Total synthesis of (+)-aspermytin A

Article abstract of DOI:10.1016/j.tetlet.2010.05.107

The first enantioselective total synthesis of aspermytin A, a new neurotrophic polyketide isolated from a cultured marine fungus of the genus Aspergillus sp., has been accomplished in 24 steps with an overall yield of 9.7% from S-(-)-citronellal.

Full text of DOI:10.1016/j.tetlet.2010.05.107

Tetrahedron Letters 51 (2010) 3966–3968
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Tetrahedron Letters
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Total synthesis of (+)-aspermytin A
*
Atsushi Inoue, 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 first enantioselective total synthesis of aspermytin A, a new neurotrophic polyketide isolated from a
cultured marine fungus of the genus Aspergillus sp., has been accomplished in 24 steps with an overall
yield of 9.7% from S-(ꢀ)-citronellal.
Received 4 May 2010
Revised 20 May 2010
Accepted 24 May 2010
Available online 27 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Aspermytin A1 has been isolated from a marine-derived fungus
of the genus Aspergillus sp. by Tsukamoto et al. The structure of this
polyketide was elucidated as 1 on the basis of spectral data and its
absolute configuration was assigned by its CD spectrum. The key
structural features of the molecule are the functionalized trans-
octahydronaphthalene skeleton and the four contiguous stereo-
genic centers, two of which are quaternary carbons, on the ring.
Aspermytin A (1) showed a significant neurotrophic effect on rat
OH
NMe
O
H
O
H
3
O
H
OH
O
4
13
OH
8
11
H
H
aspermytin A (1)
equisetin (2)
pheochromocytoma (PC-12) cells at concentration of 50 lM. The
Figure 1.
intriguing chemical structure, combined with its promising biolog-
ical profile, has made aspermytin A an attractive target for total
synthesis. During the course of our synthetic investigations, we
have reported the total synthesis of equisetin (2),2 an enantiomeric
analog of 1, in which an efficient and stereoselective strategy for
the construction of the trans-octahydronaphthalene with four
contiguous stereogenic centers has been developed by using the
AlMe3-mediated intramolecular Diels–Alder (IMDA) reaction3 as
the key step. We report here the first total synthesis of (+)-
aspermytin A (1) employing a similar IMDA reaction for the
construction of the octahydronaphthalene core and the diastereo-
selective creation of the C13 quaternary stereogenic center as the
key reaction steps (Fig. 1).
Our retrosynthetic analysis of aspermytin A is shown in Scheme
1. We envisaged the diastereoselective constructions of the C13
quaternary stereogenic center and the b-hydroxy ketone moiety
at C4 being achieved from 3 in the last stage of the synthesis.
The keto aldehyde 3 might be derived from 4, the IMDA adduct
of the triene 5 which can be prepared from S-(ꢀ)-citronellal (6),
via an oxidative cleavage of the C–C bond of the oxymethyl func-
tionality at the future C13 (Scheme 1).
TMSCl in THF4 to give the (E)-vinyl boronate 8 selectively. The
Suzuki–Miyaura coupling5 of 8 with (E)-(3-bromoallyloxy)(tert-
butyl)diphenylsilane6 provided the (E,E)-diene 9, which was ex-
posed to acidic conditions to give the monosilylated alcohol 10
selectively in 83% yield from 7. Sequential Swern oxidation, Wittig
reaction, DIBAH reduction, and MnO2 oxidation provided the triene
aldehyde 13 in 84% yield for the four steps (Scheme 2).
The key IMDA reaction of 13 was examined and the results are
shown in Table 1. After a solution of 13 in toluene was heated at
150 °C for 48 h in the presence of catalytic methylene blue7 in a
sealed tube, the cycloadduct was obtained as an inseparable 2:1
CHO
CHO
H
H
H
H
O
OR
1
3
4
The substrate 13 for the IMDA reaction was synthesized as
shown in Scheme 2. The aldehyde 7, prepared from S-(ꢀ)-citronel-
lal (6) via a four-step sequence, was treated with 2-(dichlorometh-
yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, CrCl2, Mn, LiI, and
CHO
OR
CHO
5
6
* Corresponding author. Tel.: +81 88 6337287; fax: +81 88 6339575.
E-mail address: shishido@ph.tokushima-u.ac.jp (K. Shishido).
Scheme 1. Retrosynthetic analysis of aspermytin A.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.107

A. Inoue et al. / Tetrahedron Letters 51 (2010) 3966–3968
3967
OTBS
OTBS
e
a - d
f
OR
H
HO
O
H
6
H
CHO
B
NaBH4
EtOH
OH
H
O
Me
Me
OR
7
8
4t/c
+
Me
H
H
Me
R=TBDPS
OR1
h, i
R1
14t (79%)
14c (10%)
OR2
OR2
Scheme 3. Separation of diastereomers and the stereochemistries.
11: R1=CO2Et, R2=TBDPS
12: R1=CH2OH, R2=TBDPS
13: R1=CHO, R2=TBDPS
9: R1=TBS, R2=TBDPS
10; R1=H, R2=TBDPS
j
k
g
OMOM
CO2Me
OMOM
OH
Scheme 2. Synthesis of triene 13. Reagents and conditions: (a) HO(CH2)2OH, p-
TsOHꢁH2O, benzene; (b) O3 then NaBH4, MeOH, CH2Cl2; (c) 0.5 N HCl, THF; (d) TBSCl,
imidazole, 4-DMAP, CH2Cl2, 43% from 6; (e) 2-(dichloromethyl)-4,4,5,5-tetra-
methyl-1,3,2-dioxaborolane, CrCl2 (0.6 equiv), Mn (6 equiv), LiI (4 equiv), TMSCl
(6 equiv), THF; (f) (E)-(3-bromoallyloxy)(tert-butyl) diphenylsilane, Pd2(dba)3ꢁ
CHCl3, Ph3P, 1 N NaOH, THF; (g) 0.5 N HCl, THF, 83% from 7; (h) DMSO, (COCl)2,
Et3N, CH2Cl2, 86%; (i) Ph3PC(Me)CO2Et, benzene, 99%; (j) DIBAH, THF, 99%; (k)
MnO2, CH2Cl2, quant.
H
H
H
a, b
c - e
14t
H
H
16
OMOM
CO2Me
15
OMOM
H
CO2Me
OH
f
+
mixture of the trans-isomer 4t and the cis-isomer 4c in 36% yield
(entry 1). When the reaction was conducted in the presence of
aluminum-based Lewis acids,8 good results were obtained (entries
2–5). The best result was achieved by using Me2AlCl to give an
inseparable 8:1 mixture of 4t/c in 92% yield (entry 5) (Table 1).
Separation of the diastereoisomers and structure determination
were accomplished in the next stage. Thus, reduction of the 4t/c
mixture with NaBH4 provided the chromatographically separable
14t and 14c in 79% and 10% yield, respectively. The stereochemist-
ries were determined by NOE experiments as shown in Scheme 3.
With the desired octahydronaphthalene 14t in hand, we next
examined its conversion to the enone 19. MOM protection of the
primary alcohol moiety in 14t followed by desilylation gave 15
which was converted to the methyl ester 16 in good overall yield.
Treatment of 16 with KHMDS, O2, and triethylphosphite in THF9
H
H
17
18
OH
OMOM
O
H
g
17
H
19
i
Scheme 4. Reagents and conditions: (a) MOMCl, Pr2NEt, CH2Cl2, quant.; (b) TBAF,
THF, 93%; (c) DMP, NaHCO3, CH2Cl2, 94%; (d) NaClO2, NaH2PO4, 2-methyl-2-butene,
tBuOH/THF (3/1); (e) CH2N2, Et2O, 98% (2 steps); (f) KHMDS, O2, (EtO)3P, THF, 27%
for 17, 35% for 18; (g) LiBH4 then NaIO4, 5% H3PO4 (aq), THF, 52%.
exocyclic olefin moiety. Ozonolysis followed by reductive work-
up produced the ketone 21, which was treated with IBX12 in
DMSO/toluene to provide a mixture of the two enones, 19 and 3
(11:1 from 1H NMR). The crude mixture was then subjected to
acidic hydrolysis (of the MOM ether in 19) and oxidation with
Dess–Martin periodinane (DMP) to produce the key intermediate
3 in 63% overall yield from 15 in 6 steps. Introduction of the two
methyl groups onto the C3 aldehyde and the C13 ketone carbonyls
in 3 was achieved by treatment with MeLi to give a separable mix-
ture of 22 (1:1 inseparable mixture at C3) and 23 (3:1 inseparable
mixture at C3) in 80% and 11% yield, respectively. As for the stereo-
chemical outcome at C13, the preferential introduction of the
methyl group from the si-face would be attributed to the presence
produced a separable mixture of the
the
-isomer 1810 in 27% and 35% yield, respectively. The desired
-isomer 17 was reduced with LiBH4 and the resulting diol was
a
-hydroxy ester 1710 and
c
a
oxidatively cleaved by NaIO4 to give the enone 19 in 52% yield.
To improve the yield of 19 from the methyl ester 16, we examined
several reaction conditions for the oxidative cleavage; however, we
were unable to effect a conversion in greater than 14% yield (the
overall yield of 19 from 15 was 13% for five steps). These unsuc-
cessful results therefore led us to explore another synthetic route
for obtaining the key enone 3 efficiently. (Scheme 4).
Since it was thought that the presence of a double bond would
cause a side reaction(s) and lower yields, the double bond in 15
was reduced, and the resulting primary alcohol was dehydrated
by employing the Nishizawa-Grieco protocol11 to give 20 with an
of a-methyl at C4, which would prevent an approach of the methyl
from the re-face. Thus, another key step for the construction of the
Table 1
Intramolecular Diels–Alder reaction of 13
CHO
H
CHO
H
conditions
OR
OR
+
13
H
H
4t: R=TBDPS
4c: R=TBDPS
Entry
Solvent
Additive (equiv)
Temp (°C)
Time (h)
Yield (%)
4t:4c
1
2
3
4
5
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Methylene blue
Me3Al (1.5)
Et2AlCl (0.5)
EtAlCl2 (0.5)
Me2AlCl (1.5)
150
48
1.5
2
18
8.5
36
52
78
69
92
2:1
ꢀ78 to 0
13.5:1
10:1
9:1
ꢀ78 to 0
ꢀ78 to ꢀ15
ꢀ78 to 0
8:1

3968
A. Inoue et al. / Tetrahedron Letters 51 (2010) 3966–3968
In summary, we have completed the first total synthesis of opti-
OMOM
OMOM
O
cally pure (+)-aspermytin A (1) using a diastereoselective Me2AlCl-
mediated IMDA reaction and a substrate-controlled construction of
an allylic quaternary stereogenic center as the key steps. In addi-
tion, the absolute structure of aspermytin A was unambiguously
established by total synthesis. Our synthetic studies described here
may contribute to the development of a new type of anti-Alzhei-
mer agents.
H
H
H
H
a, b
c
d
15
20
21
OMOM
CHO
H
H
H
H
O
+
O
e, f
g
3
Acknowledgments
3
19
We thank Professor Sachiko Tsukamoto of Kumamoto University
for providing us with the spectral data (1H and 13C NMR) of aspermy-
tin A. We also thank the Takasago International Co. for the generous
gift of citronellal. This work was supported financially by a Grant-in-
Aid for the Program for Promotion of Basic and Applied Research for
Innovations in the Bio-oriented Industry (BRAIN).
O
H
HO
H
i
h
OH
R
22
(+)-1
H
H
24
22: R=α-OH
23: R=β-OH
References and notes
Scheme 5. Reagents and conditions: (a) H2, Pd–C, EtOH, 96%; (b) nBu3P, o-nitro-
phenyl selenocyanate then 30% H2O2 (aq), NaHCO3, THF, quant.; (c) O3, Me2S,
MeOH, CH2Cl2, 87%; (d) IBX, DMSO, toluene; (e) 6 N HCl, THF; (f) DMP, CH2Cl2, 75%
from 21; (g) MeLi, THF, 80% for 22, 11% for 23; (h) TPAP, NMO, 4 Å MS, CH2Cl2, 92%;
(i) LDA, (1H-benzo[d][1,2,3]triazol-1-yl)methanol, THF, 95%.
1. Tsukamoto, S.; Miura, S.; Yamashita, Y.; Ohta, T. Bioorg. Med. Chem. Lett. 2004,
14, 417.
2. Yuki, K.; Shindo, M.; Shishido, K. Tetrahedron Lett. 2001, 42, 2517.
3. For a review, see: Takao, K.; Munakata, R.; Tadano, K. Chem. Rev. 2005, 105,
4779.
4. Takai, K.; Kunisada, Y.; Tachibana, Y.; Yamaji, N.; Nakatani, E. Bull. Chem. Soc.
Jpn. 2004, 77, 1581.
5. For a review, see: Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
6. Polt, R.; Sames, D.; Chruma, J. J. Org. Chem. 1999, 64, 6147; Maleczka, R. E., Jr.;
Gallagher, W. P. Org. Lett. 2001, 26, 4173.
7. Roush, W. R.; Gills, H. R.; Ko, A. I. J. Am. Chem. Soc. 1982, 104, 2269.
8. Taber, D. F.; Saleh, S. A. J. Am. Chem. Soc. 1980, 102, 5085.
9. For a review, see: Chen, B. C.; Zhou, P.; Davis, F. A.; Ciganek, E. Org. React. 2003,
62, 1.
10. These were obtained as an inseparable mixture of two diastereoisomers.
11. Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41, 1485.
12. Nicolaou, K. C.; Zhong, Y. L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596.
13. Deguest, G.; Bischoff, L.; Fruit, C.; Marsais, F. Org. Lett. 2007, 9, 1165.
14. The synthetic aspermytin A was obtained as colorless needles, mp 122.2–
122.7 °C (recrystallization from n-hexane).
C13 quaternary stereogenic center was realized. Oxidation of 22
with TPAP and NMO in the presence of 4 Å MS provided the
hydroxy ketone 24 as a single product in 92% yield. Finally, the
aldol condensation using LDA and (1H-benzo[d][1,2,3]triazol-1-
yl)methanol13 proceeded cleanly to give aspermytin A (1) in 95%
yield. The spectral data of synthetic aspermytin A were fully con-
sistent with those of the natural product. We attribute the differ-
ence in the magnitude of the optical rotation data {½a D28
ꢂ
+7.6 (c
0.97, CHCl3); lit. ½a D25
ꢂ
+1.2 (c 0.102, CHCl3)} to that of the synthetic
material having a much higher level of purity14 (Scheme 5).