Total synthesis of tyrosine-derived tetramic acid pigments from a slime mould

Article abstract of DOI:10.1002/ejoc.201000597

A method for the total synthesis of naturally occurring 3-enoyltetramic acids derived from L-tyrosine is described, allowing for three chemical transformations to occur in one pot by using a multicomponent mixture, The sequence involves (1) a base-promoted Lacey-Dieckmann condensation, (2) a Michaelis-Becker reaction, and (3) a Wittig-Horner-Emmons reaction between the resulting 3-phosphonoacetyltetramic acid and an appropriate aldehyde. This sequence of reactions was applied to the synthesis of polyenic pigments obtained from the slime mould Leocarpus fragilis starting from readily available precursors. A series of structurally related compounds was also synthesized and their antibiotic significance was evaluated to elucidate their role in nature.

Full text of DOI:10.1002/ejoc.201000597

FULL PAPER
DOI: 10.1002/ejoc.201000597
Total Synthesis of Tyrosine-Derived Tetramic Acid Pigments from a Slime
Mould
Nassima Riache,[a] Christine Bailly,[a] Alexandre Deville,[a] Lionel Dubost,[a] and
Bastien Nay*[a]
Keywords: Dyes/pigments / Total synthesis / Wittig reactions / Multicomponent reactions / Antibiotics
A method for the total synthesis of naturally occurring 3-en-
acid and an appropriate aldehyde. This sequence of reactions
oyltetramic acids derived from -tyrosine is described, al- was applied to the synthesis of polyenic pigments obtained
L
lowing for three chemical transformations to occur in one pot
by using a multicomponent mixture. The sequence involves
(1) a base-promoted Lacey–Dieckmann condensation, (2) a
Michaelis–Becker reaction, and (3) a Wittig–Horner–Emmons
reaction between the resulting 3-phosphonoacetyltetramic
from the slime mould Leocarpus fragilis starting from readily
available precursors. A series of structurally related com-
pounds was also synthesized and their antibiotic significance
was evaluated to elucidate their role in nature.
the amine thus provides a β-ketoacyl chain which un-
dergoes condensation with the acid functionality of the
proximate amino acid moiety to deliver the tetramic acid
core. Structural diversity then emerges from the amino acid
substrate and from the length and functionalization of the
β-ketoacyl chain. Cyclization of the acyl chain to give deriv-
atives, such as in the fungal metabolites trichosetin (2)[4] or
the compound GKK1032A2 (3), is possible if it is suitably
functionalized.[5]
Most frequently, 3-acyltetramic acids have been synthe-
sized using the Lacey–Dieckmann condensation,[1,6] a reac-
tion which is reminiscent of the biosynthetic route described
above. This strategy has been applied to the synthesis of
naturally occurring tetramic acids, occasionally with some
variations to introduce the acyl side chain. In the 1980s, the
method was developed by Boeckman[7] and by Schles-
singer[8] who focused on the synthesis of unsaturated 3-acyl-
tetramic acids by way of phosphorus-activated intermedi-
ates. Recent examples include the synthesis of macrocidin A
(4) by Suzuki[9] or (+)-cylindramine A by Phillips.[10] Very
recently, Schobert described a smart and versatile route to
3-acyltetramic acids, involving the acylation of a 2,4-pyrrol-
idinedione by a phosphoranylideneketene, followed by Wit-
tig reaction with an aldehyde.[11]
Introduction
3-Acyltetramic acids are widespread fungal or bacterial
metabolites which often feature important biological activi-
ties.[1] They are associated with defense or communication
processes in the microbial kingdom. Recently for instance,
the group of Janda underlined the role of the tetramic acid
C12-TA (1) as an antibiotic derived from the quorum-sens-
ing molecules of Pseudomonas aeruginosa (Figure 1).[2] It
was shown to interfere with membranes in Gram-positive
bacteria.
Figure 1. Examples of fungal tetramic acids and derivatives.
In this article we wish to report an alternative method
based on Schlessinger’s seminal work.[8] Our results provide
a general one-pot process for the synthesis of functionalized
tetramic acids. This was applied to the synthesis of pig-
ments 5 and 6 (Figure 2) responsible for the bright yellow
to orange color of the myxomycetes slime mould Leocarpus
fragilis (see the graphical abstract for a picture of the
mould).[12] To study their biological properties, a series of
structurally related compounds were synthesized along with
the shorter 3-acetyltetramic acid 7 isolated from the same
Biosynthetically, the structure of the 3-acyltetramic acids
is directly derived from an amino acid and a polyketide part
in the mixed PKS/NRPS enzymatic route.[1,3] Acylation of
[a] Molécules de Communication et Adaptation des
Micro-organismes (FRE 3206 CNRS-MNHN),
Muséum National d’Histoire Naturelle,
57 rue Cuvier (CP 54), 75005 Paris, France
Fax: +33-1-40-79-31-35
E-mail: bnay@mnhn.fr
View this journal online at
wileyonlinelibrary.com
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Total Synthesis of Tyrosine-Derived Tetramic Acid Pigments
organism. Compound 7 was synthesized by using the classi- der the basic reaction conditions used for the Lacey–Dieck-
cal Lacey–Dieckmann route. All these 3-acyltetramic acids mann condensation. The 2,4-dimethoxybenzyl (DMB)
are derived from -tyrosine. Our method for the synthesis group was chosen for amide protection on the basis of lit-
of 3-enoyltetramic acids relies on a multicomponent reac- erature precedent[8,9] and was installed on amine 9a in 83%
tion by allowing the realization of three synthetic steps in yield by reductive amination in the presence of 2,4-dimeth-
one pot: (1) base-promoted Lacey–Dieckmann condensa- oxybenzaldehyde. We will see later that this protecting
tion, (2) Michaelis–Becker reaction, (3) Wittig–Horner– group proved essential to the Lacey–Dieckmann cycliza-
Emmons reaction, giving the desired skeleton from a readily tion.[13] Due to the acid sensitivity of DMB-amides 11a, it
accessible intermediate (i.e., 11a,b).
was necessary to avoid purification steps, especially silica
gel chromatography (compound 11a was highly unstable in
these conditions). Amide 11a was thus obtained in 95%
yield from 10a without purification, whereas silica gel
chromatography only resulted in poor yields of 20–30%. All
contaminants were eliminated by aqueous extraction and
evaporation, as confirmed by NMR spectroscopic analysis
of the crude extract. Alternatively, amine 9b was protected
with the stable 4-methoxybenzyl (PMB) group while acyl-
ation in the presence of diketene/Br2 furnished amide 11b
in 58% yield from 10b after purification. However, the
PMB group later proved reluctant toward deprotection (see
below).
Figure 2. The targeted 3-acyltetramic acids from Leocarpus fragilis.
Results and Discussion
It is possible to introduce a phosphonate group on the
acyl part in C-3 of the tetramic acid to undertake a Wittig–
Horner–Emmons olefination. The acylating agent can then
be derived from diketene[8] or from the equivalent 2,2,6-
trimethyl-1,3-dioxin-4-one (Figure 3).[7,9]
Scheme 1. Synthesis of the bromoacetoacetamide precursors 11a
and 11b. Reagents and conditions: (a) TBSCl or TBDPSCl
(2.5 equiv.), NEt3 (3 equiv.), DMAP (0.2 equiv.), THF, reflux,
4 h. (b) 2,4-dimethoxybenzaldehyde or 4-methoxybenzaldehyde
(1.2 equiv.), NaBH3CN (1.5 equiv.), MeOH/AcOH (35:1), room
temp., 2 h. (c) diketene (1.5 equiv.), Br2 (1.5 equiv.), CH2Cl2,
–40 °C, then 10a or 10b, Et3N (1.5 equiv.), –40 °C Ǟ –20 °C, 1 h.
The yield of 11a is based on the crude product (no major impurity
detected by NMR spectroscopy compared to the product obtained
from purification). The yield of 11b is that after purification by
silica gel chromatography.
Figure 3. Synthetic strategies to get the 3-phosphonoacetyltetramic
acids.
It is worthy to note that the analysis of compounds 11a
and 11b was complicated by the occurrence of a ca. 1:1
mixture of the s-cis and s-trans conformers of the amide
(Figure 4). However, 2D NMR experiments allowed us to
In our work, we chose to use diketene, which reacts easily
with bromine to generate the acylating reagent 4-bromo-3-
ketobutyryl bromide. This simple reaction allowed the syn-
thesis of bromoacetoacetamides 11a and 11b by treatment
of N,O-diprotected tyrosine derivatives 10a and 10b with a
diketene/Br2 mixture in the presence of triethylamine
(Scheme 1). The choice of appropriate protecting groups
was important for this step to proceed in good yields and
efficient purification. The phenol was protected as silyl
ethers (i.e., 9a,b). The TBS group was preferred to the
TBDPS group because the former gave better yields for the
deprotection step despite the fact that it was less stable un- Figure 4. Isomers s-cis and s-trans observed for amide 11a,b.
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N. Riache, C. Bailly, A. Deville, L. Dubost, B. Nay
FULL PAPER
distinguish both forms in the mixture. The consequence of (48%). Finally, deprotection of the amine was accomplished
the s-cis ↔ s-trans isomerism for the Lacey–Dieckmann in the presence of TFA to afford native tetramic acids 5, 6,
condensation has been discussed by Suzuki in his total syn- 15, and 16 in fair to quantitative yields after purification
thesis of macrocidin A (4), but the step was performed on on Sephadex LH20. Although DMB removal proceeded
a strained macrolactam intermediate.[9] We assume that quickly (1 h), it was not possible to remove the PMB group
with our linear amides, this isomerism was not detrimental from 14e even under more harsh reaction conditions in the
to the condensation.
presence of pure TFA, CAN, or DDQ.
Treatment of substrates 11a and 11b with an excess
amount of potassium diethylphosphite (formed from an
equimolar mixture of diethylphosphite and tBuOK) gave
transient phosphonates 12a and 12b. To achieve the synthe-
sis of 3-enoyltetramic acid skeletons in a tandem fashion,
these intermediates were not isolated but directly quenched
with the aldehyde R3CHO (Scheme 2).[14] The expected
N,O-diprotected tetramic acids 13a–e were thus formed in
one pot with a multicomponent mixture involving three
chemical transformations. The base-promoted Lacey–
Dieckmann condensation was undertaken concomitantly
with the Michaelis–Becker reaction, releasing activated
phosphonates 12a,b. The Wittig–Horner–Emmons reaction
could then proceed by addition of the aldehyde. It is worth
noting that the early Lacey–Dieckmann condensation did
not proceed when the amine was not protected, an observa-
tion that had already been reported by others.[8a] Moreover,
the reagent ratio used for this step was optimized. An excess
of (EtO)2POK (3 equiv.) was used to perform the Michae-
lis–Becker step. It was reasoned that to perform the Lacey–
Dieckmann condensation simultaneously, 2 equiv. of
tBuOK were necessary to obtain double potassium adducts
12a,b.
Table 1. Compound correspondence (see Scheme 2) and yields.
[a] Yields based on bromoacetoacetamides 11a,b. [b] Yield from
13e. [c] Yield based on the starting DMB-protected compound
14a–d.
To complete this small library of molecules, we synthe-
sized natural tetramic acid 7 in two steps from -tyrosine
methyl ester 8 (Scheme 3). Acylation of 8 in the presence of
diketene afforded the corresponding acetoacetamide 17 in
89% yield. The reaction of 17 under Lacey–Dieckmann
conditions in the presence of tBuOK then afforded natural
product 7 in 68% yield. Interestingly, no N-protection was
required for the cyclization of 17 compared to substrates
11a,b, therefore allowing the reaction to be easily performed
on the gram scale.
Scheme 2. One-pot synthesis of the N,O-diprotected tetramic acids
13a–e and subsequent deprotection steps (yields and substituents
are given in Table 1). Reagents and conditions: (a) 1. 11a,b added
to (EtO)2POK (3 equiv.), tBuOK (2 equiv.), THF, 0 °C, 30 min;
2. R3CHO (1.5 equiv.), THF, 0 °C, 30 min. (b) KF (10 equiv.),
MeOH/H2O (9:1), room temp., 60 min. (c) CH2Cl2/TFA (4:1),
room temp., 60 min.
Scheme 3. Synthesis of compound 7. Reagents and conditions:
(a) diketene (1.2 equiv.), Et3N (1.3 equiv.), CH2Cl2, 0 °C Ǟ room
temp., 2 h (89%). (b) tBuOK (4 equiv.), THF, 0 °C Ǟ room temp.,
16 h (68%).
During this one-pot sequence, the TBS group was par-
tially removed, thus making the purification more difficult.
Slime moulds (Myxomycetes) are related to the Protist
Therefore, we chose to complete the removal of the TBS supergroup Amoebozoa.[15] These brightly colored microor-
group from 13a–d before purification by using a methanolic ganisms feed on fungal spores, bacteria, and other microbes
solution of potassium fluoride. All products 14a–d from growing in soils or plants. We were interested in the anti-
this four-reaction sequence were isolated in ca. 27–35% microbial and antifungal activities of the compounds we
yield by filtration through Sephadex LH20 (Table 1). Other- synthesized, being convinced that such an activity could be
wise TBDPS-protected tetramic acid 13e could be synthe- important in the life cycle of the slime mould Leocarpus
sized in 52% yield by the same one-pot process from 11b. fragilis. We evaluated their antibiotic activity against sapro-
Desilylation of 13e to give 14e still proceeded in lower yields phytic microorganisms (Fusarium oxysporum, Aspergillus
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Total Synthesis of Tyrosine-Derived Tetramic Acid Pigments
Sephadex LH20 gel. Melting points were measured with a Büchi
B-545 apparatus. Optical rotations were recorded at 589 nm with a
Perkin–Elmer polarimeter 341. UV/Vis spectra were recorded with
a Seconam Uvikon 930 spectrometer. IR spectra were recorded
with a Shimadzu 8400S FT spectrometer. NMR spectra were re-
corded with a Bruker AC 300 spectrometer (Dual probe 5 mm) or
with a Bruker Avance I DPX 400 (BBI 1H-BB prode 5 mm). Chem-
ical shifts are given in parts per million and calibrated by using
residual solvent traces as internal standards (CHCl3: 7.27 ppm;
CHD2OD: 3.31 ppm. C5H5N: 8.74/7.58/7.22 ppm). Mass spectra
were recorded with a API QSTAR Pulsar I spectrometer (ESI+).
niger), which can be competitors of the mould in nature,
and also against microorganisms with medical relevance
(Staphyllococcus aureus, Candida albicans). An inhibition of
the growth of F. oxysporum in liquid medium was observed
for 15 and 16 at 0.08 and 0.37 m, respectively, with signifi-
cant inhibition diameters on agar plates (Table 2). Com-
pound 15 was also moderately active against S. aureus. It is
important to mention that unsaturated natural product 5,
an analogue of 15, did not show any activity, making the
saturation of the side chain particularly important.
N-(2,4-Dimethoxybenzyl)-N-(bromoaceto)acetyl-O-tert-butyldi-
methylsilyl-L-tyrosine Methyl Ester (11a): Bromine (67 µL,
Table 2. Antibiotic activities of compounds 15 and 16.
Inhibition diameters[a]
[mm]
MIC90[b]
[mM]
1.3 mmol) was added dropwise at –40 °C to a solution of diketene
(100 µL, 1.3 mmol) in CH2Cl2 (3 mL). To this mixture was immedi-
ately added a solution of N,O-diprotected aminoester 10a (400 mg,
0.87 mmol) in CH2Cl2 (1 mL) followed by NEt3 (242 µL,
1.74 mmol). The temperature was slowly warmed up to –20 °C,
during this time, TLC analysis showed complete disappearance of
the starting material. A saturated solution of NaHCO3 (5 mL) was
added, and the mixture was extracted with CH2Cl2 (2ϫ10 mL).
The organic extracts were washed with brine and concentrated to
give 515 mg of crude product 11a as a clear brown resin (95%
yield). No major impurity was detected by NMR spectroscopy. Rf
= 0.7 (CH2Cl2/MeOH, 99:1). [α]2D0 = +1 (c = 0.2, MeOH). IR (film
Micro-organisms[c]
15
16
15
16
Fusarium oxysporum
Staphyllococcus aureus
18
9
15
0
0.08
–
0.37
–
[a] Agar plates were inoculated with the microorganism before de-
positing the 6 mm cellulose discs containing 10 µL of a 10 mg/mL
DMSO solution of the tested compound (except for 16: 13.7 mg/
mL). The diameters were determined after a minimum of 48 h of
incubation at 25 °C for F. oxysporum and at 30 °C for A. niger, S.
aureus, and C. albicans. [b] The determination of MIC90 (minimum
concentration needed to observe 90% inhibition) was done in 96
well plates containing spores of F. oxysporum in PDB medium and
various concentrations of the compounds. It was measured after
48 h of incubation at 25 °C. [c] No activity was observed on the
other microorganisms tested: C. albicans and A. niger.
on NaCl): ν = 3005, 2951, 2839, 1739, 1612, 1558, 1516, 1438,
˜
1346, 1269, 1211, 1033 cm–1. 1H NMR (300 MHz, CDCl3): δ =
0.19 [2 s, 6 H, (CH3)2Si], 0.99 [s, 9 H, (CH3)3CSi], 3.10 (dd, J =
14.1, 9.3 Hz, 1 H, ArCH2CH), 3.28 (m, 1 H, ArCH2CH), 3.61/3.62
(2 s, 3 H, CO2CH3, s-cis/s-trans), 3.72 (d, J = 15.8 Hz, 1 H)/3.90
(d, J = 17.0 Hz, 1/2 H)/4.26 (d, J = 15.8 Hz, 1/2 H)/ 4.33 (d, J =
17.0 Hz, 1/2 H, ArCH2N, s-cis/s-trans), 3.76/3.78/3.80/3.81 (4 s, 6
H, ArOCH3, s-cis/s-trans), 3.88 (m, 2 H, COCH2CO), 4.09 (d, J =
12.6 Hz, 1 H, COCH2Br), 4.15 (d, J = 12.6 Hz, 1 H, COCH2Br),
4.12 (dd, J = 5.5, J = 9.3 Hz, 1/2 H)/4.38 (dd, J = 6.0, J = 9.0 Hz,
1/2 H, CHN, s-cis/s-trans), 6.40 (m, 2 H, MeO-ArH), 6.74 (m, 2 H,
TBSO-ArH), 6.96 (m, 3 H, TBSO-ArH and MeO-ArH) ppm. 13C
NMR (75 MHz, CDCl3): δ = –4.4 [(CH3)2Si], 18.2 [(CH3)3CSi],
25.7 [(CH3)3CSi], 34.1 (ArCH2CH), 34.5 (COCH2Br), 45.4
(COCH2CO), 47.1/48.9 (ArCH2N, s-cis/s-trans), 52.1/52.2
(CO2CH3, s-cis/s-trans), 60.6/60.7 (CHN, s-cis/s-trans), 98.3/98.5
(MeO-ArH, s-cis/s-trans), 103.7/103.8 (MeO-ArH, s-cis/s-trans),
Conclusions
The total synthesis of 3-acyltetramic acids occurring in
myxomycetes protists has been described. It involved an
original one-pot process during which three different trans-
formations were successfully undertaken. In this work, not
only three natural products (i.e., 57) were synthesized, but
also some analogues with different 3-enoyl moieties. Our
work is complementary to those already existing and pro-
vides some more insight into the reactivity of important
chemical intermediates in tetramic acid chemistry. Further- 115.4/116.0 (MeO-Ar-ipso, s-cis/s-trans), 120.1 (TBSO-ArH), 129.4/
130.4 (MeO-ArH, s-cis/s-trans), 130.2 (TBSO-ArH), 130.6 (TBSO-
Ar-ipso), 154.3 (Ar-OTBS), 158.0/158.7 (Ar-OMe, s-cis/s-trans),
160.7/161.1 (Ar-OMe, s-cis/s-trans), 167.1/172.0 (NCOCH2, s-cis/s-
trans), 170.5/170.9 (CO2CH3, s-cis/s-trans), 196.1 (COCH2Br) ppm.
HRMS (ESI+): calcd. for C29H41NO7SiBr [M + H]+ 622.1830;
found 622.1823.
more, some analogues of the natural products showed sig-
nificant inhibitory activity against the common saprophytic
fungus Fusarium oxysporum. Although we did not observe
this activity with the natural products, the tetramic acids
could be important defensive compounds against microbial
competitors in nature.
General Method for the Synthesis of N-Protected Tetramic Acids
14a–e: (EtO)2P(O)H (66 µL, 0.52 mmol) was added to a suspension
of tBuOK (96 mg, 0.86 mmol) in THF (1 mL) at room temperature.
After stirring for 20 min, the mixture was cooled to 0 °C and a
solution of bromoacetoacetamide 11a (107 mg, 0.172 mmol) in
THF (1 mL) was added quickly. The mixture was stirred at 0 °C
for 30 min before the aldehyde was added [0.258 mmol of (2E,4E)-
2,4-hexadienal, (2E,4E,6E)-2,4,6-octatrienal,[16] hexanal or p-anis-
aldehyde]. After further stirring for 30 min at 0 °C, the reaction
was quenched by adding a saturated solution of NH4Cl and the
pH was adjusted to 3–4 with a 2  solution of citric acid. Extrac-
tion with diethyl ether (3ϫ10 mL) and evaporation of volatiles
gave yellow crude products 13a–d. Desilylation then proceeded by
treatment with a 10  solution of KF (100 µL) in methanol (1 mL)
Experimental Section
General Methods: All reactions were carried out under an atmo-
sphere of argon in anhydrous solvents. THF was distilled from so-
dium/benzophenone. CH2Cl2 and MeOH were distilled from CaH2.
Reagents and starting compounds were purchased from Sigma–Al-
drich, Fluka, Acros Organic, or Alfa Aesar and were used without
further purification, except diketene, which was distilled before use.
Reactions were monitored by TLC on silica gel 60 F254 Merck
1055540001. Visualization was done with a UV lamp and vanillin–
H2SO4 or ninhydrin stains. Purifications were performed on silica
gel 40–60 µm Geduran 9385500 for flash chromatography or on
Eur. J. Org. Chem. 2010, 5402–5408
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N. Riache, C. Bailly, A. Deville, L. Dubost, B. Nay
FULL PAPER
for 1 h at room temperature. After quenching the reaction with a
saturated solution of NH4Cl and adjusting to pH 3–4 with a 2 
solution of citric acid, the mixture was extracted with CH2Cl2
(3ϫ10 mL). Evaporation to dryness gave crude N-protected tet-
ramic acids 14a–d, which were purified by filtration through Se-
phadex LH20 (methanol).
3.90 (m, 4 H, 5-H, OCH3), 4.24 (d, J = 14.6 Hz, 1 H, 1-CH2), 5.04
(d, J = 14.6 Hz, 1 H, 1-CH2), 6.43–6.48 (m, 2 H, 1-ArH), 6.67 (d,
J = 8.3 Hz, 2 H, 5-ArH), 6.91 (d, J = 8.7 Hz, 2 H, 3-ArH), 6.97
(d, J = 8.3 Hz, 2 H, 5-ArH), 7.14 (d, J = 8.9 Hz, 1 H, 1-ArH),
7.55–7.60 (m, 1 H, 3-ArH), 7.75 (d, J = 15.9 Hz, 1 H, 3Ј-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 33.9 (5-CH2), 38.4 (1-CH2), 55.4
(OCH3), 65.1 (C-5), 98.5 (1-C-ArH), 100.7 (C-3), 104.5 (1-C-ArH),
114.5/115.3 (3-C-ArH, 5-C-ArH), 115.7 (C-2Ј), 116.2 (1-C-ipso),
126.9/127.5 (3-C-ipso, 5-C-ipso), 130.7/130.8 (3-C-ArH, 5-C-ArH),
131.4 (1-C-ArH), 143.9 (C-3Ј), 154.9 (5-C-ArO), 158.6 (1-C-ArO),
160.8 (1-C-ArO), 162.1 (3-C-ArO), 173.4 (C-2), 173.8 (C-1Ј), 194.8
(C-4) ppm. HRMS (ESI+): calcd. for C30H29NO7 [M + H]+
516.2016; found 516.2031.
(S)-1-(2,4-Dimethoxybenzyl)-5-(4-hydroxybenzyl)-3-[(2E,4E,6E)-1-hy-
droxyocta-2,4,6-trienylidene]pyrrolidine-2,4-dione (14a): Yellow
resin [29 mg, 35% from 11a and (2E,4E)-2,4-hexadienal]; Rf = 0.2
(CH2Cl2/MeOH, 98:2). [α]2D0 = –17 (c = 0.1, CHCl3). UV/Vis
(MeOH): λ (ε, Lmol–1 cm–1) = 230 (24900), 278 (12500), 392
(35000) nm. IR (film on NaCl): ν = 3350, 2931, 2840, 1735, 1697,
˜
1612, 1554, 1508, 1454, 1292, 1242, 1207, 1157, 1041, 1010 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.86 (d, J = 6.8 Hz, 3 H, 8Ј-H),
3.07 (dd, J = 14.6, 5.0 Hz, 1 H, 5-CH2), 3.15 (dd, J = 14.6, 5.5 Hz,
1 H, 5-CH2), 3.80 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3), 3.80–3.87
(m, 1 H, 5-H), 4.23 (d, J = 14.7 Hz, 1 H, 1-CH2), 5.02 (d, J =
14.7 Hz, 1 H, 1-CH2), 6.00 (dq, J = 15.1, 6.7 Hz, 1 H, 7Ј-H), 6.14–
6.40 (m, 2 H, 4Ј-H, 6Ј-H), 6.42–6.47 (m, 2 H, 1-ArH), 6.61 (dd, J
= 15.0, 10.9 Hz, 1 H, 5Ј-H), 6.66 (d, J = 8.5 Hz, 2 H, 5-ArH), 6.94
(d, J = 8.4 Hz, 2 H, 5-ArH), 7.09 (d, J = 15.1 Hz, 1 H, 2Ј-H), 7.12
(d, J = 8.9 Hz, 1 H, 1-ArH), 7.42 (dd, J = 15.1, 11.3 Hz, 1 H, 3Ј-
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 18.7 (C-8Ј), 33.9 (5-
CH2), 38.4 (1-CH2), 55.4 (OCH3), 65.1 (C-5), 98.5 (1-C-ArH),
100.7 (C-3), 104.5 (1-C-ArH), 115.3 (5-C-ArH), 116.2 (1-C-ipso),
120.5 (C-2Ј), 127.0 (5-C-ipso), 128.9 (C-4Ј), 130.7 (5-C-ArH), 131.4
(1-C-ArH), 131.7 (C-6Ј), 136.7 (C-7Ј), 143.3 (C-5Ј), 144.7 (C-3Ј),
154.7 (5-C-ArO), 158.6 (1-C-ArO), 160.9 (1-C-ArO), 172.9 (C-2),
173.7 (C-1Ј), 194.6 (C-4) ppm. HRMS (ESI+): calcd. for
C28H30NO6 [M + H]+ 476.2067; found 476.2074.
General Method for N-Deprotection: The DMB-protected tetramic
acids were stirred in CH2Cl2/TFA (4:1, 1 mL, for 0.05 mmol) at
room temperature for 1 h. Cyclohexane was then added and the
solvents were evaporated. After two successive evaporations in the
presence of cyclohexane, the crude product was purified by fil-
tration through Sephadex LH20 (methanol).
(S)-5-(4-Hydroxybenzyl)-3-[(2E,4E,6E)-1-hydroxyocta-2,4,6-trienyl-
idene]pyrrolidine-2,4-dione (5): Yellow solid [11 mg, 90% from
18 mg of 14a]; m.p. 172–173 °C; Rf = 0.3 (CH2Cl2/MeOH, 95:5).
[α]2D0 = –9 (c = 0.1, CHCl3). UV/Vis (MeOH): λ (ε, Lmol–1 cm–1) =
231 (19800), 282 (15000), 358 (16000) nm. IR (film on NaCl): ν =
˜
3280, 3063, 3020, 2924, 2854, 1643, 1612, 1597, 1550, 1516, 1431,
1375, 1246, 1203, 1168, 1103, 1037, 1006, 983 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 1.89 (d, J = 6.7 Hz, 3 H, 8Ј-H), 2.57–2.72
(m, 1 H, 5-CH2), 3.21 (dd, J = 14.0, 3.4 Hz, 1 H, 5-CH2), 3.94–
4.01 (m, 1 H, 5-H), 6.00–6.12 (m, 1 H, 7Ј-H), 6.19–6.32 (m, 1 H,
6Ј-H), 6.40 (dd, J = 14.6, 11.6 Hz, 2 H, 4Ј-H), 6.68 (dd, J = 14.9,
11.0 Hz, 1 H, 5Ј-H), 6.78 (d, J = 8.1 Hz, 2 H, 5-ArH), 7.06 (d, J =
8.1 Hz, 2 H, 5-ArH), 7.18 (d, J = 15.1 Hz, 1 H, 2Ј-H), 7.54 (dd, J
= 15.1, 11.4 Hz, 1 H, 3Ј-H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 18.8 (C-8Ј), 37.5 (5-CH2), 63.5 (C-5), 99.6 (C-3), 115.8 (5-C-
ArH), 120.3 (C-2Ј), 128.3 (5-C-ipso), 128.8 (C-4Ј), 130.3 (5-C-ArH),
131.7 (C-6Ј), 137.4 (C-7Ј), 144.2 (C-5Ј), 145.9 (C-3Ј), 155.0 (5-C-
ArO), 174.8 (C-2), 175.4 (C-1Ј), 194.1 (C-4) ppm. HRMS (ESI+):
calcd. for C19H20NO4 [M + H]+ 326.1386; found 326.1395.
(S)-1-(2,4-Dimethoxybenzyl)-5-(4-hydroxybenzyl)-3-[(2E,4E,6E,8E)-
1-hydroxydeca-2,4,6,8-tetraenylidene]pyrrolidine-2,4-dione
(14b):
Red-orange resin [23 mg, 7% from 11a and (2E,4E,6E)-2,4,6-octa-
trienal]; Rf = 0.2 (CH2Cl2/MeOH, 98:2). [α]2D0 = –19 (c = 0.1,
CHCl ). IR (film on NaCl): ν = 3333, 3020, 2935, 2839, 1616, 1573,
˜
3
1539, 1508, 1454, 1361, 1265, 1230, 1207, 1157, 1111, 1033, 1010,
987, 925, 887, 821, 736 cm–1. 1H NMR (300 MHz, CDCl3): δ =
1.84 (d, J = 6.7 Hz, 3 H, 10Ј-H), 3.10 (m, 2 H, 5-CH2), 3.80 (s, 6 H,
OCH3), 3.82 (dd, J = 8.6, 4.4 Hz, 1 H, 5-H), 4.23 (d, J = 14.7 Hz, 1
H, 1-CH2), 5.02 (d, J = 14.7 Hz, 1 H, 1-CH2), 5.84–5.98 (m, 1 H,
9Ј-H), 6.11–6.45 (m, 4 H, 4Ј-H, 6Ј-H, 7Ј-H, 8Ј-H), 6.45–6.48 (m, 2
H, 1-ArH), 6.60–6.72 (m, 3 H, 5Ј-H, 5-ArH), 6.95 (d, J = 8.3 Hz,
2 H, 5-ArH), 7.09 (d, J = 15.2 Hz, 1 H, 2Ј-H), 7.13 (d, J = 8.9 Hz,
1 H, 1-ArH), 7.44 (dd, J = 15.2, 11.4 Hz, 1 H, 3Ј-H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 18.6 (C-10Ј), 33.9 (5-CH2), 38.4 (1-
CH2), 55.4 (OCH3), 65.1 (C-5), 98.5 (1-C-ArH), 100.7 (C-3), 104.5
(1-C-ArH), 115.3 (5-C-ArH), 116.2 (1-C-ipso), 120.6 (C-2Ј), 126.9
(5-C-ipso), 129.8/130.4/131.4/131.7/134.2 (1-C-ArH, C-4Ј, C-6Ј, C-
8Ј, C-9Ј) 130.7 (5-C-ArH), 138.8 (C-7Ј), 143.3 (C-5Ј), 146.1 (C-3Ј),
154.8 (5-C-ArO), 158.6 (1-C-ArO), 160.9 (1-C-ArO), 172.8 (C-2),
173.7 (C-1Ј), 194.6 (C-4) ppm. HRMS (ESI+): calcd. for
C30H32NO6 [M + H]+ 502.2224; found 502.2218.
(S)-5-(4-Hydroxybenzyl)-3-[(2E,4E,6E,8E)-1-hydroxydeca-2,4,6,8-
tetraenylidene]pyrrolidine-2,4-dione (6): Red-orange resin [8 mg,
72% from 16 mg of 14b]; Rf = 0.3 (CH2Cl2/MeOH, 95:5). [α]2D0
=
–35 (c = 0.05, CHCl3). UV/Vis (MeOH): λ (ε, Lmol–1 cm–1) = 230
(30900), 281 (22400), 378 (34300) nm. IR (film on NaCl): ν = 3390,
˜
3020, 2920, 2855, 1651, 1616, 1573, 1539, 1516, 1427, 1230, 1172,
1
1010, 984, 895, 817, 756 cm–1. H NMR (400 MHz, CD3OD): δ =
1.82 (d, J = 6.7 Hz, 3 H, 10Ј-H), 2.84–2.90 (m, 1 H, 5-CH2), 2.99
(dd, J = 14.1, 4.4 Hz, 1 H, 5-CH2), 4.07 (br. s, 1 H, 5-H), 5.90–
5.99 (m, 1 H, 9Ј-H), 6.13–6.36 (m, 2 H, 6Ј-H, 8Ј-H), 6.42–6.55 (m,
2 H, 4Ј-H, 7Ј-H), 6.66 (d, J = 8.4 Hz, 2 H, 5-ArH), 6.77–6.82 (m,
1 H, 5Ј-H), 6.98 (d, J = 8.4 Hz, 2 H, 5-ArH), 7.08 (d, J = 15.2 Hz,
1 H, 2Ј-H), 7.53 (dd, J = 15.2, 11.4 Hz, 1 H, 3Ј-H) ppm. 13C NMR
(100 MHz, CD3OD, assignments on the basis of HSQC and
HMBC correlations): δ = 18.6 (C-10Ј), 37.5 (5-CH2), 64.0 (C-5),
116.0 (5-C-ArH), 120.9 (C-2Ј), 127.7 (5-C-ipso), 131.0 (C-6Ј), 131.3
(C-7Ј), 131.7 (5-C-ArH), 133.0 (C-8Ј), 135.1 (C-9Ј), 140.7 (C-4Ј),
145.4 (C-5Ј), 146.2 (C-3Ј), 157.2 (5-C-ArO), 174.9 (C-2, C-1Ј),
197.0 (C-4) [C-3 not assigned] ppm. HRMS (ESI+): calcd. for
C21H22NO4 [M + H]+ 352.1543; found 352.1555.
(S)-1-(2,4-Dimethoxybenzyl)-5-(4-hydroxybenzyl)-3-[(2E)-1-hy-
droxy-3-(4-methoxyphenyl)prop-2-enylidene]pyrrolidine-2,4-dione
(14d): Yellow solid [30 mg, 34% from 11a and p-anisaldehyde]; m.p.
113–114 °C; Rf = 0.6 (CH2Cl2/MeOH, 96:4). [α]2D0 = –11 (c = 0.1,
CHCl3). UV/Vis (MeOH): λ (ε, Lmol–1 cm–1) = 231 (24200), 401
(35300) nm. IR (film on NaCl): ν = 3333, 3063, 3001, 2931, 2839,
˜
1620, 1597, 1581, 1566, 1508, 1454, 1419, 1292, 1257, 1207, 1172,
1134, 1111, 1030, 979, 929, 887, 825, 783, 732 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 3.08 (dd, J = 14.4, 4.6 Hz, 1 H, 5-CH2),
(S)-5-(4-Hydroxybenzyl)-3-[(2E)-1-hydroxyocta-2-enylidene]pyrrol-
idine-2,4-dione (15): Intermediate 14c was first obtained according
to the general method described above as a pale yellow resin
3.15 (dd, J = 14.4, 3.8 Hz, 1 H, 5-CH2), 3.80 (s, 6 H, OCH3), 3.84– (25 mg, 31% from 11a and of hexanal). It was then deprotected to
5406 Eur. J. Org. Chem. 2010, 5402–5408
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Total Synthesis of Tyrosine-Derived Tetramic Acid Pigments
give compound 15 as pale yellow resin (17 mg, 99% yield). Data
for 14c: Rf = 0.2 (CH2Cl2/MeOH, 98:2). 1H NMR (300 MHz,
(COCH2CO), 52.0 (CO2CH3), 53.6 (CHN), 115.3 (C-ArH), 126.5
(C-ipso), 130.0 (C-ArH), 155.5 (C-ArO), 166.3 (NHCO), 171.7
CDCl3): δ = 0.90 (t, J = 7.0 Hz, 3 H, 8Ј-H), 1.24–1.39 (m, 4 H, 6Ј- (CO2CH3), 203.8 (COCH3) ppm. HRMS (ESI+): calcd. for
H, 7Ј-H), 1.41–1.52 (m, 2 H, 5Ј-H), 2.28 (q, J = 6.6 Hz, 2 H, 4Ј-
H), 3.07–3.13 (m, 2 H, 5-CH2), 3.80 (s, 6 H, OCH3), 3.81–3.87 (m,
1 H, 5-H), 4.23 (d, J = 14.6 Hz, 1 H, 1-CH2), 5.03 (d, J = 14.6 Hz,
1 H, 1-CH2), 6.43–6.48 (m, 2 H, 1-ArH), 6.66 (d, J = 8.4 Hz, 2 H,
5-ArH), 6.95 (d, J = 8.4 Hz, 2 H, 5-ArH), 7.00–7.22 (m, 3 H, 2Ј-
H, 3Ј-H, 1-ArH) ppm. Data for 15: Rf = 0.3 (CH2Cl2/MeOH, 95:5).
[α]2D0 = –3 (c = 0.2, CHCl3). UV/Vis (MeOH): λ (ε, Lmol–1 cm–1) =
C14H18NO5 [M + H]+ 280.1179; found 280.1178.
(S)-5-(4-Hydroxybenzyl)-3-[1-hydroxyethylidene]pyrrolidine-2,4-di-
one (7): To a solution of acetoacetamide 17 (134 mg, 0.48 mmol)
in THF (5 mL) was added tBuOK (234 mg, 1.92 mmol) at 0 °C.
The resulting mixture was stirred for 15 h at room temperature.
Quenching with 1  HCl (3 mL) was followed by extraction with
AcOEt (3ϫ5 mL). The organic extracts were combined and
washed with water (10 mL) and brine (10 mL) and dried with
MgSO4 before evaporation. Purification by silica gel chromatog-
raphy (CH2Cl2/MeOH, 1:0Ǟ8:2) gave compound 7 as a white solid
(81 mg, 68%). M.p. 185–186 °C; Rf = 0.3 (CH2Cl2/MeOH, 8:2).
[α]2D0 = +34 (c = 0.3, CHCl3). UV/Vis (MeOH): λ (ε, Lmol–1 cm–1)
234 (75600), 321 (98000) nm. IR (film on NaCl): ν = 3294, 3020,
˜
2955, 2928, 2858, 1643, 1573, 1516, 1438, 1361, 1300, 1261, 1207,
1172, 1107, 1033, 987, 929, 895, 868, 817, 756, 725 cm–1. 1H NMR
(400 MHz, CD3OD): δ = 0.93 (t, J = 6.8 Hz, 3 H, 8Ј-H), 1.32–1.39
(m, 4 H, 6Ј-H, 7Ј-H), 1.48–1.55 (m, 2 H, 5Ј-H), 2.32 (q, J = 7.5 Hz,
2 H, 4Ј-H), 2.87 (dd, J = 8.1, 6.0 Hz, 1 H 5-CH2), 2.99 (dd, J =
14.1, 4.4 Hz, 1 H, 5-CH2), 4.03–4.09 (m, 1 H, 5-H), 6.66 (d, J =
8.5 Hz, 2 H, 5-ArH), 6.98 (d, J = 8.5 Hz, 2 H, 5-ArH), 7.06 (d, J
= 15.7 Hz, 1 H, 2Ј-H), 7.16 (dt, J = 15.7, 6.6 Hz, 1 H, 3Ј-H) ppm.
13C NMR (100 MHz, CD3OD): δ = 14.3 (C-8Ј), 23.5 (C-7Ј), 28.9
(C-5Ј), 32.5 (C-6Ј), 34.1 (C-4Ј), 37.6 (5-CH2), 69.0 (C-5), 103.6 (C-
3), 116.1 (5-C-ArH), 122.2 (C-3Ј), 127.7 (5-C-ipso), 131.8 (5-C-
ArH), 151.7 (C-2Ј), 157.3 (5-C-ArO), 175.4 (C-2), 187.5 (C-1Ј),
197.6 (C-4), [C-3, C-4 and C-1Ј were assigned on the basis of
HMBC correlations] ppm. HRMS (ESI+): calcd. for C19H24NO4
[M + H]+ 330.1699; found 330.1696.
= 228 (11800), 278 (3700) nm. IR (film on NaCl): ν = 3317, 3070,
˜
3024, 2962, 2932, 1710, 1647, 1516, 1446, 1361, 1230, 1172,
1
1114 cm–1. H NMR (300 MHz, CD3OD): δ = 2.22 (s, 3 H, 2Ј-H),
3.31 (dd, J = 14.0, 7.9 Hz, 1 H, 5-CH2), 3.54 (dd, J = 14.0, 5.2 Hz,
1 H, 5-CH2), 5.46–5.38 (m, 1 H, 5-H), 7.08 (d, J = 8.4 Hz, 2 H,
ArH), 7.37 (d, J = 8.4 Hz, 2 H, ArH), 9.29 (d, J = 8.2 Hz, 1 H,
NH) ppm. 13C NMR (75 MHz, C5D5N): δ = 29.9 (C-2Ј), 37.7 (5-
CH2), 55.1 (C-5), 91.8 (C-3, weak), 116.3 (C-ArH), 128.4 (C-ipso),
131.1 (C-ArH), 157.8 (C-ArO), 166.8 (C-2), 174.7 (C-4), 203.0 (C-
4) ppm. HRMS (ESI+): calcd. for C13H14NO4 [M + H]+ 248.0917;
found 248.0926.
(S)-5-(4-Hydroxybenzyl)-3-[(2E)-1-hydroxy-3-(4-methoxyphenyl)-
prop-2-enylidene]pyrrolidine-2,4-dione (16): Yellow solid [11 mg,
83% from 19 mg of 14d]; m.p. 215–216 °C; Rf = 0.3 (CH2Cl2/
MeOH, 95:4). [α]2D0 = –7 (c = 0.1, CHCl3). UV/Vis (MeOH): λ (ε,
Lmol–1 cm–1) = 232 (18600), 248 (15200), 393 (40500) nm. IR (film
Acknowledgments
We are grateful to the French Ministry of Higher Education and
Research (MESR) for providing a research fellowship to Dr. Nas-
sima Riache (2006–2009). Mr. Jean-Louis Cheype is gratefully ac-
knowledged for providing a very nice picture of L. fragilis for the
graphical abstract.
on NaCl): ν = 3333, 3186, 2924, 2854, 1651, 1627, 1558, 1512, 1419,
˜
1246, 1168, 1103, 1022, 976, 933, 871, 810, 717 cm–1. 1H NMR
(300 MHz, CD3OD): δ = 2.93 (dd, J = 14.0, 8.2 Hz, 1 H, 5-CH2),
3.12 (dd, J = 14.0, 5.0 Hz, 1 H, 5-CH2), 3.84 (s, 3 H, OCH3), 4.65
(dd, J = 8.2, 5.0 Hz, 1 H, 5-H), 6.69 (d, J = 8.4 Hz, 2 H, 5-ArH),
6.71 (d, J = 16.1 Hz, 1 H, 2Ј-H), 6.97 (d, J = 8.7 Hz, 2 H, 5-ArH),
7.06 (d, J = 8.4 Hz, 2 H, 3-ArH), 7.57 (d, J = 8.1 Hz, 2 H, 3-
ArH), 7.61 (d, J = 16.1 Hz, 1 H, 3Ј-H) ppm. 13C NMR (75 MHz,
CD3OD): δ = 37.6 (5-CH2), 55.5 (C-5), 55.9 (OCH3), 100.7 (C-3,
weak), 115.5–116.2 (3-C-ArH, 5-C-ArH), 124.1 (C-2Ј), 128.3–128.9
(3-C-ipso, 5-C-ipso), 131.3–131.6 (3-C-ArH, 5-C-ArH), 146.1 (C-
3Ј), 157.3 (5-C-ArO), 163.6 (3-C-ArO), 169.2 (C-2), 174.6 (C-1Ј),
195.8 (C-4) ppm. HRMS (ESI+): calcd. for C21H19NO5 [M + H]+
366.1335; found 366.1342.
[1] a) B. J. L. Royles, Chem. Rev. 1995, 95, 1981–2001; b) R. Scho-
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Kobayashi, Tetrahedron 2002, 58, 6655–6658.
N-Acetoacetyl-L-tyrosine Methyl Ester (17): A solution of diketene
(600 µL, 7.8 mmol) in CH2Cl2 (6 mL) was added at 0 °C to a solu-
tion of -tyrosine methyl ester hydrochloride (1.5 g, 6.48 mmol) and
NEt3 (1.2 mL, 8.42 mmol) in CH2Cl2 (15 mL). After 2 h stirring at
room temperature, the mixture was neutralized with a 5% aqueous
HCl solution (20 mL) and extracted with CH2Cl2 (30 mL). The or-
ganic extract was washed with brine (20 mL) and dried with
Na2SO4 before evaporation. Purification by silica gel chromatog-
raphy (CH2Cl2/MeOH, 99:1) afforded 1.42 g of acetoacetamide 17
as a colorless resin (78% yield). Rf = 0.4 (CH2Cl2/MeOH, 95:5).
[5] H. Oikawa, J. Org. Chem. 2003, 68, 3552–3557.
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Angew. Chem. 2010, 122, 893–897; Angew. Chem. Int. Ed. 2010,
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[α]2D0 = +20 (c = 0.3, MeOH). IR (film on NaCl): ν = 3317, 1716,
˜
1651, 1516, 1438, 1361, 1222, 1172, 1118 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 2.21 (s, 3 H, COCH, 2Ј-H), 2.98 (dd, J =
14.0, 6.9 Hz, 1 H, ArCH2), 3.10 (dd, J = 14.0, 5.5 Hz, 1 H, ArCH2),
3.38 (s, 2 H, COCH2CO), 3.74 (s, 3 H, CO2CH3), 4.84 (m, 1 H,
CHN), 5.30 (s, 1 H, OH), 6.73 (d, J = 8.4 Hz, 2 H, ArH), 6.99 (d,
J = 8.4 Hz, 2 H, ArH), 7.41 (d, J = 7.4 Hz, 1 H, NH) ppm. 13C
NMR (75 MHz, C5D5N): δ = 30.0 (COCH3), 36.5 (ArCH2), 49.3
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[13] Other protecting groups have been reported: a) for the use of
a PMB group, see: C. V. Ramana, M. A. Mondala, V. G. Pur-
Eur. J. Org. Chem. 2010, 5402–5408
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5407

N. Riache, C. Bailly, A. Deville, L. Dubost, B. Nay
FULL PAPER
anika, M. K. Gurjar, Tetrahedron Lett. 2006, 47, 4061–4064; b)
for the use of a Boc group, see ref.[11]; c) for the use of a p-
azidobenzyl group (PAB), see ref.[9]
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[14] Purification of phosphonates 12a,b was not possible in our
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Received: April 29, 2010
Published Online: August 16, 2010
5408
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5402–5408