Enantioselective total synthesis of (+)-conicol via cascade three-component organocatalysis

Article abstract of DOI:10.1021/ol902840x

(Chemical Equatation Presentation) The first asymmetric total synthesis of (+)-conlcol has been achieved via a key step reaction involving the organocatalytic domino oxaMichael-Michael-Michael-aldol condensation of 2-((E)-2-nitrovinyl)benzene-1,4-diol and α,βunsaturated aldehydes. Structures of the threecomponent domino reaction adducts, 20 and 21, including their absolute configurations, were confirmed unambiguously by X-ray analysis. Through this work, the absolute configuration of (+)-conlcol was thereby elucidated

Full text of DOI:10.1021/ol902840x

ORGANIC
LETTERS
2010
Vol. 12, No. 4
776-779
Enantioselective Total Synthesis of
(+)-Conicol via Cascade
Three-Component Organocatalysis
Bor-Cherng Hong,* Prakash Kotame, Chih-Wei Tsai, and Ju-Hsiou Liao
Department of Chemistry and Biochemistry, National Chung Cheng UniVersity,
Chia-Yi, 621, Taiwan, R.O.C.
chebch@ccu.edu.tw
Received December 9, 2009
ABSTRACT
The first asymmetric total synthesis of (+)-conicol has been achieved via a key step reaction involving the organocatalytic domino oxa-
Michael-Michael-Michael-aldol condensation of 2-((E)-2-nitrovinyl)benzene-1,4-diol and r,ꢀ-unsaturated aldehydes. Structures of the three-
component domino reaction adducts, 20 and 21, including their absolute configurations, were confirmed unambiguously by X-ray analysis.
Through this work, the absolute configuration of (+)-conicol was thereby elucidated.
The hexahydro-6H-benzo[c]chromene system occurs widely
in a variety of natural products exhibiting various biological
activities, such as heterophylol,1 nabilone,2 murrayamine P,
murrayamine O,3 machaeriol A, machaeriol B,4 sauchinone
A,5 bisabosqual A,6 clusiacitran A, clusiacitran B,7 palode-
sangrens E,8 and the cannabinoids9 (Figure 1). Most of these
meroterpenoids were isolated from higher plants, although
recently some species were isolated from marine organisms.
For example, (+)-conicol was isolated from a marine
invertebrate, the ascidian Aplidium conicum,10 and (+)-
epiconicol,11 a marine metabolite, was isolated from
Aplidium aff. densum and exhibited antiproliferative
activity against human acute lymphoblastic leukemia
CEM-WT cells as well as antibacterial activity against
the Gram-positive bacterium Micrococcus luteus. In
addition, epiconicol, an isomer of conicol, displays
(1) A naturally occurring phenolic compound, which was isolated from
root bark of Artocarpus heterophyllus, see: Lin, C.-N.; Lu, C.-M. Tetra-
hedron Lett. 1993, 34, 8249.
(2) Nabilone, also known as cesamet, is a synthetic cannabinoid with
therapeutic use as an antiemetic and as an adjunct analgesic for neuropathic
pain, see: (a) Notcutt, W.; Price, M.; Chapman, G. Pharmacol. Sci. 1997,
3, 551. (b) Skrabek, R. Q.; Galimova, L.; Ethans, K.; Perry, D. J. Pain
2008, 9, 164.
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Y.; Matsushima, K.; Tani, H.; Ishii, K.; Tanimoto, T.; Kamigauchi, T. J.
Antibiot. 2001, 54, 890.
(3) Two novel cannabinol skeletal carbazole alkaloids, murrayamine-O
and -P, were isolated from the root bark of Murraya euchrestifolia. See:
Wu, T.-S.; Wang, M.-L.; Wu, P.-L. Tetrahedron Lett. 1995, 36, 5385.
(4) Machaeriol A and B were isolated from shrubs and the lianas
Machaerium multiflorum. Both compounds showed in vitro antimalarial
activity against a Plasmodium falciparum W-2 clone. Other derivatives
showed antimicrobial and antiparasitic activities, see: (a) Muhammad, I.;
Li, X.-C.; Dunbar, D. C.; ElSohly, M. A.; Khan, I. A. J. Nat. Prod. 2001,
64, 1322. (b) Muhammad, I.; Li, X.-C.; Jacob, M. R.; Tekwani, B. L.;
Dunbar, D. C.; Ferreira, D. J. Nat. Prod. 2003, 66, 804.
(7) The two citrans were isolated from an extract of the fruit from Clusia
multiflora, see: Gonzalez, J. G.; Olivares, E. M.; Monache, F. D. Phy-
tochemistry 1995, 38, 485.
(8) Shirota, O.; Takizawa, K.; Sekita, S.; Satake, M. J. Nat. Prod. 1997,
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71, 1427.
(5) Sauchinone A was isolated from the herb Saururus chinensis.
Incubation of cultured rat hepatocytes, intentionally injured by CCl4, with
sauchinone A significantly reduced the levels of glutamic pyruvic tran-
saminase released by the damaged hepatocytes. See: Sung, S. H.; Kim,
Y. C. J. Nat. Prod. 2000, 63, 1019.
(10) Garrido, L.; Zub´ıa, E.; Ortega, M. J.; Salva´, J. J. Nat. Prod. 2002,
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10.1021/ol902840x  2010 American Chemical Society
Published on Web 01/15/2010

infra, as well as some other natural hexahydro-6H-
benzo[c]chromens.14 Large discrepancies in optical rota-
tion for the same compound have been reported, e.g.,
epiconicol.15 Several rationalizations have been suggested,
including racemization of the compounds during isolation, the
coexistence of enantiomers in nature, and the presence of an
enantiomeric excess in the opposite sense. Despite these
speculations, the solution to this discrepancy remains elusive.
Several elegant approaches have been implemented suc-
cessfully to achieve synthesis of the natural tetrahydro-6H-
benzo[c]chromenes, for example, the total synthesis of (+)-
machaeriol A, B,16 and nabilone.17 However, the key reaction
in these synthetic approaches used optically active starting
compounds or involved reactions with chiral substrates, e.g.,
citronellal or geranyl aldehyde. The key reactions were not
innately enantioselective, and the synthetic strategies lacked
diversity. Consequently, despite the success of the previous
synthetic strategies toward hexahydro-6H-benzo[c]chro-
menes, the development of an efficient and highly enanti-
oselective as well as diversity-oriented synthetic strategy
toward this skeleton remained an appealing challenge.
Recently, we developed a concise synthesis of the skeleton
of hexahydro-6H-benzo[c]chromenes via a quadruple cas-
cade18 organocatalytic19 multicomponent reaction, with
control over five stereocenters, in a one-pot operation
(Scheme 1).20,21 The diversity of the protocol was demon-
Figure 1
chromenes.
. Selected naturally occurring hexahydro-6H-benzo[c]-
cytotoxicity against P388 (murine leukemia), A549 (hu-
man lung carcinoma), HT29 (human colon carcinoma),
and CV1 (monkey kidney fibroblast) cells.12
Scheme 1
However, as shown in Figure 1, both absolute configura-
tions at the core of hexahydro-6H-benzo[c]chromenes have
been reported from nature sources,13 and the absolute
stereochemistries of some compounds are not clear. The
absolute configurations of these compounds shown in
the literature structures have been arbitrary. For instance,
both enantiomers of epiconicol have been presented in the
literature, and no attempts have been made to determine the
absolute configurations of conicol and epiconicol, vide
strated by the chemo-differentiating three-component reaction
(ABC type) with 3-methylbut-2-enal and ꢀ-aryl-R,ꢀ-unsatur-
(18) For selected recent examples of organocatalytic domino reactions,
see: (a) Zhang, F.-L.; Xu, A.-W.; Gong, Y.-F.; Wei, M.-H.; Yang, X.-L.
Chem.sEur. J. 2009, 15, 6815. (b) Carlone, A.; Cabrera, S.; Marigo, M.;
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Hu¨ttl, M. R. M.; Runsink, J.; Raabe, G.; Wendt, B. Angew. Chem., Int. Ed.
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Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew. Chem., Int. Ed. 2009, 48,
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Chem. Soc. 2005, 127, 15710. (g) Zu, L.; Zhang, S.; Xie, H.; Wang, W.
Org. Lett. 2009, 11, 1627. (h) Franze´n, J.; Fisher, A. Angew. Chem., Int.
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(12) Carroll, A. R.; Bowden, B. F.; Coll, J. C. Aust. J. Chem. 1993, 46,
1079.
(13) For example, both enantiomers of sauchinone have been found in
nature, see: (a) Wang, E.-C.; Shih, M.-H.; Liu, M.-C.; Chen, M.-T.; Lee,
G.-H. Heterocycles 1996, 43, 969. (b) Seo, C.-S.; Lee, Y.-K.; Kim, Y.-J.;
Jung, J.-S.; Jahng, Y.; Chang, H.-W.; Song, D.-K.; Son, J.-K. Biol. Pharm.
Bull. 2008, 31, 523. (c) Sung, S. H.; Kim, Y. C. J. Nat. Prod. 2000, 63,
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Hong, Y. S.; Paik, S.-G.; Lee, J. J. Planta Med. 2003, 69, 1096.
(14) (a) Refer to footnote 6 in ref 10. (b) Both the enantiomers of
epiconicol have been drawn in the literature. See refs 10, 11, and 12.
(15) (a) Optical rotation data for epiconicol: +58° (c 0.09) in ref 12
and +1.2° (c 0.6, CHCl3) in ref 10. (b) Refer to the footnote 13 in
ref 10.
(19) For recent reviews in organocatalysis, see: (a) Palomo, C.; Oiarbide,
M.; Lo´pez, R. Chem. Soc. ReV. 2009, 38, 632. (b) Zhang, Z.; Schreiner,
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Org. Lett., Vol. 12, No. 4, 2010
777

ated aldehyde (3-arylacrylaldehyde), which afforded highly
functionalized tetrahydro-6H-benzo[c]chromenes. Herein, we
have expanded the methodology beyond the ꢀ-aryl-R,ꢀ-unsatur-
ated aldehyde system to the ꢀ-alkyl variant (an aldehyde tends
to undergo self-condensation via [4 + 2] and [3 + 3]
annulations)22 and achieved the first total synthesis of (+)-
conicol and have also defined its absolute configuration.
Initially, we envisioned that (+)-conicol could be as-
sembled from 3-methylbut-2-enal (1), (E)-2-(2-nitrovinyl)-
benzene-1,4-diol (2), and crotonaldehyde, or 4,4-dimethoxy-
but-2-enal (3), via a cascade reaction of oxa-Michael-
Michael-Michael-aldol condensation (Scheme 2). Our
Scheme 3
Scheme 2
and oxidative cleavage reaction (NaIO4, THF-H2O). Un-
fortunately, phenolic 7, instead of desired 6, was obtained
in a 35% overall yield for the three-consecutive-step reaction
without isolation of the intermediates. Apparently, the
instability of 6 resulted in a favorable aromatization and led
to the formation of para-quinone hemiketal 7.24
Consequently, aldehyde 3 was selected as a suitable
surrogate for the zwitterionic propane synthon due to its
commercial availability and its potential for offering stable
synthetic intermediates. This alternative approach started
from the domino oxa-Michael-Michael-Michael-aldol
condensation of 4 and 3 (cat. I - HOAc, CHCl3, rt, 35 h;
69%), affording the hexahydro-6H-benzo[c]chromene 8
(Scheme 4). The two-step reaction could be achieved in one
pot from 1 and 2, without isolation of the intermediate 4,
with a 55% overall isolated yield of 8. Decarbonylation of
8 with the Wilkinson catalyst in refluxing toluene afforded
the alkene 9 in 54% yield. Hydrogenation of 9 with Pd-C
in methanol provided 10 in 72% yield. Hydrolysis of the
dimethoxymethyl groups on 10 (Amberlyst 15, acetonitrile-
H2O (1:1), 80 °C, 4 h; 69% yield) gave 11 and a trace amount
of aromatic aldehyde 12. Subsequent denitration elimination
of 11 (DABCO, CH3CN, 0-20 °C, 2 h, 79% yield) afforded
14. Additionally, hydrolysis of 9 in aqueous HCl solution
(v/v 1:1, acetone-10% aq. HCl; 25 °C, 30 min) gave 71%
yield of the aromatic aldehyde 12 which was converted to
the bacteriostatic agent didehydroconicol,11 13, via Wolff-
Kishner reduction (N2H4-H2O and KOH in diethylene
glycol, 130 °C, 8 h, 63% yield). Attempts under the various
conditions of Wolff-Kishner reduction of aldehyde 14 led
to the aromatic aldehyde 13 or to decomposition. Accord-
ingly, the elaboration of the aldehyde group to a methyl group
was achieved by the following transformation: reduction of
approach started from the tandem oxa-Michael-Michael
reaction of 1 and 2 to yield 4 (cat. I - HOAc, CHCl3, rt,
1 h; 76%), followed by a domino Michael-Aldol condensa-
tion with crotonaldehyde (cat. I - HOAc, CHCl3, rt, 24 h;
74% yield), affording the hexahydro-6H-benzo[c]chromene
5 (Scheme 3). The successful cascade reaction with cro-
tonaldehyde is especially noteworthy since crotonaldehyde
has an active γ-hydrogen for γ-amination that could lead to
competing side reactions.23 Moreover, the two reactions
could be achieved in one-pot, without the isolation of 4, to
give 5 in a 66% overall yield. Transformation of 5 to 6
proceeded through a sequence of reactions: hydrogen per-
oxide epoxidation (H2O2, K2CO3), reduction (LiAlH4, THF),
(20) Kotame, P.; Hong, B.-C.; Liao, J.-H. Tetrahedron Lett. 2009, 50,
704.
(21) For our previous efforts in exploring new annulations, see: (a) Hong,
B.-C.; Jan, R.-H.; Tsai, C.-W.; Nimje, R. Y.; Liao, J.-H.; Lee, G.-H. Org.
Lett. 2009, 11, 5246. (b) Hong, B.-C.; Nimje, R. Y.; Liao, J.-H. Org. Biomol.
Chem. 2009, 7, 3095. (c) Hong, B.-C.; Nimje, R. Y.; Sadani, A. A.; Liao,
J.-H. Org. Lett. 2008, 10, 2345. (d) Hong, B.-C.; Nimje, R. Y.; Wu, M.-F.;
Sadani, A. A. Eur. J. Org. Chem. 2008, 1449. (e) Hong, B.-C.; Nimje,
R. Y.; Yang, C.-Y. Tetrahedron Lett. 2007, 48, 1121. (f) Hong, B.-C.; Chen,
F.-L.; Chen, S.-H.; Liao, J.-H.; Lee, G.-H. Org. Lett. 2005, 7, 557. (g) Hong,
B.-C.; Gupta, A. K.; Wu, M.-F.; Liao, J.-H. Tetrahedron Lett. 2004, 45,
1663. (h) Hong, B.-C.; Chen, Z. Y.; Chen, W. H. Org. Lett. 2000, 2, 2647.
(22) (a) Hong, B.-C.; Wu, M.-F.; Tseng, H.-C.; Liao, J.-H. Org. Lett.
2006, 8, 2217. (b) Hong, B.-C.; Wu, M.-F.; Tseng, H.-C.; Huang, G.-F.;
Su, C.-F.; Liao, J.-H. J. Org. Chem. 2007, 72, 8459. (c) Hong, B.-C.; Tseng,
H.-C.; Chen, S.-H. Tetrahedron 2007, 63, 2840.
(24) For studies in the oxidation of chromenols to para-quinone
hemiketals, see: (a) Patel, A.; Netscher, T.; Gille, L.; Mereiter, K.; Rosenau,
T. Tetrahedron 2007, 63, 5312. (b) Lumb, J.-P.; Choong, K. C.; Trauner,
D. J. Am. Chem. Soc. 2008, 130, 9230. (c) Lee, S. B.; Lin, C. Y.; Gill,
P. M. W.; Webster, R. D. J. Org. Chem. 2005, 70, 10466.
(23) For examples of γ-amination of R,ꢀ-unsaturated aldehydes, see:
(a) Bertelsen, S.; Marigo, M.; Brandes, S.; Dine´r, P.; Jørgensen, K. A. J. Am.
Chem. Soc. 2006, 128, 12973. (b) Bertelsen, S.; Dine´r, P.; Johansen, R. L.;
Jørgensen, K. A. J. Am. Chem. Soc. 2007, 129, 1536.
778
Org. Lett., Vol. 12, No. 4, 2010

20 (>99% ee). The structure and absolute configuration
of 20 were assigned unambiguously by X-ray analysis
(Figure 2).27 Moreover, the absolute configuration of the
Scheme 4
Figure 2. Stereo plots for X-ray crystal structures of 20 and 21: C,
gray; N, blue; O, red; Br, purple.
gem-dimethyl derivatives 21 (>99% ee), prepared from
18, 1, and 19, was elucidated by single-crystal X-ray
analysis (Figure 1).
In summary, we described the first enantioselective total
synthesis of the marine meroterpene (+)-conicol. This
synthesis demonstrates the synthetic application of the new
cascade oxa-Michael-Michael-Michael-aldol condensation
of 2-((E)-2-nitrovinyl)benzene-1,4-diol and R,ꢀ-unsaturated
aldehydes. The successful synthesis further expands the realm
of the reactant of this three-component reaction beyond
3-arylacrylaldehyde to the R,ꢀ-unsaturated aldehydes bearing
a γ-H. The structures as well as the absolute configurations
of the products were confirmed by X-ray analysis of the
appropriate cascade reaction adducts. The total synthesis
successfully assigned the absolute configuration of (+)-
conicol, which had previously been a mystery because the
stereochemistry was difficult to determine by other means.
Moreover, this methodology features the highly enantiose-
lective and expeditious construction of the hexahydro-6H-
benzo[c]chromene skeleton, a strategy that may be applied
to the synthesis of other naturally occurring derivatives for
use in bioassays or SAR studies. Extension of this methodol-
ogy to the synthesis of other natural products is under active
investigation.
14 (DIBAL-H, THF, -78 °C, 1 h, 73% yield of 15), followed
by acetylation (Ac2O, DMAP, Et3N-CH2Cl2, 76% yield of
16), and metallic reduction (Li, NH3, 73% yield) to afford
1
17. The H and 13C NMR spectroscopic data for synthetic
17 were identical to those described for the natural product
(+)-conicol.25
To confirm the absolute configuration of the adducts in
the cascade oxa-Michael-Michael-Michael-aldol con-
densation,26 the one-pot domino reaction of 2-((E)-2-
nitrovinyl)phenol (18) and 2 equiv of (E)-3-(4-bromophenyl)-
acrylaldehyde (19) was carried out to afford the adduct
25
27
(25) Synthetic 17: [R]D +51.8 (c 2, CHCl3). Natural 17: lit. [R]D
+1.0 (c 0.4, CHCl3). The measured optical rotation differed from values
reported for the natural product and raises earlier suspicions that the natural
products were present in an enantiomeric excess in the opposite sense and
were not isolated as pure single enantiomers. The lack of optical purity in
the natural products may also be due to facile racemization and/or
decomposition. We observed that storage of the neat enantiopure 17 at 25
°C for one week resulted in some decomposition products. Moreover, the
compound completely decomposed in CHCl3, and a complicated mixture
was obtained after incubation in CHCl3 for 24 h at ambient temperature.
Refer to Supporting Information and ref 10, conclusion sentences on p 1330
and footnote 13 therein.
Acknowledgment. We acknowledge the financial support
for this study from the National Science Council, ROC.
Thanks to the National Center for High-Performance Com-
puting (NCHC) for their assistance in literature searching.
Supporting Information Available: Experimental pro-
cedures and characterization data for the new compounds
and X-ray crystallographic data for compounds 20 and 21
(CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
(26) The relative stereochemistry of the cascade reaction adduct
was revealed by X-ray analysis of a product without heavy atoms.
See ref 20.
(27)
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