Singlet oxygen initiated cascade transformation of a simple difuran into the key ABC-ring motif of the pectenotoxins

Article abstract of DOI:10.1039/c0cc01341b

The key ABC-ring motif of the pectenotoxins has been synthesized, starting from a simple and readily accessible difuran precursor, using a complex singlet oxygen-mediated cascade reaction sequence.

Full text of DOI:10.1039/c0cc01341b

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Singlet oxygen initiated cascade transformation of a simple difuran into
the key ABC-ring motif of the pectenotoxinswz
Georgios Vassilikogiannakis,* Ioanna Alexopoulou, Maria Tofi and Tamsyn Montagnon
Received 11th May 2010, Accepted 24th June 2010
DOI: 10.1039/c0cc01341b
The key ABC-ring motif of the pectenotoxins has been
synthesized, starting from a simple and readily accessible difuran
precursor, using a complex singlet oxygen-mediated cascade
reaction sequence.
As a continuation of our interest in the development of new
and efficient synthetic approaches to natural products1 and
important natural products motifs2 based on implementing
cascade reaction sequences including, as the key element,
singlet oxygen-mediated photooxygenations,3 we sought to
explore the possibility of synthesising the key ABC-ring system
of polyether macrolactones pectenotoxins 2c, 8, 9 and 11c
Fig. 1 Structures of PTXs 2c, 8, 9 and 11c.
(Fig. 1) using such chemistry.
Since the first isolation of members of the pectenotoxin
(PTX) family in 1985 from Patinopecten yessoensis scallops, by
Yasumoto and his coworkers,4 more than 20 other structurally
related compounds have been isolated from Dinophysis
dinoflagellates worldwide.5 PTXs have aroused particular
interest because they interact with the actin cytoskeleton at a
new and unique site6 conferring on them potent cytotoxicity
against human lung, colon and breast cancer cell lines.5a,7
Excluding subtle variations in the oxidation state at C43
(Fig. 1), PTXs structural diversity originates mainly from
differing types and configurations of AB spiroketal subunit
that are interconvertible by means of acid equilibration.5b
Only four PTXs bear a [6,6]-spiroketal, while in the rest a
[6,5]-spiroketal is present.
methods to rapidly synthesise [6,5]- and [6,6]-spiroketals,2c,d as well
as to make 3-keto-tetrahydrofurans2e using singlet oxygen (1O2)
oxidation of an appropriately substituted simple furan precursor.
Based on this experience gained designing and implementing these
cascade reaction sequences, we thought it might be possible,
although definitely ambitious, to combine the methodologies in
one super-cascade sequence mediated by 1O2 that would yield the
key ABC-ring motif (5, Scheme 1) of PTXs 2c, 8, 9 and 11c
starting from a relatively simple difuran precursor 6.
Our investigation began by targeting the cascade reaction
sequence precursor, difuran-triol 6. We hoped to achieve the
synthesis of 6 using syn-dihydroxylation of a cis-olefin, to be
prepared by means of a Wittig reaction (Scheme 1). According
to precedent,2c,15 we believed it should be possible to introduce
all the requisite substituents at the ortho positions of the
difuran 6 using known anionic- or radical-based methods at
an early stage in the synthetic sequence.
PTX4 and PTX8 were synthesised in 2002 with characteristic
eloquence by Evans and coworkers.8 The ABC-fragment,
containing a [6,5]-spiroketal, has been synthesised by the
groups of Paquette,9 Brimble10 and Pihko11 using acid
catalysed ketalisation of hydroxyketones, or ketals, for the
formation of the C7 spiroketal, as well as a classical 5-exo
epoxide opening for the construction of the C-ring.12 More
exotic approaches, namely the cyclization of a spirodiepoxide
and reductive cyclization of a cyanoacetal for the synthesis of
the [6,5] AB-spiroketal, have recently been developed by the
groups of Williams13 and Rychnovsky,14 respectively.
The main focus of work emanating from our laboratories
has been to explore new ways of employing singlet oxygen, a
powerful, selective and green oxidant, as a cascade reaction
sequence-mediator.1–3 To this end, we have recently reported
The strategy was implemented, and, in a straightforward
manner, free radical coupling of an excess of commercially
available sylvan (7) with ethyl iodoacetate according to
Baciocchi conditions15 afforded ethyl 2-(furan-2-yl)acetate
(8, Scheme 2) in 91% yield. Reduction of 815b with LiAlH4
followed by iodination (I2, PPh3, imidazole) gave iodide 9,
which was converted to the corresponding phosphonium salt
10 in 68% overall yield (over 3 steps). Wittig coupling between
the phosphonium salt 10 and aldehyde 13 (prepared by
ortho-formylation of known furan 122c,d with DMF) afforded
Department of Chemistry, University of Crete, 71003 Iraklion, Crete,
Greece. E-mail: vasil@chemistry.uoc.gr; Fax: +30 2810 545001;
Tel: +30 2810 545074
w This article is part of the ‘Emerging Investigators’ themed issue for
ChemComm.
z Electronic supplementary information (ESI) available: Experimental
procedures, spectroscopic data and copies of 1H and 13C NMR
spectra. See DOI: 10.1039/c0cc01341b
Scheme 1 Retrosynthetic analysis of ABC motif of PTXs.
Chem. Commun., 2011, 47, 259–261 | 259
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olefin 11, as a mixture of two geometrical isomers (cis :trans = 2:1,
Scheme 2), in 73% yield. Sharpless asymmetric dihydroxylation
(SAD)16 of olefin 11 (cis : trans = 2 : 1) resulted in the
unexpected formation of a 1 : 2.6 mixture of erythro/threo
1,2-diols17 in 62% yield, while 20% of the starting material
(exclusively cis-11) was recovered. The unexpected formation
of the threo diastereoisomer of 6 as the major product of this
syn-dihydroxylation reaction of an olefin whose major
geometrical isomer is cis configured, implies a degree of
cis/trans isomerisation during the course of the reaction. The
fact that the recovered starting olefin is exclusively cis is in
agreement with the known faster dihydroxylation of a trans
olefin versus its cis isomer. When the recovered cis-11 was
resubjected to SAD conditions a 2.5 : 1 mixture of erythro/threo
1,2-diols was formed. Finally, TBAF assisted deprotection of
the primary alcohol resulted in the formation of the requisite
photooxygenation precursor difuran-triol 6 in a total of eight
simple synthetic steps.
Scheme
3
Singlet oxygen initiated cascade transformation of
difuran-triol 6 into the ABC motif of PTXs 2c, 8, 9, and 11c.
the major diastereoisomer of 14 (observation of NOE between
H3 and H11, as well as H12 and H15) prove that the relative
stereochemistries of C7 compared to C11, as well as C12
compared to C15 are correct. Similar NOE studies on 5
(observation of NOE between H3 and H11) are consistent with
the anomeric C7 spiroketal for both diastereoisomers.18
The synthetic strategy for PTXs ABC-ring motif synthesis
that had just been successfully implemented, had been
predicated on our previous experience in the field1a–c,g,2c–e
which would also support the following mechanistic rationale
(Scheme 4) for the transformation of 6 into 5. First of all, the
formation of dihydroperoxide B (Scheme 4) is expected to
occur via one intra- and one intermolecular nucleophilic opening
of fleeting diozonide A. For simplicity, only one of the two
possible regioisomers (nucleophilic openings b and c) of
dihydroperoxide B appears in Scheme 4. Each regioisomer is
in turn a mixture of diastereoisomers resulting in a very
With difuran-triol 6 in hand, the stage was now set for us to
obtain proof of principle for the ambitious singlet oxygen-
initiated cascade reaction that we had envisioned as a means of
accessing the key ABC-ring motif of the pectenotoxins. A
solution of 6 (erythro/threo = 1 : 2.6) in MeOH, containing
rose bengal as photosensitizer, was irradiated for three
minutes with visible spectrum light whilst oxygen was being
bubbled gently through it. Very careful replacement of MeOH
with either CHCl3 or CH2Cl2 followed by treatment for 72 h
with an excess of dimethyl sulfide (DMS) and then with
p-TsOH for 3 h resulted in the remarkable formation of
compound 14 (51%, mixture of 3 diastereoisomers in 5 : 3 : 2 ratio,
Scheme 3) accompanied by a chromatographically separable,
less polar, compound 5 (18%, mixture of 2 diastereoisomers in
7 : 3 ratio). When the same photooxidation conditions were
applied to 6 (erythro/threo = 2.5 : 1) formation of compound 5
(49%, mixture of 2 diastereoisomers in 7 : 3 ratio) was
accompanied by compound 14 (19%, mixture of 3 diastereo-
isomers in 5 : 3 : 2 ratio). Careful NOE studies undertaken on
1
complicated H NMR spectrum for dihydroperoxide B. The
very careful replacement of MeOH with CHCl3 followed by
treatment of the mixture of dihydroperoxides B with an excess
of dimethyl sulfide (DMS) reduces1a–c,2c–e the two hydroperoxy
groups of B, thus, affording the corresponding dihemiketal C.
A transketalisation reaction2d leads to the transformation of
the [6,5]-spiroketal of C into the [6,6]-spiroketal D. Under the
same reaction conditions the remaining hemiketal moiety of
intermediate D slowly eliminates a molecule of MeOH,1a–c,2e
thus revealing the 1,4-enedione moiety of intermediate E. In
the final step of this remarkable cascade sequence, p-TsOH
catalyses an oxo-Michael cyclisation2e between the –OH group
of E and the 1,4-enedione moiety resulting in the formation of
the sought after ABC-ring motif of PTXs in the form of
compound 5.
From a practical standpoint, it is very important to note
that during the 72 h treatment of the photooxidation mixture
with DMS the reaction was continuously monitored by 1H NMR.
The fact that the intermediates B, C, D and E (Scheme 4) are
mixtures of different regio- (not shown) and stereoisomers, and
also the fact that some of these intermediates coexist during the
1
course of the reaction, made analysis of the H NMR spectra
challenging. However, it is very important to undertake this
monitoring by 1H NMR because not only does the DMS/DMSO
ratio remain unchanged once complete reduction of all the
Scheme 2 Synthesis of the photooxygenation precursor difuran-triol 6.
260 | Chem. Commun., 2011, 47, 259–261
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Scheme 4 A mechanistic explanation.
hydroperoxy groups has been attained, but the amount of MeOH
present also becomes static once the opening of the hemiketal to
the 1,4-enedione moiety has been achieved, thus the right moment
for the addition of the p-TsOH is indicated. This final reagent
addition initiates a gross simplification of the reaction’s TLC
profile that has been complex up to this point, as two less polar
(compared to preceding intermediates) spots start to dominate.
In summary, we have designed and successfully executed a
most ambitious singlet oxygen-driven reaction cascade
sequence wherein a simple and readily accessible difuran
precursor is transformed to a complex multiringed motif
found in the pectenotoxin family of natural products. This
sequence perfectly showcases the power singlet oxygen has to
mediate intricate cascade reaction sequences and transform
simple molecules to complex ones with ease and efficiency.
This research was supported by a Marie Curie European
Integration Grant (T.M.), within the 7th European
Community Framework Programme, ELKE of the University
of Crete (K.A. 2949), as well as COST action CM0804.
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18 For detailed NOE studies see supporting information section.
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