Enantioselective syntheses of (-)- and (+)-homocitric acid lactones

Article abstract of DOI:10.1021/jo951063g

Highly enantioselective syntheses of enantiomers of homocitric acid lactones (R)-5a and (S)-5b are described. Thermal Diels-Alder cycloadditions of 2a and 2b to 1,3-butadiene produced adducts 3a and 3b, respectively. Oxidative ozonolysis of latter adducts gave products 4a and 4b which after acid treatment afforded a mixture with 5a and 5b as major component. Acid lactones 5a and 5b were converted into their dimethyl esters 6a and 6b which were purified by chromatography. After saponification, the products obtained were crystallized to yield (-)- and (+)-homocitric acid lactones ((R)-5a and (S)-5b). Diastereomeric excess (de) of Diels-Alder adducts 3a and 3b was determined by means of Mosher esters of glycols 8a, 8b, and racemic 8. Diels-Alder cycloaddition products of lactones 2a and 2b to 1,3-butadiene showed a diastereoselectivity of 96%.

Full text of DOI:10.1021/jo951063g

1822
J . Org. Chem. 1996, 61, 1822-1824
En a n tioselective Syn th eses of (-)- a n d (+)-Hom ocitr ic Acid
La cton es
Gasto´n H. Rodr´ıguez R. and J ean-Franc¸ois Biellmann*
Laboratoire de Chimie Organique Biologique Associe´ au CNRS 31, Institut de Chimie, Faculte´ de Chimie,
Universite´ Louis Pasteur, 1, rue Blaise Pascal, F67008 Strasbourg, France
Received J une 12, 1995X
Highly enantioselective syntheses of enantiomers of homocitric acid lactones (R)-5a and (S)-5b are
described. Thermal Diels-Alder cycloadditions of 2a and 2b to 1,3-butadiene produced adducts
3a and 3b, respectively. Oxidative ozonolysis of latter adducts gave products 4a and 4b which
after acid treatment afforded a mixture with 5a and 5b as major component. Acid lactones 5a and
5b were converted into their dimethyl esters 6a and 6b which were purified by chromatography.
After saponification, the products obtained were crystallized to yield (-)- and (+)-homocitric acid
lactones ((R)-5a and (S)-5b). Diastereomeric excess (de) of Diels-Alder adducts 3a and 3b was
determined by means of Mosher esters of glycols 8a , 8b, and racemic 8. Diels-Alder cycloaddition
products of lactones 2a and 2b to 1,3-butadiene showed a diastereoselectivity of 96%.
(-)-Homocitric acid (1a ), an intermediate in the bio-
synthetic pathway of lysine in yeast and some fungi, is
produced by enzymatic condensation of R-ketoglutarate
and acetylSCoA (Figure 1).1
Two syntheses of the homocitric acid lactone 5 have
been described: as a racemate, by hydrolysis of the
cyanohydrin of diethyl â-ketoadipate and as the (S)-
enantiomer by degradation of (-)-quinic acid of known
absolute configuration in order to determine the absolute
configuration of the natural product.2,3 However, no
enantioselective synthesis of the natural enantiomer of
homocitric acid 1a has ever been reported.
F igu r e 1.
Sch em e 1
In the present paper we describe enantioselective
syntheses of (-)-(R)- and (+)-(S)-homocitric acid lactones
(5a and 5b) from (-)-L-lactic acid and (-)-L-serine,
respectively. The key step in the synthetic pathway is
the highly diastereoselective Diels-Alder reaction of
dienophiles 2a and 2b with 1,3-butadiene.
A possible retrosynthetic analysis of the (-)-homocitric
acid ((R)-1) is as shown (Scheme 1). The enantioselective
step A f B relies on a highly diastereoselective Diels-
Alder reaction of dienophile 2 with 1,3-butadiene.
Dienophile 2 was selected as a synthetic equivalent of
synthon B because there is in its structure an acetal
moiety which acts not only as a chiral auxiliary in the
Diels-Alder reaction but also as a protecting group in
the subsequent degradation. This synthetic equivalent
has already been described in its enantiomeric forms: 2a
synthesized from (-)-L-lactic acid with an enantiomeric
excess (ee) of 96% and 2b from (-)-L-serine with an ee of
99% (Scheme 2).4,5
Sch em e 2
yield of 51%.6,7 For the determination of the degree of
diastereoselectivity, the adduct 3 was converted to its
Mosher ester (8) by reduction to diol 7 with lithium
aluminum hydride followed by esterification with (+)-
methoxy(trifluoromethyl)phenylacetyl chloride ((+)MT-
PACl) (Scheme 3).8 In order to distinguish the methoxyl
Heating of 1,3-butadiene and dienophile 2 at 120 °C
gave the Diels-Alder product 3 isolated as an oil in a
and trifluoromethyl resonances in the H and 19F NMR
1
spectra of the MTPA ester 8 produced from racemic
adduct 3, it was necessary to add Eu(fod)3.9,10 The ester
prepared from 3a was submitted to the same procedure,
and the ee was determined to be 92%; the diastereose-
X Abstract published in Advance ACS Abstracts, December 15, 1995.
(1) (a) Strassman, M.; Ceci, L. N. Biochem. Biophys. Res. Commun.
1964, 14, 262. (b) Strassman, M.; Ceci, L. N. J . Biol. Chem. 1965, 240,
4357. (c) Hogg, R. W.; Broquist, H. P. J . Biol. Chem. 1968, 243, 1839.
(2) Maragoudakis, M. E.; Strassman, M. J . Biol. Chem. 1966, 241,
695.
(6) The other 49% consisted of gummy polymeric products of 2 and
1,3-butadiene. Dienophile 2 proved to be an unstable compound: it
readily polymerized when left at rt for several hours.
(3) Thomas, U.; Kalyanpur, M. G.; Stevens, C. M. Biochemistry 1966,
5, 2513.
(4) (a) Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984, 40,
1313. (b) Zimmermann, J .; Seebach, D. Helv. Chim. Acta 1987, 70,
1104. (c) Mattay, J .; Mertes, J .; Maus, G. Chem. Ber. 1989,122, 327.
(5) (a) Roush, W. R.; Essenfeld, A. P.; Warmus, J . J .; Brown, B. B.
Tetrahedron Lett. 1989, 30, 7305. (b) Roush, W. R.; Brown, B. B. J .
Org. Chem. 1992, 57, 3380.
(7) (a) Ortun˜o, R. M.; Ballesteros, M.; Corbera, J .; Sa´nchez-Ferrando,
F.; Font, J . Tetrahedron 1988, 44, 1711. (b) Feringa, B. L.; de J ong, J .
C. J . Org. Chem. 1988, 53, 1125.
(8) (a) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512.
(b) Kalyanam, N.; Lightner, D. A. Tetrahedron Lett. 1979, 415.
(9) Abe, T.; Miyano, S. Bull. Chem. Soc. J pn. 1991, 64, 3390.
0022-3263/96/1961-1822$12.00/0 © 1996 American Chemical Society

Syntheses of Homocitric Acid Lactones
J . Org. Chem., Vol. 61, No. 5, 1996 1823
Sch em e 3
Saponification of the diester 6a yielded (-)-homocitric
acid lactone (5a ), whose properties were in good agree-
ment with those reported for the natural product isolated
from Sacharomyces cerevisiae.1,13
The enantioselective synthesis of (+)-homocitric acid
lactone (5b) was straightforward; it started with dieno-
phile 2b (ee ) 99%) prepared from (-)-L-serine. As
described for 2a , lactone 2b was subjected to Diels-Alder
reaction with 1,3-butadiene. Isolated adduct 3b showed
an optical rotation of [R]D ) -17.5° (c ) 1.2, CHCl3),
which compared well to the rotation of its enantiomer
3a [R]D ) +16.3° (c ) 1.0, CHCl3) described above. The
diastereoselectivity of the thermal Diels-Alder cycload-
dition of 1,3-butadiene with lactone 3b as determinated
from its Mosher ester 8b was 96%. Adduct 3b was
converted to the homocitric acid lactone 5b as described
above.14
Sch em e 4
The key step in the synthetic pathway is the formation
of the asymmetric center of the target molecule by means
of a highly stereoselective thermal Diels-Alder reaction.
This high selectivity is achieved thanks to the bulkiness
of the tert-butyl group in the acetal portion of the
dienophile, which directs the attack of the 1,3-butadiene
molecule to the opposite side of the molecule.15 There
exists in the literature only a few cases of asymmetric
thermal Diels-Alder reactions with such a high degree
of stereoselectivity; our adduct formation belongs to this
small group.4c,7 On the other hand acidic hydrolysis of
6a was avoided due to poor results obtained with 4a .
Then saponification with a NaOH solution was tried, and
this proved to work well: both esters were hydrolyzed
and the chiral center remained untouched (no racemiza-
tion was detected), meaning that the reaction proceeded
via an alkyl cleavage mechanism.
In conclusion, highly enantioselective syntheses of (+)-
and (-)-homocitric acid lactones ((R)-5a and (S)-5b) from
(-)-L-lactic acid and (-)-L-serine, respectively, have been
achieved (96% ee). The key step of the synthetic route
is a highly stereoselective thermal Diels-Alder reaction
of dienophile 2 with 1,3-butadiene (96%). These results
should induce studies on (-)-homocitric acid lactone
biosynthesis, namely, the enzymes involved in its bio-
synthetic pathway which could be targets of inhibitors
to avoid the development of certain fungi.
Exp er im en ta l Section
Gen er a l. NMR spectra were obtained on 200 or 400 MHz
spectrometers, and all 1H NMR spectra were referenced to
TMS as internal standard. [R]D values were determined at
20 °C. IR data are expressed in units of frequency (cm-1). Low-
resolution mass spectra were measured at 70 eV. Elemental
analyses were performed by Service de Microanalyse de la
Faculte´ de Chimie de l’Universite´ Louis Pasteur. Melting
points (mp) are not corrected.
Toluene, methanol, ether, and pyridine were distilled from
CaH2 under Ar just before use. Merck silica gel 60 (0.062-
0.200 mm) was used for column chromatography.
(2S ,5R )-1,3-Dioxa sp ir o[4,5]-2-t er t -b u t yld e c-7-e n -4-
on e (3a ). A solution of dienophile 2a (9.3 g, 60 mmol), toluene
lectivity of the Diels-Alder reaction of dienophile 2a with
1,3-butadiene was 96%.
Ozonolysis of the double bond in adduct 3a followed
by oxidative workup afforded 4a as an oil in a 90% yield.11
Deprotection of diacid 4a with aqueous formic acid gave
(-)-homocitric acid (1a ) which immediately cyclized to
the γ-lactone 5a (Scheme 4). However, all attemps to
crystallize the latter compound failed. Lactone 5a was
converted into its dimethyl ester by (trimethylsilyl)-
diazomethane and purified by column chromatography.12
(12) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull.
1981, 29, 1475.
(13) Our sample, mp 146-148 °C; [R]D -51° (c ) 0.19, see ref 17);
natural product, mp 145-146 °C; [R]D -52.6° (c ) 0.19, see ref 17).
(14) The (+)-homocitric acid lactone (S)-5 showed mp 144-147 °C
and [R]D +54 (c ) 0.21, see ref 17). These values are in accordance
with the ones obtained from the resolution of the racemic compound
with brucine in ref 2.
(10) The MTPA ester 8 from racemic adduct 3 did not show any
distinction of the signals produced by diastereoisomeric methoxy and
trifluoromethyl groups in 1H and 19F NMR; however, in presence of
Eu(fod)3 in a 0.3 molar ratio to the Mosher ester both signals were
split, see ref 9.
(11) (a) Bailey, P. S. J . Org. Chem. 1957, 22, 1548. (b) Bailey, P. S.
Ind. Eng. Chem. 1958, 50, 993.
(15) In 2a the attack of 1,3-butadiene is mainly on the Re face of
the molecule and in 2b is mainly on the Si face.

1824 J . Org. Chem., Vol. 61, No. 5, 1996
Rodr´ıguez R. and Biellmann
(2 mL), hydroquinone (200 mg), and 1,3-butadiene (2000 mol
%) in a sealed glass vial was heated at 120 °C for 48 h. The
reaction mixture was flash distilled to eliminate toluene and
1,3-butadiene, and then a bulb-to-bulb distillation (140 °C/2
mmHg) afforded 6.4 g (51%) of 3a : [R]D ) +16.3° (c ) 1.01,
CHCl3); IR (CHCl3) 3030, 2960; 1H NMR (CDCl3) 5.8, 5.6, 5.2,
2.3, 1.9, 0.96; MS m/z 210 (M+). Anal. Calcd for C12H18O3:
C, 68.54; H, 8.63. Found: C, 68.49; H, 8.68.
(2R ,5S )-1,3-Dioxa sp ir o[4,5]-2-t er t -b u t yld e c-7-e n -4-
on e (3b). The same procedure as for lactone 3a starting from
dienophile 2b was used. Data for lactone 3b: [R]D ) -17.2°
(c ) 1.18, CHCl3). Anal. Calcd for C12H18O3: C, 68.54; H, 8.63.
Found: C, 68.35; H, 8.61.
the mixture was evaporated, dissolved in acetone, filtered, and
again evaporated. The solid obtained was dissolved in hot
AcOEt, filtered, evaporated, and recrystallized from AcOEt-
hexane to yield 30 mg (34%) of the (-)-homocitric acid lactone
(5a ) mp 146-148 °C; [R]D ) -51° (c ) 0.19, conditions as in
ref 17); IR (KBr) 1765, 1722, 1672, 1184; 1H NMR ((CD3)2CO)
3.17, 3.03, 2.5; 13C NMR ((CD3)2CO) 176.5, 172.5, 170.5, 83.5,
41.7, 31.9, 28.3. Anal. Calcd for C7H8O6: C, 44.68; H, 4.25.
Found: C, 44.71; H, 4.58.
(+)-Hom ocitr ic Acid La cton e (5b). The same procedure
as above was used. Data for 5b: mp 144-147 °C; [R]D ) +54°
(c ) 0.21, conditions as in ref 17). Anal. Calcd for C7H8O6:
C, 44.68; H, 4.25. Found: C, 44.95; H, 4.28.
Dia ster eoisom er ic Excess Deter m in a tion of th e Di-
els-Ald er Ad d u cts. 1. 1-Hyd r oxycycloh ex-3-en em eth a -
n ol (7a ). To a suspension of LiAlH4 (200 mg) in ether (5 mL)
was added a solution of the adduct 3a (100 mg, 0.47 mmol) in
ether (10 mL). After 18 h of stirring at 20 °C, a saturated
solution of Na2SO4 was added, the obtained suspension was
filtered, and the organic layer was dried with MgSO4 and
evaporated to yield 50 mg (78%) of the glycol 7a as an oil: [R]D
(2S,5R)-2-ter t-Bu tyl-5â-(car boxyeth yl)-5-(car boxym eth -
yl)-1,3-d ioxola n -4-on e (4a ). A solution of the Diels-Alder
adduct 3a (500 mg, 2.38 mmol) in MeOH (20 mL) was ozonized
at -78 °C until the solution turned to a light blue; excess ozone
was removed with Ar (15 min). The reaction mixture was left
to reach rt, and the solvent was evaporated. The residue was
treated with a solution of 90% HCOOH (4 mL) and 30% H2O2
(4 mL) and stirred overnight. After evaporation, 600 mg (90%)
of the diacid 4a was obtained as an oil: [R]D ) -21.1° (c )
1
) +16.5° (c ) 0.36, CHCl3); H NMR (CDCl3) 5.6, 3.51, 2.12,
1
1.68.
1.10, CHCl3); H NMR (CDCl3) 5.3, 2.9, 2.8, 2.55, 2.18, 0.97.
2. 1-Hyd r oxycycloh ex-3-en em eth a n ol (7b). The same
procedure as above was used. Data for 7b: [R]D ) -17.2° (c
(2R,5S)-2-ter t-Bu tyl-5â-(car boxyeth yl)-5-(car boxym eth -
yl)-1,3-d ioxola n -4-on e (4b). The same procedure as above
was used. Data for diacid 4b: [R]D ) +20.5° (c ) 1.07, CHCl3);
1H NMR (CDCl3) 5.3, 2.9, 2.8, 2.55, 2.18, 0.97.
1
) 0.32, CHCl3); H NMR (CDCl3) 5.6, 3.51, 2.12, 1.68.
3. (+)-MTP A Ester s (8). A solution of pyridine (300 µL),
(+)-MTPA-Cl (50 µL), glycol 7a or its enantiomer 7b (20 mg,
0.148 mmol), and CCl4 (300 µL) was stirred under Ar overnight
at rt. Then (dimethylamino)propylamine (50 µL) was added,
and after 15 min the solution was diluted with ether and
washed subsequently with diluted HCl, saturated Na2CO3, and
brine. The organic layer was dried with MgSO4 and evapo-
rated. Then CCl4 was added and evaporated. This was
repeated twice. Finally Eu(fod)3 (48 mg, 0.0468 mmol) was
added, and the mixture was dissolved in CDCl3. The sample
for NMR studies was taken from this solution: 1H NMR
(CDCl3) 4.6; 19F NMR (CDCl3) -70.83.
The racemic Diels-Alder adduct 3 (prepared from racemic
lactic acid and using the same synthetic pathway as for 3a )
was subjected to reduction, and the racemic glycol was
esterified with (+)-MTPA-Cl and analyzed as previously
described. The obtained NMR results were as follows: 1H
NMR (CDCl3) 4.9, 4.85, 1:1 ratio; 19F NMR (CDCl3) -70.85,
-70.87, 1:1 ratio.
Dim eth yl Ester of (-)-Hom ocitr ic Acid La cton e (6a ).
A solution of 4a (400 mg, 1.45 mmol) in 80% HCOOH (25 mL)
was heated under reflux for 2 h, cooled, and concentrated.16
Part of the crude product obtained (200 mg) was disolved in
methanol (3 mL) and ether (6 mL); then a 2 M solution of
(CH3)3SiCHN2 in hexane was added dropwise until the reaction
mixture turned a light yellow. After 1 h of stirring, 90%
HCOOH was added to eliminate excess (CH3)3SiCHN2. The
solvent was removed, and chromatography on silica gel (hex-
ane/AcOEt 50%/50%) afforded 112 mg (48%) of 6a as an oil:
[R]D ) -10.6° (c ) 1.0, CHCl3); IR (CHCl3) 1788, 1737, 1226;
1H NMR (CDCl3) 3.76, 3.65, 3.19, 3.03, 2.5; MS m/z 216 (M+).
Anal. Calcd for C9H12O6: C, 50.00; H, 5.55. Found: C, 50.16;
H, 5.38.
Dim eth yl Ester of (+)-Hom ocitr ic Acid La cton e (6b).
The same procedure as above was used. Data for lactone 6b:
[R]D ) +11.7° (c ) 0.95, CHCl3). Anal. Calcd for C9H12O6: C,
50.00; H, 5.55. Found: C, 50.12; H, 5.41.
(-)-Hom ocitr ic Acid La cton e (5a ). The dimethyl ester
of (-)-homocitric acid lactone (6a ) (100 mg, 0.4 mmol) was
added to 0.2 N sodium hydroxide (15 mL), and the resulting
mixture was refluxed for 6 h. The reaction was cooled to rt,
and 1 N HCl was added until a pH ) 1 was obtained. Then
Ack n ow led gm en t. G.H.R.R. thanks the Consejo
Nacional de Ciencia y Tecnolog´ıa (CONACyT), Mexico,
for Financial Support.
J O951063G
(16) This afforded a mixture of compounds which showed in NMR
analysis the (-)-(R)-homocitric acid lactone 5a as the major component.
(17) Krebs, H. A.; Eggleston, L. V. Biochem. J . 1943, 37, 334.