Total synthesis of aspergillide B and structural discrepancy of aspergillide A

Article abstract of DOI:10.1016/j.tetlet.2008.10.115

Fourteen-membered cytotoxic macrolides 1 and 2 were synthesized from alcohol 10 in 15 steps utilizing stereospecific Pd(II)-catalyzed cyclization of ζ-hydroxy chiral allylic alcohol 7. Aspergillides A and B were isolated from marine fungus, and their stru

Full text of DOI:10.1016/j.tetlet.2008.10.115

Tetrahedron Letters 50 (2009) 189–192
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Total synthesis of aspergillide B and structural discrepancy of aspergillide A
*
Sudhir M. Hande, Jun’ichi Uenishi
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8412, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Fourteen-membered cytotoxic macrolides 1 and 2 were synthesized from alcohol 10 in 15 steps utilizing
stereospecific Pd(II)-catalyzed cyclization of f-hydroxy chiral allylic alcohol 7. Aspergillides A and B were
isolated from marine fungus, and their structures were proposed as 1 and 2, respectively. The synthetic 1
was not matched with aspergillide A but matched with aspergillide B. The chiral center at C-13 position of
aspergillide B was revised to be (S)-configuration. The key steps of the stereoselective synthesis include
the Sharpless asymmetric dihydroxylation, cross-metathesis, stereospecific construction of tetrahydropy-
ran ring of 16 using PdII catalyst, and the Yamaguchi macrolactonization.
Received 3 October 2008
Revised 21 October 2008
Accepted 23 October 2008
Available online 29 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Marine organisms are a rich source of natural products, which
contain novel chemical diversity and biological activity. Recently,
three 14-membered macrolides, namely aspergillides A, B, and C,
were isolated from the marine-derived fungus Aspergillus ostianus
strain 01F313, cultured in a medium composed of bromine-modi-
fied artificial water.1 The biological assay of these compounds re-
vealed a potent cytotoxicity against mouse lymphocytic leukemia
Our approach for the synthesis of aspergillides A and B is out-
lined in Scheme 1.
The intermediacy seco acids 3 and 4 can be prepared by
cross-metathesis of two alkenes 5 and 6-hepten-2-ol 6S or 6R.
trans-2,6-Disubstituted tetrahydropyran 5 will be constructed in
3
steps utilizing the stereospecific SN20-type cyclization of
f-hydroxy chiral allylic alcohol 7 by PdII catalyst. This intermediate
is derived by the cross-metathesis of compound 8 and chiral allylic
alcohol 9S.
cells (L1210) at 2–70 lg/L (LC50). Although some 14-membered
macrolides possessing bridged tetrahydropyran ring have been re-
ported,2 aspergillides are the first examples of 14-membered mac-
rolides incorporated with a trans tetrahydropyran ring.3
Therefore, the initial object was the preparation of compound 8
as shown in Scheme 2.
We were attracted to aspergillides A and B (Fig. 1) because of
their unique structural motif and interesting biological activity.
The major challenge from the synthetic point of view is the con-
struction of the bridged tetrahydropyran ring with required trans
stereochemistry. We envisioned that this goal could be achieved
by the PdII-catalyzed stereospecific synthesis of tetrahydropyrans4
that we developed for the synthesis of some natural products.5
The synthesis commenced from the known methyl (E)-7-
hydroxyhept-3-enoate (10), which was derived from tetra-
hydrofurfuryl alcohol in 3 steps.6 After the protection of the
primary alcohol of 10 with TBSCl, alkene 11 was subjected to the
Sharpless asymmetric dihydroxylation reaction using AD-mix-
a
accompanied by lactonization to give the chiral b-hydroxy-
c-lac-
tone 12 in 89% yield.7
Protection of the secondary hydroxy group with TBDPSCl and
selective deprotection of TBS group by the treatment with BF3ꢀOEt2
at ꢁ10 °C afforded 13 in 2 steps in 91% yield. The Swern oxidation
of the primary alcohol gave aldehyde 14 in 98% yield. The Wittig
olefination of 14 provided 8 in 57% yield along with 16% recovery
of starting material.8
(R)
(S)
13
O
13
O
O
O
1
1
H
H
H
H
Next, olefin 8 was subjected to the cross-metathesis reaction9
with the coupling partner (S)-5-phenylpent-1-en-3-ol (9S)10 to af-
ford 15 in 63% yield11 along with 12% recovery of 8 (Scheme 3).
Desilylation of 15 with TBAF gave the cyclization precursor 7 in
74% yield. The key cyclization of 7 was carried out by the treatment
with 15 mol % of PdCl2(CH3CN)2 in THF at 0 °C for 45 min. The de-
sired trans-(E)-tetrahydropyran 16trans was obtained in 76% yield
along with 16cis in 3% yield.
O
O
3
3
7
7
4
4
HO
HO
1
2
(aspergillide A)
(aspergillide B)
Figure 1. Proposed structures of aspergillides A and B.
A similar reaction of 8 with (R)-alcohol 9R10 gave 150 in 66%
yield11 along with 7% recovery of 8. Desilylation with TBAF
* Corresponding author.
E-mail address: juenishi@mb.kyoto-phu.ac.jp (J. Uenishi).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.115

190
S. M. Hande, J. Uenishi / Tetrahedron Letters 50 (2009) 189–192
Yamaguchi
macrolactonization
R
R
OH
O
O
HOOC
H
H
H
H
O
O
Cross
TBSO
metathesis
HO
3: R =
4: R =
CH3
CH3
1: R =
2: R =
CH3
CH3
R
BzO
Ph
6
HO
+
H
Ph
H3COOC
TBSO
H
H
O
H
O
O
Cross
O
metathesis
Pd-catalyzed
cyclization
7
5
Ph
OTBDPS
HO
O
O
8
9S
Scheme 1. Retrosynthetic analysis of aspergillides A and B.
Thus, after all three stereocenters on the tetrahydropyran ring
of 16trans were set with requisite stereochemistries, the five-
membered lactone ring was subjected to open as shown in
Scheme 4.
OH
OTBS
quant.
TBSCl, Et3N, DMAP
CH2Cl2, 3 h
MeOOC
MeOOC
10
11
Methanolysis of 16trans by treatment with sodium methoxide
in absolute methanol and successive silylation of the axial hydroxy
group with TBSOTf in the presence of 2,6-lutidine in CH3CN12 gave
5 in 60% yield in two steps. The required heptenol side chain on the
tetrahydropyran ring for the seco acid 3 was introduced through a
second cross-metathesis of the sequence with (S)-hept-6-en-2-yl
benzoate (6S).13a In fact, cross-metathesis of 5 with 6S in the pres-
ence of 10 mol % of Grubbs-II catalyst afforded 17S as a sole prod-
uct in 73% yield.11 Hydrolysis of benzoate and methyl ester of 17S
was performed in one step to give 3 in 91% yield. The standard
Yamaguchi macrolactoni-zation14 of 3 provided 18S in 86% yield.
The stereo-chemistry of the trans tetrahydropyran ring of 18S
was reconfirmed by its characteristic nOe as shown in Figure 3.
The final deprotection of silyl ether by the treatment of 18S
with TBAF gave 1 in 96% yield. However, surprisingly, after com-
parison of the spectroscopic data of 1 with those of the natural
products, we found that all the data of 115 including specific rota-
tion matched well with those of aspergillide B rather than those of
aspergillide A, as reported in the original literature.1 Based on these
results, we concluded that aspergillide B must have the C-13(S)
configuration rather than the C-13(R) configuration.
OH
OTBS
AD-mix-α
i) TBDPSCl, imidazole
DMAP, CH2Cl2, rt, 36 h
O
CH3SO2NH2
O
t-BuOH:H2O (1:1)
0 ºC, 20 h
.
ii) BF3 OEt2, CH2Cl2
89%
-10 ºC, 1.5 h
12
OTBDPS
O
OTBDPS
OH
Swern oxi.
O
O
O
O
98%
91%
(in 2 steps)
14
13
OTBDPS
57%
Ph3PCH2, toluene
-40 - 0 ºC, 30 min
O
O
8
At this point, we assumed that aspergillide A might posses the
C-13(R) configuration and sought to prove this by the synthesis
of 2. Since we have the key common intermediate 5, only the
replacement of coupling partner from (S)-benzoate 6S to (R)-ben-
zoate 6R13d in metathesis reaction and the repetition of the same
four-step sequence would give compound 2 as shown in Scheme 5.
In fact, a four-step sequence from 5 gave compound 2 in 39%
yield. However, the spectroscopic data and the specific rotation
Scheme 2.
afforded diol 70 in 67% yield, and successive cyclization of 70 gave
16cis predominantly in 80% yield along with 16trans in 2% yield.
The minor isomers were supposed to be produced via the anti-oxy-
palladation process discussed in the previous paper.4c These struc-
tures are confirmed by the nOe experiments, as shown in Figure 2.

S. M. Hande, J. Uenishi / Tetrahedron Letters 50 (2009) 189–192
191
Ph
Ph
OH
9
S
HO
OTBDPS
Ph
HO
OH
PdCl2(CH3CN)2
(15 mol%)
Ph
H
H
TBAF, THF
O
8
O
THF, 0 ºC, 45 min
O
O
-10 ºC, 15 min
Grubbs II cat. (10 mol%)
CHCl3, 40 ºC, 2 h
O
O
O
63%
15
74%
16trans 76%
(16cis 3%)
7
Ph
Ph
HO
OTBDPS
OH
HO
OH
Ph
9
Ph
R
H
H
PdCl2(CH3CN)2
(15 mol%)
O
TBAF, THF
O
O
8
O
O
THF, 0 ºC, 45 min
-10 ºC, 15 min
O
O
Grubbs II cat. (10 mol%)
CHCl3, 40 ºC, 2 h
67%
15' 66%
7'
16cis 80%
(16trans 2%)
Scheme 3.
Ph
Ph
9
H
9
H
3
H
9
H
H
H
5
H
H
3
H
H
8
H
H
H
H
5
H
7
2
1
O
8
H
8
H
6
2
7
O
H
6
4
H
2
4
O
H
O
H
3
O
1
7
H
O
O
H
5
16trans
16cis
6
4
H
Figure 2. Key nOes observed in 16trans and 16cis.
OTBS
Figure 3. NOe relations observed in 18S.
Ph
i) MeONa, MeOH
0 ºC, 30 min
H3COOC
TBSO
H
H
O
16trans
ii) TBSOTf, 2,6-lutidine
CH3CN, -20 ºC, 20 min
OBz
BzO
(R)
H3COOC
6R
H
H
5
NaOH, aq MeOH
rt, 24 h
O
5
60% in 2 steps
Grubbs II cat. (10 mol%)
CH2Cl2, 45 ºC, 2.5 h
TBSO
17R
(S)
63%
OBz
H
BzO
H3COOC
(S)
H
6S
(R)
NaOH, aq MeOH
rt, 24 h
O
OH
Grubbs II cat. (10 mol%)
CH2Cl2, 45 ºC, 2.5 h
O
O
TBSO
17S
HOOC
TBSO
Yamaguchi
H
H
TBAF, THF
H
H
O
2
O
macrolactonization
73%
rt, 3 h
93%
TBSO
(S)
(S)
4
84%
80%
18R
i) 2,4,6-trichlorobenzoyl
chloride, Et3N
OH
H
O
Scheme 5.
O
HOOC
TBSO
THF, rt, 1.5 h
H
H
H
O
O
ii) DMAP, toluene
of 2 were totally different from those of aspergillide A.15 These re-
sults prompted us to conclude that compound 2 is not the struc-
ture of aspergillide A.1
In summary, we have achieved the first enantioselective syn-
thesis of 1 as a revised structure of aspergillide B. The proposed
structure of aspergillide A is found to be incorrect and its structure
remains unclear. Besides these findings, this synthesis also under-
lined the efficiency and importance of our methodology for the ste-
reospecific construction of chiral non-racemic tetrahydropyran
slow addition, 50 ºC
TBSO
3
91%
86%
18S
TBAF, THF
rt, 3 h
1
96%
Scheme 4.

192
S. M. Hande, J. Uenishi / Tetrahedron Letters 50 (2009) 189–192
7. Wang, Z.-M.; Zhang, X.-L.; Sharpless, K. B.; Sinha, S. C.; Sinha-Bagchi, A.; Keinan,
E. Tetrahedron Lett. 1992, 33, 6407–6410.
ring that would allow easy access to the related natural products of
the biological importance. Synthesis of additional analogs, deter-
mination of the correct structure of aspergillide A,16 and their bio-
logical tests are in progress.
8. The unsatisfactory low chemical yield in methylenation is reminiscent of the
similar cases: Kapferer, T.; Brückner, R. Eur. J. Org. Chem. 2006, 2119–2133.
9. (a) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc.
2003, 125, 11360–11370; (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew.
Chem., Int. Ed. 2005, 44, 4490–4527.
10. (a) Bartels, B.; Garcia-Yebra, C.; Rominger, F.; Helmchen, G. Eur. J. Inorg. Chem.
2002, 2569–2586; (b) Sato, I.; Asakura, N.; Iwashita, T. Tetrahedron: Asymmetry
2007, 18, 2638–2642.
Acknowledgement
This work was supported by Grant-in-Aid for Scientific Re-
search on Priority Areas 17035084 and in part by the 21st COE Pro-
gram from the Ministry of Education, Culture, Sports, Science, and
Technology, Japan. We appreciate Professor Kusumi for discussing
the chemistry of asperigillides.
11. The metathesis reaction gave (E)-alkene exclusively.
12. Nishikawa, T.; Asai, M.; Isobe, M. J. Am. Chem. Soc. 2002, 124, 7847–7852.
13. For stereochemistry of corresponding alcohols see: (a) Takahata, H.; Yotsui, Y.;
Momose, T. Tetrahedron 1998, 54, 13505–13516; (b) Ramaswamy, S.;
Oehlschlager, A. C. Tetrahedron 1991, 47, 1157–1162; (c) Bussche-Hunnefeld,
J. L. V. D.; Seebach, D. Tetrahedron 1992, 48, 5719–5730; (d) Furstner, A.; Thiel,
O. R.; Ackermann, L. Org. Lett. 2001, 3, 449–451.
14. (a) Inanaga, J.; Hirata, K.; Saeki, H.; katsuki, T.; Yamaguchi, M. Bull. Chem. Soc.
Jpn. 1979, 52, 1989–1993; (b) Parenty, A.; Moreau, X.; Campagne, J.-M. Chem.
Rev. 2006, 106, 911–939.
Supplementary data
15. Compound 1; ½a D21
ꢂ
ꢁ 82:5 (c 0.16, CHCl3), ½a D20
ꢁ 90:0 (c 0.10, MeOH); Rf = 0.4
ꢂ
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.10.115.
(40% EtOAc in hexane); 1H NMR (400 MHz, C6D6) d 6.19 (dddd, 1H, J = 15.7,
10.8, 4.8, 1.8 Hz, H-9), 5.38 (br.dd, 1H, J = 15.7, 4.4 Hz, H-8), 5.09 (m, 1H, H-13),
4.30 (m, 1H, H-7), 4.08 (br.d, 1H, J = 11.3 Hz, H-3), 3.21 (br, 1H, H-4), 2.71 (dd,
1H, J = 13.7, 11.3 Hz, H-2), 2.12 (dd, 1H, J = 13.7, 1.8 Hz, H-2), 2.04 (dddd, 1H,
J = 13.3, 11.0, 4.9, 2.2 Hz), 1.86 (br, 1H), 1.78 (m, 1H), 1.74 (m, 1H), 1.61 (m, 1H),
1.55 (m, 1H), 1.52 (m, 1H), 1.37 (m, 1H), 1.34 (m, 1H), 1.31 (m, 1H), 1.07 (d, 3H,
J = 6.4 Hz), 0.99 (dddd, 1 H, J = 14.1, 4.8, 2.4, 1.2 Hz); 13C NMR (100 MHz, C6D6)
169.8, 138.2, 129.0, 71.5, 69.8, 69.5, 67.2, 39.9, 32.0, 30.7, 27.8, 25.3, 22.6, 19.1;
IR (film, cmꢁ1) 3431, 2927, 2854, 1732, 1454, 1259; MS (FAB) m/z 255 (M + H+).
HRMS calcd for C14H23O4 (M+H+): 255.1596: Found; m/z 255.1593. Compound
References and notes
1. Kito, K.; Ookura, R.; Yoshida, S.; Namikoshi, M.; Ooi, T.; Kusumi, T. Org. Lett.
2008, 10, 225–228.
2. Examples of 14-Membered macrolides possessing a bridged tetrahydropyran
ring: (a) Wright, A. E.; Botelho, J. C.; Guzman, E.; Harmody, D.; Linley, P.;
McCarthy, P. J.; Pitts, T. P.; Pomponi, S. A.; Reed, J. K. J. Nat. Prod. 2007, 70, 412–
416; (b) Zacuto, M. J.; Leighton, J. L. Org. Lett. 2005, 7, 5525–5527; (c) Vlattas, I.;
Harrison, I. T.; Tokes, L.; Fried, J. H.; Cross, A. D. J. Org. Chem. 1968, 33, 4176–
4179; (d) Prelog, V.; Gold, A. M.; Talbot, G.; Zamojski, A. Helv. Chim. Acta 1962,
2, 4–21.
2; ½a 2D3
ꢂ
ꢁ48.7 (c 0.16, CHCl3); Rf = 0.42 (40% EtOAc in hexane); 1H NMR
(300 MHz, CDCl3) d 6.47 (dddd, 1H, J = 15.3, 10.6, 4.4, 1.8 Hz, H-9), 5.61 (ddd,
1H, J = 15.3, 4.4, 1.2 Hz, H-8), 4.66 (ddq, 1H, J = 6.1, 6.1, 2.7 Hz, H-13), 4.53 (m,
1H, H-7), 4.10 (dt, 1H, J = 7.7, 1.3 Hz, H-3), 3.56 (br.d, 1H, J = 6.4 Hz, H-4), 2.54
(dd, 1H, J = 16.3, 7.9 Hz, H-2), 2.42 (dd, 1H, J = 16.3, 1.6 Hz, H-2), 2.03–2.22 (m,
3H), 1.92–2.05 (m, 2H), 1.84 (m, 2H), 1.76 (m, 1H), 1.71 (m, 1H), 1.43 (dddd,
1H, J = 14.3, 4.1, 2.8, 1.1 Hz), 1.29 (d, 3H, J = 6.4 Hz), 1.12 (dddd, 1H, J = 13.6, 4.2,
2.4, 1.3 Hz); 13C NMR (100 MHz, CDCl3) 172.7, 139.0, 126.9, 73.5, 72.1, 68.6,
68.6, 40.3, 33.2, 32.2, 27.3, 26.0, 22.5, 20.3; IR (film, cmꢁ1) 3425, 2924, 2854,
1724, 1454, 1262; MS (FAB) m/z 277 (M+Na+). HRMS calcd for C14H22O4Na
3. Some examples of macrolides possessing
a briged trans dihydro- and
tetrahydropyran rings: (a) Corley, D. G.; Herb, R.; Moore, R. E.; Scheuer, P. J.;
Paul, V. J. J. Org. Chem. 1988, 53, 3644–3645; (b) Jansen, R.; Kunze, B.;
Reichenbach, H.; Hofle, G. Eur. J. Org. Chem. 2000, 913–919; (c) Ambrosio, M.
D’.; Guerriero, A.; Debitus, C.; Pietra, F. Helv. Chim. Acta 1996, 79, 51–60.
4. (a) Uenishi, J.; Ohmi, M.; Ueda, A. Tetrahedron: Asymmetry 2005, 16, 1299–
1303; (b) Kawai, N.; Lagrange, J. M.; Ohmi, M.; Uenishi, J. J. Org. Chem. 2006, 71,
4530–4537; (c) Uenishi, J.; Vikhe, Y. S.; Kawai, N. Chem. Asian J. 2008, 3, 473–
484.
(M+Na+): 277.1416: Found; m/z 277.1412. Asperigillide A lit.; ½a 3D1
ꢁ59.5 (c
ꢂ
0.45, CHCl3).1 Asperigillide B lit.; ½a 3D1
ꢂ
ꢁ97.2 (c 0.27, MeOH).1
16. We are now anticipating that the structure of aspergillide A might possess cis
tetrahydropyran ring, which would be formed from 1 through ring-opening
and ring-closing steps by retro-O-Michael reaction and O-Michael reaction.
Based on this assumption, further efforts for the structural determination of
aspergillide A are under way by the synthesis.
5. (a) Uenishi, J.; Ohmi, M. Angew. Chem., Int. Ed. 2005, 44, 2756–2760; (b) Kawai,
N.; Hande, S. M.; Uenishi, J. Tetrahedron 2007, 63, 9049–9056.
6. Pak, C. S.; Lee, E.; Lee, G. H. J. Org. Chem. 1993, 58, 1523–1530.