A short enantioselective synthesis of homocitric acid-γ-lactone and 4-hydroxy-homocitric acid-γ-lactones

Article abstract of DOI:10.1016/j.tet.2004.07.096

A simple method for the synthesis of enantiopure homocitric acid γ-lactone and its 4-hydroxy analogues starting from spiro-γ- dilactone, in up to 74% isolated yield is described.

Full text of DOI:10.1016/j.tet.2004.07.096

Tetrahedron 60 (2004) 9081–9084
A short enantioselective synthesis of homocitric acid-g-lactone
and 4-hydroxy-homocitric acid-g-lactones
a
Anne Paju, T o˜ nis Kanger, T o˜ nis Pehk, Margus Eek and Margus Lopp
a
b
c
a,*
a
Department of Chemistry, Faculty of Science, Tallinn University of Technology, Ehitajate tee 5, 19086 Tallinn, Estonia
b
National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, Estonia
c
Prosyntest Ltd, Akadeemia tee 15, 12618 Tallinn, Estonia
Received 27 May 2004; revised 12 July 2004; accepted 28 July 2004
Available online 26 August 2004
Abstract—A simple method for the synthesis of enantiopure homocitric acid g-lactone and its 4-hydroxy analogues starting from spiro-g-
dilactone, in up to 74% isolated yield is described.
q 2004 Elsevier Ltd. All rights reserved.
1
. Introduction
the above mentioned reasons make the search for new
synthetic methods of chiral citrates, their derivatives and
analogues an important goal for synthetic chemists.
(
K)-R-Homocitrate is an intermediate in lysine biosynthesis
1
–4
pathway in yeast and some fungi. This pathway is absent
in plants and mammalians. That feature makes (K)-R-
homocitrate and various citric acid derivatives promising
candidates for anti-fungi therapy in human medicine, and
prospective anti-fungi agents for crop protection in
agriculture. The list of new antifungal citrates is far from
Asymmetric oxidation of ketones is a challenging option in
1
8,19
the synthesis of enantioenriched compounds.
previously found that 3-substituted cyclopentane-1,2-diones
can be oxidized with Ti(Oi-Pr) /(C)-diethyl tartrate/tert-
We have
4
2
0
BuOOH complex (Sharpless complex), resulting in
enantiopure 2-alkyl-g-lactone acids in the case of alkyl-
5
being exhausted. Additionally, chiral hydroxy acids are
known as useful chiral synthons, ligands and auxiliaries in
asymmetric organic synthesis.
2
1–23
substituted diketones
and spirodilactones 2 in the case
6
24
of hydroxyethyl substituted diketones 1. These stable
compounds can be used as key intermediates in many
transformations. (Scheme 1).
Maragoudakis and Strassmann accomplished the first
synthesis of racemic homocitrate in 1966. In the same
7
year, enantioenriched S-homocitric acid was synthesized
from (K)-quinic acid. In the late nineties, interest towards
8
homocitric acid increased again and it was synthesized from
L-lactic acid and L-serine, citric acid, monoethyl
9
10
1
malonate and D-Na-malate.
1
12
To the best of our knowledge, the 4-hydroxy derivatives of
homocitric acid have not been found from natural sources
yet, and have not been synthesized before. However, the
corresponding isomers of hydroxycitric acids, (2S,3S)- and
Scheme 1.
In the present paper we demonstrate how the derivatives of
hexanetriacid can be obtained starting from spirodilactone 2
according to a simple and efficient scheme (Scheme 2).
(
extensively distributed in nature and are present in
2S,3R)-2-hydroxycitric acid and their derivatives are
1
3,14
plants.
applications of these compounds are available.
Several reports pertaining to the pharmaceutical
All of
1
5–17
2
. Results and discussion.
.1. Preparation of homocitric acid-g-lactone
Homocitric acid-g-lactone was synthesized starting from
Keywords: Asymmetric oxidation; Spirodilactone; Homocitric acid;
g-Lactone; 4-Hydroxy-homocitric acid; g-Lactone.
2
*
Corresponding author. Tel.: C372 6202 808; fax: C372 6547 520;
e-mail: lopp@chemnet.ee
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.096

9082
A. Paju et al. / Tetrahedron 60 (2004) 9081–9084
Scheme 2.
spirodilactone (R)-2a (2a was obtained from asymmetric
oxidation of 3-hydroxyethyl-cyclopentane-1,2-dione
using Ti(OiPr) /(C)-diethyl tartrate/tert-BuOOH complex
4
results in R-configuration of the newly formed stereogenic
center in 2a.
2
according the described procedure ). We first made an
4
24
attempt to convert spirodilactone 2a into a diester 3a (path
(a), Scheme 3). However, trans-esterification of 2a with
methanol under basic conditions (NaHCO , K CO or
2.2. Preparation of 4-hydroxyhomocitric acid-g-lactones
3
2
3
NaOMe) resulted in a 3:7 ratio of diester 3a and lactone
ester 4a (in a 94% overall yield). The same mixture was
obtained when one of the reaction products—lactone ester
The synthesis of new homocitric acid analogs—4-hydroxy-
homocitric acids was accomplished starting from benzyl-
oxy-substituted spirodilactones (2S,3R)-2b and (2S,3S)-2c,
respectively. Preparation of the initial diketone 1b, its
asymmetric conversion into diastereomeric spirodilactones
2b:2c as a 6:1 mixture, and separation of the diastereomers
4
4
a—was treated with methanol. Diester 3a and lactone ester
a are easily separable from each other on silica gel. Jones
oxidation of the separated diester 3a followed by hydrolysis
and acidification, resulted in (R)-homocitric acid-g-lactone
2
4
has been described by us earlier. The major diastereomer
2b from this procedure (ee 86–88%) was recrystallized from
CH Cl –ether mixture affording the necessary substrate 2b
5
a in 46% yield for two steps.
2
2
The moderate yield of 3a from the trans-esterification
procedure forced us to find alternatives. So, we tried a direct
oxidation of spirodilactone 2a in a form a diacid Na—or
in good yield (73%) and high enantiomeric purity (ee
98.5%). Compound (2S,3R)-2b was subjected to oxidation
with K S O (cat. RuCl !H O) using the same procedure
2
2
8
3
2
K-salt. Indeed, using simple reagents like KMnO or
4
that is described for 2a (Scheme 4).
2
K S O (with RuCl !H O as a catalyst) in basic medium
5
2
2
8
3
2
afforded (R)-(K)-homocitric acid-g-lactone R-5a directly
from (R)-2a in 56 and 74% yield, correspondingly (path (b),
Scheme 3).
Thus, (K)-4-hydroxyhomocitric acid-g-lactone (3S,4R) 5b
was obtained from spirodilactone (2S,3R)-2b after oxi-
dation, cyclization and removing the protecting benzyl
group in 59% overall yield (Scheme 4).
Comparison of the optical rotation of the obtained product
(
confirms the (R) absolute configuration of the homocitric
acid lactone. This result is in good agreement with our
earlier suggestion that the oxidation of the substrate 1a
8
[a] ZK49.8 for 5a) with that of the natural product
An analogous process, starting from the minor isomer
(2S,3S)-2c, resulted in a mixture of two compounds: 5c and
D
1
13
7c (identified only by H and C NMR spectra) (Scheme 5).
The cis-orientation of the –OH and –CH COOH groups in
2
Scheme 3. Reagents and conditions: (a) (i) NaHCO
6 h, rt, (56%). (v) 1 M HCl, (74%) or (iv) K
3
, MeOH, rt. (ii) Jones’ reagent, 71%. (iii) LiOH, THF 6 h, then 1 M HCl, 65%. (b) (iv) KMnO
, RuCl !H O, 0.2 N KOH. (v) 1 M HCl, (74%).
4
, 1 M NaOH,
1
2
S
2
O
8
3
2
Scheme 4. Reagents and conditions: (i) K
2
S
2
O
8
, RuCl
3
!H
2
O, 0.2 M KOH. (ii) conc. HCl, CH
2
Cl
2
(61% for two steps). (iii) Pd/C, H
2
(96%).

A. Paju et al. / Tetrahedron 60 (2004) 9081–9084
9083
Scheme 5. Reagents and conditions: (i) K
2
S
2
O
8
, RuCl
3 2 2 2 2
!H O, 0.2 M KOH. (ii) conc. HCl, CH Cl . (iii) Pd/C, H .
1 13
c was also established by H and C NMR spectra
5
confirming the structure of 7c.
the remaining water was acidified to pH 1 with 6 M HCl
solution and the mixture was evaporated. The residue was
dissolved in acetone (10 mL) and the solid material was
filtered off. Removal of the acetone, followed by flash
chromatography (silica gel, petroleum ether–acetone 10:5 to
3. Conclusions
2
0
1
0
2
0:6) gave 5a as white solid (43 mg, 56%); [a] ZK49.8 (c
D
1
.36, water); H NMR ((CD ) CO): d 3.00 and 3.20 (both d,
The described method affords a simple and short access to
homocitric acid and its derivatives. The method enables
synthesis of homocitric acid g-lactones in both enantiomeric
forms starting from 3-hydroxymethyl-1,2-cyclopentane-
dione via spirodilactone 2a with the overall isolated yield
of the target compounds more than 50%. The (K)-4-
hydroxy-homocitric acid-g-lactones 5b, 5c and bilactone
acid 7c can be obtained from 4-hydroxy-3-hydroxyethyl-
cyclopentane-1,2-diones in a similar way. These are new
compounds with a furanone skeleton, and biological activity
is currently under study.
3 2
H, JZ17.1 Hz, H-2), 2.47 and 2.54 (both m, 2H, H-4), 2.60
1
3
and 2.62 (both m, 2H, H-5); C NMR ((CD ) CO): d
3 2
1
4
3
1
4
76.33 (C-6), 172.43 (3-COOH), 170.47 (C-1), 83.42 (C-3),
1.64 (C-2), 31.83 (C-5), 28.26 (C-4); IR (KBr, cm ):
K1
121, 2983, 2934, 1755, 1723, 1674, 1386, 1244, 1186,
062. Anal. calcd for C H O : C, 44.69; H, 4.29. Found: C,
4.65; H, 4.26.
7
8 6
Method B. To a solution of spirodilactone 2a (29 mg,
.19 mmol) in 0.2 M KOH (10 mL), potassium persulfate
251 mg, 0.93 mmol) followed by RuCl !H O (1 mg,
0
(
3
2
0
mixture was stirred for 24 h at room temperature. Then
.0044 mmol) was added with vigorous stirring. The
4. Experimental
Na SO (94 mg, 0.74 mmol) was added at 0 8C followed by
2
3
6
1
M HCl (2.5 mL) after 0.5 h and stirring was continued for
h at room temperature. The reaction mixture was extracted
4
.1. General
1
13
with several portions of dry EtOAc. The combined extracts
were dried (Na SO ) and the solvents were removed. The
residue was purified by flash chromatography (silica gel,
H and C NMR spectra were determined in deuterated
solvents on a Bruker AMX-500 spectrometer. Chemical
shifts are reported in delta (d) units, parts per million (ppm)
downfield from TMS. Deuterated solvent peaks were used
as internal references: deutero-methanol at 3.30 and
2
4
petroleum ether–acetone 10:5 to 10:6) to yield 5a as white
20
solid (26 mg, 74%); [a] ZK48.9 (c 0.38, water). Anal.
D
calcd for C H O : C, 44.69; H, 4.29. Found: C, 44.58; H,
4.33.
7
8 6
4
9.00 ppm, deutero-acetone at 2.05 and 29.80 ppm. IR
spectra were recorded on a Perkin–Elmer Spectrum BX
FTIR spectrometer. Elemental analyses were performed on
a Perkin–Elmer C,H,N,S-Analyzer 2400. Optical rotations
were obtained using an A. Kr u¨ ss Optronic GmbH
polarimeter P 3002. TLC was performed using DC-
4.3. (K)-4-Benzyloxyhomocitric acid lactone (6b)
To a stirred solution of spirodilactone 2b (48 mg,
0.18 mmol) in a mixture of 0.2 M KOH/CH Cl 8:1
w
Alufolien Kieselgel 60 F254 (Merck) or Silufol UV 254
2
2
silica gel plates. Merck Silica gel 60 (0.063–0.200 mm) or
Chemapol silica gel L 40/100 was used for column
chromatography. All the reactions sensitive to oxygen or
moisture were conducted under argon atmosphere in oven-
dried glassware. Commercial reagents were generally used
as received. CH Cl was distilled from CaH and stored
over 3 A molecular sieve pellets. The enantiomeric purity of
the spirodilactones 2a–c was determined on a LKB liquid,
chromatograph with Uvicord UV detector, using a Daicel
Chiracel ODH chiral column.
(10 ml), potassium persulfate (247 mg, 0.92 mmol) and
RuCl !H O (1 mg, 0.0044 mmol) were added. After
3
2
stirring for 23 h at room temperature the reaction mixture
was extracted with CH Cl (10 mL), the aqueous phase was
acidified to pH 1 with 1 M HCl and extracted with EtOAc
2
2
2
2
2
(5!10 mL). The combined extracts were dried (Na SO )
2
4
˚
and the solvents were removed. To this crude triacid dry
CH Cl (10 mL) and concentrated HCl (100 mL) were
2
2
added. The mixture was vigorously stirred for 2 h at room
temperature. Then water (12 mL) was added and the
reaction was extracted with EtOAc (3!10 mL). The
4
.2. (K)-Homocitric acid lactone (5a)
combined extracts were dried (Na SO ) and the solvents
2 4
were removed. The residue was purified by flash chroma-
tography (silica gel, petroleum ether–acetone 10:4 to 10:6)
Method A. To a solution of spirodilactone 2a (64 mg,
.41 mmol) in a mixture of 1 M NaOH/CH Cl 1:1 (4 mL),
KMnO (97 mg, 0.62 mmol) was added at 0 8C and the
2
0
0
to yield 6b as white solid (33 mg, 61%); [a]
D
ZK21 (c
1.04, acetone); H NMR (CD ODCCDCl ): d 7.2–7.4 (m,
3 3 H
2
2
1
4
mixture was stirred for 16 h at room temperature. Then
EtOH (4 mL) was added and the solution was filtered
through Celite. EtOH was removed under reduced pressure,
5H, Ph), 4.55 and 4.58 (both d, 2H, JZ11.8 Hz, PhCH2),
4.45 (dd, 1H, JZ6.1, 7.6 Hz, H-4), 3.24 and 2.85 (both d,
2H, JZ17.2 Hz, H-2), 2.87 (dd, 1H, JZ7.6, 17.8 Hz, H-5),

9084
A. Paju et al. / Tetrahedron 60 (2004) 9081–9084
1
3
2
(
.71 (dd, 1H, JZ6.1, 17.8 Hz, H-5);
C
CD ODCCDCl ): d 175.01 (C-6), 171.31 (C-1),
NMR
References and notes
3
3
C
1
70.64 (C-3COOH), 137.38 (s-Ph), 128.96 (m-Ph), 128.58
p-Ph), 128.27 (o-Ph), 87.36 (C-3), 79.11 (C-4), 73.41 (Bn
1. Strassman, M.; Ceci, L. N. Biochem. Biophys. Res. Commun.
1964, 14, 262–267.
(
CH ), 40.29 (C-2), 35.35(C-5); IR (KBr, cm ): 2948,
1787, 1725, 1433, 1232, 1095, 1077, 741, 696. Anal. calcd
for C H O : C, 57.14; H, 4.80. Found: C, 56.81; H, 4.82.
K1
2
2. Strassman, M.; Ceci, L. N. J. Biol. Chem. 1965, 240,
4357–4361.
3. Hogg, R. W.; Broquist, H. P. J. Biol. Chem. 1968, 243,
1
4 14 7
1
839–1845.
. Andi, B.; West, A. H.; Cook, P. F. Arch. Biochem. Biophys.
004, 421, 243–254.
4
5
4
.4. (K)-4-Hydroxyhomocitric acid lactone (5b)
2
. Recently, new natural alkyl citrates that exhibit high antifungal
potention were discovered: Singh, S. B.; Zink, D. L.; Doss,
G. A.; Polishook, J. D.; Ruby, C.; Register, E.; Kelly,
T. M.; Bonfiglio, C.; Williamson, J. M.; Kelly, R. Org.
Lett. 2004, 6, 337–340.
To a stirred solution of lactone 6b (30 mg, 0.10 mmol) in
MeOH (3 mL) 10% Pd/C (14 mg) was added and the
mixture was stirred for 22 h at room temperature. The
catalyst was removed by filtration through a pad of Silica
gel and the filtrate was evaporated to give 5b as white solid
6
. Coppola, G. M.; Schuster, H. F. Chiral a-Hydroxy Acids in
Enantioselective Synthesis; Wiley-VCH: Weinheim, 1997.
2
0
1
(
20 mg, 96%); [a] ZK17 (c 1.20, acetone); H NMR
D
(
2
(CD ) CO): d 4.73 (dd, 1H, JZ6.5, 7.6 Hz, H-4), 3.30 and
3 2 H
7. Maragoudakis, M.; Strassmann, M. J. Biol. Chem. 1966, 241,
95–699.
.92 (2H, both d, JZ17.1 Hz, H-2), 2.97 (1H, dd, JZ
.6, 17.6 Hz, H-5), 2.60 (1H, dd, JZ6.5, 17.6 Hz, H-5);
6
7
8
. Thomas, U.; Kalayanpur, M. G.; Stevens, C. M. Biochemistry
1966, 5, 2513–2516.
1
3
C NMR ((CD ) CO): d 174.20 (C-6), 170.67 (C-
COOH), 170.04 (C-1), 87.97 (C-3), 73.07 (C-4), 39.98
3
2
C
3
(
´
9
. Rodrıguez, G. H. R.; Biellmann, J.-F. J. Org. Chem. 1996, 61,
822–1824.
K1
C-2), 36.72 (C-5); IR (KBr, cm ): 3416, 2944, 1789,
1
1
4
737, 1408, 1202, 1176, 1068. Anal. calcd for C H O : C,
7
1.19; H, 3.95. Found: C, 41.55; H, 4.00.
10. Ancliff, R. A.; Russell, A. T.; Sanderson, A. J. Tetrahedron:
Asymmetry 1997, 8, 3379–3382.
8 7
1
1
1. Li, Z.-C.; Xu, J.-Q. Molecules 1998, 3, 31–34.
2. Ma, G.; Palmer, D. R. J. Tetrahedron Lett. 2000, 41,
4
4
.5. (C)-4-Hydroxyhomocitric acid lactone (5c) and
-hydroxyhomocitric acid dilactone (7c)
9
209–9212.
3. Lewis, Y. S.; Neelakantan, S. Phytochemistry 1965, 4,
19–625.
1
1
6
Analogously to that of 5b from lactone 2c, a mixture of (C)-
-hydroxyhomocitric acid lactone (5c), (minor com-
ponent) and 4-hydroxyhomocitric acid dilactone (7c)
major component) were obtained. (C)-4-Hydroxyhomoci-
4. Ibnusaud, I.; Thomas, P. T.; Rani, R. N.; Sasi, P. V.; Beena, T.;
Hisham, A. Tetrahedron 2002, 58, 4887–4892.
4
1
1
1
5. Lowenstein, J. M. J. Biol.Chem. 1971, 246, 629–632.
6. Triscari, J.; Sullivan, A. C. Lipids 1977, 12, 357–363.
7. Mackeen, M. M.; Ali, A. M.; Lajis, N. H.; Kawazu, K.;
Kikuzaki, H.; Nakatani, N. Zaitschrift f u¨ r Naturforschung
(
1
tric acid lactone (5c). H NMR ((CD ) CO): d 4.65 (d, 1H,
2
JZ5.6 Hz, H-4), 3.20 and 3.06 (2H, both d, JZ17.0 Hz, H-
2
1
1
3
H
), 2.96 (1H, dd, JZ5.6, 17.8 Hz, H-5), 2.39 (1H, d, JZ
2
002, 57c, 291–295.
13
7.8 Hz, H-5); C NMR ((CD ) CO): d 175.20 (C-6),
68.9 (C-1 and C-3COOH), 88.40 (C-3), 72.05 (C-4), 38.32
3
2
C
1
8. Bolm, C.; Luong, T. K. K.; Beckmann, O. Asymmetric
Oxidation Reactions; Oxford University Press: Oxford, 2001
pp 147–152.
(
(
C-2), 37.15 (C-5). 4-Hydroxyhomocitric acid dilactone
1
7c). H NMR ((CD ) CO): d 5.39 (d, 1H, JZ5.8 Hz,
3
2
H
19. Lopp, M.; Paju, A.; Kanger, T.; Pehk, T. Tetrahedron Lett.
996, 37, 7583–7586.
H-4), 3.56 and 3.00 (2H, both d, JZ18.8 Hz, H-2), 3.18
1H, dd, JZ5.8, 19.0 Hz, H-5), 2.86 (1H, d, JZ19.0 Hz,
1
(
H-5); C NMR ((CD ) CO): d 173.92, 173.06 and 168.86
2
2
2
2
0. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974–5976.
1
3
3
2
C
(
(
C-1, C-6 and C-3COOH), 88.67 (C-3), 81.33 (C-4), 37.93
C-2), 35.12 (C-5).
1. Paju, A.; Kanger, T.; Pehk, T.; M u¨ u¨ risepp, A.-M.; Lopp, M.
Tetrahedron: Asymmetry 2002, 13, 2439–2448.
2. Paju, A.; Kanger, T.; Pehk, T.; Lopp, M. Tetrahedron Lett.
2
3. Paju, A.; Kanger, T.; Pehk, T.; Lindmaa, R.; M u¨ u¨ risepp,
000, 41, 6883–6887.
Acknowledgements
A.-M.; Lopp, M. Tetrahedron: Asymmetry 2003, 14,
1
565–1573.
We would like to thank Mrs. Tiiu Kailas for performing FT
IR spectra and elemental analysis, Estonian Science
Foundation (Grants nos 4976, 5133, 5628 and Estonian
Ministry of Education (Grant 0350312s01).
24. Paju, A.; Kanger, T.; Niitsoo, O.; Pehk, T.; M u¨ u¨ risepp, A.-M.;
Lopp, M. Tetrahedron: Asymmetry 2003, 14, 2393–2399.
25. Green, G.; Griffith, W. P.; Hollinshead, D. M.; Ley, S. V.;
Schr o¨ der, M. J. Chem. Soc., Perkin Trans. 1 1984, 681–686.