Total synthesis and biological activity of neopeltolide and analogues

Article abstract of DOI:10.1002/chem.200801398

Combining the core structure of neopeltolide, lactone 16a, with the oxazole-containing side chain 23 via a Mitsunobu reaction provided the cytotoxic natural product neopeltolide (2). The side chain 23 was prepared from oxazolone 24 via the corresponding triflate. Key steps in the preparation of 23 were a Sonogashira coupling, an enamine alkylation, and a Still-Gennari Horner-Emmons reaction. By changing the Leighton reagent in the allylation step, the 11-epimer of lactone 16a, compound 50 was prepared. This led to 11-epi-neopeltolide 51. The 5-epimer of neopeltolide, compound 52, could be obtained from the minor isomer of the Prins cyclization. Furthermore, a range of analogues with modifications in the side chain were prepared. All derivatives were checked for toxicity effects on mammalian cell cultures and inhibitory effects on NADH oxidation in submitochondrial particles of bovine heart. Modifications in the lactone part are tolerated to some degree. On the other hand, shortening the distance between the oxazole and the lactone causes a significant drop in activity. Analogue 65 with an additional double bond is equally or even more active than neopeltolide itself.

Full text of DOI:10.1002/chem.200801398

DOI: 10.1002/chem.200801398
Total Synthesis and Biological Activity of Neopeltolide and Analogues
Viktor V. Vintonyak,[a] Brigitte Kunze,[b] Florenz Sasse,[c] and Martin E. Maier*[a]
Abstract: Combining the core structure
of neopeltolide, lactone 16a, with the
oxazole-containing side chain 23 via a
Mitsunobu reaction provided the cyto-
toxic natural product neopeltolide (2).
The side chain 23 was prepared from
oxazolone 24 via the corresponding tri-
flate. Key steps in the preparation of
23 were a Sonogashira coupling, an en-
amine alkylation, and a Still–Gennari
Horner–Emmons reaction. By chang-
ing the Leighton reagent in the allyla-
tion step, the 11-epimer of lactone 16a,
compound 50 was prepared. This led to
11-epi-neopeltolide 51. The 5-epimer of
neopeltolide, compound 52, could be
obtained from the minor isomer of the
Prins cyclization. Furthermore, a range
of analogues with modifications in the
side chain were prepared. All deriva-
tives were checked for toxicity effects
on mammalian cell cultures and inhibi-
tory effects on NADH oxidation in
submitochondrial particles of bovine
heart. Modifications in the lactone part
are tolerated to some degree. On the
other hand, shortening the distance be-
tween the oxazole and the lactone
causes a significant drop in activity.
Analogue 65 with an additional double
bond is equally or even more active
than neopeltolide itself.
Keywords:
allylation
·
mitochondria · natural products ·
neopeltolide · prins cyclization
Introduction
meantime it turned out that 1 is most likely the product of a
bacterium that colonized the sponge.[3] Leucascandrolide A
shows strong in vitro cytotoxicity against KB and P 388 cell
lines. Meanwhile, a range of total syntheses[4] or formal total
syntheses[5] for leucascondrolide A have appeared. However,
only recently the mode of action could be clarified. Thus,
the Kozmin group identified the cytochrome bc1 complex of
the mitochondrial respiratory chain as the principal cellular
target of these two natural products.[6,7] Recognizing the dif-
ferences in the macrolactone part of these two natural prod-
uct Kozmin et al. surmised that structural simplifications
should be tolerated. In fact, a simplified leucascandrolide
analogue (see below) was prepared and screened against a
commercially available library of 4900 yeast strains with dif-
ferent haploid nonessential gene deletions. Among the sen-
sitive mutants one was haploid in the SNF4 gene. The corre-
sponding gene product is a key regulator of glucose metabo-
lism in that it senses the cellular AMP/ATP ratio. This led
to the hypothesis that the two natural products interfere
with mitochondrial oxidative phosphorylation. This could be
supported by further studies, which revealed that the cyto-
chrome bc1 complex is the molecular target of leucascandro-
lide A and neopeltolide. This technique of target fishing
clearly is an interesting alternative to classical pull-down ap-
In recent years the search for secondary metabolites in
marine organism revealed a range of novel natural products
with interesting structures and biological activities.[1] Two il-
lustrative examples include leucascandralide A (1) and neo-
peltolide (2) (Scheme 1). Both feature an elaborate macro-
lactone to which an oxazole-containing side chain is at-
tached at C5 via an ester bond. Interestingly, this side chain
is identical in both compounds. Leucascandrolide A was iso-
lated in 1996 from the sponge Leucascandra careolata which
was collected at the east coast of New Caledonia.[2] In the
[a] Dipl.-Chem. V. V. Vintonyak, Prof. Dr. M. E. Maier
Institut fꢀr Organische Chemie, Universitꢁt Tꢀbingen
Auf der Morgenstelle 18, 72076 Tꢀbingen (Germany)
Fax : (+49)7071-295137
E-mail: martin.e.maier@uni-tuebingen.de
[b] Dr. B. Kunze
Arbeitsgruppe Mikrobielle Kommunikation
Helmholtz-Zentrum fꢀr Infektionsforschung, Inhoffenstrasse 7
38124 Braunschweig (Germany)
[c] Dr. F. Sasse
Abteilung Chemische Biologie
Helmholtz-Zentrum fꢀr Infektionsforschung, Inhoffenstrasse 7
38124 Braunschweig (Germany)
proaches. Neopeltolide (2) was also isolated from
a
sponge.[8] The sponge of the family Neopeltidae was collect-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801398.
ed off the North Jamaican coast. Neopeltolide turned out to
11132
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 11132 – 11140

FULL PAPER
be a very potent antitumor agent, inhibiting the prolifera-
tion of various cell lines in the low nanomolar range.
Through total synthesis the stereochemistry of neopeltolide
was assigned[9,10] as shown herein. In the original paper, the
configurations at C11 and C13 were inverted. Since then
other syntheses of 2 have been published.[6,11,12]
Scheme 1. Structures of the related natural products leucascandrolide A
(1) and neopeltolide (2).
Our group recently reported a concise synthesis of the ne-
opeltolide lactone 16a.[13] The seco acid 14a/b was fashioned
from pyran 13a/b; the latter is the product of a Prins cycliza-
tion between aldehyde 11 and homoallylic alcohol 12
(Scheme 2). Key steps in the synthesis of aldehyde 11 were
a Noyori reduction[14] of ketoester 3, a Leighton allylation[15]
on aldehyde 5, and a Feringa-Minnaard stereoselective
methyl cuprate addition[16,17] to the unsaturated thioester 8.
The overall sequence from ketoester 3 to macrolactone 16a
consists of 17 steps providing lactone 16a with a good over-
all yield of 23%.
In order to complete the total synthesis of neopeltolide,
the side chain acid was required. In this paper we describe a
novel synthesis of the neopeltolide side chain from a simple
oxazolone, the synthesis of neopeltolide, and the synthesis
of some analogues.
Scheme 2. Key steps in the synthesis of the neopeltolide hydroxylactone
16a; Ar=pBrC6H4.
obtain modified side chains suitable for some structure ac-
tivity studies.
The synthesis started with the known oxazolone[19] 24
which was obtained by a condensation reaction between
ethyl 3-bromopyruvate with methyl carbamate (5 equiv) in
presence of pTsOH (0.1 equiv) and AgOTf (1 equiv)
(Scheme 4). Similar to the Paterson and Panek synthesis, the
oxazolone was converted to the corresponding triflate using
triflic anhydride (Tf2O) in presence of 2,6-lutidine. Triflate
25, obtained in 88% yield was immediately subjected to a
Sonogashira coupling with alkyne[18] 26, using conditions
Results and Discussion
In the literature five syntheses for this acid or precursors
have been described. Typically they require roughly 10–13
steps (Scheme 3). In some of them an oxazole 18 is formed
from an amide 17 containing an ethanolamine subunit. In
these cases the carboxylic acid part contains the carbamate
terminus. This approach was used by the groups of Leigh-
{[PdACHTNUTGRNEUGN(PPh3)4], CuI, 2,6-lutidine, 1,4-dioxane} developed by
Panek et al.[4e,20] Subsequent Lindlar reduction of alkyne 27
provided the oxazole-4-carboxylate 28 with the Z-double
bond in the C2 substituent. The next task was to realize a
two-carbon extension to an aldehyde 22 or the correspond-
ing ester. We thought of preparing enoate 31 via a Wittig re-
action followed by selective reduction of the enoate double
bond. Accordingly, ester 28 was reduced with DIBAL-H in
CH2Cl2 furnishing aldehyde 29 (70% yield) along with small
amounts of alcohol 30. The latter could be converted to the
aldehyde 29 by simple Dess–Martin oxidation. Stirring of al-
dehyde 29 with (methoxycarbonylmethylene)triphenylphos-
phorane in CH2Cl2 led to enoate 31 in high yields. However,
we could not find conditions that would selectively reduce
the enoate double bond without affecting the Z-double
ACHTUNGTRENNUNG
ton,[4a] Wipf,[18] and Kozmin.[4b] The Kozmin route is unique
in that a rhodium-catalyzed reaction of dimethyl diazomalo-
nate with an alkynyl nitrile was used. Another strategy
starts from a 2-hydroxyketone 19 from which an oxazolone
20 is created. In the approaches of Panek[4e] and Paterson,[4d]
all or most of the atoms of the C-terminus of the side chain
are part of the starting hydroxyketone. Target compounds
are usually the aldehyde 22 or the acid 23. Our strategy is
based on a simple oxazolone as starting material which is
then extended on both sides. This way we also hoped to
Chem. Eur. J. 2008, 14, 11132 – 11140
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11133

M. E. Maier et al.
Therefore, we decided to use the two-carbon homologa-
tion method used by Kozmin[4b] in a similar context. Thus,
aldehyde 29 was reduced to alcohol 30 using NaBH4
(Scheme 5). Conversion of the primary alcohol 30 to the
corresponding bromide 32 was achieved using CBr4, PPh3,
and 2,6-lutidine in CH3CN.[23] In order for this reaction to
succeed the CBr4 should be very pure and without any trace
of water. Bromide 32 was then used as electrophile in the al-
kylation[24] of the lithium anion of imine[25] 33, derived from
acetaldehyde. Aqueous work-up afforded aldehyde 22 in
78% yield. A final olefination reaction with the Still–Gen-
nari reagent[26] 34 delivered Z-enoate 35 with high selectivity
(Z/E 11:1). Saponification of ester 35 with LiOH in H2O/
THF completed the synthesis of the side chain 23.
Scheme 3. General strategies for the synthesis of the oxazole containing
side chain of leucascandrolide A and neopeltolide.
bond. Thus, neither Mg in MeOH[21] nor the combination of
NiCl2/NaBH4 in MeOH,[22] were successful in this regard. In
both cases, LC-MS showed significant amounts of over-re-
duction products.
Scheme 5. Completion of the synthesis of acid 23 by alkylation of imine
33 with bromide 32.
Since the Prins cyclization furnished the pyran 16a with
an all-equatorial arrangement of the substituents, a Mitsuno-
bu esterification was required in order to obtain neopelto-
lide (2). Indeed, treatment of the two fragments 16a and 23
(1.6 equiv) with PPh3 and DIAD afforded neopeltolide (2)
in 80% yield (Scheme 6). The NMR spectra of 2 were in ex-
cellent agreement with those reported in the literature.[8] In
the longest linear sequence this synthesis required 18 steps
with an overall yield of 18.7%. So far it is the most efficient
synthesis of neopeltolide. The other known syntheses seem
to be less efficient [Panek synthesis[9] (19 steps, 1.3%),
Scheidt synthesis[10] (19 steps, 0.52%), Lee synthesis[11] (15
steps, 6.7%), Fuwa/Sasaki synthesis[12] (23 steps, 7.2%),
Kozmin synthesis[6] (15 steps, 5.3%, racemic material)].
Synthesis of neopeltolide analogues: The larger macrolac-
tone ring in leucascandrolide A shows that variations in the
lactone part of both compounds should be possible. By
slight variations in the synthesis we hoped to probe the role
Scheme 4. Synthesis of oxazole-4-carboxylate 28 and enoate 31.
11134
www.chemeurj.org
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 11132 – 11140

Neopeltolide and Analogues
FULL PAPER
Scheme 6. Completion of the synthesis of neopeltolide (2) by Mitsunobu
esterification.
of some of the configurations in the macrolactone part.
Moreover, we planned to probe the distance between the
macrolactone part and the oxazole ring. A first target
became 11-epi-neopeltolide (51) (Schemes 7 and 8). Accord-
Scheme 8. Completion of the synthesis of 11-epi-neopeltolide (51).
DMP=Dess Martin periodinane; DIAD=Diisopropylazodicarboxylate.
12 (1.3 equiv) in presence of trifluoroacetic acid (10 equiv)
induced the Prins cyclization[29,30] yielding pyran 43a/b in
71% yield. Treatment of the trifluoroacetate 43a/b with
K2CO3 in MeOH led to hydroxypyran 44a/b. As in the case
of the epimeric aldehyde 11, the Prins cyclization of 42 and
12 afforded a small amount (ratio major/minor=9:1) of the
5-epi-diastereomer 43b. This isomer could be separated at
the stage of lactone 49 (Scheme 8).
From pyran 44a/b the same sequence of reactions that
were used in the synthesis of neopeltolide lactone were used
(Scheme 8). Thus, MOM protection of the secondary alcohol
44a/b furnished pyran 45a/b. Debenzylation to 46a/b, oxida-
tion of 46a/b, and removal of the silyl ether from acid 47a/b
delivered seco-acid 48a/b in good yields. The crucial Yama-
guchi lactonization[31,32] provided the separable lactones 49a
and 49b with high efficiency. Cleavage of the MOM acetal
of 49a led to hydroxy lactone 50. Combination of lactone 50
with the acid 23 via Mitsunobu esterification gave rise to 11-
epi-neopeltolide (51).
A further analogue, namely 5-epi-neopeltolide (52) was
accessible from the minor diastereomer obtained in the
Prins cyclization of 11 and 12 (Schemes 2, 9). After the
Prins cyclization, the diastereomers were separated at the
stage of the MOM-protected lactone 15a/b. The minor
isomer 15b (5-epi) has an axial OH-group at C5. According-
ly, cleavage of the MOM protecting group of 15b provided
hydroxy lactone 16b. This reacted with acid 23 under Mitsu-
nobu conditions to 5-epi-neopeltolide (52). The alternative
Scheme 7. Synthesis of the carbon skeleton of 11-epi-neopeltolide.
ingly, the Leighton alkylation of aldehyde 5 was performed
with the (S,S)-reagent 6. The alcohol 36 was methylated
using the Meerwein salt in presence of proton sponge. Oxi-
dative degradation of the double bond allowed for chain ex-
tension of the resulting aldehyde to the unsaturated thioest-
er 40 with the Wittig reagent[27] 39. The stereoselective
methyl cuprate addition to 40 under Feringa–Minnaard con-
ditions[16] generated thioester 41 as a single diastereomer. A
subsequent Fukuyama-type reduction[28] of 41 produced al-
dehyde 42. Stirring of aldehyde 42 and homoallylic alcohol
Chem. Eur. J. 2008, 14, 11132 – 11140
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11135

M. E. Maier et al.
formation of 52 from hydroxy lactone 16a by classical
esterification with acid 23 was not tried, because of a possi-
ble isomerization of the side chain double bond.
Scheme 9. Synthesis of 5-epi-neopeltolide (52).
Using the 1,3-oxazole-4-carboxylate 28 and other derived
compounds a few side chain analogues were prepared
(Scheme 10). Accordingly, saponification of ester 28 provid-
ed acid 53. In a similar manner enoate 31 was hydrolyzed to
unsaturated acid 54. Extending aldehyde 22 via Wittig reac-
tion using stabilized ylide (methoxycarbonylmethylene)tri-
phenylphosphorane gave (E)-enoate 55. Saponification of
the latter furnished acid 56. Enoate 31 served also as a pre-
cursor to unsaturated aldehyde 57, which could be obtained
from 31 via a reduction/oxidation sequence. Reaction of al-
dehyde 57 with the Still–Gennari reagent 34 provided the
Z,E-dienoate 58 in reasonable yield. This was hydrolyzed to
the corresponding acid 59. Likewise, reaction of aldehyde 57
with
(methoxycarbonylmethylene)triphenylphosphorane
gave the E,E-dienoate 60 and the acid 61, respectively.
Condensation of the neopeltolide hydroxylactone 16a
with acids 53, 54, 56, 59, and 61 using the proven Mitsunobu
conditions (PPh3, DIAD, benzene or benzene/THF) pro-
duced the neopeltolide analogues 62–66 in very good yields
(Scheme 11). The benzene/THF mixture was used to en-
hance solubility of some of the carboxylic acids.
Scheme 10. Synthesis of various acids analogues of the neopeltolide side
chain.
Biological testing: Neopeltolide (2), as well as the analogues
51, 52 and 62–66 were tested for cytotoxicity against the
L929 mouse fibroblasts and A549 human lung carcinoma
cells, as well as for their inhibitory efficacy on NADH-oxi-
dation in submitochondrial particles of bovine heart. The
obtained IC50 values are listed in Table 1. The compounds
are ordered according to increasing IC50 values against the
L929 cell line, which mostly run parallel with the IC50
against A549 and the inhibition of NADH oxidation in sub-
mitochondrial particles of bovine heart, yet with some small-
er aberrations. Referring to the cytotoxicity of neopeltolides
against L929 mouse cells, Table 1 shows that the lactone
alone is not sufficient for biological activity (entry 9 and 10).
With regard to the lactone part one can conclude that some
modifications are tolerated (entry 4, 11-epi, entry 6, 5-epi).
In this context the recent study by Kozmin et al.[6] is sup-
porting our findings. Thus, natural (+)-leucascandrolide A
Scheme 11. Synthesis of neopeltolide analogues with modifications in the
side chain.
11136
www.chemeurj.org
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 11132 – 11140

Neopeltolide and Analogues
FULL PAPER
and the unnatural enantiomer, both obtained by chromato-
graphic separation of the racemic mixture, showed similar
cytotoxic profiles against various cell lines with the natural
isomer being only two to three times more active. Accord-
ingly, modifications in the lactone part seem to be well toler-
dation assays with submitochondrial particles of bovine
heart as given in Table 1.
Conclusion
ated. The Kozmin leucascandrolide
A
analogue 67
(Scheme 11) which lacks the methyl group at C12 and C21,
as well as the side-chain double bond also is still quite active
[IC50 (A549 cell line) = 0.8 nm]. Racemic neopeltolide
showed an IC50 of 0.5 nm against the same cell line[6] (cf.
entry 2, natural neopeltolide has an IC50 of 0.16 nm with this
cell line).
In this paper we describe the total synthesis of the potent
antitumor compound neopeltolide (2). This marine natural
product consists of a macrolactone part and an oxazole con-
taining side chain at C5. The macrolactone part was avail-
able by our previous developed route.[13] Key steps in this
very concise sequence include a Noyori reduction of a keto
ester, a Leighton allylation to
create the 1,3-diol subunit, a
stereoselective methyl cuprate
Table 1. Biological activity of neopeltolide (2) and the analogues.
Entry Compound
IC50 L929
[ngmLꢀ1
[nm]
IC50 A549
[ngmLꢀ1
[nm]
IC50 of NADH oxidation Description
addition to an unsaturated thio-
ester, a Prins cyclization, and a
Yamaguchi lactonization. The
required side chain, acid 23,
was fashioned from the known
ethyl 2-oxo-2,3-dihydro-1,3-oxa-
zole-4-carboxylate (24). Using
established methods the re-
quired functionalities were in-
troduced via a Sonogashira cou-
N
]
N
]
A
]
[nm]
1
2
3
4
5
6
7
8
9
65
2
0.094
0.15
1.2
1.3
2.6
5.0
630
2400
> 4000
> 4000
0.16
0.25
2.0
2.2
4.4
0.12
0.095
1.2
0.53
3.4
3.3
800
2800
>4000
>4000
0.22
0.16
2.0
0.90
5.8
7.6
6.0
38
12.9
10.2
64.6
neo-diene-Z,E
neopeltolide
neo-diene-E,E
11-epi-neo
66
51
64
52
63
62
16
50
8.2
13.9
34.5
9.8
58.4
16.6
neo-trans
5-epi-neo
8.5
5.6
1120
4500
>12000
>12000
1300
5200
>12000
>12000
2700
1850
>8097
>8097
4800
3450
>24650
>24650
neo-enoate
neo-oxazole
neo-lactone
11-epi-lactone
10
The analogues with modified side chain show that the dis-
tance of the oxazole ring to the macrolactone ring is impor-
tant. Thus, analogue 62 with a very short distance is essen-
tially inactive (entry 8). Analogue 64 with an E-double bond
is roughly 20 times less active (entry 5). A similar trend is
seen for the dienoate analogues 66 and 65. Surprisingly, the
Z,E compound is more active (IC50 =160 pm) than neopelto-
lide itself (IC50 =250 pm). The E,E-isomer 66 is about 12
times less active than the Z,E-isomer 65. It seems that the
diene part in 65 somehow corresponds to the bioactive con-
formation of the side chain. The inhibition seen in the
NADH oxidation study does roughly correlate with the cel-
lular assay data. However, the relative weak inhibition ob-
served with analogue 66 (entry 3) and analogue 64 (entry 5)
in comparison to analogue 51 (entry 4) and analogue 52
(entry 6) is striking. Compounds 51 and 52 are the analogues
with modifications in the lactone part but with an intact side
chain. This clearly underscores the importance of the correct
oxazole containing side chain at the target. It seems that an
E-double bond next to the carboxyl function of the side
chain slightly reduces the inhibition of the NADH oxida-
tion. This is evident by comparing the pairs 2/64 and 65/66.
In both pairs the corresponding E-isomer is less active.
Figure 1. L929 mouse fibroblasts (top) were incubated with
2
(50 ngmLꢀ1) for 1 d and stained with Giemsa. The treated cells are
bigger and show a widely outspread cytoplasm. The bottom picture
shows control cells.
With the L929 fibroblasts we observed typical morpholog-
ical alterations under the light microscope. The cells became
bigger and more circular in shape with an outspread cyto-
plasm (Figure 1). These changes resembled alterations that
were also induced by myxothiazol, an inhibitor of the respi-
ratory chain from myxobacteria.[33] This first hint about the
mode of action of neopeltolide was proven by NADH oxi-
pling reaction and elongation on the carboxylate position.
This way acid 23 could be obtained from oxazolone 24 in
nine steps with an overall yield of 18%. Mitsunobu esterifi-
cation led to neopeltolide. Using the 5-epimer lactone 16b,
5-epi-neopeltolide 52 was obtained. In addition, the 11-
Chem. Eur. J. 2008, 14, 11132 – 11140
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11137

M. E. Maier et al.
146.3 (C-2), 156.5 (CO2CH3), 160.3 ppm (CO2Et); HRMS (ESI): m/z:
calcd for C11H12NaN2O5: 275.06384, found 275.06386 [M+Na]+.
epimer of lactone 16a, hydroxylactone 50, was made by em-
ploying the appropriate Leighton reagent and otherwise the
same reaction sequence used for the natural product. Final-
ly, derivatives of the oxazole 28 were prepared leading to a
range of side chain acids. These were condensed with hy-
droxy lactone 16a under Mitsunobu conditions. Biological
testing revealed some interesting structure-activity informa-
tion. Thus, modifications in the stereochemistry of the mac-
rolactone part are tolerated to some degree. The drop in ac-
tivity is more pronounced if the modification is closer to the
side chain (5-epi- vs 11-epi-neo). With regard to the side
chain it seems that the distance between the lactone and the
oxazole ring is of relevance. For example, analogue 62
where the oxazole is close to the lactone is not active. The
configuration of the enoate double bond of the side chain
contributes roughly with a factor of 10 to the activity with
the Z-isomers being more active. Analogue 65 with an addi-
tional double bond is equally or even more potent than the
natural product itself (IC50 =160 vs 250 pm, L929 cells). Neo-
peltolides exert their effects by inhibition of respiration as
was clearly shown by NADH oxidation assays with submito-
chondrial particles of bovine heart. The target within the mi-
tochondrial respiratory chain by neopeltolides has been pub-
lished recently.[6]
Ethyl 2-{(1Z)-3-[(methoxycarbonyl)amino]prop-1-enyl}-1,3-oxazole-4-car-
boxylate (28): Alkyne 27 (1.21 g, 4.8 mmol, 1 equiv) and quinoline
(0.94 mL, 7.7 mmol, 1.6 equiv) were dissolved in EtOAc (280 mL), which
was followed by the addition of Lindlarꢄs catalyst (5 wt% Pd on CaCO3,
poisoned by lead (Fluka, No. 62145), 940 mg, 100 wt%). The reaction
was placed under H2 atmosphere and stirred until HPLC-MS analysis
showed complete consumption of the starting material (ca. 5–6 h). The
reaction mixture was filtered through a pad of celite and the filtrate con-
centrated in vacuo. The obtained oil was triturated with hexane (50 mL),
resulting in the crystallization of product. Hexane was decanted and this
procedure was repeated once more. Flash chromatography of the residue
(CH2Cl2/EtOAc 9:1!85:15!4:1) afforded ester (Z)-alkenoate 28
(1.085 g, 89%) as a slightly yellow solid. M.p. 92–938C. TLC (CH2Cl2/
EtOAc, 85:15): Rf =0.36; 1H NMR (400 MHz, CDCl3): d=1.33 (t, J=
7.1 Hz, 3H, CH2CH3), 3.62 (s, 3H, OCH3), 4.28–4.37 (m, 4H, CH2NH,
CH2CH3), 5.47 (brs, 1H, NH), 6.10–6.19 (m, 1H, HC=CHCH2), 6.30 (d,
J=11.9 Hz, 1H, HC=CHCH2), 8.14 ppm (s, 1H, 5-H); 13C NMR
(100 MHz, CDCl3): d=14.1 (CH2CH3), 39.6 (CH2NH), 52.1 (OCH3), 61.2
(CH2CH3), 115.2 (HC=CHCH2), 134.3 (C-4), 139.3 (HC=CHCH2), 143.1
(C-5), 157.1 (CO2CH3), 160.6 (CO2Et), 161.0 ppm (C-2); HRMS (ESI):
m/z: calcd for C11H14NaN2O5: 277.07949, found 277.07937 [M+Na]+.
Methyl
(2Z)-3-(4-formyl-1,3-oxazol-2-yl)prop-2-enylcarbamate
(29):
DIBAL-H (1m in hexane, 7.1 mL, 7.1 mmol, 2.5 equiv) was added drop-
wise at ꢀ808C to a solution of ester 28 (0.72 g, 2.83 mmol) in dry CH2Cl2
(15 mL). The reaction was stirred at ꢀ808C for 90 min, then quenched
with saturated aqueous NH4Cl solution and warmed up to room tempera-
ture. It was then treated with saturated potassium and sodium tartrate
(Rochelle salt)/EtOAc (100:100 mL) and the mixture was vigorously
stirred for 10 min. After the layers were separated, the aqueous layer was
extracted with EtOAc (3ꢃ100 mL). The combined organic extracts were
washed with saturated NaCl solution, dried over MgSO4, filtered, and
concentrated in vacuo. Flash chromatography of the residue (CH2Cl2/
MeOH 97:3!95:5) afforded aldehyde 29 (415 mg, 70%) as a colorless
solid. Besides aldehyde 29 some overreduced alcohol 30 (85 mg, 14%)
was isolated. M.p. 75–768C; TLC (CH2Cl2/MeOH 9:1): Rf =0.61;
1H NMR (400 MHz, CDCl3): d=3.66 (s, 3H, OCH3), 4.32–4.42 (m, 2H,
CH2NH), 5.39 (brs, 1H, NH), 6.20–6.29 (m, 1H, HC=CHCH2), 6.33 (d,
J=11.6 Hz, 1H, HC=CHCH2), 8.21 (s, 1H, 5-H), 9.93 ppm (s, 1H,
CHO); 13C NMR (100 MHz, CDCl3): d=39.7 (CH2NH), 52.2 (OCH3),
115.0 (HC=CHCH2), 140.4 (C-4), 141.5 (HC=CHCH2), 143.5 (C-5), 157.1
(CO2CH3), 161.1 (C-2), 184.1 ppm (CHO).
Experimental Section
General details and the experimental details for Schemes 7, 8, 10, 11, and
compounds 31, 52 are given in the Supporting Information.
Ethyl 2-{[(trifluoromethyl)sulfonyl]oxy}-1,3-oxazole-4-carboxylate (25):
A solution of oxazolone[19] 24 (2.01 g, 12.8 mmol) in CH2Cl2 (70 mL) was
cooled to ꢀ808C, before 2,6-lutidine (3.0 mL, 25.6 mmol, 2 equiv) was
added via syringe followed by the addition of Tf2O (3.21 mL, 19.2 mmol,
1.5 equiv). The reaction mixture was then allowed to warm to ambient
temperature with stirring for 40 min. The mixture was diluted with water
(150 mL) and extracted with CH2Cl2 (3ꢃ100 mL). The combined organic
layers were washed with brine, dried with MgSO4, filtered, and concen-
trated in vacuo. The residue was purified by flash chromatography (pe-
troleum ether/EtOAc, 4:1) to give triflate 25 (3.30 g, 88%) as a slightly
yellow amorphous solid. Triflate 25 was used immediately after prepara-
tion. TLC (petroleum ether/EtOAc 4:1): Rf =0.52; 1H NMR (400 MHz,
CDCl3): d=1.31 (t, J=7.2 Hz, 3H, CH3), 4.33 (q, J=7.2 Hz, 2H, CH2),
8.09 ppm (s, 1H, 5-H); 13C NMR (100 MHz, CDCl3): d=14.0 (CH3), 61.7
(CH2), 118.3 (q, J=322.0 Hz, CF3), 133.8 (C-4), 142.9 (C-5), 150.0 (C-2),
159.4 ppm (CO2Et).
Methyl (2Z)-3-[4-(hydroxymethyl)-1,3-oxazol-2-yl]prop-2-enylcarbamate
(30): To a cooled (08C) solution of aldehyde 29 (380 mg, 1.81 mmol) in a
mixture of THF/MeOH (6:2 mL) was added sodium borohydride (87 mg,
2.35 mmol) and the reaction mixture was stirred at this temperature for
1 h. Then it was treated with saturated NH4Cl solution and the layers
were separated. The aqueous layer was extracted with CH2Cl2 (3ꢃ
40 mL), and the combined organic extracts were washed with saturated
NaCl solution, dried over MgSO4, filtered and concentrated in vacuo.
Flash chromatography (CH2Cl2/MeOH 95:5) afforded alcohol 30
(364 mg, 95%) as a colorless solid. M.p. 125–1268C, lit.[4a] m.p. 124–
1258C; TLC (CH2Cl2/MeOH 9:1): Rf =0.42; 1H NMR (400 MHz,
CD3OD): d=3.53 (s, 3H, OCH3), 4.16–4.22 (m, 2H, CH2NH), 4.38 (d,
J=5.1 Hz, 2H, CH2OH), 5.21 (t, J=5.1 Hz, 1H, OH), 5.92–6.01 (m, 1H,
HC=CHCH2), 6.28 (dt, J=11.9, 2.0 Hz, 1H, HC=CHCH2), 7.46 (t, J=
5.2 Hz, 1H, NH), 7.89 ppm (s, 1H, 5-H); 13C NMR (100 MHz, CD3OD):
d=39.8 (CH2NH), 51.4 (OCH3), 55.7 (CH2OH), 114.5 (HC=CHCH2),
135.3 (C-4), 138.4 (HC=CHCH2), 142.7 (C-5), 156.8 (CO2CH3),
159.6 ppm (C-2); HRMS (ESI): m/z: calcd for C11H14NaN2O5: 235.06948,
found 235.06952 [M+Na]+.
Ethyl 2-{3-[(methoxycarbonyl)amino]prop-1-ynyl}-1,3-oxazole-4-carbox-
ylate (27): Triflate 25 (3.25 g, 11.1 mmol) and 2,6-lutidine (6.3 mL,
54.4 mmol) were dissolved in degassed 1,4-dioxane (45.0 mL) and
alkyne[18] 26 (2.51 g, 22.2 mmol), [Pd
ACHTNUTRGNEUG(N PPh3)4] (1.27 g, 1.11 mmol), and CuI
(422 mg, 2.22 mmol) were added. The reaction mixture was stirred at am-
bient temperature for 12 h, diluted with EtOAc (200 mL), filtered
through a thin pad of SiO2 and the filtrate concentrated in vacuo. Flash
chromatography (petroleum ether/EtOAc 7:3!1:1) afforded alkyne 27
(2.21 g, 79%) as a slightly yellow oil which crystallized upon standing in
the fridge (ꢀ208C). M.p. 76–788C; TLC (CH2Cl2/EtOAc 85:15): Rf =
0.35; 1H NMR (400 MHz, CDCl3): d=1.33 (t, J=7.2 Hz, 3H, CH2CH3),
3.66 (s, 3H, OCH3), 4.19 (d, J=5.6 Hz, 2H, CH2NH), 4.33 (q, J=7.2 Hz,
2H, CH2CH3), 5.36 (brs, 1H, NH), 8.14 ppm (s, 1H, 5-H); 13C NMR
(100 MHz, CDCl3): d=14.1 (CH2CH3), 31.1 (CH2NH), 52.5 (OCH3), 61.4
(CH2CH3), 70.1 (C=CCH2), 89.7 (C=CCH2), 134.1 (C-4), 144.2 (C-5),
Methyl (2Z)-3-[4-(bromomethyl)-1,3-oxazol-2-yl]prop-2-enylcarbamate
(32): A solution of alcohol 30 (62 mg, 0.29 mmol) and PPh3 (152 mg,
0.58 mmol) in CH3CN (3 mL) was treated with 2,6-lutidine (17 mL,
0.15 mmol) and CBr4 (Fluka, Nr. 86770) (192 mg, 0.58 mmol). After 1 h
the reaction mixture was partitioned between 5% solution of NaHCO3
(10 mL) and Et2O (20 mL). The organic layer was separated and the
11138
www.chemeurj.org
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 11132 – 11140

Neopeltolide and Analogues
FULL PAPER
aqueous layer extracted with Et2O (3ꢃ40 mL). The combined organic
layers were dried over MgSO4, filtered, and concentrated in vacuo. The
crude product was purified by flash chromatography (EtOAc/hexane
2:1!1:1!1:2) to give bromide 32 (64 mg, 81%) as a white solid. M.p.
85–868C, lit.[4a] m.p. 86–878C; TLC (hexane/EtOAc 1:2): Rf =0.62;
1H NMR (400 MHz, CDCl3): d=3.67 (s, 3H, OCH3), 4.28–4.36 (m, 2H,
CH2NH), 4.37 (s, 2H, CH2Br), 5.42 (brs, 1H, NH), 6.10–6.20 (m, 1H,
HC=CHCH2), 6.29 (d, J=11.6 Hz, 1H, HC=CHCH2), 7.60 ppm (s, 1H, 5-
H); 13C NMR (100 MHz, CDCl3): d=39.8 (CH2NH), 51.4 (OCH3), 55.7
(CH2OH), 114.5 (HC=CHCH2), 135.3 (C-4), 138.4 (HC=CHCH2), 142.7
(C-5), 156.8 (CO2CH3), 159.6 ppm (C-2); HRMS (ESI): m/z: calcd for
C9H11BrNaN2O3: 296.98453, found 296.98477 [M+Na]+.
5’’), 136.4 (C-4’’), 141.0 (C-2’), 148.9 (C-5’’), 157.1 (CO2CH3), 159.9 (C-
2’’), 166.7 ppm (C-1); HRMS (ESI): m/z: calcd for C13H16NaN2O5:
303.09514, found 303.09511 [M+Na]+.
Neopeltolide (2): Diisopropyl azodicarboxylate (88 mL, 0.5m solution in
benzene, 0.044 mmol, 1.76 equiv) was added to a solution of alcohol 16
(8.3 mg, 0.025 mmol, 1 equiv), acid 23 (11.2 mg, 0.04 mmol, 1.6 equiv)
and PPh3 (11.5 mg, 0.044 mmol, 1.76 equiv) in dry benzene (1 mL). After
stirring for 1 h at ambient temperature, the reaction mixture was concen-
trated in vacuo and the residue purified by flash column chromatography
(hexane/EtOAC 2:1!1:1!1:2) to afford neopeltolide (2) (12.0 mg,
80%) as a colorless oil. TLC (petroleum ether/EtOAc 1:1): Rf =0.36;
[a]2D0 =+23.8 (c = 0.24, MeOH); 1H NMR (400 MHz, CD3OD): d=0.93
(t, J=7.3 Hz, 3H, 16-H), 0.96 (d, J=6.6 Hz, 3H, 17-H), 1.06–1.14 (m,
1H, 10-H), 1.20–1.42 (m, 6H, 8-H, 9-H, 12-H, 15-H), 1.45–1.60 (m, 4H,
10-H, 4-H, 6-H, 14-H), 1.63–1.75 (m, 2H, 6-H, 14-H), 1.78–1.89 (m, 2H,
4-H, 12-H), 2.28 (dd, J=14.8, 11.0 Hz, 1H, 2-H), 2.65–2.74 (m, 3H, 2-H,
22-H), 2.96–3.04 (m, 2H, 21-H), 3.27 (s, 3H, 11-OCH3), 3.55 (apt, J=
9.9 Hz, 1H, 7-H), 3.62–3.70 (m, 4H, 29-OCH3, 11-H), 4.02–4.11 (m, 1H,
3-H), 4.29 (d, J=4.6 Hz, 2H, 28-H), 5.12–5.21 (m, 2H, 13-H, 5-H), 5.87
(d, J=11.4 Hz, 1H, 19-H), 5.98–6.07 (m, 1H, 27-H), 6.26 (dt, J=11.9,
2.0 Hz, 1H, 26-H), 6.36 (dt, J=11.6, 7.4 Hz, 1H, 20-H), 7.65 ppm (s, 1H,
24-H); 13C NMR (100 MHz, CD3OD): d=14.1 (C-16), 20.0 (C-15), 26.0
(C-17), 26.4 (C-22), 29.0 (C-21), 32.6 (C-9), 36.2 (C-4), 37.4 (C-6), 37.9
(C-14), 41.0 (C-12), 43.2 (C-2), 43.5 (C-10), 45.2 (C-8), 52.6 (29-OCH3),
56.4 (11-OCH3), 69.2 (C-5), 71.3 (C-3), 73.9 (C-13), 77.0 (C-7), 77.1 (C-
11), 115.9 (C-26), 121.7 (C-19), 135.9 (C-24), 139.2 (C-27), 142.3 (C-23),
150.0 (C-20), 159.6 (C-29), 161.9 (C-25), 166.9 (C-18), 173.0 ppm (C-1);
HRMS (ESI): m/z: calcd for C31H46NaN2O9: 613.30955, found 613.31039
[M+Na]+.
Methyl
(2Z)-3-[4-(3-oxopropyl)-1,3-oxazol-2-yl]prop-2-enylcarbamate
(22): A solution of diethylamine (52.4 mL, 0.51 mmol, 2.2 equiv) in THF
(0.5 mL) was cooled to ꢀ788C, and treated with nBuLi (2.5m solution in
hexane, 204.0 mL, 0.51 mmol, 2.2 equiv). After 15 min,
a solution of
imine[25] 33 (66.1 mg, 0.53 mmol, 2.3 equiv) in THF (0.5 mL) was added
to the reaction mixture, immediately followed by HMPA (68.2 mL,
0.393 mmol). The reaction was warmed to 08C, stirred for 10 min and
then cooled to ꢀ808C. The resulting yellow solution of the enolate was
transferred via cannula over a period of 5 min into a stirring solution of
bromide 32 (63 mg, 0.23 mmol) in THF (0.5 mL) at ꢀ308C. After 20 min
at ꢀ308C, the reaction was quenched with a 10% solution of tartaric
acid (2 mL), and allowed to warm to room temperature. After the mix-
ture was extracted with EtOAc (3ꢃ25 mL), the combined organic layers
were washed with saturated NaCl solution (10 mL), dried over MgSO4,
filtered, and concentrated in vacuo. Flash chromatography (CH2Cl2/
MeOH 98:2!95:5) afforded aldehyde 22 (43 mg, 78%) which was used
immediately in the next step. TLC (CH2Cl2/MeOH 9:1): Rf =0.48.
Biological assays: The viability/toxicity of the compounds with L929 and
A549 were tested with an MTT assay after 5 d incubation of serial dilu-
tions of the samples.[34] The cell lines were from DSMZ and kept in
DME medium (Dulbeccoꢄs Modified Eagleꢄs medium) as reported. Neo-
peltolide was checked for typical phenotypic effects with L929 cells and
Giemsa staining. Giemsaꢄs solution were from Merck. Preparations of
submitochondrial particles of bovine heart (SMP) and NADH oxidation
assays with SMP were performed as described previously.[33,35] The sam-
ples contained 52 mgmLꢀ1 of bovine heart protein. The rate of NADH
Methyl
(2Z)-5-(2-{(1Z)-3-[(methoxycarbonyl)amino]prop-1-enyl}-1,3-
oxazol-4-yl)pent-2-enoate (35): A solution of [18]crown-6, freshly recrys-
tallized from acetonitrile, (269 mg, 1.02 mmol, 6 equiv) and bis(2,2,2-tri-
fluoroethyl)(methoxycarbonylmethyl)
phosphonate
(34)
(86 mL,
0.41 mmol, 2.4 equiv) in THF (2.5 mL) was cooled to ꢀ808C, and treated
with KHMDS (0.5m solution in toluene, 0.75 mL, 0.37 mmol, 2.2 equiv).
After 1 h, the solution of aldehyde 22 (41 mg, 0.17 mmol, 1 equiv) in
THF (0.5 mL) was added over a period of 5 min. After 1 h, TLC indicat-
ed complete consumption of aldehyde. Then the reaction was quenched
with saturated NH4Cl and warmed to room temperature. After the mix-
ture was extracted with EtOAc (3ꢃ20 mL), the combined organic layers
were washed with saturated NaCl solution (10 mL), dried over MgSO4,
filtered, and concentrated in vacuo. Flash chromatography (CH2Cl2/
MeOH 98:2) afforded ester 35 (32 mg, 65% yield, 11:1 mixture of Z/E
isomers by 1H NMR analysis) as a colorless oil. TLC (CH2Cl2/MeOH
oxidation in the control without inhibitor was 1.8ꢁ0.2 mmolmgꢀ1 minꢀ1
.
Acknowledgements
1
9:1): Rf =0.55; H NMR (400 MHz, CDCl3): d=2.68 (t, J=7.2 Hz, 2H, 5-
Financial support by the Deutsche Forschungsgemeinschaft (grant Ma
1012/23-1) and the Fonds der Chemischen Industrie is gratefully acknowl-
edged. We also thank Graeme Nicholson (Institute of Organic Chemis-
try) for measuring the HRMS spectra. In addition, a graduate fellowship
for V.V.V. of the state Baden-Wꢀrttemberg (LGFG) is also acknowl-
edged. We thank Birte Engelhardt, Bettina Hinkelmann, and Lara Hoch-
feld for excellent technical assistance.
H), 2.96–3.03 (m, 2H, 4-H), 3.66 (s, 3H, OCH3), 3.69 (s, 3H, CCO2CH3),
4.25–4.32 (m, 2H, 3’-H), 5.59 (br s, 1H, NH), 5.80 (d, J=11.6 Hz, 1H, 2-
H), 6.03–6.13 (m, 1H, 2’-H), 6.21–6.30 (m, 2H, 3-H, 1’-H), 7.36 ppm (s,
1H, 5’’-H); 13C NMR (100 MHz, CDCl3): d=25.6 (C-5), 27.5 (C-4), 39.3
(C-3’), 51.1 (OCH3), 52.1 (OCH3), 116.7 (C-1’), 120.2 (C-2), 133.9 (C-5’’),
136.2 (C-4’’), 141.1 (C-2’), 148.9 (C-5’’), 157.1 (CO2CH3), 159.9 (C-2’’),
166.7 ppm (C-1); HRMS (ESI): m/z: calcd for C14H18NaN2O5: 317.11079,
found 317.11086 [M+Na]+.
Acid 23: A solution of ester 35 (15 mg, 0.05 mmol) in THF (0.5 mL) was
treated with LiOH (1n solution in water, 0.5 mL, 0.5 mmol) at ambient
temperature and the reaction mixture was vigorously stirred until TLC
indicated complete consumption of the starting material (ca. 7 h). The re-
action was cooled to 08C and neutralized with aqueous HCl (1n, 0.5 mL,
0.5 mmol). After the mixture was extracted with EtOAc (4ꢃ20 mL), the
combined organic layers were washed with saturated NaCl solution
(10 mL), dried over MgSO4, filtered, and concentrated in vacuo. Flash
chromatography (CH2Cl2/MeOH 95:5!9:1) afforded acid 23 (12.7 mg,
91%) as a colorless oil. TLC (CH2Cl2/MeOH 9:1): Rf =0.36; 1H NMR
(400 MHz, CDCl3): d=2.69 (t, J=7.3 Hz, 2H, 5-H), 2.98 (m, 2H, 4-H),
3.66 (s, 3H, OCH3), 4.25–4.32 (m, 2H, 3’-H), 5.52 (br s, 1H, NH), 5.81 (d,
J=11.5 Hz, 1H, 2-H), 6.03–6.10 (m, 1H, 2’-H), 6.25–6.32 (m, 2H, 3-H, 1’-
H), 7.34 ppm (s, 1H, 5’’-H); 13C NMR (100 MHz, CDCl3): d=25.5 (C-5),
27.4 (C-4), 39.3 (C-3’), 52.1 (OCH3), 116.6 (C-1’), 120.2 (C-2), 133.9 (C-
[1] For some reviews, see: a) A. M. S. Mayer, K. R. Gustafson, Eur. J.
Cancer 2006, 42, 2241–2270; b) M. Sasaki, Top. Heterocycl. Chem.
2006, 5, 149–178; c) M. Shindo, Top. Heterocycl. Chem. 2006, 5,
179–254; d) R. A. Hill, Annu. Rep. Prog. Chem., Sect. B: Org.
Chem. 2007, 103, 125–139; e) J. C. Morris, A. J. Phillips, Nat. Prod.
Rep. 2008, 25, 95–117; f) J. W. Blunt, B. R. Copp, W.-P. Hu, M. H. G.
Munro, P. T. Northcote, M. R. Prinsep, Nat. Prod. Rep. 2008, 25, 35–
94; g) S. Banerjee, Z. Wang, M. Mohammad, F. H. Sarkar, R. M.
Mohammad, J. Nat. Prod. 2008, 71, 492–496.
[2] M. D’Ambrosio, A. Guerriero, C. Debitus, F. Pietra, Helv. Chim.
Acta 1996, 79, 51–60.
[3] M. D’Ambrosio, M. Tato, G. Pocsfalvi, C. Debitus, F. Pietra, Helv.
Chim. Acta 1999, 82, 347–353.
[4] a) K. R. Hornberger, C. L. Hamblett, J. L. Leighton, J. Am. Chem.
Soc. 2000, 122, 12894–12895; b) Y. Wang, J. Janjic, S. A. Kozmin, J.
Chem. Eur. J. 2008, 14, 11132 – 11140
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11139

M. E. Maier et al.
Am. Chem. Soc. 2002, 124, 13670–13671; c) A. Fettes, E. M. Car-
reira, Angew. Chem. 2002, 114, 4272–4275; Angew. Chem. Int. Ed.
2002, 41, 4098–4101; A. Fettes, E. M. Carreira, J. Org. Chem. 2003,
68, 9274–9283; d) I. Paterson, M. Tudge, Angew. Chem. 2003, 115,
357–361; Angew. Chem. Int. Ed. 2003, 42, 343–347; I. Paterson, M.
Tudge, Tetrahedron 2003, 59, 6833–6849; e) Q. Su, J. S. Panek,
Angew. Chem. 2005, 117, 1249–1251; Angew. Chem. Int. Ed. 2005,
44, 1223–1225; Q. Su, L. A. Dakin, J. S. Panek, J. Org. Chem. 2007,
72, 2–24; f) L. J. Van Orden, B. D. Patterson, S. D. Rychnovsky, J.
Org. Chem. 2007, 72, 5784–5793.
[16] a) F. Lꢇpez, S. R. Harutyunyan, A. Meetsma, A. J. Minnaard, B. L.
Feringa, Angew. Chem. 2005, 117, 2812–2816; Angew. Chem. Int.
Ed. 2005, 44, 2752–2756; b) R. D. Mazery, M. Pullez, F. Lꢇpez, S. R.
Harutyunyan, A. J. Minnaard, B. L. Feringa, J. Am. Chem. Soc.
2005, 127, 9966–9967; c) S. R. Harutyunyan, F. Lopez, W. R.
Browne, A. Correa, D. Pena, R. Badorrey, A. Meetsma, A. J. Min-
naard, B. L. Feringa, J. Am. Chem. Soc. 2006, 128, 9103–9118; d) B.
ter Horst, B. L. Feringa, A. J. Minnaard, Org. Lett. 2007, 9, 3013–
3015; e) B. M. Ruiz, K. Geurts, M. A. Fernandez-Ibanez, B. ter
Horst, A. J. Minnaard, B. L. Feringa, Org. Lett. 2007, 9, 5123–5126.
[17] F. Lꢇpez, A. J. Minnaard, B. L. Feringa, Acc. Chem. Res. 2007, 40,
179–188.
[18] P. Wipf, T. H. Graham, J. Org. Chem. 2001, 66, 3242–3245.
[19] J. F. Okonya, R. V. Hoffman, M. C. Johnson, J. Org. Chem. 2002, 67,
1102–1108.
[20] a) L. A. Dakin, N. F. Langille, J. S. Panek, J. Org. Chem. 2002, 67,
6812–6815; b) N. F. Langille, L. A. Dakin, J. S. Panek, Org. Lett.
2002, 4, 2485–2488.
[21] I. K. Youn, G. H. Yon, C. S. Pak, Tetrahedron Lett. 1986, 27, 2409–
2410.
[22] T. Satoh, K. Nanba, S. Suzuki, Chem. Pharm. Bull. 1971, 19, 817–
820.
[23] J. Hooz, S. S. H. Gilani, Can. J. Chem. 1968, 46, 86–87.
[24] J. F. Le Borgne, J. Organomet. Chem. 1976, 122, 123–128.
[25] S. A. Kozmin, Org. Lett. 2001, 3, 755–758.
[26] W. C. Still, C. Gennari, Tetrahedron Lett. 1983, 24, 4405–4408.
[27] G. E. Keck, E. P. Boden, S. A. Mabury, J. Org. Chem. 1985, 50, 709–
710.
[28] a) T. Fukuyama, S. C. Lin, L. Li, J. Am. Chem. Soc. 1990, 112, 7050–
7051; b) T. Fukuyama, H. Tokuyama, Aldrichimica Acta 2004, 37,
87–96.
[29] For some reviews, see: a) L. E. Overman, L. D. Pennington, J. Org.
Chem. 2003, 68, 7143–7157; b) P. A. Clarke, S. Santos, Eur. J. Org.
Chem. 2006, 2045–2053; c) I. M. Pastor, M. Yus, Curr. Org. Chem.
2007, 11, 925–957.
[30] For recent papers, see: a) C. S. J. Barry, S. R. Crosby, J. R. Harding,
R. A. Hughes, C. D. King, G. D. Parker, C. L. Willis, Org. Lett. 2003,
5, 2429–2432; b) R. Jasti, S. D. Rychnovsky, J. Am. Chem. Soc. 2006,
128, 13640–13648, and references therein.
[31] J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull.
Chem. Soc. Jpn. 1979, 52, 1989–1993.
[32] A. Parenty, X. Moreau, J. M. Campagne, Chem. Rev. 2006, 106,
911–939.
[33] a) G. Thierbach, H. Reichenbach, Antimicrob. Agents Chemother.
1981, 19, 504–507; b) G. Thierbach, H. Reichenbach, Biochim. Bio-
phys. Acta Bioenerg. 1981, 638, 282–289.
[34] V. V. Vintonyak, M. Calꢈ, F. Lay, B. Kunze, F. Sasse, M. E. Maier,
Chem. Eur. J. 2008, 14, 3709–3720.
[35] F. Surup, H. Shojaei, P. von Zezschwitz, B. Kunze, S. Grond, Bioorg.
Med. Chem. 2008, 16, 1738–1746.
[5] a) D. J. Kopecky, S. D. Rychnovsky, J. Am. Chem. Soc. 2001, 123,
8420–8421; b) P. Wipf, J. T. Reeves, Chem. Commun. 2002, 2066–
2067; c) D. R. Williams, S. V. Plummer, S. Patnaik, Angew. Chem.
2003, 115, 4064–4068; Angew. Chem. Int. Ed. 2003, 42, 3934–3938;
D. R. Williams, S. Patnaik, S. V. Plummer, Org. Lett. 2003, 5, 5035–
5038; d) M. T. Crimmins, P. Siliphaivanh, Org. Lett. 2003, 5, 4641–
4644; e) L. Ferriꢅ, S. Reymond, P. Capdevielle, J. Cossy, Org. Lett.
2007, 9, 2461–2464; L. Ferrie, L. Boulard, F. Pradaux, S. Bouzbouz,
S. Reymond, P. Capdevielle, J. Cossy, J. Org. Chem. 2008, 73, 1864–
1880; f) H. H. Jung, J. R. SeidersII, P. E. Floreancig, Angew. Chem.
2007, 119, 8616–8619; Angew. Chem. Int. Ed. 2007, 46, 8464–8467;
g) P. A. Evans, W. J. Andrews, Angew. Chem. 2008, 120, 5506–5509;
Angew. Chem. Int. Ed. 2008, 47, 5426–5429.
[6] O. A. Ulanovskaya, J. Janjic, M. Suzuki, S. S. Sabharwal, P. T. Schu-
macker, S. J. Kron, S. A. Kozmin, Nat. Chem. Biol. 2008, 4, 418–424.
[7] For a commentary, see: K.-H. Altmann, E. M. Carreira, Nat. Chem.
Biol. 2008, 4, 388–389.
[8] A. E. Wright, J. C. Botelho, E. Guzmꢆn, D. Harmody, P. Linley, P. J.
McCarthy, T. P. Pitts, S. A. Pomponi, J. K. Reed, J. Nat. Prod. 2007,
70, 412–416.
[9] W. Youngsaye, J. T. Lowe, F. Pohlki, P. Ralifo, J. S. Panek, Angew.
Chem. 2007, 119, 9371–9374; Angew. Chem. Int. Ed. 2007, 46, 9211–
9214.
[10] D. W. Custar, T. P. Zabawa, K. A. Scheidt, J. Am. Chem. Soc. 2008,
130, 804–805.
[11] K. Woo, S. Kwon Min, E. Lee, Angew. Chem. 2008, 120, 3286–3288;
Angew. Chem. Int. Ed. 2008, 47, 3242–3244.
[12] H. Fuwa, S. Naito, T. Goto, M. Sasaki, Angew. Chem. 2008, 120,
4815–4817; Angew. Chem. Int. Ed. 2008, 47, 4737–4739.
[13] V. V. Vintonyak, M. E. Maier, Org. Lett. 2008, 10, 1239–1242.
[14] a) M. Kitamura, M. Tokunaga, T. Ohkuma, R. Noyori, Org. Synth.
1992, 71, 1–13; Org. Synth. Coll. Vol. 9, 1998, 589–597; b) J. P.
GenÞt, V. Ratovelomanana-Vidal, M. C. CaÇo de Andrade, X. Pfis-
ter, P. Guerreiro, J. Y. Lenoir, Tetrahedron Lett. 1995, 36, 4801–
4804; c) L.-S. Deng, X.-P. Huang, G. Zhao, J. Org. Chem. 2006, 71,
4625–4635.
[15] a) K. Kubota, J. L. Leighton, Angew. Chem. 2003, 115, 976–978;
Angew. Chem. Int. Ed. 2003, 42, 946–948; b) R. Berger, P. M. A.
Rabbat, J. L. Leighton, J. Am. Chem. Soc. 2003, 125, 9596–9597;
c) X. Zhang, K. N. Houk, J. L. Leighton, Angew. Chem. 2005, 117,
960–963; Angew. Chem. Int. Ed. 2005, 44, 938–941.
Received: July 9, 2008
Published online: October 31, 2008
11140
www.chemeurj.org
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 11132 – 11140