Enantioselective formation of an α, β-epoxy alcohol by reaction of methyl 13(S)-hydroperoxy-9(Z),11(E)-octadecadienoate with titanium isopropoxide

Article abstract of DOI:10.1007/s11746-997-0241-7

Methyl 11(R), 12(R)-epoxy-13(S)-hydroxy-9(Z)-octadecenoate (threo isomer) was generated from linoleic acid by the sequential action of an enzyme and two chemical reagents. Linoleic acid was treated with lipoxygenase to yield its corresponding hydroperoxide [13(S)-hydroperoxy-9(Z),11(E)-octadecadienoic acid]. After methylation with CH₂N₂, the hydroperoxide was treated with titanium (IV) isopropoxide [Ti(O-i-Pr)₄] at 5 °C for 1 h. The products were separated by normal-phase high-performance liquid chromatography and characterized with gas chromatography-mass spectrometry, infrared spectroscopy, and nuclear magnetic resonance spectroscopy. Approximately 30% of the product was methyl 13(S)-hydroxy-9(Z),11(E)-octadecadienoate. Over 60% of the isolated product was methyl 11(R),12(R)-epoxy-13(S)-hydroxy-9(Z)-octadecenoate. After quenching Ti(O-i-Pr)₄ with water, the spent catalyst could be removed from the fatty products by partitioning between CH₂Cl₂ and water. These results demonstrate that Ti(O-i-Pr)₄ selectively promotes the formation of an α-epoxide with the threo configuration. It was critically important to start with dry methyl 13(S)-hydroperoxy-9(Z),11(E)-octadecadienoate because the presence of small amounts of water in the reaction medium resulted in the complete hydrolysis of epoxy alcohol to trihydroxy products.

Full text of DOI:10.1007/s11746-997-0241-7

Enantioselective Formation of an α, β-Epoxy Alcohol
by Reaction of Methyl 13(S)-Hydroperoxy-9(Z),11(E)-
octadecadienoate with Titanium Isopropoxide
George J. Piazza*, Thomas A. Foglia, and Alberto Nuñez
ERRC, ARS, USDA, Wyndmoor, Pennsylvania 19038
ABSTRACT: Methyl 11(R),12(R)-epoxy-13(S)-hydroxy-9(Z)-oc- organic hydroperoxide as the oxygen donor (7,8). Recently, it
tadecenoate (threo isomer) was generated from linoleic acid by has been shown that complexes of titanium, vanadium, and
the sequential action of an enzyme and two chemical reagents.
Linoleic acid was treated with lipoxygenase to yield its corre-
sponding hydroperoxide [13(S)-hydroperoxy-9(Z),11(E)-oc-
tadecadienoic acid]. After methylation with CH N , the hy-
molybdenum in the presence of singlet oxygen directly convert
unsaturated compounds to epoxy alcohols (9,10). It has been
postulated that the latter materials are formed through the in-
termediacy of metal–hydroperoxide complexes.
We have investigated the possibility of forming fatty acid
epoxy alcohols with a titanium catalyst, starting with the methyl
ester of the hydroperoxide of linoleic acid [methyl 13(S)-hy-
droperoxy-9(Z),11(E)-octadecadienoate, Me-HPODE], derived
2
2
droperoxide was treated with titanium (IV) isopropoxide [Ti(O-i-
Pr) ] at 5°C for 1 h. The products were separated by normal-phase
4
high-performance liquid chromatography and characterized with
gas chromatography–mass spectrometry, infrared spectroscopy,
and nuclear magnetic resonance spectroscopy. Approximately
3
0% of the product was methyl 13(S)-hydroxy-9(Z),11(E)-oc- enzymatically with soybean lipoxygenase. The advantage of
tadecadienoate. Over 60% of the isolated product was methyl using enzymatically formed Me-HPODE is that approximately
1
1(R),12(R)-epoxy-13(S)-hydroxy-9(Z)-octadecenoate. After quench- 97% of the hydroperoxide is in the 13(S) configuration, whereas
ing Ti(O-i-Pr) with water, the spent catalyst could be removed
from the fatty products by partitioning between CH Cl2 and
water. These results demonstrate that Ti(O-i-Pr) selectively pro-
motes the formation of an α-epoxide with the threo configura-
tion. It was critically important to start with dry methyl 13(S)-hy-
droperoxy-9(Z),11(E)-octadecadienoate because the presence of
small amounts of water in the reaction medium resulted in the
complete hydrolysis of epoxy alcohol to trihydroxy products.
JAOCS 74, 1385–1390 (1997).
4
chemically formed Me-HPODE is a mixture of the 13(R,S) and
9(R,S) species (11). Previously, Hamberg (12) showed that Me-
HPODE converts to two diastereomeric α,β-epoxy alcohols in
the presence of vanadium oxyacetylacetonate.
2
4
MATERIALS AND METHODS
Materials. Soybean (Glycine max L. Merr.) lipoxygenase
(
Lipoxidase, Type 1-B), linoleic acid, and silica gel (70–230
KEY WORDS: Epoxide, hydroperoxide, linoleic acid, lipoxyge- mesh) were purchased from Sigma (St. Louis, MO). Tita-
nase, titanium isopropoxide.
nium(IV) isopropoxide [Ti(O-i-Pr) ] and vanadyl acetylacet-
4
onate [VO(acac) ] were purchased from Aldrich (Milwaukee,
2
WI). Celite 545 was purchased from Fisher Scientific (Pitts-
Fatty epoxy alcohols serve as intermediates in the facile con- burgh, PA). Water was purified to a resistance of 18 mΩ-cm
version of common fats and oils to useful polar materials. in a Barnstead (Dubuque, IA) NANOpure system. All other
Epoxy alcohols can be produced from fatty acid hydroperox- reagents were of the highest purity available.
ides by nonenzymatic catalysis with strong acid, ferrous iron,
Me-HPODE formation. Linoleic acid (80 mg) was placed
or hematin (1). They can also be produced from fatty acid hy- in a 125-mL Erlenmeyer flask, along with 80 mL 0.2 M bo-
droperoxides enzymatically by epoxygenase (2), lipoxygenase rate buffer, pH 9.0. The flask was packed in ice and stoppered
(
(
3), or cytochrome P450-dependent mixed-function oxidases with a rubber septum. The contents were stirred gently for 0.5
4). Chemical methodology for the introduction of epoxides in- h while oxygen was slowly bubbled into the buffer through a
cludes the Sharpless method (5) by using titanium complexes metal syringe needle. Four 50-µL aliquots of a lipoxygenase
and a hydroperoxide donor and the Jacobsen method (6) with a solution (32 mg/mL) in borate buffer were added at 30-min
manganese complex and sodium hypochlorite. Much work has intervals. The pH of the reaction medium was lowered to 3
been devoted to the investigation of heterogeneous titanium with 1 M HCl, and HPODE was extracted with 2 × 50 mL di-
catalysts for epoxide formation with hydrogen peroxide or an ethyl ether. The diethyl ether was dried over potassium sul-
fate, and the diethyl ether was removed under a stream of ni-
*To whom correspondence should be addressed.
trogen. HPODE was dissolved in 5 mL CH Cl and treated
2 2
E-mail: gpiazza@arserrc.gov.
with diazomethane to give the methyl ester.
Copyright © 1997 by AOCS Press
1385
JAOCS, Vol. 74, no. 11 (1997)

1386
G.J. PIAZZA ET AL.
Titanium treatment. Me-HPODE (27 mg, 83 µmol), dis- RESULTS AND DISCUSSION
solved in 4.7 mL CH Cl , was treated with 63 µL (212 µmol)
2
2
Ti(O-i-Pr) for 1 h at 5 C. The reaction was quenched by the Me-HPODE was incubated with Ti(O-i-Pr) , and the products
4
4
addition of 0.3 mL H O, and the reaction mixture was al- were analyzed by HPLC and GC–MS. Low reaction tempera-
2
lowed to stand for 30 min at room temperature. The solid mat- tures and short reaction times favored production of alcohol
ter was removed by filtration through Celite. After washing epoxide. Shown in Figure 1 is the normal-phase HPLC pro-
the Celite with 10 mL diethyl ether, the filtrate and wash were file of an incubation conducted at 5°C for 1 h. The peaks cor-
combined, and the solvent was removed under a stream of dry responding to minor products A were collected together.
nitrogen. The residue was dissolved in 6 mL CH Cl .
Their mass spectra were consistent with them being a mixture
After establishing reaction conditions for synthesis of al- of methyl linoleate and conjugated methyl linoleate.
cohol epoxide, a larger-scale synthesis was conducted: Me-
Product B constituted approximately 30% of the total
HPODE (1.9 g, 5.8 mmol), dissolved in 300 mL CH Cl , was product. Product B was identified as methyl 13-hydroxy-9,11-
2
2
2
2
treated with Ti(O-i-Pr) (1.1 mL, 3.7 mmol) for 1 h at 5°C. octadecadienoate by comparison of its mass spectrum to that
4
Spent Ti(O-i-Pr) was removed with four 100-mL water of an authentic standard purchased from Oxford Biomedical
4
washes. Each water fraction was back-washed with 100 mL Research (Oxford, MI). The mass spectrum of product B
CH Cl , and the CH Cl fractions were combined prior to the showed ions at m/z 310 (M), 292 (M − 18; loss of H O), and
2
2
2
2
2
next aqueous wash.
279 (M − 31). After preparation of the (CH ) Si derivative,
3
3
Vanadium treatment. Me-HPODE (95 mg, 291 µmol), dis- the mass spectrum showed ions at m/z 382 (M), 367 (M − 15;
solved in 14 mL CH Cl , was treated with 26 µL (1.5 µmol) loss of CH ), 311 [(CH ) SiO =CH-CH=CH-CH=CH-
+
2
2
3
3 3
VO(acac) for 1 h at 5°C. The reaction mixture was diluted (CH ) COOCH ] and 225 {CH (CH ) CH[OSi(CH ) ]-
2
2 7
3
3
2 4
3 3
+
with 50 mL diethyl ether and washed with water (3 × 30 mL). CH=CH-CH=CH }. Prior work has shown that the ion at m/z
After drying over potassium sulfate, the solvent was removed 225 is diagnostic for an n-6 hydroxy fatty acid with polyunsatu-
under a stream of nitrogen.
ration (14). The ultraviolet/visible (UV/VIS) spectrum showed
High-performance liquid chromatography (HPLC). Reac- an absorption peak with λmax 234 nm. Absorption at 234 nm
tion products were separated on a Dynamax Macro HPLC Si demonstrates that the double bonds are conjugated (14).
column (300 × 10 mm) (Rainin, Emeryville, CA), installed
The neat infrared spectrum of product B showed ab-
−
1
on a Waters (Milford, MA) LCM1 HPLC instrument. It was sorbances at 3500 cm (hydrogen-bonded hydroxyl), 1740
−
1
−1
equipped with a Waters 996 photodiode array detector in tan- cm (ester carbonyl), and 985 and 951 cm (double bonds
dem with a Varex evaporative light-scattering detector MK conjugated with a cis,trans configuration) (15).
1
3
III (Alltech, Deerfield, IL) and operated at a temperature of
The decoupled C NMR (C D O , 100 MHz) spectrum of
4 8 2
4
0°C with N as the nebulizing gas at a flow rate of 1.5 L/min. product B showed important signals at δ 52.5 (OCH ), 73.5
2
3
Mobile phase composition and linear gradient were (C-13), 126.4, 130.4, 133.2, 139.8 (C=C), and 175.1
hexane/isopropanol (97:3) to (94:6) over 28 min. The flow [C(O)OCH3].
1
rate was 2 mL/min.
Important signals in the H NMR (C D O , 400 MHz)
4
8 2
Gas chromatography–mass spectrometry (GC–MS). Gen- spectrum of product B are shown in Table 1. The coupling con-
erally, samples were analyzed before and after treatment with stant J9-10 was 10.8–11.0 Hz, and J11-12 was 15.2 Hz, demon-
N,O-bis(trimethylsilyl) trifluoroacetamide (BSFTA; Pierce, strating that the C9-10 double bond was cis, and the C11-12 dou-
Rockford, IL). Mass spectra were obtained on a Hewlett- ble bond was trans: J = 5–14 Hz for cis protons and 12–18 Hz
Packard (HP) (Wilmington, DE) 5890 Series II Plus gas chro- for trans protons (16). By assuming that the configuration of
matograph, equipped with an HP 5972 mass-selective detec- C-13 has not changed, product B is methyl 13(S)-hydroxy-
tor set to scan from m/e 10 to 600 at 1.2 scans/s. A capillary 9(Z),11(E)-octadecadienoate (methyl ester of coriolic acid).
column (HP-5MS, 30 m × 0.25 mm), coated with 0.25 µm 5%
Major product C accounted for approximately 67% of the
cross-linked phenyl methyl silicone, was used to separate the total product. Its mass spectrum showed an ion at m/z 288
products. The oven temperature was increased from 80 to [M − (18 + 31)]. After formation of the (CH ) Si derivative,
3
3
2
30°C at 10°C/min. The injector port temperature was 230°C, its mass spectrum showed ions at m/z 383 (M − 15), 367 (M −
and the detector transfer line temperature was 240°C.
31), 327 (M − 71), 270 [M − 128; rearrangement with expul-
Nuclear magnetic resonance spectrometry (NMR). Spectra sion of ·CO-CH(O·)-(CH ) -CH ] (17) and 173
2
4
3
+
were obtained on a Varian Unity Plus 400 MHz NMR spec- [(CH ) SiO =CH-(CH ) -CH ]. The UV/VIS spectrum
3
3
2 4
3
trometer in either 99 atom% p-dioxane-d or 99.6 atom% ben- showed absorbance below 210 nm. Thus, the data show that
8
zene d (Cambridge Isotope Labs, Woburn, MA). Typical ac- compound C is a monounsaturated 18-carbon epoxy alcohol
6
quisition conditions for the proton spectra were 9,600 data methyl ester with the hydroxyl group at C-13.
points; 4 kHz spectral width; 2.2 s recycle time. For carbon
spectra, typical acquisition conditions were 60,000 data band centered at 3425 cm (hydrogen-bonded hydroxyl),
The neat infrared spectrum of product C showed a broad
−
1
−
1
−1
points; 25 kHz spectral width; 21.7 s recycle time. The 90° 1739 cm (ester carbonyl), and 890 cm (trans epoxide). No
−
1
pulse was measured for both proton and carbon spectra prior absorption band appeared in the region 900–1000 cm , ex-
to acquisition. All spectra were recorded at 30°C.
cluding the presence of trans double bonds (16).
JAOCS, Vol. 74, no. 11 (1997)

EPOXY ALCOHOL FROM HYDROPEROXIDE
1387
FIG. 1. Normal-phase high-performance liquid chromatographic analysis of the
products obtained by the treatment of methyl 13(S)-hydroperoxy-9(Z),11(E)-oc-
tadecadienoate with Ti(O-i-Pr) . Structural analyses, as discussed in the text, re-
4
sulted in the following elucidations: A, methyl linoleate and its conjugated isomer;
B, methyl 13(S)-hydroxy-9(Z),11(E)-octadecadienoate; C, methyl 11(R),12(R)-epoxy-
13(S)-hydroxy-9(Z)-octadecenoate; D, trihydroxy hydrolysis product of C.
1
3
coupling constant J9-10 was 11–11.2 Hz, demonstrating that
The decoupled C NMR (100 MHz) spectrum of product C
is shown in Figure 2. Important signals in the spectrum obtained the double bond is in the cis configuration: J = 5–14 Hz for
in C D are δ 51.6 (OCH ), 52.9 (C-12), 63.7 (C-11), 71.6 (C- cis protons and 12–18 Hz for trans protons (16). The coupling
3), and 174.2 [C(O)OCH ]. The solvent signal partially ob- constant J11-12 was 2.2–2.3 Hz, demonstrating that the con-
scured those from the double-bond carbons. Thus, the C NMR figuration of the epoxide group is trans: J = 4.3 for cis and
spectrum was also obtained in C D O to give the signals for 2.1–2.4 for trans (18). The coupling constant J12-13 is 4.6 Hz,
6
6
3
1
3
13
4
8 2
the double bond: δ 129.4 (C-10) and 137.5 (C-9). Because there indicating that the relationship between the adjacent protons
are only two signals for the epoxide carbons, two signals for the of the alcohol and the epoxide is threo: J = 5 for threo and
double-bond carbons, and one signal for the alcoholic carbon, 3.25 for erythro (19). An analogous coupling constant, re-
product C is predominantly one structural isomer.
ported for the threo derivative of an alcoholic epoxide derived
The H NMR (C D , 400 MHz) spectrum of product C is from the action of the fungus Saprolegnia parasitica upon
1
6
6
shown in Figure 3. Important signals are listed in Table 1. The arachidonic acid, was 4.5 Hz (20). In support of the threo as-
TABLE 1
1
a
Diagnostic H NMR Chemical Shifts and Coupling Constants of Products B and C
Number
Chemical shift (δ) of protons
Appearance
Assignment
Coupling constant (Hz)
Product B
4.13
5.48
5.75
6.06
6.55
1H
1H
1H
1H
1H
br s
dt
dd
t
H-13
H-9
H-12
H-10
H-11
J8-9 = 7.7, J9-10 = 10.8
J11-12 = 15.2, J12-13 = 6.4
J10-11 = 11.0
dd
J10-11 = 11.2, J11-12 = 15.2
Product C
2.97
3.60
3.88
5.39
5.80
1H
1H
1H
1H
1H
dd
br s
dd
dd
dt
H-12
H-13
H-11
H-10
H-9
J11-12 = 2.2, J12-13 = 4.6
J10-11 = 8.7, J11-12 = 2.3
J9-10 = 11.0, J10-11 = 9.0
J8-9 = 7.5, J9-10 = 11.2
aNMR, nuclear magnetic resonance.
JAOCS, Vol. 74, no. 11 (1997)

1388
G.J. PIAZZA ET AL.
FIG. 2. 13C-nuclear magnetic resonance spectrum of methyl 11(R),12(R)-epoxy-13(S)-hy-
droxy-9(Z)-octadecenoate.
signment, H-13 resonates at 3.60 ppm: 3.8 ± 1 ppm for ery- (CH ) Si derivative of D showed ions at m/z 530 (M − 31),
3
3
thro and 3.5 ± 1 ppm for threo (21).
400 (M − [71 + 90]; loss of •(CH ) CH and (CH ) SiOH),
2 4 3 3 3
+
From all data, we concluded that the stereochemical struc- 285, 275 {(CH ) SiO =CH-CH[OSi(CH ) ](CH ) CH }, and
3
3
3 3
2 4
3
ture of product C is methyl 11(R),12(R)-epoxy-13(S)-hy- 173. The UV/VIS spectrum showed end absorbance below
droxy-9(Z)-octadecenoate (Figs. 2 and 3).
210 nm. Thus, the data demonstrate that product D is an 18-
Minor product D is formed from C when the epoxide is hy- carbon trihydroxy methyl ester with a single double bond.
drolyzed. This was inadvertently shown when the reaction
Larger amounts of product were subjected to HPLC analy-
was conducted with a wet sample of Me-HPODE: Product D sis, and minor peaks were collected to determine if the erythro
was the major product formed. The mass spectrum of the or other structural epoxy alcohol isomers were being formed.
1
FIG. 3. H-nuclear magnetic resonance of methyl 11(R),12(R)-epoxy-13(S)-hydroxy-9(Z)-oc-
tadecenoate.
JAOCS, Vol. 74, no. 11 (1997)

EPOXY ALCOHOL FROM HYDROPEROXIDE
1389
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2
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4
9
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1
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4
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2
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4
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4
2
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4
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4
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JAOCS, Vol. 74, no. 11 (1997)

1390
G.J. PIAZZA ET AL.
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[Received September 27, 1996; accepted July 24, 1997]
JAOCS, Vol. 74, no. 11 (1997)