3, 34.1, 33.0, 30.3, 28.4, 27.5, 24.6, 16.5 ppm; IR
(film): n˜ =2934, 1725, 1659, 1593, 1516, 1263, 1155, 1030 cmꢀ1; MS (EI):
m/z (%): 618 (5) [M+], 573 (2), 460 (2), 207 (3), 151 (100), 112 (42), 87
(75); HRMS (ESI): m/z: calcd for C34H50O10Na [M++Na]: 641.3296,
found: 641.3299.
Compound 36: Prepared analogously from acid 31 (36 mg, 0.23 mmol)
and alcohol 27 (59 mg, 0.19 mmol) as a colorless oil (74 mg, 85%). [a]D20
=
ꢀ14.1 (c=2.5, CHCl3); 1H NMR (400 MHz, CD2Cl2): d=6.94 (dt, J=
15.7, 6.4 Hz, 1H), 6.14 (dt, J=7.6, 1.5 Hz, 1H), 5.86 (dt, J=15.7, 1.6 Hz,
1H), 5.15–5.09 (m, 1H), 3.93–3.83 (m, 4H), 3.69 (s, 3H), 2.54–2.48 (m,
2H), 2.44 (dd, J=6.5, 1.0 Hz, 1H), 2.42 (dd, J=6.5, 2.0 Hz, 1H), 2.37 (d,
3H, J=1.4Hz), 2.33–2.30 (m, 2H), 1.96 (dd, J=14.8, 7.5 Hz, 1H), 1.82
(dd, J=14.8, 4.2 Hz, 1H), 1.29 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=172.0, 167.1, 147.6, 136.6, 122.3, 109.1, 96.8, 69.9, 65.1, 65.1,
51.8, 42.6, 36.4, 33.3, 28.2, 27.8, 24.6 ppm; IR (film): n˜ =2949, 1724, 1659,
1267, 1151, 1041 cmꢀ1; MS (EI): m/z (%): 437 (0.8) [M+ꢀMe], 350 (2),
294 (4), 279 (9), 210 (6), 171 (3), 141 (1), 109 (5), 87 (100); HRMS (ESI):
m/z: calcd for C17H25O6INa [M++Na]: 475.0588, found: 475.0590; ele-
mental analysis calcd (%) for C17H25O6I: C 45.14, H 5.57, found: C 45.19,
H 5.64.
Compound 52: Prepared analogously from alkyl iodide 50 (60 mg,
0.14 mmol) and vinyl iodide 35 (67 mg, 0.14 mmol) as a colorless oil
(71 mg, 79%). [a]2D0 =ꢀ32.3 (c=1.1, CH2Cl2); 1H NMR (400 MHz,
CD2Cl2): d=7.24 (d, J=8.4 Hz, 2H), 6.90 (dd, J=15.8, 8.7 Hz, 1H), 6.87
(d, J=8.4 Hz, 2H), 5.81 (dd, J=15.8, 1.3 Hz, 1H), 5.14–5.06 (m, 2H),
4.43 (d, J=11.2 Hz, 1H), 4.36 (d, J=11.2 Hz, 1H), 3.90–3.82 (m, 5H),
3.79 (s, 3H), 3.75–3.71 (m, 1H), 3.69 (s, 3H), 2.85–2.78 (m, 1H), 2.37 (dd,
J=15.4, 6.7 Hz, 1H), 2.29–2.23 (m, 3H), 2.12–1.90 (m, 3H), 1.92 (dd, J=
15.4, 7.8 Hz, 1H), 1.83 (dd, J=14.8, 3.5 Hz, 1H), 1.77 (dd, J=13.1,
3.8 Hz, 1H), 1.60 (s, 3H), 1.60–1.30 (m, 6H), 1.28 (s, 3H), 1.26 (s, 3H),
1.10 (d, J=6.8 Hz, 3H), 0.91 ppm (t, J=7.1 Hz, 3H); 13C NMR
(100 MHz, CD2Cl2): d=171.5, 167.4, 159.8, 152.9, 138.8, 131.3, 129.8,
120.3, 119.4, 114.2, 109.3, 84.7, 83.0, 82.6, 71.7, 71.2, 65.0, 65.0, 55.8, 51.8,
45.9, 43.1, 42.6, 41.2, 36.5, 34.3, 33.9, 33.5, 26.6, 24.6, 19.4, 18.4, 16.7,
15.1 ppm; IR (film): n˜ =2960, 2932, 1726, 1656, 1613, 1514, 1248, 1173,
1036 cmꢀ1; MS (EI): m/z (%): 630 (0.3) [M+], 140 (41), 121 (100), 87
(83); HRMS (ESI): m/z: calcd for C36H54O9Na [M++Na]: 653.3660,
found: 653.3662.
9-MeO-9-BBN-mediated Suzuki coupling reactions
Compound 39: A solution of tBuLi (2.2m in pentane, 180 mL, 0.39 mmol)
was added to a mixture of Et2O (90 mL) and THF (90 mL) at ꢀ788C
before a solution of iodide 19 (30 mg, 71 mmol) in THF (520 mL) was
added dropwise. The mixture was stirred for 5 min at this temperature
before 9-MeO-9-BBN (53 mL, 0.39 mmol) was added causing an immedi-
ate color change from bright yellow to colorless. Stirring was continued
for 5 min at ꢀ788C and for 1 h at ambient temperature, leading to the
formation of a white precipitate. Aq. K3PO4 (3m, 130 mL, 0.39 mmol) was
added followed by a solution of vinyl iodide 37 (35 mg, 65 mmol) in DMF
(520 mL) and a suspension of [(dppf)PdCl2]·CH2Cl2 (2.4 mg, 3.2 mmol)
and AsPh3 (2.0 mg, 6.4 mmol) in DMF (100 mL). The resulting mixture
was stirred for 90 min at ambient temperature before it was diluted with
hexanes/ethyl acetate 10:1 (2.0 mL) and filtered through a pad of basic
alumina, which was carefully rinsed (hexanes/ethyl acetate 10:1). The
combined filtrates were washed with aq. sat. NaHCO3, water, and brine,
before they were dried over Na2SO4, filtered and evaporated. The residue
was purified by flash chromatography (hexanes/ethyl acetate 15:1 + 1%
Et3N) to give compound 39 which contained traces of boron-containing
impurities. This material was used in the next step without further purifi-
cation; MS (EI): m/z (%): 690 (0.5) [M+], 361 (1), 329 (22), 207 (6), 151
(100); HRMS (ESI): m/z: calcd for C38H62O9SiNa [M++Na]: 713.4055,
found: 713.4060.
Compound 55: Prepared analogously from 50 (48 mg, 0.12 mmol) and
vinyl iodide 34 (54 mg, 0.12 mmol) as a colorless oil (46 mg, 63%).
[a]2D0 =ꢀ26.8 (c=1.1, CH2Cl2); 1H NMR (400 MHz, CD2Cl2): d=7.25 (d,
J=8.7 Hz, 2H), 6.95 (dt, J=15.7, 6.4 Hz, 1H), 6.87 (d, J=8.7 Hz, 2H),
5.85 (dt, J=15.7, 1.6 Hz, 1H), 5.07 (ddd, J=8.5, 4.5, 2.6 Hz, 1H), 5.01
(dd, J=9.4, 1.3 Hz, 1H), 4.44 (d, J=11.2 Hz, 1H), 4.36 (d, J=11.2 Hz,
1H), 3.91–3.81 (m, 5H), 3.79 (s, 3H), 3.75–3.71 (m, 1H), 3.69 (s, 3H),
2.65–2.56 (m, 1H), 2.53–2.47 (m, 2H), 2.47–2.40 (m, 2H), 2.13–1.94 (m,
2H), 1.97 (dd, J=13.1, 7.3 Hz, 1H), 1.87 (dd, J=15.0, 8.6 Hz, 1H), 1.79–
1.74 (m, 2H), 1.64 (d, J=1.3 Hz, 3H), 1.62–1.49 (m, 2H), 1.48–1.42 (m,
2H), 1.40–1.30 (m, 2H), 1.27 (s, 3H), 1.26 (s, 3H), 0.92 (t, J=7.2 Hz,
3H), 0.90 ppm (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CD2Cl2): d=
172.2, 167.2, 159.8, 147.867, 137.3, 131.3, 129.8, 125.8, 122.2, 114.2, 109.5,
84.7, 83.0, 82.5, 74.1, 71.7, 65.1, 64.9, 55.8, 51.8, 45.9, 43.1, 40.7, 37.5, 36.5,
34.0, 33.4, 27.9, 26.6, 24.5, 18.4, 17.0, 16.8, 15.1 ppm; IR (film): n˜ =2959,
2932, 1726, 1660, 1514, 1248, 1267, 1152 cmꢀ1; MS (EI): m/z (%): 615
(0.2) [M+ꢀMe], 140 (39), 121 (100), 87 (56); HRMS (ESI): m/z: calcd
for C36H54O9Na [M++Na]: 653.3660, found: 653.3665.
Compound 44: Prepared analogously from alkyl iodide 19 (43 mg,
0.10 mmol) and vinyl iodide 43 (45 mg, 0.1 mmol) as a colorless oil
(41 mg, 68%). [a]2D0 =ꢀ20.0 (c=1.0, CH2Cl2); 1H NMR (400 MHz,
CD2Cl2): d=6.91 (dd, J=15.8, 7.1 Hz, 1H), 6.87–6.82 (m, 3H), 5.82 (dd,
J=15.8, 1.4 Hz, 1H), 5.07–5.03 (m, 1H), 5.01 (dd, J=9.4, 1.1 Hz, 1H),
4.43 (d, J=11.4 Hz, 1H), 4.37 (d, J=11.4 Hz, 1H), 3.90–3.76 (m, 6H),
3.82 (s, 3H), 3.82 (s, 3H), 3.68 (s, 3H), 2.88–2.78 (m, 1H), 2.65–2.56 (m,
1H), 2.39 (dd, J=15.4, 6.8 Hz, 1H), 2.28 (dd, J=15.4, 7.4 Hz, 1H), 2.13–
2.06 (m, 1H), 2.04–1.98 (m, 1H), 1.94 (dd, J=13.0, 7.0 Hz, 1H), 1.88–
Compound 58: Prepared analogously from alkyl iodide 50 (38 mg,
91 mmol) and vinyl iodide 33 (40 mg, 83 mmol) as a colorless oil (39 mg,
1
73%). [a]2D0 =ꢀ25.2 (c=1.9, CH2Cl2); H NMR (400 MHz, C6D6): d=7.25
(d, J=8.6 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H), 5.43 (ddd, J=7.1, 4.4, 2.6 Hz,
1H), 5.28 (dd, J=9.3, 1.0 Hz, 1H), 4.36 (d, J=11.5 Hz, 1H), 4.29 (d, J=
Chem. Eur. J. 2009, 15, 4030 – 4043
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4039

A. Fꢀrstner et al.
11.5 Hz, 1H), 4.14 (dt, J=7.4, 5.0 Hz, 1H), 3.70–3.61 (m, 3H), 3.56–3.49
(m, 2H), 3.35 (s, 3H), 3.34 (s, 3H), 2.77–2.69 (m, 1H), 2.34–1.98 (m, 8H),
1.91 (dd, J=14.9, 2.5 Hz, 1H), 1.80–1.57 (m, 3H), 1.79 (dd, J=13.0,
7.3 Hz, 1H), 1.72 (dd, J=13.0, 4.1 Hz, 1H), 1.66 (d, J=1.2 Hz, 3H),
1.51–1.33 (m, 5H), 1.38 (s, 3H), 1.35 (s, 3H), 1.01 (d, J=6.9 Hz, 3H),
0.90 (t, J=7.2 Hz, 3H), 0.86 ppm (d, J=6.4 Hz, 3H); 13C NMR
(100 MHz, C6D6): d=173.3, 171.9, 159.8, 136.9, 131.2, 129.4, 126.2, 114.2,
109.4, 84.5, 82.4, 82.2, 73.2, 71.5, 64.6, 64.6, 54.9, 51.0, 45.7, 43.2, 41.9,
41.0, 37.4, 36.5, 33.9, 31.9, 31.9, 30.0, 26.4, 24.6, 19.5, 18.2, 17.0, 16.6,
HRMS (ESI): m/z: calcd for C33H48O9Na [M++Na]: 611.3191, found:
611.3196.
An aqueous phosphate buffer solution (pH 7, 0.85 mL) was added to a
solution of this carboxylic acid (20 mg, 34 mmol) in CH2Cl2 (1.0 mL)
before DDQ (23 mg, 0.10 mmol) was introduced in portions at 08C. The
resulting mixture was vigorously stirred for 5 h before it was diluted with
water (2.5 mL) and CH2Cl2 (3 mL). The aqueous layer was repeatedly ex-
tracted with CH2Cl2, the combined extracts were dried over Na2SO4, fil-
tered, and evaporated, and the residue was purified by flash chromatog-
raphy (hexanes/ethyl acetate 2:1 + 1% HOAc ! 1:1 + 1% HOAc) to
afford 46 as a colorless oil (12 mg, 81%). [a]2D0 =ꢀ25.8 (c=0.6, CH2Cl2);
1H NMR (400 MHz, CDCl3): d=6.98 (dd, J=15.7, 7.4 Hz, 1H), 5.80 (d,
J=15.7 Hz, 1H), 5.36–5.22 (m, 1H), 5.93 (d, J=9.3 Hz, 1H), 4.72 (brs,
2H), 4.12–4.08 (m, 1H), 3.83–3.73 (m, 1H), 3.14–3.01 (m, 1H), 2.86–2.79
(m, 1H), 2.67–2.31 (m, 4H), 2.15–2.06 (m, 3H), 2.12 (s, 3H), 1.83–1.79
(m, 1H), 1.70–1.57 (m, 2H), 1.59 (d, J=0.8 Hz, 3H), 1.37 (s, 3H), 1.29 (s,
3H), 1.12 (d, J=6.8 Hz, 3H), 0.92 ppm (d, J=6.9 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=205.9, 171.1, 169.2, 153.8, 136.8, 125.1, 120.3, 84.1,
84.0, 80.5, 73.7, 47.3, 46.0, 41.0, 35.9, 35.6, 33.3, 32.3, 30.3, 30.2, 28.7, 19.2,
17.4, 16.3 ppm; IR (film): n˜ =3384, 2969, 2933, 1715, 1652 cmꢀ1; MS (EI):
m/z (%): 438 (< 0.5) [M+], 280 (10), 128 (76), 97 (30), 71 (40), 55 (22),
43 (100); HRMS (ESI): m/z: calcd for C24H38O7Na [M++Na]: 461.2510,
found: 461.2510.
15.0 ppm; IR (film): n˜ =2959, 2932, 1734, 1514, 1452, 1249, 1171 cmꢀ1
;
MS (EI): m/z (%): 646 (0.3) [M+], 472 (6), 370 (4), 157 (11), 140 (36),
121 (100); HRMS (ESI): m/z: calcd for C37H58O9Na [M++Na]: 669.3973,
found: 669.3969.
Preparation of the seco-acids
Compound 40: DDQ (28 mg, 120 mmol) was added in portions to a vigo-
rously stirred solution of 39 in CH2Cl2 (1.4 mL) and aq. phosphate buffer
solution (pH 7, 1.4 mL) at 08C and the resulting mixture was stirred for
3 h at this temperature. CH2Cl2 (3.0 mL) was introduced and the reaction
quenched with aq. sat. NaHCO3 (2.5 mL). The aqueous phase was re-
peatedly extracted with CH2Cl2 and the combined organic layers were
dried over Na2SO4, filtered, and evaporated. The residue was purified by
flash chromatography (hexanes/ethyl acetate 25:1 + 1% Et3N ! 5:1 +
1% Et3N) to give compound 40 as a colorless oil (11 mg, 45% over two
steps). [a]2D0 =ꢀ36.5 (c=0.84, CH2Cl2); 1H NMR (400 MHz, CD2Cl2): d=
7.00 (dd, J=15.8, 7.2 Hz, 1H), 5.74 (dd, J=15.8, 1.3 Hz, 1H), 5.10 (dd,
J=9.3, 1.2 Hz, 1H), 4.12–4.07 (m, 1H), 3.94–3.88 (m, 1H), 3.74–3.68 (m,
1H), 3.68 (s, 3H), 3.14 (s, 3H), 2.70–2.60 (m, 1H), 2.45 (d, J=4.5 Hz,
1H), 2.41–2.31 (m, 1H), 2.18–2.04 (m, 2H), 1.99 (dd, J=13.0, 7.2 Hz,
1H), 1.94 (dd, J=12.8, 5.7 Hz, 1H), 1.84–1.72 (m, 4H), 1.70–1.54 (m,
2H), 1.63 (d, J=1.3 Hz, 3H), 1.34 (s, 3H), 1.30 (s, 3H), 1.22 (s, 3H), 1.07
(d, J=6.9 Hz, 3H), 0.83 (d, J=6.8 Hz, 3H), 0.19 ppm (s, 9H); 13C NMR
(100 MHz, CD2Cl2): d=168.1, 157.3, 134.7, 129.3, 118.6, 110.7, 85.8, 85.3,
82.8, 80.3, 76.9, 51.7, 48.7, 47.6, 44.2, 39.5, 36.3, 35.8, 32.7, 32.6, 30.6, 29.0,
22.7, 20.4, 17.4, 16.4, 2.5 ppm; IR (film): n˜ =3454, 2965, 2930, 1726, 1654,
1251, 841 cmꢀ1; MS (EI): m/z (%): 420 (27), 235 (2), 166 (3), 151 (100);
HRMS (ESI): m/z: calcd for C29H52O7SiNa [M++Na]: 563.3374, found:
563.3371.
Compound 48: Prepared analogously from ester 47 (43 mg, 70 mmol) as a
colorless oil (22 mg, 56% over two steps). [a]2D0 =ꢀ40.9 (c=1.2, CH2Cl2);
1H NMR (400 MHz, CD2Cl2): d=7.00 (dt, J=15.7, 6.5 Hz, 1H), 6.87–6.82
(m, 3H), 5.83 (dt, J=15.7, 1.5 Hz, 1H), 5.26–5.20 (m, 1H), 5.12 (dt, J=
7.4, 1.1 Hz, 1H), 4.45 (d, J=11.4 Hz, 1H), 4.37 (d, J=11.4 Hz, 1H),
3.92–3.77 (m, 2H), 3.82 (s, 3H), 3.82 (s, 3H), 2.70 (dd, J=16.7, 7.7 Hz,
1H), 2.60 (dd, J=16.7, 5.0 Hz, 1H), 2.53–2.23 (m, 6H), 2.13–1.99 (m,
2H), 2.01 (s, 3H), 1.95 (dd, J=13.0, 6.9 Hz, 1H), 1.87 (dd, J=13.0,
4.0 Hz, 1H), 1.66–1.53 (m, 2H), 1.60 (s, 3H), 1.32 (s, 3H), 1.25 ppm (s,
3H); 13C NMR (100 MHz, CD2Cl2): d=206.1, 172.0, 170.321, 149.8, 149.7,
149.4, 139., 131.7, 122.1, 120.8, 118.8, 112.1, 111.9, 84.6, 83.0, 81.0, 72.0,
70.959, 56.4, 56.3, 47.5, 44.8, 36.4, 33.8, 33.1, 32.9, 30.7, 30.3, 28.6, 28.0,
16.6 ppm; IR (film): n˜ =2968, 2934, 1716, 1656, 1593, 1515, 1420, 1260,
1156 cmꢀ1; MS (EI): m/z (%): 560 (<0.4) [M+], 416 (6), 151 (100).
Compound 46: LiI (220 mg, 1.6 mmol) was added to a solution of ester
44 (42 mg, 65 mmol) in pyridine (2 mL) and the resulting mixture was
stirred for 30 h at 1258C. After cooling to 08C, the mixture was diluted
with CH2Cl2 (10 mL) and acidified with aq. HCl (2m) to pH ꢂ2. The
aqueous phase was repeatedly extracted with CH2Cl2, the combined or-
ganic layers were dried over Na2SO4, filtered and evaporated. The resi-
due was rapidly passed through a pad of silica (hexanes/ethyl acetate 1:1
+ 1% HOAc) and the acid 45 thus formed was used in the next step
without further purification.
Compound 49: Prepared analogously from compound 48 (20 mg,
36 mmol) as a colorless oil (12 mg, 82%). [a]2D0 =ꢀ30.7 (c=1.1, CH2Cl2);
1H NMR (400 MHz, CD2Cl2): d=7.00 (dt, J=15.7, 6.4 Hz, 1H), 5.83 (dt,
J=15.7, 1.5 Hz, 1H), 5.28–5.22 (m, 1H), 5.13 (dt, J=15.7, 1.2 Hz, 1H),
4.53 (brs, 1H), 4.05 (dt, J=7.3, 5.2 Hz, 1H), 3.71 (dt, J=7.3, 5.2 Hz, 1H),
2.72 (dd, J=16.7, 7.6 Hz, 1H), 2.61 (dd, J=16.7, 5.2 Hz, 1H), 2.53–2.42
(m, 4H), 2.31–2.28 (m, 2H), 2.17–2.01 (m, 3H), 2.12 (s, 3H), 1.76 (dd,
J=12.9, 5.1 Hz, 1H), 1.68–1.53 (m, 2H), 1.61 (s, 3H), 1.32 (s, 3H),
1.24 ppm (s, 3H); 13C NMR (100 MHz, CD2Cl2): d=206.1, 172.1 (2C),
149.4, 139.2, 122.2, 119.1, 84.9, 80.6, 77.4, 71.0, 47.9, 47.7, 36.4, 33.3, 33.0,
33.0, 30.8, 30.5, 29.1, 28.0, 16.6 ppm; IR (film): n˜ =3413, 2972, 2930, 1716,
1655, 1159 cmꢀ1; MS (EI): m/z (%): 410 (<0.4) [M+], 266 (11), 248 (3),
205 (5), 181 (7), 163 (8), 115 (6), 145 (8), 137 (8), 128 (100); HRMS
(ESI): m/z: calcd for C22H34O7Na [M++Na]: 433.2197, found: 433.2197.
H2O (1.0 mL) was added to a solution of 45 in HOAc (1.0 mL) and the
resulting mixture was stirred for 30 min at 658C. After cooling to ambi-
ent temperature, the mixture was diluted with ethyl acetate (3 mL) and
H2O (3 mL), the aqueous phase was repeatedly extracted with ethyl ace-
tate, the combined extracts were dried over Na2SO4, filtered, and evapo-
rated, and the residue was purified by flash chromatography (hexanes/
ethyl acetate 2:1 + 1% HOAc) to afford the corresponding carboxylic
acid as a colorless oil (22 mg, 58% over two steps). [a]2D0 =ꢀ30.2 (c=1.1,
CH2Cl2); 1H NMR (400 MHz, CD2Cl2): d=6.99 (dd, J=15.7, 7.2 Hz,
1H), 6.87–6.82 (m, 3H), 5.78 (dd, J=15.7, 1.3 Hz, 1H), 5.21–5.16 (m,
1H), 5.01 (dd, J=9.7, 1.0 Hz, 1H), 4.45 (d, J=11.3 Hz, 1H), 4.37 (d, J=
11.3 Hz, 1H), 3.93–3.87 (m, 1H), 3.83–3.78 (m, 1H), 3.82 (s, 3H), 3.82 (s,
3H), 3.13–3.07 (m, 1H), 3.13–3.07 (m, 1H), 2.87–2.78 (m, 1H), 2.68–2.49
(m, 3H), 2.53 (dd, J=16.8, 5.0 Hz, 1H), 2.36 (d, J=6.9 Hz, 1H), 2.14–
2.01 (m, 1H), 2.08 (s, 3H), 1.97 (dd, J=13.0, 7.0 Hz, 1H), 1.88 (dd, J=
13.0, 4.0 Hz, 1H), 1.68–1.56 (m, 2H), 1.59 (d, J=1.3 Hz, 3H), 1.33 (s,
3H), 1.27 (s, 3H), 1.11 (d, J=6.8 Hz, 3H), 0.91 ppm (d, J=6.9 Hz, 3H);
13C NMR (100 MHz, CD2Cl2): d=206.4, 177.6, 171.5, 155.1, 149.7, 149.4,
137.8, 132.0, 125.4, 120.7, 120.3, 112.0, 111.8, 84.6, 83.0, 81.1, 74.0, 71.9,
56.4, 56.3, 45.8, 44.7, 41.1, 36.4, 36.2, 33.8, 30.7, 30.2, 28.5, 21.1, 19.2, 17.1,
16.7 ppm; IR (film): n˜ =3422, 2968, 2933, 1716, 1654, 1515, 1260,
1157 cmꢀ1; MS (EI): m/z (%): 588 (<0.5) [M+], 430 (8), 151 (100);
Compound 53: Prepared analogously from ester 52 (59 mg, 94 mmol) as a
colorless oil (29 mg, 54% over two steps). [a]2D0 =ꢀ33.3 (c=1.4, CH2Cl2);
1H NMR (400 MHz, CD2Cl2): d=7.25 (d, J=8.7 Hz, 2H), 6.94 (dd, J=
15.7, 7.4 Hz, 1H), 6.87 (d, J=8.7 Hz, 2H), 5.73 (dd, J=15.7, 1.3 Hz, 1H),
5.25–5.19 (m, 1H), 5.12–5.09 (m, 1H), 4.44 (d, J=11.3 Hz, 1H), 4.36 (d,
J=11.3 Hz, 1H), 3.91–3.85 (m, 1H), 3.79 (s, 3H), 3.76–3.72 (m, 1H),
2.86–2.79 (m, 1H), 2.69 (dd, J=16.7, 7.7 Hz, 1H), 2.58 (dd, J=16.7,
5.1 Hz, 1H), 2.34–2.24 (m, 3H), 2.13–2.01 (m, 3H), 2.10 (s, 3H), 1.99 (dd,
J=13.1, 7.3 Hz, 1H), 1.79 (dd, J=13.1, 4.0 Hz, 1H), 1.65–1.25 (m, 6H),
1.60 (s, 3H), 1.28 (s, 3H), 1.11 (d, J=6.8 Hz, 3H), 0.91 ppm (t, J=7.2 Hz,
3H); 13C NMR (100 MHz, CD2Cl2): d=206.0, 171.5, 170.0, 159.9, 154.3,
139.3, 131.2, 129.8, 120.5, 118.9, 114.3, 84.4, 83.6, 82.5, 71.7, 70.9, 55.8,
47.5, 45.8, 43.0, 41.2, 36.3, 34.0, 33.5, 32.9, 30.7, 26.6, 19.4, 18.5, 16.6,
15.0 ppm; IR (film): n˜ =3150, 2959, 2931, 1718, 1698, 1656, 1613, 1513,
1455, 1247 cmꢀ1; MS (EI): m/z (%): 414 (3), 190 (2), 140 (17), 121 (100);
HRMS (ESI): m/z: calcd for C33H48O8Na [M++Na]: 595.3241, found:
595.3238.
4040
www.chemeurj.org
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 4030 – 4043

Amphidinolide X and Y
FULL PAPER
Compound 54: Prepared analogously from compound 53 (25 mg,
44 mmol) as a colorless oil (14 mg, 71%). [a]2D0 =ꢀ31.6 (c=1.1, CH2Cl2);
1H NMR (400 MHz, CD2Cl2): d=6.91 (dd, J=15.7, 7.7 Hz, 1H), 5.79 (dd,
J=15.7, 1.2 Hz, 1H), 5.28–5.22 (m, 1H), 5.14–5.10 (m, 1H), 4.01 (dt, J=
7.4, 5.1 Hz, 1H), 3.74 (dt, J=7.7, 4.9 Hz, 1H), 2.87–2.80 (m, 1H), 2.71
(dd, J=16.7, 7.5 Hz, 1H), 2.58 (dd, J=16.7, 5.4 Hz, 1H), 2.40–2.27 (m,
4H), 2.15–2.06 (m, 3H), 2.11 (s, 3H), 1.69 (dd, J=13.1, 5.0 Hz, 1H),
1.66–1.42 (m, 4H), 1.60 (s, 3H), 1.37–1.27 (m, 3H), 1.30 (s, 3H), 1.11 (d,
J=6.8 Hz, 3H), 0.91 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz,
CD2Cl2): d=206.2, 171.8 (2C), 154.2, 139.1, 120.9, 119.4, 84.5, 83.6, 77.4,
71.0, 47.8, 46.4, 46.2, 41.6, 36.5, 34.3, 33.1, 32.9, 30.9, 27.3, 19.8, 18.6, 16.7,
15.2 ppm; IR (film): n˜ =3439, 2964, 2930, 1717, 1654, 1264 cmꢀ1; MS (EI):
m/z (%): 452 (0.7) [M+], 294 (16), 233 (6), 181 (8), 163 (10), 156 (89),
122 (30), 95 (53), 84 (56), 71 (52), 55 (30), 43 (100); HRMS (ESI): m/z:
calcd for C25H40O7Na [M++Na]: 475.2666, found: 475.2664.
13C NMR (100 MHz, C6D6): d=204.8, 177.4, 172.1, 137.4, 125.8, 84.0,
82.6, 77.2, 73.9, 46.4, 46.2, 45.8, 41.9, 36.6, 36.4, 32.9, 32.1, 31.8, 30.1, 30.1,
27.2, 19.7, 18.4, 17.8, 17.1, 15.1 ppm; IR (film): n˜ =3421, 2961, 2932, 1723,
1713, 1154 cmꢀ1; MS (EI): m/z (%): 308 (17), 247 (5), 211 (5), 177 (7),
156 (87), 137 (13), 107 (35), 101 (27), 84 (59), 71 (37), 55 (47), 43 (100);
HRMS (ESI): m/z: calcd for C26H44O7Na [M++Na]: 491.2979, found:
491.2981.
Yamaguchi lactonizations and elaboration of the analogues
Compound 4: Et3N (8.6 mL, 62 mmol) and 2,4,6-trichlorobenzoyl chloride
(4.8 mL, 31 mmol) were successively added to
a solution of acid 46
(9.0 mg, 21 mmol) in THF (600 mL). The mixture was stirred for 1 h at
ambient temperature before most of the THF was removed under a flow
of Ar. The residue was dissolved in toluene (8.0 mL) and added via sy-
ringe pump over 2 h to a solution of DMAP (50 mg, 0.41 mmol) in tolu-
ene (30 mL) at ambient temperature. Once the addition was complete,
the mixture was stirred for 2 h before the reaction was quenched with aq.
sat. NH4Cl. The organic layer was washed with brine, dried over Na2SO4,
filtered and evaporated, and the residue was purified by flash chromatog-
raphy (hexanes/ethyl acetate 7:1) to afford compound 4 as a colorless oil
(4.8 mg, 56%). [a]2D0 =ꢀ32.4 (c=0.5, CHCl3); 1H NMR (400 MHz,
CDCl3): d=7.12 (dd, J=15.8, 7.2 Hz, 1H), 5.78 (d, J=15.8 Hz, 1H),
5.26–5.19 (m, 2H), 4.96 (d, J=10.3 Hz, 1H), 3.97 (dt, J=11.0, 3.7 Hz,
1H), 2.81–2.66 (m, 2H), 2.69 (dd, J=16.1, 6.0 Hz, 1H), 2.61–2.55 (m,
2H), 2.41 (dd, J=13.3, 6.4 Hz, 1H), 2.20–2.08 (m, 3H), 2.14 (s, 3H),
2.00–1.92 (m, 1H), 1.85 (dd, J=13.8, 1.4 Hz, 1H), 1.55 (s, 3H), 1.60–1.52
(m, 1H), 1.34 (s, 3H), 1.32 (s, 3H), 1.15 (d, J=6.9 Hz, 3H), 0.92 ppm (d,
J=6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=205.3, 170.6, 165.7,
153.1, 135.4, 126.1, 120.2, 81.0, 80.4, 78.7, 74.3, 47.2, 45.5, 41.5, 35.6, 35.3,
33.1, 30.6, 30.3, 28.8, 26.4, 18.1, 17.5, 15.4 ppm; IR (film): n˜ =2966, 2928,
1735, 1365 cmꢀ1; MS (EI): m/z (%): 420 (29) [M+], 255 (31), 141 (14),
110 (51), 95 (32), 59 (38), 43 (100); HRMS (ESI): m/z: calcd for
C24H36O6Na [M++Na]: 443.2404, found: 443.2407.
Compound 56: Prepared analogously from ester 55 (35 mg, 55 mmol) as a
colorless oil (25 mg, 52% over two steps). [a]2D0 =ꢀ28.3 (c=0.95,
CH2Cl2); 1H NMR (400 MHz, CD2Cl2): d=7.25 (d, J=8.6 Hz, 2H), 7.02
(dt, J=15.7, 6.4 Hz, 1H), 6.87 (d, J=8.6 Hz, 2H), 5.83 (dt, J=15.7,
1.5 Hz, 1H), 5.22–5.18 (m, 1H), 5.01 (dd, J=9.4, 0.8 Hz, 1H), 4.44 (d, J=
11.2 Hz, 1H), 4.36 (d, J=11.2 Hz, 1H), 3.93–3.83 (m, 1H), 3.79 (s, 3H),
3.77–3.72 (m, 1H), 3.69 (s, 3H), 2.70–2.41 (m, 6H), 2.12–1.96 (m, 2H),
2.08 (s, 3H), 1.78 (dd, J=13.0, 4.0 Hz, 1H), 1.61 (d, J=1.2 Hz, 3H),
1.66–1.44 (m, 4H), 1.38–1.26 (m, 2H), 1.27 (s, 3H), 0.93 (d, J=6.8 Hz,
3H), 0.92 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CD2Cl2): d=
206.3, 172.1, 170.2, 159.9, 149.9, 137.9, 131.2, 129.8, 125.4, 122.0, 114.3,
84.5, 83.4, 82.5, 74.0, 71.8, 55.8, 45.9, 45.8, 43.0, 36.5, 36.3, 33.7, 33.2, 30.7,
28.1, 26.5, 18.5, 17.2, 16.7, 15.0 ppm; IR (film): n˜ =2959, 2933, 1720, 1654,
1514, 1248, 1267, 1172 cmꢀ1; MS (EI): m/z (%): 428 (3), 140 (24), 121
(100); HRMS (ESI): m/z: calcd for C33H48O8Na [M++Na]: 595.3241,
found: 595.3238.
Compound 57: Prepared analogously from compound 56 (22 mg,
38 mmol) as a colorless oil (14 mg, 81%). [a]2D0 =ꢀ28.2 (c=0.9, CH2Cl2);
1H NMR (400 MHz, CD2Cl2): d=7.02 (dt, J=15.7, 6.4 Hz, 1H), 5.84 (dt,
J=15.7, 1.3 Hz, 1H), 5.22–5.18 (m, 1H), 5.02 (dd, J=9.7, 1.0 Hz, 1H),
4.04–3.96 (m, 1H), 3.72–3.68 (m, 1H), 2.69–2.42 (m, 7H), 2.17–2.01 (m,
3H), 2.10 (s, 3H), 1.69–1.55 (m, 4H), 1.62 (d, J=1.1 Hz, 3H), 1.48–1.27
(m, 5H), 1.28 (s, 3H), 0.93 (d, J=6.7 Hz, 3H), 0.91 ppm (t, J=7.2 Hz,
3H); 13C NMR (100 MHz, CD2Cl2): d=206.4, 172.2, 169.9, 149.8, 137.7,
125.6, 122.2, 84.2, 82.9, 77.2, 74.2, 46.2, 46.2, 45.9, 36.5, 36.4, 33.3, 32.9,
30.7, 28.0, 27.1, 18.4, 17.4, 16.7, 15.0 ppm; IR (film): n˜ =2961, 2932, 1715,
1656, 1256, 1154 cmꢀ1; MS (EI): m/z (%): 452 (<0.9) [M+], 308 (20), 247
(6), 211 (7), 177 (9), 156 (100); HRMS (ESI): m/z: calcd for C25H40O7Na
[M++Na]: 475.2666, found: 475.2672.
Compound 5: Prepared analogously from seco-acid 57 (10 mg, 23 mmol)
as a colorless oil (5.8 mg, 58%). [a]2D0 =ꢀ29.4 (c=0.6, CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.12–7.05 (m, 1H), 5.85 (d, J=15.6 Hz, 1H),
5.23–5.19 (m, 1H), 5.16–5.13 (m, 1H), 4.97 (d, J=10.3 Hz, 1H), 3.94 (dt,
J=11.0, 3.7 Hz, 1H), 2.76 (dd, J=16.4, 6.0 Hz, 1H), 2.74–2.66 (m, 1H),
2.58 (dd, J=16.4, 7.2 Hz, 1H), 2.54–2.38 (m, 3H), 2.22–2.08 (m, 3H),
2.14 (s, 3H), 1.95 (tt, J=13.1, 3.3 Hz, 1H), 1.74 (dd, J=13.9, 2.5 Hz, 1H),
1.57–1.30 (m, 6H), 1.55 (s, 3H), 1.28 (s, 3H), 0.94 (d, J=6.9 Hz, 3H),
0.93 ppm (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=205.6,
172.2, 165.6, 148.1, 135.7, 126.1, 123.0, 83.0, 80.7, 78.5, 74.7, 47.0, 44.4,
43.7, 35.7, 35.5, 34.5, 30.6, 30.5, 28.5, 24.7, 18.2, 17.9, 15.4, 14.7 ppm; IR
(film): n˜ =2960, 2931, 1719, 1659 cmꢀ1; MS (EI): m/z (%): 434 (83) [M+],
308 (14), 290 (13), 269 (36), 247 (13), 193 (16), 153 (25), 138 (66), 125
(30), 107 (29), 95 (66), 82 (16), 67 (19), 55 (35), 43 (100); HRMS (ESI):
m/z: calcd for C25H38O6Na [M++Na]: 457.2561, found: 457.2557.
Compound 59: Prepared analogously from ester 58 (37 mg, 57 mmol) as a
colorless oil (23 mg, 68% over 2 steps). [a]2D0 =ꢀ29.5 (c=1.1, CH2Cl2);
1H NMR (400 MHz, C6D6): d=7.24 (d, J=8.7 Hz, 2H), 6.83 (d, J=
8.7 Hz, 2H), 5.46–5.42 (m, 1H), 5.21 (dd, J=9.6, 1.1 Hz, 1H), 4.36 (d, J=
11.5 Hz, 1H), 4.26 (d, J=11.5 Hz, 1H), 4.17–4.13 (m, 1H), 3.70–3.65 (m,
1H), 3.34 (s, 3H), 2.76 (ddd, J=9.6, 6.9, 4.3 Hz, 1H), 2.49 (dd, J=16.3,
7.7 Hz, 1H), 2.31 (dd, J=16.3, 5.4 Hz, 1H), 2.26–1.87 (m, 7H), 1.82–1.48
(m, 7H), 1.74 (s, 3H), 1.60 (d, J=1.2 Hz, 3H), 1.40–1.31 (m, 4H), 1.37 (s,
3H), 0.96 (d, J=6.9 Hz, 3H), 0.90 (t, J=7.2 Hz, 3H), 0.80 ppm (d, J=
6.4 Hz, 3H); 13C NMR (100 MHz, C6D6): d=204.3, 177.7, 171.7, 159.9,
137.3, 131.0, 129.5, 125.8, 114.2, 84.2, 83.0, 82.2, 73.5, 71.5, 54.9, 45.7, 45.5,
43.0, 41.6, 36.3, 36.1, 33.5, 31.7, 31.6, 30.0, 29.8, 26.3, 19.4, 18.2, 17.2, 16.7,
14.9 ppm; IR (film): n˜ =3114, 2961, 2932, 1731, 1711, 1514, 1456, 1248,
1172 cmꢀ1; MS (EI): m/z (%): 428 (3), 331 (2), 190 (3), 140 (23), 121
(100); HRMS (ESI): m/z: calcd for C34H52O8Na [M++Na]: 611.3554,
found: 611.3560.
Compound 6: Prepared analogously from acid 54 (15 mg, 34 mmol) as a
colorless oil (4.8 mg, 32%). Because of the sensitivity of the product, the
flash chromatography should be carried out as fast as possible. [a]D20
=
ꢀ35.4 (c=0.8, C6H6); 1H NMR (400 MHz, C6D6): d=7.00 (dd, J=15.8,
7.3 Hz, 1H), 5.92 (dd, J=15.8, 1.1 Hz, 1H), 5.47–5.41 (m, 1H), 5.27–5.19
(m, 2H), 4.14 (ddd, J=10.4, 5.3, 3.1 Hz, 1H), 2.50–2.37 (m, 1H), 2.44
(dd, J=16.1, 6.9 Hz, 1H), 2.22–2.19 (m, 2H), 2.14–1.99 (m, 7H), 1.69 (s,
3H), 1.65 (dd, J = 13.6, 3.9 Hz, 1H), 1.53–1.25 (m, 5H), 1.38 (s, 3H),
1.23 (s, 3H), 0.85 (t, J=7.1 Hz, 3H), 0.70 ppm (d, J=7.0 Hz, 3H);
13C NMR (100 MHz, C6D6): d=203.6, 170.7, 165.2, 151.8, 136.3, 121.3,
121.0, 82.2, 80.3, 78.8, 70.3, 47.5, 44.8, 44.4, 41.0, 35.5, 33.9, 32.5, 31.2,
29.7, 25.4, 19.1, 18.0, 15.5, 14.8 ppm; IR: n˜ =2961, 2932, 1717, 1654,
1268 cmꢀ1; MS (EI): m/z (%): 434 (62) [M+], 309 (7), 294 (36), 283 (17),
233 (9), 181 (8), 151 (16), 138 (100), 123 (25), 113 (25), 95 (82), 81 (24),
55 (25), 43 (93); HRMS (ESI): m/z: calcd for C25H38O6Na [M++Na]:
457.2561, found: 457.2560.
Compound 60: Prepared analogously from compound 59 (22 mg,
37 mmol) as
a
colorless oil (12.5 mg, 71%). [a]2D0 =ꢀ28.2 (c=1.1,
CH2Cl2); 1H NMR (400 MHz, C6D6): d=5.43 (dt, J=7.2, 5.2 Hz, 1H),
5.29 (brs, 2H), 5.23 (dd, J=9.6, 1.0 Hz, 1H), 3.91–3.85 (m, 2H), 2.75–
2.64 (m, 1H), 2.49 (dd, J=16.3, 7.5 Hz, 1H), 2.31 (dd, J=16.3, 5.4 Hz,
1H), 2.25–2.08 (m, 5H), 2.02–1.88 (m, 3H), 1.81–1.57 (m, 4H), 1.75 (s,
3H), 1.59 (d, J=1.0 Hz, 3H), 1.49–1.25 (m, 5H), 1.35 (s, 3H), 0.95 (d, J=
6.8 Hz, 3H), 0.87 (t, J=7.1 Hz, 3H), 0.80 ppm (d, J=6.2 Hz, 3H);
Compound 7: Prepared analogously from seco-acid 49 (6.0 mg, 15 mmol)
as a colorless oil (0.9 mg, 16%). Because of the sensitivity of the product,
the flash chromatography should be carried out as fast as possible. [a]D20
=
ꢀ24 (c=0.3, C6H6); 1H NMR (400 MHz, C6D6): d=6.96 (dt, J=15.8,
6.5 Hz, 1H), 5.86 (d, J=15.8 Hz, 1H), 5.37 (dq, J=6.4, 4.2 Hz, 1H), 5.27
Chem. Eur. J. 2009, 15, 4030 – 4043
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4041

A. Fꢀrstner et al.
(ddd, J=8.6, 5.1, 3.7 Hz, 1H), 5.17 (t, J=6.6 Hz, 1H), 4.09 (ddd, J=8.2,
5.1, 3.1 Hz, 1H), 2.45 (dd, J=16.2, 6.6 Hz, 1H), 2.23–2.20 (m, 2H), 2.14–
1.92 (m, 9H), 1.72–1.64 (m, 1H), 1.68 (s, 3H), 1.50–1.42 (m, 1H), 1.37 (s,
3H), 1.24 (s, 3H), 1.17 ppm (s, 3H); 13C NMR (100 MHz, C6D6): d=
203.6, 171.2, 165.0, 147.2, 136.2, 123.1, 121.0, 80.6, 79.9, 78.8, 70.6, 47.3,
45.9, 35.4, 33.4, 32.3, 31.3, 29.7, 29.2, 27.7, 27.1, 15.2 ppm; HRMS (ESI):
m/z: calcd for C22H32O6Na [M++Na]: 415.2091, found: 415.2091.
(film): n˜ =3491, 2970, 2929, 1717 cmꢀ1; HRMS (ESI): m/z: calcd for
C24H38O6Na [M++Na]: 445.2561, found: 445.2563.
Cytotoxicity assays: Six of the ten cell lines were established from pa-
tient-derived tumor xenografts passaged subcutaneously in nude mice;
the origin of the donor xenografts has already been described.[46,47] The
other four cell lines were obtained from American Type Culture Collec-
tion (22RV1), Rockville, MD, USA or the National Cancer Institute
(HT29, OVCAR-3, PC3M), Bethesda, MD, USA. All cells were grown at
378C in a humidified atmosphere (95% air, 5% CO2) in RPMI 1640
medium (PAA, Cçlbe, Germany) supplemented with 10% fetal calf
serum (PAA) and 0.1 mgmLꢀ1 gentamicin (PAA). A modified propidium
iodide assay was used to assess the effects of the compounds.[48] Tumor
derived cell lines were incubated in 96 multi-well plates. After one day,
the compounds under test were added to the plates at five concentrations
in the range from 0.001 mg up to 10 mgmLꢀ1 and left for further four
days. The inhibition of proliferation was determined by measuring the
DNA content using an aqueous propidium iodide solution (7 mgmLꢀ1).
Fluorescence was measured using the Cytofluor 4000. In each experi-
ment, all data points were determined in triplicate.
Compound 8: Prepared analogously from seco-acid 60 (10 mg, 21 mmol)
as a colorless oil (5.7 mg, 59%). [a]2D0 =ꢀ25.2 (c=0.8, CHCl3); 1H NMR
(400 MHz, CDCl3): d=5.18 (ddd, J=7.6, 5.6, 2.3 Hz, 1H), 5.05 (ddd, J=
7.3, 6.5, 2.9 Hz, 1H), 5.00 (dd, J=10.2, 0.7 Hz, 1H), 4.05 (ddd, J=8.9,
5.7, 3.9 Hz, 1H), 2.72 (dd, J=16.7, 5.5 Hz, 1H), 2.75–2.66 (m, 1H), 2.61
(dd, J=16.7, 7.5 Hz, 1H), 2.51–2.43 (m, 1H), 2.40–2.33 (m, 1H), 2.28–
1.99 (m, 5H), 2.25 (dd, J=6.3, 3.5 Hz, 1H), 2.14 (s, 3H), 1.83–1.61 (m,
4H), 1.71 (dd, J=13.8, 2.5 Hz, 1H), 1.57 (s, 3H), 1.54–1.44 (m, 2H),
1.39–1.29 (m, 2H), 1.27 (s, 3H), 1.02 (d, J=6.7 Hz, 3H), 0.98 (d, J=
6.9 Hz, 3H), 0.93 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=205.6, 172.6, 171.7, 135.0, 125.7, 82.9, 80.3, 79.1, 74.4, 46.8, 45.0, 43.0,
41.2, 35.5, 34.7, 32.5, 31.5, 31.1, 30.4, 29.6, 25.7, 20.1, 18.4, 17.9, 16.6,
14.6 ppm; IR (film): n˜ =2960, 2929, 1731, 1256 cmꢀ1; MS (EI): m/z (%):
450 (61) [M+], 392 (10), 311 (11), 308 (11), 290 (22), 285 (90), 247 (17),
198 (22), 138 (100), 125 (70), 107 (48), 95 (54), 82 (26), 69 (25), 43 (88);
HRMS (ESI): m/z: calcd for C26H42O6Na [M++Na]: 473.2874, found:
473.2876.
Acknowledgements
Compound 9: A solution of LiOH (11 mg, 44 mmol) in MeOH (400 mL)
was added to a solution of ester 40 (8.0 mg, 15 mmol) in THF/H2O 1:1
(200 mL). The mixture was stirred for 15 h at ambient temperature,
cooled to 08C and diluted with tert-butyl methyl ether (2 mL) before the
reaction was quenched with aq. sat. NH4Cl (300 mL). The aqueous phase
was rapidly extracted with tert-butyl methyl ether and the combined or-
ganic layers were dried over Na2SO4 and filtered. Et3N (10 mL, 74 mmol)
was added before the filtrate was evaporated and the triethylammonium
salt 41 was immediately used in the next step without further purifica-
tion.
Generous financial support by the MPG, the Chemical Genomics Center
(CGC Initiative of the MPG), and the Fonds der Chemischen Industrie is
gratefully acknowledged. We would also like to thank the NMR, MS and
chromatography departments of our Institute for excellent support of our
program.
[1] a) J. Kobayashi, J. Antibiot. 2008, 61, 271–284; b) J. Kobayashi, T.
Kubota, J. Nat. Prod. 2007, 70, 451–460; c) J. Kobayashi, M. Tsuda,
Nat. Prod. Rep. 2004, 21, 77–93.
[2] T. K. Chakraborty, S. Das, Curr. Med. Chem. Anti-Cancer Agents
2001, 1, 131–149.
2,4,6-Trichlorobenzoyl chloride (3.5 mL, 22 mmol) was added to a solution
of this compound and Et3N (10 mL, 74 mmol) in THF (550 mL). The mix-
ture was stirred for 1 h at ambient temperature before it was filtered
under Argon through a pad of Celite which had been treated with dry
THF. The Celite was carefully rinsed with dry THF before most of the
solvent was removed under a flow of argon. The residue was diluted with
toluene (4.5 mL) and the resulting solution was added dropwise over 2 h
via syringe pump to a solution of DMAP (36 mg, 300 mmol) in toluene
(20 mL). Once the addition was complete, stirring was continued for 2 h,
before the mixture was neutralized with aq. sat. NaHCO3 (3.0 mL). The
organic layer was washed with brine, dried over Na2SO4, and evaporated,
and the residue filtered through a pad of silica (hexanes/ethyl acetate
10:1 + 1% Et3N) to remove the DMAP. Evaporation of the filtrate af-
forded 42, which was used in the next step without further purification.
[3] For the synthesis of various amphidinolides, see ref. [4–10,17] and
the following: a) D. R. Williams, W. S. Kissel, J. Am. Chem. Soc.
1998, 120, 11198–11199; b) D. R. Williams, B. J. Myers, L. Mi, Org.
Lett. 2000, 2, 945–948; c) D. R. Williams, K. G. Meyer, J. Am.
Chem. Soc. 2001, 123, 765–766; d) H. W. Lam, G. Pattenden,
Angew. Chem. 2002, 114, 526–529; Angew. Chem. Int. Ed. 2002, 41,
508–511; e) R. E. Maleczka, Jr., L. R. Terrell, F. Geng, J. S. Ward,
Org. Lett. 2002, 4, 2841–2844; f) B. M. Trost, P. E. Harrington, J. D.
Chisholm, S. T. Wrobleski, J. Am. Chem. Soc. 2005, 127, 13598–
13610; g) B. M. Trost, S. T. Wrobelski, J. D. Chisholm, P. E. Harring-
ton, M. Jung, J. Am. Chem. Soc. 2005, 127, 13589–13597; h) P. Va,
W. R. Roush, J. Am. Chem. Soc. 2006, 128, 15960–15961; i) C. H.
Kim, H. J. An, W. K. Shin, W. Yu, S. K. Woo, S. K. Jung, E. Lee,
Angew. Chem. 2006, 118, 8187–8189; Angew. Chem. Int. Ed. 2006,
45, 8019–8021; j) K. C. Nicolaou, W. E. Brenzovich, P. G. Bulger,
T. M. Francis, Org. Biomol. Chem. 2006, 4, 2119–2157; k) K. C. Nic-
olaou, P. G. Bulger, W. E. Brenzovich, Org. Biomol. Chem. 2006, 4,
2158–2183; l) B. M. Trost, J. P. N. Papillon, T. Nussbaumer, J. Am.
Chem. Soc. 2005, 127, 17921–17937; m) A. K. Ghosh, G. Gong, J.
Org. Chem. 2006, 71, 1085–1093; n) E. A. Colby, K. C. OꢂBrien,
T. F. Jamison, J. Am. Chem. Soc. 2005, 127, 4297–4307; o) E. A.
Colby, T. F. Jamison, Org. Biomol. Chem. 2005, 3, 2675–2684; p) L.-
S. Deng, X.-P. Huang, G. Zhao, J. Org. Chem. 2006, 71, 4625–4635;
q) P. Va, W. R. Roush, Tetrahedron 2007, 63, 5768–5796; r) C. H.
Kim, H. J. An, W. K. Shin, W. Yu, S. K. Woo, S. K. Jung, E. Lee,
Chem. Asian J. 2008, 3, 1523–1534; s) L. Lu, W. Zhang, R. G.
Carter, J. Am. Chem. Soc. 2008, 130, 7253–7355; correction: L. Lu,
W. Zhang, R. G. Carter, J. Am. Chem. Soc. 2008, 130, 11834.
[4] A. Fꢀrstner, L. C. Bouchez, L. Morency, J.-A. Funel, V. Liepins, F.-
H. Porꢃe, R. Gilmour, D. Laurich, F. Beaufils, M. Tamiya, Chem.
Eur. J. 2009, 15, 3983–4010.
The material thus obtained was dissolved in HOAc/THF/H2O 4:1:1
(600 mL) and the resulting solution was stirred for 2.5 h at ambient tem-
perature. The mixture was diluted with ethyl acetate (1.5 mL) and the re-
action quenched with aq. sat. NaHCO3. The aqueous layer was repeated-
ly extracted with ethyl acetate, the combined organic phases were dried
over Na2SO4, filtered and evaporated. The residue was purified by flash
chromatography (hexanes/ethyl acetate 4:1) to give compound 9 as a col-
orless oil (2.7 mg, 43% over three steps; ratio of the 6-ketone/6(9)-hemi-
acetal form in CDCl3 = 4.8:1). [a]2D0 =ꢀ36.7 (c=0.56, CHCl3); 1H NMR
(ketone form, 400 MHz, CDCl3): d=6.60 (dd, J=15.7, 9.4 Hz, 1H), 5.78
(d, J=15.7 Hz, 1H), 4.93–4.89 (m, 1H), 4.87 (d, J=8.8 Hz, 1H), 4.35 (s,
1H), 3.92 (dt, J=6.9, 3.9 Hz, 1H), 3.11 (dt, J=9.1, 1.3 Hz, 1H), 3.08–3.03
(m, 1H), 2.94 (dd, J=17.6, 11.4 Hz, 1H), 2.37 (dd, J=17.6, 2.4 Hz, 1H),
2.26 (dt, J=9.3, 6.7 Hz, 1H), 2.16–2.13 (m, 2H), 2.08 (dd, J=14.0, 7.4 Hz,
1H), 2.03–1.95 (m, 2H), 1.93–1.81 (m, 1H), 1.86 (dd, J=14.0, 2.6 Hz,
1H), 1.77 (dd, J=14.7, 9.0 Hz, 1H), 1.71 (d, J=1.2 Hz, 3H), 1.66–1.49
(m, 1H), 1.36 (s, 3H), 1.29 (s, 3H), 1.28 (s, 3H), 1.10 (d, J=6.8 Hz, 3H),
0.87 ppm (d, J=6.7 Hz, 3H); 13C NMR (ketone form, 100 MHz, CDCl3):
d=211.3, 166.0, 153.8, 138.3, 128.8, 120.2, 80.7, 80.6, 79.1, 77.4, 71.2, 45.1,
44.8, 42.8, 39.4, 34.9, 34.3, 32.2, 29.8, 27.7, 26.8, 20.0, 17.7, 17.0 ppm; IR
4042
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Chem. Eur. J. 2009, 15, 4030 – 4043

Amphidinolide X and Y
FULL PAPER
[5] A. Fꢀrstner, L. C. Bouchez, J.-A. Funel, V. Liepins, F.-H. Porꢃe, R.
Gilmour, F. Beaufils, D. Laurich, M. Tamiya, Angew. Chem. 2007,
119, 9425–9430; Angew. Chem. Int. Ed. 2007, 46, 9265–9270.
[6] a) C. Aꢄssa, R. Riveiros, J. Ragot, A. Fꢀrstner, J. Am. Chem. Soc.
2003, 125, 15512–15520; b) A. Fꢀrstner, C. Aꢄssa, R. Riveiros, J.
Ragot, Angew. Chem. 2002, 114, 4958–4960; Angew. Chem. Int. Ed.
2002, 41, 4763–4766.
[7] A. Fꢀrstner, O. Larionov, S. Flꢀgge, Angew. Chem. 2007, 119, 5641–
5644; Angew. Chem. Int. Ed. 2007, 46, 5545–5548.
[8] A. Fꢀrstner, S. Flꢀgge, O. Larionov, Y. Takahashi, T. Kubota, J. Ko-
bayashi, Chem. Eur. J. 2009, 15, 4011–4029.
[9] O. Lepage, E. Kattnig, A. Fꢀrstner, J. Am. Chem. Soc. 2004, 126,
15970–15971.
[10] A. Fꢀrstner, E. Kattnig, O. Lepage, J. Am. Chem. Soc. 2006, 128,
9194–9204.
[11] A. Fꢀrstner, Angew. Chem. 2000, 112, 3140–3172; Angew. Chem.
Int. Ed. 2000, 39, 3012–3043.
[12] A. Fꢀrstner, P. W. Davies, Chem. Commun. 2005, 2307–2320.
[13] a) B. D. Sherry, A. Fꢀrstner, Acc. Chem. Res. 2008, 41, 1500–1511;
b) A. Fꢀrstner, R. Martin, Chem. Lett. 2005, 624–629.
[24] For a mechanistic discussion of iron catalysis, see ref. [13] and the
following: A. Fꢀrstner, R. Martin, H. Krause, G. Seidel, R. God-
dard, C. W. Lehmann, J. Am. Chem. Soc. 2008, 130, 8773–8787.
[25] a) A. Fꢀrstner, D. Kirk, M. D. B. Fenster, C. Aꢄssa, D. De Souza, O.
Mꢀller, Proc. Natl. Acad. Sci. USA 2005, 102, 8103–8108; b) A.
Fꢀrstner, D. De Souza, L. Turet, M. D. B. Fenster, L. Parra-Rapado,
C. Wirtz, R. Mynott, C. W. Lehmann, Chem. Eur. J. 2007, 13, 115–
134; c) A. Fꢀrstner, D. Kirk, M. D. B. Fenster, C. Aꢄssa, D. De Sou-
za, C. Nevado, T. Tuttle, W. Thiel, O. Mꢀller, Chem. Eur. J. 2007, 13,
135–149.
[26] D. A. Evans, S. W. Tregay, C. S. Burgey, N. A. Paras, T. Vojkovsky, J.
Am. Chem. Soc. 2000, 122, 7936–7943.
[27] M. T. Reetz, Acc. Chem. Res. 1993, 26, 462–468 and references
therein.
[28] T. Oishi, T. Nakata, Acc. Chem. Res. 1984, 17, 338–344.
[29] E. J. Corey, C. J. Helal, Angew. Chem. 1998, 110, 2092–2118;
Angew. Chem. Int. Ed. 1998, 37, 1986–2012.
[30] M. Yotagai, T. Ohnuki, J. Chem. Soc. Perkin Trans. 1 1990, 1826–
1828.
[31] S. D. Rychnovsky, P. A. Bartlett, J. Am. Chem. Soc. 1981, 103, 3963–
3964.
[32] K. Inoue, A. Sawada, I. Shibata, A. Baba, J. Am. Chem. Soc. 2002,
124, 906–907.
[33] a) M. Tokunaga, J. F. Larrow, F. Kakiuchi, E. N. Jacobsen, Science
1997, 277, 936–938; b) M. E. Furrow, S. E. Schaus, E. N. Jacobsen, J.
Org. Chem. 1998, 63, 6776–6777.
[34] D. R. Williams, D. A. Brooks, M. A. Berliner, J. Am. Chem. Soc.
1999, 121, 4924–4925.
[35] The fact that product 22 was optically pure (>98% ee) showed that
the alkylation step must have occurred selectively at the chloride
rather than the oxirane site of 21, which would have led to the enan-
tiomeric product and hence should show up in a diminished ee.
[36] K. C. Nicolaou, M. E. Bunnage, D. G. McGarry, S. Shi, P. K. Somers,
P. A. Wallace, X.-J. Chu, K. A. Agrios, J. L. Gunzner, Z. Yang,
Chem. Eur. J. 1999, 5, 599–617.
[37] Attempts to effect this protecting group interchange in two steps
failed because of the exceptional sensitivity of the intermediate hy-
droxy-ketone even under mildly acidic conditions.
[38] a) J. Schwartz, J. A. Labinger, Angew. Chem. 1976, 88, 402–409;
Angew. Chem. Int. Ed. Engl. 1976, 15, 333–340; b) D. W. Hart, J.
Schwartz, J. Am. Chem. Soc. 1974, 96, 8115–8116.
[39] T. Hu, J. S. Panek, J. Am. Chem. Soc. 2002, 124, 11368–11378.
[40] Y. Oikawa, T. Yoshioka, O. Yonemitsu, Tetrahedron Lett. 1982, 23,
885–888.
[14] R. M. Wilson, S. J. Danishefsky, J. Org. Chem. 2006, 71, 8329–8351.
[15] M. Tsuda, N. Izui, K. Shimbo, M. Sato, E. Fukushi, J. Kawabata, K.
Katsumata, T. Horiguchi, J. Kobayashi, J. Org. Chem. 2003, 68,
5339–5345.
[16] M. Tsuda, N. Izui, K. Shimbo, M. Sato, E. Fukushi, J. Kawabata, J.
Kobayashi, J. Org. Chem. 2003, 68, 9109–9112.
[17] For other total syntheses of amphidinolide X and Y see: a) W.-M.
Dai, Y. Chen, J. Jin, J. Wu, J. Lou, Q. He, Synlett 2008, 1737–1741;
b) J. Jin, Y. Chen, Y. Li, J. Wu, W.-M. Dai, Org. Lett. 2007, 9, 2585–
2588; c) C. Rodrꢅguez-Escrich, F. Urpꢅ, J. Vilarrasa, Org. Lett. 2008,
10, 5191–5194; for studies towards these targets, see: d) H. D.
Doan, J. Gallon, A. Piou, J.-M. Vatꢆle, Synlett 2007, 983–985; e) Y.
Chen, J. Jin, J. Wu, W.-M. Dai, Synlett 2006, 1177–1180; f) C. Rodrꢅ-
guez-Escrich, A. Olivella, F. Urpꢅ, J. Vilarrasa, Org. Lett. 2007, 9,
989–992.
[18] a) A. Fꢀrstner, G. Seidel, Tetrahedron 1995, 51, 11165–11176;
b) the method was independently reported by: J. A. Soderquist, K.
Matos, A. Rane, J. Ramos, Tetrahedron Lett. 1995, 36, 2401–2402.
[19] Selected applications: a) A. Fꢀrstner, M. M. Domostoj, B. Scheiper,
J. Am. Chem. Soc. 2006, 128, 8087–8094; b) A. Fꢀrstner, L. Turet,
Angew. Chem. 2005, 117, 3528–3532; Angew. Chem. Int. Ed. 2005,
44, 3462–3466; c) A. Fꢀrstner, J. W. J. Kennedy, Chem. Eur. J. 2006,
12, 7398–7410; d) A. Fꢀrstner, A. Leitner, Synlett 2001, 290–292;
e) A. Fꢀrstner, K. Nikolakis, Liebigs Ann. 1996, 2107–2113; f) J. A.
Marshall, B. A. Johns, J. Org. Chem. 1998, 63, 7885–7892; g) Y.
Yuan, H. Men, C. Lee, J. Am. Chem. Soc. 2004, 126, 14720–14721;
h) S. J. Mickel, Org. Process Res. Dev. 2004, 8, 113–121; i) M. Ebine,
H. Fuwa, M. Sasaki, Org. Lett. 2008, 10, 2275–2278; j) G. R. Cum-
ming, G. Bernardinelli, E. P. Kꢀndig, Chem. Asian J. 2006, 1, 459–
468; k) I. Hayakawa, M. Ueda, M. Yamaura, Y. Ikeda, Y. Suzuki, K.
Yoshizato, H. Kigoshi, Org. Lett. 2008, 10, 1859–1862; l) L. C. Dias,
P. R. R. Meira, J. Org. Chem. 2005, 70, 4762–4773; m) J. A. Mar-
shall, M. P. Bourbeau, J. Org. Chem. 2002, 67, 2751–2754.
[20] J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull.
Chem. Soc. Jpn. 1979, 52, 1989–1993.
[41] S. J. Connon, S. Blechert, Angew. Chem. 2003, 115, 1944–1968;
Angew. Chem. Int. Ed. 2003, 42, 1900–1923.
[42] A. H. Hoveyda, D. G. Gillingham, J. J. van Veldhiuzen, O. Kataoka,
S. B. Garber, J. S. Kingsbury, J. P. A. Harrity, Org. Biomol. Chem.
2004, 2, 8–23.
[43] Review on alkyl-Suzuki reactions: S. R. Chemler, D. Trauner, S. J.
Danishefsky, Angew. Chem. 2001, 113, 4676–4701; Angew. Chem.
Int. Ed. 2001, 40, 4544–4568.
[44] For Yamaguchi lactonizations of very sensitive seco acids, see: D. A.
Evans, B. T. Connell, J. Am. Chem. Soc. 2003, 125, 10899–10905.
[45] T. J. Hunter, G. A. OꢂDoherty, Org. Lett. 2002, 4, 4447–4450.
[46] H. H. Fiebig, D. P. Berger, W. A. Dengler, E. Wallbrecher, B. R.
Winterhalter, in “Immunodeficient Mice in Oncology”, Contrib.
Oncol., Vol. 42 (Eds.: H. H. Fiebig, D. P. Berger), Karger, Basel,
1992, pp. 321–351.
[21] Review: A. Parenty, X. Moreau, J.-M. Campagne, Chem. Rev. 2006,
106, 911–939.
[22] Selected applications from this laboratory: a) A. Fꢀrstner, C.
[47] T. Roth, A. M. Burger, W. Dengler, H. Willmann, H. H. Fiebig, in
“Relevance of Tumor Models for Anticancer Drug Development”,
Contrib. Oncol., Vol. 54 (Eds.: H. H. Fiebig, A. M. Burger), Karger,
Basel, 1999, pp. 145–156.
´
Nevado, M. Waser, M. Tremblay, C. Chevrier, F. Teply, C. Aꢄssa, E.
Moulin, O. Mꢀller, J. Am. Chem. Soc. 2007, 129, 9150–9161; b) A.
´
Fꢀrstner, C. Aꢄssa, C. Chevrier, F. Teply, C. Nevado, M. Tremblay,
Angew. Chem. 2006, 118, 5964–5969; Angew. Chem. Int. Ed. 2006,
45, 5832–5837; c) J. Mlynarski, J. Ruiz-Caro, A. Fꢀrstner, Chem.
Eur. J. 2004, 10, 2214–2222.
[48] W. A. Dengler, J. Schulte, D. P. Berger, R. Mertelsmann, H. H.
Fiebig, Anti-Cancer Drugs 1995, 6, 522–532.
[23] A. Fꢀrstner, M. Mꢃndez, Angew. Chem. 2003, 115, 5513–5515;
Angew. Chem. Int. Ed. 2003, 42, 5355–5357.
Received: October 7, 2008
Published online: February 24, 2009
Chem. Eur. J. 2009, 15, 4030 – 4043
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4043