A stereoselective oxidative polycyclization process mediated by a hypervalent iodine reagent

Article abstract of DOI:10.1021/ol201149u

Activation of phenol derivatives with a hypervalent iodine reagent promotes the formation of bicyclic and tricyclic products via a cationic cyclization process. The method allows efficient one-step syntheses of scaffolds present in several natural product

Full text of DOI:10.1021/ol201149u

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3406–3409
A Stereoselective Oxidative
Polycyclization Process Mediated by
a Hypervalent Iodine Reagent
Samuel Desjardins, Jean-Christophe Andrez, and Sylvain Canesi*
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Laboratoire de Methodologie et Synthese de Produits Naturels, Universite du Quebec a
Montreal, C.P. 8888, Succ. Centre-Ville, Montreal, H3C 3P8, Quebec, Canada
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canesi.sylvain@uqam.ca
Received April 29, 2011
ABSTRACT
Activation of phenol derivatives with a hypervalent iodine reagent promotes the formation of bicyclic and tricyclic products via a cationic
cyclization process. The method allows efficient one-step syntheses of scaffolds present in several natural products and occurs with total
stereocontrol, governed by 1,3 allylic strain interactions and by the configuration of the side chain double bonds.
The use of cationic polycyclizations of polyunsaturated
compounds in biomimetic syntheses allows rapid access to
complex architectures with excellent diastereoselectivity.
The first remarkable examples can be attributed to Johnson
et al. for the syntheses of steroids in 1976;1 however such
strategies are still under intensive investigation.2 Our own
interest in oxidative dearomatization of electron-rich aro-
matics involving carbon-based nucleophiles3 led us to
question whether an oxidative cationic polycyclization
could be triggered by activation of a phenol. Although
electron-rich aromatic compounds such as phenols and
their derivatives normally react as nucleophiles, oxidative
activation4,5 can transform these compounds into highly
reactive electrophilic species such as 2. This phenoxonium
ion6 2 could be intercepted in an intramolecular fashion
by appropriate carbon-based nucleophiles such as π
bonds, thus initiating a diastereoselective polycyclization
leading to tricyclic core 3. This phenol reversal of reactivity
may be thought of as involving an “aromatic ring umpo-
lung”. The oxidative process could rapidly generate the
core of several natural products such as the human
(1) (a) Johnson, W. S.; DuBois, G. E. J. Am. Chem. Soc. 1976, 98,
1038. (b) Gravestock, M. B.; Johnson, W. S.; McCarry, B. E.; Ratcliffe,
B. E. J. Am. Chem. Soc. 1978, 100, 4274.
(2) (a) Yamamoto, H.; Ishihara, K.; Ishibashi, H. J. Am. Chem. Soc.
2004, 126, 11122 and references therein. (b) Mullen, C. A.; Campbell,
M. A.; Gagne, M. R. Angew. Chem., Int. Ed. 2008, 47, 6011. (c)
Surendra, K.; Corey, E. J. J. Am. Chem. Soc. 2009, 131, 13928. (d)
Topczewski, J. J.; Callahan, M. P.; Neighbors, J. D.; Wiemer, D. F.
J. Am. Chem. Soc. 2009, 131, 14630. (e) Zhao, Y. J.; Li, B.; Serena Tan,
L. J.; Shen, Z. L.; Loh, T. P. J. Am. Chem. Soc. 2010, 132, 4274. (f)
Sethofer, S. G.; Mayer, T.; Toste, F. D. J. Am. Chem. Soc. 2010, 132,
8276.
(4) (a) Gates, B. D.; Dalidowicz, P.; Tebben, A.; Wang, S.; Swenton,
J. S. J. Org. Chem. 1992, 57, 2135. (b) Quideau, S.; Looney, M. A.;
ꢀ
Pouysegu, L. Org. Lett. 1999, 1, 1651. (c) Braun, N. A.; Bray, J.; Ousmer,
M.; Peters, K.; Peters, E. M.; Bouchu, D.; Ciufolini, M. A. J. Org. Chem.
2000, 65, 4397. (d) Ousmer, M.; Braun, N. A.; Bavoux, C.; Perrin, M.;
Ciufolini, M. A. J. Am. Chem. Soc. 2001, 123, 7534. (e) Canesi, S.;
Belmont, P.; Bouchu, D.; Rousset, L.; Ciufolini, M. A. Tetrahedron Lett.
2002, 43, 5193. (f) Canesi, S.; Bouchu, D.; Ciufolini, M. A. Angew.
Chem., Int. Ed. 2004, 43, 4336. (g) Canesi, S.; Bouchu, D.; Ciufolini,
M. A. Org. Lett. 2005, 7, 175. (h) Nicolaou, K. C.; Edmonds, D. J.; Li,
A.; Tria, G. S. Angew. Chem. 2007, 119, 4016. (i) Liang, H.; Ciufolini,
ꢀ
(3) (a) Berard, D.; Giroux, M. A.; Racicot, L.; Sabot, C.; Canesi, S.
ꢀ
Tetrahedron 2008, 7537. (b) Sabot, C.; Berard, D.; Canesi, S. Org. Lett.
2008, 10, 4629. (c) Sabot, C.; Commare, B.; Nahi, S.; Duceppe, M. A.;
ꢀ
ꢀ
Guerard, K. C.; Canesi, S. Synlett 2008, 3226. (d) Guerard, K. C.; Sabot,
C.; Racicot, L.; Canesi, S. J. Org. Chem. 2009, 74, 2039. (e) Sabot, C.;
ꢀ
ꢀ
Guerard, K. C.; Canesi, S. Chem. Commun. 2009, 2941. (f) Guerard,
K. C.; Chapelle, C.; Giroux, M. A.; Sabot, C.; Beaulieu, M. A.; Achache,
ꢀ
M. A. J. Org. Chem. 2008, 4299. (j) Giroux, M. A.; Guerard, K. C.;
ꢀ
N.; Canesi, S. Org. Lett. 2009, 11, 4756. (g) Guerard, K. C.; Sabot, C.;
Beaulieu, M. A.; Sabot, C.; Canesi, S. Eur. J. Org. Chem. 2009, 3871. (k)
Mendelsohn, B. A.; Ciufolini, M. A. Org. Lett. 2009, 11, 4736. (l)
Quideau, S.; Lyvinec, G.; Marguerit, Bathany, K.; Ozanne-Beaudenon,
A.; Bufeteau, T.; Cavagnat, D.; Chenede, A. Angew. Chem., Int. Ed.
2009, 48, 4605. (m) Liang, H.; Ciufolini., M. A. Org. Lett. 2010, 12, 1760.
Beaulieu, M. A.; Giroux, M. A.; Canesi, S. Tetrahedron 2010, 66, 5893.
(h) Andrez, J. A.; Giroux, M. A.; Lucien, J.; Canesi, S. Org. Lett. 2010,
ꢀ
12, 4368. (i) Beaulieu, M. A.; Sabot, C.; Achache, N.; Guerard, K. C.;
Canesi, S. Chem.;Eur. J. 2010, 16, 11224.
r
10.1021/ol201149u
Published on Web 05/27/2011
2011 American Chemical Society

steroidal hormone skeleton 4,1 or cassaic acid 5 and its
derivatives,7 Figure 1.
Scheme 1. Formation of Functionalized Decalin Cores
The strain created by the transient sp-hybridized carbo-
nium ion in species 8 resulted in the intermediate being
highly electrophilic and enabled it to react with the weakly
reactive nucleophile HFIP,8f normally used as an inert
solvent. This reaction produced the highly functionalized
bicyclic system 9 containing a quaternary carbon center, a
dienone functionality, and an enol-ether as a masked
carbonyl. In order to determine the scope and limitations
of this new transformation, substituents were introduced
on the lateral chain, on the aromatic ring, and at the para
position to produce the elaborated bicyclic cores 11. In
addition, the new process can efficiently afford the tricyclic
core 11h in excellent yield from a simple tetralone deriva-
tive 10h, Table 1.
Figure 1. Oxidative cationic polycyclization cascade.
An indication of how the necessary phenol activation
can be efficiently achieved is apparent in the work of Kita,8
who demonstrated that phenols react under the influence of
hypervalent iodine reagents9 suchas(diacetoxyiodo)benzene
(DIB), an environmentally benign and inexpensive re-
agent. This reaction is best performed in solvents such as
hexafluoroisopropanol (HFIP).8f In our first study, an
oxidative vicinal fused carbocycle formation was per-
formed with a terminal alkyne on a lateral chain at the
meta-position relative to the phenol group 6. During the
umpolung activation, we speculate that a strained half-
chair intermediate 8 was generated which strongly favored
nucleophile capture, leading to the unsaturated decalin
system 9, Scheme 1.
Table 1. Oxidative Bicyclization Process
ꢀ
(5) (a) Quideau, S.; Looney, M. A.; Pouysegu, L. J. Org. Chem. 1998,
63, 9597. (b) Ozanne-Beaudenon, A.; Quideau, S. Angew. Chem., Int. Ed.
2005, 44, 7065. (c) Ciufolini, M. A.; Canesi, S.; Ousmer, M.; Braun, N. A.
ꢀ
Tetrahedron 2006, 62, 5318. (d) Berard, D.; Jean, A.; Canesi, S. Tetra-
ꢀ
hedron Lett. 2007, 48, 8238. (e) Jean, A.; Cantat, J.; Berard, D.; Bouchu,
ꢀ
D.; Canesi, S. Org. Lett. 2007, 9, 2553. (f) Pouysegu, L.; Chassaing, S.;
Dejugnac, D.; Lamidey, A. M.; Miqueu, K.; Sotiropoulos, J. M.;
entry
R1
R2
R3
R4
R3/R4
yield (%)
ꢀ
Quideau, S. Angew. Chem., Int. Ed. 2008, 47, 3552. (g) Berard, D.;
ꢀ
Racicot, L.; Sabot, C.; Canesi, S. Synlett 2008, 1076. (h) Pouysegu, L.;
Marguerit, M.; Gagnepain, J.; Lyvinec, G.; Eatherton, A. J.; Quideau, S.
Org. Lett. 2008, 10, 5211. (i) Mendelsohn, B. A.; Lee, S.; Kim, S.;
Teyssier, F.; Aulakh, V. S.; Ciufolini, M. A. Org. Lett. 2009, 11, 1539. (j)
a
b
c
d
e
f
H
H
Me
Me
Me
Me
Et
H
H
43
86
50
70
91
85
79
90
Br
H
Br
H
Me
Me
H
trans
trans
ꢀ
Traore, M.; Ahmed-Ali, S.; Peuchmaur, M.; Wong, Y. S. Tetrahedron
H
Br
Br
Br
Br
Br
2010, 66, 5863. (k) Liang, H.; Ciufolini, M. A. Tetrahedron 2010, 66,
Br
Br
Br
Br
ꢀ
5884. (l) Pouysegu, L.; Sylla, T.; Garnier, T.; Rojas, L. B.; L., B.; Charris,
J.; Deffieux, D.; Quideau, S. Tetrahedron 2010, 66, 5908. (m) Jen, T.;
Mendelsohn, B. A.; Ciufolini, M. A. J. Org. Chem. 2011, 76, 728. (n)
Bn
H
g
h
n-Pr
H
ꢀ
Traore, M.; Ahmed-Ali, S.; Peuchmaur, M.; Wong, Y. S. J. Org. Chem.
H2CÀCH2ÀCH2
cis
2011, 76, 1409.
(6) Hanway, P. J.; Winter, A. H. J. Am. Chem. Soc. 2011, 133, 5086.
(7) Clarke, R. L.; Daum, S. J.; Shaw, P. E.; Kullnig, R. J. Am. Chem.
Soc. 1966, 88, 5865.
This bicyclization reaction produced vicinal fused car-
bocycles in very good yields. However, the oxidation of
compounds containing open ortho-positions (entries 10a
and 10c) occurred in lower yields compared to the dibromo
analogs. This may be explainedbyconsidering thatthe first
intermediate is a highly delocalized carbonium ion, which
can be represented by 7 (Scheme 1, R = Br) as one of its
resonance structures. We believe that because of the pre-
sence of the electron-withdrawing bromine atoms, 7 is the
more dominant resonance form rather than the ortho
mesomer. Consequently the cyclization occurs mainly at
(8) (a) Tamura, Y.; Yakura, T.; Haruta, J.; Kita, Y. J. Org. Chem.
1987, 52, 3927. (b) Kita, Y.; Tohma, H.; Hatanaka, K.; Takada, T.;
Fujita, S.; Mitoh, S.; Sakurai, H.; Oka, S. J. Am. Chem. Soc. 1994, 116,
3684. (c) Dohi, T.; Maruyama, A.; Takenaga, N.; Senami, K.;
Minamitsuji, Y.; Fujioka, H.; Caemmerer, S. B.; Kita, Y. Angew. Chem.,
Int. Ed. 2008, 47, 3787. (d) Dohi, T.; Kita, Y. Chem. Commun. 2009,
2073. (e) Dohi, T.; Itob, M.; Yamaokaa, N.; Morimotoa, K.; Fujiokab,
H.; Kita, Y. Tetrahedron 2009, 65, 10797. (f) Dohi, T.; Yamaoka, N.;
Kita, Y. Tetrahedron 2010, 66, 5775.
(9) (a) Wirth, T., Ed. Hypervalent Iodine Chemistry: Modern Devel-
opments in Organic Synthesis; Topics in Current Chemistry; Springer:
2003; Vol. 224. (b) Ciufolini, M. A.; Braun, N. A.; Canesi, S.; Ousmer, M.;
Chang, J.; Chai, D. Synthesis 2007, 24, 3759. (c) Zhdankin, V. V.; Stang,
ꢀ
P. J. Chem. Rev. 2008, 108, 5299. (d) Pouysegu, L.; Deffieux, D.;
Quideau, S. Tetrahedron 2010, 66, 2235.
Org. Lett., Vol. 13, No. 13, 2011
3407

the desired para-position when bromines are protecting the
ortho-positions. An added advantage is that the bromine
atoms could be used subsequently to introduce others
substitutents, using transition metal chemistry. Further-
more, entries 10c and 10d (R4 = Me) led exclusively to the
trans diastereoisomer.10 This stereoselectivity could be
explained by the required minimal 1,3 allylic strain inter-
actions between the two methyl groups during the transi-
tion state 7 (Scheme 1, R2 = Me). These observations
demonstrate the high diastereoselectivity of this new pro-
cess and could have applications in asymmetric synthesis
governed by the meta first stereogenic benzilic center. Such
scaffolds are present in numeral natural products such as
anominine11 12, andrographolide12 13, or the decalin core
of azadirachtin13 14, Figure 2.
the diastereoselectivityof the cyclization withrespect tothe
configuration of the central double bond in compound 20.
A Wittig reaction transformed aldehyde 17 into an inse-
parable mixture of cis and trans alkenes 19 in a 2:1 ratio in
favor of the (Z)-isomer. The mixture was further trans-
formed in two steps into a diastereoisomeric mixture of
phenols 20. The same umpolung activation led to the
desired tricyclic systems 21 and 22 in 41% yield.16 The
cyclization reaction occurred with total stereocontrol in
agreement with the configuration of the starting olefin
(Z or E), since a 2:1 mixture of diastereomers10 was
obtained. It should be stressed that compound 21 repre-
sents the main core of cassaic acid 5, Scheme 3.
Scheme 3. Oxidative Tricyclization Process
Figure 2. Natural products containing a decalin core.
The required starting materials were obtained from
tetralone 15, via a reduction/elimination sequence14 lead-
ing to 16 followed by ozonolysis and reductive treatment
with H2/Pd to provide aldehyde 17 in 54% overall yield.
This substrate was further easily transformed into product
18 using a CoreyÀFuchs strategy,15 Scheme 2.
To verify the high diastereoselectivity of this process, cis-
20 was efficiently synthesized by a Lindlar reduction of an
internal triple bond. The requisite alkyne was prepared via
oxetane ring opening by the lithium salt of 18 (made
directly from the dibromoalkene precursor) and then
further transformed into the cis compound 19 via a
CoreyÀFuchs reaction in 62% overall yield from com-
pound 23. The oxidation of cis-20 led exclusively to the
tricyclic core 22 in 43% yield,10 Scheme 4.
Scheme 2. Formation of Starting Materials
Scheme 4. Diastereoselective Tricyclization Process
We were also interested in the possible extension of this
process to the formation of tricyclic systems as well as in
(10) The stereoselectivity was verified and attributed by 1H NMR
and 1H NMR NOE.
(11) Gloer, J. B.; Rinderknecht, B. L.; Wicklow, D. T.; Dowd, P. F.
J. Org. Chem. 1989, 54, 2530.
(12) Puri, A.; Saxena, R.; Saxena, R. P.; Saxena, K. C.; Srivastava,
V.; Tandon., J. S. J. Nat. Prod. 1993, 56, 995.
(13) Nicolaou, K. C.; Roecker, A. J.; Follmann, M.; Baati, R. Angew.
Chem. Int.Ed. 2002, 41, 2107.
In summary, an unprecedented oxidative polycycliza-
tion process has been developed that enables rapid access
to bicyclic and tricyclic systems present in several natural
(14) Grignard reageants were used to produce more elaborate phe-
nols: Beaubien, S.; Deslongchamps, P. Can. J. Chem. 2006, 84, 29.
(15) Synthetic details are provided as Supporting Information.
(16) The two diastereomers were separated by chromatography at
this point.
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Org. Lett., Vol. 13, No. 13, 2011

products, from inexpensive phenol derivatives. This
method is an efficient means of diastereoselectively intro-
ducing several stereogenic centers in one step, with total
stereocontrol, governed by 1,3 allylic strain interactions
and by the configuration of the side chain double bonds.
Ongoing investigations of this process and potential appli-
cations will be disclosed in due course.
(NSERC), the Canada Foundation for Innovation (CFI),
the provincial government of Quebec (FQRNT and
CCVC), and Boehringer Ingelheim (Canada) Ltd. for their
precious financial support in this research.
Supporting Information Available. Experimental pro-
cedures and spectral data for key compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We are very grateful to the Natural
Sciences and Engineering Research Council of Canada
Org. Lett., Vol. 13, No. 13, 2011
3409