First total syntheses of (±)-penicillones A and B

Article abstract of DOI:10.1021/ol702062p

(Chemical Equation Presented) The first total syntheses of (±)-penicillones A (1) and B (2) have been accomplished from 2-methoxy-4,6-dimethylphenol (7) in 9 and 8 synthetic steps, respectively. Intramolecular Diels-Alder reaction of masked o-benzoquinone

Full text of DOI:10.1021/ol702062p

ORGANIC
LETTERS
2
007
Vol. 9, No. 22
563-4565
First Total Syntheses of (
A and B
±)-Penicillones
4
Day-Shin Hsu and Chun-Chen Liao*
Department of Chemistry, National Tsing Hua UniVersity, Hsinchu 300, Taiwan
ccliao@mx.nthu.edu.tw
Received August 22, 2007
ABSTRACT
The first total syntheses of (±)-penicillones A (1) and B (2) have been accomplished from 2-methoxy-4,6-dimethylphenol (7) in 9 and 8 synthetic
steps, respectively. Intramolecular Diels−Alder reaction of masked o-benzoquinone 8 and aqueous acid-catalyzed intramolecular aldol reaction
are the key steps.
3
,8
Recent synthetic efforts in our laboratory were focused on
the utilization of masked o-benzoquinones (MOBs) and
demonstrated that MOBs are valuable intermediates in
organic synthesis. Among these, we have developed several
strategies to construct various natural product skeletons,
tricyclo[5.3.1.0 ]undecane skeleton. Compound 1 showed
cytotoxicity against P-388 and A-549 cancer cell lines, while
2 was inactive against P-388. Penicillone contains a bicyclo-
[2.2.2]octane core structure, which can be easily constructed
from MOB through the Diels-Alder reaction with an
appropriate dienophile. Retrosynthetically, we envisaged the
hydrolysis of acetal 3 followed by intramolecular aldol
reaction to be a potential synthetic sequence to acquire
requisite penicillone B (2), which could be further oxidized
into penicillone A (1) (Scheme 1). The aldol precursor 3
could be generated from aldehyde 4, and the triol moiety 5
would be obtained from tricyclic â,γ-enone 6. Access to this
cycloadduct was to be gained from 2-methoxy-4,6-dimethyl-
phenol (7) and trans-crotyl alcohol via intramolecular Diels-
Alder cycloaddition of in situ generated MOB 8.
1
2
,3
2a,4
including cis-decalins, bicyclo[4.2.2]decenones,
iri-
5
6
doids, and triquinanes. In this paper, we report a new
3,8
strategy to construct a tricyclo[5.3.1.0 ]undecane skeleton
employing our MOB strategy and apply to the total syntheses
of penicillones A (1) and B (2).
Penicillones A (1) and B (2) have been isolated recently
from a fungus Penicillium terrestre obtained from the marine
7
sediment in Jiaozhou Bay of Qingdao, which possess a novel
(
1) (a) Liao, C.-C.; Peddinti, R. K. Acc. Chem. Res. 2002, 856. (b) Liao,
C.-C. Pure Appl. Chem. 2005, 77, 1221.
2) (a) Lee, T.-H.; Liao, C.-C.; Liu, W.-C. Tetrahedron Lett. 1996, 37,
8
(
The tricyclic â,γ-enone 6 was obtained in 87% yield via
intramolecular Diels-Alder reaction of MOB 8, produced
in situ from oxidative addition of trans-crotyl alcohol to
2-methoxy-4,6-dimethylphenol (7) in the presence of di-
acetoxyiodobenzene (DAIB) (Scheme 2). Reduction of
ketone 6 with samarium diiodide in THF in the presence
5
6
4
897. (b) Hsu, P.-Y.; Lee, Y.-C.; Liao, C.-C. Tetrahedron Lett. 1998, 39,
59. (c) Tsai, Y.-F.; Peddinti, R. K.; Liao, C.-C. Chem. Commun. 2000,
75. (d) Chen, C.-H.; Peddinti, R. K.; Rao, N. S. K.; Liao, C.-C. J. Org.
9
Chem. 2004, 69, 5365. (e) Hsu, P.-Y.; Peddinti, R. K.; Chittimalla, S. K.;
Liao, C.-C. J. Org. Chem. 2005, 70, 9156.
10
(3) (a) Lee, T.-H.; Liao, C.-C. Tetrahedron Lett. 1996, 37, 6869. (b)
1
1
Liu, W.-C.; Liao, C.-C. Synlett 1998, 912. (c) Hsu, D.-S.; Hsu, P.-Y.; Liao,
C.-C. Org. Lett. 2001, 3, 263. (d) Hsu, D.-S.; Liao, C.-C. Org. Lett. 2003,
1
5
, 4741.
(8) All new compounds were satisfactorily characterized by IR, H (600
(
(
(
4) Liu, W.-C.; Liao, C.-C. Chem. Commun. 1999, 117.
5) Liao, C.-C.; Wei, C.-P. Tetrahedron Lett. 1989, 30, 2255.
6) (a) Hwang, J.-T.; Liao, C.-C. Tetrahedron Lett. 1991, 32, 6583. (b)
MHz), 13C (150 MHz) NMR, DEPT, and low- and high-resolution MS
analyses.
(9) (a) Olcay, A. J. Org. Chem. 1962, 27, 1783. (b) We prepared
2-methoxy-4,6-dimethylphenol (7) from creosol via o-hydroxymethylation
and hydrogenolysis in 91 % overall yield. See the Supporting Information.
(10) Chu, C.-S.; Lee, T.-H.; Rao, P. D.; Song, L.-D.; Liao, C.-C. J. Org.
Chem. 1999, 64, 4111.
Hsu, D.-S.; Rao, P. D.; Liao, C.-C. Chem. Commun. 1998, 1795. (c) Yen,
C.-F.; Liao, C.-C. Angew. Chem., Int. Ed. 2002, 41, 4090.
(7) Liu, W.; Gu, Q.; Zhu, W.; Cui, C.; Fan, G.; Zhu, T.; Liu, H.; Fang,
Y. Tetrahedron Lett. 2005, 46, 4993.
1
0.1021/ol702062p CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/29/2007

Scheme 1. Retrosynthetic Analysis
Scheme 2. Preparation of Triol 5
of MeOH as proton source furnished alcohol 9 in 91% yield.
The next step was stereocontrolled installation of the C-5
hydroxyl group. Initial attempts were centered on Wood-
12
ward’s dihydroxylation protocol, which is the best method
for the preparation of cis-diols with the hydroxyl groups on
the more hindered side of the molecule. However, these
reaction conditions or other modifications13 were not suc-
cessful, only providing the allylic oxidation14 product 10.
We therefore turned our attention to an anti-dihydroxylation
strategy; this was achieved via sequential epoxidation, ring-
opening of the epoxide, and saponification.15 The direction
of epoxidation was controlled by the C-7 methyl group (more
hindered π-face); the epoxide was cleaved by back-side
nucleophilic attack. The stereostructure of the triol 5 was
alcohols were first oxidized to the aldehyde and ketone
simultaneously with o-iodoxybenzoic acid (IBX)16 in 83%
yield (Scheme 3). Two-carbon homologation on the aldehyde
in 4 was achieved by Wittig reaction with (1,3-dioxolan-2-
ylmethyl)triphenylphosphonium bromide and t-BuOK to
give the unsaturated dioxolane intermediate 11 as an E/Z
mixture (E/Z ) 1:5). Hydrogenation of the unsaturated
dioxolane 11 over 5% Rh on alumina, a catalyst that was
selected to minimize hydrogenolysis of the allylic acetal,19
afforded the aldol precursor 3 in 76% yield. Aqueous acid-
catalyzed hydrolysis and aldol reaction were carried out in
1
7
18
1
determined with H NMR nuclear Overhauser enhancement
(NOE) experiments (Figure 1).
2 4
refluxing THF with 2 M H SO to generate the desired
product penicillone B (2) as the only epimer. The reason
for formation of a single endo-epimer is presumably due to
(
11) Molander, G. A. Org. React. 1994, 46, 211.
(12) Woodward, R. B.; Brutcher, F. V., Jr. J. Am. Chem. Soc. 1958, 80,
2
09.
(13) (a) Mangoni, L.; Adinolfi, M.; Barone, G.; Parrilli, M. Tetrahedron
Lett. 1973, 14, 4485. (b) Emmanuvel, L.; Shaikh, T. M. A.; Sudalai, A.
Org. Lett. 2005, 7, 5071.
(
14) Briggs, L. H.; Cain, B. F.; Cambie, R. C.; Davis, B. R.; Rutledge,
P. S. J. Chem. Soc. 1962, 1850.
15) Swern, D.; Billen, G. N.; Findley, T. W.; Scanlan, J. T. J. Am. Chem.
(
Soc. 1946, 68, 1504.
(16) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019.
Figure 1. 1H NMR studies of NOE (%) for 5.
(
17) Cresp, T. M.; Sargent, M. V.; Vogel, P. J. Chem. Soc., Perkin Trans.
1974, 37.
18) Michel, P.; Rassat, A.; Daly, J. W.; Spande, T. F. J. Org. Chem.
2000, 65, 8908.
19) Pour, M.; Kraft-Klaunzer, P.; Furber, M.; Mander, L. N.; Twitchin,
1
(
Having secured the stereochemistry of the C-5 hydroxyl,
the stage was set for the elongation of the C-8 hydroxymethyl
side chain. Toward this end, the primary and secondary
(
B.; Oyama, N.; Murofushi, N.; Yamane, H.; Yamauchi, T. Aust. J. Chem.
1997, 50, 289.
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Org. Lett., Vol. 9, No. 22, 2007

Scheme 3. Complete the Total Synthesis of Penicillones A (1)
and B (2)
Figure 2. Structures of penicillone B (2) and 12.
In conclusion, we have accomplished the total syntheses
of penicillones A (1) and B (2) from 2-methoxy-4,6-
dimethylphenol (7) in 9 and 8 synthetic steps, respectively,
using the MOB strategy.
Acknowledgment. We thank the National Science Coun-
cil (NSC), Taiwan, for financial support and Dr. Rama
Krishna Peddinti for helpful discussions. D.-S.H. thanks NSC
for a postdoctoral fellowship.
Supporting Information Available: Experimental pro-
cedures and spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL702062P
the 1,3-diaxial interaction present in the exo-epimer 12
20
(Figure 2). Finally, oxidation of penicillone B (2) with IBX
(20) De Santis, B.; Laura Iamiceli, A.; Marini Bettolo, R.; Maria
furnished penicillone A (1). The spectra of the synthetic
Migneco, L.; Scarpelli, R.; Cerichelli, G.; Fabrizi, G.; Lamba, D. HelV.
Chim. Acta 1998, 81, 2375.
7
materials were fully consistent with the literature data.
Org. Lett., Vol. 9, No. 22, 2007
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