Regioselective Ring Opening of Malic Acid Anhydrides by Carbon Nucleophiles. Application in the Synthesis of Chiral Tetronic Acids

Full text of DOI:10.1021/jo0004660

5
852
J . Org. Chem. 2000, 65, 5852-5853
Regioselective Rin g Op en in g of Ma lic Acid
An h yd r id es by Ca r bon Nu cleop h iles.
Ap p lica tion in th e Syn th esis of Ch ir a l
Tetr on ic Acid s
Christos A. Mitsos, Alexandros L. Zografos, and
Olga Igglessi-Markopoulou*
F igu r e 1.
National Technical University of Athens, Department of
Chemical Engineering, Laboratory of Organic Chemistry,
Zografou Campus, Athens 157 73, Greece
Sch em e 1a
ojmark@orfeas.chemeng.ntua.gr
Received March 28, 2000
S-Malic acid is an important chiral building block
which has found wide application in the enantioselective
synthesis of chiral compounds.1 Manipulation of this
polyfunctional synthon requires the selective protection
of the different functionalities and the distinction of the
two carboxyl groups present. The O-protected hydroxy-
succinic anhydrides (I) derived from malic acid offer a
unique way to achieve both these tasks. These anhy-
drides react regioselectively at the C-2 site with oxygen
and nitrogen nucleophiles providing malic acid mo-
2
3
noesters and monoamides, respectively. However, no
report has appeared concerning similar behavior toward
carbon nucleophiles.
a
Key: (i) NaH, THF; (ii) NaOH, H2O, MeOH.
The use of malic acid anhydride as starting material
for the preparation of 5-carboxymethyl substituted tetron-
ic acids would overcome the time-consuming hydrolysis
step. The basic framework of a 3-acyl-5-carboxymeth-
yltetronic acid can be constructed through a regioselective
ring opening of malic acid anhydride by the anion of an
appropriate â-ketoester, as outlined in Figure 1.
To exploit this approach, at first we attempted the
synthesis of racemic tetronic acids of this type. The
requisite RS-malic acid anhydride (RS-1) was easily
prepared from RS-malic acid upon heating at reflux with
In the course of our studies on the synthesis of
heterocyclic systems comprising a â-dicarbonyl moiety4
we required a facile route to tetronic acid derivatives (II).
5
The appreciable number of tetronic acids found in nature
and the antibiotic activity displayed by many of them6
has attracted the interest of many research groups on
the synthesis of this class of heterocyclic compounds.
Among the natural occurring tetronic acids a number of
compounds bearing a 5-carboxymethyl substituent have
been isolated as fungal metabolites, namely carlosic,
3
.5 equiv of acetyl chloride. This anhydride was found to
react regioselectively at the C-2 site with anions
of â-ketoesters (2a -e) to afford â-hydroxy-γ-acetoxy-
butenoates of type 3 (Scheme 1). The protocol used
requires the reaction of 1 with 2 equiv of the anion of
the appropriate â-ketoester, generated with sodium hy-
dride. After acidification with 10% hydrochloric acid,
intermediates 3 were obtained in an oily form containing
small amounts of the corresponding â-ketoester, as
7
8
carlic, and viridicatic acid. Although, several procedures
for the preparation of these compounds have appeared
in the literature, they require not readily available
6
starting materials, as â-ketothioesters and 1,3-dioxin-
1
evidenced from the H NMR spectra. Deacetylation and
subsequent cyclization of 3 was effected under basic
hydrolytic conditions to provide the desired 3-acyl-5-
9
4
-ones, and comprise a final hydrolysis step in order to
afford the free carboxyl functionality.
carboxymethyltetronic acids (4, R ) Me, n-Pr, n-C
9 19
H ,
*
To whom correspondence should be addressed. Tel: +301 7723259,
301 7723074. Fax: +301 7723072.
1) Coppola, G. M.; Schuster, H. F. R-Hydroxy Acids in Enantiose-
lective Synthesis; VCH: Weinheim, 1997; Chapter 3.
Ph) in good overall yields (51-79% from RS-1).
+
Application of this methodology in the synthesis of
(
5-(S)-carboxymethyltetronic acids is straightforward uti-
(2) Bajwa, J . S.; Miller, M. J . J . Org. Chem. 1983, 48, 1114.
(3) Liesen, G. P.; Sukenik, C. N. J . Org. Chem. 1987, 52, 455.
(4) Zografos, A. L.; Mitsos, C. A.; Igglessi-Markopoulou, O. Org. Lett.
10
lizing S-malic acid anhydride (S-1). Thus, S-carlosic
acid (S-4b) was obtained from S-1 and ethyl butyryl
2
1
1
999, 1, 1953.
acetate (2b) in 70% yield (2 steps), [R]
-125 (c 0.28,
D
(
(
5) Pattenden, G. Fortschr. Chem. Org. Naturst. 1978, 35, 133.
6) Booth, B. M.; Fox, C. M. J .; Ley, S. V. J . Chem. Soc., Perkin
O) [lit.6 [R]
21
H
2
D
-138 (c 0.28, H
2
O)]. Similarly, S-
viridicatic acid (S-4c) was obtained from S-1 and methyl
hexanoyl acetate (2c) in 62% yield: [R] 546 -101 (c 1,
Trans. 1 1987, 121, and references therein.
7) Clutterbuck, P. W.; Raistrick, H.; Reuter, F. Biochem. J . 1935,
9, 300.
(
21
2
(
(
8) Birkinshaw, J . H.; Samant, M. S. J . Biochem. 1960, 74, 369.
9) Sato, M.; Sakaki, J .; Takayama, K.; Kobayashi, S.; Suzuki, M.;
(10) Henrot, S.; Larchev eˆ que, M.; Petit, Y. Synth. Commun. 1986,
16, 183.
Kaneko, C. Chem. Pharm. Bull. 1990, 38, 94.
1
0.1021/jo0004660 CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/15/2000

Notes
J . Org. Chem., Vol. 65, No. 18, 2000 5853
Ta ble 1. Tetr on ic Acid s Obta in ed w ith th e P r op osed
Meth od ology
dd, J ) 16, 9.2 Hz), 2.70 (1H, dd, J ) 16, 3.4 Hz), 4.40 (1H, dd,
1
3
6
J ) 9.2, 3.4 Hz). C NMR (75 MHz, DMSO-d ): δ 28.0, 37.4,
7
6.2, 95.3, 172.1, 174.7, 192.0, 194.5.
-Acetyl-5-(S)-ca r boxym eth yltetr on ic Acid (S-4a ). Start-
product
R1
â-ketoester
yield (%)
3
RS-4a
S-4a
RS-4b
S-4b
S-4c
RS-4d
RS-4e
Me
Me
n-Pr
n-Pr
n-C5H11
n-C9H19
Ph
2a
2a
2b
2b
2c
2d
2e
75
62
72
70
62
51
79
ing from S-1 (5.0 mmol, 0.79 g), the title compound was obtained
13
as a pale yellow solid (0.62 g, 62%). Mp: 183-184 °C (lit. mp
21
6
1
3
2
82-184 °C). [R]
D
: -107 (c 3.58, acetone) [lit. [R]
D
-36.4 (c
): δ 2.36 (3H, s),
.53 (1H, dd, J ) 17, 7.3 Hz), 2.79 (1H, dd, J ) 17, 3.4 Hz), 4.77
1
.58, acetone)]. H NMR (300 MHz, DMSO-d
6
(
1H, dd, J ) 7.3, 3.4 Hz), 9.57 (2H, br).
3
-Bu ta n oyl-5-ca r boxym eth yltetr on ic Acid (RS-Ca r losic
Acid ) (RS-4b). Starting from RS-1 (5.0 mmol, 0.79 g), the title
EtOH) [lit. [R]21546 -105 (c 1, EtOH)]. Tetronic acids
synthesized with the above methodology are summarized
in Table 1.
9
compound was obtained as a beige solid (0.82 g, 72%). Mp: 177-
1
78 °C (lit.13 mp 178-179 °C). H NMR (300 MHz, DMSO-d
1
6
):
δ 0.86 (3H, t, J ) 7.1 Hz), 1.44-1.60 (2H, m), 2.54 (1H, dd, J )
1
4
7, 7.6 Hz), 2.68-2.75 (2H, m), 2.83 (1H, dd, J ) 17, 3.8 Hz),
In conclusion, the regioselectivity of the reaction of
O-acetylmalic acid anhydride (1) with carbanions has
been established. This anhydride represents a versatile
derivative of malic acid where the selective activation and
protection of the carboxyl groups are simultaneously
achieved. The reaction of 1 with the anions of â-keto-
esters leads to â-hydroxy-γ-acetoxybutenoates of type 3,
which are useful intermediates for the synthesis of
certain tetronic acid natural products.
.82 (1H, dd, J ) 7.6, 3.8 Hz), 9.62 (2H, br). 13C NMR (75 MHz,
DMSO-d
6
): δ 13.7, 18.2, 36.2, 38.9, 76.0, 98.3, 170.9, 171.0, 192.7.
3
-Bu ta n oyl-5-(S)-ca r boxym eth yltetr on ic Acid (S-Ca r -
losic Acid ) (S-4b). Starting from S-1 (2.3 mmol, 0.36 g),
S-carlosic acid (S-4b) was obtained as a white solid (0.36 g, 70%).
9
21
Mp: 176-177 °C (lit. mp 176.5-177.5 °C). [R]
D
: -125 (c 0.28,
O)]. H NMR (300 MHz, DMSO-
): δ 0.86 (3H, t, J ) 7.3 Hz), 1.44-1.58 (2H, m), 2.50 (1H, dd,
6
21
1
H
2
O) [lit. [R]
D
-138 (c 0.28, H
2
d
6
J ) 17, 7.8 Hz), 2.66-2.74 (2H, m), 2.81 (1H, dd, J ) 17, 3.9
Hz), 4.77 (1H, dd, J ) 7.8, 3.9 Hz), 7.72 (2H, br).
5
-(S)-Ca r boxym eth yl-3-h exa n oyltetr on ic Acid (S-Vir i-
d ica tic Acid ) (S-4c). Starting from S-1 (10 mmol, 1.59 g),
S-viridicatic acid was obtained as a pale yellow solid (1.58 g,
Exp er im en ta l Section
9
2
1
Gen er a l Meth od s. All the commercial available starting
materials were used without further purification. The â-keto-
esters used were either purchased from Fluka or prepared by a
6
2%). Mp: 173-174 °C (lit. mp 172-173 °C). [R] -101 (c 1,
546
21
8
-105 (c 1, EtOH)]. 1H NMR (300 MHz,
46
EtOH) [lit. [R]
DMSO-d
1
2
7
3
5
6
): δ 0.83 (3H, t, J ) 6.8 Hz), 1.18-1.32 (4H, m), 1.44-
.56 (2H, m), 2.57 (1H, dd, J ) 17, 7.3 Hz), 2.70-2.77 (2H, m),
.82 (1H, dd, J ) 17, 3.9 Hz), 4.85 (1H, dd, J ) 7.3, 3.9 Hz),
1
1
literature procedure. Commercially available THF and di-
chloromethane were dried prior to use by refluxing over sodium
and phosphorus pentoxide, respectively. Melting points are
uncorrected. Chemical shifts are quoted in ppm (t ) triplet, dd
13
.21 (2H, br). C NMR (75 MHz, DMSO-d
0.9, 36.1, 36.5, 76.0, 98.5, 170.5, 171.0, 192.6, 192.7.
-Car boxym eth yl-3-decan oyltetr on ic Acid (RS-4d). Start-
6
): δ 13.8, 21.8, 24.5,
)
doublet of doublets, m ) multiplet, br ) broad).
Gen er a l P r oced u r e for th e P r ep a r a tion of 3-Acyl-5-
5
ing from RS-1 (2.0 mmol, 0.32 g), the title compound was
ca r boxym eth yltetr on ic Acid s. To a suspension of sodium
hydride (10 mmol) in anhydrous THF (30 mL), chilled at 0 °C,
is added dropwise the appropriate 2 (10 mmol) and, after stirring
at 0 °C for 30 min, a clear solution results. A solution of 1 (5.0
mmol) in anhydrous THF (5 mL) is added at once. The mixture
is stirred at 0 °C for 30 min, and after the addition of water (10
mL), the mixture is concentrated in a rotary evaporator. The
aquatic residue is washed with ether (5 mL) and then acidified
with 10% hydrochloric acid under cooling in an ice-water bath.
The acidified mixture is extracted with dichloromethane, and
the combined extracts dried over sodium sulfate and evaporated
to afford the crude â-hydroxy-γ-acetoxybutenoate 3 in an oily
form. A solution of crude 3 (∼4 mmol) in methanol (2 mL) is
chilled at 0 °C, and a 2 N NaOH solution (6 mL) is added
dropwise. The solution is stirred at room temperature for 2-3
h and then acidified with 10% hydrochloric acid under cooling
in an ice-water bath. The product 4 is either filtered off or
extracted with ethyl acetate.
obtained as a pale yellow solid (0.32 g, 51%). Mp: 151-153 °C.
1
H NMR (300 MHz, DMSO-d ): δ 0.83 (3H, t, J ) 6.8 Hz), 1.22
6
(
12H, br), 1.45 (2H, m), 2.42 (1H, dd, J ) 17, 8.3 Hz), 2.67 (2H,
t, J ) 7.3 Hz), 2.76 (1H, dd, J ) 17, 3.9 Hz), 4.66 (1H, dd, J )
13
8
2
1
.3, 3.9 Hz). C NMR (75 MHz, DMSO-d
8.7, 28.8, 28.85, 28.9, 31.3, 36.3, 37.0, 76.0, 97.9, 171.2, 171.3,
92.9, 193.1. Anal. Calcd for C16 C, 61.52; H, 7.74.
6
): δ 13.9, 22.1, 24.8,
24 6
H O :
Found: C, 61.42; H, 7.76.
3
-Ben zoyl-5-ca r boxym eth yltetr on ic Acid (RS-4e). Start-
ing from RS-1 (10 mmol, 1.59 g), the title compound was
1
obtained as a beige solid (2.08 g, 79%). Mp: 165-167 °C. H NMR
6
(300 MHz, DMSO-d ): δ 2.61 (1H, dd, J ) 17, 7.6 Hz), 2.89 (1H,
dd, J ) 17, 3.5 Hz), 4.97 (1H, dd, J ) 7.6, 3.5 Hz), 7.38-7.76
5H, m). 13C NMR (75 MHz, DMSO-d
): δ 36.4, 74.9, 98.6, 128.1,
29.2, 132.3, 137.9, 171.0, 171.1, 187.4, 187.8. Anal. Calcd for
: C, 59.55; H, 3.84. Found: C, 59.51; H, 3.90.
(
6
1
13 10 6
C H O
Ack n ow led gm en t. We thank the Research Com-
3
-Acetyl-5-ca r boxym eth yltetr on ic Acid (RS-4a ). Starting
from RS-1 (5.0 mmol, 0.79 g), the title compound was obtained
mittee of the National Technical University of Athens
for a doctoral assistantship (C.A.M.).
1
2
as a white solid (0.75 g, 75%). Mp: 172-174 °C (lit. mp 178-
1
1
6
80 °C). H NMR (300 MHz, DMSO-d ): δ 2.15 (3H, s), 2.20 (1H,
J O0004660
(
11) Oikawa, Y.; Yoshioka, T.; Sugano, K.; Yonemitsu, O. Organic
Syntheses; Wiley: New York, 1990; Collect. Vol. VII, p 359.
12) Svendsen, A.; Boll, P. M. J . Org. Chem. 1975, 40, 1927.
(13) Bloomer, J . L.; Kappler, F. E. J . Chem. Soc., Perkin Trans. 1
1976, 1485.
(