Diastereoface-differentiating oxidation of 1-cyclohexenyl ether using a 2,4-pentanediol tether

Article abstract of DOI:10.1016/S0957-4166(98)00046-9

Diastereoface-differentiating oxidation of the chiral enol ether prepared from cyclohexanone and optically active 2,4-pentanediol gave a diastereomeric mixture of the corresponding 2-hydroxycyclohexanone acetal. The diastereomeric excess of the product reached over 99% by oxidation with m-chloroperbenzoic acid at -78°C. Oxidation with t-butyl hydroperoxide in the presence of metal catalysts also resulted in high diastereomeric excesses of up to 97%.

Full text of DOI:10.1016/S0957-4166(98)00046-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1007–1013
Diastereoface-differentiating oxidation of 1-cyclohexenyl ether
using a 2,4-pentanediol tether
Takashi Sugimura,a,∗ Hiromitsu Iguchi,a Rumiko Tsuchida,a Akira Tai,a Norio Nishiyamab
and Tadao Hakushi b
aFaculty of Science, Himeji Institute of Technology, Kanaji, Kamigori, Ako-gun, Hyogo 678-1297, Japan
bFaculty of Engineering, Himeji Institute of Technology, 2167 Shosha, Himeji, Hyogo 671-2201, Japan
Received 16 January 1998; accepted 28 January 1998
Abstract
Diastereoface-differentiating oxidation of the chiral enol ether prepared from cyclohexanone and optically
active 2,4-pentanediol gave a diastereomeric mixture of the corresponding 2-hydroxycyclohexanone acetal. The
diastereomeric excess of the product reached over 99% by oxidation with m-chloroperbenzoic acid at −78°C.
Oxidation with t-butyl hydroperoxide in the presence of metal catalysts also resulted in high diastereomeric
excesses of up to 97%. © 1998 Elsevier Science Ltd. All rights reserved.
Development of facile methods to synthesize optically active products is a key issue in recent organic
chemistry, and various reactions have been studied based on different stereocontrol designs: incorporation
of a chiral source into a substrate, a reagent, or a catalyst. Although catalytic asymmetric reactions are
the best for the production of large amounts of optically active compounds, stoichiometric use of a chiral
source is also useful if the product is much more valuable than the chiral source. The requirement
for synthetic chemicals with minimum delay, especially in the pharmaceutical field, necessitates not
only a low-cost process for the synthesis, but also leaves only a short time to establish the process.
Accordingly, a handy and reliable method for asymmetrization of a process resulting in high optical yield
is desired. Intending to obtain such a method, we have been developing a stereocontroller applicable
to various asymmetric reactions, where a chiral source is not simply incorporated into a substrate
and/or a reagent, but acts as a chiral tether between a reagent and a substrate. As a chiral tether,
we employed optically active 2,4-pentanediol (PD), a chiral diol commercially available and readily
obtainable on a large scale by asymmetric catalytic hydrogenation of 2,4-pentanedione.1 Because the
PD part is flexible, long enough for the intramolecular reaction, inert to most reagents and sterically
small, many types of reactions can be applied for this stereocontroller. In addition, the PD tether can be
removed from the products by several methods under mild conditions. Based on this reaction design, we
have reported several different types of highly diastereodifferentiating asymmetric reactions to produce
∗
Corresponding author. E-mail: hayamizu@nimc.go.jp
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00046-9

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enantiomerically pure compounds after elimination of the PD unit.2 The connection of a reagent to the
PD tether can be a covalent bond of an ether or ester, and also an in situ formed coordination bonding
to the hydroxyl group on the PD part. In this report, we would like to present a reaction in the latter
category, the oxidation of the olefin in 1 with oxidants having coordination ability to the hydroxyl group
as shown in Scheme 1.3,4
Scheme 1.
1. Peracid oxidation
Peracid oxidation of some allylic alcohols is known to give predominantly one diastereomer of
the corresponding epoxide.5 Because this diastereodifferentiation originated by coordination of the
peracid to the hydroxyl group before the epoxidation, 1 is also expected to react with peracid through
intramolecular oxidation with aid from the hydroxyl group of the PD unit, and chirality on the PD tether
can control the diastereoface differentiation of the oxidation. The substrate 1 was prepared by the reported
method2b from (2R,4R)-PD and cyclohexanone (two steps, 85–95% yield). When m-chloroperbenzoic
acid (MCPBA, 1.05–1.2 eq.) was added to a solution of 1 in dichloromethane, the oxidation proceeded
smoothly at reaction temperatures from 39 to −72°C to give a mixture of one pair of diastereomers.
1
From the following H NMR study, the product’s structures were determined not to be the primary
produced epoxides, but 2 and 3 of the intramolecular acetal exchanged products.5 By acetylation of
the products, the spectrum pattern was almost unchanged, except for one proton on the cyclohexane
ring that was shifted downfield. The configuration of the major product 2 was determined to be 7R by
chemical correlation with (2R)-(+)-2-hydroxycyclohexanone 56 and (2R)-(+)-2-acetoxycyclohexanone 6
(Scheme 2). The minor isomer 3 was isolated from a mixture of 2 and 3 by acetylation, MPLC separation,
and saponification (Scheme 3).
Scheme 2.
Scheme 3.

T. Sugimura et al. / Tetrahedron: Asymmetry 9 (1998) 1007–1013
1009
Table 1
Diastereomeric excess of the MCPBA oxidation product of 1 at varied temperaturesa
The isomer ratio was determined by capillary GLC analysis (PEG-20M, 50 m) after a part of
the reaction mixture was converted to the trimethylsilyl ethers with trimethylsilyl imidazole. The de
{diastereomeric excess=(2−3)/(2+3)×100} of the product was 90% when the reaction was performed
in dichloromethane at 0°C, but was 28% in ether and −9% in THF at the same temperature. The de in
dichloromethane increased with decreasing reaction temperature, and 3 became undetectable (<0.5%) at
−72°C; 2 of over 99% de was obtained in an almost quantitative yield (see Table 1). Thus, it appeared
that 1 could be oxidized with complete diastereoface differentiation. On the other hand, the poor de using
ether or THF as a solvent was not improved by decreasing the reaction temperature. In ether, the de was
even decreased with decreasing temperature. The lower des could be explained in that the coordination to
the hydroxyl group was not strong enough in ethereal solvents and intermolecular oxidation took place.
Supporting this, reverse addition in ether (1 was added to MCPBA) somewhat affected the de.
The large solvent effect for the diastereoface differentiation of 1 with MCPBA sharply contrasted to
that of allylic alcohols. When 2-cyclohexenol, a typical example of allylic alcohols, was treated with
MCPBA, diastereodifferentiations in ether and THF were as high as that in dichloromethane to give over
99% de of the product, and the diastereomeric mixture was obtained (syn:anti=76:23) only in methanol.7
The difference between 1 and 2-cyclohexenol can be attributed to the length of the tether between a
reaction site and the reagent. In the case of 2-cyclohexanol, the coordinated reagent is placed close to the
olefin, and thus the intramolecular reaction with favorable entropy is much faster than the intermolecular
reaction. On the other hand, the MCPBA coordinated to the hydroxyl group in 1 was placed away from
the reaction site, and the acceleration of the intramolecular reaction is not expected.
The temperature effect in dichloromethane, if the coordination was strong enough to proceed with
most of the oxidation through the intramolecular path, indicated the stereodifferentiating ability of the
PD part as a chiral tether. The Arrhenius-like plot, the natural logarithm of the relative rate constants to
give 2 and 3 plotted against the reciprocal reaction temperature, was linear (r=0.996), and the differential
enthalpy and entropy were calculated as ∆H‡(R)−∆H‡(S)=−4.8 kcal/mol and ∆S‡(R)−∆S‡(S)=−11.9
cal/mol K.
2. Metal-catalyzed oxidation with t-butyl hydroperoxide
Other than peracids, several oxidants convert allylic alcohol to the corresponding epoxide with di-
astereomeric differentiation by the control of the hydroxyl group direction. With the rhenium oxide of
such an oxidant, Kennedy et al. have reported that the oxidation of 1 could convert to a single diastere-
omer quantitatively.4b Surprisingly, the diastereodifferentiation was in contrast to the peracid oxidation,
and 3 was obtained as the sole product. The opposing diastereoface differentiations with MCPBA and
rhenium oxide for the same substrate of 1 prompted us to a further study of the oxidation of 1 with the
other hydroxyl group directed oxidant. Allylic alcohols can be converted with diastereodifferentiation to
epoxides with t-butyl hydroperoxide (TBHP) catalyzed with various metal catalysts.5 The oxidation of 1

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T. Sugimura et al. / Tetrahedron: Asymmetry 9 (1998) 1007–1013
Table 2
Diastereomeric excess of TBHP oxidation of 1
was carried out by the addition of metal catalysts listed in Table 2 at 0°C to a solution of 1 and TBHP
in the presence of molecular sieves 4 Å. The mixture was stirred until no reactant was detected on TLC
analysis. The diastereomeric excess of the product after proper workup (21–40% yield) is summarized
in Table 2. In all cases, the major isomer was 2, and the lowest de so far examined was 75% with
MoO2(acac)2 (run 6). In the case of the reaction with Ti(OiPr)4, the de at 25°C was lower than that
at 0°C. Differing from MCPBA oxidation, the use of THF as the reaction solvent did not decrease the
diastereodifferentiation, but resulted in 97% of the highest de with TBHP, which was higher than that by
MCPBA oxidation at the same temperature. The reaction at −20°C with Ti(OiPr)4 became sluggish, and
only 10% of the product was yielded.
3. Discussion
Enantiodifferentiating α-hydroxylations of prochiral ketones with chiral oxaziridines8 or with chiral
phase transfer catalysts9 have been reported, but these processes resulted in a synthetically acceptable
ee only from ketones having a particular substituent.10 The present study succeeded with a simple
ketone of cyclohexanone and thus will open a secure way to convert prochiral ketones to optically
pure α-hydroxyketones. Because the carbonyl group of the product in the present process is protected
as an acetal, the epimerization of the produced hydroxyl bearing carbon is restrained. The use of an
alternative chiral auxiliary (3S,5S)-2,6-dimethyl-3,5-heptanediol instead of (2R,4R)-PD has been found to
be effective for diastereoface differentiating zinc carbenoid addition.2b Unfortunately, this bulky analog
of 1 was not effective for MCPBA oxidation. The reaction in dichloromethane at 0°C resulted in 89% de
and in 95% de at −78°C. The details will be published elsewhere.
The diastereoface of 1 to be oxidized was found to be the si–re face in both reactions with MCPBA and
TBHP, and the size of the TBHP-catalyst complex did not greatly affect the diastereoface differentiation.
Zinc carbenoid addition to 1 occurs predominantly at the same si–re face, and the intramolecular
cyclopropanation of a diazo ester of 1 also gave the product by the same diastereoface attack.2 In these
respects, the reverse differentiation with rhenium oxide, perfect re–si face attack, is exceptional in the
diastereodifferentiation using a chiral PD tether. Expected structures of the reaction transition states of
si–re and re–si face-attacks are shown in Fig. 1. Elucidation of the reverse differentiation needs a detailed
study of the conformation of the transition state.
4. Conclusions
The asymmetric reaction design using a PD tether, although it needs multi-steps to convert a prochiral
substrate to an optically active product, is secure and results in a high optical yield. Concerning the

T. Sugimura et al. / Tetrahedron: Asymmetry 9 (1998) 1007–1013
1011
Fig. 1.
availability of both enantiomers of PD, this method is proved to be effective to obtain optically pure
products on a kilogram scale by a simple operation.
5. Experimental
5.1. General
All temperatures are uncorrected. 1H NMR (400 MHz) was recorded on a JEOL GX-400 spectrometer
in CDCl3 as a solvent and as an internal standard (CHCl3=7.26 ppm). IR spectra were obtained
on a JASCO IR-810 spectrophotometer. Optical rotations were measured on a Perkin–Elmer 243B
polarimeter. Analytical GLC was conducted with a Shimadzu GC-17A chromatograph. MPLC was
carried out using an FMI pump (10 ml min−1) and a Lobar column (Merck Si-60, type B). All dry solvents
were distilled from calcium hydride. All reactions were carried out under a dry nitrogen atmosphere.
5.2. Oxidation of 1 with m-chloroperbenzoic acid
A typical experiment is as follows: A solution of 1 (350 mg, 1.9 mmol) in dry dichloromethane (20 ml)
was placed in a two-necked flask (50 ml) equipped with a three-way stopcock and a thermometer. The
mixture was cooled to −72°C in a dry ice–ethanol bath, and m-chloroperbenzoic acid (purity 82%, 348.1
mg, 1.05 eq.) was added to this at once. After 15 min, a saturated aqueous solution of NaHCO3 was
added at the same temperature, and the mixture was allowed to warm up. Extraction of the mixture
with dichloromethane (4×), drying (MgSO4) and concentration afforded 2 (352 mg). After MPLC
purification, 234.0 mg of colorless oil was obtained (61.6% yield). [α]D20=−22.8 (c 1.1, CHCl3). IR
(neat), 3500 cm−1 (OH). 1H NMR (CDCl3) δ 4.20 (m, 1H), 4.06 (m, 1H), 3.63 (dd, J=7.3, 3.9 Hz, 1H),
2.15 (brs, 1H, OH), 1.91 (ddd, J=12.2, 7.3, 4.2 Hz, 1H), 1.74 (m, 1H), 1.70–1.41 (m, 7H), 1.27 (m, 1H),
1.23 (d, J=6.3 Hz, 3H), 1.20 (d, J=6.3 Hz, 3H). Anal. calcd for C11H20O3: C, 65.97; H, 10.07. Found: C,
65.66; H, 10.06. MS, m/z (M+) calcd for C11H20O3, 200.1412; found, 200.1413.
5.3. Analysis of diastereomeric excess of a mixture of 2 and 3
A ratio of 2 and 3 in the reaction mixture was determined by capillary GLC after conversion to
trimethylsilyl ethers. A small part of the extract was treated with excess trimethylsilyl imidazole and
subjected to GLC on a PEG-20 M capillary column (50 m) at 70°C. The peaks appeared with baseline
separation at 70.5 min for the trimethylsilyl ether of 2 and at 72.5 min for that of 3. The diastereomeric
excess was calculated from the integration of these peaks as (2−3)/(2+3)×100.

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5.4. Oxidation of 1 with t-butyl hydroperoxide in the presence of metal catalyst
A typical experiment is as follows: A solution of 1 (60 mg, 0.36 mmol) and the metal catalyst (0.05
eq.) in anhydrous dichloromethane (1 ml) and molecular sieves (4 Å, powder, 0.1 g) were placed in a 30
ml flask and cooled to 0°C. To this solution, t-butyl hydroperoxide (3.6 N dichloromethane solution, 0.15
ml, 1.5 eq.) was added, and the mixture was stirred for 7 h. After the usual work up, a mixture of 2 and 3
was obtained in 21 to 40% yield and subjected to the previous analysis.
5.5. Preparation of (2R)-2-hydroxycyclohexanone (5) from 2
A solution of 2 (98% de, 23 mg, 0.11 mmol) in ether (2 ml) was stirred with p-TsOH·H2O at room
temperature for 1.5 h. The mixture after extraction was purified by silica gel column chromatography
(elution with 15% ethyl acetate in hexane) to give 5 (4.0 mg) as a colorless oil (31% yield). Optical
rotation of 5 depended on the hydrolysis conditions. The maximum optical rotation: [α]D20=10.4 (c 0.6,
CHCl3), lit.6 [α]D=−13.3 (c 0.53, CHCl3) for (2S)-(−)-5 of 91% ee.
5.6. Preparation of (2R)-2-acetoxycyclohexanone (6) from 2
To a solution of 2 (1.00 g, 5.42 mmol) in dry pyridine (5 ml), acetic anhydride (1.5 ml, 3.03 eq.) was
added at room temperature. After 24 h, the mixture was extracted with ether (×3) and washed with a
saturated aqueous solution of CuSO4 and then water. Drying over MgSO4, concentration, and column
chromatography (silica gel, elution with 20% ethyl acetate in hexane) afforded 0.948 g of 4 as a colorless
oil. [α]D20=−40.3 (c 0.7, methanol), IR (neat) 1750 cm−1 (C_O), 1H NMR (CDCl3) δ 4.90 (m, 1H), 4.18
(m, 1H), 4.02 (m, 1H), 1.82 (m, 1H), 1.65–1.73 (m, 2H), 1.45–1.65 (m, 7H), 1.25 (d, J=6.3 Hz, 3H), 1.11
(d, J=6.3 Hz, 3H). MS, m/z (M+) calcd for C13H22O4, 242.1518; found, 242.1498. A solution of 4 (300
mg, 1.24 mmol) in ether (20 ml) was stirred with 2 N hydrochloric acid (2 ml) at room temperature for
24 h. Extraction and purification by column chromatography (silica gel, elution with 30% ethyl acetate
in hexane) afforded 6 (58.5 mg, 30.3%) as a colorless oil. [α]D20=89.3 (c 1.0, methanol). Authentic (R)-
6 was prepared by oxidation of (1R,2R)-2-acetoxycyclohexanol with pyridinium chlorochromate (80%
yield). [α]D20=89.5 (c 1.0, methanol).
5.7. Isolation of diastereomerically pure 3
Diastereomerically pure 3 was isolated through the following method: A mixture of 2 and 3 in a 1:1
ratio was acetylated and separated by MPLC on silica gel (elution with 15% ethyl acetate in hexane).
Acetate of 3 (35% yield from a mixture): [α]D20=−6.4 (c 0.6, methanol), IR (neat) 1740 cm−1 (C_O),
1H NMR (CDCl3) δ 5.15 (s, 1H), 4.05 (m, 1H), 3.92 (m, 1H), 1.81–1.66 (m, 2H), 1.65–1.35 (m, 9H), 1.17
(d, J=6.3 Hz, 3H), 1.08 (d, J=6.3 Hz, 3H). MS, m/z (M+) calcd for C13H22O4, 242.1518; found, 242.1517.
The obtained diastereomerically pure acetate (280 mg) was dissolved in a mixture of methanol (10 ml)
and 1 N NaOH aqueous solution (0.5 ml) and allowed to stand for 24 h. The mixture was extracted
with dichloromethane (3×10 ml), dried over sodium sulfate, and purified on a short column (silica gel,
elution with 20% ethyl acetate in hexane) to give 175.5 mg of 3 as a colorless oil (75.9% yield). The
diastereomeric purity of this sample was over 99% by GLC analysis. [α]D20=−10.5 (c 1.7, CHCl3), IR
(neat) 3500 cm−1 (OH), 1H NMR (CDCl3) δ 4.10 (m, 1H), 4.02 (m, 1H), 3.73 (m, 1H), 2.21 (m, 1H),
1.80 (m, 1H), 1.72–1.65 (m, 2H), 1.65–1.56 (m, 2H), 1.54–1.38 (m, 2H), 1.33 (m, 1H), 1.18 (d, J=6.1
Hz, 3H), 1.02 (d, J=6.1 Hz, 3H). MS, m/z (M+) calcd for C11H20O3, 200.1412; found, 200.1413.

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