A selective 3-acylation of tetramic acids and the first synthesis of ravenic acid

Article abstract of DOI:10.1002/chem.200902544

3-Acyltetramic acids, including delicate 3-oligoenoyl derivatives, such as the Penicillium metabolite ravenic acid, were prepared in two highyielding steps. Reaction of tetramic acids with the ylide Ph₃PCCO afforded exclusively the corresponding 3-acylylidenetetramic acids. These were amenable to Wittig olefinations with aliphatic, aromatic, saturated and unsaturated aldehydes after deprotonation with KOtBu. Due to its simplicity, selectivity and tolerance of pH-sensitive groups this method is superior to the established acylation protocols by Jones and Yoshii. It is also applicable to the synthesis of 3-acyltetronic acids. The new 3-oligoenoyl tetramic acids exhibited structure-dependent antimicrobial and cytotoxic activity.

Full text of DOI:10.1002/chem.200902544

FULL PAPER
DOI: 10.1002/chem.200902544
A Selective 3-Acylation of Tetramic Acids and the First Synthesis
of Ravenic Acid
Andrea Schlenk,[a] Randi Diestel,[b] Florenz Sasse,[b] and Rainer Schobert*[a]
Abstract: 3-Acyltetramic acids, includ-
ing delicate 3-oligoenoyl derivatives,
such as the Penicillium metabolite rav-
enic acid, were prepared in two high-
yielding steps. Reaction of tetramic
acids with the ylide Ph3PCCO afforded
exclusively the corresponding 3-acylyli-
denetetramic acids. These were amena-
ble to Wittig olefinations with aliphatic,
aromatic, saturated and unsaturated al-
dehydes after deprotonation with
KOtBu. Due to its simplicity, selectivity
and tolerance of pH-sensitive groups
this method is superior to the estab-
lished acylation protocols by Jones and
Yoshii. It is also applicable to the syn-
thesis of 3-acyltetronic acids. The new
3-oligoenoyl tetramic acids exhibited
structure-dependent antimicrobial and
cytotoxic activity.
Keywords: acylation · antibiotics ·
ravenic acid · tetramic acids · ylides
Introduction
onstrated by Jones et al.[9] or with carboxylic acids and N,N-
dicyclohexylcarbodiimide/4-dimethylaminopyridine as dem-
onstrated by Yoshii et al.[10] Both acylation methods are
tricky. The former is not compatible with acid-sensitive func-
tionalities and skipped carbon–carbon double bonds, where-
as the latter tends to fail erratically or to yield 4-O-acylated
products instead. Herein, we report a new selective 3-acyla-
tion of tetramic and tetronic acids with ylide 1 and a down-
stream Wittig alkenation with the so-formed acyl ylides.
Tetramic acids (i.e., pyrrolidine-2,4-diones) and tetronic
acids (i.e., dihydrofuran-2,4-diones) are widespread in
nature.[1–3] They are produced by a variety of marine and ter-
restrial organisms including bacteria, algae, sponges, fungi
and lichens. The 3-acyl-substituted derivatives are particular-
ly often associated with biological activity. Various strategies
exist for their synthesis. Among these, the base-induced
Lacey–Dieckmann cyclisation[4] of N-(b-ketoacyl)-a-amino
esters is the most widely adopted one,[5] since it directly af-
fords the 3-acyltetramic acids. A potential drawback of this
protocol is the frequently observed racemisation at C-5 of
the pyrrolidine-2,4-dione core.[6] An alternative two-step ap-
proach first generates the tetramate by condensation of a-
amino acids or esters with a dipolar C2-building block, such
as Meldrumꢀs acid[7] or the stable ylide Ph3PCCO (1).[8] The
tetramic acids thus obtained are subsequently acylated at C-
3 either with acyl chlorides and BF3-diethyl etherate as dem-
Results and Discussion
We had long since observed that tetronic acids, 4-hydroxy-
coumarins and pyrazol-5-ones, reacted with Ph3PCCO (1)
under mild, pH-neutral conditions to leave exclusively the
corresponding 3-phosphoranylideneacyltetronic acids, 3-
phosphoranylideneacyl-4-oxocoumarins or 4-phosphoranyli-
deneacylpyrazol-5-ones, respectively.[11] Unfortunately, these
products failed to undergo Wittig olefination with aldehydes,
a reaction that would provide access to, for example, the 3-
oligoenoyltetronic acid motif occurring in dozens of natural
products. X-ray and NMR spectroscopic studies had re-
vealed p-delocalisation, as well as H-chelate or even phos-
phonium salt character of the tricarbonyl ylide moiety in
these compounds as a reason for their inactivity. Desultory
attempts to “switch” them active by removal of the chelated
proton with various bases were all unsuccessful. For a more
systematic study, we now prepared the congenerous 3-acyl-
ylidic tetramic acids, for example, 3, in virtually quantitative
yield by treating the well-soluble N-tert-butoxycarbonyl
[a] A. Schlenk, Prof. Dr. R. Schobert
Organic Chemistry Laboratory, University of Bayreuth
Universitaetsstrasse 30/NW 1
95440 Bayreuth (Germany)
Fax : (+49)921552671
E-mail: Rainer.Schobert@uni-bayreuth.de
[b] R. Diestel, Dr. F. Sasse
Helmholtz Centre for Infection Research (HZI)
Department of Chemical Biology, Inhoffenstrasse 7
38124 Braunschweig (Germany)
Chem. Eur. J. 2010, 16, 2599 – 2604
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2599

Table 1. 3-Alkenoyltetramic acids 4 by acylation with Ph3PCCO (1)/alde-
hydes.
(Boc)-protected tetramic acids 2 with Ph3PCCO. Next, we
identified potassium tert-butoxide in THF as a base appro-
priate for the deprotonation/activation of ylides 3. The re-
sulting potassium salts were not normally isolated but react-
ed right away with the respective aldehyde as solutions in
THF at reflux. This afforded the corresponding N-Boc-3-(a-
hydroxydienyl)pyrrolidine-2,4-diones, which were not puri-
fied but treated with trifluoroacetic acid (TFA) to liberate
the target compounds 4 in yields ranging from 60 to 80%
(Table 1). The same conversion was possible with N-alkyl-
and N,H-substituted tetramic acids, for example, 5, and with
tetronic acids, such as 7 (Scheme 1). All steps proceeded
with retention of the configuration at C-5 of the starting tet-
ramic or tetronic acids as determined by HPLC comparison
with authentic racemic product samples. It is also worth
noting that the E-configured C=C bond introduced in the
course of the Wittig alkenation can be removed by catalytic
hydrogenation without affecting the formal C=C bond at C-
3.
Compounds 4
R1
R2
(CH2)8Me
Yield
[%]
Made
via ylide
4a
4b
H
H
G
76
84
3a
3a
p
ACHTUGNRTNE(NUGN C6H4)OMe
4c
H
78
3a
4d[a]
4e
(5S)-p(OH)Bn
(5S)-CH2Ph
66
62
3b
6
p
AHCTUNGTRENNUNG
[a] Precursors 2b and 3b: R1 =(5S)-CH2-p
ACHTUNGTRENNUNG
(11) in 72% yield. Acid 11 was treated with SOCl2 in di-
chloromethane and the resulting crude acid chloride was im-
mediately reduced with an excess of LiAlHACTHNURGTNEUNG(OtBu)3 at
À708C to afford aldehyde 12 in 50% yield after purifica-
tion.
Table 2 summarizes the results of agar diffusion assays
with compounds 4. In line with the original report,[12] we
found antimicrobial activity for ravenic acid 4 f against
The merits of this new acylation protocol are its regiose-
lectivity and mildness of conditions that allow for the pres-
ence of acid-sensitive function-
alities, such as conjugated C=C
bonds. We demonstrate this by
the first synthesis of ravenic
acid (4 f) that was originally ob-
tained from a microfungus Pen-
icillium sp. (MINAP9902) iso-
lated from the interior of fruit-
ing bodies of the myxomycete
Lycogala epidendrum collected
in
south-east
Queensland.
Larger amounts of 4 f were
later extracted from culture
broths of this fungus. It was
found to be active against me-
thicillin-resistant Staphylococ-
cus aureus.[12]
Ylide 3a, accessible by acyla-
tion of N-Boc-pyrrolidine-2,4-
dione (2a; R1 =H)[7b] with
Ph3PCCO in 98% yield, was
first deprotonated with KOtBu
in THF and then treated with 2-
methylocta-2E,4E,6E-trienal
(12) to leave 4 f after deprotec-
tion with TFA (Scheme 2).
HPLC purification eventually
afforded an orange crystalline
solid in 62% yield with respect
to 2a. Aldehyde 12 was readily
Scheme 1. Selective 3-acylation of tetronic and tetramic acids.
prepared.
An
E-selective
Horner–Emmons alkenation of
sorbinaldehyde with the dianion
of
pionic acid (10)[13] gave 2-meth-
ylocta-2E,4E,6E-trienoic
2-diethoxyphosphorylpro-
acid Scheme 2. Synthesis of ravenic acid (4 f).
2600
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Chem. Eur. J. 2010, 16, 2599 – 2604

A Selective 3-Acylation of Tetramic Acids
FULL PAPER
Table 2. Antibiotic activity[a] of tetramic acids 4 against selected Gram-
acids. We are currently applying it to the synthesis of more
complex natural compounds and we also want to gain struc-
tural information on the potassium ylide salt intermediates
to better understand the origin of their reactivity.
positive bacteria.[b]
4a
4c
4e
4 f
Staphylococcus aureus
Micrococcus luteus
Mycobacterium phlei
11
8
11
0
0
8
0
0
9
11
0
9
[a] Agar plates inoculated with the respective microrganisms were incu-
bated with 6 mm cellulose discs containing 20 mL of a methanolic solution
(1 mgmLÀ1) of the compounds tested. The diameters (in mm) of the re-
sulting growth-inhibition zones were determined after 24 h of incubation
at 308C and are cited here. [b] None of the compounds inhibited the
growth of the Gram-negative bacteria E. coli tolC and Klebsiella pneu-
moniae. Compounds 4b, 4d and 9 were inactive in all tested bacteria.
Experimental Section
General methods: Melting points were recorded on an Electrothermal
9100 apparatus and are uncorrected. IR spectra were recorded on a
Perkin–Elmer Spectrum One FTIR spectrophotometer equipped with an
ATR sampling unit. NMR spectra were recorded under conditions indi-
cated on a Bruker Avance 300 spectrometer. Chemical shifts (d) are
given in parts per million downfield from TMS as an internal standard.
Mass spectra were recorded by using a Varian MAT 311A (EI). Micro-
analyses were carried out with a Perkin–Elmer 2400 CHN elemental ana-
lyser. For column chromatography, Merck silica gel 60 (230–400 mesh)
was used. TLC: silica gel 60 F254 (Merck). Optical rotations were record-
ed at 589 nm with a Perkin–Elmer polarimeter 241. A Knauer system
with UV detector K-2000 and pump K-1800 was used for preparative
HPLC. Analytical HPLC was performed on a Beckman system with sol-
vent module 126 and a diode array detector 168 equipped with a Nucleo-
dex CD-ß-PM column (Macherey–Nagel). Prontosil Solvents (HPLC
grade) were purchased from Merck. THF was dried over a Na/K-alloy
and CH2Cl2 was dried over P2O5. Starting compounds were prepared ac-
cording to literature procedures or purchased from Fluka, Aldrich or
Acros Organic and were used without further purification. The weak acid
anion exchanger Dowex MPWA was bought from Aldrich.
Staphylococcus aureus. It was also active against Mycobacte-
rium phlei. Analogue 4a was equally active against S. aureus
and even more active than 4 f against Mycobacterium phlei
and Micrococcus luteus. A high degree of unsaturation of
the side chain at C-3 seems not to be a prerequisite for anti-
biotic activity of 3-acyltetramic acids in these bacteria.
Some derivatives of 4 were also noticeably cytotoxic. For
instance, in MTT tests compounds 4a and 4e exhibited an
IC
(48 h) value of <15 mm against HL-60 human leukemia
50A(48 h) value of 22 mm against multidrug-re-
cells. With an IC CHTUNGTRENNUNG
sistant KB-V1 human cervix carcinoma cells, compound 4e
even surpassed the efficacy of the clinical anticancer drug
doxorubicin. This efficiency is not merely due to the deter-
gent-like nature of compounds such as 4a and 4e. For in-
stance, tetramic acid 4a, while active also against primary
human umbilical vein endothelial cells (HUVEC; from
Lonza) with an IC50 of 9.3 mm, had a distinct impact on cellu-
lar membranes only at much higher concentrations. In he-
molysis assays with red blood cells from sheep (from Fiebig
Nꢂhrstofftechnik, Idstein-Niederauroff, Germany) we found
an ED50 of 250 mm. In contrast, ravenic acid (4 f) had little
effect both on HUVEC and on erythrocyte membranes with
IC50 and ED50 values of >100 mm. A detailed study including
more 3-acyltetramic acids and tumour cell lines will be dis-
closed elsewhere.
Synthesis of 3-triphenylphosphoranylideneacetyltetramic acids 3 or 6—
general procedure: Under an inert atmosphere, a solution of Ph3PCCO
(302 mg, 1.0 mmol) in dry THF (20 mL) was added dropwise over a
period of 20 min to a refluxing solution of the respective pyrrolidine-2,4-
dione 2 or 5 (1.0 mmol) in dry THF (60 mL). Heating was continued for
another 16 h, then half of the solvent was evaporated, pentane was added
to the remainder and the product was allowed to precipitate. It was col-
lected by filtration, washed and dried or recrystallised.
1-tert-Butoxycarbonyl-3-[(triphenylphosphoranylidene)acetyl]pyrroli-
dine-2,4-dione (3a): White solid (495 mg, 98%) from 1-tert-butoxycarbo-
nylpyrrolidine-2,4-dione (2a)[7b] (199 mg); m.p. 1948C; IR (ATR): n˜ =
1751, 1620, 1557, 1436, 1328, 1153, 1103, 844, 690 cmÀ1
;
1H NMR
(CDCl3): 2:1 mixture of ylide (a) and betaine (b): d=1.45 (s, 9H; Me3b),
a
1.48 (s, 9H; Me3 ), 3.77 (s, 2H; 5-Hb), 3.94 (s, 2H; 5-Ha), 5.12 (d, J=
12.5 Hz, 1H; CH2P), 5.27 (d, J=20.5 Hz, 1H; P=CH), 7.47–7.74 (m,
15H; PPh3), 12.38 ppm (brs., 1H; OH); 13C NMR (75.5 MHz, CDCl3):
ylide (two rotamers): d=27.6 (Me3), 51.2/54.0 (C-5), 55.7 (d, JPC
=
106.9 Hz; P=CH), 56.3 (d, JPC =106.8 Hz; P=CH), 81.3/81.5 (CMe3), 93.2/
95.8 (C-3), 124.1 (d, JPC =93.7 Hz; Cipso), 150.7 (CO2), 168.2 (C-2), 187.6
(C-1’), 191.9 ppm (C-4); betaine: d=27.5 (Me3), 35.1 (d; JPC =52.8 Hz; P-
CH2), 52.4 (C-5), 81.1 (CMe3), 103.4 (C-3), 119.8 (d, JPC =88.5 Hz; Cipso),
150.3 (CO2), 172.2 (C-2), 178.7 (C-1’), 189.9 ppm (C-4); further unassign-
able phenyl signals of both isomers: 128.4, 128.5, 128.6, 129.3, 129.4,
129.7, 129.8, 129.9, 131.8, 131.9, 132.1, 133.0, 133.1, 133.2, 133.3, 133.8,
133.9, 134.4, 134.5 ppm; 31P NMR (161.7 MHz, H3PO4/ext, CDCl3): d=
15.6 (ylide), 22.8 ppm (betaine); MS (EI): m/z (%): 501 (8) [M]+, 401
(10), 301 (100), 262 (20) [PPh3]+, 183 (35), 151 (15), 77 (30), 57 (29); ele-
mental analysis calcd (%) for C29H28NO5P: C 69.45, H 5.63, N 2.79;
found: C 69.51, H 5.66, N 2.83.
Conclusion
We have developed a protocol for the synthesis of 3-acyltetr-
amic acids based upon the regioselective C-3-acylation of
tetramic acids with the phosphorus ylide Ph3PCCO. The re-
sulting
3-triphenylphosphoranylideneacyltetramic
acids
could be deprotonated with potassium tert-butoxide afford-
ing salts of yet unknown structure that underwent Wittig al-
kenations with various types of aldehydes. The conditions
are mild enough to avoid racemisation of sensitive stereo-
centres and to allow the introduction of highly unsaturated
side chains at C-3, which are prone to rearrangements and
polymerisations under the acidic conditions of the Jones
acylation protocol. If undesired, the newly formed C=C
bond can be removed selectively by catalytic hydrogenation.
The same protocol is applicable to the acylation of tetronic
(5S)-5-(4-tert-Butoxybenzyl)-1-(tert-butoxycarbonyl)-3-[(triphenylphos-
phoranylidene)acetyl]pyrrolidine-2,4-dione (3b): White solid (663 mg,
99%) from (5S)-5-(4-tert-butoxybenzyl)-1-(tert-butoxycarbonyl)pyrroli-
dine-2,4-dione (2b)[14] (361 mg); m.p. >2108C (decomp); [a]2D5 =À28 (c=
1.0 in CHCl3); IR (ATR): n˜ =2976, 1750, 1692, 1624, 1505, 1333, 1154,
896, 690 cmÀ1 1H NMR (CDCl3): 1:0.3 mixture of ylide and betaine: d=
;
1.26 (s, 9H; Me3), 1.53 (s, 9H; Me3), 2.54 (dd, J=3.2, 10.4 Hz, 1H;
CH2Ar), 3.24 (dd, J=3.2, 10.4 Hz, 1H; CH2Ar), 3.94 (dd, J=3.2, 10.4 Hz,
1H; 5-H), 5.24 (d, J=19.4 Hz, 1H; P=CH), 6.76 (d, J=8.9 Hz, 2H; Har),
6.99 (d, J=8.9 Hz, 2H; Har), 7.48–7.72 (m, 15H; PPh3), 12.20 ppm (brs,
Chem. Eur. J. 2010, 16, 2599 – 2604
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2601

R. Schobert et al.
1H; OH); 13C NMR (75.5 MHz, CDCl3): ylide: d=28.3 (Me3), 28.7
(Me3), 36.4 (CH2Ar), 56.7 (d, J=108.6 Hz; P=CH), 63.0 (C-5), 78.2
(OCtBu), 81.6 (CMe3), 98.2, 98.8 (each a d, J=12.1 Hz; C-3), 124.0 (d J=
column by eluting it first with a mixture of 1m aq. KHSO4/methanol (1:1;
100 mL), then with neat methanol. The combined eluates were concen-
trated and the remaining aqueous phase was extracted several times with
chloroform. The extracts were dried with NaSO4, filtered and concentrat-
ed in vacuum to yield the crude 3-acyltetramic acids. The protecting
groups of products 4a–d were removed by treating their solutions in
CH2Cl2 (1.0 mmol in 20 mL) with trifluoroacetic acid (TFA; 3 mL) and
stirring them at room temperature for 30 min. Hexane (50 mL) was
added and all volatiles were evaporated under reduced pressure. This op-
eration was repeated twice. The resulting 3-acyltetramic acids 4 were pu-
rified by preparative HPLC (Prontosil column RP-18 250ꢃ20 mm, 5 mm;
gradient: ascending from 30:70 MeCN/H2O to 80:20 MeCN/H2O over
35 min; flow rate: 20 mLminÀ1).
92.5 Hz; Cipso), 149.7 (CO2), 153.8 (O Cipso), 173.2 (C-2), 189.9 (C-1’),
À
193.2 ppm (C-4); betaine: d=28.2 (Me3), 28.5 (Me3), 34.4 (d, J=50.6 Hz;
P-CH2), 36.0 (CH2Ar), 61.5 (C-5), 77.8 (OCMe3), 80.3 (CMe3), 103.2 (C-
3), 119.5 (d, J=88.4 Hz; Cipso), 149.1 (CO2), 153.5 (O Cipso), 168.6 (C-2),
À
179.2 (C-1’), 192.2 ppm (C-4); further unassignable phenyl signals of both
isomers: 123.2, 123.4, 123.5, 123.6, 124.7, 128.4, 128.6, 128.7, 129.1, 129.2,
129.3, 129.4, 129.8, 129.9, 130.1, 130.2, 130.3, 130.4, 130.5, 130.6, 130.8,
131.9, 132.0, 132.1, 133.0, 133.1, 133.2, 133.3, 133.7, 133.8, 134.3, 134.4,
134.9 ppm; 31P NMR (161.7 MHz, H3PO4/ext, CDCl3): d=15.5/15.6 (ylide),
22.6 ppm (betaine); MS (EI): m/z (%): 663 (10) [M]+, 563 (3), 400 (10),
205 (18), 183 (15), 107 (100); elemental analysis calcd (%) for
C40H42NO6P: C 72.38, H 6.38, N 2.11; found: C 72.37, H 6.44, N 2.14.
3-[(E)-1-Hydroxydodec-2-enylidene]pyrrolidine-2,4-dione (4a): White
solid (210 mg, 76%) from ylide 3a (501 mg) and decanal (188 mL); m.p.
98–1008C (methanol/pentane 1:2); IR (ATR): n˜ =3196, 2918, 2848, 1709,
(5S)-5-Benzyl-3-[(triphenylphosphoranylidene)acetyl]pyrrolidine-2,4-
dione (6): White solid (485 mg, 98%) from (5S)-5-benzylpyrrolidine-2,4-
dione (5)[15] (189 mg); m.p. >2008C (decomp); [a]2D5 =À119 (c=0.5 in
CHCl3); IR (ATR): n˜ =1661, 1622, 1542, 1410, 1333, 1184, 1104, 742,
1664, 1651, 1591, 1459, 1253, 980, 701 cmÀ1 1H NMR ((CD3)2SO): d=
;
0.85 (t, J=6.6 Hz, 3H; Me), 1.18–1.40 (m, 12H; CH2), 1.45–1.64 (m, 2H;
CH2), 2.30 (dt, J=13.3, 6.6 Hz, 2H; CH2C=C), 3.77 (s, 2H; 5-H), 7.05 (d,
J=15.4 Hz, 1H; 2’-H), 7.21–7.30 ppm (m, 1H; 3’-H); 13C NMR
(75.5 MHz, (CD3)2SO): d=13.9 (Me), 22.1 (CMe), 27.6, 29.0, 29.1, 29.2,
29.3, 29.4 (CH2), 31.6 (CH2C=C), 51.3 (C-5), 100.1 (C-3), 120.9 (C-2’),
149.7 (C-3’), 172.6 (C-2), 176.2 (C-1), 193.9 ppm (C-4); MS (EI): m/z
(%): 279 (30) [M]+, 180 (12), 152 (100); HRMS (EI): m/z: calcd for
C16H24NO3À: 278.1756; found: 278.1751; calcd for C16H26NO3+: 280.1905;
found: 280.1900; elemental analysis calcd (%) for C16H25NO3: C 68.79, H
9.02, N 5.01; found: C 68.82, H 8.89, N 5.07.
690 cmÀ1 1H NMR (CDCl3): 1:1 mixture of ylide (a) and betaine (b): d=
;
2.23–2.40 (m, 1H; CH2Arb), 2.44–2.60 (m, 1H; CH2Ara), 3.07–3.36 (m,
2H; CH2Ara+b), 3.56–3.67 (m, 1H; 5-Hb), 3.76–3.79 (m, 1H; 5-Ha), 4.91–
5.16 (m, 2H; CH2P), 5.34 (d, J=20.3 Hz, 1H; P=CH), 7.02–7.26 (m, 5H;
Har), 7.35–7.73 (m, 30H; PPh3), 12.56 ppm (brs, 1H; OH); 13C NMR
(75.5 MHz, CDCl3): ylide: d=38.9 (CH2Ar), 53.6 (d, JPC =108.6 Hz; P=
CH), 62.4 (C-5), 90.4/94.0 (each a d, JPC =12.1 Hz; C-3), 124.5 (d, J=
ipso
92.1 Hz; P C ), 138.7 (C Cipso), 173.8 (C-2), 178.3 (C-1’), 195.0 ppm (C-
À
À
À
4); betaine: d=34.4 (d, JPC =52.2 Hz; P CH2), 38.4 (CH2Ar), 60.2 (C-5),
3-[(E)-1-Hydroxy-3-(4-methoxyphenyl)allylidene]pyrrolidine-2,4-dione
(4b): Yellow solid (220 mg, 84%) from ylide 3a (501 mg) and anisalde-
hyde (136 mL); m.p. 119–1218C (methanol/pentane 1:2); IR (ATR): n˜ =
101.6 (C-3), 119.8 (d, JPC =87.4 Hz; P C ), 138.5 (C Cipso), 173.1 (C-2),
177.8 (C-1’), 191.7 ppm (C-4); further unassignable phenyl signals of both
isomers: 126.4, 127.0, 128.4, 128.5, 128.6, 129.1, 129.2, 129.4, 129.7, 129.9,
130.2, 130.3, 130.4, 130.5, 131.6, 131.7, 131.8, 131.9, 132.0, 132.1, 133.1,
ipso
À
À
2976, 1660, 1635, 1600, 1581, 1511, 1335, 1263, 1161, 1036, 836, 775 cmÀ1
;
1H NMR (CDCl3): d=3.84 (brs, 5H; OMe, 5-H), 6.13 (brs, 1H; NH),
6.92 (d, J=9.1 Hz, 2H; Har), 7.62 (d, J=9.1 Hz, 2H; Har), 7.66 (d, J=
15.5 Hz, 1H; =CH), 7.85 ppm (d, J=15.5 Hz, 1H; =CH); 13C NMR
(75.5 MHz, CDCl3): d=49.6 (Me), 51.6 (C-5), 92.0 (C-3), 113.7 (Car),
118.7 (C-2’), 128.6 (Car), 133.7 (Cipso), 145.1 (C-3’), 162.4 (Cipso), 174.9 (C-
2), 176.7 (C-1’), 192.6 ppm (C-4); MS (EI): m/z (%): 259 (100) [M]+, 216
133.2, 133.4, 133.9, 134.0, 134.4 ppm; 31P NMR (161.7 MHz, H3PO4/ext
,
CDCl3): d=15.5/15.8 (ylide), 22.9 ppm (betaine); MS (EI): m/z (%): 491
(5) [M]+, 400 (10), 301 (25), 262 (15), 201 (35), 183 (35), 151 (20), 91
(100); elemental analysis calcd (%) for C31H26NO3P: C 75.75, H 5.33, N
2.85; found: C 75.77, H 5.33, N 2.92.
(52), 201 (49), 161 (53), 133 (40), 103 (20), 89 (60); HRMS (EI): m/z:
Synthesis of (5S)-5-methyl-3-[(triphenylphosphoranylidene)acetyl]dihy-
drofuran-2,4-dione (8): Analogously to compounds 3, lactone 8 was ob-
tained as a white solid (400 mg, 96%) from (5S)-5-methyltetronic acid
(7)[16] (114 mg, 1.0 mmol); m.p. >2008C (decomp); [a]2D5 =À8.9 (c=1.0 in
calcd for C14H12NO4À: 258.0772; found: 258.0766; calcd for C14H14NO4
:
+
260.0917; found: 260.0923; elemental analysis calcd (%) for C14H13NO4:
C 64.86, H 5.05, N 5.40; found: C 64.86, H 5.09, N 5.44.
CHCl3); IR (ATR): n˜ =1732, 1657, 1622, 1433, 1108, 996, 745, 688 cmÀ1
;
3-[(2E,4E)-1-Hydroxy-5-phenylpenta-2,4-dienylidene]pyrrolidine-2,4-
dione (4c): Orange solid (200 mg, 78%) from ylide 3a (501 mg) and cin-
namic aldehyde (82 mL); m.p. 118–1198C (methanol/pentane 1:2); IR
1H NMR (CDCl3): 1:3 mixture of ylide (a) and betaine (b): d=1.17 (d,
J=6.7 Hz, 3H; Meb), 1.33 (d, J=7.3 Hz, 3H; Mea), 4.15 (q, J=6.7 Hz,
1H; 5-Hb), 4.41 (q, J=7.3 Hz, 1H; 5-Ha), 4.90 (d, J=14.2 Hz, 2H;
PCH2), 4.92–5.00 (m, 1H; P=CH), 7.38–7.68 (m, 15H; Har), 11.17 ppm
(brs, 1H; OH); 13C NMR (75.5 MHz, CDCl3): ylides: d=17.6 (Me), 56.4
(d, JPC =109.2 Hz; P=CH), 75.4 (C-5), 99.6 (C-3), 123.6 (d, JPC =92.5 Hz;
Cipso), 175.3 (C-2), 185.3 (C-1’), 197.5 ppm (C-4); betaines: d=17.2 (Me),
(ATR): n˜ =3204, 1664, 1621, 1609, 1558, 1456, 1244, 990, 749 cmÀ1
;
1H NMR ((CD3)2SO): d=3.79 (s, 2H; 5-H), 7.22–7.25 (m, 2H; 2’-H, 3’-
H), 7.29–7.46 (m, 5H; Har), 7.59–7.62 (m, 2H; 4’-H, 5’-H), 8.77 ppm (brs;
NH); 13C NMR (75.5 MHz, (CD3)2SO): d=51.4 (C-5), 100.5 (C-3), 121.0
(C-2’), 127.4 (C-4’), 127.7, 128.2, 128.9, 129.5, 135.9 (Cipso), 142.8 (C-3’),
143.9 (C-5’), 172.4 (C-2), 175.6 (C-1’), 193.3 ppm (C-4); MS (EI): m/z
(%): 255 (100) [M]+, 226 (60), 197 (40), 141 (42), 127 (100), 99 (65), 77
(35); HRMS (EI): m/z: calcd for C15H12NO3À: 254.0823; found: 254.0817;
calcd for C15H14NO4+: 256.0968; found: 256.0974; elemental analysis
calcd (%) for C15H13NO3: C 70.58, H 5.13, N 5.49; found: C 70.56, H
5.14, N 5.55.
34.9 (d, JPC =52.9 Hz; PCH2), 76.1 (C-5), 96.0 (C-3), 119.2 (d, JPC
=
87.9 Hz; Cipso), 172.3 (C-2), 179.1 (C-1’), 192.1 ppm (C-4); further un-
assignable phenyl signals of both isomers: 128.4, 128.6, 129.3, 129.5,
129.8, 129.9, 130.4, 130.5, 130.6, 133.1, 133.3, 133.4, 133.8, 133.9, 134.6,
134.7 ppm; 31P NMR (161.7 MHz, H3PO4/ext, CDCl3): d=15.4 (ylide),
22.7 ppm (betaine); MS (EI): m/z (%): 416 (45) [M]+, 316 (10), 301
(100), 262 (30), 201 (20), 183 (55), 77 (21); elemental analysis calcd (%)
for C25H21O4P: C 72.11, H 5.08; found: C 72.08, H 5.00.
(S)-5-(4-Hydroxybenzyl)-3-[(2E,4E,6E)-1-hydroxyocta-2,4,6-trienylide-
ne]pyrrolidine-2,4-dione (4d): Yellow solid (211 mg, 66%) from ylide 3b
(633 mg) and sorbinaldehyde (96 mL); m.p. 169–1708C; [a]2D5 =À15 (c=
0.05 in CHCl3); IR (ATR): n˜ =3257, 1643, 1617, 1593, 1515, 1203, 1175,
Wittig reaction affording 3-acyltetramic acids 4—general procedure:
Under an inert atmosphere a solution of the respective ylide 3 or 6
(1.0 mmol) in dry THF (40 mL) was treated with potassium tert-butoxide
(112 mg, 1.0 mmol) and the resulting mixture was heated at reflux for
20 min. A solution of the respective aldehyde (1.0 mmol) in dry THF
(10 mL) was added dropwise and the mixture thus obtained was heated
at reflux for another 6 h. The solution was chilled to room temperature
and filtered through a column (2ꢃ5 cm) charged with Dowex MPWA
anion exchanger resin to remove most of the byproduct phosphine oxide.
The resin was rinsed several times with 50 mL each of ethyl acetate,
methanol, THF and CH2Cl2. Finally, the product was recovered from the
1024, 814, 721 cmÀ1 1H NMR (MeOD): d=1.84 (d, J=6.9 Hz, 3H; Me),
;
2.85 (dd, J=9.5, 5.4 Hz, 1H; 5-CH2), 2.99 (dd, J=9.5, 5.4 Hz, 1H; 5-
CH2), 4.05 (q, J=6.9 Hz, 1H; 5-H), 6.09 (dq, J=15.2, 6.9 Hz, 1H;
MeCH), 6.20–6.47 (m, 2H; CH, 5’-H, 6’-H), 6.66 (d, J=7.7 Hz, 2H; Har),
6.70–6.88 (m, 1H; 4’-H), 6.98 (d, J=7.7 Hz, 2H; Har), 7.07 (d, J=
15.4 Hz, 1H; 2’-H), 7.41–7.49 ppm (m, 1H; 3’-H); 13C NMR (75.5 MHz,
MeOD): d=17.5 (Me), 36.2 (5-CH2), 53.9 (C-5), 102.2 (C-3), 114.7 (Car),
115.5 (C-2’), 126.4 (C-4’), 128.5 (Cipso), 130.2 (C-6’), 130.4 (Car), 131.6 (C-
7’), 137.0 (C-5’), 144.1 (C-3’), 155.9 (O Cipso), 170.0 (C-2), 173.7 (C-1’),
À
2602
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Chem. Eur. J. 2010, 16, 2599 – 2604

A Selective 3-Acylation of Tetramic Acids
FULL PAPER
195.8 ppm (C-4); MS (EI): m/z (%): 325 (10) [M]+, 262 (12), 107 (100),
H), 6.21 (dd, J=15.1, 10.4 Hz, 1H; 6-H), 6.53 (dd, J=14.8, 10.4 Hz, 1H;
4-H), 6.81 (dd, J=14.8, 10.4 Hz, 1H; 5-H), 7.31 (d, J=14.8 Hz, 1H; 3-H),
9.41 ppm (s, 1H; CHO); 13C NMR (75.5 MHz, CDCl3): d=13.8 (Me),
18.6 (Me), 126.8 (C-3), 127.1 (C-2), 131.6 (C-5), 136.0 (C-4), 141.7 (C-6),
148.9 (C-7), 194.5 ppm (C-1); MS (EI): m/z (%): 136 (100) [M]+, 121
(40), 107 (36), 93 (62), 91 (78), 77 (58), 65 (26); HRMS (EI): m/z: calcd
for C9H12O2: 136.08882; found: 136.08880; elemental analysis calcd (%)
for C9H12O: C 79.37, H 8.88; found: C 79.30, H 8.78.
À
91 (43); HRMS (EI): m/z: calcd for C19H18NO4
: 324.1241; found:
324.1236; calcd for C19H20NO4+: 326.1387; found: 326.1392; elemental
analysis calcd (%) for C19H19NO4: C 70.14, H 5.89, N 4.31; found: C
70.21, H 5.88, N 4.33.
(S)-5-Benzyl-3-[(E)-1-hydroxy-3-(4-methoxyphenyl)allylidene]pyrroli-
dine-2,4-dione (4e): Yellow solid (219 mg, 62%) from ylide 6 (491 mg)
and anisaldehyde (136 mL); m.p. 158–1608C (methanol/pentane 1:2);
[a]2D5 =44 (c=0.05 in CHCl3); IR (ATR): n˜ =3185, 1661, 1630, 1553, 1421,
(S)-3-[(E)-1-Hydroxy-3-(4-methoxyphenyl)allylidene]-5-methyldihydro-
furan-2,4-dione (9): Analogously to compounds 4, lactone 9 was obtained
as a yellow solid (180 mg, 66%) from ylide 8 (416 mg, 1.0 mmol) and ani-
saldehyde (136 mL); m.p. 97–988C; [a]2D5 =À56 (c=0.1 in CHCl3); IR
(ATR): n˜ =2933, 1753, 1683, 1624, 1593, 1576, 1512, 1375, 1259, 1171,
1252, 1171, 977, 824, 698 cmÀ1 1H NMR ((CD3)2SO): d=2.95–2.98 (m,
;
2H; 5-CH2), 3.83 (s, 3H; Me), 4.21 (t, J=6.0 Hz, 1H; 5-H), 7.04 (d, J=
8.4 Hz, 2H; Har), 7.11–7.28 (m, 5H; Har), 7.47 (d, J=15.6 Hz, 1H; 2’-H),
7.66 (d, J=8.4 Hz, 2H; Har), 7.75 (d, J=15.6 Hz, 1H; 3’-H), 8.92 ppm (s,
1H; NH); 13C NMR (75.5 MHz, (CD3)2SO): d=36.7 (5-CH2), 55.5 (Me),
103.5 (C-3), 114.8 (C-2’), 114.9 (Car), 126.6, 126.8 (Cipso), 128.1 (Car),
129.7, (Car), 130.7, 136.0 (Cipso), 143.4 (C-3’), 162.0 (OCipso), 173.0 (C-2),
175.1 (C-1’), 194.9 ppm (C-4); MS (EI): m/z (%): 349 (100) [M]+, 258
(100), 201 (12), 161 (80), 133 (19), 91 (48); HRMS (EI): m/z calcd for
C21H18NO4À: 348.1236; found: 348.1236; calcd. for C21H20NO4+; 350.1507;
found: 350.1502; elemental analysis calcd (%) for C21H19NO4: C 72.19, H
5.48, N 4.01; found: C 72.22, H 5.52, N 3.98.
1020 cmÀ1 1H NMR (CDCl3): d=1.45 (d, J=6.9 Hz, 3H; Me), 3.80 (s,
;
3H; OMe), 4.57–4.75 (m, 1H; 5-H), 6.86 (d, J=8.9 Hz, 2H; Har), 7.51 (d,
J=15.2 Hz, 1H; 2’-H), 7.58 (d, J=8.9 Hz, 2H; Har), 7.92 (d, J=15.2 Hz,
1H; 3’-H), 10.45 ppm (brs, 1H; OH); 13C NMR (75.5 MHz, CDCl3): d=
16.6 (Me), 55.3 (OMe), 81.2 (C-5), 96.3 (C-3), 113.6 (C-2’), 114.5 (Car),
126.6 (Cipso), 131.6 (Car), 147.7 (C-3’), 163.0 (Cipso), 176.6 (C-2), 181.2 (C-
1’), 203.9 ppm (C-4); MS (EI): m/z (%): 274 (100) [M]+, 245 (12), 201
À
(50), 174 (73), 131 (40), 77 (30); HRMS: m/z: calcd for C15H13O5
273.0768; found: 273.0763; calcd for C15H15O5
:
+
: 275.0914; found:
Ravenic acid (4 f): Tangerine solid (160 mg, 62%) from ylide 3a (501 mg)
and (2E,4E,6E)-2-methylocta-2,4,6-trienal (12) (136 mg); m.p. 133–
1368C; IR (ATR): n˜ =3238, 1662, 1616, 1557, 1440, 1252, 1096, 1024,
275.0919; elemental analysis calcd (%) for C15H14O5: C 65.69, H 5.15;
found: C 65.73, H 5.15.
1
798 cmÀ1; H NMR (CDCl3): d=1.86 (d, J=6.9 Hz, 3H; CHCH3), 2.03 (s,
3H; CH3), 3.84 (s, 2H; 5-H), 5.95 (dq, J=15.1, 6.9 Hz, 1H; CHCH3),
6.23 (ddd, J=15.1, 10.4, 1.7 Hz, 1H; 8’-H), 6.45–6.55 (m, 2H; 6’-H, 7’-H),
6.56 (d, J=11.1 Hz, 1H; 5’-H), 7.19 (d, J=15.2 Hz, 1H; 2’-H), 7.59 ppm
(d, J=15.2 Hz, 1H; 3’-H); 13C NMR (75.5 MHz, CDCl3): d=12.5 (4’-
Me), 18.7 (CHMe), 51.5 (C-5), 99.7 (C-3), 116.4 (C-2’), 126.4 (C-6’), 132.1
(Cq-4’), 134.5 (C-9’), 139.5 (C-7’), 142.6 (C-3’), 174.6 (C-2), 176.7 (C-1’),
192.5 ppm (C-4); MS (EI): m/z (%): 259 (25) [M]+, 241 (10), 149 (10),
126 (42), 44 (100); HRMS (EI): m/z: calcd for C15H16NO3À: 258.1136;
found: 258.1130; calcd for C15H18NO3+: 260.1281; found: 260.1287; ele-
mental analysis calcd (%) for C15H17NO3: C 69.48, H 6.61, N 5.40; found:
C 69.50, H 6.66, N 5.48.
Acknowledgements
We are grateful to the Deutsche Forschungsgemeinschaft for financial
support (grants Scho 402/9–1 and Sa 365/3–1) and to Miroslava Zoldako-
va for running MTT tests.
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ACHTUNGTRENNUNG(2E,4E,6E)-2-Methylocta-2,4,6-trienoic acid (11): Compound 11 was ob-
tained from 2-diethoxyphosphorylpropionic acid (10) (4.20 g, 20.0 mmol)
and sorbinaldehyde (2.10 mL, 20.0 mmol) according to a general litera-
ture procedure.[13b] Recrystallisation from hexane/diethyl ether (2:1) left
a white solid of m.p. 125–1308C; yield: 2.17 g (72%); IR (ATR): n˜ =
1
2999, 2520, 1675, 1600, 1418, 1267, 988, 923, 749 cmÀ1; H NMR (CDCl3):
d=1.81 (d, J=7.0 Hz, 3H; CHCH3), 1.93 (s, 3H; CH3), 5.92 (dq, J=15.1,
7.0 Hz, 1H; 7-H), 6.20 (dd, J=15.1, 10.4 Hz, 1H; 6-H), 6.35 (dd, J=14.8,
11.5 Hz, 1H; 4-H), 6.52 (dd, J=14.8, 10.4 Hz, 1H; 5-H), 7.30 ppm (d, J=
14.8 Hz, 1H; 3-H); 13C NMR (75.5 MHz, CDCl3): d=12.8 (Me), 18.7
(Me), 126.7 (C-3), 127.2 (C-2), 133.2 (C-5), 135.1 (C-4), 140.4 (C-6), 141.4
(C-7), 172.1 ppm (C-1); MS (EI): m/z (%): 152 (50) [M]+, 137 (10), 107
(100), 105 (18), 91 (75), 79 (36), 77 (23), 65 (19); HRMS (EI): m/z: calcd
for C9H12O2: 152.08373; found: 152.08370; elemental analysis calcd (%)
for C9H12O2: C 71.03, H 7.95; found: C 70.88, H 7.89.
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mixture of acid 11 (3.04 g, 20.0 mmol), freshly distilled SOCl2 (3.0 mL,
42 mmol), dry CH2Cl2 (50 mL) and two drops of dry DMF was stirred at
room temperature overnight. All volatiles were removed and the crude
acid chloride was redissolved in THF (70 mL). The resulting solution was
chilled to À708C and treated dropwise with a 1m solution of LiAlH-
ACHTUNGTRENNUNG(OtBu)3 in THF (1.5 equiv, 30 mL, 30.0 mmol). Stirring was continued at
this temperature for a further 2 h, then 2m aq. HCl (25 mL) was added
and the mixture was allowed to warm to room temperature. The aqueous
layer was extracted with diethyl ether (3ꢃ25 mL), the combined organic
layers were washed with 2ꢃ25 mL each of saturated aq. NaHCO3, satu-
rated aq. NaCl and water. After drying with NaSO4 the solvent was re-
moved and the crude product was purified by column chromatography
on silica gel to give aldehyde 12 (1.36 g, 50%) as a colourless oil; Rf =
0.44 (hexane/diethyl ether 2:1); IR (ATR): n˜ =2927, 2715, 1782, 1675,
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;
1H NMR (CDCl3): d=1.81 (d, J=
7.0 Hz, 3H; CHCH3), 1.93 (s, 3H; CH3), 5.94 (dq, J=15.1, 7.0 Hz, 1H; 7-
Chem. Eur. J. 2010, 16, 2599 – 2604
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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Received: September 15, 2009
Revised: November 24, 2009
Published online: January 11, 2010
2604
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 2599 – 2604