Using water, light, air and spirulina to access a wide variety of polyoxygenated compounds

Article abstract of DOI:10.1039/c2gc16397g

A new set of completely green methods utilising air, light, water and spirulina to transform readily accessible furan substrates into a diverse range of synthetically useful polyoxygenated motifs commonly found in natural products is presented herein. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2gc16397g

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Green Chemistry
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COMMUNICATION
Using water, light, air and spirulina to access a wide variety of
polyoxygenated compounds†
Dimitris Noutsias, Ioanna Alexopoulou, Tamsyn Montagnon and Georgios Vassilikogiannakis*
Received 4th November 2011, Accepted 16th December 2011
DOI: 10.1039/c2gc16397g
The orchestrating reagent at the heart of this new set of
A new set of completely green methods utilising air, light,
water and spirulina to transform readily accessible furan
substrates into a diverse range of synthetically useful poly-
oxygenated motifs commonly found in natural products is
presented herein.
methods is singlet oxygen (1O2). Singlet oxygen has been shown
to be an excellent initiator for complexity-enhancing cascade
sequences,5 and, unlike so many of the oxidants currently
employed in synthetic chemistry that are either based on heavy
metal compounds or hypervalent iodine compounds, singlet
oxygen (1O2) is both non-toxic and completely atom economic.
All the methods presented herein, begin from simple furan
substrates that are easy to access. The oxidation of furans has
long been recognized as a productive and important transform-
ation in organic synthesis; for example, literature protocols for
the direct oxidation of furans to 1,4-enediones are known, but
frequently involve treatment with hazardous and/or dangerous
chemicals, including; Br2, NBS, peracids, dioxiranes, Crvi-based
oxidants.
The ideal green methodology encompasses a host of very differ-
ent concepts, and, as such, is a far from simple goal to achieve.
The practitioner is not just looking for non-polluting and non-
toxic reagents to be used in reactions devoid of the traditionally-
employed organic solvents, but must also consider ideas such as
atom-1 and step-economy,2 elimination of protecting group
usage3 (and other non-constructive refunctionalisation steps),4
and overall efficiency for the operation (e.g. the degree to which
structural complexity is increased). Indeed, in these latter themes
the goals of green chemistry coalesce with those of organic syn-
thesis as a whole where the application of ideal synthetic prin-
ciples is seen as the only way to overcome factors that have been
limiting further progress in the field.4 Many claim green creden-
tials for their new methods by honing one out of the many cri-
teria identified above, but few actually endow chemistry with
technologies that embrace the whole package. Herein is pre-
sented a powerful set of new methods, targeting a range of
complex polyoxygenated motifs (to be found in an array of
different bioactive natural products or other important synthetic
targets), that meet the green ideal completely. The methods use
oxygen from the air as the reagent, water as solvent, visible spec-
trum light as the energy source, spirulina (a commercial cyano-
bacteria product) as a source of photosensitizers, atom economy
is maximized (both oxygen atoms are added into the substrates)
and each of the methods involves a complex cascade of reactions
that induces a dramatic increase in molecular complexity in a
single operation. Furthermore, the individual oxidation reactions
employed are so specific (or can be tailored and controlled by
engaging with their kinetics) that protecting groups are rendered
essentially redundant; a feature that is extremely rare in any strat-
egy targeting such polyoxygenated structures which are tra-
ditionally rife with oxygen functionality protections and
deprotections and/or oxidation level adjustments.
In a specific example, 2-(α-hydroxyalkyl) furans can be
oxidised to afford the corresponding and synthetically highly
valuable, 6-hydroxy-3(2H)-pyranones (Scheme 1), under a
variety of conditions including; Br2/MeOH,6 peracids (e.g. m-
CPBA,7 magnesium monoperoxypthalate8), NBS,9 dioxiranes
(DMDO10), metal-based oxidations (PCC,11 VO(acac)2/t-
BuOOH12). The proliferation of methods available to undertake
this particular transformation attests to the synthetic versatility of
the 6-hydroxy-3(2H)-pyranone unit; and, yet, major problems
remain to anyone wishing to apply these protocols within a syn-
thetic context, mostly arising from the harshness/lack of selectiv-
ity associated with the existing methods. Within the set of new
methods highlighted herein, a solution is offered to this problem
in the form of a new mild green alternative for this (and other)
key transformations.
In recent years the primary focus of our research has been the
development of new methodologies based on singlet oxygen-
mediated furan oxidation13,14 cascades which lead to the for-
mation of a diverse array of important polyoxygenated motifs,
including; γ-spiroketal-γ-lactones,15 [6,6]-spiroketals,16 [5,5,5]-,17
[6,5,6]-17 and [6,6,5]-bis-spiroketals,16 4-hydroxy-cyclopen-
tenones,18 3-keto-tetrahydrofurans,19 [5,6]-spiroperoxylactones20
as well as 6,8-dioxabicyclo[3.2.1]oct-3-en-2-ones.21 Some of the
developed methodologies have been successfully applied to the
University of Crete, Department of Chemistry, Vasilika Vouton, 71003
Iraklion, Crete, Greece. E-mail: vasil@chemistry.uoc.gr; Fax: +30 2810
545001; Tel: +30 2810 545074
†Electronic supplementary information (ESI) available: Full experimen-
tal procedures, analytical data and copies of all relevant 1H and 13C
NMR spectra are presented. See DOI: 10.1039/c2gc16397g
Scheme 1 The synthetically useful Achmatowicz rearrangement.
Green Chem., 2012, 14, 601–604 | 601
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previously used rose bengal or methylene blue systems. A
human/animal nutritional supplement named Spirulina, which is
widely available in a powdered water-soluble form, was found to
work very well. Spirulina is made primarily from two easily cul-
tivated species of cyanobacteria - Arthrospira platensis and
Arthrospira maxima.22,23 With this last innovation, every single
aspect of the new protocols (detailed herein) should be more
than acceptable to any researcher undertaking a green audit of
this very synthetically useful chemistry.
Turning to the details of each of these new methods, the first
involves the oxidation of 2-(α-hydroxyalkyl) furans to 6-
hydroxy-3(2H)-pyranones, also known as Achmatowicz-type
rearrangement (Scheme 1), which is a widely-used key trans-
formation in synthetic chemistry, and, as such, provided the ideal
testing ground for the proposed new water-mediated green
photooxidations. In previous studies21 into the photooxygenation
of 2-(α-hydroxyalkyl) furans in MeOH with subsequent in situ
reduction of the intermediate hydroperoxides (type C,
Scheme 2), the formation of mixtures of 6-hydroxy-3(2H)-pyra-
nones and 5-hydroxy-2(5H)-furanones had been seen. Indeed,
the relative ratio of the final products had been shown to be
highly dependent on the 5-substitution of the starting furan sub-
strate.21 In search of improved product distribution, as well as, a
greener reaction protocol, 2-(α-hydroxyalkyl) furans 1a–1f
(Scheme 3) were dissolved in H2O and powdered spirulina was
added, at which point the solution took on a green colour (green
by appearance, as well as by credentials!). Singlet oxygen (1O2)
photooxygenation conditions (oxygen or air, bubbling through
the reaction mixture with irradiation from a visible spectrum
light source) were applied for 30–60 mins resulting in the direct
(no reducing agent is now required) formation of 6-hydroxy-3
(2H)-pyranones 2, accompanied in some cases, by the fragmen-
tation product 5-hydroxy-2(5H)-furanones 3 (Scheme 3). In
ALL cases, the 2 : 3 relative ratios were much improved relative
to those previously reported21 for reactions run in MeOH with a
reducing agent. Even the substrates previously found to deliver
exclusively the fragmentation product 3, namely 1b and 1c, now
afforded substantial amounts of the 6-hydroxy-3(2H)-pyranones
Scheme 2 The singlet oxygen mediated oxidation of furans to the cor-
responding 1,4-enedione; the traditional (path a) versus the proposed
(path b).
total synthesis of natural products. In all cases, intra- or inter-
molecular opening of the intermediate ozonide B (Scheme 2) by
either a hydroxyl of the 2-alkyl furan substituent (not shown), or
by MeOH, led to the formation of hydroperoxide C (Scheme 2,
path a). Reduction of C (with Me2S or Ph3P) followed by slow
elimination of MeOH from the intermediate hemiketal D resulted
in the formation of 1,4-enedione E, which is a highly flexible
intermediate capable of participating in a slew of different reac-
tion sequences15–21 depending on the nature of R1 and R2.
Despite the green nature of singlet oxygen itself, and, the
achievement of step- and atom-economies, the developed metho-
dologies were still off-target in terms of the green ideal,
because: a) the oxidations were all performed in organic sol-
vents; b) organic photosensitizers were used; and, c) additional
reducing agents were required. All of these hindrances have now
been addressed.
The first major discrepancy from the green ideal in these
methodologies is the reaction solvent. It was felt that because all
the substrates contained one or more hydroxyl functionalities
they should be water-soluble enough for unhindered reaction.
Furthermore, it was hoped that with this change to a green
solvent, the need for an “ungreen” reducing agent (C → D,
Scheme 2) to be included in the reaction protocol would be con-
comitantly eliminated because a subtle alteration in reaction
mechanism would be engendered. The mechanistic deviation
was expected to occur because water would now open the
fleeting ozonide B, yielding intermediate hydroperoxide F
(Scheme 2, path b), which might then eliminate a molecule of
H2O2 without recourse to the use of any reducing agents; thus,
affording the requisite 1,4-enedione E, directly. In order to
achieve a clean sweep, it was also considered necessary to look
for a water-soluble, natural, photosensitizer to replace the
Scheme 3 Results obtained for the photooxidation of furans 1a–1f
under the newly developed green conditions.
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Scheme 4 Fragmentation of ozonide intermediate G to yield 5-
hydroxy-2(5H)-furanones.
2 under the newly developed reaction conditions (Scheme 3). In
all cases where the substrate bears a substituent at the 5-position
of the furan (1d, 1e and 1f), the reaction affords exclusively the
corresponding 6-hydroxy-3(2H)-pyranones.
The improved 2 : 3 relative ratio may be attributed to a more
effective hydrogen bonding environment for the –OH group in
the intermediate ozonide, which is now surrounded by molecules
of water instead of methanol, (G, Scheme 4); thus, making the
unpaired electrons on the oxygen less available for initiation of
the unwanted fragmentation pathway. The reduced steric demand
of water, in comparison to methanol, may also enhance the rate
of the productive pathway b (B → F, Scheme 2).
With the goal of extending these principles to a diverse array
of other targets of synthesis, so that a whole new set of improved
green methodologies could be delineated, a variety of furanols
(4,24 625 and 13, Scheme 5) and furan-diols (7, 9 and 11,
Scheme 4) were photooxidized. All these substrates showed
good solubility in water. Photooxygenations of substrates (4, 7,
9, 11, and 13) in organic solvents required the addition of an
ungreen reducing agent (Me2S or Ph3P) for the reduction of the
intermediate hydroperoxides of type C (Scheme 2) and the sub-
sequent formation of the polyoxygenated skeletons 5, 8, 10, 12
and 14 (it should be noted that these products are very important
because they are all key motifs from bioactive natural products
frequently targeted in synthetic organic chemistry). In the new
highly efficient water-mediated photooxidations using spirulina
as the photosensitiser, addition of an ungreen reducing agent is
NOT required. Specifically, water-mediated photooxidation 2-
(δ-hydroxyalkyl) furan 4 followed by treatment of the intermedi-
ate spiro-hydroperoxide (not shown) with either silica gel, or p-
TsOH, or Ac2O/Py, resulted in its clean conversion to δ-spiro-
ketal γ-lactone 5. The final product, a [6,5]-spiroketal, is reminis-
cent of the AB-spiroketal motif from pectenotoxins 1–7 (PTXs
1–7).26 Furthermore, photooxygenation in water of the furfural
derivative 6 afforded, directly, the same δ-spiroketal γ-lactone 5,
via decarboxylation of a 4-membered dioxetane intermediate,25
without the use of any additives. Moving on to the synthesis of
yet another important motif present in many biologically active
natural products, such as, the terrestrially derived ionophore anti-
biotics salinomycin27 and narasin,28 as well as, the marine
derived cytotoxic compounds PTX2c, PTX8–10, and PTX11c;26
photooxidation of the readily accessible 2-(α-hydroxyalkyl)-5-
(δ-hydroxyalkyl) furan 7, followed by treatment with a catalytic
amount of p-TsOH, afforded the [6,6]-spiroketal 8 (5 : 1 mixture
of anomers) accompanied by only small amounts of the fragmen-
tation product 5. Even more impressively, the one-pot formation
Scheme 5 Examples proving that a diverse array of target motifs may
be made using these new green methods.
[6,5,6]-bis-spiroketal 10 (1 : 1 mixture of anomers, Scheme 5)
was observed upon exposure of the very simple and readily
accessible 2-(δ-hydroxyalkyl)-5-(δ-hydroxyalkyl) furan 9 to
singlet oxygen in aqueous media. Several different classes of fre-
quently targeted marine toxins including, the pinnatoxins,29 pter-
iatoxins,30 and the azaspiracids,31 contain such
a motif.
Spiroketals are very common within a range of different syn-
thetic targets; however, they are most frequently made using one
method, namely, stepwise acid-mediated spiroketalizations; a
strategy that innately carries a need for protecting groups and the
shuttling back and forth between oxidation levels of the various
oxygen functionalities. In other words, the method reported
herein, not only uses green reaction conditions, but offers very
significant improvements in overall efficiency and step- and
atom-economies.
In the next example (Scheme 5), a dramatic increase in mol-
ecular complexity is once again achieved in a simple to execute
green operation. Thus, photooxygenation of 2-(α, β-dihydroxy-
alkyl) furan 11 in water, followed by in situ ketalization of the
intermediate 6-hydroxy-3(2H)-pyranone of type 2 (not shown)
using acid catalysis, cleanly provides the 6,8-dioxabicyclo[3.2.1]
oct-3-en-2-one framework 12. This particular motif can be found
in several different classes of natural products including the
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pinnatoxins,29 pteriatoxins,30 didemniserinolipids,32 as well as,
in 2-hydroxy-exo-brevicomin.33 Finally, water mediated photo-
oxygenation of 2-(β-hydroxyalkyl) furan 13, followed by in situ
treatment with trace acid, affords, in one synthetic operation, 3-
keto-tetrahydrofuran motif 14. This reaction proceeds via an
intramolecular oxa-Michael addition to the intermediate 1,4- ene-
dione (type E, Scheme 2). Similar 3-ketotetrahydrofuran motifs
can be found in a variety of natural products, including; phyl-
lanthocin,34 and pectenotoxins.26
With regard to the photosensitizer, similar results (product dis-
tribution and isolated yields) were observed when either macer-
ated leaves of spinach (a source of chlorophyll), or rose bengal
were used as the photosensitizer instead of spirulina. It was true
that in the case of chopped spinach leaves as the source of the
photosensitizer, the irradiation times were 2–3 times longer than
those needed when using spirulina. When rose bengal was used
as the photosensitizer the irradiation time was reduced to one
fourth of that required by the spirulina system.
5 I. Margaros, T. Montagnon, M. Tofi, E. Pavlakos and
G. Vassilikogiannakis, Tetrahedron, 2006, 62, 5308; T. Montagnon,
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T. Montagnon, D. Noutsias, I. Alexopoulou, M. Tofi and
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15 E. Pavlakos, T. Georgiou, M. Tofi, T. Montagnon and
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In summary, a diverse array of polyoxygenated motifs, found
in many different bioactive natural products, has been syn-
thesized with ease. Each of the new methods employed begins
from simple and readily accessible furan precursors and uses
completely green protocols. The protocols; employ green, non-
toxic reagents and conditions (water, light, air and spirulina); are
highly step-economic (simple precursor → complex motif in one
operation) in a field (namely, the construction of polyoxygenated
molecules) that has traditionally employed many non-construc-
tive steps (protections/deprotections and redox shuttling); and
are highly efficient from the perspective of atom economy.
22 A. Vonshak, Spirulina Platensis (Arthrospira): Physiology, Cell-biology
and Biotechnology, Taylor & Francis, London, 1997.
23 O. Ciferri, Microbiol. Rev., 1983, 47, 551.
General procedure for photooxidations. A solution of fura-
nols 1a–f, 4, 6, 13, or furan-diols 7, 9 and 11, (0.5 mmol) in
water (10 mL), containing spirulina (20 mg) as the photosensiti-
zer, was placed in a test tube and cooled with an ice bath (5 °C).
Oxygen was bubbled through the solution immediately before
and during its irradiation by a xenon Variac Eimac Cermax 300
W visible spectrum lamp. More spirulina (20 mg) was added for
every 15 min of irradiation. Complete consumption of the start-
ing material was observed by TLC after 20–110 mins of
irradiation. In the case of 1a–f, 6 and 9 the reaction mixture was
extracted with EtOAc (3×), the combined organics were dried
(Na2SO4), concentrated in vacuo and purified (when necessary)
by flash column chromatography to afford pure 2a–f, 5 and 10,
respectively. In the case of furans 4, 7, 11 and 13 the EtOAc
extracts were treated with catalytic amounts of p-TsOH (see
ESI†).
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The research leading to these results has received funding
from the European Research Council under the European
Union’s Seventh Framework Programme (FP7/2007-2013)/ERC
grant agreement no. 277588.
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