Direct stereocontrolled synthesis of polyoxygenated hydrobenzofurans and hydrobenzopyrans from p-peroxy quinols

Article abstract of DOI:10.1021/ol702236e

An acidic-basic tandem catalytic process on p-peroxy quinols with hydroxy alkyl chains at C-4 allowed the one-pot synthesis of hydrobenzofuran and hydrobenzopyran tricyclic epoxides. In this transformation, two new cycles and four new stereogenic centers

Full text of DOI:10.1021/ol702236e

ORGANIC
LETTERS
2007
Vol. 9, No. 24
5019-5022
Direct Stereocontrolled Synthesis of
Polyoxygenated Hydrobenzofurans and
Hydrobenzopyrans from p-Peroxy
Quinols
Silvia Barradas, M. Carmen Carren˜o,* Marcos Gonza´lez-Lo´pez,
Alfonso Latorre, and Antonio Urbano*
Departamento de Qu´ımica Orga´nica (C-I), UniVersidad Auto´noma de Madrid,
Cantoblanco, 28049-Madrid, Spain
carmen.carrenno@uam.es; antonio.urbano@uam.es
Received September 12, 2007
ABSTRACT
An acidic−basic tandem catalytic process on p-peroxy quinols with hydroxy alkyl chains at C-4 allowed the one-pot synthesis of hydrobenzofuran
and hydrobenzopyran tricyclic epoxides. In this transformation, two new cycles and four new stereogenic centers are created in a highly
stereocontrolled manner. The usefulness of the strategy is illustrated with the first total synthesis and structural revision of natural product
Cleroindicin D.
Stereoselective approaches to hydrobenzofurans and hydro-
benzopyrans continue to attract considerable attention due
to the widespread appearance of these structural motifs in
natural products.1 Although different strategies have been
applied for the construction of these fused heterocycles2 when
dealing with highly substituted systems, multistep syntheses
have been reported. Thus, new methodologies3 allowing short
and stereocontrolled routes to such naturally occurring
moieties are necessary to achieve high efficiency and atom
economy.4
We have recently reported a practical method for the
simple and selective oxidative dearomatization of p-alkyl
phenols into p-peroxy quinols and p-quinols using Oxone
and NaHCO3 as a source of singlet oxygen (Scheme 1).5
For example, the reaction of p-(2-hydroxyethyl)phenol (1)
with Oxone afforded p-peroxy quinol 2, and if this reaction
was followed by the addition of Na2S2O3, phenol 1 directly
furnished rengyolone (4), a natural cis-fused hydrobenzo-
furan, formed by intramolecular conjugate addition of the
hydroxy ethyl chain into the cyclohexadienone framework
of the initially formed p-quinol 3. Taking into account this
result, as well as the presence of the hydroperoxide function
in p-peroxy quinol 2, we decided to investigate the use of
(1) Hydrobenzofurans: (a) Wu, Q.-H.; Liu, Ch.-M.; Chen, Y.-J.; Gao,
K. HelV. Chim. Acta 2006, 89, 915-922. (b) Shibano, M.; Okuno, A.;
Taniguchi, M.; Baba, K.; Wang, N.-H. J. Nat. Prod. 2005, 68, 1445-1449.
Hydrobenzopyrans: (c) Isaka, M.; Tanticharoen, M.; Kongsaeree, P.;
Thebtaranonth, Y. J. Org. Chem. 2001, 66, 4803-4808. (d) Delgado, G.;
Olivares, M. S.; Cha´vez, M. I.; Ram´ırez-Apan, T.; Linares, E.; Bye, R.;
Espinosa-Garc´ıa, F. J. J. Nat. Prod. 2001, 64, 861-864.
(2) Hydrobenzopyrans: Recent review: (a) Tang, Y.; Oppenheimer, J.;
Song, Z.; You, L.; Zhang, X.; Hsung, R. P. Tetrahedron 2006, 62, 10785-
10813. Hydrobenzofurans: Recent work: (b) Yamashita, M.; Ohta, N.;
Shimizu, T.; Matsumoto, K.; Matsuura, Y.; Kawasaki, I.; Tanaka, T.;
Maezaki, N.; Ohta, S. J. Org. Chem. 2003, 68, 1216-1224. (c) Clive, D.
L. J.; Fletcher, S. P. Chem. Commun. 2003, 2464-2465.
(3) Hydrobenzopyrans: (a) Go´mez-Arraya´s, R.; Yin, J.; Liebeskind, L.
S. J. Am. Chem. Soc. 2007, 129, 1816-1825. Hydrobenzofurans: (b) Liu,
Q.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2552-2553.
(4) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259-281.
(5) Carren˜o, M. C.; Gonza´lez-Lo´pez, M.; Urbano, A. Angew. Chem.,
Int. Ed. 2006, 45, 2737-2741.
10.1021/ol702236e CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/01/2007

Scheme 1. Stereocontrolled Synthesis of Tricyclic Epoxide 5
from p-Peroxy Quinol 2 under Basic Conditions
Scheme 2. Diastereoselective Synthesis of Hydrobenzofurans
5 and 6 and Completion of the Synthesis of Cleroindicin D
tricyclic epoxide 5 as the unique diastereomer in an excellent
95% yield (Scheme 2). The formation of the epoxide took
place exclusively on the same face of the cyclohexenone
bearing the OOH group of derivative 6 probably through
the evolution of a dioxetane intermediate such as I,9 formed
after intramolecular conjugate addition of the hydroperoxide
anion to the cyclohexenone moiety, under the basic condi-
tions. This result evidenced that compound 6 must be an
intermediate in the one-pot synthesis of 5 from p-peroxy
quinol 2 under basic conditions (Scheme 1).
With a synthetic improvement in mind, we thought of
performing the transformation of p-peroxy quinol 2 into
tricyclic epoxide 5, without isolating the bicyclic hydroper-
oxide intermediate 6, in a tandem catalytic process.10 Thus,
we treated sequentially p-peroxy quinol 2 with p-TsOH (0.12
equiv) and Triton-B (0.24 equiv), observing the exclusive
formation of tricyclic epoxide 5, out of the four possible
diastereoisomers (Scheme 2). This tandem process including
an acid-catalyzed intramolecular conjugate addition and a
base-catalyzed epoxide formation improved the yield of 5
obtained in the direct base-promoted synthesis (85 vs 66%
yield).
such readily accessible starting materials in the synthesis of
polyoxygenated fused heterocyclic derivatives.
Herein, we describe a one-pot diastereoselective access
to polyoxygenated hydrobenzofurans and hydrobenzopyrans
from p-peroxy quinols, using an efficient tandem acidic-
basic catalytic process. The usefulness of the method is
illustrated with the first synthesis and structure revision of
natural hydrobenzofuran Cleroindicin D.
Initially, we chose p-peroxy quinol 2, lacking stereogenic
centers to avoid added stereochemical complexities, as a
model substrate to test the key bond-forming reactions under
basic conditions (Scheme 1). After trying several bases
(NaHCO3, K2CO3, Na2CO3, Triton-B) and solvents (H2O,
MeOH, EtOH, CH2Cl2), the best results were achieved by
treatment of p-peroxy quinol 2 with 2.2 equiv of K2CO3 in
EtOH. Under these conditions, diastereomerically pure
tricyclic epoxide 5 was obtained in 66% yield. Compound 5
resulted from the domino process6 including intramolecular
cyclization of the 2-hydroxy ethyl chain at C-4 to the
cyclohexadienone moiety of 2 and epoxidation. It is note-
worthy that two new rings and four new stereogenic centers
were created in only one step in a complete diastereoselective
manner. The cis junction7 between the six- and five-
membered rings and the syn orientation of the epoxide with
respect to the angular OH at C-3a were demonstrated after
X-ray analysis of 5.8
Then, we tried to perform the cyclization process under
acidic conditions. To our delight, the treatment of p-peroxy
quinol 2 with 0.12 equiv of p-TsOH in CHCl3 at rt (Scheme
2) promoted the fast and diastereoselective intramolecular
conjugate addition of the primary OH, affording in 90% yield
hydrobenzofuran 6,7 still bearing an enone fragment and the
hydroperoxide group. Upon treatment with 0.12 equiv of
Triton-B in CHCl3, bicyclic hydroperoxide 6 provided
With compound 5 in hand, we undertook the regioselective
opening of the epoxide ring en route to the cis-diol 7 (Scheme
2), an isomer of the natural product Cleroindicin D, isolated
by Sun et al. from the aerial parts of Clerodendrum indicum
in 1997,11 to which a trans disposition for the diol moiety
was initially assigned. After much experimentation, we found
that treatment of epoxide 5 with Na-Hg in EtOH12 furnished
1
diol 7 in 53% yield. All H and 13C NMR data of synthetic
7 matched exactly with those published by Sun.11,13 Then,
in accordance with the stereochemical course of our synthetic
approach, the structure of natural Cleroindicin D should be
revised to 7, with the two OH groups in a cis disposition.
We were also interested in the diastereoselective approach
to the parent hydrobenzopyrans starting from the correspond-
(6) Tietze, L. F.; Brasche, G.; Gericke, K. M. In Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2006.
(7) The cis junction was deduced from the small coupling constants (J
) 1.8-5.5 Hz) shown by the angular hydrogen next to the heterocyclic
oxygen, indicating an equatorial disposition for this proton.
(8) CCDC 655110, 655111, and 655112 for 5, 21, and 27, respectively,
contain the supplementary crystallographic 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.
(9) Hu, Y.; Floss, H. G. J. Am. Chem. Soc. 2004, 126, 3837-3844.
(10) Chapman, Ch. J.; Frost, Ch. G. Synthesis 2007, 1-21.
(11) Tian, J.; Zhao, Q.-S.; Zhang, H.-J.; Lin, Z.-W.; Sun, H.-D. J. Nat.
Prod. 1997, 60, 766-769.
(12) Honzumi, M.; Ogasawara, K. Tetrahedron Lett. 2002, 43, 1047-
1049.
(13) We thank Prof. Sun for providing us with 1H and 13C NMR spectra
of natural Cleroindicin D (see Supporting Information).
5020
Org. Lett., Vol. 9, No. 24, 2007

ing p-peroxy quinol 8 or p-quinol 9, bearing a 3-hydroxy-
propyl chain at C-4 (Scheme 3). When we submitted these
Scheme 4. Oxidative Dearomatization of Phenol 13 and
Diastereoselective Synthesis of Racemic 2-Methyl-Substituted
Hydrobenzofurans
Scheme 3. Diastereoselective Synthesis of Hydrobenzopyrans
10-12 from p-Peroxy Quinol 8 and p-Quinol 9
compounds to reaction with K2CO3 in EtOH, complex
reaction mixtures containing unreacted starting material were
observed. Fortunately, under catalytic acidic conditions,
p-peroxy quinol 8 evolved into bicyclic hydroperoxide 107
with an excellent 91% yield. The p-quinol 9, in the presence
of p-TsOH, afforded hydrobenzopyran 117 with 88% yield.14
Moreover, when p-peroxy quinol 8 was submitted to the
tandem catalytic process, p-TsOH followed by Triton-B,
tricyclic epoxide 12,7 bearing four stereogenic centers, was
exclusively obtained in 81% yield.
Once we optimized the conditions for the diastereoselective
intramolecular cyclization process, we turned our attention
to the synthesis of p-peroxy quinols and p-quinols bearing a
stereogenic center at the hydroxy alkyl chain at C-4 in order
to study the influence of such a stereocenter on the
intramolecular differentiation of the two diastereotopic double
bonds of the cyclohexadienone system.
As depicted in Scheme 4, the oxidative dearomatization
of phenol 13 with Oxone/NaHCO3 in H2O afforded in 47%
yield p-peroxy quinol 14, bearing a 2-hydroxypropyl chain
at C-4. The sequential treatment of 13 with Oxone and
Na2S2O3 gave the p-quinol 15 in 46% yield when the reaction
was quenched immediately after the addition of Na2S2O3 (1.5
min). When longer reaction times were used (24 h), phenol
13 evolved directly into an 80:20 mixture of hydrobenzo-
furans 167,15 and 177,15 (51% yield), resulting from the
intramolecular conjugate addition of the 2-hydroxypropyl
chain at C-4 to both conjugate positions of the cyclohexa-
dienone moiety of the presumed intermediate 15. The major
formation of diastereoisomer 16 indicated that an efficient
intramolecular differentiation of the two diastereotopic double
bonds in such systems was possible.
presence of p-TsOH, giving rise to a 15:85 mixture of peroxy
hydrobenzofurans 187,15 and 197,15 in 47% yield. A similar
diastereoselection was observed in the sequential treatment
of p-peroxy quinol 14 with catalytic amounts of p-TsOH and
Triton-B. In this case, a 15:85 mixture of epoxy hydroben-
zofurans 207,15 and 217,15 was directly formed in 54% yield
after the intramolecular conjugate addition/epoxidation pro-
cess. The relative configuration of compound 21 was
confirmed by X-ray analysis (Scheme 4).
More interesting and synthetically useful results were
obtained in the analogous reactions carried out from p-peroxy
quinol 23 and p-quinol 24, bearing a 3-hydroxybutyl chain
at C-4 (Scheme 5). In this case, we decide to use nonracemic
starting materials en route to enantiopure hydrobenzopyrans.
Thus, when (+)-Rhododendrol (S)-22 (ee >99%), obtained
by enzymatic resolution of the racemic derivative,16 was
reacted with Oxone in a mixture of H2O and CH3CN,
p-peroxy quinol (S)-23 was obtained in 65% yield. The
corresponding p-quinol (S)-24 was directly synthesized from
(S)-22 after the Oxone/Na2S2O3 sequential treatment in 53%
yield. Reaction of p-peroxy quinol (S)-23 under the acid-
catalyzed conditions (0.12 equiv of p-TsOH, CHCl3, -20
°C) afforded bicyclic hydroperoxide (2S,4aR,8aR)-257,15 in
56% yield after chromatographic separation of the initially
formed 95:5 mixture. When p-quinol (S)-24 was sub-
mitted to the same experimental conditions, hydrobenzopyran
(2S,4aR,8aR)-267,15 was obtained in an excellent 94:6 dia-
stereoisomeric mixture, being isolated pure, after flash
Surprisingly, upon acidic catalysis at -40 °C, p-quinol
15 also gave a mixture of 16 and 17 (82% yield), but with
the opposite diastereoselection (16/17 ) 30:70). This dif-
ference could be a consequence of a kinetic (p-TsOH, -40
°C) versus thermodynamic control (NaCO3H, rt). The p-
peroxy quinol 14 also suffered the cyclization process in the
(14) The only similar example found in the literature for this type of
acid-promoted cyclization in derivatives lacking the angular OH group
afforded bicycles with a trans junction under thermodynamic control:
Duhamel, P.; Deyine, A.; Dujardin, G.; Ple´, G.; Poirier, J.-M. J. Chem Soc.,
Perkin Trans. 1 1995, 2103-2114.
(15) The relative configuration of 2-methyl hydrobenzofurans and
hydrobenzopyrans synthesized was deduced after NOESY experiments. The
mixtures 16/17, 18/19, and 20/21 could not be separated.
(16) Yuasa, Y.; Shibuya, S.; Yuasa, Y. Synth. Commun. 2003, 33, 1469-
1475.
Org. Lett., Vol. 9, No. 24, 2007
5021

lecular conjugate addition process, through the efficient
differentiation of the two diastereotopic faces and the two
diastereotopic double bonds (four possible diastereoisomers)
of the cyclohexadienone moiety of p-peroxy quinol 23 and
p-quinol 24. As depicted in Figure 1, the intramolecular
Scheme 5. Oxidative Dearomatization of Phenol (S)-22 and
Stereoselective Synthesis of Enantiopure 2-Methyl-Substituted
Hydrobenzofurans 25-27
Figure 1. Proposed model for the acid-catalyzed intramolecular
conjugate addition of p-peroxy quinol 23 and p-quinol 24.
nucleophilic attack of the OH of the 3-hydroxybutyl chain
must occur from the opposite face of the OR group at C-4
to avoid destabilizing electrostatic interactions between both
oxygens to give exclusively the cis-fused heterocycles. The
differentiation of the two double bonds of the cyclohexadi-
enone framework is due to the stereoselective intramolecular
conjugate attack of the hydroxy alkyl chain at C-4 on the
pro-R double bond of the system (represented as TS-A in
Figure 1), which is favored over that on the pro-S bond
(TS-B) due to the preferred equatorial disposition of the
methyl substituent in the chair-like tetrahydropyran forming
ring TS-A if compared with the axial arrangement of the
same group in TS-B, thus justifying the observed diastereo-
selection.
In summary, we have described a new, short, and efficient
protocol for the stereoselective preparation of polysubstituted
hydrobenzofurans and hydrobenzopyrans with up to five
stereogenic centers. Applying this strategy, we achieved the
first total synthesis and structural revision of natural Clero-
indicin D in three steps and 36% overall yield from a
commercially available phenol.
chromatography, in 79% yield and >99% ee.17 These results
indicated an excellent stereocontrol of the process since
almost only one out of the four possible diastereoisomers
was obtained in enantiomerically pure form.
In an even more efficient way, the p-TsOH-Triton-B
tandem catalytic process on p-peroxy quinol (S)-23 furnished,
out of the eight possible isomers, enantiopure17 tricyclic
epoxide (2S,4aR,5S,6S,8aR)-277,15 after separation of the
initially formed 5:95 mixture in 47% yield. The relative
configuration of the five stereocenters of compound 27 was
demonstrated after X-ray analysis.
Acknowledgment. We thank MCYT (Grant CTQ2005-
02095/BQU) and UAM-CAM (Grant CCG07-UAM/PPQ-
1451) for financial support. S.B. and A.L. wish to thank
MEC, and M.G.-L. thanks CAM for fellowships.
The excellent diastereoselectivity achieved in the synthesis
of hydrobenzopyrans 25-27 was defined in the formation
of the tetrahydropyran ring by the acid-catalyzed intramo-
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and copies of 1H NMR and 13
C
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
(17) The enantiomeric purities were determined by chiral HPLC (see
Supporting Information).
OL702236E
5022
Org. Lett., Vol. 9, No. 24, 2007