An efficient synthetic approach towards fully functionalized tetronic acids: The use of 1,3-dioxolane-2,4-diones as novel protected-activated synthons of α-hydroxy acids

Article abstract of DOI:10.1016/j.tet.2015.09.017

A new strategy for the synthesis of tetronic acids with control over the regioselective introduction of substituents at the C-5 position has been developed. The construction of the densely functionalized quaternary carbon center within these molecules is of great importance. The key element for the proposed protocol was the utilization of O-carboxyanhydrides (OCA's) of optically active α-hydroxy acids, as promising bidentate protective/activating precursors. The structure of the new compounds was investigated by using NMR spectral data and X-ray structural analyses.

Full text of DOI:10.1016/j.tet.2015.09.017

Accepted Manuscript
An efficient synthetic approach towards fully functionalized tetronic acids: The use of
1,3-dioxolane-2,4-diones as novel protected-activated synthons of α-hydroxy acids
Kyriakos C. Prousis, John Markopoulos, Vickie Mckee, Olga Igglessi-Markopoulou
PII:
S0040-4020(15)30044-2
10.1016/j.tet.2015.09.017
TET 27114
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 May 2015
Revised Date: 19 August 2015
Accepted Date: 4 September 2015
Please cite this article as: Prousis KC, Markopoulos J, Mckee V, Igglessi-Markopoulou O, An
efficient synthetic approach towards fully functionalized tetronic acids: The use of 1,3-dioxolane-2,4-
diones as novel protected-activated synthons of α-hydroxy acids, Tetrahedron (2015), doi: 10.1016/
j.tet.2015.09.017.
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ACCEPTED MANUSCRIPT
An efficient synthetic approach towards fully functionalized
tetronic acids: The use of 1,3-dioxolane-2,4-diones as novel
protected-activated synthons of α-hydroxy acids.
a
b
c
a,*
Kyriakos C. Prousis , John Markopoulos , Vickie Mckee , Olga Igglessi-Markopoulou
a
National Technical University of Athens, School of Chemical Engineering, Laboratory of Organic Chemistry,
Greece.
b
Laboratory of Inorganic Chemistry, Department of Chemistry, University of Athens, Greece.
c
School of Chemical Sciences, Dublin City University, Glasnevil, Dublin 9, Ireland
ojmark@orfeas.chemeng.ntua.gr

ACCEPTED MANUSCRIPT
An efficient synthetic approach towards fully
functionalized tetronic acids: The use of 1,3-
dioxolane-2,4-diones as novel protected-activated
synthons of α-hydroxy acids.
§
‡
†
§
Kyriakos C. Prousis, John Markopoulos, Vickie Mckee, Olga Igglessi-Markopoulou*
NationalTechnical University of Athens, School of Chemical Engineering, Laboratory of
‡
Organic Chemistry, Greece. Laboratory of Inorganic Chemistry, Department of Chemistry,
†
University of Athens, Greece. School of Chemical Sciences, Dublin City University, Glasnevil,
Dublin 9, Ireland
ojmark@orfeas.chemeng.ntua.gr
O
HO
R'
R''
R
R'
O
R'
OH
R
HO
O
O
O
O
R
O
Keywords:
Tetronic Acids,
O-carboxyahydrides,
Chirality
X-Ray
Abstract.
A new strategy for the synthesis of tetronic acids with control over the regioselective
introduction of substituents at the C-5 position has been developed. The construction of the
densely functionalized quaternary carbon center within these molecules is of great importance.
The key element for the proposed protocol was the utilization of O-carboxyanhydrides (OCA’s)
of optically active α-hydroxy acids, as promising bidentate protective/activating precursors. The
1

ACCEPTED MANUSCRIPT
structure of the new compounds was investigated by using ΝΜR spectral data and X-ray
structural analyses.
Introduction.
Tetronic acid derivatives (4-hydroxy-5[H]-furan-2-ones) represent a unique class of five-
membered heterocyclic compounds that have attracted significant attention over the years due to
their occurrence in naturally bioactive materials, and their synthetic utility as versatile
1
intermediates for the construction of highly functionalized heterocycles. Many natural products
containing the 2,4-furanodione ring have been isolated displaying a wide variety of biological
2
3
4
5
6
7
functions properties such as antibiotic, anticoagulant, antiepileptic, antifungal, insecticidal,
8
9
10
anti-inflammatory, antitumour, and skin-whitening effects. In addition, 3-carboxamide
tetronic acids were investigated as inhibitors of undecaprenyl pyrophosphate synthase (UPPS)
1
1
for use as antimicrobial agents, while compounds that have been isolated from natural products
1
2
and exhibit such activity are: tetronasin, RK-682 (3-alkanoyl-5-hydroxymethyl tetronic acid) as
1
3
14
selective inhibitors of protein tyrosine phosphatases (PTPs), HIV protease inhibitors, and the
1
5
well-known family of compounds named vulpinic acids. Moreover, several non-natural 3-
functionalized tetronic acids have been reported as antioxidant and anti-inflammatory
1
6
compounds.
The wide range of biological properties and the potency of pharmaceutical applications have
attracted continuous interest in the development of new methods for the synthesis of optically
1
7
active tetronic acids. Several methodologies include
Dieckmann cyclization, [2+2]-
1
8
19
photocycloaddition, reaction of active methylene compounds with activated α-hydroxy acids,
2
0
21
Wittig-Claisen reaction of α-hydroxyesters, lactonization and enzymatic reactions.
We have been interested in the chemistry and new strategies for the preparation of functionalized
2
2
five-membered oxygen heterocycles, containing the β-diketo moiety, as well as their study as
model ligands” for binding with divalent metal ions, which are critical cofactors at the
“
2
3
enzymes’ catalytic site. Additionally, these scaffolds are revealed as promising systems for the
2
4
development of new supramolecular architectures.
Results and discussion
2

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Our continuing interest on the chemistry of five-membered heterocyclic systems, tetramic,
2
5
tetronic, thiotetronic acids, as pharmacological agents, we would provide an alternative and
ultimately more general approach for the construction of the tetronic acid nucleus with control
over the regioselective introduction of substituents at the C-5 position. Construction of the
densely functionalized quaternary carbon center found within these molecules is of great
2
6
importance.
The key control element of the proposed protocol was the utilization of O-carboxyanhydrides
OCA’s) of optically active α-hydroxy acids as promising bidendate protecting/activating
(
precursors. Our interest in OCAs of α-hydroxy acids stems from their possible use as chiral
scaffolds to introduce a quaternary carbon within the γ-lactone core. Consequently, we saw in
them a potential class of building blocks that would provide access to highly functionalized
tetronic acids with retention of chirality of the C-5 stereogenic center, under the proposed
reaction conditions.
a
Scheme 1 . Synthesis of O-carboxyanhydrides from α-hydroxy acids
a
27
Reagents and Conditions: Method A, phosgene solution, THF, 50–60 °C, 24 h,
Method B, diphosgene, activated charcoal, THF, 8−16 h, r.t.
28
The synthesis of the requisite anhydrides followed a modified procedure reported by
2
8
Toyooka,
trichloromethyl chloroformate) and activated charcoal (see experimental). Following this
modified procedure, the OCA’s of optically active α-hydroxy acids, the 1,3-dioxolan-2,4-diones
6a−e), have been prepared, as acylating scaffolds, in very good yields. The whole process is
which involves the reaction of (S)-mandelic acid (3) with diphosgene
2
7
(
(
outlined in Scheme 1
To explore this approach, we first attempted the synthesis of tetronic acids starting from the
O-carboxyanhydride of (S)-mandelic acid, the (S)-phenyl-1,3-dioxolan-2,4-dione (6c). It is
3

ACCEPTED MANUSCRIPT
worthwhile to note that the requisite anhydride was found to react in a regioselective manner at
the C-4 site, with carbon nucleophiles derived from anions of β-ketoesters (7−9) Scheme 2, or
appropriately substituted ethyl acetates (11−13), Scheme 3, to generate the desired 5-(S)-phenyl-
3
-functionalized tetronic acids 10c, 10d and 14a−14c, respectively, with retention of the integrity
of the stereogenic center C-5 in a great extent. The OCAs of mandelic acid is an important agent
for the preparation of cephalosporin antibiotics. Many mandelic acid derivatives also act as chiral
2
9
auxiliaries for the introduction of chiral centers in stereoselective transformations. To our
knowledge, there has been no previous report concerning an analogous nucleophilic attack of
OCA’s by active methylene compounds.
Encouraged by these interesting results, we continued to focus on the optimization of reaction
conditions, and on the screening of various OCAs of α-hydroxy acids for their efficiency as
acylating agents to the proposed reaction.
Owing to the importance of the naturally occurring 3-acyl-tetronic acids, our initial
investigations focused on the C-acylation reaction of β-ketoesters (7−9) Scheme 2. The proposed
protocol involves (i) deprotonation of an active methylene compound, (ii) nucleophilic attack at
the C-4 carbonyl of the 5-substituted 1,3-dioxolan-2,4-dione, and (iii) in situ intramolecular
cyclization of the “intermediate” precursor X, affording the tetronic acids 10a−g, with flexible
substituents, incorporating the chiral center of the starting α-hydroxy acid into the final spatial
arrangement of the C-5 carbon of the γ-lactone nucleus.
Scheme 2. Synthesis of 3-alkoxy- and 3-keto-substituted tetronic acids
entry
R
1
R
2
Yields %
4

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1
0a
0b
0c
0d
0e
0f
0g
H
Me
Ph
Ph
Bn
Bn
iPr
OEt
Me
65
60
80
70
73
67
78
1
1
OMe
OEt
OEt
Me
1
1
1
1
OMe
Reagents and Conditions: (i) NaH, THF, 0 °C to r.t., 2−4 h.
Application of this methodology was further evaluated using as carbon nucleophiles lithium
enolates derived from arylacetates (11-13) Scheme 3.
Scheme 3. Synthesis of 3-aryl-5-substituted tetronic acids
entry
R1
R2
Yields (%)
5

ACCEPTED MANUSCRIPT
1
4a
4b
4c
4d
4e
4f
4g
4h
Ph
Ph
Ph
Ph
65
70
72
80
70
55
56
60
1
3-OMe-Ph
4-OMe-Ph
Ph
1
1
CH
CH
2
2
)
)
Ph
Ph
1
4-OMe-Ph
Ph
1
(CH
(CH
(CH
3
3
3
2
2
2
CH
1
CH
CH
3-OMe-Ph
4-OMe-Ph
1
)
Reagents and Conditions: (i) LDA, THF, 1 h, −78 °C, 1 h r.t.
The corresponding optically active 3-aryl-5-substituted tetronic acids (14a−h) were isolated from
“one-pot” reactions in good yields. The C-acylation/cyclization experiments were conducted at
o
−
78 C using lithium base (LDA), in THF, to achieve the desired tetronic acids possessing an
aromatic ring at position 3.
3
0
A single crystal X-ray structure determination was carried out on compound 14f to determine
the structure in the solid state. The molecular structure and numbering scheme for compound 14f
are shown in Figure 1, and bond lengths and angles are given in Table I. There is some double
bond character evident in the O1-C1 bond (1.354(2) Å), and C2-C9 bond (1.354(2) Å), compared
to the O1-C10 bond (1.4463(18) Å) and the O3-C9 bond is distinctly longer than the
conventional carbonyl distance for O2-C1, (1.3228(19) Å) and 1.222(2) Å), respectively. There
is an angle of 17.456(71)° between the mean planes of the two rings. An intermolecular
6

ACCEPTED MANUSCRIPT
hydrogen bond between the alcohol and the carbonyl of an adjacent molecule forms hydrogen
….
bonded chains running parallel to the c axis ((O3 O2A 2.6355(17) Å, Figure 2). There are no
other striking intermolecular interactions.
Figure 1, Perspective view of 14f with thermal ellipsoids drawn at the 50% probability level.
Figure 2.Unit cell packing diagram for 14f, dashed lines represent hydrogen bonds.
Table I
o
Bond lengths [Å] and angles [ ] for 14f.
O1—C1
O1—C10
C1—O2
C1—C2
C2—C9
C2—C3
C3—C8
C3—C4
C4—C5
1.354 (2)
1.4463 (18)
1.222 (2)
1.454 (2)
1.354 (2)
1.474 (2)
1.394 (2)
1.404 (2)
1.389 (2)
C5—C6
1.386 (3)
1.378 (3)
1.391 (3)
1.3228 (19)
1.501 (2)
1.532 (2)
1.529 (3)
1.528 (3)
C6—C7
C7—C8
C9—O3
C9—C10
C10—C11
C11—C12
C11—C13
7

ACCEPTED MANUSCRIPT
C1—O1—C10
O2—C1—O1
O2—C1—C2
O1—C1—C2
C9—C2—C1
C9—C2—C3
C1—C2—C3
C8—C3—C4
C8—C3—C2
C4—C3—C2
C5—C4—C3
C6—C5—C4
108.99 (12)
C7—C6—C5
119.40 (17)
120.86 (18)
120.50 (17)
127.48 (15)
121.60 (14)
110.90 (14)
103.05 (13)
110.09 (13)
114.05 (14)
111.43 (16)
110.10 (16)
112.05 (15)
118.94 (15)
129.75 (16)
111.30 (13)
105.46 (14)
129.42 (15)
125.13 (14)
118.20 (16)
120.58 (15)
121.21 (15)
120.66 (17)
120.36 (18)
C6—C7—C8
C7—C8—C3
O3—C9—C2
O3—C9—C10
C2—C9—C10
O1—C10—C9
O1—C10—C11
C9—C10—C11
C12—C11—C13
C12—C11—C10
C13—C11—C10
Table II
Hydrogen bond geometry for 14f [Å, ].
o
D—H···A
D—H
H···A
D···A
D—H···A
173 (2)
i
O3—H3···O2
0.86 (2)
1.78 (2)
2.6355 (17)
Symmetry code: (i) −x+1/2, −y, z+1/2.
The next challenge was to examine the validity of our strategy to access functionalized tetronic
acids, generating a quaternary carbon stereocenter at the 5-position of the γ-lactone core. In this
aim, the 5,5-disubstituted-1,3-dioxolane-2,4-diones (24a−c) Scheme 4, were used as scaffolds to
generate the functionalized tetronic acids with different patterns of substitution at C-5. The
construction of such architectures with a quaternary pattern is of particular importance and
attracts continuing interest because such motifs exist in a great number of natural products and
pharmaceutically relevant compounds. Thus, treatment of (R,S)-mandelic acid 15 with acetone
o
under acidic conditions (c. H SO /−20 C) generates 2,2-dimethyl-5-phenyl-1,3-dioxolane-4-
2
4
3
2b
one 16 (Scheme 4). Deprotonation of this dioxolanone with LDA led to the corresponding
lithium enolate which was alkylated by an appropriate halide (R X), introducing a second
Sodium hydroxide hydrolysis of compounds 17 and 18, in methanol,
1
31,32b
substituent at C-5.
generates the α-methyl- and α-butyl-mandelic acids 21 and 22,
3
2c
which undergo a new
transformation to 5,5-disubstituted-1,3-dioxolane-2,4-dione 24a and 24b. Adopting the one-pot
protocol as our standard, substitution of the phenyl group on 24a for methyl, the 5,5-dimethyl-
1
,3-dioxolane-2,4-dione (24c) was produced.
8

ACCEPTED MANUSCRIPT
Scheme 4. Synthetic procedure for preparation of 1,3-dioxolane-2,4-diones
Reagents and Conditions: (i) acetone / c. H SO / −20 °C 1 h, (ii) LDA / R X / −78 °C, (iii) aq.
2
4
1
NaOH 2 N / MeOH / 2 h reflux, (iv) triphosgene / Et N / THF reflux 24 h.
3
It is worthwhile to note that the proposed methodology proceeded to generate 5,5-disubstituted
tetronic acids, 26a−c and 25a−c, using the sodium enolate of malonic esters (8) or the lithium
enolate of ethyl phenyl acetate (11), Scheme 5.
9

ACCEPTED MANUSCRIPT
Scheme 5 . Synthesis of 5,5-disubstituted tetronic acids
entry
R1
R2
Yields (%)
2
5a
5b
5c
6a
6b
6c
Me
Bu
Me
Me
Bu
Me
Ph
Ph
67
55
62
50
45
66
2
2
Me
Ph
2
2
Ph
2
Me
Reagents and Conditions: Route A, 8, NaH, THF, at 0 °C to r.t. 4 h; Route B, 11, LDA, THF,
h −78 °C, 1 h r.t.
1
A single crystal X-ray structure analysis of 26a was carried out to determine the structure in the
solid state. The molecular structure and the numbering scheme for compound 26a are shown in
Figure 3, and bond lengths and angles are given in Table III. The structure resembles the enol-
tautomer with an endocyclic C=C bond. There is some double bond character evident in the
C2−C6 bond (1.344(2)
Å), and the O5−C6 bond is distinctly longer than the conventional
carbonyl distance for O2−C1, 1.3188(18) and 1.1953(18) Å , respectively. The hydrogen atom
bonded to O5 was located in the difference Fourier maps. The alcohol group acts as donor for a
10

ACCEPTED MANUSCRIPT
…
bifurcated hydrogen bond with both an intramolecular component (O-5 O-3 2.7717(15) Å) and
an intermolecular component (O-5 … O-3 2.9905(15) Å under symmetry operation −x+2, −y+1,
−
z+2), resulting in formation of hydrogen bonded dimers (Figure 4). There is some π-stacking
involving the carbonyl groups which packs the dimers into columns; surprisingly, there is no
indication of significant π−π interactions between the phenyl groups.
Figure 3. Perspective view of 26a with 50% displacement ellipsoids.
Figure 4. Unit cell packing diagram for 26a. Dashed lines represent hydrogen bonds, hydrogen
atoms omitted for clarity.
Table III.
Geometric parameters (Å, º) for for 26a
11

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O1—C1
O1—C7
C1—O2
C1—C2
C2—C6
C2—C3
C3—O3
C3—O4
O4—C4
C4—C5
1.3821 (18)
C6—O5
1.3188 (18)
1.514 (2)
1.520 (2)
1.525 (2)
1.387 (2)
1.395 (2)
1.392 (2)
1.378 (2)
1.383 (2)
1.384 (2)
1.4557 (17)
1.1953 (18)
1.467 (2)
C6—C7
C7—C14
C7—C8
1.344 (2)
C8—C9
1.459 (2)
C8—C13
C9—C10
C10—C11
C11—C12
C12—C13
1.2232 (18)
1.3194 (17)
1.4608 (18)
1.502 (2)
C1—O1—C7
O2—C1—O1
O2—C1—C2
O1—C1—C2
C6—C2—C3
C6—C2—C1
C3—C2—C1
O3—C3—O4
O3—C3—C2
O4—C3—C2
C3—O4—C4
O4—C4—C5
O5—C6—C2
O5—C6—C7
C2—C6—C7
111.40 (11)
120.62 (14)
131.74 (14)
107.64 (12)
122.83 (14)
108.05 (13)
129.11 (13)
125.16 (14)
121.00 (13)
113.84 (13)
116.68 (12)
107.26 (13)
129.82 (14)
119.02 (12)
111.15 (13)
O1—C7—C6
O1—C7—C14
C6—C7—C14
O1—C7—C8
C6—C7—C8
101.70 (11)
107.81 (12)
112.26 (12)
108.96 (11)
110.18 (12)
115.01 (12)
118.85 (14)
121.79 (13)
119.27 (13)
120.19 (15)
120.49 (15)
119.73 (15)
120.08 (15)
120.65 (14)
C14—C7—C8
C9—C8—C13
C9—C8—C7
C13—C8—C7
C8—C9—C10
C11—C10—C9
C10—C11—C12
C11—C12—C13
C12—C13—C8
Table IV
Hydrogen-bond geometry (Å, º) for 26a
D—H···A
D—H
H···A
D···A
D—H···A
O5—H5···O3
O5—H5···O3
0.857 (19)
0.857 (19)
2.074 (18)
2.336 (18)
2.7717 (15)
2.9905 (15)
138.2 (16)
133.4 (15)
i
Symmetry code: (i) −x+2, −y+1, −z+2.
The successful synthesis of tetronic acids with a quaternary carbon at C-5 prompted us to
α
investigate the synthesis of optically active C -tetrasubstituted α-hydroxy acids and the
12

ACCEPTED MANUSCRIPT
chemistry that incorporates their chiral center into the final spatial arrangement of atoms at the
C-5 tetrasubstituted stereocenter of compound 30 (Scheme 6).
The asymmetric synthesis of optically active α-hydroxy acids with a quaternary stereocenter has
3
3
been exploited by Seebach and co-workers. Mandelic acid derivatives were utilized as
3
4
convenient precursors for the introduction of a chiral center in stereoselective transformations.
For this transformation we employed the “self-reproduction chirality” approach of Seebach,
3
5
which incorporates lactic acid into a dioxolane ring to direct alkylation at the C-5 carbon, taking
advantage of the bulky [R] group of the newly formed stereocenter at C-2. Thus, the 1,3-
dioxolanone 27 is formed by treating (S)-mandelic acid 3 with pivaldehyde under acidic
catalysis Scheme 6 .
a
Scheme 6 Enantioselective synthesis of 5,5-disubstituted tetronic acids.
a
Reagents and Conditions: (i) Trifluoromethanesulphonic acid, pentane / Dean-Stark, reflux,
3
5
36
(
3
ii) LDA / MeI / −78 °C, (iii) aq. KOH 2.5 M / MeOH / 2 h, (iv) triphosgene / Et N / THF
37
reflux 24 h, (v) 11, LDA, THF, 1h, −78 °C, 1 h r.t.
o
Treatment of 27 with LDA at −78 C followed by alkylation with methyl iodide proceeds in 90%
yield to provide a cis:trans mixture 93:7 of 28. Potassium hydroxide hydrolysis in methanol
affords (S)-atrolactic acid 29 after two recrystallizations from toluene, possessing [α] +35.2° (c
2
0
3
7
0
.99 in ethanol), 99% ee.
13

ACCEPTED MANUSCRIPT
Excellent results were obtained when this optically active α-hydroxy acid was transformed to
the corresponding carboxyanhydride 30, bearing a methyl group and the bulky phenyl group at
the C-5 stereogenic carbon. Interestingly, when lithium phenylacetate was used as the enolate
source, the corresponding (S)-5-methyl-3,5-diphenyl tetronic acid (31) was obtained from the
attack of the enolate on the carbonyl at position 4, in 60% yield and high optical purity (99:1 e.r.,
9
8% e.e.).
In conclusion we have developed a convenient and efficient methodology for the construction
of functionally substituted tetronic acids possessing a quaternary stereocenter with high
diastereo- and enantiostereo-control. The chiral C-5 carbon was constructed by introducing new
activated precursors, the 1,3-dioxolane-2,4-diones as chiral synthons. Of particular significance
is the generality of this reaction and the stereoselectivity achieved under mild reaction
conditions. Our efforts are directed towards the synthesis of more complex ligands in the
“tetronate” series.
Experimental section
All reagents and solvents were commercial grade and purified prior to use when necessary.
Tetrahydrofuran (THF) was freshly distilled before use from Na/Ph CO. Melting points were
2
determined with a Gallenkamp MFB-595 melting point apparatus. Thin layer chromatography
(TLC) was performed using pre-coated TLC plates with Silica Gel 60 F254 (Macherey Nagel).
Flash column chromatography was carried out on silica gel Macherey-Nagel 0.063-0.2 mm/70-
2
30 mesh.
Nuclear magnetic resonance spectra (NMR) were recorded with a Varian Gemini-2000 300
1
13
MHz spectrometer operating at 300 MHz ( H) and 75 MHz ( C). Chemical shifts are reported in
1
13
parts per million relative to CDCl ( H: δ = 7.26 ppm, C: δ = 77.16 ppm). Optical Rotations
3
were measured on a Perkin-Elmer 241 polarimeter. HRMS spectra were recorded on UHPLC
LC-MSn Orbitrap Velos-Thermo instrument in the Institute of Biology, Medicinal Chemistry
and Biotechnology of the National Hellenic Research Foundation, in Greece. Some of HRMS
were carried out in the Department of Chemistry & Biochemistry of the University Notre Dame,
IN, USA, on a micrOTOF, ESI instrument. HPLC separations were performed by using a
DAICEL CHIRALPAK AS (4.6 mm x 250 mm) column, incorporated in an HPLC system
consisting of a Varian 2510 HPLC pump, and UV detector. (Conditions for the analysis of
14

ACCEPTED MANUSCRIPT
compounds 14a−c and 31 were:flow rate = 0.8 mL/min, eluent solvent system = isocratic
ethanol/hexane (50:50) with 0.1% trifluoroacetic acid and wave length = 210 nm).
General procedure for the synthesis of 1,3-dioxolane-2,4-diones (6a−e).
Method A: To a solution of α-hydroxy acid (13.0 mmol) in anhydrous THF (10 mL), a
phosgene solution (20% in toluene) (14.95 mmol, 7.40 mL) was added at once, and the resulting
mixture was stirred at 50-55 °C for 1 h. Then an additional aliquot of phosgene (3.25 mmol, 1.60
mL) was added and the reaction mixture stirred for 24 h at r.t.. The solvents were evaporated and
the anhydrides 6a−e were isolated in an oily form or precipitated as solids after triturating with
petroleum ether and were collected by filtration. The final products were dried under high
vacuum over P O for 2 h.
2
5
Method B: Diphosgene (1.50 mL, 11.26 mmol) was added to a solution of α-hydroxy acid (10
mmol) in anhydrous THF (10 mL), and the reaction mixture was treated with activated charcoal
(50 mg). The resulting suspension was stirred overnight at r.t. Then the mixture was filtered
through a small celite pad, the filtrates were concentrated and dried under high vacuum (2 h over
P O ) in order to give the desired anhydrides.
2
5
1,3-Dioxolane-2,4-dione (6a). (According to method B) Starting from glycolic acid (1) (0.76
g, 10.0 mmol), the title compound was obtained as brownish oil and used in the next step without
1
any further purification, (1.86 g, 97%). H NMR (300 MHz, CDCl /drops DMSO-d ): δ 4.85
3
6
1
3
(
2H, s). C NMR (75 MHz, CDCl drops DMSO-d ): δ 67.6, 149.2, 165.1.
3 6
(S)-5-methyl-1,3-dioxolane-2,4-dione (6b). (According to method A) Starting from (S)-lactic
acid (2) (1.17 g, 13.0 mmol), the title compound was obtained as colorless oil and used in the
next step without any further purification. The crude product was solidified on addition of n-
2
8a
hexane. The solid was crystallized from ether to give the title compound 6b (83%).
Mp:
o
28a
o
5
4−56 C (Lit. mp 58−60 C).
S)-5-phenyl-1,3-dioxolane-2,4-dione (6c). (According to method B) Starting from (S)-
mandelic acid (3) (1.52 g, 13.0 mmol), the title compound was obtained as a white solid (1.74 g,
(
2
7
o
28a
o
1
9
7
8%). Mp: 78−80 C (Lit. mp 74−75 C). H NMR (300 MHz, CDCl
3
): δ 6.01 (1H, s), 7.41-
1
3
.51 (5H, m). C NMR (75 MHz, CDCl ): δ 80.6, 126.3, 129.4, 129.7, 130.9, 148.2, 165.5.
3
15

ACCEPTED MANUSCRIPT
2
8b
(
S)-5-benzyl-1,3-dioxolane-2,4-dione (6d). (According to method B) Starting from (S)-2-
hydroxy-3-phenylpropanoic acid (4) (1.66 g, 10.0 mmol), compound 6d was obtained as a white
o
1
solid (1.86 g, 97%). Mp: 101−103 C H NMR (300 MHz, CDCl ): δ 3.25 (1H, dd, J = 4.8, 15.0
3
Hz ) 3.39 (1H, dd, J = 4.8, 15.0 Hz ) 5.30 (1H, t, J = 4.8 Hz ) 7.21 – 7.24 (2H, m), 7.33 – 7.38
1
3
(
3H, m). C NMR (75 MHz, CDCl ): δ 36.6, 80.0, 128.6, 129.3, 129.8, 131.7, 147.9, 166.4.
3
2
8b
(S)-5-isopropyl-1,3-dioxolane-2,4-dione (6e).
(According to method B) Starting from (S)-
2
-hydroxy-3-methylbutanoic acid (5) (1.18 g, 10.0 mmol), the title compound was obtained as a
1
white solid (1.60 g, 87%). H NMR (300 MHz, CDCl ): δ 1.08 (3H, d, J = 6.9 Hz ), 1.15 (3H, d,
3
1
3
J = 6.9 Hz ), 2.33 – 2.39 (1H, m ), 4.90 (1H, d, J = 2.7 Hz ). C NMR (75 MHz, CDCl
7.5, 30.7, 84.2, 148.6, 166.6.
General procedure for the synthesis of tetronic acids 10a−g. The appropriate active
3
): δ 16.1,
1
methylene compound 7−9 (4.0 mmol) was added in a dropwise manner to an ice-cooled
suspension of sodium hydride (60% in oil, 0.16 g, 4.0 mmol) in freshly distilled THF (10 mL)
and the mixture was stirred at 0 °C for 30 min under nitrogen. Then, a solution of the appropriate
1
,3-dioxolane-2,4-dione (6a−e) (2.0 mmol) in anhydrous THF (2 mL) was added, and the
reaction mixture was allowed to warm to r.t. and stirred for 2−4 h. Water (5 mL) was added to
the reaction mixture and the THF evaporated under vacuum. The aqueous layer was then washed
with Et O (15 mL), acidified with HCl10% in an ice-water bath. Compounds 10c−e were
2
precipitated as white solids, collected by filtration, washed with Et
2
O and dried under high
vacuum over P O for 2 h. In case of compounds 10a, 10b, 10f, 10g, the acidified aqueous layer
2
5
2 2
was extracted three times with CH Cl (3 x 20 mL) and the combined organic extracts were dried
over anhydrous Na SO and concentrated under reduced pressure to afford the crude product
2
4
which was solidified after triturating with diethyl ether or petroleum ether, collected by filtration,
and dried for 3 – 4 h under high vacuum over P
-Ethoxycarbonyltetronic acid (10a). Starting from 1,3-dioxolane-2,4-dione (6a) (2.0 mmol,
.20 g) and using diethyl malonate 8 (4.0 mmol, 0.64 g) the title compound was obtained as a
2
5
O .
3
0
1
9c
o
1
white solid (0.20 g,65%). Mp: 110–112 °C (Lit. mp 112–114 C). H NMR (300 MHz,
1
3
DMSO-d ): δ 1.21 (3H, t, J = 6.9 Hz ), 4.14 (2H, q, J = 6.9 Hz), 4.68 (2H, s). C NMR (75
6
–
MHz, DMSO-d
6
): δ 14.3, 59.2, 66.4, 92.0, 161.0, 169.5, 185.9. ESI – MS:m/z 171.25 [M – H] .
(S)-3-Acetyl-5-methyltetronic acid (10b). Starting from (S)-5-methyl-1,3-dioxolane-2,4-
dione (6b) (2.0 mmol, 0.23 g) and using ethyl acetoacetate 9 (4.0 mmol, 0.52 g) the title
16

ACCEPTED MANUSCRIPT
3
e
19d
compound was obtained as a white solid (0.19 g, 60%). Mp: 63–65 °C (Lit. m.p. 70–71 °C),
2
0
1
[
α]D –8.74 (c 0.5, MeOH). H NMR (300 MHz, CDCl ): δ 1.49 (3H, t, J = 6.9 Hz ), 2.52 (3H,
3
1
3
s), 4.68 (0.4H, q, J = 6.9 Hz ), 4.81 (0.6H, q, J = 6.9 Hz ), 12.96 (1H, br s). C NMR (75 MHz,
CDCl
3
): δ16.7/16.9, 19.6/22.4, 76.4/81.9, 97.3/100.2, 99.1/101.2, 127.3/127.4, 128.6/128.7,
–
1
29.8, 134.1/134.6, 167.8/175.8, 188.5/194.5, 195.3/200.3. ESI – MS: m/z 155.17 [M – H] .
–
ESI-HRMS : m/z [M – H ] calcd for C
S)-3-Methoxycarbonyl-5-phenyltetronic acid (10c). Starting from (S)-5-phenyl-1,3-
dioxolane-2,4-dione (6c) (2.0 mmol, 0.36 g) and using dimethyl malonate 7 (4.0 mmol, 0.53 g)
7 7 4
H O 155.0347, found 155.0339.
(
1
9c
the title compound was obtained as a white solid (0.37 g, 80%). Mp: 176–178 °C (Lit. mp
2
0
19c
20
1
1
d
7
88–189 °C), [α]D +81.0 (c 1.0, MeOH), (Lit. [α]D +86.6). H NMR (300 MHz, DMSO-
1
3
6
): δ 3.66 (3H, s), 5.77 (1H, s), 7.34 - 7.44 (5H, m). C NMR (75 MHz, DMSO-d
6
): δ 50.7,
–
8.8, 90.8, 127.3, 128.8, 129.1, 135.1, 162.1, 169.3, 186.9. ESI – MS: m/z 233.15 [M – H] .
(S)-3-Ethoxycarbonyl-5-phenyltetronic acid (10d). Starting from (S)-5-phenyl-1,3-
dioxolane-2,4-dione (6c) (2.0 mmol, 0.36 g) and using diethyl malonate 8 (4.0 mmol, 0.64 g) the
1
9c
title compound was obtained as a white solid (0.35 g, 70%). Mp: 166−168 °C (Lit. mp 156–
2
0
19c
20
1
1
57 °C), [α]
D
+ 83.1 (c 1.0, MeOH), (Lit. [α]
D
3
+71,1). H NMR (300 MHz, CDCl ), δ 1.42
1
3
(
3H, t, J = 6.9 Hz), 4.44 (2H, q, J = 14.4, 6.9 Hz), 5.82 (1H, s), 7.35-7.44 (5H, m). C NMR (75
MHz, CDCl ): δ 14.3, 62.4, 78.6, 94.3, 126.5, 129.2, 129.9, 132.5, 166.3, 166.5, 190.2. ESI –
3
–
MS: m/z 247.33 [M – H] .
(S)-5-Benzyl-3-ethoxycarbonyl tetronic acid (10e). Starting from (S)-5-benzyl-1,3-
dioxolane-2,4-dione (6d) (2.0 mmol, 0.38 g) and using diethyl malonate 8 (4.0 mmol, 0.64 g) the
2
0
title compound was obtained as a white solid (0.38 g, 73 %). Mp: 166–168 °C, [α]D –76.0 (c
-1
0
.5, MeOH); νmax(KBr) 3200, 2950, 1740, 1650, 1610, 1345 cm ; 1H NMR (300 MHz, CDCl ):
3
δ 1.36 (3H, t, J = 7.2 Hz ), 3.06 (1H, dd, J = 6.6, 14.7 Hz ) 3.33 (1H, dd, J = 4.2, 14.7 Hz ), 4.30-
1
3
4
.41 (2H, m), 5.11 (1H, dd, J = 7.2, 3.9 Hz ), 5.29 (1H, t, J = 4.8), 7.23-7.31 (5H, m). C NMR
75 MHz, CDCl ): δ 14.1, 37.4, 62.2, 95.8, 127.6, 128.7, 129.7, 133.7, 166.1, 166.4, 190.4. ESI –
MS: m/z 261.33 [M – H ] . ESI-HRMS : m/z [M – H ] calcd for C H O 261.0768, found
(
3
–
–
1
4
13
5
2
61.0757.
S)-3-Acetyl-5-benzyltetronic acid (10f). Starting from (S)-5-benzyl-1,3-dioxolane-2,4-dione
6d) (2.0 mmol, 0.38 g) and using ethyl acetoacetate 9 (4.0 mmol, 0.52 g) the title compound
(
(
2
0
was obtained as a white solid (0.31 g, 67 % yield; Mp: 90–92 °C; [α]D –179.7 (c 0.3, MeOH);
17

ACCEPTED MANUSCRIPT
-1 1
ν
max(KBr) 3120, 2950, 1745, 1642, 1594, 1187 cm ; H NMR (300 MHz, CDCl
3
): δ 2.30/2.34
(3H, two s), 2.88-2.94 (1H, m), 3.14 (1H, dd, J = 4.2, 14.1 Hz ), 4.70 (0.4H, dd, J = 3.9, 6.9 Hz ),
1
3
4
.83 (0.6H, dd, J = 4.2, 6.6 Hz ), 7.07-7.17 (5H, m), 11.57 (1H, br); C NMR (75 MHz, CDCl ):
3
δ19.6/22.1, 37.1/37.2, 80.2/85.5, 99.1/101.2, 127.3/127.4, 128.6/128.7, 129.7, 134.1/134.6,
–
1
67.6/175.7, 188./199.1, 193.9/194.1. ESI – MS: m/z 231.25 [M – H] . ESI-HRMS : m/z [M –
–
H ] calcd for C13
H
11
O
4
231.0652, found 231.0655.
(S)-3-Methoxycarbonyl-5-isopropyltetronic acid (10g). Starting from (S)-5-isopropyl-1,3-
dioxolane-2,4-dione (6e) (2.0 mmol, 0.29 g) and using dimethyl malonate 7 (4.0 mmol, 0.53 g)
1
9c
the title compound was obtained as a white solid (0.31 g, 78 %). Mp: 80 – 82 °C (Lit. mp 57–
2
0
19c
20
1
5
8 °C); [α]D –69.1 (c 1.0, MeOH), (Lit [α]D –73.5). H NMR (300 MHz, DMSO-d ): δ 0.69
6
(3H, d, J = 6.9 Hz ), 1.02 (3H, d, J = 6.9 Hz ), 2.15 – 2.25 (1H, m ), 3.66 (3H, s ), 4.74 (1H, d, J
1
3
=
3.0 Hz ), 9.92 (1H, br). C NMR (75 MHz, DMSO-d ): δ 14.1, 19.0, 29.0, 50.8, 80.8, 92.8,
6
–
1
61.6, 168.8, 186.8. ESI – MS: m/z 199.25 [M – H ] .
General procedure for the synthesis of compounds 14a-h. A solution of the appropriate aryl
acetates 11-13 (4 mmol) in THF (2 mL) was added drop wise via a syringe over a period of 10
min to a solution of lithium diisopropylamide (LDA) 2.0 M solution in THF/hexane/
ethylbenzene (4 mmol, 2 ml) in THF (10 mL) at −78°C under nitrogen. The mixture was stirred
for 45 min, then the appropriate 1,3-dioxolane-2,4-dione (6c-d) (2.0 mmol) in THF (2 mL) was
added drop wise over 10 min. The reaction mixture was stirred for 1h at −78 °C and 1 h at room
temperature, quenched with water (5 mL), and the THF evaporated in vacuum. The resulting
2
aqueous layer was then washed with Et O (15 mL) and acidified with HCl 10% to pH=1 – 2 in
an ice-water bath, to give the corresponding compounds (14a-e) as solid products, which were
dried in vacuum over P O for 2–3 hours. Otherwise 14a-e were isolated by extraction of
2
5
aqueous layer with CH
2
Cl
2
2 4
(3 x 30 mL), the combined organic layers were dried over Na SO
and concentrated under reduced pressure, to give the final products.
S)-3,5-Diphenyltetronic acid (14a). Starting from (S)-5-phenyl-1,3-dioxolane-2,4-dione (6c)
2.0 mmol, 0.36 g) and using ethyl phenyl acetate 11 (4.0 mmol, 0.66 g) the title compound was
(
(
2
0
obtained as a white solid, (0.33 g, 65%). Mp: 207–209 °C, [α]D –24.8 (c 0.5, MeOH), d.r. 97:3,
-1
1
e.e. 94%; νmax(KBr) 2945, 2655, 1690, 1642, 1605, 1573, 1490 cm ; H NMR (300 MHz,
DMSO-d ): δ 5.94 (1H, s), 7.27 (1H, t, J = 7.5 Hz), 7.38-7.47 (7H, m), 7.92 (2H, d, J = 7.5 Hz).
6
1
3
C NMR (75 MHz, DMSO-d ): δ 78.2, 98.6, 126.6, 126.8, 128.1, 128.1, 128.8, 129.4, 130.3,
6
18

ACCEPTED MANUSCRIPT
–
–
1
35.2, 172.1, 175.3. ESI – MS: m/z 251.17 [M – H ] . ESI-HRMS : m/z [M – H ] calcd for
C H O 251.0703, found 251.0703.
16
11
3
(S)-3-(3-Methoxyphenyl)-5-phenyltetronic acid (14b). Starting from (S)-5-phenyl-1,3-
dioxolane-2,4-dione (6c) (2.0 mmol, 0.36 g) and using ethyl 2-(3-methoxyphenyl)acetate 12 (4.0
mmol, 0.78 g) the title compound was obtained as a white solid (0.40 g, 70%). Mp: 168–170 °C,
2
0
[
α]D –33.5 (c 0.5, MeOH), d.r. 97:3, e.e. 94%; νmax(KBr) 2960, 2635, 1685, 1605, 1510, 1370
-1
1
cm ; H NMR (300 MHz, DMSO-d ): δ 3.77 (3H, s), 5.93 (1H, s), 6.84-6.88 (1H, m), 7.30-7.48
6
1
3
(
6H, m), 7.56-7.58 (2H, m); C NMR (75 MHz, DMSO-d
6
): δ 54.7, 78.2, 98.5, 112.1, 112.5,
+
1
19.3, 128.1, 128.9, 129.1, 129.4, 131.5, 135.1, 159.0, 172.0, 175.5. ESI-HRMS: m/z [M+H]
calcd for C H O 283.0965, found 283.0963.
1
7
15
4
(S)-3-(4-Methoxyphenyl)-5-phenyltetronic acid (14c). Starting from (S)-5-phenyl-1,3-
dioxolane-2,4-dione (6c) (2.0 mmol, 0.36 g) and using ethyl 2-(4-methoxyphenyl)acetate 13 (4.0
mmol, 0.78 g) the title compound was obtained as a white solid (0.41 g, 72%). Mp: 179–181 °C;
2
D
0
[α]
–34.8 (c 0.5, MeOH), d.r. 95:5, e.e. 90%;
νmax(KBr) 2950, 2644, 1680, 1645, 1610, 1523,
-1 1
1
385 cm ; H NMR (300 MHz, DMSO-d ): δ 3.77 (3H, s), 5.91 (1H, s), 6.99 (2H, d, J = 9.0
6
1
3
Hz), 7.37-7.46 (5H, m), 7.90 (2H, d, J = 9.0 Hz ). C NMR (75 MHz, DMSO-d ): δ 55.1, 78.2,
6
9
8.6, 113.6, 122.6, 128.1, 128.2, 128.8, 129.4, 135.3, 157.9, 172.2,173.6. ESI – MS: m/z 281.17
–
+
[
M – H] . ESI-HRMS : m/z [M + H ] calcd for C H O 283.0965, found 261.0956
17 15 4
(S)-5-Benzyl-3-phenyltetronic acid (14d). Starting from (S)-5-benzyl-1,3-dioxolane-2,4-
dione (6d) (2.0 mmol, 0.38 g) and using ethyl phenyl acetate 11 (4.0 mmol, 0.66 g) the title
2
0
compound was obtained as a white solid (0.43 g, 80%). Mp: 228–230 °C; [α]D –168.3 (c 0.2,
-1 1
MeOH); νmax(KBr) 2982, 2620, 1682, 1605, 1573, 1564 cm ; H NMR (300 MHz, DMSO-d ): δ
6
2
7
1
.94 (1H, dd, J = 7.2, 14.4 Hz), 3.38 (1H, dd, J = 3.0, 14.4 Hz), 5.15 (1H, dd, J = 3.0, 7.2 Hz),
1
3
.17-7.35 (8H, m), 7.77 (2H, d, J = 7.8 Hz); C NMR (75 MHz, DMSO-d
6
): δ 37.4, 76.8, 99.1,
26.6, 126.7, 126.8, 128.1, 128.2, 129.5, 130.4, 135.7, 171.8, 175.5. ESI – MS: m/z 265.25 [M –
–
–
H ] . ESI-HRMS : m/z [M – H ] calcd for C H O 265.0859, found 265.0859.
1
7
13
3
(S)-5-Benzyl-3-(4-methoxyphenyl)tetronic acid (14e). Starting from (S)-5-benzyl-1,3-
dioxolane-2,4-dione (6d) (2.0 mmol, 0.38 g) and using ethyl 2-(4-methoxyphenyl)acetate 13 (4.0
mmol, 0.78 g) the title compound was obtained as a white solid (0.42 g, 70%). Mp: 212–214 °C;
2
D
0
-1
1
[α]
–168.5 (c 0.5, MeOH); νmax(KBr) 2980, 2640, 1645, 1612, 1520, 1164 cm ; H NMR
19

ACCEPTED MANUSCRIPT
(
300 MHz, DMSO-d
6
): δ 2.93 (1H, dd, J = 7.5, 14.4 Hz), 3.38 (1H, dd, J = 3.3, 14.4 Hz), 3.74
(3H, s), 5.13 (1H, dd, J = 3.3, 7.5 Hz), 6.89 – 6.94 (2H, m), 7.16-7.35 (5H, m), 7.70 – 7.75 (2H,
1
3
m); C NMR (75 MHz, DMSO-d ): δ 37.4, 55.0, 76.6, 98.7, 113.5, 122.7, 126.6, 127.8, 128.1,
6
+
1
29.4, 135.8, 157.7, 171.8, 173.9. ESI-HRMS : m/z [M+H] calcd for C18
H
17
O
4
297.1121,
found 297.1132.
S)-5-Isopropyl-3-phenyltetronic acid (14f). Starting from (S)-5-isopropyl-1,3-dioxolane-
,4-dione (6e) (2.0 mmol, 0.29 g) and using ethyl phenyl acetate (11) (4.0 mmol, 0.66 g) the title
compound was obtained as a colorless crystalline solid after crystallization with diethyl ether/
(
2
2
0
petroleum ether (0.24 g, 55%). Mp: 132–134 °C; [α]D –106.9 (c 0.3, MeOH); νmax(KBr) 2950,
-
1 1
2
1
680, 1710, 1605, 1520, 1163 cm ; H NMR (300 MHz, CDCl ): δ 0.83 (3H, d, J = 6.9 Hz ),
3
.15 (3H, d, J = 6.9 Hz ), 2.35 – 245 (1H, m ), 4.78 (1H, d, J = 2.7 Hz ), 7.27 (1H, t, J = 7.2 Hz
1
3
)
, 7.38 (2H, t, J = 7.2 Hz ), 7.71 (2H, d, J = 7.2 Hz), 9.98 (1H, br s ). C NMR (75 MHz,
CDCl
3
): δ 14.3, 19.5, 29.9, 82.5, 102.4, 127.7, 127.8, 128.7, 128.8, 159.0, 175.5, 175.7. ESI –
–
MS: m/z 217.22 [M–H ] .
(S)-5-Isopropyl-3-(3-methoxyphenyl)tetronic acid (14g). Starting from (S)-5-isopropyl-1,3-
dioxolane-2,4-dione (6e) (2.0 mmol, 0.29 g) and using ethyl 2-(3-methoxyphenyl)acetate (12)
(4.0 mmol, 0.78 g) the title compound was obtained as a white solid (0.28 g, 56%). Mp: 202–
20
-1 1
2
04 °C; [α]D –88.5 (c 0.5, MeOH); νmax(KBr) 2955, 2705, 1631, 1605, 1514, 1392 cm ; H
NMR (300 MHz, DMSO-d ): δ 0.67 (3H, d, J = 6.9 Hz ), 1.10 (3H, d, J = 6.9 Hz ), 2.36 (1H, m
6
), 3.75 (3H, s ), 4.82 (1H, s ), 6.82 (1H, d, J = 6.9 Hz), 7.28 (2H, t, J = 8.1 Hz), 7.50 (2H, m ).
1
3
C NMR (75 MHz, DMSO-d ): δ 13.4, 19.6, 28.7, 54.9, 80.2, 98.7, 111.9, 112.3, 119.1, 129.1,
6
+
1
2
31.7, 159.0, 173.2, 175.9. ESI-HRMS: m/z [M+H] calcd for C H O 249.1121, found
1
7
14
4
49.1120.
S)-5-Isopropyl-3-(4-methoxyphenyl)tetronic acid (14h). Starting from (S)-5-isopropyl-1,3-
dioxolane-2,4-dione (6e) (2.0 mmol, 0.29 g) and using ethyl 2-(4-methoxyphenyl)acetate (13)
(
(4.0 mmol, 0.78 g) the title compound was obtained as a white solid (0.30 g, 60%). Mp: 164–
2
0
-1
1
1
66 °C; [α]D –97.6 (c = 0.5 in MeOH); νmax(KBr) 3067, 1660, 1608, 1516, 1374 cm ;
H
NMR (300 MHz, CDCl / drop DMSO-d ): δ 0.79 (3H, d, J = 6.9 Hz ), 1.14 (3H, d, J = 6.9 Hz ),
3
6
2
.30 – 2.36 (1H, m ), 3.78 (3H, s ), 4.67 (1H, d, J = 2.4 Hz ), 6.89 (2H, d, J = 8.4 Hz), 7.77 (2H,
1
3
d, J = 8.4 Hz), 10.82 (1H, br s). C NMR (75 MHz, CDCl /drop DMSO-d ): δ 14.0, 19.6, 29.7,
3
6
20

ACCEPTED MANUSCRIPT
–
5
5.3, 81.7, 101.2, 113.8, 122.3, 129.0, 158.6, 173.8, 174.5. ESI – MS: m/z 247.17 [M – H ] .
+
ESI-HRMS: m/z [M +H] calcd for C H O 249.1121, found 249.1120.
1
7
14
4
Procedure for the synthesis of (R,S)-2,2-dimethyl-5-phenyl-1,3-dioxolane-4-one (16).
3
2a
Prepared according literature procedure with some modifications. To a solution of (R,S)-
3
2a,b
mandelic acid
5.6 mmol) at −10 C. The reaction mixture was allowed to stir for 1h at this temperature, then
poured into a solution of Na CO (16.67 g) in water (60 mL) and crushed ice (60 g). The
(10.0 g, 65.6 mmol) in acetone (30 mL) was added dropwise c.H SO (6.33 g,
o
2 4
6
2
3
precipitated white solid was collected by filtration, and dissolved in dichloromethane (60 mL).
The solution dried over Na SO , filtered and the solvent removed under reduced pressure. The
oily residue was solidified to a white solid (10.08 g, 80%), after extensive drying under high
2
4
3
8
1
vacuum (2h) over P
2
O
5
. Mp: 51−53 °C (Lit. mp 50−52 °C ) ; H NMR (300 MHz, CDCl
3
): δ
1
3
1
2
.75 (3H, s), 1.80 (3H, s), 5.40 (1H, s), 7.37-7.49 (5H, m); C NMR (75 MHz, CDCl ): δ, 27.2,
3
7.3, 76.0, 111.0, 126.5, 128.8, 129.0, 134.5, 171.5.
General procedure for the preparation of compounds 17, 18. To a solution of freshly
3
1
distilled diisopropylamine (1.27 g, 12.5 mmol) in anhydrous THF (25 mL) was added dropwise a
solution of n-BuLi 2.5 M in hexane (4.4 mL, 11.0 mmol) at 0 ºC, under nitrogen, then the
solution was stirred for 20–30 min, and cooled to –78 ºC. After 5 min a solution of 2,2-
dimethyl-5-phenyl-1,3-dioxolan-4-one (16), (1.92 g, 10.0 mmol) in THF (10 mL) was added
dropwise. The resulting solution was stirred at –78 ºC for 30–40 min, then a solution of the
corresponding alkyl halide (1.25 mmol) in THF (5 mL) was added dropwise. The reaction
mixture was warmed to r t. and stirred for 2–3 h. The progress of the reaction was monitored by
TLC. The reaction mixture was quenched by addition of sat aqueous NH
4
Cl (30 mL), extracted
with diethylether (3 x 50 mL) and the combined organic layers washed with 50 ml aqueous
Na
2
S
2
O
3
4
(5%), brine, dried (NaSO ), filtered and concentrated under vacuum.
(R,S)-2,2,5-trimethyl-5-phenyl-1,3-dioxolane-4-one (17). Starting from 2,2-dimethyl-5-
phenyl-1,3-dioxolane-4-one (16), (1.92 g, 10.0 mmol), and iodomethane (1.56 g, 11.0 mmol),
the title compound was isolated after drying under high vacuum for 2 h over P O and used
2
5
3
2b 1
without any further purification (1.85 g, 90%).
H NMR (300 MHz, CDCl ) δ 1.45 (3H, s),
3
1
3
1
2
.70 (3H, s), 1.76 (3H, s), 7.31−7.40 (3H, m), 7.61–7.64 (2H, m); C NMR (75 MHz, CDCl
7.8, 28.6, 29.4, 80.7, 110.2, 124.7, 128.2, 128.6, 141.1.
3
) δ
21

ACCEPTED MANUSCRIPT
(R,S)-5-butyl-2,2-dimethyl-5-phenyl-1,3-dioxolane-4-one (18). Starting from 2,2-dimethyl-
5
-phenyl-1,3-dioxolane-4-one (16), (1.92 g, 10.0 mmol), and iodobutane (2.02 g, 11.0 mmol),
the title compound was isolated after purification by column chromatography on siliga gel
(
(
(
petroleum ether/diethylether (95:5), R
f
= 0.65) and dried under high vacuum for 2 h over P
2 5
O
3
9 1
2.3 g, 93%). H NMR (300 MHz, CDCl ) δ 0.87 (3H, t, J = 6.9 Hz), 1.70 (3H, s), 1.25-1.36
3
1
3
4H, m), 1.41 (3H, s), 1.69 (3H, s), 1.87-2.03 (2H, m), 7.27-7.38 (3H, m), 7.59-7.63 (2H, m); C
NMR (75 MHz, CDCl )δ 13.9, 22.6, 26.3, 27.9, 41.8, 83.7, 110.1, 124.9, 128.0, 128.5, 140.3,
3
1
73.4.
Synthesis of (R,S)-2-hydroxy-2-phenylalkanoic acids 19, 20. Compounds 19 and 20 were
3
2a,b
synthesized as previously described according to the literature procedure,
and used in the next
step without any further purrification.
3
2b
(
R,S)-2-hydroxy-2-phenylpropanoic acid (19). The title compound was isolated as white
3
9
1
solid, (97% yield). Mp: 114–116 °C (Lit. mp 115–116 °C); H NMR (300 MHz, CDCl
3
) δ 1.75
1
3
(
3H, s), 7.44-7.48 (3H, m), 7.52-7.55 (2H, m); C NMR (75 MHz, CDCl ) δ 26.8, 75.8, 125.3,
3
1
28.3, 128.6, 141.9, 180.2.
R,S)-2-hydroxy-2-phenylhexanoic acid (20). The title compound was isolated as white
3
2c
(
3
2c
1
solid, (98% yield). Mp: 100–102 °C (Lit. mp 101–102 °C); H NMR (300 MHz, CDCl ) δ
3
0
7
1
.90 (3H, t, J = 6.9 Hz), 1.26-1.45 (4H, m), 2.00-2.10 (1H, m), 2.27 (1H, m), 7.28-7.40 (3H, m),
1
3
.60-7.64 (2H, m); C NMR (75 MHz, CDCl ) δ 14.0, 22.9, 25.8, 39.5, 78.5, 125.6, 128.1,
3
28.5, 141.1, 180.8.
3
7a,b
General procedure for the synthesis of 1,3-dioxolane-2,4-diones (24a-c).
To a solution
of the appropriate α-hydroxy acid 21-23 (7 mmol) and dry triethylamine (14 mmol, 1.42 g) in
anhydrous THF (16 mL), was added dropwise a solution of triphosgene (4.69 mmol, 1.39 g) in
THF (3.5 mL) over 30 min, and the resulting mixture was refluxed overnight. After the reaction
mixture was cooled to r.t., diethylether (50 mL) was added, the hydrochloride salt of
triethylamine was filtered off, and the solvents were evaporated under reduced pressure. The 1,3-
dioxolane-2,4-diones 24a-c were isolated in an brownish oily form, dried under high vacuum for
2
2 5
h over P O and were used immediately to the next step without any further purification.
(R,S)-5-Methyl-5-phenyl-1,3-dioxolane-2,4-dione (24a). Starting from the α-hydroxy acid 21
1
(
7 mmol, 1.16 g) the title compound was obtained as an oil (1.35 g, quantitative yield). H NMR
22

ACCEPTED MANUSCRIPT
1
3
(300 MHz, CDCl
3
) δ 2.03 (3H, s), 7.44-7.48 (3H, m), 7.52-7.55 (2H, m); C NMR (75 MHz,
CDCl ): δ 25.7, 87.1, 124.3, 129.4, 130.1, 134.6, 147.5, 168.5.
3
(R,S)-5-Butyl-5-phenyl-1,3-dioxolane-2,4-dione (24b). Starting from the α-hydroxy acid 22
1
(
(
(
7 mmol, 1.46 g) the title compound was obtained as an oil (1.74 g, quantitative yield); H NMR
300 MHz, CDCl ) δ 0.91 (3H, t, J = 7.2 Hz), 1.3-1.45 (4H, m), 2.22-2.29 (2H, m), 7.43-7.47
3
1
3
3
3H, m), 7.52-7.56 (2H, m); C NMR (75 MHz, CDCl ): δ 13.7, 22.2, 25.3, 39.2, 90.2, 124.4,
1
29.3, 129.8, 134.0, 147.8, 168.3.
5,5-Dimethyl-1,3-dioxolane-2,4-dione (24c). Starting from the α-hydroxy acid 23 (7 mmol,
1
0
.73 g) the title compound was obtained as an oil (1.01 g, quantitative yield). H NMR (300
1
3
MHz, CDCl ) δ 1.69 (6H, s); C NMR (75 MHz, CDCl ): δ 23.7, 84.8, 147.6, 170.3.
3
3
General procedure for the synthesis of tetronic acids 25a-c. The final compounds 25a-c
were prepared as described in general procedure for compounds 14a-h with some modifications,
using lithium diisopropylamide 2.0 M solution in THF/hexane/ethylbenzene (9 mmol, 4.5 mL) in
THF (22.5 mL), ethyl phenylacetate (9 mmol, 1.48 g) and the appropriate 1,3-dioxolane-2,4-
dione 24a-c (3 mmol). Tetronic acids 25a-c were isolated by extraction of the acidified aqueous
2 4
layer with ethyl acetate (3 x 30 mL), the combined organic layers were dried over Na SO and
concentrated under reduced pressure. The crude oily products were purified by silica column
chromatography, otherwise by crystallization, and dried under high vacuum for 2 h over P O .
2
5
(R,S)-5-Methyl-3,5-phenyltetronic acid (25a). Starting from (R,S)-5-methyl-5-phenyl-1,3-
dioxolane-2,4-dione (24a) (3.0 mmol, 0.58 g), the title compound was obtained as a white solid
after purification by column chromatography (silica gel, petroleum ether/ethyl acetate/acetic
acid, 70:28:2), (0.54 g, 67% yield). Mp: 165–167 °C;
ν
max(KBr) 2960, 1775, 1680, 1605, 1545,
-1
1
cm ; H NMR (300 MHz, CDCl
3
) δ 1.95 (3H, s), 7.23 (1H, t, J = 7.8 Hz), 7.32-7.38 (5H, m),
1
3
7
1
.50 (2H, d, J = 8.1 Hz), 7.80 (2H, d, J = 8.1 Hz). C NMR (75 MHz, CDCl ): δ, 23.8, 83.6,
3
01.0, 125.7, 128.0, 128.6, 128.77, 128.81, 128.9, 137.8, 172.9, 176.9. ESI-HRMS : m/z [M
+
+
Na] calcd for C17
H14NaO
3
289.0835, found 289.0828.
(R,S)-5-Butyl-3,5-phenyltetronic acid (25b). Starting from (R,S)-5-butyl-5-phenyl-1,3-
dioxolane-2,4-dione (24b) (3.0 mmol, 0.70 g), the title compound was obtained as a white
crystalline solid after purification by crystallization with hexane/diethylether at −18° C, (0.51 g,
-1
1
5
5% yield). Mp: 127–129 °C; νmax(KBr) 2950, 1780, 1682, 1605, 1550 cm ; H NMR (300
MHz, DMSO-d ): δ 0.88 (3H, t, J = 6.9 Hz), 1.32 (4H, m), 2.14-2.34 (2H, m), 7.20-7.42 (6H, m),
6
23

ACCEPTED MANUSCRIPT
1
3
7
1
.48-7.53 (4H, m), 8.96 (1H, br s); C NMR (75 MHz, CDCl
3
): δ 22.3, 25.4, 36.6, 86.3, 101.8,
+
25.5, 128.0, 128.1, 128.4, 128.6, 128.7, 128.8, 138.0, 173.3, 175.9. ESI-HRMS : m/z [M+Na]
calcd for C H NaO 331.1305, found 331.1297.
2
0
20
3
(
R,S)-5,5-Dimethyl-3-phenyltetronic acid (25c). Starting from 5,5-dimethyl-1,3-dioxolane-
,4-dione (24c) (3.0 mmol, 0.39 g), the title compound was obtained as a white crystalline solid
after purification by crystallization with hexane/diethylether at −18 °C, (0.24 g, 62%). Mp: 208–
2
4
0
1
2
11 °C (Lit. m.p. 210–213 °C); H NMR (300 MHz, CDCl /DMSO d ): δ 1.53 (6H, s), 7.20
3 6
1
3
(
1H, pt), 7.33 (2H, pt), 7.81 (2H, pd); C NMR (75 MHz, CDCl ): δ 14.0, 80.3, 98.8, 126.9,
3
–
1
27.9, 128.2, 130.3, 172.1, 178.9. ESI–MS: m/z 203.16 [M – H]
General procedure for the synthesis of tetronic acids 26a-c. Final compounds 26a-c were
prepared as described in general procedure for compounds 10a-g, with some modifications,
using diethylmalonate (8) (0.96 g, 6 mmol,), sodium hydride (0.24 g, 6 mmol, 60% in oil) in
THF (15 mL), and appropriate 1,3-dioxolane-2,4-dione (24a-c) (2 mmol) in THF (3 mL). The
oily crude products were purified by column chromatography on silica gel otherwise with
crystallization, and dried under high vacuum for 2 h over P O .
2
5
(R,S)-3-Ethoxycarbonyl-5-methyl-5-phenyltetronic acid (26a). Starting from (R,S)-5-
methyl-5-phenyl-1,3-dioxolane-2,4-dione (24a) (3.0 mmol, 0.58 g), the title compound was
isolated as an orange crystalline solid after purification by crystallization with hexane/
dichloromethane at −18 °C, (0.39 g, 50% yield). Mp: 90–92 °C; νmax(KBr) 3100, 2705, 1720,
-1 1
1
612, 1540 cm ; H NMR (300 MHz, CDCl / drop DMSO-d ): δ 1.39 (3H, t, J = 6.9 Hz), 1.83
3 6
1
3
(
3H, s), 4.41 (2H, q, J = 6.9 Hz), 7.33-7.43 (3H, m), 7.48-7.54 (2H, m), 10.49 (1H, br s); C
NMR (75 MHz, CDCl ): δ 14.3, 24.8, 62.3, 83.3, 93.0, 125.1, 128.9, 129.1, 137.2, 165.6, 166.9,
3
+
1
93.4. ESI-HRMS : m/z [M+Na] calcd for C14
H14NaO
5
285.0733, found 285.0730.
(R,S)-3-Ethoxycarbonyl-5-butyl-5-phenyltetronic acid (26b). Starting from (R,S)-5-butyl-5-
phenyl-1,3-dioxolane-2,4-dione (24b) (3.0 mmol, 0.70 g), the title compound was isolated as a
solid after purification by column chromatography (silica gel, dichloromethane/methanol/acetic
-1
acid (95:5:5), (0.39 g, 45%). νmax(KBr) 3150, 2705, 1750, 1692, 1625, 1540 cm ; NMR (300
MHz, DMSO-d recorded at 85°C): δ 0.83 (3H, t, J = 6.9 Hz), 1.14-1.27 (7H, m), 1.90 (2H, t, J =
6
1
3
3
.6 Hz), 4.00 (2H, q, J = 6.9 Hz), 7.19-7.31 (3H, m), 7.48 (2H, d, J = 7.5 Hz); C NMR (75
MHz, CDCl ): δ NMR (75 MHz, DMSO-d ): δ 13.9, 14.6, 22.2, 25.0/25.3, 36,8/37.3, 58.0/59.7,
3
6
24

ACCEPTED MANUSCRIPT
8
3.0/85.5, 124.8, 126.9, 127.8/128.0, 139.9/141.0, 166.0, 172.5, 194.8. ESI-HRMS : m/z [M+
+
H] calcd for C H O 305.1384, found 305.1373.
1
7
21
5
(R,S)-5,5-Dimethyl-3-ethoxycarbonyltetronic acid (26c). Starting from 5,5-dimethyl-1,3-
dioxolane-2,4-dione (24c) (3.0 mmol, 0.39 g), the title compound was solidified after
refrigerated overnight, triturated with petroleum ether and isolated as white solid (0.40 g, 66%
41
1
yield). Mp: 82–84 °C (Lit. m.p. 83–84 °C); H NMR (300 MHz, CDCl
3 6
/drops DMSO-d ): δ
13
1
.37 (3H, t, J = 6.9 Hz), 1.54 (6H, s), 4.38 (2H, q, J = 6.9 Hz); C NMR (75 MHz,
CDCl /drops DMSO-d ): δ 14.2, 23.9, 62.1, 80.8, 93.3, 165.6, 166.7, 194.6. ESI – MS: m/z
3
6
–
1
99.24 [M – H ]
(2S,5S)-cis-2-tert-butyl-5-phenyl-1,3-dioxolane-4-one (27). Compound 27 was synthesized
3
5
according to the literature procedure starting from (S)-mandelic acid and pivalaldehyde, and
3
5
used in the next step without any further purrification. Mp: 138–140 °C (Lit. m.p. 140 °C),
2
0
35
20
D
1
[
α]D +87.4 (c 1.2, chloroform), (Lit. [α] + 88.7 (c 1.2, chloroform); H NMR (300 MHz,
DMSO-d
6
) δ 1.01 (9H, s), 5.47 (1H, d, J = 1.5 Hz), 5.56 (1H, d, J = 1.5 Hz), 7.41-7.45 (5H, m);
1
3
C NMR (75 MHz, DMSO-d ) δ 23.3, 33.9, 76.5, 108.2, 127.4, 128.7, 129.1, 134.2, 172.0.
6
(2S,5S)-2-tert-butyl-5-methyl-5-phenyl-1,3-dioxolane-4-one (28). To a solution of (2S,5S)-
cis-2-tert-butyl-5-phenyl-1,3-dioxolane-4-one (27) (0.7 g, 3.18 mmol) in anhydrous THF (18
mL) was added dropwise at −78 ºC a solution of lithium diisopropylamide (2.0 M in
THF/hexane/ ethylbenzene), (1.75 mL, 3.5 mmol). The resulting solution was stirred at –78 ºC
for 30–40 min and then a solution of iodomethane (0.68 g, 4.77 mmol) in THF (1 mL) was added
dropwise. The reaction mixture was allowed to warm to 0 ºC and stirred for 2–3 h. The progress
of the reaction was monitored by TLC. After this time, the reaction mixture was poured into satd
aqueous NH Cl (30 mL), extracted with Et O (3 x 30 mL), the combined organic layers washed
4
2
with a 5% aqueous Na
2
S
2
O
3
2 4
(50 mL), brine, dried (Na SO ) and concentrated under reduced
pressure. The crude product was purified by column chromatography on silica gel (petroleum
ether/Et O 95:5) to afford the compound 28 as colorless oil (0.64 g, 87%, mixture of
diastereomers d.r. 93:7). H NMR (300 MHz, CDCl ) δ 1.03 (9H, s), 1.76 (3H, s), 5.39 (1H, s),
2
3
5 1
3
1
3
7
1
.31-7.46 (3H, m), 7.63-7.66 (2H, m); C NMR (75 MHz, CDCl ) δ 23.5, 23.8, 34.8, 79.9, 99.4,
3
07.8, 125.0, 125.9, 128.3, 139.3, 174.34.
(S)-2-Hydroxy-2-phenylpropanoic acid (29).
25

ACCEPTED MANUSCRIPT
The title compound was sythesized according to the general procedure for the preparation of
3
6
20
D
compounds 19 and 20; m.p. 111–113°C (Lit. m.p. 112−114 °C), [α] +36.5 (c 0.2, ethanol),
3
6
20
1
(
Lit. [α] + 36.0 (c 0.99, ethanol); H NMR (300 MHz, CDCl /DMSO-d ) δ 2.92 (1H, dd, J =
D 3 6
1
3
7
.2, 13.8 Hz), 3.14 (1H, dd, J = 3.9, 13.8 Hz), 4.38 (1H, dd, J = 7.2, 3.9 Hz), 7.15 (5H, m); C
NMR (75 MHz, CDCl / DMSO-d ) δ 40.3, 70.9, 126.6, 128.2, 129.6, 137.0, 176.2.
3
6
(S)-5-Methyl-5-phenyl-1,3-dioxolane-2,4-dione (30). Compound 30 was synthesized according
to the method for the synthesis of compounds 24a−c. Starting from α-hydroxy acid 29 (3 mmol,
0
.50 g) the title compound was obtained as a brown oil (0.58 g, quantitative yield) which was
1
used to the next step without any further purification. H NMR (300 MHz, CDCl
3
): δ 2.03 (3H,
1
3
s), 7.4–7.47 (3H, m), 7.51–7.55 (2H, m). C NMR (75 MHz, CDCl ): δ 25.7, 87.1, 124.3, 129.4,
3
1
30.1, 134.6, 147.5, 168.5.
(S)-5-methyl-3,5-phenyltetronic acid (31). Compound 31 was synthesized according to general
method for the synthesis of compounds 25a−c. Starting from (S)-5-methyl-5-phenyl-1,3-
dioxolane-2,4-dione (30) (3.0 mmol, 0.58 g), the title compound was obtained as a white solid
after purification by column chromatography (silica gel, petroleum ether/ethyl acetate/acetic
2
0
acid, 70:28:2), (0.50 g, 62% yield). M.p. 166–168°C [α]
D
−6.3 (c 0.2, methanol), d.r. 99:1, e.e.
max(KBr) 2955, 1780, 1684, 1605, 1552, cm ; H NMR (300 MHz, DMSO-d ) δ 1.93
3H, s), 7.24 (1H, t, J = 7.2 Hz), 7.36–7.48 (6H, m), 7.80 (2H, d, J = 7.5 Hz). C NMR (75
MHz, CDCl /drop DMSO-d ) δ, 23.1, 82.8, 99.6, 126.1, 127.1, 128.1, 128.3, 128.5, 128.6, 129.9,
-
1
1
9
8%;
ν
6
1
3
(
3
6
–
1
13 3
38.6, 172.6, 177.8. ESI-HRMS : m/z [M–H] calcd for C17H O 265.0859, found 265.0859.
Acknowledgements
We thank the National Technical University of Athens (NTUA), for providing financial
support.
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2
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Chem. 2009, 74, 1124; (e) Vieweg, L.; Reichau, S.; Schobert, R.; Leadlay, P.F.; Sussmuth, R.D.
26

ACCEPTED MANUSCRIPT
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1
0
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4. (a) Roggo, B. E.; Hug, P.; Moss, S.; Raschdorf, F.; Peter, H. H. J.Antibiot. 1994, 47, 143; (b)
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