Ortho-dearomatization of phenols creating all-carbon spiro-bicycles

Article abstract of DOI:10.1021/ol401863k

A range of alkene-linked phenols are generally and reliably dearomatized specifically at their ortho-positions to create all-carbon quaternary stereogenic centers at the corresponding spiro-ring junctions, thus establishing a viable solution to the long-standing synthetic challenge.

Full text of DOI:10.1021/ol401863k

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Ortho-Dearomatization of Phenols
Creating All-Carbon Spiro-Bicycles
Chao Zheng, Lu Wang, Jingjie Li, Leifeng Wang, and David Zhigang Wang*
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology,
Shenzhen Graduate School of Peking University, Shenzhen, China 518055
dzw@pkusz.edu.cn
Received April 26, 2013
ABSTRACT
A range of alkene-linked phenols are generally and reliably dearomatized specifically at their ortho-positions to create all-carbon quaternary
stereogenic centers at the corresponding spiro-ring junctions, thus establishing a viable solution to the long-standing synthetic challenge.
Ortho-fused spiro-[6-5]-bicycles and their architectural
derivatives, generally summarized as structure Ain Scheme 1,
represent some of the most frequently encountered motifs1
that are present in many interesting bioactive natural pro-
ducts, such as anticardiovascular magellanine,2aÀc cytotoxic
daphnilongeranin C,2d neurotrophic tricycloillicinone,2e and
antitubercular colombiasin A.2f
Conceptually, as already hypothesized in relevant
retrosynthesis3 and biosynthesis proposals,4 these structural
motifs could all be directly and atom-economically accessed
simply by site-specific dearomatizations of appropriate
phenols5 bearing a pendant olefinic side chain at their
corresponding ortho-position. The broad range of structural
as well as functional diversities conferred by these fascinating
ortho-fused spiro-[6-5]-bicycles are unusual and attention-
demanding. Thus it is surprising to observe that up to the
present there is still no generally applicable method available
allowing for their facile construction.3 Indeed, in contrast to
the voluminous literature on various methods for dearoma-
tization of phenolic substances,5 particularly those involving
hypervalent iodine reagent6-mediated formation of widely
useful ortho- and para-quinone monoketals5,7 (i.e., dearoma-
tized rings featuring the formed CÀO or CÀN bonds), very
few studies are known to tackle the arguably more difficult
problem of site-selective dearomatization of phenols via
(1) (a) Huang, J.; Wang, H.; Wu, C.; Wulff, W. D. Org. Lett. 2007, 9,
2799. (b) Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc. 2013, 135, 1268.
(c) Vo, N. T.; Pace, R. D. M.; O’Hara, F.; Gaunt, M. J. J. Am. Chem.
Soc. 2008, 130, 404. (d) Imbos, R.; Minnaard, A. J.; Feringa, B. L. J. Am.
Chem. Soc. 2002, 124, 184. (e) Canesi, S.; Bouchu, D.; Ciufolini, M. A.
Angew. Chem., Int. Ed. 2004, 43, 4336.
(6) For reviews on hypervalent iodine chemistry: (a) Wirth, T.
Angew. Chem., Int. Ed. 2005, 44, 3656. (b) Zhdankin, V. V.; Stang,
P. J. Chem. Rev. 2002, 102, 2523. (c) Stang, P. J.; Zhdankin, V. V. Chem.
Rev. 1996, 96, 1123.
(2) (a) Castillo, M.; Loyola, L. A.; Morales, G.; Singh, I.; Calvo, C.;
Holland, H. L.; MacLean, D. B. Can. J. Chem. 1976, 54, 2893. (b)
Castillo, M.; Morales, G.; Loyola, L. A.; Singh, I.; Calvo, C.; Holland,
H. L.; McLean, D. B. Can. J. Chem. 1976, 54, 2900. (c) Loyola, L. A.;
Morales, G.; Castillo, M. Phytochemistry 1979, 18, 1721. (d) Kobayashi,
J.; Kubota, T. Nat. Prod. Rep. 2009, 26, 936. (e) Fukuyama, Y.; Shida,
N.; Kodama, M.; Chaki, H.; Yugami, T. Chem. Pharm. Bull. 1995, 43,
(7) (a) Swenton, J. S. Chemistry of Quinone Bis- and Monoketals. In
The Chemistry of Quinonoid Compounds; Patai, S., Rappoport, Z., Eds.; Wiley:
New York, 1988; Vol. II, Part 2, pp 899À962 and references cited therein.
ꢀ
Ortho-dearomatized rings featuring the formed CÀO bond: (b) Pouysegu,
´
´
2270. (f) RodrUguez, A. D.; RamUrez, C. Org. Lett. 2000, 2, 507.
(3) (a) Green, J. C.; Pettus, T. R. R. J. Am. Chem. Soc. 2011, 133,
1603. (b) Rudolph, A.; Bos, P. H.; Meetsma, A.; Minnaard, A. J.;
Feringa, B. L. Angew. Chem., Int. Ed. 2011, 50, 5834. (c) Oguma, T.;
Katsuki, T. J. Am. Chem. Soc. 2012, 134, 20017.
L.; Chassaing, S.; Dejugnac, D.; Lamidey, A.-M.; Miqueu, K.; Sotiropoulos,
J.-M.; Quideau, S. Angew. Chem., Int. Ed. 2008, 47, 3552. (c) Uyanik, M.;
Yasui, T.; Ishihara, K. Angew. Chem., Int. Ed. 2010, 49, 2175.
(8) Selected examples of the uses of carbon nucleophiles in the
ꢀ
oxidative dearomatization of phenols; see: (a) Guerard, K. C.; Chapelle,
(4) Parker, W.; Roberts, J. S.; Ramage, R. Q. Rev. Chem. Soc. 1967,
21, 331.
C.; Giroux, M.-A.; Sabot, C.; Beaulieu, M.-A.; Achache, N.; Canesi, S.
Org. Lett. 2009, 11, 4756. (b) Desjardins, S.; Andrez, J.-C.; Canesi, S.
Org. Lett. 2011, 13, 3406. (c) Hempel, C.; Weckenmann, N. M.; Maichle-
Moessmer, C.; Nachtsheim, B. J. Org. Biomol. Chem. 2012, 10, 9325.
(9) Of considerable relevance is the recently discovered enantioselec-
tive dearomatizations of phenols involving CÀF bond formations; see:
Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc. 2013, 135, 1268.
ꢀ
(5) Selected reviews on oxidative dearomatizations: (a) Pouysegu, L.;
ꢀ
Deffieux, D.; Quideau, S. Tetrahedron 2010, 66, 2235. (b) Stephane,
R. P.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2011, 50, 4068. (c) Zhuo,
C. X.; Zhang, W.; You, S.-L. Angew. Chem., Int. Ed. 2012, 51, 12662. (d)
ꢀ
Quideau, S.; Pouysegu, L.; Deffieux, D. Synlett 2008, 4, 467.
r
10.1021/ol401863k
XXXX American Chemical Society

design concept was sketched in Scheme 2. We envisioned
that a phenolic substrate B tethered with a carbon-based
nucleophile, preferably a CdC double bond moiety, at its
ortho-position would likely undergo ortho-oxidative dear-
omative spiro-carbocyclization under appropriate oxida-
tion stimulation to directly yield the desired spiro-
cyclohexadienone skeleton A, which would subsequently
serve as a shared facile entry point to other derived spiro-[6-
5]-bicycles. Although it might initially be conceived that
simple alkene-substituted phenols structured as B1 would
function as reasonable substrates, our own experiments and
literature reviews5,8 had in fact unanimously pointed to the
lesson that it is very difficult to obtain generally efficient and
reproducible ortho-dearomatization events on this type of
substrates. This may in fact explain the extreme scarcity of
literature disclosures on B1-type phenols. Our failure-in-
spired recognition is thus that a reliable B-to-A conversion
would require new types of phenolic substrates in which the
incorporated electron-rich double bond is capable of not
only initiating ortho-nucleophilic trapping toward the dear-
omatized cationic ring but also stabilizing thus the formed
carbocation against competing decompositions. Guided by
this recognition, we decided to focus on phenols that are
ortho-substituted by either a pendant allylsilane (B2) or
vinyl ether (B3). It is important to note that oxidative
dearomatization of an allylsilane-functionalized phenol13
had previously been reported by Nicolaou et al. under the
influence of PhI(OAc)2 oxidation, albeit in the para- rather
than ortho-spiroannulation manner.10a,b
The implementations of B2- and B3-type substrates in
the intended ortho-dearomative spirocarbocyclizations,
however, turned out to be nontrivial. With S1 and S2 as
the standard substrates (Scheme 2), it was only through the
repeated interactions of purposeful screening and fortu-
nate serendipity that we eventually were able to identify
optimal conditions capable of bringing about the desired
transformations on each of them (see Supporting Informa-
tion for details of substrate syntheses and experimental
screening). Both cases employed PhI(OAc)2 asthe oxidant,
thereby significantly enhancing the method’s practicality
and ease in implementation. For S1, the standard condi-
tion I recruited a mixture of CF3CH2OH (TFE) and
CH2Cl2 (volume ratio 1/1) as the reaction solvent and
0.02 M substrate concentration; for S2 (in 1/1 geometric
E/Z mixtures), the standard condition II utilized pure TFE
as the solvent and maintained the 0.02M substrate concen-
tration. The additive effect in both conditions had proved
Scheme 1. Biologically Active Natural Products Featuring
Functionalized Ortho-Spiro-[6-5]-bicyclic Cores
concomitant CÀC bond construction,8,9 particularly in an
ortho- rather than para-selective manner.10 The challenge
escalates in the fact that such fully CÀC bond formation-
enabled phenol dearomatization inevitably incurs the emer-
gence of so-called all-carbon quaternary stereogenic centers11
that situate exactly at the corresponding spiro-ring
junctions.12 To the best of our knowledge, there appears to
be only two studies by Pettus3a and Feringa3b and co-work-
ers, respectively, both reported in 2011, that have successfully
realized selective ortho-dearomatization of phenols and
naphthols with strategic CÀC bonds formation for the
targeted construction of spiro-carbocycles. The substrate
scopes they examined appeared to be limited, and phenols
have proven to be more challenging motifs than naphthols for
the events of oxidative dearomatizations.3b,c Thus it remains
to be seen if a more generally applicable ortho-oxidative
phenol dearomatization protocol can be established to enable
the facile construction of all-carbon quaternary spiro-carbo-
cycles, and ideally with more readily commercially available
and user-friendly oxidants such as PhI(OAc)2.6
Stimulated by this challenge, we initiated a program that
attempts to explore a potentially general solution. Our
(10) Selected dearomatizations of phenols leading to para-selective all-
carbon spiro-cycles; see: (a) Nicolaou, K. C.; Edmonds, D. J.; Li, A.; Tria,
G. S. Angew. Chem., Int. Ed. 2007, 46, 3942. (b) Nicolaou, K. C.; Li, A.;
Edmonds, D. J.; Tria, G. S.; Ellery, S. P. J. Am. Chem. Soc. 2009, 131, 16905.
(c) Honda, T.; Shigehisa, H. Org. Lett. 2006, 8, 657. (d) Beaulieu, M.-A.;
to be remarkable: while the 4 e molecular sieve was selected
´
ꢀ
Guerard, K. C.; Maertens, G.; Sabot, C.; Canesi, S. J. Org. Chem. 2011, 76,
9460. (e) Andrez, J.-C.; Giroux, M.-A.; Lucien, J.; Canesi, S. Org. Lett. 2010,
12, 4368. (f) Nemoto, T.; Zhao, Z.; Yokosaka, T.; Suzuki, Y.; Wu, R.;
Hamada, Y. Angew. Chem., Int. Ed. 2013, 52, 2217. (g) Rousseaux, S.;
for the former case, MgSO4 was chosen in the latter. Under
those defined conditions, the reactions proceeded quickly
even at a very low temperature of À40 °C, delivering the
desired ortho-spirobicyclic products P1 and P2 in 57% and
66% isolated yield, respectively. These yields are respectable,
´
GarcUa-Fortanet, J.; Angel Del Aguila Sanchez, M.; Buchwald, S. L. J. Am.
Chem. Soc. 2011, 133, 9282. (h) Dohi, Y.; Minamitsuji, Y.; Maruyama, A.;
Hirose, S.; Kita, Y. Org. Lett. 2008, 10, 3559. (i) Dohi, T.; Nakae, T.;
Ishikado, T.; Kato, D.; Kita, Y. Org. Biomol. Chem. 2011, 9, 6899.
(11) For a review on constructions of all-carbon quaternary stereo-
centers, see: Trost, B. M.; Jiang, C. H. Synthesis 2006, 3, 369.
(12) For general synthesis methods on spiro compounds, see: (a)
Rios, R. Chem. Soc. Rev. 2012, 41, 1060. (b) Asaoka, M.; Takenouchi,
K.; Takei, H. Chem. Lett. 1988, 17, 1225. (c) Sannigrahi, M. Tetrahedron
1999, 55, 9007. (d) Zhang, E.; Fan, C.-A.; Tu, Y.-Q.; Zhang, F.-M.;
Song, Y.-L. J. Am. Chem. Soc. 2009, 131, 14626. (e) Trost, B. M.; Chen,
D. W. C. J. Am. Chem. Soc. 1996, 118, 12541.
(13) For examples of the oxidative HosomiÀSakurai-type dearoma-
ꢀ
tizations, see: (a) Guerard, K. C.; Sabot, C.; Beaulieu, M.-A.; Giroux,
ꢀ
M.-A.; Canesi, S. Tetrahedron 2010, 66, 5893. (b) Quideau, S.; Pouysegu,
L.; Oxoby, M.; Looney, M. A. Tetrahedron 2001, 57, 319. (c) Quideau,
ꢀ
S.; Looney, M. A.; Pouysegu, L. Org. Lett. 1999, 1, 1651. (d) Sabot, C.;
ꢀ
Guerard, K. C.; Canesi, S. Chem. Commun. 2009, 2941.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Design Concept on Potential Substrates for
Ortho-Dearomative Spiro-carbocyclization of Phenols
Scheme 3. Reaction Scope of Ortho-Spiro-carbocyclization of
B2-Type Phenol Substrates
spectroscopically characterized and stored under an inert
atmosphere for a prolonged time. We were also able to grow
single crystals of the DielsÀAlder adduct 3 which was
prepared in 63% yield by heating 2d with N-phenylmalei-
mide in xylene, thereby confirming unambiguously its spiro-
structural identity by X-ray crystallographic analysis.14
The applications of the standard condition II on several
vinyl methyl ether functionalized phenols 4 are summa-
rized in Scheme 4. In complete analogy to the transforma-
tion of S2 to P2, these ortho-oxidative dearomatizations
progressed uneventfully to give their corresponding acetal-
terminated spiro-carbocyclization products 5 in nearly 1/1
diastereomeric ratios relative to the star-labeled stereo-
genic centers.15 Once again, the phenols possessing either
electron-donating (4aÀ4c) or electron-withdrawing (4d)
substituents are suitable substrates. 2-Naphthol 4e worked
in comparable efficiency to that of allylsilane-modified
counterpart 1h (entry 8, Scheme 3), producing the desired
spiro-tricycle 5e in 43% yield. Single crystals of a diaster-
eomer of product 5c were fortunately obtained and then
analyzed by X-ray crystallography, thus confirming di-
rectly its structure and stereochemistry.16 A very interest-
ing observation made on 4f was that, apparently owing to
the inherent instability of its product 5f, tricyclic enone 6
given the high degrees of unsaturations in the structures of P1
and P2 and occurrences of many possible side reactions on
such inherently reactive skeletal identities. The proposed key
intermediates were illustrated in C and D,5 respectively
(Schemes 3 and 4). The use of pure TFE as the solvent in
the standard condition II for S2 apparently secures an
advantage in that TFE itself engages on cationic stabilization
toward D to furnish the product P2 in its acetal-protected
form. With the above identified standard condition I, a range
of B2-type allyltrimethylsilane (TMS)-linked phenols 1 were
subsequently examined and the results are compiled in
Scheme 3. In each case except 1g the desired ortho-spirobi-
cyclic product 2 was obtained in moderate to good isolated
yield and, perhaps more significantly, in excellent reproduci-
bility over multiple runnings. In general, phenols bearing
electron-donating ring substituents (1aÀ1e), presumably due
to their beneficial carbocationic stabilization effects, tend to
give higher yields as compared to those with electron-with-
drawing groups (1fÀ1g). The highest yield (85%) was
obtained on phenol 1d with two methoxyl substituents,
while for 1g having the strongly electron-withdrawing tri-
fluoromethyl group the spiroannulation was practically
inhibited, and the obtained product 2g was formally the
result of the HosomiÀSakurai-type process.13 For
2-naphthol 1h, the protocol is equally competent, leading
to the product 2h in 49% isolated yield. Although these
dearomatized spiro-carbocycles evidently possess high re-
activities, when isolated pure, they could be routinely
(14) The crystal structure of 3 was deposited at the Cambridge
Crystallographic Data Centre (tracking number: 922541).
(15) As an illustrative example, mild acidic hydrolysis of each dia-
stereomer of 5c with 2 M HCl was shown to give accordingly their
diastereomeric aldehydes (see Supporting Information for details).
(16) The crystal structure of 5c was deposited at the Cambridge
Crystallographic Data Centre (tracking number: 945361).
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Reaction Scope of Ortho-Spiro-carbocyclization of
B3-Type Phenol Substrates
Scheme 5. Representative Reactions on Spiro-dearomatized
Products
The reactivities unlocked by such ortho-oxidative dear-
omatization technology are highly diverse, and it must await
further studies to define its full scope. Outlined in Scheme 5
are some initial illustrative results. When activated by acidic
PPTS in heated toluene, ortho-spiro-bicycle 2c rearranges to
the fused tricyclic cyclohexadienone 7 in 46% isolated yield;
upon reduction of 2c by the Luche reagent, the in situ
generated intermediate J undergoes efficient dehydration
to give a new spiro-bicycle 8 in 92% yield. It merits attention
that in this straightforward conversion an important ortho-
to-para pattern switch was accomplished. This discovery
demonstrated that, by the simple introduction of an alkoxyl
(i.e., OMe) substituent onto the meta- position of a phenolic
substrate, both ortho- and para-spiro-regioisomeric pro-
ducts could be efficiently obtained from the same starting
material, thus significantly enhancing the methodology’s
synthetic utilities. Finally, spiro-cycle P1 was subjected to
Pd/C-promoted hydrogenation to produce fully saturated
spiro-bicyclic ketone 9 in nearly quantitative yield (97%),
and its acetal moiety can be easily removed by acidic
hydrolysis to furnish ketoaldehyde 10 in 94% yield.
In summary, with well-optimized reaction conditions,
we were able to demonstrate here that a range of alkene-
linked phenols are reliably dearomatized specifically at
their ortho-positions to create all-carbon quaternary
stereogenic centers at the corresponding spiro-ring junc-
tions, thus establishing a viable solution to the long-
standing synthetic challenge. The new reactivities unlocked
by breaking aromaticity in such processes are evidently very
rich, and we hope to communicate in due course further in-
depth investigations on these exciting possibilities.
was isolated (64% yield) whose structure was again un-
ambiguously established by X-ray crystallographic
analysis.17 The formation of 6 should have originated from
cationic rearrangements18 on the initially formed 5f. The
vinyl methyl ether moiety-triggered cationic cascade trap-
ping may occur either through intermediates E and F to
give 6 or, alternatively, through the sequence E-G-H to
complete the rearrangement. It is interesting to note that 6
represents a common [6-5-5] fused tricyclic skeleton found
in many useful natural products.19
(17) The crystal structure of 6 was deposited at the Cambridge
Crystallographic Data Centre (tracking number: 921696).
(18) For a recent review on carbocationic rearrangements, see:
Tantillo, D. J. Chem. Soc. Rev. 2010, 39, 2847.
Acknowledgment. We thank the National Science Foun-
dation of China, the national “973 Project” of the State Ministry
of Science and Technology of China, and the Shenzhen Bureau
of Science and Technology for financial support.
(19) For selected natural products containing such fused [6-5-5]
tricyclic rings, see: (a) Singh, I. P.; Bharate, S. B. Nat. Prod. Rep.
2006, 23, 558. (b) Ciochina, R.; Grossman, R. B. Chem. Rev. 2006, 106,
3963. (c) George, J. H.; Hesse, M. D.; Baldwin, J. E.; Adlington, R. M.
Org. Lett. 2010, 12, 3532. (d) Winkelmann, K.; Heilmann, J.; Zerbe, O.;
Rali, T.; Sticher, O. J. Nat. Prod. 2000, 63, 104. For dearomatization
annulation: (e) Zhang, Q.; Mitasev, B.; Qi, J.; Porco, J. A., Jr. J. Am.
Chem. Soc. 2010, 132, 14212.
(20) Under the standard condition II, compound 4a was transformed to
diastereomeric acetals and quinine monoketal (see Supporting Information
for details), and subsequent acidic hydrolysis of the mixture produced the
desired aldehydes. Similar reactivities were observed for compound 4e.
Supporting Information Available. Experimental proce-
dures, X-ray crystallographic analysis, and 1Hand13CNMR
spectra for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX