Total synthesis of (+)-aspergillide C

Article abstract of DOI:10.1016/j.tetlet.2011.01.078

The enantioselective total synthesis of aspergillide C, a member of a novel class of 14-membered macrolides isolated from the marine-derived fungus Aspergillus ostianus strain 01F313, has been accomplished employing a highly diastereoselective intramolecu

Full text of DOI:10.1016/j.tetlet.2011.01.078

Tetrahedron Letters 52 (2011) 1372–1374
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Total synthesis of (+)-aspergillide C
⇑
Makoto Kanematsu, Masahiro Yoshida, Kozo Shishido
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective total synthesis of aspergillide C, a member of a novel class of 14-membered macro-
lides isolated from the marine-derived fungus Aspergillus ostianus strain 01F313, has been accomplished
employing a highly diastereoselective intramolecular oxy-Michael reaction as the key step.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 14 December 2010
Revised 6 January 2011
Accepted 17 January 2011
Available online 20 January 2011
Aspergillide C1 (1), along with aspergillides A (2) and B (3),1,2 has
been isolated from the marine-derived fungus Aspergillus ostianus
strain 01F313, culturedin a mediumcomposed ofbromine-modified
artificial sea water, by Kusumi and co-workers. Its structure was
determined on the basis of extensive spectroscopic studies and its
absolute configuration was assigned by the modified Mosher
method and chemical conversion. The key structural feature of the
molecule is a novel 14-membered macrolide in which a 2,6-anti-
dihydropyran moiety, having three stereogenic centers, is incorpo-
rated. The aspergillides A–C showed cytotoxicity against mouse
lymphocytic leukemia cells (L1210), the most potent activity being
H
HO
H
HO
3
O
7
H
R
O
O
H
H
O
O
O
R=β-H: aspergillide A (2)
R=α-H: aspergillide B (3)
aspergillide C (1)
Figure 1.
found in aspergillide C (1) with an LD50 value of 2.0 lg/mL. These
intriguing chemical structures, combined with their promising
biological profiles, have made the aspergillides attractive synthetic
targets. To date, four total syntheses of 23 and six of 33c,4 have been
reported; however, only two reports on aspergillide C5 have been
published. We report here the total synthesis of (+)-aspergillide C
(1) employing asthe keystepa highlydiastereoselective intramolec-
ular oxy-Michael (IMOM) reaction of the substrate with a cis-epox-
ide,6 which may play a key role not only in the stereochemical
control during the cycloaddition but also in the further transforma-
tion to the allylic alcohol moiety on the pyran ring (Fig. 1).
Our retrosynthetic analysis of aspergillide C is shown in Scheme
1. We envisaged the macrolactonization being achieved in the last
stage of the synthesis. The seco acid would be derived from 4, the
IMOM adduct of the hydroxy enoate 5 which can be prepared from
R-(ꢀ)-benzyl glycidyl ether (6), via a sequential C8 olefination,
transformation of the epoxide to the allyl alcohol, and standard
functionalization. From an examination of molecular models, it
was thought that the Z-enoate (Z in 5) might produce the syn-ad-
duct preferentially in the key IMOM reaction; therefore, in order
to obtain the requisite anti-adduct, we chose the E-enoate 5 as
the substrate (Scheme 1).
H
HO
O
H
H
H
olefination
H
H
O
H
O
OBn
O
O
RO2C
4
macro-
lactonization
IMOM
H
1
O
O
H
OBn
OBn
HO
6
H
RO2C
5
Scheme 1. Retrosynthetic analysis of aspegillide C.
The substrate 10 for the IMOM reaction was synthesized as
shown in Scheme 2. The diene 7, prepared from R-(ꢀ)-benzyl glyc-
idyl ether (6) via a two-step sequence, was treated with 0.5 mol %
7
of the Grubbs’ 2nd generation catalyst in refluxing CH2Cl2 to give
lactone 8.8 Diastereoselective epoxidation9 followed by DIBAL-H
reduction and Horner–Wadsworth–Emmons reaction of 9 pro-
vided E-hydroxy enoate 10 in 64% yield for the six steps (Scheme
2).
⇑
The key IMOM reaction of 10 was examined and the results are
shown in Table 1. Treatment of a solution of 10 in THF with KH at
Corresponding author. Tel.: +81 88 6337287; fax: +81 88 6339575.
E-mail address: shishido@ph.tokushima-u.ac.jp (K. Shishido).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.078

M. Kanematsu et al. / Tetrahedron Letters 52 (2011) 1372–1374
1373
of the carboxylic acids (14 and 15) in slightly lower yields and
diastereoselectivities along with a small amount of the uncyclized
carboxylic acid 11.11 It was found that addition of water was essen-
tial for acceleration of the reaction and for obtaining the anti-ad-
duct with higher yield and diastereoselectivity, however, the role
of it remains unclear (Table 1).
In the cases of entries 4–6, the formation of 12 can be moni-
tored by TLC analysis. In addition, treatment of carboxylic acid
11, prepared from 10, with the conditions of entries 4 provided a
trace amount of the cyclized product 14. These indicated that the
IMOM reaction would proceed before hydrolysis of the ester moi-
ety. As a possible mechanism, the high anti-selectivity of the cyclo-
addition (Table 1, entry 4) can be explained by comparing the two
possible lithium-chelated transition states T1 and T2, in which the
less strained six-membered chair-like transition state T1 might
predominate, and the anti-pyran would be generated as the sole
product (Scheme 3). The stereochemistry in 14 was established
by the diagnostic 1H–1H NOE between the C2 and C7 protons
and by the vicinal coupling constant (J3,4 = 3.8 Hz).
c
a, b
O
OBn
OBn
OBn
O
O
O
O
H
H
6
7
8
O
H
O
H
e, f
d
H
H
O
OBn
OBn
O
HO
H
H
EtO2C
9
10
Scheme 2. Synthesis of hydroxy enoate 10. Reagents and conditions: (a) vinyl-
magnesium chloride, CuI (0.1 equiv), THF, 0 °C, 1 h; (b) acryloyl chloride, EtMgBr,
THF, rt, 1.5 h, quant (2 steps); (c) Grubbs’ 2nd cat. (0.5 mol %), CH2Cl2, reflux, 6 h,
96%; (d) H2O2 (30% aq), NaOH (aq), MeOH, 0 °C, 1 min, 74%; (e) DIBAL-H, toluene,
ꢀ78 °C, 1 h; (f) (EtO)2POCH2CO2Et, DBU, NaI, THF, ꢀ40 °C, 1 h, 90% (2 steps).
Table 1
IMOM reaction of 10
With the desired anti-pyran 14 in hand, we next examined its
conversion to the dihydropyran 20. Reduction of the carboxylic
acid followed by silylation of the resulting primary alcohol moiety
in 16 and debenzylation gave 17. IBX oxidation12 gave the alde-
hyde, which was subjected to Kocienski-Julia olefination13 with
184d in the presence of LiHMDS to provide 19 as E-olefin (>10:1).
Various conditions for the direct conversion of the epoxide to
allylic alcohol in 19 were examined (LDA, LiNEt2;14 LiTMP,
Et2AlCl;15 Al(OiPr)3;16 etc.), but none provided the desired product.
The conversion was successfully achieved by treatment of 19 with
TBSOTf, Hunig’s base, and DBU17 to give the desired dihydropyran
20 in 51% yield, accompanied by 20% of the chromatographically
separable rearranged product 21. The syn-stereochemistry on the
tetrahydrofuran ring of 21 was confirmed by NOE experiments
(Scheme 4).
O
H
O
H
H
H
O
H
conditions
H
2
H
H
3
7
+
O
R
O
R
R
HO
H
H
H
R'O2C
R'O2C
R'O2C
13: R'=Et
15: R'=H
12: R'=Et
14: R'=H
10: R'=Et
11: R'=H
R=CH2OBn
Entry Conditions
Yield
(%)
Product ratio
1
2
3
4
KH (1.3 equiv), THF, ꢀ78 °C, 3 h
74
48
13
94
12/13 = 1.3:1
12/13 = 1.3:1
12/13 = 2.5:1
14
NaHMDS (1.3 equiv), THF, ꢀ60 °C, 0.5 h
LiHMDS (1.3 equiv), THF, ꢀ50 °C, 3 h
LiOHꢁH2O (2 equiv), THF/H2O = 3:1, rt,
12 h
5
6
NaOH (2 equiv), THF/H2O = 3:1, rt, 9 h
79a
85a
14/
15 = 6.1:1b
14/
KOH (2 equiv), THF/H2O = 3:1, rt, 11 h
Selective deprotection of the two TBS ethers in 20 followed by
oxidation of the primary alcohol moiety with catalytic TEMPO
and PhI(OAc)2 provided lactone 23. Standard functional group
transformations of 23 via a four-step sequence of reactions pro-
duced hydroxy acid 26, which was exposed to Yamaguchi macrol-
actonization conditions to give lactone 27. Finally, acidic
15 = 6.3:1b
a
The uncyclized carboxylic acid 11 was obtained in 8% (entry 4) and 10% (entry
5) yield, respectively.
The ratio was determined by 1H NMR.
b
hydrolysis produced aspergillide C (1), {½a D28
ꢂ
= +77.5(c 0.11,
MeOH); lit.1
½
a 2D5
ꢂ
= +66.2 (c 0.19, MeOH); lit.5a
½
a 2D5
ꢂ
= +83 (c 0.14,
H
H
OBn
OBn
Li
O
O
O
H
O
H
H
O
O
O
H
Li
a - c
EtO
H
H
OR2
HO2C
OBn
O
O
OEt
R1O
d
O
O
H
T1
T2
H
H
H
14
16: R1=H, R2=Bn
17: R1=TBS, R2=H
H
anti-pyran
syn-pyran
O2
S
H
N
N
N
H
Scheme 3. Transition state for the IMOM reaction.
e, f
TBSO
O
H
PhN
TBDPSO
18
TBDPSO
ꢀ78 °C for 3 h produced the cycloadduct as a separable 1.3:1 mix-
ture of anti 12 and syn 13 pyran isomers in 74% yield (entry 1).
When the reaction was conducted in the presence of NaHMDS
and LiHMDS as bases, the yields obtained were poorer (entries 2
and 3).10
Since the use of LiHMDS resulted in a slight increase in the for-
mation of the requisite anti-pyran 12, we focused our attention on
lithium bases for the cycloaddition. After numerous attempts, we
isolated pyran carboxylic acid 14 with the anti-configuration as a
single product in 94% yield after conducting the reaction with
LiOHꢁH2O in THF/H2O (3:1) at room temperature. To compare the
effect of counter cation, we examined the reaction using NaOH
and KOH as bases under the similar conditions (entries 5 and 6).
Both cases resulted in the formation of a diastereomeric mixture
19
g
H
H
TBSO
TBSO
TBDPSO
TBSO
H
O
H
+
O
H
H
TBSO
OTBDPS
n.O.e.
20
21
Scheme 4. Synthesis of 20. Reagents and conditions: (a) ClCO2Et, Et3N, CH2Cl2, 0 °C,
15 min; (b) NaBH4, EtOH, 0 °C, 2 h, 87% from 10; (c) TBSOTf, DBU, CH2Cl2, ꢀ78 °C,
2 min, 95%; (d) Pd(OH)2–C, EtOH, cyclohexene, 60 °C, 24 h, 94%; (e) IBX, tBuOH,
60 °C, 1 h; (f) 18, LiHMDS, DMF/HMPA (4:1), rt, 1 h, 54% (2 steps); (g) TBSOTf,
iPr2NEt then DBU, benzene, rt, 2 h, 51% for 20, 20% for 21.

1374
M. Kanematsu et al. / Tetrahedron Letters 52 (2011) 1372–1374
H
H
for the Promotion of Basic and Applied Research for Innovations
in the Bio-oriented Industry (BRAIN).
H
H
HO
O
O
H
H
O
HO
O
b
a
c, d
References and notes
20
TBDPSO
TBDPSO
H
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H
MOMO
R1O2C
MOMO
H
H
g
O
h
O
H
H
O
(+)-1
O
R2O
27
24: R1=MOM, R2=TBDPS
25: R1=MOM, R2=H
26: R1=R2=H
e
f
Scheme 5. Synthesis of (+)-1. Reagents and conditions: (a) 3 M HCl, THF, rt, 2 h,
90%; (b) TEMPO (10 mol %), PhI(OAc)2, CH2Cl2, rt, 1.5 h, 93%; (c) LiOHꢁH2O, THF/H2O
(1:1), rt, 3 h; (d) MOMCl, iPr2NEt, CH2Cl2, 0 °C, 2 h, 90% (2 steps); (e) HFꢁpyridine,
THF/pyridine (1:1), 0 °C, 8 h, 90%; (f) LiOHꢁH2O, THF/H2O (1:1), rt, 3 h; (g) 2,4,6-
trichlorobenzoyl chloride, Et3N, THF, rt, 2 h then 4-DMAP, toluene, 80 °C, 5 h (76%,
2 steps); (h) 6 M HCl, THF, rt, 3 h, 49%.
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10. The lower diastereoselectivity would be attributed to the epimerization at C3,
via a retro-Michael process, and the lower yield is undoubtedly due to the
lability of the epoxide in the product under strong basic conditions.
11. In the reactions using NaOH and KOH, the hydrolysis of the ester moiety seems
to be somewhat faster than in the case of LiOH, therefore the yields are slightly
lower.
MeOH)}, the spectroscopic properties of which matched those re-
ported for the natural product (Scheme 5).
In summary, we have completed an enantioselective total syn-
thesis of (+)-aspergillide C (1) using an efficient and highly diaste-
reoselective IMOM reaction of the substrate with a cis-epoxide and
an E-enoate as the key step. It was found that addition of water is
important in promoting the IMOM reaction and providing higher
yield and diastereoselectivity. In addition, we demonstrated that
a cis-epoxide on the pyran ring can play a key role in assembling
the hydroxy dihydropyran moiety of the natural product. Our syn-
thetic studies described here may contribute to the synthesis of
other related natural products.
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Acknowledgments
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We thank SANYO FINE Co. Ltd for providing R-(ꢀ)-benzyl glyc-
idyl ether. This work was supported financially by a Grant-in-Aid