A new expedient synthesis of 3-methyl-2(5 H)-furanone, the common substructure in strigolactones, and its proposed biosynthesis

Article abstract of DOI:10.1055/s-0030-1257911

3-Methyl-2(5H)-furanone is the common structural unit in natural and several synthetic strigolactones, which are germination stimulants for seeds of the parasitic weeds Striga and Orobanche spp. A simple, one-step, ring-closing metathesis of allyl methacrylate using an appropriate Grubbs catalyst gives this furanone in good yield. Acid-catalyzed condensation of glyoxal and methylmalonic acid gives 5-hydroxy-3-methyl-2(5H)-furanone, which is another synthon for the introduction of the furanone unit into strigolactones. In addition, a biosynthetic pathway is presented for the incorporation of the furanone unit into strigolactones, which is relevant in view of the current interest in the newly discovered biological functions of strigolactones. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1257911

SHORT PAPER
3271
A New Expedient Synthesis of 3-Methyl-2(5H)-furanone, the Common
Substructure in Strigolactones, and Its Proposed Biosynthesis
E
xpedient Synthe
s
e
is of 3-Met
e
hyl-2(5
H
)-f
t
uranon
i
e
ka Malik, Floris P. J. T. Rutjes,* Binne Zwanenburg*
Institute for Molecules and Materials, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
Fax +31(24)3653393; E-mail: b.zwanenburg@science.ru.nl
Received 27 March 2010; revised 15 June 2010
tones and their synthetic analogues is 3-methyl-2(5H)-
furanone (1). The preparation of this butenolide is not as
easy as it seems. An early synthesis involved bromination
and dehydrobromination of commercially available but
Abstract: 3-Methyl-2(5H)-furanone is the common structural unit
in natural and several synthetic strigolactones, which are germina-
tion stimulants for seeds of the parasitic weeds Striga and
Orobanche spp. A simple, one-step, ring-closing metathesis of allyl
methacrylate using an appropriate Grubbs catalyst gives this fur- expensive 3-methyl-2,3-dihydro-2(3H)-furanone, in 53%
yield.5 A four-step sequence starting from ethyl a-bro-
anone in good yield. Acid-catalyzed condensation of glyoxal and
methylmalonic acid gives 5-hydroxy-3-methyl-2(5H)-furanone,
which is another synthon for the introduction of the furanone unit
yield.6 Citraconic anhydride (2) seemingly is a suitable
into strigolactones. In addition, a biosynthetic pathway is presented
for the incorporation of the furanone unit into strigolactones, which
mopropionate resulted in furanone 1 in 75% overall
starting material and reductive removal of the carbonyl
group would give the desired compound 1. Unfortunately,
metal hydride reducing agents invariably lead to the 4-
methyl-substituted butenolide.7 This problem has been
overcome by first converting citraconic anhydride into the
Diels–Alder adduct of cyclopentadiene, then carrying out
the reduction of the desired carbonyl group, followed by
cycloreversion using flash-vacuum thermolysis.8 Alterna-
tively, the anhydride was first opened with dicyclohexyl-
amine in a regiospecific manner, converted into the mixed
anhydride and subsequently reduced to 1 in 80% yield.9
is relevant in view of the current interest in the newly discovered
biological functions of strigolactones.
Key words: ring-closing metathesis, Grubbs catalyst, allyl meth-
acrylate, strigolactones, aldol condensation, biosynthesis
Strigolactones constitute a family of compounds which
induce the germination of seeds of the parasitic weeds
Striga and Orobanche spp. These weeds pose a great
threat to food crops in third world countries and around
the Mediterranean Sea.1 Several germination stimulants
have been isolated from root exudates of host plants
(Figure 1).2
O
O
O
CO2Me
N
O
O
O
O
O
O
O
O
O
O
O
C
OX
A
B
nijmegen-1
GR24
sorgolactone
O
O
O
D
O
O
O
O
O
O
O
OH
(+)-strigol
1
2
OX
Y
X
Figure 2 Synthetic strigolactones and D-ring precursors
Y = OH: orobanchol
Y = H: deoxystrigol
In this paper we describe an expedient one-step synthesis
of furanone 1. Readily available allyl methacrylate (3) un-
derwent a smooth ring-closing metathesis (RCM) in 91%
yield using a recently developed Grubbs catalyst.10 The
choice of the catalyst, however, appeared to be crucial. It
should be emphasized that the RCM could be accom-
plished smoothly in high yield only with catalyst Grubbs–
Hoveyda-IIB (Scheme 1). In contrast, with catalyst
Grubbs–Hoveyda-IIA, RCM to furanone 1 took place
only to a minor extent. Interestingly, with catalysts
Grubbs-IIA and -IIB, the reaction did not result in any
product formation. One of the known limitations of RCM
is the restricted tolerance of steric congestion on or around
the reactive olefin moiety. Catalysts Grubbs-IIA and -IIB
Figure 1 Naturally occurring strigolactones
In all of the strigolactones isolated from root exudates, the
D-ring is the butenolide X (Figure 1). A series of synthetic
analogues have been reported, e.g. nijmegen-1 and GR24
(Figure 2), all of them containing the same D-ring.3 It has
been demonstrated that this particular D-ring is essential
for the germination activity.3,4 The commonly used syn-
thon for the D-ring in the synthesis of natural strigolac-
SYNTHESIS 2010, No. 19, pp 3271–3273
x
x.
x
x
.
2
0
1
0
Advanced online publication: 30.07.2010
DOI: 10.1055/s-0030-1257911; Art ID: T07610SS
© Georg Thieme Verlag Stuttgart · New York

3272
H. Malik et al.
SHORT PAPER
are especially sensitive to steric hinderance, although ex- ly present in nature and their coupling could proceed as
ceptions are known. A notable example is a RCM of an shown in Scheme 3. Formylation of the ABC skeleton
acrylate with catalyst Grubbs-I employing high catalyst produces the aldehyde 7, which is in equilibrium with its
concentration.11 Catalyst Grubbs–Hoveyda-IIB gives the enol form. Addition of the hydroxy substituent of 4 to 7
best performance with sterically hindered olefins.10 This provides the hemiacetal 8, which upon loss of water pro-
new RCM method for the preparation of furanone 1 is duces the D-ring-coupled product, i.e. the strigolactone 9.
very attractive as it combines the use of an inexpensive Alternatively, one can envisage the initial formation of an
starting material with a high yielding, single-step opera- oxonium ion from 4 which then reacts with the enol of 7
tion.
to give 9. The stereochemistry at the 2¢-position of the D-
ring may be enzymatically controlled, however, natural
strigolactones with a 2¢-epimeric structure have been iso-
lated.2b
Grubbs catalyst
O
O
toluene, 70 °C
18 h
O
O
OH
O
O
3
1 (91%)
O
HO
O
O
O
H
O
O
H
N
N
R
R
enzymatic
aldol reaction
N
N
R
H
HO
Cl
R
O
OH
OH
Cl
Ru
O
OH
Ru
Cl
5
6
4
Cl
Ph
PCy3
O
C
i-Pr
O
R = Mes: Grubbs–Hoveyda-IIA
R = o-Tol: Grubbs–Hoveyda-IIB
R = Mes: Grubbs-IIA
R = o-Tol: Grubbs-IIB
O
O
C
O
O
H
C
O
Scheme 1 One-step synthesis of 3-methyl-2(5H)-furanone (1)
7
– H2O
O
OH
coupling
to ABC
O
D
O
D
O
O
O
An alternative synthon for the introduction of the D-ring
is 5-hydroxy-3-methyl-2(5H)-furanone (4). This com-
pound has previously been prepared in a multistep process
from crotonal using p-toluenesulfinic acid as a synthetic
auxiliary7 and by photooxygenation of 3-methylfuroic ac-
id.12 We found that the hydroxy-substituted butenolide 4
can simply be obtained by an acid-catalyzed aldol-type
condensation of glyoxal with methylmalonic acid, albeit
in moderate yield (Scheme 2). In a water–toluene mixture
as the reaction medium and in the presence of acetic acid,
the yield ranged between 5–20% depending on the quality
of the glyoxal solution. By replacing toluene with tetrahy-
drofuran, the yield was improved to 30%.
9
8
Scheme 3 Proposed biosynthesis of the D-ring fragment
In summary, an expedient one-step synthesis of 3-methyl-
2(5H)-furanone is described. This furanone is the sub-
structure in natural and synthetic strigolactones, which are
germination stimulants for seeds of the parasitic weeds
Striga and Orobanche spp. Recently, it was discovered
that natural strigolactones have two additional important
biological functions.14 They are the principal branching
factor of Arbuscular mycorrhizal fungi and, most interest-
ingly, are a new type of plant hormone that serves as a
plant growth regulator. In view of these newly discovered
functions of natural strigolactones and the synthetic ana-
logue GR24, there is an increasing demand for these com-
pounds. The furanone 1 is indispensable in their synthesis.
We have also presented a simple preparation of the corre-
sponding 5-hydroxyfuranone. In connection herewith, we
have provided insight into the biosynthetic incorporation
of the furanone into strigolactones.
OH
O
THF–H2O
AcOH (cat.)
H
+
O
H
HO2C
CO2H
O
O
4 (30%)
Scheme 2 Synthesis of 5-hydroxy-3-methyl-2(5H)-furanone (4)
This aldol-type synthesis of butenolide 4 sheds some light
on the biosynthesis of the D-ring and its coupling to the
ABC skeleton in strigolactones. In a recent paper, a plau-
sible biosynthesis of the ABC skeleton of natural strigo-
lactones was described, but without any comment on the
incorporation of the D-ring.3,13
All glass apparatus was oven dried prior to use. H and 13C NMR
1
spectra were recorded on a Bruker DRX-300 spectrometer (operat-
ing at 300 MHz for 1H and at 75 MHz for 13C) using CDCl3 as sol-
1
vent. TMS (0.00 ppm) served as an internal standard in H NMR
and CDCl3 (77.0 ppm) in 13C NMR spectra. Reactions were moni-
tored on silica gel TLC plates (Merck). Detection was performed
with UV light and/or by charring at ~150 °C after dipping into a
soln of either 2% anisaldehyde in EtOH–H2SO4 or
(NH4)6Mo7O24·4H2O (25 g/L) or KMnO4. Column chromatography
was performed over silica gel (0.035–0.070 mm) using freshly dis-
The biosynthesis of the D-ring conceivably could proceed
similar to the reaction shown in Scheme 2, starting with
an enzymatic aldol-type condensation of glyoxal with
propionic acid, of which methylmalonic acid is a synthetic
equivalent. Glyoxal and propionic acid both are abundant-
Synthesis 2010, No. 19, 3271–3273 © Thieme Stuttgart · New York

SHORT PAPER
Expedient Synthesis of 3-Methyl-2(5H)-furanone
3273
tilled solvents. Air- and moisture-sensitive reactions were carried
out under an inert atmosphere of dry argon.
References
(1) Parker, C. Pest Manag. Sci. 2009, 65, 453; and references
cited therein.
3-Methyl-2(5H)-furanone (1) via Ring-Closing Metathesis
Catalyst Grubbs–Hoveyda-IIB (45 mg, 5 mol%) was added to a soln
of allyl methacrylate (200 mg, 1.58 mmol) in toluene (5 mL) and the
reaction mixture was heated at 70 °C for 18 h. After completion of
the reaction, the resultant mixture was chromatographed on a silica
gel column (EtOAc–n-pentane, 1:3). Due to the volatile nature of
the product, toluene was not removed from the reaction mixture pri-
or to the chromatography.
(2) (a) Cook, C. E.; Whichard, L. P.; Wall, M. E.; Egley, G. H.;
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(3) Zwanenburg, B.; Mwakaboko, A. S.; Reizelman, A.;
Anilkumar, G.; Sethumadhavan, D. Pest Manag. Sci. 2009,
65, 478.
Yield: 140 mg (91%).
1H NMR (300 MHz, CDCl3): d = 1.90 (s, 3 H), 4.73 (br s, 2 H), 7.12
(br s, 1 H).
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The rest of the spectroscopic properties were as reported previous-
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5-Hydroxy-3-methyl-2(5H)-furanone (4)
A 40 wt % soln of aqueous glyoxal (1.85 g, 12.7 mmol), methylma-
lonic acid (1.00 g, ca. 8.5 mmol) and glacial AcOH (0.1 mL) in H2O
(5 mL) and THF (20 mL) was heated under reflux with stirring at
120 °C for 26 h. The progress of the reaction was monitored by TLC
1
and H NMR spectroscopy. After cooling, a small amount of the
product was present in the THF layer. By excessive extraction of the
aqueous layer with EtOAc an additional amount of product 4 was
obtained, mixed with methylmalonic acid. After removal of sol-
vents, the residue was triturated with CH2Cl2, then filtered, thereby
leaving methylmalonic acid behind. Product 4 was then obtained as
a white solid upon concentration; yield: 290 mg (30%). The spec-
troscopic properties were as reported previously.7
Acknowledgment
Financial support provided by Radboud University Nijmegen and
Wageningen University is fully acknowledged.
Synthesis 2010, No. 19, 3271–3273 © Thieme Stuttgart · New York