Dipyrone approach toward the synthesis of the cytotoxic natural product auripyrone A

Article abstract of DOI:10.1016/j.tetlet.2010.07.034

An approach to the synthesis of the cytotoxic natural product auripyrone A 1 via the cyclization of an alcohol onto a γ-pyrone in 3 is described. The bis(pyrone) alcohol 3 was prepared efficiently from the advanced aldolate 4 via silyl ether cleavage, oxidation, pyrone formation, and PMB ether removal. Instead of providing auripyrone A 1, the attempted cyclization of 3 gave the product of 1,5-acyl migration 8. Model studies show this to be a general process; therefore, cyclization of an alcohol on such a hindered γ-pyrone under normal conditions is very difficult.

Full text of DOI:10.1016/j.tetlet.2010.07.034

Tetrahedron Letters 51 (2010) 4931–4933
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Tetrahedron Letters
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Dipyrone approach toward the synthesis of the cytotoxic natural product
auripyrone A
*
Michael E. Jung , Ramin Salehi-Rad
Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095-1569, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An approach to the synthesis of the cytotoxic natural product auripyrone A 1 via the cyclization of an
Received 4 June 2010
Revised 2 July 2010
Accepted 6 July 2010
Available online 21 July 2010
alcohol onto a c-pyrone in 3 is described. The bis(pyrone) alcohol 3 was prepared efficiently from the
advanced aldolate 4 via silyl ether cleavage, oxidation, pyrone formation, and PMB ether removal. Instead
of providing auripyrone A 1, the attempted cyclization of 3 gave the product of 1,5-acyl migration 8.
Model studies show this to be a general process; therefore, cyclization of an alcohol on such a hindered
c-pyrone under normal conditions is very difficult.
Ó 2010 Elsevier Ltd. All rights reserved.
In 1996, Yamada and co-workers reported the isolation and
characterization of the two polypropionate natural products,
auripyrone A 1 and B 2, from the Japanese specimens of the sea
hare Dolabella auricularia (Fig. 1).1 Extensive NMR investigation
of these natural products revealed a complex, fully-substituted spi-
from the key aldolate 4 through a sequence of deprotection, double
oxidation, and cyclization under Yamamura conditions.7 The key
intermediate 4 could be obtained from the optically active epoxy
silyl ether 5 as previously described by our group.3
Treatment of the optically active aldolate 43 with HFÁpyridine
provided the diol 6 in 95% yield (Scheme 2). Double oxidation of
the diol with Dess–Martin periodinane8 followed by cyclization
of the resulting triketone under Yamamura conditions7 furnished
the dipyrone 7 in 47% yield over two steps. Deprotection of the
PMB ether of the dipyrone 7 with DDQ provided the alcohol 3 in
78% yield, which was subjected to Crimmins’ conditions6 for spiro-
ketalization. However, treatment with TFA led to rapid equilibra-
tion to afford a 2:1 mixture of the starting material 3 and the
product of acyl migration, isomer 8. Treatment with other acids
such as CSA and TsOH also resulted in the formation of a similar
mixture. Furthermore, regardless of the acyl migration, no spiroke-
talization was observed upon prolonged exposure of the mixture of
the starting material 3 and its acyl shift isomer 8 to strong acid.
roketal core, capped at one end by a tetrasubstituted
c-pyrone,
residing in an anomerically favored configuration where all the
substituents are positioned equatorially except the C-10 methyl
and the C-11 acyloxy group. Biological evaluation of auripyrone
A 1 and B 2, which differ only in the nature of their C-11 acyloxy
side chains, revealed potent cytotoxicity against HeLa S3 cells with
IC50 values of 260 and 480 ng/mL, respectively.
To date, two total syntheses of auripyrone A 1 have been re-
ported, one by Perkins2 and one by our group,3 and two total syn-
theses of auripyrone
B 2
by Kigoshi4 and our group.5 The
synthetic approaches of Perkins and Kigoshi toward the natural
products rely on an analogous biomimetic cyclization of acyclic
triketone intermediates to generate the common spiroketal moi-
ety of auripyrone A 1 and B 2, while our strategy utilizes a regio-
selective hemiketalization of keto diol intermediates followed by
spiroketalization onto the stable hemiketal platform. Herein, we
wish to report a different spiroketalization approach toward
auripyrone A 1.
28
27
Me Me
H
20
Et
O
Me
O
26
Me
Me
Me
O
15 17
O
Me
Me
H
Me
Et
O
5
21
Me
Me 25
OR
Our alternate retrosynthetic analysis toward auripyrone A 1 is
presented in Scheme 1. The spiroketal moiety of auripyrone A 1
was envisioned to arise from the acid-catalyzed cyclization of the
O
H
O
13
22
OR
O
O
H
Me
Me
Me
H
O
3
7
9
11
H
Me
1
Me Me
23 24
secondary alcohol of 3 onto the
conditions following the protocol developed by Crimmins and
Omahony.6 The
-pyrone B in 3 was in turn anticipated to originate
c-pyrone B under thermodynamic
H
Me
Auripyrone A (1)
Auripyrone B (2)
c
O
5'
O
1'
Me
2'
R =
1'
R =
Me
4'
Me
4'
* Corresponding author. Tel.: +1 310 825 7954; fax: +1 310 206 3722.
E-mail address: jung@chem.ucla.edu (M.E. Jung).
Me
5'
NIH Chemistry-Biology Interface (CBI) trainee, 2005–8. R.S.-R. thanks the Medical
Scientist Training Program (MSTP) for generous financial support.
Figure 1. Structures of auripyrones A and B.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.034

4932
M. E. Jung, R. Salehi-Rad / Tetrahedron Letters 51 (2010) 4931–4933
Me Me
O
O
Me
R
Me
Me
OR OTES OTBDPS
b
O
O
Me
Me
O
Me
Me
O
O
O
Me
Me Me Me
O
9 R = PMB
10 R = H
a
Me
Me Me
1 R = CH2CHMe2
O
O
R
O
O
R
O
Me
Me
Me
Me
Et
Me
Me
O
OTES OTBDPS
c
OH
O
A
B
O
O
O
Me
Me Me Me
11 R = CH2CHMe2
Me
Me Me Me
3 R = CH2CHMe2
Me
O
O
R
O
O
R
O
O
O
R
O
O
Me
Me
Me
Me
Me
Me
Me
OPMBO
OH
O
OTES
O
9
OH OTBDPS
OH
O
OTBDPS
Et
+
9
11
11
Me
Me Me Me Me Me
4 R = CH2CHMe2
Me
Me Me Me
12 R = CH2CHMe2
Me
Me Me Me
13 R = CH2CHMe2
OTBDPS
O
TESO
Scheme 3. Reagents and conditions: (a) DDQ, CH2Cl2/pH 7 buffer (2:1), 1 h, 88%; (b)
2,4,6-trichlorobenzoyl chloride, DMAP, Et3N, Me2CHCH2CO2H, 95%; (c) PPTS,
CH2Cl2/MeOH (3:1), 68% 12, 23% 13.
Me Me
5
Scheme 1. Retrosynthetic analysis for auripyrone A.
O
Me
Me
Me
OR''
R
R =
O
O
R
O
OH
O
H
Me
Me
Me
9
OPMBO
OH
O
OR'
Me
H
11
R'
Me
R' =
Me
OTBDPS
Me
Me
Me Me Me Me Me
O
Me
4 R = CH2CHMe2, R' = TES
6 R = CH2CHMe2, R' = H
a
R'' =
I
Me
O
R
O
O
Figure 2. Local conformation of polyketide 12.
Me
Me
Me
Me
b,c
e
OR'
O
O
O
Me
O
Me
Me Me Me
7 R = CH2CHMe2, R' = PMB
3 R = CH2CHMe2, R' = H
Me
Me
Me
OR OTES OTBDPS
d
O
Me
Me Me Me
O
O
O
O
O
R
9 R = PMB
Me
Me
Me
Me
O
HO
O
3
+
Me
Me
Me
OH OH OTBDPS
Me
Me Me Me
8 R = CH2CHMe2
Me
a,b
O
Me
Me Me Me
Scheme 2. Reagents and conditions: (a) HFÁpyr, CH3CN, 95%; (b) DMP, CH2Cl2,
NaHCO3, 3 h; (c) PPh3, CCl4, THF, 38 h, 47% over two steps; (d) DDQ, CH2Cl2/pH 7
buffer (4:1), 1 h, 78%; (e) TFA, benzene, 1 d.
14
Me
O
Me
O
Me
OTBDPS
Me
HO
c
O
A simpler control system, bearing similar functionalities to the
intermediate 3, was devised to further study this spiroketalization
process (Scheme 3). Oxidative removal of the PMB ether group of
Me Me
the c
-pyrone 9,3 obtained in 8 steps from the optically active epoxy
15
silyl ether 5, with DDQ provided the alcohol 10 in 88% yield, which
was acylated under Yamaguchi conditions9 to afford the ester 11 in
95% yield. Selective acid-catalyzed deprotection of the TES group of
Scheme 4. Reagents and conditions: (a) PPTS, CH2Cl2/MeOH (3:1), 96%; (b) DDQ,
CH2Cl2/pH 7 buffer (2:1), 1 h, 74%; (c) TFA, C6H6.
the
c-pyrone 11 under mildly acidic conditions afforded the de-
sired alcohol 12 in 68% yield, along with the alcohol 13 in 23%
yield.10 The formation of the alcohol 13 even under mildly acidic
conditions illustrates the high propensity of our system for 1,5-acyl
migration which presumably arises from the inherent preference
of our acyclic polyketide chain11 to populate the local conforma-
tion (I) (Fig. 2) where the C-9 and C-11 oxygen moieties reside in
close spatial proximity.12 In fact, the use of a variety of Brønsted
and Lewis acids (p-TsOH, LiBF4, SnCl4, TiCl4, and EtAlCl2), including
Crimmins conditions (TFA)6 for the cyclization of the alcohol 12 led
to rapid formation of a mixture of the isomers 12 and 13 and no
cyclization product was observed.

M. E. Jung, R. Salehi-Rad / Tetrahedron Letters 51 (2010) 4931–4933
4933
7. (a) Arimoto, H.; Nishiyama, S.; Yamamura, S. Tetrahedron Lett. 1990, 31, 5619–
5620; (b) Yamamura, S.; Nishiyama, S. Bull. Chem. Soc. Jpn. 1997, 70, 2025–
2037.
8. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156; (b) Dess, D. B.;
Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
9. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1979, 52, 1989–1993.
10. The structures of these two products were confirmed by protecting both
alcohols separately with the TES group. Only the corresponding silyl ether of
Finally, we attempted Crimmins cyclization conditions on the
diol 14, synthesized from the pyrone 9 in two steps, but did not ob-
serve any cyclized product (Scheme 4). A significant difference be-
tween our system and all the reported cyclizations by Crimmins
and co-workers is the presence of methyl substituents
a to the
ketone of the -pyrone, presumably increasing the steric conges-
c
tion of the transition state for cyclization. However, more experi-
ments are necessary to study the variables involved in this
reaction.
In conclusion, we have reported an efficient synthesis of the key
bis(pyrone) alcohol 3, a precursor for the Crimmins cyclization, to
accomplish a novel synthesis of auripyrone A 1. This approach
failed to provide the desired spiroketal natural product and rather
resulted in 1,5-acyl migration to give a mixture of the compounds
3 and 8. Similar treatment of structurally analogous compounds
also gave mostly acyl transfer.
the alcohol 12 exhibited identical spectral data with the
c-pyrone 11, thus
confirming the structure of 12. The minor isomeric alcohol 13 was
consequently assigned as the product of the acyl migration of the alcohol 12.
11. Hoffmann, R. W. Angew. Chem., Int. Ed. 2000, 39, 2054–2070.
12. Analysis of the relevant coupling constants in these systems indicates that a
local conformation such as I is likely. For example, in 12, Ha appears as a dd,
J = 9.0, 3.1 Hz while Hb is obscured. In 13, Ha appears as a dd, J = 8.5, 2.7 Hz and
Hb appears as a dd, J = 7.3, 3.5 Hz. Similarly in 3, Hb appears as a dd, J = 9.0,
3.0 Hz, while Ha is obscured. This pattern of one large and one small coupling
constant is consistent with the structures proposed since both Ha and Hb
should have one dihedral angle with a vicinal proton of about 180° and a
second of about 60°. Other related compounds in this series showed a similar
coupling constant pattern.
Acknowledgment
We thank the National Science Foundation (CHE 0614591) for
generous support of this work.
OR3
O
O
R1
O
O
OR4
Ha
Hb
Me
Me
Me
Me
Me
Me
Me
H
Me
R1 =
9
R1 =
R2 =
References and notes
11
Me
H
R2
O
Me
Et
1. Suenaga, K.; Kigoshi, H.; Yamada, K. Tetrahedron Lett. 1996, 37, 5151–5154.
2. Lister, T.; Perkins, M. V. Angew. Chem., Int. Ed. 2006, 45, 2560–2564.
3. Jung, M. E.; Salehi-Rad, R. Angew. Chem., Int. Ed. 2009, 48, 8766–8769.
4. Hayakawa, I.; Takemura, T.; Fukasawa, E.; Ebihara, Y.; Sato, N.; Nakamura, T.;
Suenaga, K.; Kigoshi, H. Angew. Chem., Int. Ed. 2010, 2401–2404.
H
OTBDPS
Me
R2
=
O
Me
3 R3 = H R4 = COCH2CHMe2
12 R3 = COCH2CHMe2 R4 = H
13 R3 = H R4 = COCH2CHMe2
5. Jung, M. E.; Chaumontet, M.; Salehi-Rad, R. Org. Lett. 2010, 12, 2872–2875.
6. Crimmins, M. T.; Omahony, R. J. Org. Chem. 1990, 55, 5894–5900.