Singlet-oxygen-mediated one-pot synthesis of 3-keto-tetrahydrofurans from 2-(β-hydroxyalkyl) furans

Article abstract of DOI:10.1021/ol8024742

(Chemical Equation Presented) Photooxygenation of 2-(β-hydroxyalkyl) furans affords, in one synthetic operation and in high yields, 3-keto-tetrhydrofuran motifs via intramolecular Michael-type addition to the 1,4-enedione intermediate.

Full text of DOI:10.1021/ol8024742

ORGANIC
LETTERS
2009
Vol. 11, No. 2
313-316
Singlet-Oxygen-Mediated One-Pot
Synthesis of 3-Keto-tetrahydrofurans
from 2-(ꢀ-Hydroxyalkyl) Furans
Maria Tofi, Konstantina Koltsida, and Georgios Vassilikogiannakis*
Department of Chemistry, UniVersity of Crete, Vasilika Vouton, 71003 Iraklion,
Crete, Greece
Vasil@chemistry.uoc.gr
Received October 27, 2008
ABSTRACT
Photooxygenation of 2-(ꢀ-hydroxyalkyl) furans affords, in one synthetic operation and in high yields, 3-keto-tetrhydrofuran motifs via intramolecular
Michael-type addition to the 1,4-enedione intermediate.
As a continuation of our intrest in the development and
application of tandem and cascade reaction sequences,
mediated by singlet oxygen (1O2), for the synthesis of natural
products and important natural products motifs,1 we sought
to explore the potential of the photooxygenation of 2-(ꢀ-
hydroxyalkyl) furans2 as means to prepare 3-keto-tetrahy-
drofuran motifs. The 3-keto-tetrahydrofuran motif is of
interest because it exists in a wide variety of natural products
including the scabrolides3 and pectenotoxins (PTXs).4
The new approach to 3-keto-tetrahydrofurans that is
successfully developed herein is particularly advantageous
as a result of the atom economy and intrinsic efficiency of
the cascade reaction sequence that is employed. Furthermore,
the 2-(ꢀ-hydroxyalkyl) furan precursors, with a wide variety
of appended substituents and functionalities, are readily
accessible; thus, a highly effective method has been delin-
eated.
Previous studies emanating from our laboratories had
shown what happened if a furan photooxygenation substrate
had a γ- or δ-hydroxyl appended on the 2-alkyl substituent;
the corresponding spiroketal was furnished via intramolecular
trapping.5 On the other hand, it has been known for some
time that an R-hydroxyl at the 2-alkyl substituent leads to
rapid fragmentation of the substrate yielding the correspond-
ing 4-hydroxy butenolide.6 Despite these seemingly com-
prehensive investigations, the effect of placing the hydroxyl
at the ꢀ-position (A, Scheme 1) had never been probed prior
to this study.
Obviously, an intramolecular nucleophilic opening of
ozonide B (Scheme 1), of the sort seen with the γ- and
δ-hydroxyls, is unlikely because it would require an unfavor-
able 4-exo-cyclization compared to 5-exo- and 6-exo-
cyclizations observed in the previous cases.5a Drawing on
experience garnered during the synthesis of the litseaverti-
cillol family of natural products,7 it was interesting to wonder
whether, when employing MeOH as the photooxygenation
solvent, the analogous 1,4-enedione (see F, Scheme 1) might
(1) For a recent account, see: Montagnon, T.; Tofi, M.; Vassilikogian-
nakis, G. Acc. Chem. Res. 2008, 41, 1001–1011.
(2) For general reviews of furan photooxygenation, see: (a) Gollnick,
K.; Griesbeck, A. Tetrahedron 1985, 41, 2057–2068. (b) Feringa, B. L.
Recl. TraV. Chim. Pays-Bas 1987, 106, 469–488.
(3) (a) Sheu, J.-H.; Ahmed, A. F.; Shiue, R.-T.; Dai, C.-F.; Kuo, Y.-H.
J. Nat. Prod. 2002, 65, 1904–1908. (b) Ahmed, A. F.; Su, J.-H.; Kuo, Y.-
H.; Sheu, J.-H. J. Nat. Prod. 2004, 67, 2079–2082.
(5) (a) Georgiou, T.; Tofi, M; Montagnon, T.; Vassilikogiannakis, G.
Org. Lett. 2006, 8, 1945–1948. (b) Tofi, M.; Montagnon, T.; Georgiou, T.;
Vassilikogiannakis, G. Org. Biomol. Chem. 2007, 5, 772–777.
(6) Lee, G. C. M.; Syage, E. T.; Harcourt, D. A.; Holmes, J. M.; Garst,
M. E. J. Org. Chem. 1991, 56, 7007–7014.
(4) For original isolation, see: (a) Yasumoto, T.; Murata, M.; Oshima,
Y.; Sano, M.; Mastumoto, G. K.; Clardy, J. Tetrahedron 1985, 41, 1019–
1025. For total synthesis of PTX4 and PTX8, see: (b) Evans, D. A.;
Rajapakse, H. A.; Stenkamp, D. Angew. Chem., Int. Ed. 2002, 41, 4569–
4573. (c) Evans, D. A.; Rajapakse, H. A.; Chiu, A.; Stenkamp, D. Angew.
Chem., Int. Ed. 2002, 41, 4573–4576.
(7) (a) Vassilikogiannakis, G.; Stratakis, M. Angew. Chem., Int. Ed. 2003,
42, 5465–5468. (b) Vassilikogiannakis, G.; Margaros, I.; Montagnon, T.
Org. Lett. 2004, 6, 2039–2042. (c) Vassilikogiannakis, G.; Margaros, I.;
Montagnon, T.; Stratakis, M. Chem. Eur. J. 2005, 11, 5899–5907.
10.1021/ol8024742 CCC: $40.75
Published on Web 12/11/2008
2009 American Chemical Society

Scheme 1
.
Concept
Scheme 3
.
Validation of Proposed Reaction Sequence: Synthesis
2,5-Substituted-3-keto-tetrahydrofurans
dimethylsulfide (DMS) afforded the desired enedione (analo-
1
gous to F), as seen by H NMR, which could be coaxed
into cyclizing in the desired manner upon addition of catalytic
amounts of p-TsOH and after 30 min of stirring. Removal
of MeOH before the addition of DMS is important for the
fast elimination of MeOH from intermediate of type E (E
f F, Scheme 1). The overall yield of this one-pot multistep
sequence was 83%, and the final product 7a (dr ) 3.3:1,
Scheme 3) was obtained in a highly pure form, such that no
chromatographic purification was needed.
be obtained. This unsaturated 1,4-enedione F might then
become the subject of an intramolecular Michael-type
addition to yield the final cyclized motif seen in G (Scheme
1).
To test this hypothesis and gain proof of principle, furan
3a (Scheme 2) was easily prepared upon nucleophilic
Once this proof of principle had been obtained, the scope
and limitations of this synthetic technology needed to be
delineated. To this end, a range of different 2-(ꢀ-hydroxy-
alkyl) furans were synthesized. First was furan 3b, prepared
by nucleophilic opening of styrene oxide 2b (Scheme 2) and
chosen as a target substrate in order to ascertain whether
the cyclization of the enedione (of type F) was faster than
the possible dehydration of the benzylic hydroxyl in the
presence of p-TSOH. Under the experimental conditions
reported above, clean formation of the intemediate cis-
endione of type F (R1 ) Ph, R2 ) H, R3 ) H, R4 ) Me)
Scheme 2. Synthesis of Key Precursor 3a,b, 4, 6
1
was observed by H NMR. Treatment of this intermediate
with catalytic amount of p-TSOH for 30 min resulted in
isomerizion to the corresponding trans geometrical isomer.
Further stirring for 3 h gave clean conversion to the cyclized
product 7b (dr ) 2.5:1, Scheme 3). NOE experiments
revealed that the relative stereochemistry of the minor
diastereoisomer of 7b is syn while the major one is anti. It
should be noted that similar NOE experiments had proven
inconclusive in the case of 7a.
Having established that the technology works very ef-
ficiently for secondary alcohols, such us 3a and 3b, it was
hoped that it might be extended to include tertiary alcohols,
such as 4 and 6. Alcohol 4 was readily prepared by IBX
oxidation of 3a followed by addition of MeLi (70% over
two steps). Homochiral alcohol 6 was synthesized by
alkylation of 2-methylfuran with 3-bromo-2-methylpropene
followed by Sharpless asymmetric dihydroxylation and
selective protection of the primary alcohol as the TBS ether.
Protection of the primary alcohol was essential in order to
avoid the fast intramolecular nucleophilic opening of ozonide
of type B, which leads to the formation of a [5,5]
opening of 1,2-epoxyhexane (2a) by 2-methylfuryllithium.
The resulting furan was then subjected to a standard set of
1O2 photooxygenation conditions (rose bengal as photosen-
sitizer, oxygen bubbling through the reaction mixture, and
irradiation with visible spectrum light, Scheme 3) for 2 min.
Following a change of solvent (removal of MeOH in vacuo
and replacement with CH2Cl2), an in situ reduction of the
hydroperoxides (analogous to C and D, Scheme 1) using
314
Org. Lett., Vol. 11, No. 2, 2009

spiroketal.1,5a Application of the developed protocol to furan
4 furnished cleanly, in 90% yield, 3-keto-tetrahydrofuran 7c
as a 2:1 mixture of diastereoisomers. The analogous proce-
dure transformed furan 6 into 3-keto-tetrahydrofuran 7d in
85% yield and as a 1.2:1 mixture of diastereoisomers
(Scheme 3). Once again, cis-trans isomerization of the
intermediate enedione (of type F), prior to the cyclization
p-TsOH. Prolonged treatment with p-TsOH (6 h) cleanly
afforded the cyclized product 11b.
With these results in hand, it seemed pertinent to next
explore whether the protocol could be extended to the
preparation of 2,4,5-trisubstituted-3-keto-tetrahydrofurans.
Furan 12 was synthesized via stereoselective nucleophilic
opening of cyclohexene oxide with 2-methylfuryllithium
(Scheme 5). Application of the newly developed tandem
1
that afforded 7d, was observed by H NMR. Removal of
the TBS group from 3-keto-tetrahydrofuran 7d with TBAF
gave a 2.2:1 mixture of diastereomeric primary alcohols. This
finding is consistent with the easy epimerization of the
stereogenic center R to the ketone (C2, Scheme 3). On the
basis of NOE experiments, the minor stereoisomer of 3-keto-
tetrahydrofuran 7d (dr ) 1.2:1) has the syn stereochemistry.
The C-ring of the pectenotoxins8 exhibits this relative
stereochemistry.
Scheme 5. Synthesis 2,4,5-Trisubstituted-3-keto-tetrahydrofurans
Next we sought to clarify the ease with which different
substitution patterns could be targeted using this newly
developed methodology. To this end, furans 10a,b were
synthesized using the four-step sequence shown in Scheme
4 in order to attempt the synthesis of 2,4-disubstituted-3-
sequence, with furan 12 as substrate, then afforded the
expected trans-fused bicycle 13 as an 1:1 mixture of
diastereoisomers. Fast epimerization of the trans-fused
bicycle 13, to the more thermodynamically stable cis-fused
isomer 14 (dr ) 2:1), was observed upon purification using
silica gel. In this instance particularly the potential of this
method is highlighted because a relatively complex fused
bicyclic motif has been accessed directly from a simple
substrate using a dependable and high-yielding cascade
sequence. Similar [6,5]-fused bicyclic motifs can be found
in a variety of natural products, including (+)-phyllanthocin,9
(+)-phyllanthocindiol,9 (+)-phyllantoside,10 and phyllan-
tostatins.11
Scheme 4
. Synthesis of
2,4-Disubstituted-3-keto-tetrahydrofurans
When the developed tandem reaction sequence was applied
to monosubstituted furan 15, no 3-keto-tetrahydrofuran
formation was observed. This failure was attributed to the
fast decomposition of the unstable intermediate 1,4-keto-
aldehyde 16.
1
keto-tetrahydrofurans. Application of the developed O2-
protocol in substrates 10a and 10b resulted in the clean
formation of 2,4-disubstituted-3-keto-tetrahydrofurans 11a
and 11b, respectively, in high yields and as mixtures of two
diastereoisomers (Scheme 4). In contrast to the previously
investigated cases (e.g., 7b and 7d), NOE studies proved in
the case of 11a that the relative stereochemistry of the major
diastereoisomer was syn. In the case of 10b, completion of
the E f F transformation (Scheme 1) was observed after
5 h of treatment with DMS. Prolonged reaction times (18 h)
led to complete cis-trans isomerization of this intermediate
(type F). Similar cis-trans isomerization of the intermediate
type F enedione was observed after 20 min of treatment with
In all of the substrates examined thus far, the final Michael-
type attack (F f G, Scheme 1) occurs onto a monosubsti-
(8) For the classical syntheses of the C-ring of pectenotoxins based on
a 5-exo epoxide opening, see: (a) Halim, R.; Brimble, M. A.; Merten, J.
Org. Lett. 2005, 7, 2659–2662. (b) O’Connor, P., D.; Knight, C. K.;
Friedrich, D.; Peng, X.; Paquette, L. A J. Org. Chem. 2007, 72, 1747–
1754. (c) Aho, J. E.; Salomaki, E.; Rissanen, K.; Pihko, P. M. Org. Lett.
2008, 10, 4179–4182.
(9) For total synthesis, see: Smith, A. B., III; Fukui, M.; Vaccaro, H. A.;
Empfield, J. R. J. Am. Chem. Soc. 1991, 113, 2071–2092.
(10) For total synthesis, see: Smith, A. B., III; Rivero, R. A.; Hale, K. J.;
Vaccaro, H. A. J. Am. Chem. Soc. 1991, 113, 2092–2112.
(11) For total synthesis, see: Smith, A. B., III; Hale, K. J.; Vaccaro,
H. A.; Rivero, R. A. J. Am. Chem. Soc. 1991, 113, 2112–2122.
Org. Lett., Vol. 11, No. 2, 2009
315

tuted olefinic carbon. In order to expand the limitations of
the newly developed protocol, 2-(ꢀ-hydroxyalkyl) furan 18
(Scheme 6) was synthesized starting from commercially
from the other two by column chromatography and has the
anti relative stereochemistry in the 3-keto-tetrahydrofuran
ring (based on NOE studies). The major diastereoisomer of
the remaining more polar inseparable mixture (dr ) 3:1) also
has the anti relative stereochemistry in the 3-keto-tetrahy-
drofuran ring.
Scheme 6. Application of Developed Protocol for
2-(ꢀ-Hydroxyalkyl)-3-substituted Furan 18
In summary, a rapid and highly efficient synthesis of a
range of variably substituted 3-keto-tetrahydrofuran motifs
starting from readily accessible furan precursors has been
developed and explored. This new strategy for the one-pot
synthesis of 3-keto-tetrahydrofurans from furans makes use
of an attractive singlet-oxygen-mediated cascade reaction
sequence.
Acknowledgment. We are grateful to Dr. Tamsyn Mon-
tagnon and Prof. Manolis Stratakis (University of Crete) for
valuable discusions and comments. Financial support from
the INTERREG IIIA Greece-Cyprus (K2301.004) and from
ELKE of the University of Crete (K.A. 2747) is gragefully
acknowledged.
available (+)-menthofuran (17). The important characteristic
of this substrate is the substitution at the 3-position of the
furan (with a methyl group). Gratifyingly, application of the
developed technology to furan 18 led to the formation of
desired compound 20 (as a mixture of three diastereoiso-
mers). The less polar and major diastereoisomer is separable
Supporting Information Available: Experimental pro-
1
cedures, full spectroscopic data, and copies of H and 13C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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Org. Lett., Vol. 11, No. 2, 2009