Stereoselective synthesis of biologically active tetronic acids

Article abstract of DOI:10.1016/S0957-4166(98)00040-8

(4R)-3-Amino-4-trimethylsilyloxy-2-alkenoates (R)-3, obtained from O- trimethylsilyl protected optically active cyanohydrins (R)-1 via the Blaise reaction, are hydrolyzed under mildly acidic conditions to give optically active tetronic acids (R)-4 without

Full text of DOI:10.1016/S0957-4166(98)00040-8

Pergamon
Tetrahedron: Asymmetry 9 (1998) 817–825
Stereoselective synthesis of biologically active tetronic acids1
Franz Effenberger ∗ and Jana Syed †
Institut für Organische Chemie der Universität Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
Received 5 January 1998; accepted 26 January 1998
Abstract
(4R)-3-Amino-4-trimethylsilyloxy-2-alkenoates (R)-3, obtained from O-trimethylsilyl protected optically active
cyanohydrins (R)-1 via the Blaise reaction, are hydrolyzed under mildly acidic conditions to give optically active
tetronic acids (R)-4 without racemization. From the follow-up reactions of (R)-4 investigated, only methylation
with diazomethane afforded the biologically active tetronic acid derivative (R)-5a without racemization whereas
acylation and reductive alkylation, respectively, resulted in partial racemization or failed on the whole. © 1998
Elsevier Science Ltd. All rights reserved.
Tetronic acid derivatives and their metabolites are widespread in nature, whereof vitamin C and
penicillic acid are undoubtedly the most important.2 Natural 4-ylidenetetronic acid derivatives known
as pulvinic acids have been found as pigments in lichens and higher fungi.3 Tetronic acid derivatives
are interesting because of their antibiotic,4 antitumor,5 anticoagulant,6 antiepileptic,7 antifungal,4b,8
insecticidal,9 analgesic10 and antiinflammatory10b,11 properties. In recent times tetronic acid derivatives
have also become important as HIV-1 protease inhibitors.12 Most of the investigated tetronic acids with
chiral centres are applied only as racemates.5c,6b,c,7,8a,13
Optically active tetronic acid derivatives were synthesized mostly by Dieckmann cyclizations starting
from ‘chiral pool’ compounds such as (S)-lactic acid, (S)-mandelic acid, (S)-malic acid or (R,R)-tartaric
acid.14 For the preparation of 5-aryl-3-hydroxytetronic acids, which are very sensitive to racemization,
O-protected mandelaldehydes were used as starting materials.15 The enantioselective synthesis of 5-
substituted 3-methyltetronic acids, starting from chiral ethyl 2-methyl-3-(1-phenylethoxy)acrylate, was
achieved by optical induction with very high enantiomeric excesses.16
Only two papers have been published on the synthesis of chiral tetronic acids starting from optically
active cyanohydrins. In the first one, the Blaise reaction was applied to the O-protected optically
active cyanohydrin from trifluoroacetaldehyde.17 Acidic workup of the addition products gave the
corresponding trifluoromethyl tetronic acid derivatives.17 The optical purity of the obtained products
∗
†
Corresponding author. E-mail: franz.effenberger@po.uni-stuttgart.de
Part of dissertation, Universität Stuttgart, 1997.
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00040-8

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was not determined.17 In the second publication, which appeared very recently,18 the synthesis of four
chiral 5-substituted 3-methyltetronic acids is described.
In the preceding paper, the synthesis of (4R)-3-amino-4-hydroxyalkenoates by Blaise reaction with
(R)-cyanohydrins is described.1 We have now used these γ-hydroxy esters for the preparation of the
corresponding chiral tetronic acid derivatives. In follow-up reactions the possibilities of the preparation
of specially substituted tetronic acid derivatives with known biological activities were investigated.
1. Hydrolysis and cyclization of (R)-tert-butyl 3-amino-4-trimethylsilyloxyalkenoates (R)-3 to (R)-
tetronic acids (R)-4
The (R)-enaminoesters (R)-3, derived from O-trimethylsilylated (R)-cyanohydrins (R)-1 by Blaise
reaction with the Reformatsky reagents 2,1 were lactonized under acid catalysis in tetrahydrofuran (THF)
or methanol with removal of the O-protecting group via intermediates A to (R)-tetronic acids (R)-4
(Scheme 1, Table 1).
Scheme 1.
Table 1
Acid-catalyzed cyclization of (R)-enaminoesters 3 to (R)-tetronic acids 4

F. Effenberger, J. Syed / Tetrahedron: Asymmetry 9 (1998) 817–825
819
The lactonization of the aliphatic enaminoesters (R)-3b–d proceeded without racemization. After re-
crystallization the (R)-tetronic acids (R)-4b–d were isolated with high ee values of 94–96% (Table 1). (R)-
3a, however, was cyclized to (R)-4-hydroxy-5-phenyl-2(5H)-furanone (R)-4a with partial racemization.
The enantiomeric excess could be increased to 93% by recrystallization. Only the 5-octyltetronic acid
derivative (R)-4e was obtained, also after recrystallization, with only 79% ee (Table 1).
While hydrolysis of the enamino group is finished after just 1 hour, the cyclization, especially of
sterically hindered intermediates A, requires a reaction time of several days. In the case of 3a, using a
10% HCl/diethyl ether system as a milder hydrolysis medium, we were able to isolate intermediate A
(R=Ph, R1=H) in 55% yield after 4 hours reaction time.
Also the enaminoesters 3f–h, derived from the corresponding O-protected ketone cyanohydrins, were
converted under acid catalysis to tetronic acids 4f–h with good yields (Scheme 2, Table 1).
Scheme 2.
Tetronic acid derivatives are known to exist as solids and in alcoholic solution in their enol form.2b For
solutions of 4 in chloroform we have found the enol form to be dominant for tetronic acids (R)-4a,c,d
and 4g,h while the keto form predominates in derivatives (R)-4b,e and 4f (see Experimental).
2. Follow-up reactions of tetronic acids 4 to compounds of known biological activity
O-Methylation, α-acylation and α-alkylation of (R)-tetronic acids (R)-4 should offer an approach to
optically active derivatives which are of pharmacological interest and are known so far only as racemates.
As starting compounds for the follow-up reactions we have applied (R)-4a and 4f. In Scheme 3 both
methylation and acylation of these derivatives are illustrated.
Scheme 3.
Methylation was examined first with racemic tetronic acid 4a. 4a was reacted with methanolic HCl
solution (1%) according to literature-known procedures19 to give the 4-methoxy substituted derivative 5a
in 47% yield. Methylation of the caesium salt of 4a with iodomethane gave compound 5a in 50% yield.
In this case, methylation at the 3-position also occurred to give 4-methoxy-3-methyl-5-phenyl-2(5H)-
furanone in 10% yield besides 5a.

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F. Effenberger, J. Syed / Tetrahedron: Asymmetry 9 (1998) 817–825
Methylation with diazomethane in diethyl ether/methanol at 0°C, giving the best results with racemic
4a, was also used for (R)-4a (93% ee) (Scheme 3). By this procedure we are able to obtain optically
active (R)-5a without any racemization in 62% yield and 93% ee, which, in racemic form, is known to
be more than 30 times as active as the natural antibiotic penicillic acid.20 The isomeric 2-O-methylated
(R)-5a0 formed as a by-product in 14% yield, could be separated readily by chromatography on silica
gel.
Under analogous conditions the methylated tetronic acids 5b and 5b0 were obtained (Scheme 3). After
chromatographic separation, 5b0 was isolated in 18% yield while the yield of the desired 5b (37%) is
clearly lower than that of (R)-5a.
Acetylation of (R)-4a appeared to open an access to optically active α-acetyl-γ-phenyltetronic acid 6,
which has been synthesized so far in racemic form as an antitumor agent.5c The reaction of (R)-4a, based
on the Friedel–Crafts acylation of racemic 4a described by Andresen et al.,21 with acetyl chloride in the
presence of TiCl4 gave compound 6 in 45% yield, but with complete racemization (Scheme 3). On the
other hand, all attempts failed to prepare 6 in pure form by conversion of 4a with acetic anhydride in the
presence of triethylamine and 4-dimethylaminopyridine and subsequent Fries rearrangement.
As a further pharmacologically potent tetronic acid we have chosen 3-[1-(4-chlorophenyl)butyl]-5-
phenyltetronic acid derivative 8,6a,c which should be accessible by direct alkylation of γ-phenyltetronic
acid 4a. However, neither the alkylation of 4a with α-(n-propyl)-p-chlorobenzyl alcohol22 in the presence
of BF3·Et2O in dioxane nor the sodium iodide assisted reaction of the lithium salt of 4a with α-(n-
propyl)-p-chlorobenzyl bromide23 in THF/tetramethylenediamine has been successful.
The alternative route to tetronic acid derivative 8, based on a known methodology,12b is outlined
in Scheme 4. The reaction sequence involves an aldol condensation with p-chlorobenzaldehyde to
intermediate 7 and subsequent addition of propylmagnesium bromide to give compound 8.
Scheme 4.
The aldol condensation in THF in the presence of a twofold excess of AlCl3 (based on 4a) gave
compound 7 as a yellow fluorescent oil in 88% crude yield. 7 was reacted without purification with the
Grignard reagent at −78°C in THF under catalysis by a CuBr·SMe2 complex to give regioselectively
tetronic acid derivative 8 as a congealing yellow oil in 90% crude yield. In contrast to intermediate 7,
derivative 8 is stable. We were not able to obtain 8 in pure form by this procedure because impurities could
not be separated either by distillation or by chromatography, and recrystallization was not successful.
For characterization, compound 8 was derivatized with diazomethane as described above to give
the corresponding 4-O- and 2-O-methylated derivatives 9 and 90 in 24% and 14% yield (based on

F. Effenberger, J. Syed / Tetrahedron: Asymmetry 9 (1998) 817–825
821
1
4a), respectively, after chromatography on silica gel. As stated by H NMR spectra, all tetronic acid
derivatives 8 and 9, 90 exist in a diastereomeric ratio of 1:1.
3. Experimental
3.1. Materials and methods
AlCl3 was purchased from Aldrich, p-chlorobenzaldehyde, TiCl4 and CuBr·SMe2 complex from
Fluka, and Celite 503 from Roth. (4R)-tert-butyl 3-amino-4-trimethylsilyloxy-2-alkenoates 3 were
prepared according to methods described elsewhere.1 All solvents were purified and dried as described
in the literature. Melting points were determined on a Büchi SMP-20 apparatus and are uncorrected.
1H NMR spectra were recorded on a Bruker AC 250 F with TMS as an internal standard. Optical
rotations were determined in a Perkin–Elmer polarimeter 241 LC. Preparative column chromatography
was performed with glass columns of different sizes packed with silica gel S, grain size 0.032–0.063
mm (Riedel-de Haen). GC for the determination of enantiomeric excess: Carlo Erba HRGC 5300 Mega
Series with FID, Carlo Erba Mega Series integrator, 0.4–0.5 bar hydrogen, column 20 m, phase OV
1701 or PS086 with bonded β-cyclodextrin Bondex-un-5.5-Et-105. High resolution mass spectra were
obtained with a Varian MAT 711 electron impact spectrometer by using the peak-matching method.
3.2. Acid-catalyzed cyclization of (R)-3a–e to (R)-tetronic acids (R)-4a–e; general procedure
Aqueous HCl (20%, 2 and 15 ml for 3e,a; 10%, 20–38 ml) was added to an ice-cold solution of (R)-
3a–d (3.1–7.5 mmol) in THF or (R)-3e (2.8 mmol) in methanol under a nitrogen atmosphere, and the
reaction mixture was stirred at room temperature for the given time (Table 1). The reaction mixture was
saturated with NaCl and extracted several times with diethyl ether. The combined extracts were dried
(MgSO4), concentrated, and the crude products (R)-4 recrystallized from ethyl acetate/petroleum ether
(4a,b,d), from ethyl acetate (4c), and from n-hexane (4e).
3.3. Determination of enantiomeric excesses of (R)-4a–e
Pyridine (5 µl) and acetic anhydride (20 µl) were added to a solution of 4 (5 mg) in 200 µl
dichloromethane. The reaction mixture was heated to 60°C for 2 h and then filtered through a silica
gel column (0.5×3 cm) with 5 ml dichloromethane. The enantiomeric excess was determined by gas
chromatography directly from the filtrate on Bondex-unβ-5.5-Et-105.
3.4. Acid-catalyzed cyclization of 3f–h to tetronic acids 4f–h; general procedure
Aqueous 20% HCl (3–15 ml) was added to an ice-cold solution of 3 (6.8–25.6 mmol) in THF or
methanol (for 3h) under an N2 atmosphere, and the reaction mixture was stirred for the time given in
Table 1. The tetronic acids 4 were worked up as follows: 4f: the reaction mixture was set to pH 8 with
sat. Na2CO3 solution and extracted with ethyl acetate. The aqueous phase was again acidified with HCl
and extracted several times with ethyl acetate. The combined organic phases were dried (MgSO4) and
concentrated to yield 4f as an orange oil;24 4g25: as described above (Section 3.2); 4h25: after removal
of methanol in vacuo, the residual aqueous phase was extracted several times with ethyl acetate. The

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F. Effenberger, J. Syed / Tetrahedron: Asymmetry 9 (1998) 817–825
combined extracts were dried (MgSO4), concentrated and the product (white crystals) washed with ethyl
acetate and dried.
3.5. Methylation of (R)-4a to 4-O- and 2-O-methylated furanones (R)-5a and (R)-5a0
A solution of 0.2 M diazomethane in diethyl ether was added dropwise to a solution of (R)-4a (105.3
mg, 0.6 mmol) in 8 ml diethyl ether/2.6 ml methanol at 0°C. The reaction mixture was stirred for a
further 2 h at 0°C. After removal of the solvent, the crude product was chromatographed on silica gel
with petroleum ether:ethyl acetate (65:35) to give (R)-5a and (R)-5a0.
1
(R)-5a: 71.2 mg (62%) as white crystals, m.p. 77–78°C, 93% ee; H NMR (CDCl3) δ=3.80 (s, 3H,
OCH3), 5.16 (d, J=1.3 Hz, 1H, CH), 5.70 (d, J=1.3 Hz, 1H, CH), 7.20–7.40 (m, 5H, Ph). Anal. Calcd for
C11H10O3: C, 69.46; H, 5.30. Found: C, 69.60; H, 5.45.
1
(R)-5a0: 16 mg (14%) as white crystals; H NMR (CDCl3) δ=4.05 (s, 3H, OCH3), 4.86 (s, 1H, CH),
5.53 (s, 1H, CH), 7.36–7.43 (m, 5H, Ph).

F. Effenberger, J. Syed / Tetrahedron: Asymmetry 9 (1998) 817–825
823
3.6. Methylation of 4f to 4-O- and 2-O-methylated furanones 5b and 5b0
A solution of 0.4 M diazomethane in diethyl ether was added dropwise to a solution of 4f (830 mg, 4.27
mmol) in dry diethyl ether and 25 ml dry ethanol at 0°C. After stirring for a further 2 h at 0°C, solvents
were removed, and the crude product was chromatographed on silica gel with petroleum ether:ethyl
acetate (1:1) to give 5b and 5b0.
5b:26 325 mg (37%) as a light yellow oil; 1H NMR (CDCl3) δ=1.00 (t, J=7.5 Hz, 3H, CH3), 1.56 (s,
3H, CH3), 2.11 (dq, J=7.3 Hz, 2H, CH2CH), 3.88 (s, 3H, OCH3), 4.96 (s, 1H, CH), 5.56 (d, J=15.4 Hz,
1H, _CH), 5.83 (dt, J=6.3, 15.2 Hz, 1H, CH2CH), 6.00 (dd, J=10.0, 15.2 Hz, 1H, _CH–CH), 6.34 (dd,
J=10.1, 15.4 Hz, 1H, CH–CH_).
1
5b0: 164.2 mg (18%) as white solid; H NMR (CDCl3) δ=0.99 (t, J=7.4 Hz, 3H, CH3), 1.56 (s, 3H,
CH3), 2.10 (dq, J=7.0 Hz, 2H, CH2CH), 3.99 (s, 3H, OCH3), 4.70 (s, 1H, CH), 5.60 (d, J=15.4 Hz,
1H, _CH), 5.81 (dt, J=6.4, 15.1 Hz, 1H, CH2CH), 6.00 (dd, J=10.4, 15.1 Hz, 1H, _CH–CH), 6.33 (dd,
J=10.2, 15.4 Hz, 1H, CH–CH_).
3.7. α-Acylation of (R)-4a to tetronic acid derivative 6 according to Andresen et al.21
A mixture of (R)-4a (273 mg, 1.55 mmol), acetyl chloride (119 µl, 1.7 mmol) and TiCl4 (350 µl, 3.3
mmol) was stirred at room temperature for 5 min followed by heating to 110°C for 3 h. The reaction
mixture was then poured into an ice-cold 4 N solution of HCl and extracted with chloroform. The
combined organic phases were extracted with a solution of Na2CO3 (10%). The aqueous phase was
acidified with conc. HCl and extracted several times with chloroform. The combined extracts were dried
(MgSO4), concentrated, and the remaining crystals recrystallized from ethyl acetate/petroleum ether to
give 152 mg (45%) racemic 6 as white crystals, m.p. 104–105°C.
3.8. Preparation of tetronic acid derivative 8
(a) According to Chrusciel et al12b p-chlorobenzaldehyde (0.8 g, 5.7 mmol) and AlCl3 (1.42 g, 10.6
mmol) were added to a solution of 4a (0.96 g, 5.4 mmol) in 38 ml THF, and the reaction mixture was
stirred for 46 h at room temperature in the absence of light. After addition of Na2CO3·10H2O (1.1 g
Na2CO3 and 1.9 ml H2O) followed by anhydrous Na2CO3 (1.1 g), the reaction mixture was stirred for
10 min and then filtered through a short Celite column. The filtrate was concentrated in vacuo, and the
residue taken up in 40 ml ethyl acetate and filtered once more through a Celite column. The filtrate was
concentrated and dried under high vacuum to give 1.42 g crude 7 as a fluorescent yellow oil. 7 was
converted without further purification.

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F. Effenberger, J. Syed / Tetrahedron: Asymmetry 9 (1998) 817–825
(b) At −78°C a 0.5 M solution of propylmagnesium bromide in THF, prepared from propyl bromide
(3.16 g, 25.8 mmol) and Mg (0.63 g, 25.9 mmol) in 53 ml THF, was added dropwise to a mixture of 7
(2.19 g, 7.3 mmol) and the catalyst CuBr·SMe2 (151.1 mg, 0.74 mmol) in 50 ml dry THF. The reaction
mixture was stirred for 2 h. After addition of a 5% solution of acetic acid in n-hexane (15 ml) and stirring
for a further 10 min at −78°C, the reaction mixture was allowed to warm to room temperature. Then
ethyl acetate and 1 N HCl were added. The organic phase was separated, washed with sat. NaCl solution,
dried (MgSO4), concentrated and dried under high vacuum to give 1.7 g (90%, based on 4a) of crude 8
as an orange oil. For characterization, 8 was methylated with diazomethane as described above to give
derivatives 9 and 90.
9: 24% yield, light yellow congealing oil, diastereomeric ratio 1:1; 1H NMR (CDCl3) δ=0.95 (t, J=7.2
Hz, 6H, 2CH3), 1.22–1.43 (m, 4H, 2CH2), 1.92–2.09 (m, 2H, 2 2-CHaHb), 2.09–2.24 (m, 2H, 2 2-
CHaHb), 3.66 and 3.67 (each s, 3H, OCH3), 3.81 and 3.82 (each t, J=8.1 Hz, 1H, 2CH), 5.71 (s, 2H,
2CH–O), 7.20–7.42 (m, 10H, 2Ph). Anal. Calcd for C21H21ClO3: C, 70.68; H, 5.93; Cl, 9.94. Found: C,
70.46; H, 6.00; Cl, 10.12.
90: 14%, colourless oil, diastereomeric ratio 1:1; 1H NMR (CDCl3) δ=0.88 and 0.90 (each t, J=7.3 Hz,
3H, CH3), 1.15–1.31 (m, 4H, 2CH3CH2), 1.81–2.12 (m, 4H, 2CH2), 3.57 and 3.58 (each t, J=8.0 Hz,
1H, 2CH), 4.08 (s, 6H, 2OCH3), 5.41 and 5.43 (each s, 1H, 2CH–O), 7.19–7.40 (m, 10H, 2Ph). Anal.
Calcd for C21H21ClO3: C, 70.68; H, 5.93; Cl, 9.94. Found: C, 70.61; H, 5.96; Cl, 9.74.
Acknowledgements
This work was generously supported by the Bundesministerium für Bildung und Forschung (Zentrales
Schwerpunktprogramm Bioverfahrenstechnik, Stuttgart).
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