Syntheses of (-)-isocitric acid lactone and (-)-homoisocitric acid. A new method of conversion of alkynylsilanes into the alkynyl thioether and corresponding carboxylic acids

Article abstract of DOI:10.1021/jo951062o

A simple, stereoselective synthesis of natural isocitric and homoisocitric acids from a common alkynylsilane correlates the stereochemistry of these acids. Starting with dimethyl D-malate dianion, methyl 2-hydroxy-3-carbomethoxy-6-(trimethylsilyl)-5-hexynoate (6a) was prepared with a good stereoselectivity (threo/erythro 90/10). Oxidative cleavage of the triple bond provided isocitric acid lactone (8') in 15% overall yield starting from D-malic acid diester 1. The synthesis of homoisocitric acid relied on a new method of conversion of alkynylsilane to alkynyl thioether, which is converted to the carboxylic acid of the same chain length. Addition of benzenesulfenyl chloride to (trimethylsilyl)alkyne 6b and elimination of trimethylsilyl chloride gave the corresponding thioether 10, which by acid hydrolysis gave homoisocitric acid (11) in a 24% yield from D-malic acid ester. This novel method of conversion of alkynylsilane to the corresponding acid was illustrated with several other alkynyltrimethylsilanes.

Full text of DOI:10.1021/jo951062o

J . Org. Chem. 1996, 61, 1817-1821
1817
Syn th eses of (-)-Isocitr ic Acid La cton e a n d (-)-Hom oisocitr ic
Acid . A New Meth od of Con ver sion of Alk yn ylsila n es in to th e
Alk yn yl Th ioeth er a n d Cor r esp on d in g Ca r boxylic Acid s
Carole Schmitz, Anne-Claire Rouanet-Dreyfuss, Marie Tueni, and J ean-Franc¸ois Biellmann*
Laboratoire de Chimie Organique Biologique associe´ au CNRS, Universite´ Louis Pasteur,
Faculte´ de Chimie, 1 rue Blaise Pascal, 67003 Strasbourg, France
Received J une 12, 1995X
A simple, stereoselective synthesis of natural isocitric and homoisocitric acids from a common
alkynylsilane correlates the stereochemistry of these acids. Starting with dimethyl D-malate dianion,
methyl 2-hydroxy-3-carbomethoxy-6-(trimethylsilyl)-5-hexynoate (6a ) was prepared with a good
stereoselectivity (threo/erythro 90/10). Oxidative cleavage of the triple bond provided isocitric acid
lactone (8′) in 15% overall yield starting from D-malic acid diester 1. The synthesis of homoisocitric
acid relied on a new method of conversion of alkynylsilane to alkynyl thioether, which is converted
to the carboxylic acid of the same chain length. Addition of benzenesulfenyl chloride to
(trimethylsilyl)alkyne 6b and elimination of trimethylsilyl chloride gave the corresponding thioether
10, which by acid hydrolysis gave homoisocitric acid (11) in a 24% yield from D-malic acid ester.
This novel method of conversion of alkynylsilane to the corresponding acid was illustrated with
several other alkynyltrimethylsilanes.
Sch em e 1
In tr od u ction
Isocitric acid (8), which is an intermediate in the Krebs
cycle,1 is produced from citric acid by acotinase2 and is
converted into R-ketoglutaric acid by isocitric acid dehy-
drogenase. Of the four stereoisomers of isocitric acid,
only the (-)-D-threo isomer is a substrate for acotinase
and for the NADP+-linked isocitrate dehydrogenase from
porcine heart3 and NAD+-linked enzyme from bovine
heart.4 Racemic isocitric acid was first prepared by R.
Fittig,5 and two other syntheses of racemic isocitric acid
were reported later.6,7 The absolute configuration of
isocitric acid lactone has been established by a stereose-
lective synthesis based upon the condensation of methyl
(-)-trans-epoxysuccinate with dimethyl malonate.8
A
stereoselective synthesis of isocitric acid lactone relying
on the stereoselective alkylation of L-malic acid9,10 has
been reported.
four isomers of homoisocitric acid have been established
by synthesis from the corresponding 2-hydroxy-3-cyclo-
hexenecarboxylic acids14 of known absolute configura-
tion.15 The threo D isomer of homoisocitric acid is a
substrate for homoisocitric acid dehydrogenase.16 How-
ever further study of the enzymes involved in this
biosynthetic pathway is hampered by the unavailability
of the intermediates: homoisocitric and homocitric acids.
The enzymes involved in this specific biosynthetic path-
way are targets for inhibitors, potential antibiotics, and
fungicides.
The aim of our work17 was to develop a specific syn-
thesis of the (-)-D-threo isomers of isocitric and ho-
moisocitric acids. Our synthesis starts from D-malic acid
and correlates the stereochemistry of isocitric and ho-
moisocitric acids. It constitutes the first chiral synthesis
of (-)-D-homoisocitric acid and illustrates a novel method
of conversion of alkynylsilanes to their carboxylic acids.
Homoisocitric acid (11) is involved in the R-aminoadi-
pate pathway of lysine synthesis in yeasts and certain
fungi. The synthesis of homoisocitric acid from homo-
citric acid is catalyzed by homoaconitate hydratase.11 The
enzymatic conversion of homoisocitric acid into R-keto-
adipic acid is catalyzed by homoisocitric acid dehydro-
genase.12 Racemic homoisocitric acid has been synthe-
sized by condensation of diethyl glutarate with diethyl
oxalate to triethyl 2-oxaloglutarate, which was reduced
to the corresponding hydroxy ester and saponified to the
racemic free acid.13 The absolute configurations of the
X Abstract published in Advance ACS Abstracts, December 15, 1995.
(1) Plaut, G. W. E.; Sung S. C. J . Biol. Chem. 1954, 207, 305.
(2) Rose, I. A.; O’Connell, E. L. J . Biol. Chem . 1967, 242, 1870.
(3) Ochoa, S. Enzymes 1951, 929.
(4) Plaut, G. W. E.; Sung, S. C. Methods Enzymol. 1955, 1, 710.
(5) Fittig, R.; Miller, H. E. Ann. Chem. 1889, 255, 43.
(6) Wislicenus, W.; Nassauer, M. Ann. Chem. 1885, 285, 1.
(7) (a) Greenstein, J . P. J . Biol. Chem. 1935, 109, 529. (b) Greenstein,
J . P. J . Biol. Chem. 1936, 116, 463.
(8) Kaneko, T.; Katsura, H. Chem. Ind. (London) 1960, 1188.
(9) Compound 8: [R]D -60 (H2O, c 1.03) (lit. [R]D +61.7 (H2O, c 0.985)
for the enantiomer) Aebi, J . D.; Sutter, M. A.; Wasmuth, D.; Seebach,
D. Liebigs Ann. Chem. l983, 2114.
(10) Seebach, D.; Wasmuth, D. Helv. Chem. Acta 1980, 63, 197.
(11) Strassman, M.; Ceci, L. N. J . Biol. Chem. 1966, 241, 5401.
(12) Strassman, M.; Ceci, L. N. J . Biol. Chem. 1965, 240, 4357.
(13) Yamashita, M. J . Org. Chem. 1958, 23, 835.
(14) Compound 11: [R]D -10 (c 2.05, acetone) (lit. [R]D -8 to -13 (c
1.22, acetone). Chilina, K.; Thomas, U.; Tucci, A. F.; McMichael, K.
D.; Stevens, C. M. Biochemistry 1969, 8, 2846.
(15) Febrer, M. A.; Gomis, P.; Pascual, J . An. R. Soc. Esp. Fis. Quim.
1964, 60B, 671.
(16) Rowley, B.; Tucci, A. F. Arch. Biochem. Biophys. 1970, 141, 499.
(17) Schmitz, C. Ph.D. Thesis, ULP, 1992.
(18) Schmitz, C.; Rouanet-Dreyfuss, A. C.; Tueni, M.; Biellmann, J .
F. Tetrahedron Lett. 1992, 33, 4911.
0022-3263/96/1961-1817$12.00/0 © 1996 American Chemical Society

1818 J . Org. Chem., Vol. 61, No. 5, 1996
Schmitz et al.
Sch em e 2
F igu r e 1.
Sch em e 3
In a previous paper18 we reported our preliminary find-
ings on the synthesis of isocitric and homoisocitric acids
making use of this method.
Resu lts a n d Discu ssion
Our approach19 to homoisocitric acid (11) (Scheme 1)
is based on the procedure used by Seebach for the
synthesis of isocitric acid.9
(8′), whose properties9 corresponded to the natural isomer
of the Krebs cycle (Scheme 2).
Reaction of D-malic dimethyl ester (1) dianion with
1-bromo-3-butene gave the alkylation product 2 in 15%
yield (threo/erythro selectivity of 80/20). Acetylation of
the hydroxy function of compound 2 (85%), oxidation of
the double bond (68%), and subsequent deprotection of
the alcohol and esterification of the free acid functions
gave the homoisocitric acid triester 5 (90%). In view of
the low overall yield of 5 (<10%) based on D-malic ester
1, and the low stereoselectivity (threo/erythro:80/20), we
planed a more direct approach. Attempts to react the
dianion of malic diester with 1-(1′, 3′-dioxolan-2′-yl)-2-
bromoethane or with ethyl acrylate were unsuccessful,
with starting material being recovered.
Our second approach (Figure 1) made use of a common
alkynylsilane, which would be converted to both isocitric
and homoisocitric acids. In order to accomplish this, the
(trimethylsilyl)propargyl group was chosen. Oxidative
cleavage of the triple bond would give isocitric acid; anti-
Markovnikov addition of water to the alkyne functional-
ity followed by oxidation would provide homoisocitric
acid.
The diastereoselective alkylation of the dianion9 of the
dimethyl ester of D-malic acid (1), generated at -78 °C
with 2.5 equiv of (trimethylsilyl)propargyl bromide,20,21
gave the dimethyl 3-[(trimethylsilyl)propynyl]malate (threo
6a /erythro 90/10) in 51% yield. After acetylation of the
hydroxyl group the two C-3 diastereoisomers were sepa-
rated by column chromatography. The major diastere-
oisomer (2R,3S) had the stereochemistry indicated in
formula 6b, as shown by the correlation with isocitric
acid. Ruthenium tetroxide22 oxidation of the silylated
triple bond provided the corresponding carboxylic acid
with one less carbon atom, which was converted to its
methyl ester 7 for purification purposes. Acid hydrolysis
of the triester 7 afforded in 61% yield isocitric acid lactone
Conversion of the alkynylsilane 6b to homoisocitric
acid required the transformation of the silylated triple
bond to the corresponding carboxylic acid 8 without
carbon loss. Zweifel reported that hydroboration of
(trimethylsilyl)alkynes with dicyclohexylborane followed
by oxidation under basic conditions gives the correspond-
ing acid in good yield.23 However in our hands the use
of this method for the transformation of compound 6b to
the corresponding acid failed, starting material being
recovered. The bulky trimethylsilyl group may hinder
the addition of dicyclohexylborane. Thus the terminal
alkyne 12 was obtained by desilylation with tetrabutyl-
ammonium fluoride in 60% yield. This intermediate was
then hydroborated with disiamylborane, and after oxida-
tion aldehyde 13 was obtained in only 7% yield (Scheme
3).
Several other methods for the preparation of carboxylic
acids from acetylenes without loss of a carbon have been
described,24-26 but these methods have only been used
on aliphatic or aromatic acetylenes lacking other func-
tional groups and failed when applied to compound 6b.
Thus we had to develop a method for the preparation of
the carboxylic acid from a silylated triple bond. Abrams
has reported a method of conversion of terminal alkynes
into carboxylic acids via an acetylenic thioether.27 Un-
fortunately all attempts to obtain the thioether by
reaction of diphenyl disulfide on the propargylic carban-
ion, generated by 1 equiv of LDA, failed.
F. Cooke reported the addition of arenesulfenyl chlo-
rides to vinyltrimethylsilane.28 Reaction of benzenesul-
(23) Zweifel, G.; Backlund, S. J . J . Am. Chem. Soc. 1977, 99, 3184.
(24) McDonald, R. N.; Schwab, P. A. J . Am. Chem. Soc. 1964, 86,
4866.
(25) Tamao, K.; Kumada, M. Tetrahedron Lett. 1984, 25, 321.
(26) Moriarty, R. M.; Vaid, R. K.; Duncan, M. P.; Vaid, B. K.
Tetrahedron Lett. 1987, 28, 2845.
(27) Abrams, S. R. Can. J . Chem. 1983, 61, 2423.
(28) Cooke, F.; Moerck, R.; Schwindemann, J .; Magnus, P. J . Org.
Chem. 1980, 45, 1046.
(19) Rouanet-Dreyfuss, A. C. Ph.D. Thesis, ULP, 1989.
(20) J ones, T. K.; Denmark, S. E. Org. Synth. 1985, 64, 182.
(21) Miller, R. B. Synth. Commun. 1972, 2, 267.
(22) Zibuck, R.; Seebach, D. Helv. Chem. Acta 1988, 71, 237.

Synthesis of Isocitric and Homoisocitric Acids
J . Org. Chem., Vol. 61, No. 5, 1996 1819
Sch em e 4
Sch em e 5
from D-malic acid ester. This novel method of oxidation
was applied with success to different trimethylsilanes
devoid of functional groups. The facile synthesis of
homoisocitric acid will now make studies of homoiso-
citrate dehydrogenase activity feasible.
Ta ble 1
overall
yield, %
yield, %
yield, %
14 into 16 16 into 17 14 into 17
14a (R ) C6H5)
84
95
55
70 A
61 B
50 A
25 B
54 B
59 A
51 B
47 A
23 B
30 B
Exp er im en ta l Section
Gen er a l. Experiments requiring anhydrous conditions
were performed in an atmosphere of dry argon. Unless
otherwise indicated, all reagents were obtained from com-
mercial suppliers and were used without purification. Solvents
were dried according to established protocols:33 distillation
under argon from an appropriate drying agent. THF was
distilled from sodium/benzophenone immediatly prior to use.
CH2Cl2, Et2O, DMSO, and CHCl3 were distilled from calcium
hydride. Glassware was dried at 120 °C in an oven overnight
and assembled under a stream of argon.
14b (R ) CH3(CH2)5)
14c (R ) TMSOCH2(CH2)2)
fenyl chloride with compound 6b gave the vinylic addition
product 9 in 92 % yield. â-Elimination with potassium
fluoride in dimethyl sulfoxide29 afforded thioether 10 in
92% yield. To our knowledge, this is the shortest route
to alkynyl thioethers reported to date. The last step of
the synthesis was the conversion of thioether 10 to the
carboxylic acid 11. Following a published procedure,30,31
acid hydrolysis of thioether 10 was performed in water
in the presence of ion exchange resin DOWEX 50X
impregnated with 20% mercuric sulfate. The natural
homoisocitric acid (11) was isolated as an oil14 (yield 75%)
(Scheme 4).
This result encouraged us to extend this method of
conversion of a silylated triple bond to the carboxylic acid
to other alkynylsilanes, such as phenyl-2-(trimethylsilyl)-
ethyne (14a ), 1-(trimethylsilyl)octyne (14b), and 6-[(tri-
methylsilyl)oxy]-1-(trimethylsilyl)-1-hexyne (14c) (Table
1).
Conversion of the (trimethylsilyl)acetylenes 14 to the
thioethers 15 was achieved in two steps: benzenesulfenyl
chloride addition to the silylated triple bond followed by
â-elimination of the chloride and trimethylsilyl groups.
In this way alkynyl thioethers 16a , 16b, and 16c were
obtained in good yields. Two different sets of conditions
were employed for the hydrolysis of thioether 16 to the
carboxylic acid: method A, sulfuric acid in the presence
of mercuric sulfate, and method B, acid resin impreg-
nated with mercuric ions. Carboxylic acids 17a , 17b, and
17c were isolated in 59, 47, and 30% yields, respectively
(Scheme 5).
Analytical thin layer chromatography (TLC) was conducted
on precoated silica gel plates (Merck Kieselgel 60F254, 0.25 mm
thickness). For visualization, TLC plates were either placed
under ultraviolet light or stained with phosphomolybdic acid
solution (25% in ethanol). Flash column chromatography was
performed using flash grade Merck silica gel 60 (230-400
mesh). Mixtures of hexane and ethyl acetate were used as
eluants. Optical rotations were recorded at the sodium D line
at ambient temperature.
1H NMR spectra were taken in CDCl3 unless otherwise
noted and are referenced to the appropriate solvent signal.
Chemical shifts are reported in ppm units downfield from
tetramethylsilane. IR spectra are reported as υmax in cm-1
.
Melting points are uncorrected. Elemental analyses were
determined by the Analytical Laboratory of the Faculte´ de
Chimie de l’Universite´ Louis Pasteur. Mass spectra were
obtained by the chemical ionization technique.
Meth yl 2-Hyd r oxy-3-ca r bom eth oxy-6-(tr im eth ylsilyl)-
5-h exyn oa te (6a ). To a solution of 2.1 g of dimethyl D-malate
(13 mmol) in 10 mL of anhydrous THF was added dropwise
at -78 °C a solution of LDA (26 mmol, 2 equiv) in 20 mL of
anhydrous THF. The mixture was warmed up to -20 °C and
stirred at this temperature for 30 min. After cooling to -78
°C, (trimethylsilyl)propargyl bromide (6.3 g, 33 mmol) was
added dropwise, and the reaction mixture was stirred at -78
°C for 18 h and then was allowed to return to -20 °C over a
3 h period. Acetic acid (3 mL) diluted in ether (6 mL) was
added after cooling to -50°C. After warming up to room
temperature the reaction mixture was poured into water (100
mL) and the aqueous phase was extracted with ether (3 × 100
mL). The combined organic layers were washed with 50 mL
of saturated NaHCO3 and 50 mL of saturated NaCl and dried
over MgSO4. After evaporation of the solvent under reduced
pressure, the residue was purified by column chromatography
(eluant, hexane/AcOEt 70/30) to afford (trimethylsilyl)pro-
pargyl bromide (3.5 g) and (eluant, hexane/AcOEt 60/40)
methyl 2-hydroxy-3-carbomethoxy-6-(trimethylsilyl)-5-hex-
ynoate (1.7 g, 51%): 1H NMR (CDCl3) δ 4.57-4.55 (d, 2H, J )
2.6 Hz), 3.85-3.80 and 3.75-3.69 (2s, 6H) (erythro/threo: 10/
90), 3.16-3.12 (mABX, 1H, J 1 ) 10 Hz, J 2 ) 2 Hz), 2.84-2.70
Con clu sion
A new method of conversion of a silylated triple bond
to the carboxylic acid of the same chain length is
illustrated here. Transformation of the (trimethylsilyl)-
alkyne 6b to the corresponding thioether 10 followed by
acid hydrolysis gave homoisocitric acid (11) in a 24% yield
(29) Cunico, R. F.; Dexheimer, E. M. J . Am. Chem. Soc. 1972, 94,
2868.
(30) Newman, M. S. J . Am. Chem. Soc. 1953, 75, 4740.
(31) Billimoria, J . D.; MacLagan, N. F. J . Chem. Soc. 1954, 3257
(32) Casara, P.; Danzin, C.; Metcalf, B.; J ung, M. J . Chem. Soc.,
Perkin Trans. 1 1985, 2201.
(33) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd. ed.; Pergamon Press: Oxford, 1988.

1820 J . Org. Chem., Vol. 61, No. 5, 1996
Schmitz et al.
(mABX, 2H, J ) 14.7 Hz), 0.15 (s, 9H); IR 3600, 2960, 1745,
1440, 1250, 850 cm-1. Anal. Calcd for C12H20O5Si: C, 52.92;
H, 7.4. Found: C, 52.72; H, 7.31.
Met h yl 2-Acet oxy-3-ca r b om et h oxy-6-(p h en ylt h io)-5-
h exyn oa te (10). To a solution of 9 (500 mg, 1.08 mmol) in
15 mL of anhydrous DMSO was added anhydrous KF (62 mg,
1.08 mmol). After stirring 4 h at room temperature, the
solvent was removed and the residue was purified by column
chromatography (eluant, hexane/AcOEt 90/10) to yield com-
pound 10 as an oil (280 mg, 94%): 1H NMR (CDCl3) δ 7.43-
7.19 (m, 5H, SPh), 5.58-5.56 (d, 1H, J ) 4 Hz), 3.8, 3.75 (2s,
6H), 3.45-3.35 (mABX, 1H, J ) 14.7 Hz), 2.14 (s, 3H); [R]D +5.18
(MeOH, c ) 1.6 g/100 mL); IR (CCl4) 2960, 2196, 1750, 1582,
1210 cm-1; mass spectrum, m/ e 350 (M+), 307, 291, 241, 217,
147, 121. Anal. Calcd for C17H18O6S: C, 58.27; H, 5.17.
Found: C, 58.19; H, 5.2.
Hom oisocitr ic Acid (11). A suspension of 10 (0.4 g, 1.13
mmol) and DOWEX 50 × 830,31 20% Hg2+ resin (2 g) in 20
mL of water was heated at 100 °C for 72 h. After cooling, the
solution was filtered and the aqueous phase was washed with
CH2Cl2 (2 × 50 mL). After evaporation of the water, compound
11 was isolated as a yellow oil (177 mg, 76%): 1H NMR (CD3-
OD) δ 4.3-4.28 (d, 1H, J ) 3 Hz), 2.91-2.84 (mABX, 1H), 2.47-
1.9 (m, 4H), [R]D -10 (acetone, c ) 2 g/100 mL).
Hom oisocitr ic Acid Tr iester . To a solution of homoiso-
citric acid (11) (0.177 g, 0.85 mmol) in 10 mL of AcOEt was
added dropwise a solution of diazomethane (0.74 M) (1.15 mL)
at 0 °C. After stirring for 1 h at room temperature, the solvent
was evaporated and the crude product was purified by column
chromatography (eluant, hexane/AcOEt 90/10) to yield
homoisocitric acid trimethyl ester as an oil (0.138 g, 66%): 1H
NMR (CDCl3) δ 4.37-4.36 (d, 1H, J ) 3 Hz), 3.81, 3.77, 3.67
(s, 9H), 3.16-3.04 (m, 1H), 2.53-1.96 (m, 4H); IR (CCl4) 3537,
2987, 1740 cm-1; [R]D -7.4 (MeOH, c ) 1.2 g/100 mL); mass
spectrum, m/ e 217, 189, 161, 157, 87. Anal. Calcd for
C10H16O7: C, 48.38; H, 6.49. Found: C, 48.19; H, 6.3.
Gen er a l P r oced u r e for th e Ad d ition of Ben zen esu l-
fen yl Ch lor id e to th e Alk yn ylsila n e. To a solution of
(trimethylsilyl)alkyne (8.61 mmol) in anhydrous CH2Cl2 (10
mL) was added dropwise a solution of benzenesulfenyl chloride
(8.61 mmol) at -78 °C. After stirring for 16 h at room
temperature, the solvent was evaporated and the residue was
purified by column chromatography.
Meth yl 2-Acetoxy-3-ca r bom eth oxy-6-(tr im eth ylsilyl)-
5-h exyn oa te (6b). To a mixture of 6a (3.78 g, 13.9 mmol)
and 4-(dimethylamino)pyridine (0.17 g, 1.4 mmol) were con-
secutively added 2.9 mL (20.8 mmol) of triethylamine and 1.96
mL of acetic anhydride. After being stirred overnight at room
temperature the mixture was hydrolyzed by addition of diluted
hydrochloric acid (20 mL). This was extracted with 3 × 100
mL of ether, washed with 50 mL of saturated NaHCO3 and
50 mL of saturated NaCl, dried over MgSO4, filtered, and
evaporated. The crude mixture of two diastereoisomers was
chromatographed on silica gel (eluant, hexane/AcOEt 95/5) to
afford minor diastereoisomer II (2S,3S) (196 mg) and major
diastereoisomer I (2R,3S) (3.12 g). Intermediate fractions were
considered for the global yield (3.62 g, 83%). Dia ster eoiso-
m er I: 1H NMR (CDCl3) δ 5.54-5.52 (d, 1H, J ) 4 Hz), 3.79-
1
3.72 (2s, 6H), 3.37-3.27 (mABX, H, J 1 ) 4 Hz, J 2 ) 6 Hz, J 3
)
4 Hz), 2.8-2.47 (mABX, 2H, J ) 14.7 Hz), 2.12 (s, 3H), 0.15 (s,
9H); IR (CCl4) 2940, 1745, 1440, 1215 cm-1; [R]D +27.8 (MeOH,
c ) 1.5 g/100 mL). Anal. Calcd for C14H22O6Si: C, 53.48;
H,7.05. Found: C, 53.29; H, 6.88. Dia ster eoisom er II: 1H
NMR (CDCl3) δ 5.54-5.52 (d, 1H, J ) 5 Hz), 3.77-3.74 (2s,
6H), 3.26-3.16 (mABX, 1H, J 1 ) 4 Hz, J 2 ) 7 Hz, J 3 ) 7 Hz),
2.85-2.57 (mABX, 2H, J ) 14.7 Hz), 2.15 (s, 3H), 0.15 (s, 9H);
IR (CCl4) 2940, 1745, 1440, 1215 cm-1; [R]D -5.2 (MeOH, c )
1.5 g/100 mL). Anal. Calcd for C14H22O6Si: C, 53.48; H, 7.05.
Found: C, 53.62; H, 7.21
Meth yl 2-Acetoxy-3,5-d ica r bom eth oxyp en ta n oa te (7).
To a solution of 6b (dia I) (0.38 g, 1.21 mmol) in a mixture of
CCl4/CH3CN/H2O (6/6/10) was added NaIO4 (1.05 g, 4.9 mmol)
at room temperature. The mixture was stirred vigorously at
room temperature. After two clear phases resulted, RuO2‚H2O
(3.8 mg; 0.025 mmol) was added. The mixture turned black
followed by pink with formation of a white precipitate. After
stirring at room temperature for 20 h, the mixture was poured
into 30 mL of H2O, and the aqueous phase was acidified with
a 10% solution of sulfuric acid and extracted with 3 × 10 mL
of ether. The combined organic phases were washed by a
saturated solution of NaCl, dried over MgSO4 and evaporated
to give a colorless oil (0.3 g). A solution of diazomethane (0.74
M) (1.63 mL, 1.21 mmol) was added dropwise to a solution of
the crude oil in 10 mL of AcOEt at 0 °C. After stirring for 30
min. at room temperature, the solvent was evaporated and
the yellow oil was purified by column chromatography to afford
triester 7 (0.25g, 75%): 1H NMR (CDCl3) δ 5.54 (d, 1H, J )
3.8 Hz), 3.76, 3.72, 3.7 (3s, 9H), 3.66-3.57 (m, 1H), 2.94-2.78
(mABX, 2H, J 1 ) 26 Hz, J 2 ) 9 Hz, J 3 ) 5.4 Hz), 2.14 (s, 3H);
IR (CCl4) 2957, 1750, 1213 cm-1; [R]D: +24.7 (MeOH, c ) 1.16
g/100 mL), mass spectrum, m/ e 245, 217, 208, 145. Anal.
Calcd for C11H16O8: C, 47.82; H, 5.83. Found: C, 47.97; H,
5.67.
1-Ch lor o-1-p h en yl-2-(p h en ylt h io)-2-(t r im et h ylsilyl)-
eth en e (15a ) was prepared from 14a 32 and purified by column
chromatography (eluant, hexane): 86% yield; 1H NMR (CDCl3)
δ 7.41-7.08 (m, 5H), 0.42 (s, 9H).
1-(P h en ylth io)-1-(tr im eth ylsilyl)-2-ch lor o-1-octen e (15b)
was prepared from 14b32 and purified by column chromatog-
1
raphy (eluant, hexane): 95% yield; H NMR (CDCl3) δ 7.32-
7.18 (m, 5H), 2.44-2.36 (t, 2H, J ) 5.8), 1.27-1.20 (m, 8H),
0.85 (t, 3H, J ) 6.4), 0.31 (s, 9H).
6-[(Tr im et h ylsilyl)oxy]-2-ch lor o-1-(t r im et h ylsilyl)-1-
(p h en ylth io)-1-h exen e (15c) was prepared from 14c30 and
purified by column chromatography (eluant, hexane): 91%
yield; 1H NMR (CDCl3) δ 7.37-7.19 (m, 5H), 3.60-3.53 (t, 2H,
J ) 6.4 Hz), 2.52-2.43 (t, 2H, J ) 6.8 Hz), 1.64-1.49 (m, 4H),
0.35 (s, 9H), 0.1 (s, 9H).
Gen er a l P r oced u r e for t h e P r ep a r a t ion of Th io-
a lk yn es. To a solution of 2-(phenylthio)-2-(trimethylsilyl)-1-
chloroalkene (3.76 mmol) in 3 mL of anhydrous DMSO was
added anhydrous KF (4.41 mmol). The reaction mixture was
heated at 100 °C for 2 h, then the crude reaction mixture was
purified by column chromatography.
Isocitr ic Acid La cton e (8′). A solution of triester 7 (0.4
g; 1.45 mmol) in 30 mL of 6 N HCl was refluxed for 20 h. After
evaporation of the solvent, the residue was crystallized from
AcOEt/hexane to give white needles (153 mg, 61%): mp 150-
1
152 °C; H NMR (acetone d6) δ 5.19 (d, 1H, J ) 8 Hz), 3.92
(quad, 1H, J ) 8 Hz), 2.84 (mABX, 2H, J ) 8 Hz); IR (KBr)
2900, 1810, 1760 cm-1; [R]D -60.3 (H2O, c ) 1.03 g/100 mL)
lit. [R]D +61.7 (H2O, c ) 0.98 g/100 mL). Anal. Calcd for
C6H6O6: C, 41.4; H, 3.44 Found: C, 41.31; H, 3.39.
1-P h en yl-2-(p h en ylth io) eth yn e (16a ) was prepared from
1-phenyl-2-(phenylthio)-2-(trimethylsilyl)-1-chloroethene (15a )
and purified by column chromatography (eluant, hexane:
Met h yl 2-Acet oxy-3-ca r b om et h oxy-5-ch lor o-6-(p h en -
ylth io)-6-(tr im eth ylsilyl)-5-h exyn oa te (9). To a solution
of 6b (0.5 g, 1.59 mmol) in 5 mL of anhydrous CH2Cl2 was
added dropwise a solution of benzenesulfenyl chloride (0.23
g; 1.59 mmol) at -78 °C. After stirring at room temperature
for 16 h, the solvent was evaporated and the residue was
purified by column chromatography (eluant, hexane/AcOEt 90/
10) to give compound 9 (0.68 mg, 95%) as white needles: mp
1
100%): 98% yield; H NMR δ 7.55-7.13 (m, 10H).
1-(P h en ylth io)-1-octyn e (16b) was prepared from 15b and
purified by column chromatography (eluant, hexane): 95%
yield; 1H NMR (CDCl3) δ 7.43-6.96 (m, 5H), 2.48-2.41 (t, 2H,
J ) 6.8 Hz), 1.67-1.25 (m, 8H), 0.91-0.85 (t, 3H, J ) 6.4).
6-[(Tr im eth ylsilyl)oxy]-1-(p h en ylth io)-1-h exyn e (16c)
was prepared from 15c and purified by column chromatogra-
phy (eluant, hexane 100%): 57% yield; 1H NMR; δ 7.43-7.18
(m, 5H), 3.65-3.59 (t, 2H, J ) 4.1 Hz), 2.48-2.44 (t, 2H), 1.70-
1.54 (m, 4H), 0.11 (s, 9H).
1
88-89 °C; H NMR (CDCl3) δ 7.41-7.21 (m, 5H), 5.23-5.21
(d, 1H, J ) 4 Hz), 3.76-3.72 (2s, 6H), 3.7-3.58 (mABX, J 1 ) 6
Hz, J 2) 10 Hz), 3.07-2.78 (mABX, 2H, J ) 14.7 Hz), 2.17 (s,
3H), 0.38 (s, 1H); IR (CCl4) 2958, 1750, 1640, 1580, 1250 cm-1
;
[R]D -23.37 (MeOH, c ) 1.5 g/100 mL). Anal. Calcd for C20
H27O6SiSCl: C, 52.3; H, 5.53. Found: C, 52.33; H, 5.77.
-
Gen er a l P r oced u r e for th e Hyd r olysis of Alk yn yl
Th ioet h er s. Met h od A. A suspension of thioether (2.37

Synthesis of Isocitric and Homoisocitric Acids
J . Org. Chem., Vol. 61, No. 5, 1996 1821
mmol) and mercuric sulfate in 2 N sulfuric acid (10 mL) and
acetic acid (30 mL) was heated at 80 °C for 24 h. The aqueous
phase was extracted with chloroform (3 × 50 mL), and the
combined organic phases were washed with water (50 mL) and
a saturated solution of NaCl (20 mL). After evaporation of
the solvant, the crude product was dissolved in ether and
extracted by a saturated solution of NaHCO3 (3 × 50 mL). The
combined basic phases were acidified by HCl and then
extracted with chloroform (3 × 50 mL). The combined organic
phases were washed with a saturated solution of NaCl and
dried over Na2SO4. After evaporation of the solvent the crude
product was purified by column chromatography.
the crude compound which was purified by column chroma-
tography.
P h en yla cetic a cid (17a ) was prepared from 16a and
purified by column chromatography (eluant, hexane/AcOEt 70/
30) to give white crystals: 70% yield for method A, 61% yield
for method B. Mp 77-78 °C. 1H NMR (CDCl3): δ 7.37-7.24
(m, 5H), 3.65 (s, 2H).
Octa n oic a cid (17b) was prepared from 1-(phenylthio)-1-
octyne (16b) and purified by column chromatography (eluant,
hexane/AcOEt 70/30): 50% yield for method A, 25% yield for
method B. 1H NMR (CDCl3): δ 2.38-2.31 (t, 2H, J ) 7.2 Hz),
1.66-1.56 (t, 2H, J ) 7.5 Hz), 1.34-1.25 (m, 8H), 0.91-0.84
(t, 3H, J ) 7 Hz).
6-Hyd r oxyh exa n oic a cid (17c) was prepared from 6-[(tri-
methylsilyl)oxy]-1-(phenylthio)-1-hexyne (16c) and purified by
column chromatography (eluant, hexane/AcOEt 70/30): 54%
yield for method B: 1H NMR (CDCl3) δ 4.06-4.02 (t, 2H, J )
6.6 Hz), 2.39-2.32 (t, 2H, J ) 7.2), 1.71-1.35 (m, 6H).
Meth od B. A solution of 1-alkynyl thioether (1.66 mmol)
in a mixture of water (1 mL) and acetic acid (5 mL) was heated
at 80-90 °C in the presence of DOWEX 50 × 830,31 20% Hg2+
resin for 72 h. After cooling the solution was filtered and the
resin washed with water. The aqueous phase was washed
with CH2Cl2 (20 mL), and the water was evaporated to give
J O951062O