Stereoselective total synthesis of arenastatin A, a spongean cytotoxic depsipeptide

Article abstract of DOI:10.1016/j.tetlet.2007.07.193

A highly stereoselective total synthesis of arenastatin A, an extremely potent cytotoxic cyclic depsipeptide from marine sponge, was developed. The desired 7,8-β-epoxide in arenastatin A was constructed by asymmetric sulfur ylide-mediated epoxidation in g

Full text of DOI:10.1016/j.tetlet.2007.07.193

Tetrahedron Letters 48 (2007) 7147–7150
Stereoselective total synthesis of arenastatin A,
a spongean cytotoxic depsipeptide
Naoyuki Kotoku, Fuminori Narumi, Tomoya Kato, Miho Yamaguchi and
Motomasa Kobayashi*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
Received 28 June 2007; revised 27 July 2007; accepted 30 July 2007
Available online 2 August 2007
Abstract—A highly stereoselective total synthesis of arenastatin A, an extremely potent cytotoxic cyclic depsipeptide from marine
sponge, was developed. The desired 7,8-b-epoxide in arenastatin A was constructed by asymmetric sulfur ylide-mediated epoxida-
tion in good yield and highly stereoselective manner.
Ó 2007 Elsevier Ltd. All rights reserved.
In the course of our search for bioactive substances from
marine organisms, we isolated and characterized are-
nastatin A (1), a cyclic depsipeptide having an extremely
potent antiproliferative activity against KB cells (IC50
5 pg/mL), from the Okinawan marine sponge of Dysidea
arenaria.1 Thereafter, we achieved the first total synthe-
sis of 1,2 and many synthetic studies toward 1 and its
analogues have been reported so far, because of its syn-
thetically attractive structure and potent biological
activity (Fig. 1).3
the epoxy function in 1 is labile under acidic condition,
so it should be introduced at the final stage of the syn-
thesis. The most reliable method for the stereoselective
construction of the 7,8-b-epoxide would be the epoxida-
tion of the 7,8-E-olefin of 2 with dimethyldioxirane
developed by our group (Scheme 1).2a,4 However, the
stereoselective ratio is b:a = 2.2:1, and reversed-phase
HPLC separation should be needed to isolate pure prod-
uct. Furthermore, the epoxidation with other bulky
oxirane reagents gave 7,8-epoxide with poor or inverse
selectivity. In the synthetic study of cryptophycin 52, a
closely related depsipeptide, Moher and co-workers4
reported that the selective (b:a = 5–9.5:1) introduction
of the 7,8-b-epoxide to the acyclic intermediates has
been performed by using Shi epoxidation. However,
Arenastatin A (1) has a 7R,8R-b-epoxy moiety on its
molecule. Some structure–activity relationship (SAR)
studies have revealed that the b-epoxy moiety plays
critical role for the potent cytotoxic activity of 1, and
the a-epoxy isomer has no biological activity. However,
8
O
1
O
O
7
O
O
O
HN
HN
O
O
O
HN
HN
15
O
OMe
O
OMe
20
O
O
2
arenastatin A (1)
Figure 1. Chemical structure of arenastatin A (1).
O
O
O
+
1
O
O
CH2Cl2-MeOH
Keywords: Arenastatin A; Depsipeptide; Total synthesis; Asymmetric
epoxidation.
β:α = 2.2:1
7,8-epi-1
*
Corresponding author. Tel.: +81 6 6879 8215; fax: +81 6 6879
8219; e-mail: kobayasi@phs.osaka-u.ac.jp
Scheme 1.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.193

7148
N. Kotoku et al. / Tetrahedron Letters 48 (2007) 7147–7150
Shi epoxidation of the substrate having cyclic depsipep-
tide structure resulted in very low conversion, because of
steric hindrance. Thus, another method for the construc-
tion of the 7,8-b-epoxide in a highly stereoselective man-
ner is strongly needed from the viewpoint of synthetic
utility and atom economy. Here, we present our new
synthetic procedure for the stereoselective total synthesis
of arenastatin A (1) by using asymmetric sulfur ylide-
mediated epoxidation.5
ture of the diastereomers in a 13/1 ratio. Removal of
p-methoxybenzyl (MPM) group of 10 and subsequent
protection of the primary hydroxyl group of 11 by
tert-butyldiphenylsilyl (TBDPS) group afforded
desired segment A (6).
a
Segment A (6) was coupled with segment C (7), prepared
from L-leucic acid,2 to give segment AC (12) in 87%
yield. Oxidative cleavage of the terminal olefin of 12
smoothly proceeded to give an aldehyde 4, and subse-
quent Horner–Emmons reaction with segment B (5)
afforded an a,b-unsaturated amide 13. It revealed that
the choice of base was important in this reaction. The
results are summarized in Table 1. Thus, the use of
NaH as a base (entry 1) resulted in disappointing yield
of the desired product, and considerable amount of
a,b-unsaturated aldehyde 14 was obtained as a byprod-
uct. On the other hand, the Masamune–Roush condi-
tion7 using DBU and LiCl (entry 2), which was
developed for base-sensitive aldehydes, afforded 14 as
a sole product. Among tested, the use of activated
Ba(OH)28 (entry 6) gave the best result to afford the cou-
pling product 13 in 60% yield (three steps from 12).
The synthetic strategy was shown in Figure 2. An aryl
moiety and a 7R,8R-epoxide of 1 could be introduced
in one operation by the Corey–Chaycovsky reaction
between a chiral benzyl sulfur ylide and an aldehyde 3
having cyclic depsipeptide structure. Compound 3 could
be synthesized through the similar manner as our previ-
ous total synthesis of 1,2 that is, the successive conden-
sation of the four segments A (6), B (5), C (7), and D (8).
Cyclic peptide 3 was synthesized as follows (Schemes 2,
3). First of all, segment A (6) was prepared with a
known method.6 Thus, Lewis acid-promoted allylation
of aldehyde 9 gave a homoallylic alcohol 10, as a mix-
8
O
S
5
O
O
3
∗
6
7
O
O
O
HN
HN
O
O
O
HN
HN
20
O
O
OMe
O
OMe
O
O
15
1
O
P
MeO
MeO
O
TBDPSO
O
TBDPSO
HN
O
OH
segment A (6)
O
O
O
OMe
OMPM
TMS
OH NHBoc
HO
O
4
segment B (5)
OMPM
segment C (7)
O
segment D (8)
Figure 2. Retrosynthetic analysis.
TBDPSO
b, c
d
a
RO
MPMO
MPMO
O
O
OH
O
OH
10 (13:1 dr)
9
11: R = H
OMPM
6: R = TBDPS
12
TBDPSO
O
O
TBDPSO
g
e, f
O
O
HN
O
O
O
TBDPSO
OMPM
O
OMe
14
O
OMPM
4
TMS
13
Scheme 2. Reagents and conditions: (a) allyltributylstannane, SnCl4, CH2Cl2, À78 °C, 75%, 13:1 dr; (b) HCl/MeOH, reflux, 80%; (c) TBDPSCl,
Et3N, DMAP, CH2Cl2, 95%; (d) 7, EDCIÆHCl, DMAP, CH2Cl2, 87%; (e) OsO4, NMO, THF/pH 7.0 buffer; (f) NaIO4, THF/pH 7.0 buffer; (g) 5,
Ba(OH)2, THF/H2O (40:1), 60% (three steps).

N. Kotoku et al. / Tetrahedron Letters 48 (2007) 7147–7150
7149
BF4
S
TBDPSO
O
O
O
O
HN
RO
a, b
13
O
O
OMe
O
OTBS
19
P2-Et, CH2Cl2, —78 °C
O
NHBoc
H
O
O
15: R = (CH2)2TMS
NHBoc
18
RO
O
c, d
O
O
HN
HN
OTBS
O
O
O
O
OTBS
O
O
OMe
H
O
NHBoc
21
16: R = TBDPS
17: R = H
20
OTBS
O
22
O
O
O
e, f
O
O
O
HN
HN
O
O
O
OMe
as above
79%
O
O
HN
HN
3
O
O
OMe
2 steps
3
from 17
O
arenastatin A (1)
β:α = ~100:1, trans:cis = ~30:1
Scheme 3. Reagents and conditions: (a) BF3ÆEt2O, PhSH, CH2Cl2,
À45 °C, 71%; (b) 8, EDCIÆHCl, DMAP, CH2Cl2, 98%; (c) TFA,
CH2Cl2, 0 °C; (d) DPPA, NaHCO3, DMF, 61% (two steps); (e) HF-
pyridine, THF, 84%; (f) Dess–Martin periodinane, CH2Cl2.
Scheme 4.
Table 1. Conditions of Horner–Emmons reaction between 4 and 5
stoichiometric amount, a,b-unsaturated aldehyde 21
was obtained as a sole product, which was produced
by b-elimination of the leucine moiety from 18. The
use of increased amount of the sulfur ylide tended to
give a desired epoxide 20 together with an epoxide 22,
Entry
Base
Yielda (%)
1
2
3
4
5
6
NaH
LiCl, DBU
t-BuOK
n-BuLi, DMSO
Ba(OH)2 (2.0 equiv)
Ba(OH)2 (0.8 equiv)
33
Decomp.
Decomp.
55
56
60
1
which was produced from 21 and sulfur ylide. The H
NMR spectrum and HPLC analysis of 20 revealed that
epoxide 20 was obtained as almost single stereoisomer!
The stereochemistry of 20 was ascertained by NOESY
experiment. However, even in the optimized reaction
condition, the desired epoxide 20 was obtained in low
yield (ꢀ25%), and the b-elimination reaction could not
be avoided.
a Isolated yield of 13 in three steps from 12.
Removal of the MPM group of 13 using PhSH and
BF3ÆEt2O and subsequent condensation with segment
D (8) using the conventional method2a afforded 15 in
good yield. Finally, removal of both (trimethylsilyl)ethyl
group and tert-butoxycarbonyl (Boc) group by trifluoro-
acetic acid (TFA) and subsequent intramolecular mac-
rocyclization using diphenylphosphoryl azide (DPPA)
furnished a cyclic depsipeptide 16. Removal of the
TBDPS protecting group and Dess–Martin oxidation
gave a desired aldehyde 3 (Scheme 3).
Fortunately, the same reaction using cyclic peptide 3 as
a substrate proceeded smoothly to give arenastatin A (1)
in good yield (79%, two steps from 17). The side product
derived from the elimination of the ester moiety was not
detected, probably because of the stability of the cyclic
structure in 3. The HPLC analysis of the reaction prod-
uct revealed that the reaction proceeded with excellent
stereoselectivity (b:a = ꢀ100:1, trans:cis = ꢀ30:1).2a,9
Recently, Sherman and co-workers10 reported that the
stereoselective epoxidation of the 7,8-E-olefin in the cyc-
lic precursor of cryptophycin 2 was succeeded by using
cryptophycin CYP450 epoxidase, which was obtained
by overexpression of the cyanobacterial gene in Esche-
richia coli.
In the final stage of the synthesis, that is, the introduc-
tion of the aryl moiety and 7R,8R-epoxide, we used
asymmetric Corey–Chaycovsky reaction mediated by
D-camphor-derived chiral sulfide, which has been devel-
oped by Aggarwal’s group.5 In order to optimize the
reaction condition, the condensation between alde-
hyde 18 and sulfur ylide, which was generated by depro-
tonation from sulfonium salt 19 using phosphazene base
P2–Et, was examined (Scheme 4). In the case using
In summary, we developed a convergent synthetic proce-
dure of arenastatin A (1) by using asymmetric sulfur

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N. Kotoku et al. / Tetrahedron Letters 48 (2007) 7147–7150
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7R,8R-b-epoxide moiety in 1.
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Acknowledgment
This study was financially supported by the Takeda
Science Foundation, and Grant-in-Aid for Scientific
research from the Ministry of Education, Science, Sport,
and Culture of Japan.
References and notes
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9. The isomeric ratio of the epoxide was determined by
reversed-phase HPLC. The stereochemistry of the cis-
epimer was deduced by the coupling constant of the 1H
NMR signal of H-8 (d 4.05, J = 4.5 Hz), which was
characteristic for the cis-epoxide.
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Huber, U.; Hemscheidt, T. K.; Abelson, D.; Moore, R. E.;
Sherman, D. H. ACS Chem. Biol. 2006, 1, 766–779.