Total synthesis of citridone A

Article abstract of DOI:10.1021/ol200022a

The first total synthesis of citridone A has been achieved through regioselective intramolecular iodocyclization and regio-and stereoselective Pd(0)-catalyzed coupling as key reactions.(Figure Presented)

Full text of DOI:10.1021/ol200022a

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1158–1161
Total Synthesis of Citridone A
Tomoko Miyagawa, Keisuke Nagai, Asami Yamada, Yoshinori Sugihara,
Takeo Fukuda, Takashi Fukuda, Ryuji Uchida, Hiroshi Tomoda, Satoshi Omura,* and
Tohru Nagamitsu*
School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641,
Japan
omura-s@kitasato.or.jp; nagamitsut@pharm.kitasato-u.ac.jp
Received January 4, 2011
ABSTRACT
The first total synthesis of citridone A has been achieved through regioselective intramolecular iodocyclization and regio- and stereoselective
Pd(0)-catalyzed coupling as key reactions.
Patients with compromised immune systems, e.g. those
receiving organ transplants, undergoing cancer chemo-
therapy, or those infected by the humanimmunodeficiency
virus (HIV) are particularly prone to opportunistic infec-
tions caused by Candida albicans,1a problematic fungi.
Unfortunately, azole antifungals havebecome increasingly
ineffective, thus prompting the development of various
inhibitors that can overcome the resistance mechanisms of
azole-resistant C. albicans. Continuous screening for such
inhibitors has resulted in the discovery of a novel natural
product, citridone A (1), which was isolated from the
fermentation broth of Penicillium sp. FKI-1938.2
Although 1 itself does not possess antimicrobial activity,
it has exhibited reinforcement effects toward miconazole
activity against C. albicans. However, a detailed mode of
action has yet to be defined. Although natural products
that possess a phenyl-R-furopyridone subunit have been
reported, we believe that this is the first incidence of a novel
6-6/5/5 ring system. Due toits biological properties and the
uniqueness of the structure, we decided to undertake its
synthesis. Herein we report the total synthesis of 1, along
with the determination of its absolute configuration.
As shown in a retrosynthetic analysis of 1 (Scheme 1),
the dihydrofuran unit of 1 was envisioned to arise via
iodocyclization of the 4-hydroxy-2-pyridone 2. In turn,
precursor 2 would be constructed via a coupling reaction
between enamide 3 and allylic carbonate 4, followed by the
formation of the pyridine ring. Enamide 3 and allylic
carbonate 4 would be obtained from known isocyanate
53 and carboxylic acid 6,4 respectively.
Scheme 1. Retrosynthetic Analysis of Citridone A (1)
(1) Nishiyama, Y.; Yamaguchi, H. Antibiot. Chemother. 2000, 16,
19–26.
Our synthesis began with the preparation of trans-iso-
propylidenecyclopentane 7 via a known carboxylic acid 64
derived from (þ)-pulegone (Scheme 2). The carboxylic
acid moiety of 6 was reduced with LiAlH4, followed by
(2) (a) Fukuda, T.; Yamaguchi, Y.; Masuma, R.; Tomoda, H.;
Omura, S. J. Antibiot. 2005, 58, 309–314. (b) Fukuda, T.; Tomoda,
H.; Omura, S. J. Antibiot. 2005, 58, 315–321 and references for other
natural products including the phenyl-R-furopyridone unit are cited
therein.
r
10.1021/ol200022a
Published on Web 02/09/2011
2011 American Chemical Society

Asshown in Scheme 3, the allylic alkylation nucleophile 3
waspreparedfrom known isocyanate5 which was obtained
from trans-cinnamic acid via Curtius rearrangement.3 In
the critical coupling step, 5 was exposed to the lithium
enolate derived from ethyl acetate at -78 °C to afford 3 in
55% yield (four steps).
Scheme 2. Synthesis of Key Intermediate 4
Next, the Pd(0)-catalyzed coupling reaction between 3
and 4 was investigated using various palladium catalysts
and phosphine ligands. After considerable experimenta-
tion, the optimal conditions for accessing 125 with high
efficiency and excellent regio- and stereocontrol were
determined to be a combination of an allylpalladium(II)
chloride dimer and dppf.6 Gratifyingly, heating of 12 led to
pyridine ring formation7 and afforded the advanced inter-
mediate 2 in 66% yield.
Scheme 4. Synthesis of 4-Hydroxy-2-pyridone 2
protection as the TBDPS ether to afford 7. Overall, the
conversion of (þ)-pulegone to 7 was carried out in 60%
yield over five steps, with purification only required in the
final step. Ozonolysis of 7 furnished trans-cyclopentanone
8 (88% yield) which was converted to 9 by R-selenenyla-
tion/oxidation/elimination (80% yield, two steps). The
derived enone 9 underwent iodination/dehydrohalogenation
to provide the vinyl iodide, which was subsequently employed
in a Stille coupling with Me4Sn, affording trans-cyclopente-
none 10 in quantitative yield. After screening several reduc-
tants, DIBAL was selected for the subsequent stereoselective
1,2-reduction to produce the desired β-allyl alcohol 11 in 66%
yield. As a note, the undesired R-allyl alcohol was also ob-
tained (30% yield) and could be recycled to 11 via Dess-
Martin oxidation followed by DIBAL reduction. Treatment
of 11 with methyl chloroformate provided the key intermedi-
ate for the allylic alkylation 4,5 in quantitative yield.
With 2 in hand, the stage was set for the intramolecular
iodocyclization. A C-4 regioselective cyclization was re-
quired for the total synthesis of 1; however, undesi-
red iodocyclization at the C-2 position as a concomitant
reaction was also considered due to the 4-hydroxy-2-
pyridone 2 tautomeric equilibrium as depicted in Scheme
4. To the best of our knowledge, only a few regioselective
reactions of 4-hydroxy-5-phenyl-2-pyridones have been
reported8 in which C-4 position-selective cyclization pro-
ceeds preferentially, but the respective reaction mechan-
isms are not clear. At the outset, treatment of 2 with I2 in
CH2Cl2 at rt furnished the undesired iodocyclized
(3) (a) Jones, L. W.; Mason, J. P. J. Am. Chem. Soc. 1927, 49, 2528–
2536. (b) Rigby, J. H.; Balasubramanian, N. J. Org. Chem. 1989, 54,
224–228.
Scheme 3. Synthesis of the Allylic Alkylation Nucleophile 3
(4) (a) Marx, J. N.; Norman, L. R. J. Org. Chem. 1975, 11, 1602–
1606. (b) Wolinsky, J.; Chan, D. J. Org. Chem. 1965, 30, 41–43.
(5) The relative stereochemical configurations were confirmed by
NOE experiments on each compound; also see the Supporting
Information.
(6) (a) Acharya, H. P.; Kobayashi, Y. Tetrahedron 2006, 62, 3329–
3343. (b) Hoke, M. E.; Brescia, M. R.; Bogaczyk, S.; Deshong, P. J. Org.
Chem. 2002, 67, 327–335.
(7) (a) Rigby, J. H.; Qabar, M. J. Org. Chem. 1989, 54, 5852–5853. (b)
Zhang, Q.; Rivkin, A.; Curran, D. P. J. Am. Chem. Soc. 2002, 124, 5774–
5781.
€
(8) (a) Intramolecular 1,4-addition: Furstner, A.; Feyen, F.; Prinz,
H.; Waldmann, H. Angew. Chem., Int. Ed. 2003, 42, 5361–5364. (b)
Intramolecular lactonization and nonregioselective intramolecular cy-
clization: Snider, B. B.; Che, Q. Org. Lett. 2004, 6, 2877–2880.
Org. Lett., Vol. 13, No. 5, 2011
1159

Table 1. Regioselective Intramolecular Iodocyclization of 2
entry
reagent
solvent
temp (°C)
product (%)a
1
2
3
4
5
6
7
8
9
I2
CH2Cl2
CH2Cl2
rt
0
0
0
0
0
0
0
0
14 (66)
14 (63)
13 (67)
13 (67)
13 (70)
13 (70)
13 (61)
13 (68)
13 (67)
NIS
NIS
NIS
NIS
NIS
NIS
NIS
CH2Cl2/DBU = 10:1
CH2Cl2/Et3N = 10:1
CH2Cl2/pyridine = 10:1
MeCN/pyridine = 10:1
MeOH/pyridine = 10:1
THF/pyridine = 10:1
THF
(1) BuLi (2 equiv)
(2) NIS
a Isolated yield.
compound 14 as the major product (66% yield); merely a
trace amount of desired product 13 was observed (Table 1,
entry 1). Similar results were obtained using N-iodosucci-
nimide (NIS) in place of I2 at 0 °C (entry 2). Interestingly,
the addition of DBU as a cosolvent in CH2Cl2 (entry 3)
shifted the regioselectivity of the reaction to give the
desired intramolecular iodocyclization product 13 in
67% yield with a trace amount of undesired product 14.
Similar effects were observed using bases such as Et3N and
pyridine (entries 4 and 5, respectively). Changing solvents
also did not affect the regioselectivity (entries 6-8). More-
over, iodocyclization with NIS after stoichiometric depro-
tonation of 2 by treatment with 2 equiv of n-butyllithium
afforded similar results (entry 9). The structures of 13
and 14 were determined by NMR and UV spectra,9 and
their stereochemical configurations were confirmed by
NOE experiments.5 Mechanistically, the regioselective in-
tramolecular iodocyclization in the presence of only I2 or
NIS (without added base) can be rationalized as proceed-
ing via reaction at the least hindered C-2 oxygen. On the
other hand, in the presence of added base, the anion of 2
could form an ion-pair aggregate with the corresponding
cationic species at the least hindered C-2 position. How-
ever, the similar formation at the C-4 position could be
prevented by steric hindrance of the two ortho-substitu-
ents. Therefore, the nucleophilicity of the C-4 alkoxide
could be higher than that of the C-2 alkoxide, leading to
C-4 regioselective intramolecular iodocyclization under
basic conditions.
Scheme 5. Completion of the Total Synthesis of Citridone A (1)
Dess-Martin oxidation of 15 followed by β-elimination
promoted by DBU furnished R,β-unsaturated aldehyde
16 in 99% yield (two steps). Dithioacetalization of 16 gave
17 (86% yield) which was subjected to radical reduction
using Bu3SnH to provide 1 in 64% yield. Although
synthetic 1 exhibited biological activity and spectra (1H
and 13C NMR, IR, and FAB-MS) thatwere comparable to
those of the natural compound, the values of their
optical rotation were not comparable. Upon remeasure-
ment, the optical rotation of natural 1 was found to be
TBDPS ether 13 was deprotected by treatment with
TBAF to give alcohol 15 in 88% yield (Scheme 5).
(9) Sakemi, S.; Border, J.; Decosta, D. L.; Dekker, K. A.; Hirai, H.;
Inagaki, T.; Kim, Y. J.; Kojima, N.; Sims, J. C.; Sugie, Y.; Sugiura, A.;
Sutcliffe, J. A.; Tachikawa, K.; Truesdell, S. J.; Wong, J. W.; Toshikawa,
N.; Kozima, Y. J. Antibiot. 2002, 55, 6–18.
1160
Org. Lett., Vol. 13, No. 5, 2011

variable,10 which can be attributed to the tautomeriza-
tion of the 2-pyridone moiety of 1. Consequently, to
prevent the tautomerization of the 2-pyridone moiety,
O-MOM-protected 1 (18s and 18n) were prepared from
natural and synthetic 1, respectively. Importantly, optical
rotation data obtained for O-MOM protected 18s and 18n
were comparable [18n: þ3.3 (c 1.0, CH3OH), 18s: þ3.5
(c 1.0, CH3OH)]. Given the known absolute stereochem-
istry of the starting material (þ)-pulegone, this result
establishes the absolute configuration of 1 to be as
depicted.
In conclusion, we have achieved the first total synthesis of
citridone A (1) in 3.2% overall yield over 24 steps from
trans-cinnamic acid and (þ)-pulegone via a regioselective
intramolecular iodocyclization that was developed as a key
step. Furthermore, our synthetic scheme allowed for the
determination of the absolute configuration of 1. Applica-
tions of the regioselective intramolecular iodocyclization of
3-allyl-5-phenyl-2,4-dihydroxypyridine derivatives toward
the syntheses of other natural products and efficient synth-
esis of di- and tricyclic compounds including pyridine and
dihydroxyfuran and pyran rings are currently underway in
our laboratory.
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research (C) and a Kitasato
Universityresearchgrant for youngresearchers(T.N.). We
also thank Ms. N. Sato and Dr. K. Nagai (Kitasato
University) for kindly measuring NMR and MS spectra.
Supporting Information Available. Experimental pro-
cedures and characterization data for new compounds,
1
plus copies of H and 13C NMR spectra of new com-
(10) Lit. -1.6 (c 1.0, CH3OH),2b observed: -4.7 to þ10.0 (c 1.0,
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
CH3OH).
Org. Lett., Vol. 13, No. 5, 2011
1161