Total synthesis of natural p -quinol cochinchinenone

Article abstract of DOI:10.1021/ol302858r

Cochinchinenone has been synthesized in only five steps and four pots and in 58% overall yield from commercially available 2,3-dimethoxy-4-hydroxy- benzaldehyde and OPMB-protected p-hydroxy acetophenone, the key step being the oxone-mediated oxidative dea

Full text of DOI:10.1021/ol302858r

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Total Synthesis of Natural p‑Quinol
Cochinchinenone
ꢀ
Silvia Barradas, Gloria Hernandez-Torres, Antonio Urbano,* and M. Carmen Carreno*
~
´
ꢀ
ꢀ
Departamento de Quımica Organica (Modulo 01), Facultad de Ciencias,
ꢀ
ꢀ
Universidad Autonoma de Madrid, c/Francisco Tomas y Valiente 7, Cantoblanco,
28049-Madrid, Spain
antonio.urbano@uam.es; carmen.carrenno@uam.es
Received October 17, 2012
ABSTRACT
Cochinchinenone has been synthesized in only five steps and four pots and in 58% overall yield from commercially available 2,3-dimethoxy-4-
hydroxy-benzaldehyde and OPMB-protected p-hydroxy acetophenone, the key step being the oxone-mediated oxidative dearomatization of the
corresponding ketone-containing p-substituted phenol.
A group of important natural products with a central
scaffold of aromatic ketone is known collectively as
chalcones. These compounds possess different biologi-
cal properties such as antifungal, antitumor, and anti-
inflammatory.1 Cardamonin (1, Figure 1), isolated from
Alpinia rafflesiana, inhibits pro-inflammatory mediators in
activated RAW 264.7 cells and whole blood.2 Compound
2, an analogue of chalcones from the trunk exudates of
Dalbergia sissoo, is one of the most potent nitric oxide
production inhibitors.3 Tarennane (3) was first isolated
in 20074a from the whole plants of Tarenna attenuate and,
in 2009, in minor quantities from the bark of Magnolia
officinalis.4b Compound 3 was shown to have a potent
antioxidant activity against H2O2-induced impairment in
PC12 cells in vitro. Very recently, the first total synthesis of
tarennane (3) has been reported.5
Cochinchinenone (4), a novel chalcone constituent hav-
ing a p-quinol (2,5-cyclohexadien-1-one) moiety in ring A
of its structure, was isolated in 2007 from the stems of
Dracaena cochinchinensis and shows growth inhibitory
effects against Helicobacter pylori (ATCC43504).6 To the
best of our knowledge, no total synthesis of this natural
p-quinol derivative has been reported to date.
(1) (a) Srinivasan, B.; Johnson, T. E.; Lad, R.; Xing, C. J. Med.
Chem. 2009, 52, 7228. (b) Shen, K. H.; Chang, J. K.; Hsu, Y. L.; Kuo,
P. L. Basic Clin. Pharmacol. Toxicol. 2007, 101, 254. (c) Kim, D. Y.;
Kim, K. H.; Kim, N. D.; Lee, K. Y.; Han, C. K.; Yoon, J. H.; Moon,
S. K.; Lee, S. S.; Seong, B. L. J. Med. Chem. 2006, 49, 5664. (d)
Modzelewska, A.; Pettit, C.; Achanta, G.; Davidson, N. E.; Huang,
P.; Khan, S. R. Bioorg. Med. Chem. 2006, 14, 3491. (e) Zi, X.; Simoneau,
A. R. Cancer Res. 2005, 65, 3479.
(2) Ahmad, S.; Israf, D. A.; Lajis, N. H.; Shaari, K.; Mohamed, H.;
Wahab, A. A.; Ariffin, K. T.; Hoo, W. Y.; Aziz, N. A.; Kadir, A. A.;
Sulaiman, M. R.; Somchit, M. N. Eur. J. Pharmacol. 2006, 538, 188.
(3) Shrestha, S. P.; Amano, Y.; Narukawa, Y.; Takeda, T. J. Nat.
Prod. 2008, 71, 98.
(4) (a) Yang, X. W.; Wang, J. S.; Wang, Y. H.; Xiao, H. T.; Hu, X. J.;
Mu, S. Z.; Ma, Y. L.; Lin, H.; He, H. P.; Li, L.; Hao, X. J. Planta Med.
2007, 73, 496. (b) Shen, C. C.; Ni, C. L.; Shen, Y. C.; Huang, Y. L.; Kuo,
C. H.; Wu, T. S.; Chen, C. C. J. Nat. Prod. 2009, 72, 168.
Figure 1. Natural p-quinol cochinchinenone (4) and its analogues.
(5) Yang, J.; Yang, T.; Luoa, Y.; Heb, J.; Shic, J.; Peng, A. Lett. Org.
Chem. 2011, 8, 258.
(6) Zhu, Y. D.; Zhang, P.; Yu, H. P.; Li, J.; Wang, M. W.; Zhao,
W. M. J. Nat. Prod. 2007, 70, 1570.
r
10.1021/ol302858r
XXXX American Chemical Society

Among the numerous methods described in the litera-
ture for the preparation of p-quinols,7 the oxidative dear-
omatization process8 of the corresponding p-alkyl phenols
using hypervalent iodine(III) oxidants9 have been the most
frequently used. This has been the method of choice to
effect the transformation of adequately substituted phe-
nols in the key step of a number of syntheses of complex
natural products.10
We have recently reported a practical method for the
simple and selective oxidative dearomatization of differ-
ently substituted p-alkyl phenols into p-peroxy quinols and
p-quinols11 using oxone in the presence of NaHCO3, as a
source of singlet oxygen.12 We herein extend the oxone-
mediated oxidative dearomatization of p-alkyl phenols to
several ketone-containing derivatives, not previously stu-
died, and apply this reaction to the first total synthesis of the
natural p-quinol cochinchinenone (4), in a short synthetic
sequence from suitable starting materials.
Thus, the reaction of p-alkyl phenol 8, containing
a methyl ketone substituent, under the typical oxidative
dearomatization conditions [oxone, NaHCO3, H2O/
CH3CN, rt, 40 min] afforded, in 52% yield, a 19:81 equilib-
rium mixture formed by the expected open chain p-peroxy
quinol 9 and the corresponding spirocyclic peroxyhemiketal
10 (Scheme 2). Compound 9 was formed after [4 þ 2]
cycloaddition of 8 and 1O2,11a,13 followed by in situ open-
ing of the initially formed endoperoxide intermediate B.
Cyclic peroxides such as 10 are found in the structure of
several antimalarial derivatives.14
When the same reaction was followed by the addition of
a reducing agent such as Na2S2O3 (Scheme 2), the p-quinol
11 was formed and characterized also as a 74:26 equilib-
rium mixture of 11 and the corresponding spirocyclic
hemiketal 12 (40% yield). This type of cyclic spirocyclo-
hexadienone structure is also found in several natural
products with significant biological properties such as
aculeatins and amomols.15
The retrosynthetic analysis of natural cochinchinenone
(4) is depicted in Scheme 1. As can be seen, the p-quinol
moiety present in 4 could be directly obtained from the
ketone-containing p-alkyl bis-phenol 5, by applying our
oxone-mediated oxidative dearomatization process if the
reaction took place exclusively on the more electron-rich
phenol moiety A. This chemoselective transformation would
be the expected one taking into account the mechanism of
this reaction.11a Compound 5, possessing all carbons present
in the natural product, could be constructed from the
disconnection shown in Scheme 1, through the aldol con-
densation between both commercially available aldehyde 6
and acetophenone 7, followed by hydrogenation of the
double bond of the corresponding chalcone initially formed.
Considering that the key step of this very short synthetic
sequence would be the reaction of a ketone-contain-
ing p-alkyl phenol with oxone, not previously studied, we
decided to perform the oxidative dearomatization process
with differently substituted phenols with the aim of evaluat-
ing the influence of the ketone functionality on the reaction.
Scheme 2. Oxone-Mediated Oxidative Dearomatization of
Methylketone-Containing p-Alkyl Phenol 8
We were also interested in performing the oxidative
dearomatization process with a phenylketone-containing
phenol such as 14 (Scheme 3). This compound was pre-
pared from commercially available chalcone 13 after
double bond reduction [H2, Pd(C), THF, rt, 17 h], in
79% yield. The reaction of 14 with oxone, in the pres-
ence of KOH as the base (H2O/CH3CN, rt, 2 h), gave
rise to p-peroxy quinol 15, as the unique product, in
62% yield.
Scheme 1. Retrosynthesis towards Cochinchinenone (4)
~
ꢀ
ꢀ
(11) (a) Carreno, M. C.; Gonzalez-Lopez, M.; Urbano, A. Angew.
~
Chem., Int. Ed. 2006, 45, 2737. (b) Barradas, S.; Carreno, M. C.;
Gonzalez-Lopez, M.; Latorre, A.; Urbano, A. Org. Lett. 2007, 9,
~
5019. (c) Barradas, S.; Urbano, A.; Carreno, M. C. Chem.;Eur. J.
ꢀ
ꢀ
2009, 15, 9286.
(12) Oxone is a 2:1:1 mixture of KOSO2OOH, KHSO4, and K2SO4
and decomposes in an aqueous basic medium to generate 1O2. See: Ball,
D. L.; Edwards, J. O. J. Am. Chem. Soc. 1956, 78, 1125.
(13) Clennan, E. L.; Pace, A. Tetrahedron 2005, 61, 6665.
(14) (a) Jefford, C. W. Curr. Top. Med. Chem. 2012, 12, 373. (b) Slack,
R. D.; Jacobine, A. M.; Posner, G. H. Med. Chem. Commun. 2012,
3, 281.
(15) (a) Das, B.; Krishnaiah, M.; Nagendra, S.; Reddy, C. R. Lett.
Org. Chem. 2011, 8, 244. (b) Traore, M.; Maynadier, M.; Souard, F.;
Choisnard, L.; Vial, H.; Wong, Y.-S. J. Org. Chem. 2011, 76, 1409.
(7) Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. Rev. 2004, 104,
1383.
(8) Moriarty, R. M.; Prakash, O. Org. React. 2001, 57, 327.
(9) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299.
(10) (a) Roche, S. P.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2011, 50,
4068. (b) Pouysegu, L.; Deffieux, D.; Quideau, S. Tetrahedron 2010, 66,
2235.
B
Org. Lett., Vol. XX, No. XX, XXXX

was assigned as the spirolactone 1818 and unequivocally
confirmed by X-ray diffraction (Scheme 3).19 The forma-
tion of 18 should start with the desired oxone-mediated
oxidative dearomatization of the A ring of 5, through an
intermediate similar to B shown in Scheme 2, to afford the
expected p-peroxyquinol intermediate I. Traces of the
peroxy hemiketal II could explain the BaeyerꢀVilliger
migration of the B free phenol ring, favored by deprotona-
tion, to the corresponding hydroxy ester III. This inter-
mediate would suffer an intramolecular transesterification
to afford the spirolactone 18.
Scheme 3. Oxone-Mediated Oxidative Dearomatization of
Phenylketone-Containing p-Alkyl Phenol 14
Scheme 4. Oxidative Dearomatization of 4-Hydroxyphenylke-
tone-Containing p-Alkyl Phenol 5 en Route to Cochinchine-
none
When we performed the same oxidative dearomatiza-
tion process on 14 followed by the addition of Na2S2O3
(Scheme 3), the corresponding p-quinol derivative 16 was
obtained in 42% yield, again as the only reaction product.
With these preliminary results in hand, we turned our
attention to the total synthesis of the natural p-quinol
Cochinchinenone (4). As indicated in the retrosynthetic
Scheme 1, the aldol reaction between commercially avail-
able aldehyde 6 and acetophenone 7 would allow us to
construct the complete carbon skeleton of the natural
product. Nevertheless, this was not an easy task. We tried
several experimental conditions, under both acidic16 or basic17
conditions, to carry out this condensation. Finally, the best
result was obtained working with an excess of the ketone 7
and KOH as the base, at 85 °C for 2 days (Scheme 4).
Under these conditions, the reaction took place with 85%
conversion and 77% yield, giving rise to the corresponding
chalcone 17.
The following step of the synthetic sequence, the reduc-
tionofthe double bondof17, was performedwithH2 inthe
presence of catalytic amounts of Pd(C) in THF at rt for 1 h,
to obtain the ketone-containing p-alkyl bis-phenol 5 in
73% yield, after chromatographic purification (Scheme 4).
With bis-phenol 5 in hand, we undertook the final key
step of the synthetic sequence en route to natural p-quinol
cochinchinenone, the oxone-mediated oxidative dearoma-
tization of this unprotected phenol, with the aim of
achieving the selective reaction of the more electron-rich
phenol ring A in 5 (Scheme 3). Thus, the reaction of bis-
phenol 5 with oxone in the presence of KOH as the base
(H2O/CH3CN, rt, 45 min) gave rise to a sole product, as a
white solid, albeit in a low 26% yield. Unfortunately, the
NMR parameters ofthis newcompounddidn’tmatch with
those reported for the natural derivative and its structure
We thus decided to use an OH protected derivative of 5
to decrease the electron-donating character of the B phenol
ring of intermedite II, thus avoiding the strongly favored
rearrangement in the final oxidative dearomatization key
step. To repeat the same synthetic sequence, we needed a
protected 4-hydroxyacetophenone 7 as the starting mate-
rial. The choice of the correct protective group was not an
easy task since derivatives such as OMOM, OTBDMS,
OTBDPS, OTHP, and OBn gave rise to negative results
in the different steps of the planned synthesis. Finally,
use of the OPMB protecting group was the only option
which allowed us to complete the total synthesis of natural
cochinchinenone (4) as explained in Scheme 5.
(16) (a) Kaniappan, K.; Murugavel, S. C. J. Appl. Polym. Sci. 2009,
111, 1606. (b) Diniz, A. M.; Gomes, R.; Parola, A. J.; Laia, C. A. T.;
Pina, F. J. Phys. Chem. B. 2009, 113, 719.
(17) Rao, Y. K.; Fang, S.; Tzeng, Y. Bioorg. Med. Chem. 2004, 12,
2679.
(18) Spirolactones: (a) Ye, Y.; Zhang, L.; Fan, R. Org. Lett. 2012, 14,
2114. (b) Dohi, T.; Nakae, T.; Ishikado, Y.; Kato, D.; Kita, Y. Org.
Biomol. Chem. 2011, 9, 6899. (c) Dohi, T.; Kato, D.; Hyodo, R.;
Yamashita, D.; Shiro, M.; Kita, Y. Angew. Chem., Int. Ed. 2011, 50,
3784. (d) Cha, J. Y.; Burnett, G. L.; Huang, Y.; Davidson, J. B.; Pettus,
T. R. R. J. Org. Chem. 2011, 76, 1361. (e) Cha, J. Y.; Huang, Y.; Pettus,
T. R. R. Angew. Chem., Int. Ed. 2009, 48, 9519.
(19) CCDC-873559 for 18 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
Org. Lett., Vol. XX, No. XX, XXXX
C

Pd(C) (THF, rt, 20 h) giving rise to the OPMB-protected
bis-phenol 21 in quantitative yield, without the need for
chromatographic purification. In this case, the oxidative
dearomatization of 21 (Oxone, KOH, H2O/CH3CN, rt,
30 min), followed by in situ Na2S2O3 reduction of the ini-
tially formed p-peroxy quinol, afforded the corresponding
OPMB-protected p-quinol 22, in an excellent 96% yield.
At this point, the last step of the synthesis of cochinch-
inenone (4), the OPMB deprotection of derivative 22,
was again troublesome. The use of typical oxidative [DDQ
or DDQ (cat.)/Mn(OAC)3] or reductive conditions [H2,
Pd(OH)2] gave rise in all cases to complex mixtures of reac-
tion. Finally, treatment of OPMB-protected compound 22
with trifluoroacetic acid (TFA) in the presence of anisole21
(CH2Cl2, rt, 1 h) afforded, in 78% yield, cochinchinenone
(4) whose physical and spectroscopic data were identical to
those described for the natural product.6
Scheme 5. Total Synthesis of Natural p-Quinol Cochinchine-
none (4)
In conclusion, we have described a very short and
efficient synthesis of natural p-quinol cochinchinenone
in only five steps and four pots and in 58% overall yield,
using the Oxone-mediated oxidative dearomatization of
the corresponding ketone-containing p-substituted phenol
as the key step. We have also established that this reaction
can be applied to methylketone-containing p-alkyl phenols to
obtain peroxy derivatives that may be potentially useful as
antimalarial agents. The oxone dearomatization reaction did
not work when free-OH aromatic ketones are present since
the BaeyerꢀVilliger evolution of the latter was preferred.
The first step of the synthesis was the aldol reaction
between aldehyde 6 and OPMB-protected acetophenone
19, prepared from phenol 7 under typical conditions
(PMBBr, K2CO3, acetone, 56 °C, 15 h, 77%). When we
used the above-mentioned experimental conditions (excess
of ketone 19 and KOH as the base, at 85 °C for 2 days)
moderate yields were obtained due to several problems
in the chromatographic purification. Finally, the use of
a tandem silyl enol ether formationꢀMukaiyama aldol
reaction mediated by TMSOTf20 between 6 and 19 allowed
us to synthesize chalcone 20, in 78% yield (DIPEA,
TMSOTf, CH2Cl2, 0 °C to rt, overnight).
Acknowledgment. We thank MICINN (Grant CTQ2011-
24783) for financial support. S.B. thanks MEC for a FPU
fellowship.
Supporting Information Available. Experimental pro-
cedures, characterization data, NMR spectra, and X-ray
data (CIF) for 18. This material is available free of charge
via the Internet at http://pubs.acs.org.
The reduction of the double bond of 20 was accom-
plished after hydrogenation in the presence of catalytic
(21) (a) Yan, L.; Kahne, D. Synlett 1995, 523. (b) Stallforth, P.;
Adibekian, A.; Seeberger, P. H. Org. Lett. 2008, 10, 1573.
(20) Downey, C. W.; Johnson, M. W. Tetrahedron Lett. 2007, 48,
3559.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX