Rapid formation of hindered cores using an oxidative prins process

Article abstract of DOI:10.1021/ol101851z

Figure Presented. An unprecedented oxidative Prins transformation on phenol derivatives mediated by a hypervalent iodine reagent has been developed. This method allows a rapid access to highly substituted compact systems present in several natural products via a carbon-based addition on an aromatic core. Substitution at each ring position has been demonstrated, enabling synthesis of molecules with up to two contiguous quaternary carbon centers in good yield.

Full text of DOI:10.1021/ol101851z

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4368-4371
Rapid Formation of Hindered Cores
Using an Oxidative Prins Process
Jean-Christophe Andrez, Marc-Andre´ Giroux, Jessica Lucien, and
Sylvain Canesi*
Laboratoire de Me´thodologie et Synthe`se de Produits Naturels, UniVersite´ du Que´bec
a` Montre´al, C.P. 8888, Succ. Centre-Ville, Montre´al, H3C 3P8, Que´bec, Canada
canesi.sylVain@uqam.ca
Received August 7, 2010
ABSTRACT
An unprecedented oxidative Prins transformation on phenol derivatives mediated by a hypervalent iodine reagent has been developed. This
method allows a rapid access to highly substituted compact systems present in several natural products via a carbon-based addition on an
aromatic core. Substitution at each ring position has been demonstrated, enabling synthesis of molecules with up to two contiguous quaternary
carbon centers in good yield.
The well-known Prins transformation1 was first reported by
Kriewitz.2 The reaction involves addition of an oxonium
species to an alkene or an alkyne followed by capture of a
nucleophile or elimination of hydrogen. Since there are
several competing reaction pathways, it is important to
control the reactivity of species 3 to generate only the desired
product (Figure 1).
oxidative dearomatization of electron-rich aromatics involv-
ing carbon-based nucleophiles4 led us to question whether
an oxidative variant of the Prins process could be initiated
by oxidative activation of a phenol. Electron-rich aromatic
compounds such as phenols and their derivatives normally
react as nucleophiles. However, an oxidative activation5,6
can transform these compounds into highly reactive elec-
trophilic species such as 5, which may be intercepted with
appropriate nucleophiles. This reversal of reactivity may be
thought of as involving “aromatic ring umpolung”.4 The
phenoxonium ion 5 could be trapped by an intramolecular
π bond via a chairlike transition state, leading to a spiro-
(3) (a) Hirst, G. C.; Johnson, T. O.; Overman, L. E. J. Am. Chem. Soc.
1993, 115, 2992. (b) MacMillan, D. W. C.; Overman, L. E. J. Am. Chem.
Soc. 1995, 117, 10391. (c) Lebsack, A. D.; Overman, L. E.; Valentkovitch,
R. J. J. Am. Chem. Soc. 2001, 123, 4851. (d) Lavigne, R. M. A.; Riou, M.;
Girardin, M.; Morency, L.; Barriault, L. Org. Lett. 2005, 7, 5921. (e)
Overman, L. E.; Velthuisen, E. J. J. Org. Chem. 2006, 71, 1581. (f)
Armstrong, A.; Bhonoah, Y.; Shanahan, S. E. J. Org. Chem. 2007, 72, 8019.
(4) (a) Be´rard, D.; Giroux, M. A.; Racicot, L.; Sabot, C.; Canesi, S.
Tetrahedron 2008, 7537. (b) Sabot, C.; Be´rard, D.; Canesi, S. Org. Lett.
2008, 10, 4629. (c) Sabot, C.; Commare, B.; Nahi, S.; Duceppe, M. A.;
Gue´rard, K. C.; Canesi, S. Synlett 2008, 3226. (d) Gue´rard, K. C.; Sabot,
C.; Racicot, L.; Canesi, S. J. Org. Chem. 2009, 74, 2039. (e) Sabot, C.;
Gue´rard, K. C.; Canesi, S. Chem. Commun. 2009, 2941. (f) Gue´rard, K. C.;
Chapelle, C.; Giroux, M. A.; Sabot, C.; Beaulieu, M. A.; Achache, N.;
Canesi, S. Org. Lett. 2009, 11, 4756. (g) Gue´rard, K. C.; Sabot, C.; Beaulieu,
M. A.; Giroux, M. A.; Canesi, S. Tetrahedron 2010, 66, 5893.
Figure 1. Prins transformation.
One control method was proposed by Overman3 et al. in
the famous Prins-pinacol tandem process. This method
considerably reduces the formation of byproducts from
intermediate 3 and often forms an efficient key step in the
synthesis of complex natural products. Our own interest in
(1) (a) Prins, H. J. Chem. Weekblad 1919, 16, 64, 1072, 1510. (b)
Arundale, E.; Mikeska, L. A. Chem. ReV. 1952, 51, 505.
(2) (a) Kriewitz, O. Ber. 1899, 32, 57.
10.1021/ol101851z  2010 American Chemical Society
Published on Web 09/02/2010

dienone species 6 similar to the previous Prins intermediate
3 (Figure 2).
As expected, activation of phenol 4 leads to a mixture of
products representing the different plausible pathways beginning
with intermediate 6.9 To limit the formation of side products,
the reaction was investigated using a free alkyne moiety as the
nucleophile. It was rationalized that the geometry of the strained
half-chair species 8 would strongly favor nucleophile capture,
leading to a spiro[5.5]undecanyl core 9. This valuable bicyclic
system is found in natural products such as laurencenone B10
and platencin11 (Figure 3).
Figure 2. Oxidative Prins process.
An indication of how the formation of the corresponding
phenol activation can be achieved is apparent in the work
of Kita,7 who has demonstrated that phenols react under the
influence of hypervalent iodine reagents8 such as (diacetoxy-
iodo)benzene (DIB), an environmentally benign and inex-
pensive reagent. This reaction is best performed in solvents
such as hexafluoroisopropanol (HFIP).7k
(5) (a) Gates, B. D.; Dalidowicz, P.; Tebben, A.; Wang, S.; Swenton,
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L. Org. Lett. 1999, 1, 1651. (e) Braun, N. A.; Bray, J.; Ousmer, M.; Peters,
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4397. (f) Ousmer, M.; Braun, N. A.; Bavoux, C.; Perrin, M.; Ciufolini,
M. A. J. Am. Chem. Soc. 2001, 123, 7534. (g) Quideau, S.; Pouyse´gu, L.;
Oxoby, M.; Looney, M. A. Tetrahedron 2001, 57, 319. (h) Canesi, S.;
Belmont, P.; Bouchu, D.; Rousset, L.; Ciufolini, M. A. Tetrahedron Lett.
2002, 43, 5193. (i) Canesi, S.; Bouchu, D.; Ciufolini, M. A. Angew. Chem.,
Int. Ed. 2004, 43, 4336. (j) Quideau, S.; Pouyse´gu, L.; Deffieux, D. Curr.
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Lett. 2005, 7, 175. (l) Honda, T.; Shigehisa, H. Org. Lett. 2006, 8, 657.
(m) Nicolaou, K. C.; Edmonds, D. J.; Li, A.; Tria, G. S. Angew. Chem.
2007, 119, 4016. (n) Quideau, S.; Pouyse´gu, L.; Deffieux, D. Synlett 2008,
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Giroux, M. A.; Gue´rard, K. C.; Beaulieu, M. A.; Sabot, C.; Canesi, S. Eur.
J. Org. Chem. 2009, 3871. (q) Mendelsohn, B. A.; Ciufolini, M. A. Org.
Lett. 2009, 11, 4736. (r) Quideau, S.; Lyvinec, G.; Marguerit, B. K.; Ozanne-
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Int. Ed. 2009, 48, 4605. (s) Liang, H.; Ciufolini, M. A. Org. Lett. 2010, 12,
1760.
Figure 3. Formation of spiro[5.5]undecanyl cores.
The strain generated by the transient sp-hybridized carbon
in species 8 rendered the intermediate highly electrophilic
and enabled it to react with weakly reactive nucleophiles,
including some normally used as inert solvents such as
HFIP,7k dichloromethane (DCM) (as a chloride donor),12
trifluoroacetic acid (TFA), and benzene. This last example
can be considered as a tandem oxidative Prins/Friedel-Crafts
process, demonstrating the potential utility of this strategy
for further domino applications. A summary of experiments
is presented in Table 1.
Table 1. Nucleophile Additions
(6) (a) Quideau, S.; Looney, M. A.; Pouyse´gu, 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) Be´rard, D.; Jean, A.; Canesi, S. Tetrahedron
Lett. 2007, 48, 8238. (e) Jean, A.; Cantat, J.; Be´rard, D.; Bouchu, D.; Canesi,
S. Org. Lett. 2007, 9, 2553. (f) Pouyse´gu, L.; Chassaing, S.; Dejugnac, D.;
Lamidey, A. M.; Miqueu, K.; Sotiropoulos, J. M.; Quideau, S. Angew.
Chem., Int. Ed. 2008, 47, 3552. (g) Be´rard, D.; Racicot, L.; Sabot, C.; Canesi,
S. Synlett 2008, 1076. (h) Pouyse´gu, 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,
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Rojas, L. B.; Charris, J.; Deffieux, D.; Quideau, S. Tetrahedron 2010, 66,
5908.
entry
R
solvent
HFIP
HFIP/DCM
HFIP/DCM
TFA
Nu
yield (%)
a
b
c
d
e
H
H
Br
H
H
OCH(CF3)2
61
57
73
62
50
Cl
Cl
OCOCF3
Ph
HFIP/PhH
(7) (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)
Kita, Y.; Takada, T.; Gyoten, M.; Tohma, H.; Zenk, M. H.; Eichhorn, J. J.
Org. Chem. 1996, 61, 5854. (d) Kita, Y.; Gyoten, M.; Ohtsubo, M.; Tohma,
H.; Takada, T. Chem. Commun. 1996, 1481. (e) Takada, T.; Arisawa, M.;
Gyoten, M.; Hamada, R.; Tohma, H.; Kita, Y. J. Org. Chem. 1998, 63,
7698. (f) Arisawa, M.; Utsumi, S.; Nakajima, M.; Ramesh, N. G.; Tohma,
H.; Kita, Y. Chem. Commun. 1999, 469. (g) Akai, S.; Kawashita, N.; Morita,
N.; Nakamura, Y.; Iio, K.; Kita, Y. Heterocycles 2002, 58, 75. (h) Dohi,
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Dohi, T.; Kita, Y. Chem. Commun. 2009, 2073. (j) Dohi, T.; Itob, M.;
Yamaokaa, N.; Morimotoa, K.; Fujiokab, H.; Kita, Y. Tetrahedron 2009,
65, 10797. (k) Dohi, T.; Yamaoka, N.; Kita, Y. Tetrahedron 2010, 66, 5775.
It appears that all of the heteronucleophiles react similarly.
In the case of compound 9d, the fragile enol-ether is rapidly
(8) (a) Wirth, T. Hypervalent Iodine Chemistry: Modern Developments
in Organic Synthesis. Top. Curr. Chem. 2003, 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.
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Quideau, S. Tetrahedron 2010, 66, 2235.
(9) The presence of a mixture of isomers providing from an elimination
and a nucleophilic addition has been verified by mass spectroscopy.
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27, 1761.
Org. Lett., Vol. 12, No. 19, 2010
4369

hydrolyzed during workup into the corresponding ketone 10;
this transformation is formally an oxidative Claisen/Dieck-
mann-type condensation (Scheme 1).
highly hindered cores containing contiguous quaternary
carbon centers. Indeed, the elaboration of such challenging
systems is often restricted by the steric hindrance of the first
quaternary carbon center. The introduction of two substitu-
ents in position 1 would help stabilize the phenoxonium ion
generated during the umpolung activation and would create
a contiguous spiro quaternary center. The difficulty normally
associated with the synthesis of such frameworks would turn
into an advantage. To verify this hypothesis, a second
substituent was introduced at position 1 (Scheme 2).
Scheme 1. Oxidative Claisen/Dieckmann Process
Scheme 2. Contiguous Quaternary Carbon Center Formation
To determine the scope and limitations of this novel
transformation, various substituents were introduced on the
lateral chain to generate more elaborate bicyclic systems. A
summary of experiments performed using 1- or 2-substituted
phenols is presented in Table 2.
We were pleased to observe the formation of the desired
compounds in good yields considering the architecture
produced. We have also investigated the effect of a methyl
group in position 3, and the formation of a spiro[4.5]decanyl
core 18 via a Wagner-Meerwein transposition process has
been observed. The electron density provided by the methyl
group in position 3 probably favored a ring contraction
process on the species 16. The corresponding carbocation
17 was trapped by various nucleophiles present in the
medium to afford compound 18 (Scheme 3).
Table 2. Effects of Substituents at Positions 1 and 2
entry
R
R1
R2
Nu
yield (%)
i
i
a
b
c
d
e
f
H
H
H
H
H
H
H
Br
Me
H
Me
H
Me
H
H
Me
H
Me
H
Me
H
OCH(CF3)2
OCH(CF3)2
71
59
83
57
79
60
81
74
ii
OCOCF3
OCOCF3
ii
Cliii
Cliii
Cliii
Cliii
Scheme 3. Ring Contraction
g
h
CH2CHdCH2
PH
H
i HFIP used as solvent. ii TFA used as solvent. iii Mixture of DCM/
HFIP, 9:1, used as solvent.
Substitution at position 2 (R2) seems to have no influence
on the yield of this reaction. However, the presence of
bromine atoms in the ortho positions or more importantly a
substituent in position 1 (R1) clearly increases the yield. This
result could be rationalized by considering that a common
limitation of oxidative processes is competitive hydrogen
elimination during formation of the phenoxonium ion 5,
leading to an easily polymerizable quinone methide. The
presence of only one hydrogen atom would limit this side
reaction. In addition, the weak electron-donating effect of
the substituent in position 1 could slightly increase the
stability of the phenoxonium ion, favoring nucleophilic
addition. These results suggest the potential for constructing
This transposition may be easily avoided by introducing
a methylene group in position 3; indeed, the sp2 hybridization
in this position now retards the ring contraction process in
favor of nucleophilic capture. To produce a potential
precursor of laurencenone B 10, methyl groups were
introduced at the meta positions (Scheme 4).
Scheme 4. Substituent in Position 3
(11) Jayasuriya, H.; Herath, K. B.; Zhang, C.; Zink, D. L.; Basilio, A.;
Genilloud, O.; Teresa Diez, M.; Vicente, F.; Gonzalez, I.; Salazar, O.; Pelaez,
F.; Cummings, R.; Ha, S.; Wang, J.; Singh, S. B. Angew. Chem., Int. Ed.
2007, 46, 4684.
(12) (a) Kropp, P. J.; McNeely, S. A.; Davis, R. D. J. Am. Chem. Soc.
1983, 105, 6907. (b) Miyamoto, K.; Shiro, M.; Ochiai, M. Angew. Chem.,
Int. Ed. 2009, 48, 8931. The nucleophilic capture of 9 by a chloride can
sometimes be accompanied by a small amount (∼5%) of HFIP capture.
4370
Org. Lett., Vol. 12, No. 19, 2010

After having placed substituents at all positions on the
aromatic core and the lateral chain, the free alkyne moiety
was functionalized. The introduction of a protected methylene
alcohol at this position resulted in the formation of the
spiro[4.5]decanyl system 23. This can be attributed to the
steric bulk of the substituent forcing the π bond to react in
a 5-exo-dig mode instead of the standard 6-endo-dig observed
with free alkynes. The formation of compound 23 could
occur via hydrolysis of a potential allene intermediate 22 or
more probably through a pinacol-type process. A good
diastereoselectivity (9:1)13 in favor of the (E)-isomer was
observed. This new selectivity of the alkyne functionality
during the oxidative Prins transformation presents novel
opportunities such as the facile construction of the subunit
present in the natural product hispidospermidin14 (Scheme
5).
Scheme 5. Formation of a Spiro[4.5]decanyl Core
Acknowledgment. We would like to acknowledge the
donors to the American Chemical Society Petroleum Re-
search Fund (ACS PRF) for supporting this research. We
are very grateful to the Natural Sciences and Engineering
Research Council of Canada (NSERC), the Canada Founda-
tion for Innovation (CFI), and Boehringer Ingelheim (Canada)
Ltd. for their financial support.
In summary, a new oxidative Prins process has been
developed that enables rapid access to functionalized and
highly hindered spirocyclic compounds such as those present
in numerous natural products. This method is an efficient
means of producing two contiguous quaternary carbon
centers. Ongoing investigations of this process and potential
applications will be disclosed in due course.
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.
(13) The ratio has been determined by NMR 300 MHz.
(14) Yanagisawa, M.; Sakai, A.; Adachi, K.; Sano, T.; Watanabe, K.;
Tanaka, Y.; Okuda, T. J. Antibiot. 1994, 47, 1.
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