Synthesis of the germination stimulant 3-methyl-2H-furo[2,3-c]pyran-2-one and analogous compounds from carbohydrates

Article abstract of DOI:10.1002/ejoc.200700334

An efficacious synthetic route to the recently identified, potent germination stimulant 3-methyl-2H-furo[2,3-c]pyran-2-one and analogous compounds, using carbohydrate substrates, is described. D-Xylose and D-glucuronic acid γ-lactone were used in the preparation of the parent heterocycle and its 5-methoxycarbonyl analogue, respectively. These compounds were elaborated using various methods to furnish the natural product and a suite of its analogues. The germination stimulant was thus prepared on a multi-gram scale in nine steps from inexpensive, commercially available 1,2-O-isopropylidene-D-xylofuranose in an overall yield of 30 %, vastly improving upon the only method published to date. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700334

FULL PAPER
DOI: 10.1002/ejoc.200700334
Synthesis of the Germination Stimulant 3-Methyl-2H-furo[2,3-c]pyran-2-one
and Analogous Compounds from Carbohydrates
Ethan D. Goddard-Borger,*[a] Emilio L. Ghisalberti,[a] and Robert V. Stick[a]
Keywords: Carbohydrates / Total synthesis / Germination stimulant / Heterocylces
An efficacious synthetic route to the recently identified, po-
tent germination stimulant 3-methyl-2H-furo[2,3-c]pyran-2-
one and analogous compounds, using carbohydrate sub-
germination stimulant was thus prepared on a multi-gram
scale in nine steps from inexpensive, commercially available
1,2-O-isopropylidene-D-xylofuranose in an overall yield of
strates, is described.
D
-Xylose and
D
-glucuronic acid γ-lac-
30%, vastly improving upon the only method published to
date.
tone were used in the preparation of the parent heterocycle
and its 5-methoxycarbonyl analogue, respectively. These
compounds were elaborated using various methods to fur-
nish the natural product and a suite of its analogues. The
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
thesis converts a rather expensive substrate, pyromeconic
acid (2), into the stimulant 1 in three steps but in a poor
overall yield of around 10% (Scheme 1). Further, this
method returns still lower yields on larger scales with the
isolation of 1 from the complex reaction mixture proving to
be laborious, impractical and inefficient.
Introduction
Many plant species native to areas frequented by wild-
fire have evolved traits allowing them to synchronise many
key biological events, such as regrowth, reproduction and
germination, with an incidence of fire.[1] Such adaptations
allow these species to capitalise upon the opportunities of-
fered by their post-fire environment. Perhaps the most re-
markable of these adaptations is the tendency of some spe-
cies to germinate readily only after an outbreak of fire.[2,3]
The cue for this post-fire emergence was found to be smoke
derived from plant material, the stimulation chemical in ori-
gin.[4,5]
Scheme 1.
Over the years many attempts at elucidating the nature
of the compound(s) in smoke responsible for promoting
germination proved to be fruitless, in no small part due to
the complexity of the mixture of chemicals that is smoke.[6]
Recently, Flematti et al. isolated and characterised 3-
methyl-2H-furo[2,3-c]pyran-2-one (1) from “cellulose-de-
rived” smoke and demonstrated its ability to promote the
germination of both “smoke responsive” and “non-smoke
responsive” plant species from Africa, Australia and North
America.[7] This remarkable germination stimulant exhib-
ited incredible potency, with effective germination pro-
motion observed at concentrations of less than one part-
per-billion. The authors went on to postulate upon the pos-
sible benefits 1 could offer the agricultural, horticultural
and even mining (environmental rehabilitation) industries.[7]
Despite these predictions of industrial application, only
one synthesis of 1 has been published to date.[8] This syn-
Given the intriguing nature of the novel ring system of
compound 1, its potent biological activity and potential in-
dustrial applications, we embarked upon developing an im-
proved synthesis of 1 with the added intention of concur-
rently preparing a number of analogues. With this in mind,
our retrosynthetic analysis focussed on the formation of the
2H-furo[2,3-c]pyran-2-one ring system 3, with the later
functionalisation of this molecule offering a convergent syn-
thesis of 1 (Scheme 2) and analogues. Presumably, 3 could
be prepared from a molecule of general structure 4 by way
of lactonisation and eliminations across both C4–C5 and
C7–C7a. A molecule of structure 4 could, in turn, be ob-
tained through the olefination of a ketone resembling ge-
neric compound 5. Such a ketone is quite clearly the prod-
uct of a carbohydrate, more specifically a pentose. Further
thought reveals that the utilisation of a hexose in such a
synthesis would extend the carbon skeleton of 3 at C5, thus
providing further scope for synthetic exploration. Given
that the germination stimulant’s origin within Nature ap-
pears to lie in carbohydrates (cellulose)[7] and in keeping
[a] Chemistry M313, School of Biomedical, Biomolecular
Chemical Sciences, The University of Western Australia,
Crawley WA 6009, Australia
&
Fax: +61-8-6488-1005
E-mail: goddae01@student.uwa.edu.au
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E. D. Goddard-Borger, E. L. Ghisalberti, R. V. Stick
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with mankind’s inclination to mimic Nature, it seemed fit- the undesired (E) isomer 10. Treatment of 9 with aqueous
ting that our retrosynthetic analysis of 1 had ultimately led trifluoroacetic acid, in a rapid reaction, resulted in hydroly-
us to a carbohydrate starting material (albeit one unrelated sis of the trityl ether and acetonide, lactonisation and re-
to cellulose). Herein, we report the outcomes of our investi- arrangement of the resulting hemiacetal (though not neces-
gations into the use of carbohydrates in the preparation of sarily in that order) to give the butenolide 11 in excellent
the potent germination stimulant 1 and analogous com- yield.
pounds.
Hypothetically, compound 3 could be obtained from 11
by way of two eliminations, formally dehydrations, one ac-
ross C4–C5 and the other across C7–C7a (formerly C1–C2
of -xylose). Many attempts at the dehydration of 11 di-
rectly to 3 were unsuccessful, typically resulting in dark in-
tractable mixtures of products. Treatment of 11 with acetic
anhydride in pyridine gave exclusively the α-diacetate 12,
which when treated with triethylamine underwent elimi-
nation across C7–C7a to give 13 (Scheme 4). It occurred to
us that perhaps 13 could be obtained directly from 11 by
performing an acetylation in the presence of a base stronger
than pyridine. Curiously, the use of triethylamine in such
an acetylation resulted in the exclusive formation of the fu-
ran 14. If nothing else, this result suggested that perhaps
the elimination across C7–C7a occurs by way of a stabilised
furyl oxide intermediate.
Scheme 2. Retrosynthetic analysis of 1.
Results and Discussion
Utilisation of a Pentose in the Preparation of 3
The aforementioned retrosynthetic analysis revealed that
a pentose was required for the proposed synthesis, with the
obvious choice being abundant and inexpensive -xylose.
Protection of -xylose was required to enable oxidation and
subsequent olefination of C3 (Scheme 2). This requirement
was satisfied in an efficacious manner by the regioselective
tritylation of 1,2-O-isopropylidene--xylofuranose (6) (an
inexpensive, commercially available substrate easily ob-
tained from -xylose), which gave the alcohol
7
(Scheme 3).[9] Oxidation of 7, according to a literature pro-
cedure, returned the ketone 8.[9] Several attempts at Wittig
olefination of 8 went unrewarded; however, adoption of the
Horner–Wadsworth–Emmons methodology returned the
Scheme 4. (a) Ac2O, C5H5N, 95%; (b) EtOCOCl, C5H5N, 93%; (c)
Et3N, CH2Cl2, 94% or 95%; (d) Ac2O, Et3N, C5H5N, 91%; (e)
desired (Z)-olefin 9 in high yield and in 19-fold excess of (Ph3P)4Pd, THF, 84%.
Scheme 3. (a) (i) Me2CO, H2SO4, (ii) AcOH, H2O; (b) TrCl, Et3N, CH2Cl2; (c) Ac2O, Me2SO; (d) NaH, (EtO)2POCH2CO2Et, THF (10/
9, 1:19), 5% and 74% from 7, respectively; (e) CF3CO2H, H2O, 83 %.
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Efforts at conducting the remaining elimination across synthesis, we decided to use a hexuronic acid ester substrate,
C4–C5 of 13, through the use of various bases and acids, enhancing the acidity of H5 and possibly allowing for the
went unrewarded. In contrast to the previous case, elec- elimination to be performed without the assistance of a pal-
tronic and stereochemical factors disfavour this elimination. ladium(0) catalyst. A convenient substrate for this purpose
With both product and substrate possessing acid-sensitive was inexpensive and commercially available -glucuronic
(enol-ether) and base-sensitive (lactone) moieties an alter- acid γ-lactone (17), as both the acid moiety and O3 are
native approach to this elimination was required. Our solu- already masked as the lactone (Scheme 5). The acetonide
tion was drawn from the work of Tsuji and Trost,[10,11] who 18 was prepared from 17 in accordance with the procedure
independently demonstrated that the treatment of allylic of Fleet and co-workers.[14] A modified procedure for the
acetates, carbonates or halides with palladium(0) catalysts, benzoylation and methanolysis of the lactone 18 gave the
in the absence of suitable nucleophiles and where possible, alcohol 19.[15] Oxidation of 19 with pyridinium dichromate
resulted in the formation of 1,3-dienes. The mechanism of (PDC) presumably gave the ketone, which underwent Wittig
this reaction has been investigated.[12] This mild method of olefination to give the desired (Z) isomer 20 almost exclu-
elimination appeared ideal as it may be conducted under sively. Deprotection of the benzoate 20 by the action of al-
neutral conditions and the substrate 13, fortuitously, hap- kali resulted in a complex mixture of products. A catalytic,
pened to be an allylic acetate. Indeed, treatment of 13 with nucleophilic transesterification using sodium cyanide in
tetrakis(triphenylphosphane)palladium(0) in refluxing methanol proved to be more successful in unmasking O5;[16]
tetrahydrofuran (THF) returned the desired compound 3. however, a mixture of two products was obtained owing to
Our elation was somewhat tempered by the reaction’s neces- the slow concomitant transesterification of the ethyl ester.
sarily high catalyst loading (20 mol-%), long reaction time This mixture was treated with aqueous trifluoroacetic acid,
(2 d) and moderate yield (61%). In general, allylic carbon- incurring a transformation analogous to that observed be-
ates have proven to be better substrates than allylic acetates fore, to return the butenolides 22 in good yield.
in these Tsuji–Trost eliminations.[13] With this in mind, we
Acetylation of 22 under the usual conditions gave a mix-
prepared the dicarbonate 15, which underwent elimination ture of three compounds that, by NMR spectroscopy, ap-
to give 16 in a fashion analogous to the conversion of 12 peared to be the α- and β-anomers of the diacetate in ad-
into 13. This effort was greatly rewarded when the carbon- dition to the product of C7–C7a elimination. This mixture
ate 16 was treated with the same palladium(0) catalyst as of compounds was treated with 1,8-diazabicyclo[5.4.0]un-
before in refluxing THF; smooth conversion into 3 was ob- dec-7-ene (DBU) in dichloromethane to furnish the furopy-
served in high yield (84%), reasonable time (8 h) and with ranone 23 in excellent yield over the two steps. Several
standard catalyst loadings (4 mol-%). This method has been attempts at the direct conversion of 22 into 23 by per-
employed in the preparation of 3 on a multigram scale with- forming the acetylation in the presence of strong base were
out incident.
unsuccessful, most likely owing to the formation of acyloxy-
furans as was observed in the previous synthesis
(Scheme 4).
The Utilisation of a Hexose in the Synthetic Strategy
With a good synthetic route to 3 from a pentose estab-
lished, we elected to extend this strategy further and investi-
gate the utilisation of a hexose in the synthesis of an ana-
Electrophilic Substitution of 3 and 23 (at C3)
With the construction of the parent heterocycle 3 and a
logue substituted at C5. With the elimination across C4–C5 C5 analogue 23 accomplished, elaboration at C3 was now
proving the more challenging step in the aforementioned required to prepare the natural product 1 and a suite of its
Scheme 5. (a) Me2CO, H2SO4; (b) BzCl, C5H5N; (c) Et3N, MeOH, 79% from 18; (d) PDC, Ac2O, CH2Cl2; (e) Ph3PCHCO2Et, CH2Cl2
(21/20, 1:99), 0.8% and 88% from 19, respectively; (f) NaCN, MeOH; (g) CF3CO2H, H2O, 81% from 20; (h) Ac2O, C5H5N; (i) DBU,
CH2Cl2, 68% from 22.
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E. D. Goddard-Borger, E. L. Ghisalberti, R. V. Stick
FULL PAPER
analogues. It was suspected that H3 of the 2H-furo[2,3-c]-
The regiospecificity of these substitutions can be ration-
pyran-2-one ring system may be susceptible to electrophilic alised by complementary kinetic and thermodynamic argu-
substitution. Formylation at C3 was investigated first as the ments. By inspection, C3 appears to be the more electron-
main target 1 requires the extension of compound 3 by a rich and therefore the most nucleophilic carbon atom in
single carbon atom at this position. Treatment of 3 with compounds 3 and 23. One would anticipate this to result in
the Vilsmeier reagent, followed by base hydrolysis, gave the favourable kinetics for the formation of the C3-electrophile
aldehyde 24 exclusively and in excellent yield (Scheme 6, adduct. Additionally, attack of an electrophile at C3 gives
Table 1). A similar treatment of 23 was equally rewarding, a stable (aromatic) pyrylium ion intermediate, making sub-
furnishing the aldehyde 25, though, in contrast to the pre- stitution at this position energetically favoured (Scheme 7).
vious formylation, this reaction required more time at a
higher temperature to reach completion. This is most prob-
ably a result of the diminished nucleophilicity of C3 given
the conjugation of the relevant double bond (C3–C3a) with
the electron-withdrawing methyl ester.
Scheme 7. Rationalisation for the regiospecific electrophilic substi-
tution of 3 (at C3).
Reductions in the Preparation of 1 and Analogues Thereof
To complete the synthesis of 1 we sought a sufficiently
mild method for the reductive deoxygenation of the alde-
hyde 24. Investigations of numerous methods showed that
the tert-butylamine–borane/aluminium(III) chloride rea-
gent system of Lau and co-workers was the superior option
in this instance;[18] compound 1 was obtained in high yield
from 24 (Scheme 8, Table 2). This completed our synthesis
of the natural product 1, obtained from -xylose in ten
steps and an overall yield of 19%, or 30% in nine steps
from 1,2-O-isopropylidene--xylofuranose (6).
Scheme 6.
Table 1. Electrophilic substitution of compounds 3 and 23 at C3.
Substrate
Product
Conditions[a]
Yield%
3
23
3
24
25
27
28
29
30
1
1
2
2
2
3
92
90
91
89
85
48
Scheme 8.
3
3
3
Table 2. Reductions utilising tBuNH2·BH3 and AlCl3.[a]
Substrate
Product
Yield%
[a] (1) (i) POCl3, DMF, (ii) satd. aq. NaHCO3; (2) AlCl3, CH2Cl2,
RCOCl; (3) NaNO3, CF3CO2H.
24
27
28
25
23
23
1
31
83
79
77
42
74
46
32
Attempts at performing a Vilsmeier acetylation (phos-
phoryl chloride, dimethylacetamide) were unsuccessful,
with 3 offering no reaction and 23 presumably reacting with
liberated dimethylamine to give the amide 26. Friedel–
Crafts acylation proved to be more fruitful; the action of a
number of acyl chlorides and aluminium(III) chloride on 3
produced the ketones 27–29, all in excellent yield. These
acylations also proved to be regiospecific (for C3).
33
34
35[b]
[a] tBuNH2·BH3 (6 mol-equiv.), AlCl3 (3 mol-equiv.), CH2Cl2 (re-
flux, 30 min). [b] Extended reaction time of 48 h.
The same borane reagent system was used in the prepa-
ration of further analogues; it proved effective in the re-
Whilst several nitration protocols were employed on the duction of the ketones 27 and 28 to 31 and 32, respectively.
substrate 3, only the combination of sodium nitrate and An analogous reduction of the aldehyde 25 gave 33, albeit
trifluoroacetic acid returned isolable quantities of the nitro in modest yield, where the formyl group had been com-
compound 30, albeit in modest yield.[17] Once again, the pletely reduced but reduction of the ester moiety ceased at
substitution occurred exclusively at C3.
the primary alcohol. Given the previous outcome, identical
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Synthesis of a Germination Stimulant
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reaction conditions were employed to produce the alcohol methyl ether 41. Condensation of 24 with hydroxylamine
34 from the ester 23; prolonged reaction times produced gave but one oxime 42 of (E) configuration.[20] Thionyl
the chloride 35. The alcohol 34 was also converted into the chloride was utilised in the dehydration of 42 to the nitrile
fluoride 36 by treatment with diethylaminosulfur trifluoride 43.
(DAST).
Conclusions
The Versatility of Aldehyde 24 in Preparing Differently
We have established an efficacious route to the novel het-
erocycles 3 and 23 from a pentose (-xylose) and hexose (-
glucuronic acid γ-lactone), respectively. In our work com-
pound 3 has served as an intermediate in the preparation
of the potent germination stimulant 1, which has been pre-
pared on a multi-gram scale in nine steps with an overall
yield of 30% from 1,2-O-isopropylidene--xylofuranose 6;
this is a vast improvement on the only method published to
date.[8] Additionally, compounds 3 and 23 have allowed for
the preparation of a further 22 analogues of 1 with differing
substitutions at both C3 and C5. Several of these analogues
have structural features that make them suitable as “mode-
of-action” probes in future work.
Substituted Analogues at C3
Further analogues of 1 were obtained by capitalising on
the versatility of the formyl moiety in organic synthesis
(Scheme 9). Reductive amination of 24 with dimethylam-
monium chloride and sodium cyanoborohydride returned
the amine 37. Prolonged treatment of 24 with DAST pro-
duced the difluoromethyl analogue 38. Olefination of the
aldehyde 24 yielded the dibromo olefin 39; all attempts at
converting this olefin into an alkyne through treatment with
strong lithium bases went unrewarded.[19] Treatment of al-
dehyde 24 with tert-butylamine–borane returned the
alcohol 40. This alcohol was elaborated further, using
methyl iodide in the presence of silver(I) oxide, to give the
Experimental Section
General: General experimental procedures have been given pre-
viously.[21]
Other General Procedures
Procedure A. Formylation: Phosphoryl chloride (0.70 mL,
7.5 mmol) was added dropwise to the substrate (0.50 mmol) in
DMF (3 mL) and the solution stirred at the given temperature for
the given period of time. The cooled solution was diluted with
CH2Cl2 (5 mL), poured into saturated aqueous NaHCO3 (30 mL)
and the mixture stirred (15 min). The mixture was extracted with
CH2Cl2 (3ϫ10 mL), the combined organic layers were dried
(MgSO4), filtered and concentrated. Flash chromatography gave
the aldehyde.
Procedure B. Acylation: Aluminium(III) chloride (0.67 g, 5.0 mmol)
was added to the acid chloride (2.5 mmol) and the substrate
(0.50 mmol) in CH2Cl2 (4 mL) and the mixture stirred at room tem-
perature for the given period of time. The mixture was cooled to
0 °C, and hydrochloric acid (10 mL, 1 ) was added dropwise with
stirring. The mixture was extracted with CH2Cl2 (3ϫ10 mL), the
combined organic layers were dried (MgSO4), filtered and concen-
trated. Flash chromatography gave the ketone.
Procedure C. Reduction: Aluminium(III) chloride (0.12 g,
0.90 mmol) was added to tBuNH2·BH3 (0.16 g, 1.8 mmol) and the
substrate (0.30 mmol) in CH2Cl2 (6 mL) and the mixture refluxed
(20 min). Additional AlCl3 (40 mg, 0.30 mmol) was added periodi-
cally (every 10 min) until the reaction was complete (TLC). The
mixture was cooled to 0 °C, and hydrochloric acid (10 mL, 1 )
was added dropwise with stirring. The mixture was extracted with
CH2Cl2 (3ϫ10 mL), the combined organic layers were dried
(MgSO4), filtered and concentrated. Flash chromatography gave
the product.
(E)- and (Z)-3-Deoxy-3-C-[(ethoxycarbonyl)methylene]-1,2-O-iso-
propylidene-5-O-triphenylmethyl-α-D-erythro-pentose (10 and 9):
Scheme 9. (a) Me2NH·HCl, NaBH3CN, MeOH, 62%; (b) DAST,
CH2Cl2, 79%; (c) CBr4, Ph3P, Zn, CH2Cl2, 42%; (d) tBuNH2·BH3,
CH2Cl2, 86 %; (e) MeI, Ag2O, CH2Cl2, 87 %; (f) HONH2·HCl,
MeOH, 80%; (g) SOCl2, Et3N, CH2Cl2, 82%.
Triethyl phosphonoacetate (4.0 mL, 20 mmol) was added dropwise
to NaH (0.80 g, 20 mmol, 60% dispersion in mineral oil) in THF
(20 mL) at –10 °C, and the mixture stirred (15 min). The crude
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E. D. Goddard-Borger, E. L. Ghisalberti, R. V. Stick
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ketone 8 [obtained from the alcohol 7[9] (4.3 g, 10 mmol)] in THF
(20 mL) was added dropwise and the red solution stirred (15 min).
Concentration of the mixture and a standard workup (EtOAc) was
followed by flash chromatography (EtOAc/petrol, 1:19). The (E)
(4S)-4-Acetoxy-4,5-dihydro-2H-furo[2,3-c]pyran-2-one (13): Tri-
ethylamine (1 mL) was added to the diacetate 12 (0.26 mg,
1.0 mmol) in CH2Cl2 (5 mL) and the solution kept at room tem-
perature (5 min). Concentration of the mixture and flash
chromatography (EtOAc/petrol, 1:3) gave the butenolide 13 as a
isomer 10 was first to elute as a colourless oil (0.25 g, 5%). [α]D
+186 (CHCl3). H NMR (500 MHz, CDCl3): δ = 1.22 (t, JH,H
=
=
1
3
pale yellow oil (0.18 g, 94 %). [α]D = +84.7 (CHCl3). 1H NMR
3
7.1 Hz, 3 H, CH2CH3), 1.44, 1.50 [2 s, 6 H, C(CH3)2], 3.43 [dd, (500 MHz, CDCl3): δ = 2.13 (s, 3 H, OCOCH3), 4.19 (dd, JH,H
=
=
2
3
2
2
3
2
3JH,H = 2.0, JH,H = 9.9 Hz, 1 H, H5], 3.53 [dd, JH,H = 2.4, JH,H
3.5, JH,H = 12.6 Hz, 1 H, H5), 4.33 (dd, JH,H = 4.1, JH,H
= 9.9 Hz, 1 H, H5], 4.00–4.09 (m, 2 H, CH2CH3), 5.31 (ddd, 4JH,H 12.6 Hz, 1 H, H5), 5.84 (ddd, JH,H = 0.7, JH,H = 3.5, 4.1 Hz, 1
4
3
3
4
4
5
= 1.9, 1.9, JH,H = 4.6 Hz, 1 H, H2), 5.61 (dddd, JH,H = 1.9, 1.9, H, H4), 5.92 (dd, JH,H = 0.7, JH,H = 1.8 Hz, 1 H, H3), 7.07 (d,
3JH,H = 2.0, 2.4 Hz, 1 H, H4), 6.09 (dd, JH,H = 1.9, 1.9 Hz, 1 H,
5JH,H = 1.8 Hz, 1 H, H7) ppm. 13C NMR (125.8 MHz, CDCl3): δ
4
3
=CH), 6.26 (d, JH,H = 4.6 Hz, 1 H, H1), 7.22–7.39 (m, 15 H, Ph) = 20.7 (OCOCH3), 62.7 (C4), 69.3 (C5), 109.5 (C7), 133.1 (C3),
ppm. 13C NMR (125.8 MHz, CDCl3): δ = 14.2 (CH2CH3), 27.9, 138.3 (C7a), 145.5 (C3a), 168.8, 169.8 (C2, C=O) ppm. HRMS
28.0 [C(CH3)2], 60.5 (CH2CH3), 66.0 (C5), 81.2, 82.6 (C2,4), 87.3 (FAB): m/z = 197.0448; [M + H]+ requires 197.0450.
(CPh3), 104.7 (C1), 113.5 [C(CH3)2], 116.8 (=CH), 127.2–143.8
(4S,7R)-2,4,7-Triacetoxy-4,7-dihydro-5H-furo[2,3-c]pyran (14): Tri-
(Ph), 160.1 (C3), 165.2 (C=O) ppm. HRMS (FAB): m/z = 500.2196;
ethylamine (0.5 mL) was added to the butenolide 11 (86 mg,
[M]+· requires 500.2199. Next to elute was the (Z) isomer 9 as a
0.50 mmol) and Ac2O (0.22 mL, 2.0 mmol) in CH2Cl2 (2 mL) and
the mixture stirred (30 min). Concentration of the mixture and
colourless oil (3.7 g, 74%). [α]D = +96.3 (CHCl3). 1H NMR
3
(500 MHz, CDCl3): δ = 1.32 (t, JH,H = 7.1 Hz, 3 H, CH2CH3),
flash chromatography (EtOAc/petrol, 1:3) gave the furan 14 as a
3
2
1.48, 1.54 [2 s, 6 H, C(CH3)2], 3.27 (dd, JH,H = 4.0, JH,H
=
pale yellow oil (0.14 g, 91 %). [α]D = +2.7 (CHCl3). 1H NMR
(600 MHz, CDCl3): δ = 2.05, 2.13, 2.27 (3 s, 9 H, OCOCH3), 4.18
3
2
10.0 Hz, 1 H, H5), 3.42 (dd, JH,H = 4.1, JH,H = 10.0 Hz, 1 H,
H5), 4.25 (q, JH,H = 7.1 Hz, 2 H, CH2CH3), 4.98 (dddd, JH,H
4.0, 4.1, JH,H = 1.7, 1.7 Hz, 1 H, H4), 5.75–5.78 (m, 2 H, H2,
=CH), 6.08 (d, JH,H = 4.0 Hz, 1 H, H1), 7.24–7.48 (m, 15 H, Ph)
3
3
=
3
2
3
(dd, JH,H = 6.4, JH,H = 12.0 Hz, 1 H, H5), 4.41 (dd, JH,H = 3.9,
4
2JH,H = 12.0 Hz, 1 H, H5), 5.92 (ddd, JH,H = 1.1, JH,H = 3.9,
6.4 Hz, 1 H, H4), 6.14 (dd, JH,H = 0.6, 1.1 Hz, 1 H, H3), 7.52 (d,
4
3
3
4
ppm. 13C NMR (125.8 MHz, CDCl3): δ = 14.2 (CH2CH3), 27.3,
27.6 [C(CH3)2], 60.7 (CH2CH3), 65.6 (C5), 78.8, 79.8 (C2,4), 87.1
(CPh3), 105.5 (C1), 113.0 [C(CH3)2], 116.7 (=CH), 127.2–143.6
(Ph), 156.4 (C3), 165.0 (C=O) ppm. HRMS (FAB): m/z = 500.2178.
4JH,H = 0.6 Hz, 1 H, H7) ppm. 13C NMR (150.9 MHz, CDCl3): δ
= 20.5, 20.6, 20.8 (3 C, OCOCH3), 64.5 (C5), 66.3 (C4), 116.4 (C3),
120.2 (C7), 136.2 (C7a), 153.6 (C2), 166.4, 169.4, 170.5 (3 C, C=O),
166.7 (C3a) ppm. HRMS (FAB): m/z = 299.0762; [M + H]+ re-
quires 299.0767.
(4S,7S,7aR)-4,7-Dihydroxy-4,5,7,7a-tetrahydro-2H-furo[2,3-c]pyran-
2-one (11): Trifluoroacetic acid/H2O (5 mL, 4:1) was added to the
alkene 9 (0.50 g, 1.0 mmol) in CH2Cl2 (3 mL) and the yellow solu-
tion kept at room temperature (5 min). The solvent was removed,
H2O added and the aqueous solution washed with EtOAc. Concen-
tration of the aqueous layer and recrystallisation of the residue gave
the butenolide 11 as colourless needles (0.14 g, 83%); m.p. 184–
185.5 °C (MeOH). [α]D = +168 (H2O). 1H NMR [500 MHz, (CD3)2-
(4S,7R,7aR)-4,7-Bis(ethoxycarbonyloxy)-4,5,7,7a-tetrahydro-2H-
furo[2,3-c]pyran-2-one (15): Ethyl chloroformate (3.82 mL,
40.0 mmol) was added dropwise to the butenolide 11 (1.72 g,
10.0 mmol) in C5H5N (20 mL) at 0 °C and the mixture stirred
(room temp., 1 h). Concentration of the mixture and a standard
workup (EtOAc) followed by flash chromatography (EtOAc/petrol,
1:3) gave the carbonate 15 as colourless needles (2.94 g, 93%); m.p.
121–124 °C (EtOAc/petrol). [α]D = +120 (CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 1.24–1.35 (m, 6 H, CH2CH3), 3.66 (dd,
3
2
SO]: δ = 3.42 (dd, JH,H = 10.1, JH,H = 10.1 Hz, 1 H, H5), 3.75
3
2
4
(dd, JH,H = 7.5, JH,H = 10.1 Hz, 1 H, H5), 4.50 (dddd, JH,H
1.4, JH,H = 5.9, 7.5, 10.1 Hz, 1 H, H4), 4.94 (ddd, JH,H = 0.8,
1.4, JH,H = 4.6 Hz, 1 H, H7a), 5.43 (dd, JH,H = 4.6, 4.8 Hz, 1 H,
H7), 5.87 (dd, JH,H = 1.4, 1.4 Hz, 1 H, H3), 5.89 (d, JH,H
5.9 Hz, 1 H, 4-OH), 6.97 (dd, JH,H = 0.8, JH,H = 4.8 Hz, 1 H, 7-
OH) ppm. 13C NMR [125.8 MHz, (CD3)2SO]: δ = 62.6 (C5), 65.5,
78.4 (C4,7a), 90.3 (C7), 111.1 (C3), 170.3 (C3a), 172.8 (C2) ppm.
HRMS (FAB): m/z = 173.0449; [M + H]+ requires 173.0450.
=
3
4
2
3JH,H = 10.1, JH,H = 10.6 Hz, 1 H, H5), 4.15–4.28 (m, 5 H,
3
3
4
3
CH2CH3,H5), 5.01 (ddd, JH,H = 0.8, 0.8, JH,H = 4.6 Hz, 1 H,
4
3
=
4
3
H7a), 5.56 (dddd, JH,H = 0.8, 1.9, JH,H = 7.1, 10.1 Hz, 1 H, H4),
4
3
4
3
6.01 (dd, JH,H = 0.8, 1.9 Hz, 1 H, H3), 6.37 (d, JH,H = 4.6 Hz, 1
H, H7) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 14.1, 14.2 (2 C,
CH2CH3), 62.4 (C5), 65.2, 65.4 (2 C, CH2CH3), 69.0, 76.3 (C4,7a),
92.0 (C7), 114.5 (C3), 152.9, 153.7 (2 C, OCO2), 160.3 (C3a), 171.0
(C2) ppm. HRMS (FAB): m/z = 317.0870; [M + H]+ requires
317.0873.
(4S,7S,7aR)-4,7-Diacetoxy-4,5,7,7a-tetrahydro-2H-furo[2,3-c]pyran-
2-one (12): Acetic anhydride (0.76 mL, 8.0 mmol) was added to the
butenolide 11 (0.34 g, 2.0 mmol) in C5H5N (8 mL) and the mixture
stirred (2 h). Methanol (1 mL) was added and the solution allowed
to stand (10 min). The solvent was removed and a standard workup
(EtOAc) followed by flash chromatography (EtOAc/petrol, 1:3)
gave the diacetate 12 as a colourless oil (0.49 g, 95%). [α]D = +188
(CHCl3). 1H NMR (500 MHz, CDCl3): δ = 2.06, 2.18 (2 s, 6 H,
(4S)-4,5-Dihydro-4-ethoxycarbonyloxy-2H-furo[2,3-c]pyran-2-one
(16): Triethylamine (5 mL) was added to the dicarbonate 15 (2.85 g,
9.00 mmol) in CH2Cl2 (30 mL) and the solution kept at room tem-
perature (5 min). Concentration of the mixture and flash
chromatography (EtOAc/petrol, 1:3) gave the butenolide 16 as a
pale yellow oil (1.93 g, 95 %). [α]D = +84.7 (CHCl3). 1H NMR
OCOCH3), 3.54 (dd, 3JH,H = 10.1, 2JH,H = 10.4 Hz, 1 H, H5), 4.16 (500 MHz, CDCl3): δ = 1.31 (t, JH,H = 7.1 Hz, 3 H, CH2CH3),
3
3
2
4
3
2
3
(dd, JH,H = 7.2, JH,H = 10.4 Hz, 1 H, H5), 5.02 (dd, JH,H = 1.4,
4.20 (dd, JH,H = 3.4, JH,H = 12.7 Hz, 1 H, H5), 4.24 (q, JH,H =
3JH,H = 4.6 Hz, 1 H, H7a), 5.69 (ddd, JH,H = 1.4, JH,H = 7.2,
7.1 Hz, 2 H, CH2CH3), 4.40 (dd, JH,H = 4.0, JH,H = 12.7 Hz, 1
4
3
3
2
4
3
10.1 Hz, 1 H, H4), 6.01 (dd, JH,H = 1.4, 1.4 Hz, 1 H, H3), 6.52
H, H5), 5.70 (ddd, 4JH,H = 0.8, JH,H = 3.4, 4.0 Hz, 1 H, H4), 5.98
(d, 3JH,H = 4.6 Hz, 1 H, H7) ppm. 13C NMR (125.8 MHz, CDCl3): (dd, 4JH,H = 0.8, 5JH,H = 1.8 Hz, 1 H, H3), 7.07 (d, 5JH,H = 1.8 Hz,
δ = 20.6, 20.7 (2 C, OCOCH3), 62.6 (C5), 66.2, 76.5 (C7a, C4), 1 H, H7) ppm. 1 3C NMR (125.8 MHz, CDCl3 ): δ = 14.2
88.8 (C7), 114.0 (C3), 161.5 (C3a), 168.5, 169.3, 171.2 (3 C, C2,
C=O) ppm. HRMS (FAB): m/z = 257.0664; [M + H]+ requires
257.0661.
(CH2CH3), 65.3 (CH2CH3), 65.9 (C4), 69.2 (C5), 109.9 (C3), 133.3
(C7), 138.2 (C7a), 144.8 (C3a), 154.1 (OCO2), 168.9 (C2) ppm.
HRMS (FAB): m/z = 227.0551; [M + H]+ requires 227.0556.
3930
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3925–3934

Synthesis of a Germination Stimulant
FULL PAPER
2H-Furo[2,3-c]pyran-2-one (3): (a) Tetrakis(triphenylphosphane)- 1.42, 1.46 [2 s, 6 H, C(CH3)2], 3.78 (s, 3 H, CO2CH3), 4.24 (q, 3JH,H
3
palladium(0) (0.12 g, 0.1 mmol) was added to the acetate 13
= 7.1 Hz, 2 H, CH2CH3), 5.37–5.39 (m, 1 H, H4), 5.60 (d, JH,H
=
(98 mg, 0.50 mmol) in THF (4 mL) and the solution refluxed 2.8 Hz, 1 H, H5), 5.80 (ddd, 4JH,H = 1.9, 1.9, JH,H = 4.2 Hz, 1 H,
3
3
4
(48 h). Concentration of the mixture and flash chromatography
H2), 5.89 (d, JH,H = 4.2 Hz, 1 H, H1), 5.98 (dd, JH,H = 1.9,
(EtOAc/petrol, 1:3) gave the butenolide 3 as tan needles (42 mg,
1.9 Hz, 1 H, =CH), 7.43–8.04 (m, 5 H, Ph) ppm. 13C NMR
1
61%); m.p. 109–110 °C (iPr2O). H NMR [600 MHz, (CD3)2CO]: (150.9 MHz, CDCl3): δ = 14.2 (CH2CH3), 27.4, 27.6 [C(CH3)2],
δ = 5.40 (dd, 4JH,H = 0.5, 5JH,H = 1.5 Hz, 1 H, H3), 6.91 (dd, 4JH,H
= 0.5, 3JH,H = 5.5 Hz, 1 H, H4), 7.72 (d, 3JH,H = 5.5 Hz, 1 H, H5),
52.9 (CO2CH3), 60.9 (CH2CH3), 74.9, 78.9, 80.4 (C2,4,5), 106.1
(C1), 113.4 [C(CH3)2], 118.2 (=CH), 128.7–133.8 (Ph), 154.1 (C3),
164.5, 165.4, 167.2 (3 C, C=O) ppm. HRMS (FAB): m/z =
5
7.93 (d, JH,H = 1.5 Hz, 1 H, H7) ppm. 13C NMR [150.9 MHz,
(CD3)2CO]: δ = 90.8 (C3), 105.6 (C4), 129.5 (C7), 144.2 (C7a), 421.1510.
146.3 (C3a), 151.2 (C5), 170.6 (C2) ppm. HRMS (EI): m/z =
(4S,5S,7R/7S,7aR)-4,7-Dihydroxy-5-methoxycarbonyl-4,5,7,7a-tetra-
136.0161; [M]+· requires 136.0160. (b) Tetrakis(triphenylphos-
phane)palladium(0) (370 mg, 0.320 mmol) was added to the car-
bonate 16 (1.81 g, 8.00 mmol) in THF (20 mL) and the solution
refluxed (8 h). Concentration of the mixture and flash chromatog-
raphy (EtOAc/petrol, 1:3) gave the butenolide 3 as tan needles
(915 mg, 84 %); melting point, 1H and 13C NMR spectra and
HRMS data agree with those reported above in (a).
hydro-2H-furo[2,3-c]pyran-2-one (22): Sodium cyanide (0.12 g,
2.4 mmol) was added to the alkene 20 (3.4 g, 8.0 mmol) in MeOH
(30 mL) and the mixture stirred (5 h). Concentration of the mixture
and a standard workup (EtOAc) returned a brown gum. Trifluoro-
acetic acid/H2O (10 mL, 4:1) was added to this gum and the solu-
tion kept at room temperature (5 min). The solvent was removed,
H2O added and the aqueous solution washed with Et2O. Concen-
tration of the aqueous layer (room temp.) and flash chromatog-
raphy (EtOAc/petrol, 7:3) gave the esters 22 as a colourless oil
Methyl 5-O-Benzoyl-1,2-O-isopropylidene-α-D-glucuronate (19):
Benzoyl chloride (4.2 mL, 36 mmol) was added dropwise to the lac-
tone 18[14] (6.5 g, 30 mmol) in C5H5N (24 mL) at 0 °C and the mix-
ture stirred (room temp., 30 min). Water (1.1 mL) was added and
the mixture stirred (room temp., 30 min). Concentration of the
mixture and a standard workup (EtOAc) gave the crude benzoate
as a colourless glass. Triethylamine (1.0 mL) was added to the resi-
due in MeOH (24 mL) at 0 °C and the mixture stirred (1 h). Fil-
tration of the mixture gave the methyl ester 19 as colourless needles
(8.4 g, 79%); m.p. 146–148.5 °C (MeOH). [α]D = +18.9 (CHCl3).
1H NMR (600 MHz, CDCl3): δ = 1.32, 1.51 [2 s, 6 H, C(CH3)2],
3.23 (br. d, 3JH,H = 5.0 Hz, 1 H, OH), 3.84 (s, 3 H, CO2CH3), 4.30–
4.34 (m, 1 H, H3), 4.54 (dd, 3JH,H = 2.8, 7.2 Hz, 1 H, H4), 4.57 (d,
1
(1.5 g, 81%). H NMR [500 MHz, (CD3)2SO]: δ = 3.73 (s, 3 H, β-
3
CO2CH3), 3.74 (s, 3 H, α-CO2CH3), 3.81 (d, JH,H = 9.2 Hz, 1 H,
3
3
α-H5), 4.04 (d, JH,H = 9.2 Hz, 1 H, β-H5), 4.53 (dd, JH,H = 6.7,
4
7.0 Hz, 1 H, α-H7), 4.57–4.64 (m, 2 H, α,β-H4), 4.74 (dd, JH,H
1.7, JH,H = 7.0 Hz, 1 H, α-H7a), 5.08 (dd, JH,H = 1.8, JH,H
4.5 Hz, 1 H, β-H7a), 5.54 (dd, JH,H = 4.5, 4.8 Hz, 1 H, β-H7),
=
=
3
4
3
3
4
4
5.97 (dd, JH,H = 1.8, 1.8 Hz, 1 H, β-H3), 6.01 (dd, JH,H = 1.7,
1.7 Hz, 1 H, α-H3), 6.31 (d, 3JH,H = 6.7 Hz, 1 H, β-4-OH), 6.37 (d,
3JH,H = 6.1 Hz, 1 H, α-4-OH), 7.43 (d, JH,H = 4.8 Hz, 1 H, β-
3
7-OH), 7.43 (d, JH,H = 6.7 Hz, 1 H, α-7-OH) ppm. 13C NMR
3
[125.8 MHz, (CD3)2SO]: δ = 52.5 (α,β-CO2CH3), 67.5 (β-C5), 68.0
(α-C5), 72.4, 78.1 (β-C4,7a), 77.5, 81.5 (α-C4,7a), 91.0 (β-C7), 98.7
(α-C7), 112.7 (α,β-C3), 168.4–172.5 (6 C, α,β-C2,3a,C=O) ppm.
HRMS (FAB): m/z = 231.0500; [M + H]+ requires 231.0505.
3
3JH,H = 3.6 Hz, 1 H, H2), 5.55 (d, JH,H = 7.2 Hz, 1 H, H5), 5.98
3
(d, JH,H = 3.6 Hz, 1 H, H1), 7.44–8.08 (m, 5 H, Ph) ppm. 13C
NMR (150.9 MHz, CDCl3): δ = 26.4, 27.0 [C(CH3)2], 53.2
(CO2CH3), 70.6, 74.9, 79.7, 84.9 (C2,3,4,5), 105.3 (C1), 112.4
[C(CH3)2], 128.7–134.1 (Ph), 165.9, 169.3 (2 C, C=O) ppm. HRMS
(FAB): m/z = 353.1231; [M + H]+ requires 353.1236.
5-Methoxycarbonyl-2H-furo[2,3-c]pyran-2-one (23): Acetic anhy-
dride (5.7 mL, 60 mmol) was added to the ester 22 (4.6 g, 20 mmol)
in C5H5N (30 mL) and the solution allowed to stand (2 h). Meth-
anol (2 mL) was added and the solution again allowed to stand
(15 min). The mixture was concentrated, diluted with EtOAc
(60 mL) and poured into hydrochloric acid (50 mL, 1 ). A stan-
dard workup (omitting the use of saturated aqueous NaHCO3)
gave a dark syrup that, after rapid silica gel filtration (EtOAc/pet-
rol, 1:1), returned a pale yellow gum. 1,8-Diazabicyclo[5.4.0]undec-
7-ene (7.5 mL, 50 mmol) was added dropwise to this gum in
CH2Cl2 (20 mL) and the dark mixture stirred (10 min). The mix-
ture was diluted with CH2Cl2 (40 mL) and poured into hydrochlo-
ric acid (50 mL, 1 ). The organic layer was washed with H2O
(3ϫ50 mL), dried (MgSO4), filtered and concentrated before flash
chromatography (EtOAc/CH2Cl2, 3:97) gave the ester 23 as tan
needles (2.7 g, 68%); sublimation at 151–154 °C (CH2Cl2/petrol).
1H NMR [600 MHz, (CD3)2CO]: δ = 3.95 (s, 3 H, CO2CH3), 5.70
Methyl (E)- and (Z)-5-O-Benzoyl-3-deoxy-3-C-[(ethoxycarbonyl)-
methylene]-1,2-O-isopropylidene-α-D-erythro-penturonate (21 and
20): Acetic anhydride (4.7 mL, 50 mmol) was added to PDC (3.8 g,
10 mmol) and the methyl ester 19 (3.5 g, 10 mmol) in CH2Cl2 and
the mixture refluxed (1 h). The mixture was concentrated, and ra-
pid silica gel filtration (EtOAc/petrol, 4:1) gave the crude ketone as
a pale green oil. Ethyl (triphenylphosphoranylidene)acetate (8.7 g,
25 mmol) was added to the crude ketone in CH2Cl2 (40 mL) and
the mixture stirred (room temp., 2.5 h). The solution was poured
into hydrochloric acid (80 mL, 1 ) followed by a standard workup
and flash chromatography (EtOAc/petrol, 1:4). The (E) isomer 21
was first to elute as a colourless oil (34 mg, 0.8%). [α]D = +154
(CHCl3). 1H NMR (600 MHz, CDCl3): δ = 1.25 (t, 3JH,H = 7.1 Hz,
3 H, CH2CH3), 1.38, 1.42 (2 s, 6 H, C(CH3)2), 3.71 (s, 3 H,
3
CO2CH3), 4.11–4.23 (m, 2 H, CH2CH3), 5.30 (ddd, JH,H = 1.7,
5
5
(d, JH,H = 1.5 Hz, 1 H, H3), 7.69 (d, JH,H = 0.5 Hz, 1 H, H4),
3
4JH,H = 2.3, 2.3 Hz, 1 H, H4), 5.80 (d, JH,H = 1.7 Hz, 1 H, H5),
8.00 (dd, JH , H = 0.5, 1.5 Hz, 1 H, H7) ppm. 1 3 C NMR
5
5.83 (d, 3JH,H = 4.7 Hz, 1 H, H1), 5.94 (ddd, 4JH,H = 2.3, 2.3, 3JH,H
= 4.7 Hz, 1 H, H2), 6.27 (dd, 4JH,H = 2.3, 2.3 Hz, 1 H, =CH), 7.42–
8.12 (m, 5 H, Ph) ppm. 13C NMR (150.9 MHz, CDCl3): δ = 14.2
(CH2CH3), 27.7, 27.8 [C(CH3)2], 52.8 (CO2CH3), 61.0 (CH2CH3),
75.4, 81.3, 82.0 (C2,4,5), 104.8 (C1), 113.4 [C(CH3)2], 118.6 (=CH),
[150.9 MHz, (CD3)2CO]: δ = 53.6 (CO2CH3), 94.8 (C3), 109.3 (C4),
128.7 (C7), 144.2 (C7a), 145.7, 147.8 (C3a,CO2CH3), 160.6 (C5),
170.2 (C2) ppm. HRMS (EI): m/z = 194.0216; [M]+· requires
194.0215.
128.5–133.6 (Ph), 157.4 (C3), 165.38, 165.44, 168.3 (3 C, C=O) 3-Formyl-2H-furo[2,3-c]pyran-2-one (24): The butenolide 3 (136 mg,
ppm. HRMS (FAB): m/z = 421.1518; [M + H]+ requires 421.1499.
Next to elute was the (Z) isomer 20 as colourless needles (3.7 g,
1.00 mmol) was treated according to Procedure A [50 °C, 15 min,
flash chromatography (EtOAc/PhMe, 1:2)] to give the aldehyde 24
88 %); m.p. 95–96 °C (iPr2O). [α]D = +158 (CHCl3). 1H NMR as tan needles (151 mg, 92%); m.p. 216–217.5 °C (iPr2O). 1H NMR
3
3
(600 MHz, CDCl3): δ = 1.30 (t, JH,H = 7.1 Hz, 3 H, CH2CH3), [600 MHz, (CD3)2CO]: δ = 7.73 (d, JH,H = 5.1 Hz, 1 H, H5), 8.41
Eur. J. Org. Chem. 2007, 3925–3934
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3931

E. D. Goddard-Borger, E. L. Ghisalberti, R. V. Stick
FULL PAPER
(d, 3JH,H = 5.1 Hz, 1 H, H4), 8.60 (s, 1 H, H7), 9.82 (s, 1 H, CHO)
3-Nitro-2H-furo[2,3-c]pyran-2-one (30): Sodium nitrate (0.21 g,
2.5 mmol) was added to the butenolide 3 (69 mg, 0.50 mmol) in
ppm. 13C NMR [150.9 MHz, (CD3)2CO]: δ = 100.4 (C3), 108.1
(C4), 136.0 (C7), 143.7 (C7a), 147.8 (C3a), 156.6 (C5), 168.6 (C2), CF3CO2H (3 mL) and the mixture stirred (15 min). The dark mix-
185.1 (CHO) ppm. HRMS (FAB): m/z = 165.0196; [M + H]+ re-
quires 165.0190.
ture was diluted with CH2Cl2 (5 mL) and poured into saturated
aqueous NaHCO3 (30 mL). Standard workup (CH2Cl2) and flash
chromatography (EtOAc/petrol, 1:1) gave the butenolide 30 as yel-
low plates (44 mg, 48 %); m.p. 207–208 °C (Et2O). 1H NMR
[600 MHz, (CD3)2CO]: δ = 7.91 (dd, JH,H = 0.6, JH,H = 5.0 Hz,
1 H, H5), 8.67 (d, 3JH,H = 5.0 Hz, 1 H, H4), 8.82 (d, 4JH,H = 0.6 Hz,
1 H, H7) ppm. 13C NMR [150.9 MHz, (CD3)2CO]: δ = 107.9
(C3,4), 137.8 (C7), 140.5 (C7a), 144.2 (C3a), 158.2 (C5), 159.3 (C2)
ppm. HRMS (EI): m/z = 181.0018; [M]+· requires 181.0012.
3-Formyl-5-methoxycarbonyl-2H-furo[2,3-c]pyran-2-one (25): The
butenolide 23 (97 mg, 0.50 mmol) was treated according to Pro-
cedure A [80 °C, 1 h, flash chromatography (EtOAc/petrol, 1:2)] to
give the aldehyde 25 as yellow needles (100 mg, 90%); m.p. 158.5–
4
3
1
159 °C (Et2O). H NMR [600 MHz, (CD3)2CO]: δ = 4.03 (s, 3 H,
CO2CH3), 8.27 (s, 1 H, H4), 8.65 (s, 1 H, H7), 9.87 (s, 1 H, CHO)
ppm. 13C NMR [150.9 MHz, (CD3)2CO]: δ = 54.1 (CO2CH3),
102.7 (C3), 110.2 (C4), 135.3 (C7), 143.9 (C7a), 147.6, 151.9 (C3a, 3-Methyl-2H-furo[2,3-c]pyran-2-one (1): The aldehyde 24 (49 mg,
CO2CH3), 159.8 (C5), 168.2 (C2), 185.4 (CHO) ppm. HRMS 0.30 mmol) was treated according to Procedure C [flash
(FAB): m/z = 223.0250; [M + H]+ requires 223.0243.
chromatography (EtOAc/petrol, 1:3)] to give the butenolide 1 as
colourless needles (37 mg, 83 %); m.p. 118–120 °C (petrol; ref.[7]
5-(Dimethylaminocarbonyl)-2H-furo[2,3-c]pyran-2-one (26): Phos-
phoryl chloride (0.70 mL, 7.5 mmol) was added dropwise to the
ester 23 (97 mg, 0.50 mmol) in dimethylacetamide (5 mL) and the
solution stirred (120 °C, 36 h). The cooled solution was diluted
with CH2Cl2 (5 mL), poured into saturated aqueous NaHCO3
(30 mL) and stirred (15 min). Standard workup (CH2Cl2) and flash
chromatography (EtOAc/petrol, 7:3) gave the amide 26 as colour-
less needles (76 mg, 73 %); m.p. 147–149 °C (EtOAc/petrol). 1H
NMR [600 MHz, (CD3)2CO]: δ = 3.03, 3.12 [2 br. s, 6 H,
1
118–119 °C); the H and 13C NMR spectra and HRMS data agree
with those reported.[8]
3-Ethyl-2H-furo[2,3-c]pyran-2-one (31): The ketone 27 (53 mg,
0.30 mmol) was treated according to Procedure C [flash
chromatography (EtOAc/petrol, 1:3)] to give the butenolide 31 as a
1
colourless oil (39 mg, 79%). H NMR [600 MHz, (CD3)2CO]: δ =
3
3
1.13 (t, JH,H = 7.6 Hz, 3 H, CH2CH3), 2.37 (q, JH,H = 7.6 Hz, 2
3
3
H, CH2CH3), 6.85 (d, JH,H = 5.5 Hz, 1 H, H5), 7.63 (d, JH,H
5.5 Hz, 1 H, H4), 7.79 (s, 1 H, H7) ppm. 13C NMR [150.9 MHz,
0.5 Hz, 1 H, H4), 7.95 (dd, JH,H = 0.5, JH,H = 1.5 Hz, 1 H, H7) (CD3)2CO]: δ = 13.2 (CH2CH3), 17.1 (CH2CH3), 104.2 (C4), 106.0
=
5
4
CON(CH3)2], 5.54 (d, JH,H = 1.5 Hz, 1 H, H3), 7.14 (d, JH,H
=
4
5
ppm. 1 3 C NMR [150.9 MHz, (CD3 )2 CO]: δ = 35.6, 38.3
[CON(CH3)2], 92.8 (C3), 105.5 (C4), 128.3 (C7), 143.9 (C7a), 146.1
(C3a), 154.2 [CON(CH3)2], 162.3 (C5), 170.4 (C2) ppm. HRMS
(FAB): m/z = 208.0617; [M + H]+ requires 208.0610.
(C3), 128.4 (C7), 140.2 (C7a), 143.1 (C3a), 150.0 (C5), 170.8 (C2)
ppm. HRMS (EI): m/z = 164.0472; [M]+· requires 164.0473.
3-Propyl-2H-furo[2,3-c]pyran-2-one (32): The ketone 28 (58 mg,
0.30 mmol) was treated according to Procedure C [flash
chromatography (EtOAc/petrol, 1:4)] to give the butenolide 32 as a
3-Acetyl-2H-furo[2,3-c]pyran-2-one (27): The butenolide 3 (69 mg,
0.50 mmol) was treated according to Procedure B [AcCl, 20 min,
flash chromatography (EtOAc/petrol, 2:3)] to give the ketone 27
1
colourless oil (41 mg, 77%). H NMR [600 MHz, (CD3)2CO]: δ =
3
3
0.91 (t, JH,H = 7.4 Hz, 3 H, CH2CH2CH3), 1.57 (tq, JH,H = 7.4,
1
3
as colourless needles (81 mg, 91%); m.p. 185–185.5 °C (petrol). H
7.4 Hz, 2 H, CH2CH2CH3), 2.33 (t, JH,H = 7.4 Hz, 2 H,
NMR [600 MHz, (CD3)2CO]: δ = 2.42 (s, 3 H, CH3), 7.78 (d, 3JH,H
CH2CH2CH3), 6.84 (d, JH,H = 5.5 Hz, 1 H, H5), 7.63 (d, JH,H
=
3
3
3
= 5.1 Hz, 1 H, H5), 8.29 (d, JH,H = 5.1 Hz, 1 H, H4), 8.49 (s, 1
5.5 Hz, 1 H, H4), 7.78 (s, 1 H, H7) ppm. 13C NMR [150.9 MHz,
H, H7) ppm. 13C NMR [150.9 MHz, (CD3)2CO]: δ = 28.9 (CH3), (CD3)2CO]: δ = 14.1 (CH2CH2CH3), 22.4 (CH2CH2CH3), 25.6
101.1 (C3), 108.5 (C4), 135.0 (C7), 143.4 (C7a), 149.0 (C3a), 155.8 (CH2CH2CH3), 104.3 (C4), 104.5 (C3), 128.3 (C7), 140.9 (C7a),
(C5), 168.3 (C2), 193.4 (C=O) ppm. HRMS (EI): m/z = 178.0265;
143.1 (C3a), 150.1 (C5), 171.0 (C2) ppm. HRMS (EI): m/z =
[M]+· requires 178.0266.
170.0628; [M]+· requires 170.0630.
3-Propanoyl-2H-furo[2,3-c]pyran-2-one (28): The butenolide 3
(69 mg, 0.50 mmol) was treated according to Procedure B
[CH3CH2COCl, 20 min, flash chromatography (EtOAc/petrol, 1:2)]
to give the ketone 28 as colourless plates (86 mg, 89%); m.p. 185–
186 °C (petrol). 1H NMR [600 MHz, (CD3)2CO]: δ = 1.08 (t, 3JH,H
5-Hydroxymethyl-3-methyl-2H-furo[2,3-c]pyran-2-one (33): The al-
dehyde 25 (0.1 g, 0.50 mmol) was treated according to Procedure
C [flash chromatography (EtOAc/petrol, 4:1)] to give the alcohol
33 as colourless needles (38 mg, 42%); m.p. 133.5–134.5 °C (iPr2O/
petrol). 1H NMR [600 MHz, (CD3)2CO]: δ = 1.87 (s, 3 H, CH3),
3
4
3
3
= 7.3 Hz, 3 H, CH2CH3), 2.87 (q, JH,H = 7.3 Hz, 2 H, CH2CH3),
4.44 (dd, JH,H = 0.8, JH,H = 6.2 Hz, 2 H, CH2), 4.76 (t, JH,H =
3
3
4
7.80 (d, JH,H = 5.1 Hz, 1 H, H5), 8.29 (d, JH,H = 5.1 Hz, 1 H,
H4), 8.47 (s, 1 H, H7) ppm. 13C NMR [150.9 MHz, (CD3)2CO]: δ H7) ppm. 13C NMR [150.9 MHz, (CD3)2CO]: δ = 7.6 (CH3), 61.3
= 8.1 (CH2CH3), 34.8 (CH2CH3), 100.7 (C3), 108.5 (C4), 134.8 (CH2), 99.4 (C4), 99.7 (C3), 127.4 (C7), 141.8 (C7a), 142.6 (C3a),
6.2 Hz, 1 H, OH), 6.78 (d, JH,H = 0.8 Hz, 1 H, H4), 7.74 (s, 1 H,
(C7), 143.5 (C7a), 149.1 (C3a), 155.6 (C5), 168.1 (C2), 196.7 (C=O) 162.5 (C5), 171.4 (C2) ppm. HRMS (FAB): m/z = 181.0499; [M +
ppm. HRMS (EI): m/z = 192.0423; [M]+· requires 192.0423.
H]+ requires 181.0501.
3-Cyclopropylcarbonyl-2H-furo[2,3-c]pyran-2-one (29): The butenol-
ide 3 (69 mg, 0.50 mmol) was treated according to Procedure B
5-Hydroxymethyl-2H-furo[2,3-c]pyran-2-one (34): Aluminium(III)
chloride (0.12 g, 0.90 mmol) was added to tBuNH2·BH3 (0.16 g,
[cyclopropylcarbonyl chloride, 40 min, flash chromatography 1.8 mmol) and the ester 23 (58 mg, 0.30 mmol) in CH2Cl2 (6 mL)
(EtOAc/petrol, 1:3)] to give the ketone 29 as colourless plates
and the mixture refluxed (10 min). The mixture was cooled to 0 °C,
and hydrochloric acid (10 mL, 1 ) was added dropwise with stir-
(87 mg, 85 %); m.p. 239–241 °C (petrol). 1H NMR [600 MHz,
(CD3)2CO]: δ = 0.92–1.05 (m, 4 H, CH2), 3.13–3.18 (m, 1 H, CH), ring. Standard workup (CH2Cl2) and flash chromatography
3
3
7.80 (d, JH,H = 5.1 Hz, 1 H, H5), 8.29 (d, JH,H = 5.1 Hz, 1 H,
(EtOAc/petrol, 4:1) gave the alcohol 34 as colourless needles
H4), 8.50 (s, 1 H, H7) ppm. 13C NMR [150.9 MHz, (CD3)2CO]: δ (37 mg, 74 %); m.p. 163–164.5 °C (Et2O). 1H NMR [600 MHz,
= 11.3 (CH2), 18.2 (CH), 101.0 (C3), 108.7 (C4), 135.0 (C7), 143.3
(C7a), 148.8 (C3a), 155.8 (C5), 168.6 (C2), 196.0 (C=O) ppm. 4.82 (t, JH,H = 6.2 Hz, 1 H, OH), 5.37 (d, JH,H = 1.5 Hz, 1 H,
HRMS (EI): m/z = 204.0414; [M]+· requires 204.0421. H3), 6.89 (dt, 5JH,H = 0.5, 4JH,H = 0.9 Hz, 1 H, H4), 7.87 (dd, 5JH,H
4
3
(CD3)2CO]: δ = 4.47 (dd, JH,H = 0.9, JH,H = 6.2 Hz, 2 H, CH2),
3
5
3932
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3925–3934

Synthesis of a Germination Stimulant
FULL PAPER
= 0.5, 1.5 Hz, 1 H, H7) ppm. 13C NMR [150.9 MHz, (CD3)2CO]: stirred (0 °C, 15 min). The aldehyde 24 (0.12 g, 0.75 mmol) was
δ = 61.2 (CH2), 90.5 (C3), 100.8 (C4), 128.6 (C7), 143.7 (C7a), added and the mixture stirred (3 h). The mixture was filtered
147.4 (C3a), 163.9 (C5), 170.8 (C2) ppm. HRMS (FAB): m/z = through Celite and concentrated, before flash chromatography
167.0344; [M + H]+ requires 167.0344.
(EtOAc/petrol, 1:9) gave the alkene 39 as yellow needles (0.10 g,
42%); m.p. 130–132 °C (Et2O/hexane). 1H NMR [600 MHz, (CD3)2-
CO]: δ = 7.10 (d, 3JH,H = 5.5 Hz, 1 H, H5), 7.32 (s, 1 H, CHCBr2),
7.98 (d, 3JH,H = 5.5 Hz, 1 H, H4), 8.17 (s, 1 H, H7) ppm. 13C NMR
[150.9 MHz, (CD3)2CO]: δ = 91.5 (CHCBr2), 100.1 (C3), 107.3
(C4), 129.5 (CHCBr2), 131.5 (C7), 140.6 (C7a), 143.7 (C3a), 151.8
(C5), 167.9 (C2) ppm. HRMS (FAB): m/z = 318.8600; [M + H]+
requires 318.8605.
5-Chloromethyl-2H-furo[2,3-c]pyran-2-one (35): The ester 23
(58 mg, 0.30 mmol) was treated as above for the synthesis of the
alcohol 35, except that the mixture was refluxed for 48 h. Flash
chromatography (EtOAc/petrol, 1:4) gave the chloride 35 as pale
yellow needles (27 mg, 46%); m.p. 125–125.5 °C (petrol). 1H NMR
5
[600 MHz, (CD3)2CO]: δ = 4.64 (s, 2 H, CH2), 5.49 (d, JH,H
=
1.5 Hz, 1 H, H3), 7.07 (d, 5JH,H = 0.4 Hz, 1 H, H4), 7.95 (dd, 5JH,H
= 0.4, 1.5 Hz, 1 H, H7) ppm. 13C NMR [150.9 MHz, (CD3)2CO]:
δ = 42.4 (CH2), 92.5 (C3), 104.7 (C4), 129.2 (C7), 143.7 (C7a),
146.8 (C3a), 158.0 (C5), 170.6 (C2) ppm. HRMS (EI): m/z =
183.9930; [M]+· requires 183.9927.
3-Hydroxymethyl-2H-furo[2,3-c]pyran-2-one (40): tert-Butylamine–
borane complex (78 mg, 0.90 mmol) was added to the aldehyde 24
(49 mg, 0.30 mmol) in CH2Cl2 (4 mL) and the solution stirred
(1 h). Concentrated of the solution and flash chromatography
(EtOAc/petrol, 4:1) gave the alcohol 40 as colourless needles
5-Fluoromethyl-2H-furo[2,3-c]pyran-2-one (36): Diethylaminosulfur
trifluoride (80 µL, 0.6 mmol) was added to the alcohol 34 (33 mg,
0.20 mmol) in CH2Cl2 (4 mL) and the solution stirred (0 °C, 1 h).
The solution was diluted with CH2Cl2 (5 mL), poured into satu-
rated aqueous NaHCO3 (10 mL) and the mixture stirred (15 min).
Standard workup (CH2Cl2) and flash chromatography (EtOAc/pet-
rol, 1:4) gave the fluoride 36 as colourless needles (29 mg, 87%);
m.p. 99–99.5 °C (petrol). 1H NMR [600 MHz, (CD3)2CO]: δ = 5.30
1
(43 mg, 86%); m.p. 144 °C (decomp.) (Et2O). H NMR [600 MHz,
3
3
(CD3)2CO]: δ = 4.04 (t, JH,H = 5.6 Hz, 1 H, OH), 4.43 (d, JH,H
3
= 5.6 Hz, 2 H, CH2), 7.01 (d, JH,H = 5.5 Hz, 1 H, H5), 7.70 (d,
3JH,H = 5.5 Hz, 1 H, H4), 7.89 (s, 1 H, H7) ppm. 13C NMR
[150.9 MHz, (CD3)2CO]: δ = 55.2 (CH2), 104.3 (C3), 105.1 (C4),
129.4 (C7), 142.2, 143.2 (C3a,7a), 150.4 (C5), 169.9 (C2) ppm.
HRMS (EI): m/z = 166.0268; [M]+· requires 166.0266.
2
5
6
(d, JH,F = 46.8 Hz, 2 H, CH2F), 5.50 (dd, JH,H = 1.5, JH,F
=
3-Methoxymethyl-2H-furo[2,3-c]pyran-2-one (41): Methyl iodide
(0.13 mL, 2.0 mmol) was added to the alcohol 40 (33 mg,
0.20 mmol) and silver(I) oxide (0. 12 g, 0.50 mmol) in CH2Cl2
(5 mL) and the mixture refluxed (16 h). The mixture was filtered
through Celite and concentrated, before flash chromatography
(EtOAc/petrol, 1:4) gave the methyl ether 41 as colourless needles
4
5
0.8 Hz, 1 H, H3), 7.06 (d, JH,F = 2.2 Hz, 1 H, H4), 7.96 (d, JH,H
= 1.5 Hz, 1 H, H7) ppm. 13C NMR [150.9 MHz, (CD3)2CO]: δ =
1
80.8 (d, JC,F = 169 Hz, CH2F), 92.5 (d, 5JC,F = 1.8 Hz, C3), 104.5
(d, 3JC,F = 6.5 Hz, C4), 129.0 (C7), 143.9 (C7a), 146.6 (C3a), 157.1
2
(d, JC,F = 18.2 Hz, C5), 170.6 (C2) ppm. HRMS: (FAB) m/z =
169.0300; [M + H]+ requires 169.0301.
(31 mg, 87%); m.p. 63–63.5 °C (petrol). 1H NMR [600 MHz, (CD3)2-
3
CO]: δ = 3.30 (s, 3 H, CH3), 4.25 (s, 2 H, CH2), 6.98 (d, JH,H
=
3-(Dimethylamino)methyl-2H-furo[2,3-c]pyran-2-one (37): Dimeth-
ylammonium chloride (0.24 g, 3.0 mmol) was added to the alde-
hyde 24 (49 mg, 0.30 mmol) in MeOH (5 mL) and the mixture
stirred (4 h). Sodium cyanoborohydride (28 mg, 0.45 mmol) was
added to the yellow solution and the mixture stirred (16 h). Water
(1 mL) was added and the mixture stirred (10 min). Concentration
of the mixture and flash chromatography (EtOAc/petrol/Et3N,
90:9:1) gave the amine 37 as a pale yellow oil (36 mg, 62%). 1H
NMR [600 MHz, (CD3)2CO]: δ = 2.39 (s, 6 H, CH3), 3.46 (s, 2 H,
3
5.5 Hz, 1 H, H5), 7.77 (d, JH,H = 5.5 Hz, 1 H, H4), 7.95 (s, 1 H,
H7) ppm. 13C NMR [150.9 MHz, (CD3)2CO]: δ = 58.2 (CH3), 64.5
(CH2), 100.7 (C3), 104.9 (C4), 129.9 (C7), 143.1, 143.5 (C3a,7a),
151.1 (C5), 170.0 (C2) ppm. HRMS (EI): m/z = 180.0420; [M]+·
requires 180.0423.
(E)-3-Hydroxyimino-2H-furo[2,3-c]pyran-2-one (42): Sodium ace-
tate (49 mg, 0.60 mmol) was added to NH2OH·HCl (42 mg,
0.60 mmol) and the aldehyde 24 (49 mg, 0.30 mmol) in MeOH and
the mixture refluxed (2 h). The mixture was concentrated and a
standard workup (CH2Cl2) before flash chromatography (EtOAc/
petrol, 3:1) gave the oxime 42 as yellow crystals (43 mg, 80%); m.p.
197 °C (decomp.) (Et2O). 1H NMR [600 MHz, (CD3)2CO]: δ = 7.24
(d, 3JH,H = 5.3 Hz, 1 H, H5), 7.93 (s, 1 H, CHNOH), 7.97 (d, 3JH,H
= 5.3 Hz, 1 H, H4), 8.16 (s, 1 H, H7), 10.42 (s, 1 H, CHNOH)
ppm. 13C NMR [150.9 MHz, (CD3)2CO]: δ = 96.7 (C3), 107.2 (C4),
131.7 (C7), 140.7 (C7a), 142.1 (CHNOH), 143.7 (C3a), 153.1 (C5),
168.8 (C2) ppm. HRMS (EI): m/z = 179.0216; [M]+· requires
179.0219.
3
3
CH2), 6.98 (d, JH,H = 5.5 Hz, 1 H, H5), 7.71 (d, JH,H = 5.5 Hz,
1 H, H4), 7.89 (s, 1 H, H7) ppm. 13C NMR [150.9 MHz, (CD3)2-
CO]: δ = 42.7 (CH3), 53.5 (CH2), 100.0 (C3), 105.2 (C4), 130.2
(C7), 142.0 (C7a), 143.9 (C3a), 150.7 (C5), 171.2 (C2) ppm. HRMS
(EI): m/z = 193.0741; [M]+· requires 193.0739.
3-Difluoromethyl-2H-furo[2,3-c]pyran-2-one (38): Diethylaminosul-
fur trifluoride (0.20 mL, 1.5 mmol) was added to the aldehyde 24
(49 mg, 0.30 mmol) in CH2Cl2 (4 mL) and the solution stirred
(35 °C, 24 h). The solution was diluted with CH2Cl2 (5 mL), poured
into saturated aqueous NaHCO3 (30 mL) and the mixture stirred
(15 min). Standard workup (CH2Cl2) and flash chromatography
(EtOAc/petrol, 1:4) gave the difluoride 38 as tan needles (44 mg,
79%); m.p. 136–138 °C (decomp.) (petrol). 1H NMR [600 MHz,
(CD3)2CO]: δ = 6.77 (t, 2JH,F = 54.8 Hz, 1 H, CHF2), 7.18 (d, 3JH,H
3-Cyano-2H-furo[2,3-c]pyran-2-one (43): Thionyl chloride (70 µL,
1.0 mmol) was added to Et3N (0.14 mL, 1.0 mmol) and the oxime
42 (36 mg, 0.20 mmol) in CH2Cl2 (3 mL) at 0 °C and the mixture
stirred (30 min). The solution was diluted with CH2Cl2 (5 mL),
poured into saturated aqueous NaHCO3 (30 mL) and stirred
(15 min). Standard workup (CH2Cl2) and flash chromatography
(EtOAc/petrol, 1:4) gave the nitrile 43 as colourless needles (26 mg,
3
= 5.4 Hz, 1 H, H5), 8.07 (d, JH,H = 5.4 Hz, 1 H, H4), 8.28 (s, 1
H, H7) ppm. 13C NMR [150.9 MHz, (CD3)2CO]: δ = 96.2 (t, JC,F
2
1
= 26.7 Hz, C3), 105.3 (C4), 112.7 (t, JC,F = 231.8 Hz, CHF2),
3
133.0 (C7), 142.8 (C7a), 144.7 (t, JC,F = 2.3 Hz, C3a), 153.6 (C5),
1
82%); m.p. 192–193 °C (iPr2O). H NMR [600 MHz, (CD3)2CO]:
3
167.2 (t, JC,F = 6.9 Hz, C2) ppm. HRMS (FAB): m/z = 187.0213;
3
3
δ = 7.41 (d, JH,H = 5.2 Hz, 1 H, H5), 8.38 (d, JH,H = 5.2 Hz, 1
H, H4), 8.52 (s, 1 H, H7) ppm. 13C NMR [150.9 MHz, (CD3)2CO]:
δ = 75.6 (C3), 106.7 (C4), 113.1 (CN), 134.9 (C7), 143.3 (C7a),
150.8 (C3a), 155.8 (C5), 166.7 (C2) ppm. HRMS (EI): m/z =
161.0115; [M]+· requires 161.0113.
[M + H]+ requires 187.0207.
3-(2,2-Dibromovinyl)-2H-furo[2,3-c]pyran-2-one (39): Carbon tetra-
bromide (0.73 g, 2.2 mmol) was added to Ph3P (0.58 g, 2.2 mmol)
and Zn (0.14 g, 2.2 mmol) in CH2Cl2 (3 mL) and the mixture
Eur. J. Org. Chem. 2007, 3925–3934
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3933

E. D. Goddard-Borger, E. L. Ghisalberti, R. V. Stick
FULL PAPER
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Received: April 15, 2007
Published Online: June 19, 2007
3934
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3925–3934