Asymmetric synthesis of cis-and trans-2-aryl-6-methylpyrans from D-glucose by arylation and inversion of configuration at the C-2 position

Article abstract of DOI:10.1002/ejoc.201301376

Asymmetric synthesis of optically active cis-and trans-2-aryl-6- methylpyrans from commercially available tetra-O-acetyl-D-glucopyranosyl bromide has been developed. The reaction proceeds by two important steps. One is the arylation, and the other is deox

Full text of DOI:10.1002/ejoc.201301376

FULL PAPER
DOI: 10.1002/ejoc.201301376
Asymmetric Synthesis of cis- and trans-2-Aryl-6-methylpyrans from -Glucose
D
by Arylation and Inversion of Configuration at the C-2 Position
Kyosuke Michigami,[a] Atsuko Shimazaki,[a] and Masahiko Hayashi*[a]
Keywords: Carbohydrates / Asymmetric synthesis / Medicinal chemistry / Oxygen heterocycles / Arylation /
Deoxygenation / Chiral pool
Asymmetric synthesis of optically active cis- and trans-2-
aryl-6-methylpyrans from commercially available tetra-O-
acetyl-D-glucopyranosyl bromide has been developed. The
reaction proceeds by two important steps. One is the aryl-
ation, and the other is deoxygenation at the C-3 position and
inversion of configuration at the C-2 position during the
preparation of the cis-isomer, when 2-aryl-3-hydroxy-6-
(hydroxymethyl)pyrans were treated with trimethylsilyl
chloride and sodium iodide.
been reported.[8] Michael reactions[9] and Hetero-Diels–Al-
der reactions[10] have been recognized as efficient methods
to synthesize optically active pyrans. Naturally occurring
carbohydrates are readily available chiral starting materials.
In this paper, we report a method for the highly controlled
synthesis of cis- and trans-2-arylpyran derivatives starting
from d-glucose.
Introduction
Many well-known naturally occurring and synthetic chi-
ral pyran derivatives are biologically active, and such com-
pounds have been widely used as aroma compounds (in this
manuscript we use the term “pyran” to indicate oxacy-
clohexanes). Their good aromas are associated with herbs
and flowers such as geraniums. The biological activity of 2-
arylpyran derivatives has also been exploited for medicinal
and pharmaceutical use.[1] For example, (–)-centorolobine
has been found to have both antiviral and anti-inflamma-
tory activity.[2] Dapagliflozin behaves as a hypoglycemic
drug by inhibiting the sodium glucose co-transporter-2
(SGLT-2) and lowering the level of blood sugar.[3] The
properties of aroma and biologically active compounds are
highly dependent on their diastereomeric and enantiomeric
nature. Thus, there is a huge demand for the development
of synthetic methods that selectively control the formation
of diastereomers and enantiomers. Various synthetic meth-
ods aimed at constructing 2-arylpyran blocks have been re-
ported. These include, among others, the direct substitution
of 2-benzenesulfonyl cyclic ethers with nucleophiles,[4] the
photoreaction of N-(pent-4-enyl-1-oxy)pyridine-2(1H)-
thiones via alkoxy radicals,[5] the Prins reaction,[6] and the
cyclization reaction of siloxy carbonyl compounds catalysed
by a Lewis acid.[7] Although these methods have made a
variety of cyclic ether substituents accessible, only racemic
products were obtained. Synthetic methods for obtaining
optically active 2-arylpyrans from glycals, d-glucose deriva-
tives, or arylketones with α,β-unsaturated ester groups have
Results and Discussion
In 2000, we reported the HF·pyridine-promoted Friedel–
Crafts arylation of 2-acetoxy-d-glucal.[11] We now describe
the synthesis of chiral cis- and trans-2-arylpyrans using the
same method (Scheme 1).
Scheme 1. Strategy for the synthesis of cis- and trans-2-arylpyans.
[a] Department of Chemistry, Graduate School of Science, Kobe
University
Tetra-O-acetyl-d-glucopyranosyl bromide (1) was treated
with diethylamine and tetrabutylammonium bromide to
give 2-acetoxy-3,4,6-tri-O-acetyl-d-glucal (2) in good yield
(Scheme 2).[12] Glycosidation of 2 with aryl compounds
1-1 Rokkodai-cho, Nada-ku, Hyogo 657-8501, Japan
E-mail: mhayashi@kobe-u.ac.jp
http://www2.kobe-u.ac.jp/~mhayashi/index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301376.
244
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Eur. J. Org. Chem. 2014, 244–253

Synthesis of 2-Aryl-6-methylpyrans from d-Glucose
(mesitylene, p-xylene, toluene) using HF·pyridine as a pro-
moter gave C-glycosides 3a–3c in good to excellent yield.[11]
To prepare (2R,3R,6S)-2-aryl-3-hydroxy-6-(hydroxymeth-
yl)pyrans 6a–6c, C-glycosides 3a–3c were reduced using
NaBH4. The reduction of C-glycoside 3a gave only alcohol
5a, but alcohols 5b and 5c were formed together with cyclic
olefins 4b and 4c when 3b and p-3c were used as the sub-
strates. In these cases, the reaction mixture was worked up
by quenching, extraction, drying, and concentration, and
then the crude product was directly subjected to hydrogena-
tion using H2 and Pd/C in ethanol to give alcohols 5b and
5c. Next, the acetate groups in alcohols 5a–5c were depro-
tected using NaOMe in MeOH to give the corresponding
diols (i.e., 6a–6c). Based on NOE experiments and coupling
constants [J2,3 = 1.6 Hz (ax–eq)], we confirmed that com-
pound 6a preferred the 1C4 conformation over the 4C1 con-
formation. The other diols (i.e., 6b and 6c) also showed a
Scheme 3. Preparation of xanthates 7a–7c.
Next, the conditions for the deoxygenation reaction were
optimized (Table 1). Addition of azobisisobutyronitrile
(AIBN) and nBu3SnH to a solution of substrate 7a in tolu-
ene at 100 °C gave trans-2-aryl-6-methylpyran 8a in only
15% yield (Table 1, entry 1). A mixture of AIBN and
nBu3SnH in toluene was added dropwise to the solution
containing ester 7a in toluene at 100 °C to give 8a in 63%
yield (Table 1, entry 2). Deoxygenation of xanthates 7b and
7c under the conditions of Table 1, entry 2 gave correspond-
ing trans-2-aryl-6-methylpyrans (i.e., 8b and 8c) in competi-
tive yields (69 and 68%, respectively; Table 1, entries 6 and
7). In all cases, the formation of by-products reduced the
yields of the products. Based on NOE experiments and cou-
pling constants [J2,3 = 11.4 Hz (ax–ax)], we confirmed that
1
similar preference for the C4 conformation.
1
compound 8a preferred the C4 conformation.
Table 1. Deoxygenation of xanthates using AIBN and nBu3SnH.
Entry[a] Ar
Temp. [°C] Time [h]
Product Yield[b] [%]
1[c]
2
3
4
5
mesityl
100
100
110
90
80
100
100
1
1
0.5
1
2
1
8a
8a
8a
8a
8a
8b
8c
15
63
57
47
43
69
68
mesityl
mesityl
mesityl
mesityl
p-xylyl
p-tolyl
6
7
1
[a] A mixture of nBu3SnH and AIBN in toluene (0.47 m and
0.016 m, respectively) was added dropwise over 15 min to a solution
of substrate (7a–7c) in toluene (0.051–0.053 m), and the mixture
was stirred under the conditions indicated. [b] Isolated yield after
silica gel column chromatography. [c] nBu3SnH and AIBN were
added to a solution of substrate 7a in toluene (0.078 m).
Scheme 2.
Synthesis
of
(2S,3S,6R)-2-aryl-3-hydroxy-6-(hy-
droxymethyl)pyrans 6a–6c. Reagents: a) Et2NH, Bu4NBr, MeCN,
77%; b) aryl compound (mesitylene, p-xylene, toluene),
HF·pyridine, 3a: 83% (α/β = 90:10), 3b: 85% (α only), 3c: 51%
[α only (o:p = 75:25)]; c) (i) NaBH4, MeOH, (ii) NaOMe, 80%;
d) H2, 10% Pd/C, EtOH; e) NaOMe, MeOH, 6a: 80% (2 steps),
6b: 51% (3 steps), 6c: 41% (3 steps).
Treatment of diols 6a–6c with sodium iodide and tri-
methylsilyl chloride in acetonitrile converted the diols into
The synthesis of (2S,6R)-2-aryl-6-methylpyrans 8a–8c cis analogues 9a–9c (Scheme 4), removing the secondary
was achieved using the Barton–McCombie method.[13] 2- hydroxy group at the C-3 position. Trimethylsilyl iodide,
Aryldiols 6a–6c were treated with NaH, CS2, and then MeI which can be generated in situ using Me3SiCN, NaI, and
to give the corresponding xanthates (i.e., 7a–7c; Scheme 3). MeCN,[14] has been widely used in organic synthesis.[15–17]
1
We confirmed that compound 7a preferred the C4 confor- To the best of our knowledge, deoxygenation using trimeth-
mation based on NOE experiments and coupling constants ylsilyl chloride and sodium iodide involving inversion of
[J2,3 = 2.4 Hz (ax–eq)].
configuration at C-2 has not been reported before.
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245

K. Michigami, A. Shimazaki, M. Hayashi
FULL PAPER
11a. The NMR spectra of compound 11a prepared by the
two routes (routes A and B) were identical, which con-
firmed the cis configuration of compounds 9a and 10a.
Table 2 summarizes the effects of trimethylsilyl reagents
and additives on the reaction. By changing the nature of
the iodide additive (LiI, CsI, and nBu4NI were also tested),
we found that the best reaction yield of 56% was obtained
with NaI (Table 2, entries 1–4).
Scheme 4. Deoxygenation at the C-3 position and inversion of con-
figuration at the C-2 position using sodium iodide and trimethyl-
silyl chloride.
Table 2. Effect of trimethylsilyl reagents and additives.
4
Compound 9a preferred the C1 conformation over the
1C4 conformation, as suggested by NOE measurements and
the coupling constant between 2-H and 3-H (J2,3
=
11.2 Hz). These results also indicated that the reaction pro-
ceeded with inversion of configuration at the C-2 position.
Additional experiments shown in Scheme 5 were carried
out to confirm the structure of 9a.
Entry[a]
Me3SiX
Additive
Yield[b] [%]
1
2
3
4
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiI
NaI
LiI
CsI
nBu4NI
none
none
56 (0)
12 (22)
0 (80)
trace (85)
0 (95)
5
6[c]
6 (0)[d]
[a] Me3SiCl (4.0 equiv.) was added to a mixture of substrate 6a and
additive (4.0 equiv.) in MeCN, and the mixture was stirred for 24 h
at 22–28 °C. [b] Isolated yield after silica gel column chromatog-
raphy. Values in parentheses indicate the yield of recovered starting
material. [c] Me3SiI (4 m in MeCN, 4.0 equiv.) was added dropwise
over 5 min to a solution of substrate 6a in MeCN (1 m), and the
mixture was stirred for 1 h at 26–28 °C. [d] Determined by 1H
NMR spectroscopy.
These results suggested that the active species was Me3SiI
formed (along with NaCl) by the reaction of sodium iodide
with Me3SiCl. Contrary to expectations, the use of Me3SiI
gave the product only in 6% yield (Table 2, entry 6). We
concluded that the existence of a large amount of Me3SiI in
the reaction mixture may lead to the by-product formation
because of the high reactivity of Me3SiI, and that a slow
formation of Me3SiI from the reaction of Me3SiCl and NaI
was crucial for the high yield obtained in Table 2, entry 1.
1
We analysed the reaction of Me3SiCl and NaI by H NMR
Scheme 5. Confirmation of the structure of 9a. Reagents: a) mesit-
ylene, HF·pyridine, 83% (α/β = 90:10); b) (i) NaBH4, MeOH,
(ii) NaOMe, 80%; c) (i) Me3SiCl, NaI, MeCN (ii) Na2S2O3 (satd.
aq.) 56%; d) pTsCl, pyridine, 72%; e) LiAlH4, THF, 95%:
f) (i) NaBH4, MeOH, (ii) NaOMe, 67% (52:48 dr); g) NaH, CS2,
MeI, 98% (58:42 dr); h) nBu3SnH, AIBN, toluene, 37%.
spectroscopy. Although the exact reaction rate could not be
determined because a peak of the Me3SiI·MeCN com-
plex[14] (i.e., [Me3SiNCMe]+I–) overlapped with a peak of
the Me3SiCl·MeCN complex (i.e., [Me3SiNCMe]+Cl–; δ =
0.05 ppm, CDCl3), we confirmed that 22% of the Me3SiCl
still remained even after 24 h (δ = 0.43 ppm, CDCl3). These
As shown in route A (Scheme 5), alcohol 9a was tosyl- results suggest that the formation of Me3SiI from Me3SiCl
ated, and subsequent treatment with LiAlH4 gave cis-2- and sodium iodide is slow enough for Me3SiI to be released
aryl-6-methylpyran 11a. As mentioned above, the reaction slowly, leading to smaller amounts of by-products. We as-
between mesitylene and 2-acetoxy-3,4,6-tri-O-acetyl-d- sume that the low solubility of sodium iodide in the solvent
glucal (2) using HF·pyridine yielded C-glycoside 3a as an makes the formation of Me3SiI slow.
α/β-mixture in the ratio 90:10. The β-isomer was separated
We tried to elucidate the reaction mechanism by observ-
by silica gel column chromatography, and reduced using ing the co-products and by-products formed when 6a was
NaBH4. Deprotection of the acetyl groups gave an epimeric used as a substrate (Scheme 6). We isolated acyclic olefinic
mixture of compounds 12a and 12b. The mixture of diols compound 14a in 13% yield. We also observed the triiodide
–
1
12a and 12b was converted into xanthates 13a and 13b, and ion I3 by MS (ESI–) analysis, and (Me3Si)2O by H NMR
subsequent deoxygenation using AIBN and nBu3SnH gave analysis [δ = 0.06 ppm, CDCl3, tetramethylsilane (δ =
246
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Synthesis of 2-Aryl-6-methylpyrans from d-Glucose
0 ppm)]. These results suggested that the I– ion is converted generated from C and acetonitrile under acidic condi-
into I2 during the reaction, thereby acting as a reductant.
tions.[22]
Scheme 8. Proposed reaction mechanism for the deoxygenation at
the C-3 position and inversion of configuration at the C-2 position.
Scheme 6. Investigation of co-products and by-products formed in
the deoxygenation reaction.
This was followed by the formation of the triiodide ion
by the combination of I2 and I–. The synthesis of olefins
via silylated iodohydrin intermediates by treatment of sub-
stituted epoxides with iodide has been reported pre-
viously.[18] Other synthetic methods, starting from vicinal
dimesylates or ditosylates, not going via silylated iodohyd-
rins, have also been reported.[19] Next, 2-mesityl-3-hydroxy-
6-methylpyran (15a) was used as a substrate to give cis-2-
mesityl-6-methylpyran (11a) in 48% yield (Scheme 7).
Conclusions
In summary, we have accomplished the synthesis of op-
tically active cis- and trans-2-arylpyran derivatives starting
from tetra-O-acetyl-α-d-glucopyranosyl bromide. We also
discuss the conformations adopted by the products and the
mechanism of the inversion of configuration in 2-aryl-3-
hydroxypyrans in the presence of trimethylsilyl chloride and
sodium iodide.
Experimental Section
General Remarks: All reactions were carried out in well-cleaned
oven-dried glassware with magnetic stirring. Operations were per-
formed under an atmosphere of dry argon using Schlenk and vac-
uum techniques. All starting materials were obtained from com-
mercial suppliers, and were used without further purification unless
otherwise stated. Melting points were measured with a Yanaco
MP-500D instrument. 1H and 13C NMR spectra (400 and
100.6 MHz, respectively) were recorded with a JEOL JNM-LA 400
instrument, using Me4Si as an internal standard (δ = 0 ppm). The
following abbreviations are used in connection with NMR spectra:
s = singlet, d = doublet, and m = multiplet. Mass spectra were
measured with a Thermo Quest LCQ DECA plus instrument. IR
spectra were measured with a Thermo Scientific NICOLET iS 5
instrument. High-resolution mass spectra (HRMS) were measured
with a JEOL JMS-T100LP AccuTOF LC-Plus (ESI) mass spec-
trometer. Optical rotations were measured with a HORIBA SEPA-
300 polarimeter in solution in a 1 dm cell. Elemental analyses were
Scheme 7. Reaction using 2-mesityl-3-hydroxy-6-methylpyran (15a)
as the substrate.
Based on the above observations, we propose the follow-
ing mechanism for the reaction involving deoxygenation at
the C-3 position and inversion of configuration at the C-2
position (Scheme 8). First, diol 6a is converted into silylated
intermediate A, and its benzylic C–O bond is cleaved by
Me3SiI.[20] This is followed by I– addition to give silylated
iodohydrin B. Nucleophilic attack of I– onto the iodine
atom of B induces E2 elimination to give olefin C.[18,19] The
cyclization of C via thermodynamically favourable con- carried out using a Yanako CHN recorder MT-5.
former D gives 9a with a cis configuration, so resulting in
an inversion of configuration at the C-2 position. Acetyl-
Synthesis of trans-2-Aryl-6-methylpyrans by C-Aryl Glycosidation
2-Acetoxy-3,4,6-tri-O-acetyl-D-glucal (2): Tetrabutylammonium
ated compound 14a is also formed from C, by SN2 reaction
on the carbon bearing the terminal alcohol[21] and acetyl-
ation of the secondary alcohol. A deuterium labelling ex-
periment using CD3CN revealed that the acetyl group
comes from an acetonitrile solvent molecule. A plausible
bromide (2.3 g, 7.3 mmol) and diethylamine (2.2 mL, 22 mmol)
were added to a solution of 2,3,4,6-tetra-O-acetyl-α-d-glucopyr-
anosyl bromide (3.0 g, 7.3 mmol) in MeCN (4 mL). The mixture
was stirred for 2 h, then the reaction was quenched by the addition
of HCl (1 n aq.). The mixture was extracted with chloroform. The
intermediate in the formation of 14a is an imidate salt E combined organic extracts were washed with brine and dried with
Eur. J. Org. Chem. 2014, 244–253
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247

K. Michigami, A. Shimazaki, M. Hayashi
FULL PAPER
Na2SO4, and the solvents were evaporated. The residue was puri-
fied by silica gel column chromatography (hexane/ethyl acetate, 4:1
then 2:1) to give glucal 2 (1.8 g, 77%) as a white solid; m.p. 61–
H), 4.45 (dd, J = 11.5, 6.0 Hz, 1 H, 7Ј-H), 5.47 (s, 1 H, 2-H), 6.40
(d, J = 10.6 Hz, 1 H, 4-H), 6.81 (s, 1 H, ArH), 7.02 (dd, J = 10.6,
2.2 Hz, 1 H, 5-H), 7.07 (d, J = 7.8 Hz, 1 H, ArH), 7.13 (d, J =
7.8 Hz, 1 H, ArH) ppm. 13C NMR (100.4 MHz, CDCl3): δ = 18.9,
62 °C. [α]2D9 = –30.8 (c 1.0, CHCl ). IR (KBr): ν = 1738, 1376, 1226,
˜
3
1172, 1164, 1129, 1077, 1047, 1035, 1011, 960, 945, 909, 596 cm–1. 20.7, 20.9, 64.1, 68.4, 78.4, 128.1, 129.0, 129.8, 131.1, 132.5, 135.1,
1H NMR (400.0 MHz, CDCl3): δ = 2.07 (s, 3 H, CH3CO2), 2.1–
135.6, 147.1, 170.7, 195.6 ppm. MS (ESI): m/z = 297.3 [M + Na]+.
2.2 (m, 9 H, 3 Ac), 4.23 (dd, J = 11.9, 3.6 Hz, 1 H, 7-H), 4.3–4.4 C16H18O4 (274.32): calcd. C 70.06, H 6.61; found C 69.67, H 6.60.
(m, 1 H, 6-H), 4.43 (dd, J = 11.9, 6.6 Hz, 1 H, 7Ј-H), 5.24 (dd, J
(2R,6S)-6-(Acetoxymethyl)-2-(p-tolyl)oxacyclohex-4-en-3-one (3c):
= 5.6, 4.0 Hz, 1 H, 5-H), 5.57 (d, J = 4.0 Hz, 1 H, 4-H), 6.64 (s, 1
HF·pyridine (7.5 mL) was added slowly to a mixture of glucal 2
H, 2-H) ppm. 13C NMR (100.4 MHz, CDCl3): δ = 20.4, 20.7, 20.7,
(3.0 g, 9.1 mmol) and toluene (27 mL, 250 mmol) in a polyethylene
60.9, 66.3, 67.4, 74.1, 127.4, 139.3, 169.7, 169.8, 170.3, 170.7 ppm.
bottle at 0 °C. The mixture was stirred for 15 h at room tempera-
ture, then the reaction was quenched by the addition of NaHCO3
(satd. aq.). The mixture was extracted with ethyl acetate. The com-
MS (ESI+): m/z = 353.4 [M + Na]+. C14H18O9 (330.29): calcd. C
50.91, H 5.49; found C 50.76, H 5.47.
(2R,6S)-6-(Acetoxymethyl)-2-mesityloxacyclohex-4-en-3-one (α-3a):
HF·pyridine (4.8 mL) was added slowly to a mixture of glucal 2
(2.0 g, 6.1 mmol) and mesitylene (1.7 mL, 12 mmol) in a polyethyl-
ene bottle at 0 °C. The mixture was stirred for 1 h, then the reaction
was quenched by the addition of NaHCO3 (satd. aq.). The mixture
was extracted with ethyl acetate. The combined organic extracts
were washed with brine and dried with Na2SO4, and the solvents
were evaporated. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate, 7:1) to give ketone 3a (1.5 g,
83%, α:β = 89:11) as a yellow syrup. [α]2D9 = –147.8 (c 1.0, CHCl3).
bined organic extracts were washed with brine and dried with
Na2SO4, and the solvents were evaporated. The residue was puri-
fied by silica gel column chromatography (hexane/ethyl acetate, 4:1)
to give ketone 3c (900 mg, 38%) as a yellow syrup. [α]3D0 = +46.9 (c
1.3, CHCl ). IR (KBr): ν = 3000–2800 (br), 1739, 1687, 1513, 1450,
˜
3
1380, 1365, 1223, 1177, 1157, 1092, 1042, 877, 808, 776, 740,
603 cm–1. 1H NMR (400.0 MHz, CDCl3): δ = 2.10 (s, 3 H, Ac),
2.35 (s, 3 H, ArMe), 4.18 (dd, J = 11.3, 4.2 Hz, 1 H, 7-H), 4.42
(dd, J = 11.3, 5.4 Hz, 1 H, 7Ј-H), 4.4–4.5 (m, 1 H, 6-H), 5.32 (s, 1
H, 2-H), 6.31 (dd, J = 10.5, 2.6 Hz, 1 H, 4-H), 6.93 (dd, J = 10.5,
1.8 Hz, 1 H, 5-H), 7.1–7.3 (m, 4 H, 4 ArH) ppm. 13C NMR
(100.4 MHz, CDCl3): δ = 20.6, 21.0, 64.4, 67.9, 79.8, 127.3, 128.2,
129.4, 130.8, 138.6, 147.0, 170.7, 194.3 ppm. HRMS (ESI-TOF):
IR (KBr): ν = 3000–2800 (br), 1740, 1687, 1610, 1446, 1378, 1220,
˜
1161, 1093, 1037, 850, 746, 631 cm–1. 1H NMR (400.0 MHz,
CDCl3): δ = 2.09 (s, 3 H, Ac), 2.2–2.5 (m, 9 H, 3 ArMe), 4.27 (dd,
J = 11.8, 3.6 Hz, 1 H, 7-H), 4.71 (dd, J = 11.8, 6.8 Hz, 1 H, 7Ј-H), calcd. for C15H16NaO4 [M + Na]+ 283.0946; found 283.0946.
4.7–4.9 (m, 1 H, 6-H), 5.80 (s, 1 H, 2-H), 6.35 (dd, J = 10.4, 1.8 Hz,
1 H, 3-H), 6.86 (s, 2 H, 2 ArH), 7.01 (dd, J = 10.4, 3.8 Hz, 1 H, 5-
H) ppm. 13C NMR (100.4 MHz, CDCl3): δ = 20.3, 20.5, 20.7, 62.4,
71.2, 75.2, 128.1, 130.4, 137.5, 138.3, 145.2, 170.5, 195.4 ppm.
HRMS (ESI-TOF): calcd. for C17H20NaO4 [M + Na]+ 311.1259;
found 311.1258. C17H20O4 (288.34): calcd. C 70.81, H 6.99; found
C 70.56, H 7.06.
C15H16O4 (260.29): calcd. C 69.22, H 6.20; found C 69.19, H 6.35.
(2R,3R,6S)-6-(Acetoxymethyl)-3-hydroxy-2-mesityloxacyclohexane
(5a): A solution of ketone α-3a (2.0 g, 6.9 mmol) in MeOH
(4.0 mL) was added slowly to a solution of NaBH4 (525 mg,
14 mmol) in MeOH (6.0 mL) at 0 °C. The mixture was stirred for
1 h, then the reaction was quenched by the addition of water. The
mixture was evaporated to remove the methanol. The mixture was
then extracted with ethyl acetate, the organic extracts were dried
with Na2SO4, and the solvents were evaporated. The residue was
purified by silica gel column chromatography (hexane/ethyl acetate,
(2S,6S)-6-(Acetoxymethyl)-2-mesityloxacyclohex-4-en-3-one (β-3a):
Yellow syrup. [α]2D9 –60.2 (c 1.0, CHCl ). IR (KBr): ν = 3000–2800
˜
3
(br), 1739, 1688, 1611, 1448, 1379, 1217, 1159, 1092, 1045, 850,
758, 602 cm–1. 1H NMR (400.0 MHz, CDCl3): δ = 2.09 (s, 3 H, 4:1 then 3:2) to give alcohol 5a (1.1 g, 53%) as a colourless syrup,
Ac), 2.21 (s, 3 H, ArMe), 2.25 (s, 3 H, ArMe), 2.36 (s, 3 H, ArMe),
4.29 (dd, J = 11.4, 4.6 Hz, 1 H, 7-H), 4.39 (dd, J = 11.4, 5.0 Hz, 1
H, 7Ј-H), 4.7–4.8 (m, 1 H, 6-H), 5.42 (d, J = 2 Hz, 1 H, 2-H), 6.36
and 6a (504 mg, 29%). Data for 5a: [α]2D9 = –12.2 (c 1.0, CHCl3).
IR (KBr): ν = 3600–3400 (br), 3000–2800 (br), 1738, 1611, 1448,
˜
1371, 1231, 1110, 1021, 852, 801, 718, 603 cm–1 1H NMR
.
(dd, J = 10.6, 2.4 Hz, 1 H, 4-H), 6.86 (s, 2 H, 2 ArH), 7.04 (dd, J (400.0 MHz, CDCl3): δ = 1.4–1.5 (m, 1 H, 5-H), 1.9–2.1 (m, 5 H,
= 10.6, 1.6 Hz, 1 H, 5-H) ppm. 13C NMR (100.4 MHz, CDCl3): δ 4-H, 4Ј-H, Ac), 2.2–2.4 (m, 4 H, 5Ј-H, ArMe), 2.42 (s, 6 H, 2
= 20.3, 20.5, 20.8, 20.8, 64.9, 72.6, 79.5, 128.6, 128.8, 130.3, 130.4, ArMe), 3.8–3.9 (m, 1 H, 3-H), 4.12 (dd, J = 11.6, 5.2 Hz, 1 H, 7-
137.2, 137.5, 138.3, 147.0, 170.7, 195.8 ppm. HRMS (ESI+): calcd.
for C17H20NaO4 [M + Na]+ 311.1259; found 311.1258. C17H20O4
(288.34): calcd. C 70.81, H 6.99; found C 70.78, H 7.01.
H), 4.2–4.4 (m, 1 H, 6-H), 4.61 (dd, J = 11.6, 7.6 Hz, 1 H, 7Ј-H),
5.12 (d, J = 2.0 Hz, 1 H, 2-H), 6.84 (s, 2 H, 2 ArH) ppm. 13C NMR
(100.4 MHz, CDCl3): δ = 19.2, 20.5, 20.9, 21.5, 25.6, 62.4, 66.8,
70.2, 73.0, 130.4, 131.6, 136.7, 136.8, 171.1 ppm. MS (ESI): m/z =
315.3 [M + Na]+. C17H24O4 (292.37): calcd. C 69.84, H 8.27; found
C 69.68, H 8.10.
(2R,6S)-6-(Acetoxymethyl)-2-(p-xylyl)-4-oxacyclohexen-3-one (3b):
HF·pyridine (2.5 mL) was added slowly to a mixture of glucal 2
(1.0 g, 3.0 mmol) and p-xylene (10 mL, 81 mmol) in a polyethylene
bottle at 0 °C. The mixture was stirred for 11 h at room tempera-
ture, then the reaction was quenched by the addition of NaHCO3
(satd. aq.). The mixture was extracted with ethyl acetate. The com-
bined organic extracts were washed with brine and dried with
Na2SO4, and the solvents were evaporated. The residue was puri-
fied by silica gel column chromatography (hexane/ethyl acetate, 6:1
then 2:1) to give ketone 3b (706 mg, 85%) as white needles; m.p.
(2R,3R,6S)-6-(Acetoxymethyl)-3-hydroxy-2-(p-xylyl)oxacyclo-
hexane (5b): A solution of ketone 3b (2.0 g, 7.3 mmol) in MeOH
(60 mL) was added slowly to a solution of NaBH4 (552 mg,
15 mmol) in MeOH (60 mL) at 0 °C. The mixture was stirred for
20 min, then the reaction was quenched by the addition of water.
The mixture was evaporated (20 °C) to remove the methanol. The
mixture was extracted with ethyl acetate, the organic extracts were
dried with Na2SO4, and the solvents were evaporated. The residue
was dissolved in EtOH (3.0 mL), and this solution was added to a
mixture of Pd/C (10 %; 400 mg) and EtOH (3.0 mL) in a two-
necked flask under hydrogen. After TLC confirmed that the reac-
89–90 °C. [α]3D1 = –14.9 (c 1.0, CHCl ). IR (KBr): ν = 3000–2800
˜
3
(br), 1737, 1694, 1502, 1459, 1440, 1377, 1334, 1231, 1158, 1090,
1046, 956, 896, 847, 818, 789, 634 cm–1. 1H NMR (400.0 MHz,
CDCl3): δ = 2.09 (s, 3 H, Ac), 2.26 (s, 3 H, ArMe), 2.38 (s, 3 H,
ArMe), 4.18 (dd, J = 11.5, 3.6 Hz, 1 H, 7-H), 4.3–4.4 (m, 1 H, 6- tion was complete, the Pd/C was removed by filtration through
248 Eur. J. Org. Chem. 2014, 244–253
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Synthesis of 2-Aryl-6-methylpyrans from d-Glucose
Celite. The filtrate was evaporated, and the residue was purified by
silica gel column chromatography (hexane/ethyl acetate, 7:1 then
was dissolved in EtOH (2.3 mL), and the solution was added to a
mixture of Pd/C (10 %; 160 mg) and EtOH (1.2 mL) in a two-
necked flask under hydrogen. After TLC confirmed that the reac-
tion was complete, the Pd/C was removed by filtration through
Celite. The filtrate was evaporated, and te residue was purified by
silica gel column chromatography (hexane/ethyl acetate, 1:1, then
3:1) to give alcohol 5b (1.3 g, 62%) as a colourless syrup. [α]3D1
=
–15.5 (c 1.0, CHCl ). IR (KBr): ν = 3600–3400 (br), 3000–2800
˜
3
(br), 1736, 1447, 1370, 1231, 1110, 1038, 1023, 897, 806, 604 cm–1.
1H NMR (400.0 MHz, CDCl3): δ = 1.4–1.6 (m, 1 H, 5-H), 1.9–2.1
(m, 2 H, 4-H, 4Ј-H), 2.06 (s, 3 H, Ac), 2.2–2.4 (m, 7 H, 5Ј-H, 2 ethyl acetate only) to give alcohol 5c (526 mg, 41%) as a colourless
ArMe), 3.8–3.9 (m, 1 H, 3-H), 4.17 (dd, J = 11.4, 5.4 Hz, 1 H, 7- syrup. [α]2D8 = 19.8 (c 1.0, CHCl ). IR (KBr): ν = 3500–3300 (br),
˜
3
H), 4.3–4.4 (m, 1 H, 6-H), 4.63 (dd, J = 11.4, 8.2 Hz, 1 H, 7Ј-H),
4.9–5.0 (m, 1 H, 2-H), 7.01 (d, J = 7.8 Hz, 1 H, ArH), 7.06 (d, J = 932, 873, 814, 793, 773, 735, 574 cm–1
7.8 Hz, 1 H, ArH), 7.39 (s, 1 H, ArH) ppm. 13C NMR (100.4 MHz,
CDCl3): δ = 1.4–1.5 (m, 1 H, 5-H), 1.8–2.1 (m, 2 H, 4-H, 4Ј-H),
CDCl3): δ = 18.7, 19.1, 20.9, 21.1, 25.5, 62.3, 64.9, 70.8, 71.0, 127.3, 2.1–2.3 (m, 1 H, 5Ј-H), 2.35 (s, 3 H, ArMe), 3.4–3.6 (m, 1 H, 7-H),
3000–2800 (br), 1733, 1514, 1442, 1373, 1243, 1100, 1033, 1011,
.
1H NMR (400.0 MHz,
128.2, 130.6, 131.0, 135.7, 136.7, 171.1 ppm. HRMS (ESI-TOF):
calcd. for C16H22NaO4 [M + Na]+ 301.1416; found 301.1416.
C16H22O4 (278.35): calcd. C 69.04, H 7.97; found C 68.82, H 7.87.
3.9–4.0 (m, 1 H, 3-H), 4.0–4.3 (m, 2 H, 6-H, 6Ј-H), 4.7–4.8 (m, 1
H, 2-H), 7.20 (d, J = 8.0 Hz, 2 H, 2 ArH), 7.32 (d, J = 8.0 Hz, 2
H, 2 ArH) ppm. 13C NMR (100.4 MHz, CDCl3): δ = 19.2, 21.0,
25.9, 60.7, 67.9, 73.1, 73.2, 126.2, 129.3, 136.0, 137.4 ppm. HRMS
(ESI-TOF): calcd. for C13H18NaO3 [M + Na]+ 245.1154; found
245.1154.
(2R,3R,6S)-3-Hydroxy-6-(hydroxymethyl)-2-mesityloxacyclohexane
(6a): Sodium methoxide (19 mg, 0.34 mmol) was added to a solu-
tion of alcohol 5a (500 mg, 1.7 mmol) in MeOH (10 mL). The mix-
ture was stirred for 40 min, then cation exchange resin (DOWEXTM
50WX2 50–100 mesh) was added. The mixture was stirred for
15 min, then it was filtered, and the filtrate was evaporated to give
diol 6a (428 mg, Ͼ99%) as a colourless syrup. [α]2D9 = –20.6 (c 1.0,
(2R,3R,6S)-3-O-(S-Methylxanthate)-6-O-(S-methylxanthatemeth-
yl)-2-mesityloxacyclohexane (7a): A solution of diol 6a (500 mg,
2.0 mmol) in THF (7.0 mL) was added slowly to a solution of NaH
(50% in oil; 384 mg, 8.0 mmol) in THF (5.0 mL) at 0 °C, and the
mixture was stirred for 30 min at room temperature. After that, CS2
(480 μL, 8.0 mmol) was added at 0 °C, and the reaction mixture
was stirred for 30 min at room temperature. Finally, MeI (500 μL,
8.0 mmol) was added to the reaction mixture at 0 °C. The mixture
was stirred for 30 min at room temperature, then the reaction was
quenched by the addition of HCl (1 n aq.). The mixture was ex-
tracted with dichloromethane. The combined organic extracts were
washed with brine and dried with Na2SO4, and the solvents were
evaporated. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate, 20:1 then 10:1) to give
xanthic acid ester 7a (791 mg, 92%) as a yellow syrup. [α]2D6 = –12.4
CHCl ). IR (KBr): ν = 3600–3200 (br), 3000–2800 (br), 1737, 1611,
˜
3
1448, 1374, 1215, 1100, 1011, 800, 716, 575 cm–1 1H NMR
.
(400.0 MHz, CDCl3): δ = 1.3–1.5 (m, 1 H, 5-H), 1.8–2.0 (m, 2 H,
4-H, 4Ј-H), 2.1–2.4 (m, 4 H, ArMe, 5Ј-H), 2.43 (s, 6 H, 2 ArMe),
3.4–3.5 (m, 1 H, 7-H), 3.8–3.9 (m, 1 H, 3-H), 4.10 (dd, J = 11.0,
11.0 Hz, 1 H, 7Ј-H), 4.1–4.3 (m, 1 H, 6-H), 5.06 (d, J = 1.6 Hz, 1
H, 2-H), 6.86 (s, 2 H, 2 ArH) ppm. 13C NMR (100.4 MHz, CDCl3):
δ = 18.8, 20.5, 21.4, 25.8, 60.2, 67.0, 72.1, 72.8, 130.4, 131.5, 136.7,
136.8 ppm. HRMS (ESI-TOF): calcd. for C15H22NaO3 [M + Na]+
273.1467; found 273.1468. C15H22O3 (250.34): calcd. C 71.97, H
8.86; found C 71.86, H 8.65.
(c 1.0, CHCl ). IR (KBr): ν = 3000–2800 (br), 1611, 1447, 1423,
˜
3
1377, 1198, 1118, 1047, 994, 964, 851 cm–1. 1H NMR (400.0 MHz,
CDCl3): δ = 1.6–1.7 (m, 1 H, 5-H), 2.1–2.3 (m, 5 H, 4-H, 4Ј-H,
ArMe), 2.4–2.5 (m, 10 H, 5Ј-H, 2 ArMe, SMe), 2.55 (s, 3 H, SMe),
4.5–4.6 (m, 1 H, 6-H), 4.76 (dd, J = 11.4, 5.4 Hz, 1 H, 7-H), 5.08
(dd, J = 11.4, 6.6 Hz, 1 H, 7Ј-H), 5.32 (d, J = 2.4 Hz, 1 H, 2-H),
5.8–5.9 (m, 1 H, 3-H), 6.76 (s, 2 H, 2 ArH) ppm. 13C NMR
(100.4 MHz, CDCl3): δ = 19.1, 19.1, 20.1, 20.3, 20.6, 21.4, 23.7,
69.9, 72.5, 72.7, 78.1, 130.1, 130.6, 136.7, 215.8, 216.3 ppm. HRMS
(ESI-TOF): calcd. for C19H26NaO3S4 [M + Na]+ 453.0663; found
453.0663.
(2R,3R,6S)-3-Hydroxy-6-(hydroxymethyl)-2-(p-xylyl)oxacyclo-
hexane (6b): Sodium methoxide (0.048 g, 0.90 mmol) was added to
a solution of alcohol 5b (1.3 g, 4.5 mmol) in MeOH (9.0 mL). The
mixture was stirred for 1 h, then cation exchange resin (DOWEXTM
50WX2 50–100 mesh) was added. The reaction mixture was stirred
for 15 min, then it was filtered, and the solvents were evaporated.
The residue was purified by silica gel column chromatography (hex-
ane/ethyl acetate, 2:1, then ethyl acetate only) to give diol 6b
(875 mg, 82%) as a white solid; m.p. 125–126 °C. [α]3D1 = –18.8 (c
1.0, CHCl ). IR (KBr): ν = 3500–3300 (br), 3000–2800 (br), 1453,
˜
3
1349, 1111, 1087, 1071, 1065, 1036, 1011, 993, 920, 847, 831, 804,
742, 575 cm–1. 1H NMR (400.0 MHz, CDCl3): δ = 1.3–1.5 (m, 1
H, 5-H), 1.8–2.1 (m, 2 H, 4-H, 4Ј-H), 2.2–2.4 (m, 7 H, 5Ј-H, 2
ArMe), 3.4–3.6 (m, 1 H, 7-H), 3.8–3.9 (m, 1 H, 3-H), 4.14 (dd, J
= 10.6, 10.6 Hz, 1 H, 7Ј-H), 4.2–4.3 (m, 1 H, 6-H), 4.9–5.0 (m, 1
H, 2-H), 7.03 (d, J = 7.6 Hz, 1 H, ArH), 7.06 (d, J = 7.6 Hz, 1 H,
ArH), 7.43 (s, 1 H, ArH) ppm. 13C NMR (100.4 MHz, CDCl3): δ
= 18.6, 18.7, 21.0, 25.8, 60.4, 65.1, 70.2, 73.4, 127.3, 128.2, 130.5,
130.9, 135.6, 136.7 ppm. HRMS (ESI-TOF): calcd. for
C14H20NaO3 [M + Na]+ 259.1310; found 259.1314. C14H20O3
(236.31): calcd. C 71.16, H 8.53; found C 70.88, H 8.51.
(2R,3R,6S)-3-O-(S-Methylxanthate)-6-O-(S-methylxanthatemeth-
yl)-2-(p-xylyl)oxacyclohexane (7b): A solution of diol 6b (500 mg,
2.1 mmol) in THF (45 mL) was added slowly to a solution of NaH
(50% in oil; 406 mg, 8.5 mmol) in THF (5.0 mL) at 0 °C, and the
mixture was stirred for 30 min at room temperature. After that, CS2
(510 μL, 8.5 mmol) was added at 0 °C, and the reaction mixture
was stirred for 30 min at room temperature. Finally, MeI (530 μL,
8.5 mmol) was added to the reaction mixture at 0 °C. The mixture
was stirred for 30 min at room temperature, then the reaction was
quenched by the addition of HCl (1 n aq.). The mixture was ex-
tracted with dichloromethane. The combined organic extracts were
(2R,3R,6S)-3-Hydroxy-6-(hydroxymethyl)-2-(p-tolyl)oxacyclo- washed with brine and dried with Na2SO4, and the solvents were
hexane (6c): A solution of ketone 3c (1.5 g, 5.8 mmol) in MeOH
(7.0 mL) was added slowly to a solution of NaBH4 (884 mg,
23 mmol) in MeOH (8.0 mL) at 0 °C. The mixture was stirred for
30 min, then the reaction was quenched by the addition of water.
The mixture was evaporated (20 °C) to remove the methanol. The
mixture was extracted with ethyl acetate, the organic extracts were
dried with Na2SO4, and the solvents were evaporated. The residue
evaporated. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate, 10:1) to give xanthate 7b
(873 mg, 99%) as a yellow solid; m.p. 93–95 °C. [α]3D1 = +2.2 (c 1.0,
CHCl ). IR (KBr): ν = 3000–2800 (br), 1709, 1501, 1441, 1386,
˜
3
1239, 1203, 1120, 1062, 1042, 1003, 964, 914, 886, 818, 793,
1
732 cm–1. H NMR (400.0 MHz, CDCl3): δ = 1.6–1.8 (m, 1 H, 5-
H), 2.1–2.4 (m, 9 H, 4-H, 4Ј-H, 5Ј-H, 2 ArMe), 2.45 (s, 3 H, SMe),
Eur. J. Org. Chem. 2014, 244–253
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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249

K. Michigami, A. Shimazaki, M. Hayashi
FULL PAPER
2.56 (s, 3 H, SMe), 4.5–4.6 (m, 1 H, 6-H), 4.80 (dd, J = 11.5,
5.0 Hz, 1 H, 7-H), 5.08 (dd, J = 11.5, 6.8 Hz, 1 H, 7Ј-H), 5.17 (d,
J = 1.6 Hz, 1 H, 2-H), 5.9–6.0 (m, 1 H, 3-H), 6.9–7.0 (m, 2 H, 2
1
891, 869, 806, 570 cm–1. H NMR (400.0 MHz, CDCl3): δ = 1.35
(d, J = 6.8 Hz, 3 H, Me), 1.4–1.6 (m, 1 H, 4-H), 1.6–1.8 (m, 1 H,
3-H), 1.8–2.0 (m, 4 H, 3Ј-H, 4Ј-H, 5-H, 5Ј-H), 2.31 (s, 6 H, 2
ArH), 7.36 (s, 1 H, ArH) ppm. 13C NMR (100.4 MHz, CDCl3): δ ArMe), 4.2–4.3 (m, 1 H, 6-H), 4.87 (dd, J = 10.2, 2.2 Hz, 1 H, 2-
= 18.4, 18.8, 19.1, 20.7, 21.0, 23.6, 31.7, 70.2, 70.7, 72.5, 128.2, H), 6.96 (d, J = 7.6 Hz, 1 H, ArH), 7.01 (d, J = 7.6 Hz, 1 H, ArH),
128.3, 130.1, 131.3, 134.9, 135.5, 215.0, 216.3 ppm. MS (ESI): m/z
7.27 (s, 1 H, ArH) ppm. 13C NMR (100.4 MHz, CDCl3): δ = 17.2,
= 439.3 [M + Na]+. C18H24O3S4 (416.63): calcd. C 51.89, H 5.81; 18.7, 18.9, 21.0, 29.8, 31.6, 68.2, 69.1, 126.6, 127.7, 130.3, 132.0,
found C 52.05, H 5.90.
135.5, 140.9 ppm. HRMS (ESI-TOF): calcd. for C14H20NaO [M +
Na]+ 227.1412; found 227.1412.
(2R,3R,6S)-3-O-(S-Methylxanthate)-6-O-(S-methylxanthatemeth-
yl)-2-(p-tolyl)oxacyclohexane (7c): A solution of diol 6c (200 mg,
0.90 mmol) in THF (3.0 mL) was added slowly to a solution of
NaH (50% in oil; 173 mg, 3.6 mmol) in THF (2.0 mL) at 0 °C, and
the mixture was stirred for 30 min at room temperature. After that,
CS2 (220 μL, 3.6 mmol) was added at 0 °C, and the reaction mix-
ture was stirred for 30 min at room temperature. Finally, MeI
(220 μL, 3.6 mmol) was added to the reaction mixture at 0 °C. The
mixture was stirred for 30 min at room temperature, then the reac-
tion was quenched by the addition of HCl (1 n aq.). The mixture
was extracted with dichloromethane. The combined organic ex-
tracts were washed with brine and dried with Na2SO4, and the
solvents were evaporated. The residue was purified by silica gel
column chromatography (hexane/ethyl acetate, 70:1) to give xanthic
acid ester 7c (300 mg, 83%) as a yellow syrup. [α]2D5 = +20.0 (c 1.0,
(2S,6R)-2-(p-Tolyl)-6-methyloxacyclohexane (8c): A solution of
xanthic acid ester 7c (150 mg, 0.37 mmol) in toluene (7.0 mL) was
heated to 100 °C with stirring. A solution of tributyltin hydride
(300 μL, 1.1 mmol) and AIBN (6.1 mg, 0.037 mmol) in toluene
(2.3 mL) was added dropwise over 15 min. After TLC showed that
the reaction was complete, the reaction mixture was evaporated.
The residue was purified by silica gel column chromatography (hex-
ane/ethyl acetate, 150:1) to give 8c (48 mg, 68%) as a colourless oil.
[α]2D4 = –13.8 (c 1.0, CHCl ). IR (KBr): ν = 3000–2800 (br), 1514,
˜
3
1446, 1378, 1260, 1211, 1182, 1132, 1075, 1041, 1007, 971, 854,
805, 754 cm–1. 1H NMR (400.0 MHz, CDCl3): δ = 1.25 (d, J =
6.8 Hz, 3 H, Me), 1.3–1.5 (m, 1 H, 5-H), 1.6–1.8 (m, 3 H, 4-H, 4Ј-
H, 5Ј-H), 1.8–2.0 (m, 2 H, 3-H, 3Ј-H), 2.34 (s, 3 H, ArMe), 3.9–
4.0 (m, 1 H, 6-H), 4.85 (dd, J = 5.6, 5.6 Hz, 1 H, 1-H), 7.16 (d, J
= 8.2 Hz, 2 H, 2 ArH), 7.28 (d, J = 8.2 Hz, 2 H, 2 ArH) ppm. 13C
NMR (100.4 MHz, CDCl3): δ = 18.7, 19.4, 21.0, 30.0, 31.4, 67.7,
72.2, 126.4, 129.1, 136.5, 139.3 ppm. HRMS (ESI-TOF): calcd. for
C13H18NaO [M + Na]+ 213.1255; found 213.1254.
CHCl ). IR (KBr): ν = 3000–2800 (br), 1733, 1515, 1421, 1317,
˜
3
1198, 1117, 1044, 965, 925, 817, 776, 722, 610, 578 cm–1. 1H NMR
(400.0 MHz, CDCl3): δ = 1.6–1.7 (m, 1 H, 5-H), 2.1–2.2 (m, 2 H,
4-H, 5Ј-H), 2.3–2.4 (m, 4 H, 4Ј-H, ArMe), 2.46 (s, 3 H, SMe), 2.57
(s, 3 H, SMe), 4.4–4.5 (m, 1 H, 6-H), 4.75 (dd, J = 11.3, 5.0 Hz, 1
H, 7-H), 4.96 (dd, J = 11.3, 7.2 Hz, 1 H, 7Ј-H), 5.06 (d, J = 2.4 Hz,
1 H, 2-H), 5.9–6.0 (m, 1 H, 3-H), 7.14 (d, J = 7.8 Hz, 2 H, 2 ArH),
7.31 (d, J = 7.8 Hz, 2 H, 2 ArH) ppm. 13C NMR (100.4 MHz,
CDCl3): δ = 18.7, 19.0, 21.0, 21.6, 23.2, 69.5, 72.4, 73.3, 78.6, 126.7,
128.9, 134.8, 137.3, 215.1, 216.1 ppm. HRMS (ESI-TOF): calcd.
for C17H22NaO3S4 [M + Na]+ 425.0350; found 425.0349.
Synthesis of cis-2-Aryl-6-methylpyrans by C-Aryl Glycosidation and
Inversion of Configuration at C-2
(2R,6S)-6-(Hydroxymethyl)-2-mesityloxacyclohexane (9a) and
(S,E)-5-Acetoxy-6-iodo-1-mesityl-1-hexene (14a): Trimethylsilyl
chloride (253 μL, 4.0 mmol) was added to a mixture of diol 6a
(125 mg, 0.5 mmol), sodium iodide (300 mg, 2.0 mmol), and
MeCN (1.0 mL). The mixture was stirred for 24 h, then the reac-
tion was quenched by the addition of Na2S2O3 (satd. aq.). The
mixture was extracted with ethyl acetate. The combined organic
extracts were washed with NaHCO3 (satd. aq.) and brine, and dried
with Na2SO4, and the solvents were evaporated. The residue was
purified by silica gel column chromatography (hexane/ethyl acetate,
30:1 then 3:1) to give 9a (65 mg, 56%) as a colourless oil, and 14a
(25 mg, 13%) as a yellow oil.
(2S,6R)-2-Mesityl-6-methyloxacyclohexane (8a): A solution of
xanthic acid ester 7a (100 mg, 0.23 mmol) in toluene (4.5 mL) was
heated to 100 °C with stirring. A solution of tributyltin hydride
(190 μL, 0.70 mmol) and AIBN (3.8 mg, 0.023 mmol) in toluene
(1.5 mL) was added dropwise over 15 min. After TLC showed that
the reaction was complete, the reaction mixture was evaporated.
The residue was purified by silica gel column chromatography (hex-
ane/ethyl acetate, 300:1) to give 8a (31.8 mg, 63%) as a colourless
oil. [α]2D9 = –20.7 (c 1.0, CHCl ). IR (KBr): ν = 3000–2800 (br),
Data for 9a: [α]2D5 = +77.7 (c 1.0, CHCl ). IR (KBr): ν = 3600–
˜
˜
3
3
1612, 1451, 1374, 1198, 1131, 1116, 1049, 1025, 1003, 884, 848,
733, 571 cm–1. 1H NMR (400.0 MHz, CDCl3): δ = 1.40 (d, J =
6.8 Hz, 3 H, Me), 1.4–1.6 (m, 2 H, 4-H, 4Ј-H), 1.7–1.9 (m, 1 H, 5-
H), 1.9–2.0 (m, 3 H, 3-H, 3Ј-H, 5Ј-H), 2.25 (s, 3 H, ArMe), 2.45
(s, 6 H, 2 ArMe), 4.3–4.5 (m, 1 H, 6-H), 5.11 (dd, J = 11.4, 2.6 Hz,
1 H, 2-H), 6.83 (s, 2 H, 2 ArH) ppm. 13C NMR (100.4 MHz,
CDCl3): δ = 16.2, 18.6, 20.6, 20.7, 29.1, 29.4, 68.2, 69.0, 130.0,
135.7, 136.1, 136.2 ppm. HRMS (ESI-TOF): calcd. for C15H23O
[M + H]+ 219.1749; found 219.1743.
3100 (br), 3000–2800 (br), 1453, 1375, 1078, 1215, 982, 940, 886,
848, 734, 573 cm–1. 1H NMR (400.0 MHz, CDCl3): δ = 1.3–2.1 (m,
6 H, 3-H, 3Ј-H, 4-H, 4Ј-H, 5-H, 5Ј-H), 2.25 (s, 3 H, ArMe), 2.41
(s, 6 H, 2 ArMe), 3.5–3.7 (m, 3 H, 6-H, 7-H, 7Ј-H), 4.80 (dd, J =
11.6, 2.4 Hz, 1 H, 2-H), 6.84 (s, 2 H, 2 ArH) ppm. 13C NMR
(100.4 MHz, CDCl3): δ = 20.6, 20.9, 23.6, 26.8, 29.1, 66.4, 130.0,
135.4, 135.8, 136.5 ppm. HRMS (ESI-TOF): calcd. for
C15H22O2Na [M + Na]+ 257.1518; found 257.1518. C15H22O2
(234.34): calcd. C 76.57, H 9.46; found C 76.88, H 9.30.
(2S,6R)-2-(p-Xylyl)-6-methyloxacyclohexane (8b): A solution of Data for 14a: [α]3D2 –8.0 (c 0.1, CHCl ). IR (KBr): ν = 3100–2800
˜
3
xanthic acid ester 7b (200 mg, 0.48 mmol) in toluene (9.0 mL) was
heated to 100 °C with stirring. A solution of tributyltin hydride
(390 μL, 1.4 mmol) and AIBN (7.9 mg, 0.048 mmol) in toluene
(br), 1453, 1375, 1739, 1611, 1480, 1441, 1371, 1229, 1185, 1020,
1
973, 852, 714, 600 cm–1. H NMR (400.0 MHz, CDCl3): δ = 1.8–
1.9 (m, 2 H, 5-H, 5Ј-H), 2.19 (s, 3 H, Ac), 2.2–2.3 (m, 11 H, 4-H,
(3.0 mL) was added dropwise over 15 min. After TLC showed that 4Ј-H, 3 ArMe), 3.31 (dd, J = 10.6, 5.2 Hz, 1 H, 7-H), 3.40 (dd, J
the reaction was complete, the reaction mixture was evaporated.
The residue was purified by silica gel column chromatography (hex-
ane/ethyl acetate, 150:1 then 50:1) to give 8b (67.4 mg, 69%) as a
= 10.6, 4.8 Hz, 1 H, 7Ј-H), 4.79 (ddd, J = 12.7, 5.5, 5.5 Hz, 1 H,
6-H), 5.61 (ddd, J = 16.0, 6.8, 6.8 Hz, 1 H, 3-H), 6.33 (d, J =
16.0 Hz, 1 H, 2-H), 6.85 (s, 2 H, 2 ArH) ppm. 13C NMR
(100.4 MHz, CDCl3): δ = 8.1, 20.9, 29.0, 34.0, 71.8, 128.6, 133.5,
134.2, 135.9, 136.0, 170.5 ppm. HRMS (ESI-TOF): calcd. for
yellow oil. [α]3D2 = –32.4 (c 1.0, CHCl ). IR (KBr): ν = 3000–2800
˜
3
(br), 1501, 1453, 1376, 1262, 1201, 1183, 1131, 1044, 1029, 1007,
250
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 244–253

Synthesis of 2-Aryl-6-methylpyrans from d-Glucose
C17H23IO2Na [M + Na]+ 409.0640; found 409.0640. C17H23IO2
(386.27): calcd. C 52.86, H 6.00; found C 53.13, H 6.29.
5-H, 5Ј-H), 2.23 (s, 3 H, ArMe), 2.29 (s, 6 H, 2 ArMe), 2.41 (s, 3
H, ArMe), 3.6–3.7 (m, 1 H, 6-H), 4.01 (dd, J = 10.3, 4.4 Hz, 1 H,
7-H), 4.07 (dd, J = 10.3, 5.8 Hz, 1 H, 7Ј-H), 4.66 (dd, J = 11.6,
2.4 Hz, 1 H, 2-H), 6.78 (s, 2 H, ArH ϫ 2), 7.22 (d, J = 8.0 Hz, 2
H, 2 ArH), 7.74 (d, J = 8.0 Hz, 2 H, 2 ArH) ppm. 13C NMR
(100.4 MHz, CDCl3): δ = 20.7, 20.8, 21.5, 23.5, 27.0, 28.8, 72.6,
75.4, 128.0, 129.0, 130.0, 133.1, 135.0, 135.7, 136.4, 144.6 ppm.
HRMS (ESI-TOF): calcd. for C22H28O4SNa [M + Na]+ 411.1606;
found 411.1607. C22H28O4S (388.52): calcd. C 68.01, H 7.26; found
C 67.90, H 7.46.
(2R,6S)-6-(Hydroxymethyl)-2-(p-xylyl)oxacyclohexane (9b): Tri-
methylsilyl chloride (253 μL, 4.0 mmol) was added to a mixture of
diol 6b (118 mg, 0.5 mmol), sodium iodide (300 mg, 2.0 mmol), and
MeCN (1.0 mL). The mixture was stirred for 24 h, then the reac-
tion was quenched by addition of Na2S2O3 (satd. aq.). The mixture
was extracted with ethyl acetate. The combined organic extracts
were washed with NaHCO3 (satd. aq.) and brine, and dried with
Na2SO4, and the solvents were evaporated. The residue was puri-
fied by silica gel column chromatography (hexane/ethyl acetate, 3:1)
(2R,6R)-6-Methyl-2-mesityloxacyclohexane (11a): LiAlH4 (68 mg,
1.8 mmol) was added to a solution of 10a (140 mg, 0.36 mmol) in
to give 9b (56 mg, 51%) as a white solid; m.p. 54–55 °C. [α]2D5
=
+62.7 (c 1.1, CHCl ). IR (KBr): ν = 3500–3100 (br), 3000–2800 THF (2.0 mL) at 0 °C. The mixture was stirred for 24 h at room
˜
3
(br), 1501, 1459, 1353, 1334, 1198, 1093, 1047, 1039, 933, 897, 882, temperature, then the reaction was quenched by the addition of
1
850, 827, 804, 718 cm–1. H NMR (400.0 MHz, CDCl3): δ = 1.3– H2O and HCl (1 n aq.) at 0 °C. The mixture was extracted with
2.1 (m, 6 H, 3-H, 3Ј-H, 4-H, 4Ј-H, 5-H, 5Ј-H), 2.1–2.2 (m, 1 H,
OH), 2.29 (s, 3 H, ArMe), 2.33 (s, 3 H, ArMe), 3.6–3.7 (m, 3 H,
ethyl acetate. The combined organic extracts were washed with
NaHCO3 (satd. aq.) and brine, and dried with Na2SO4, and the
6-H, 7-H, 7Ј-H), 4.55 (dd, J = 11.2, 2.0 Hz, 1 H, 2-H), 6.99 (d, J solvents were evaporated. The residue was purified by silica gel
= 7.6 Hz, 1 H, ArH), 7.03 (d, J = 7.6 Hz, 1 H, ArH), 7.25 (s, 1 H,
ArH) ppm. 13C NMR (100.4 MHz, CDCl3): δ = 18.6, 21.1, 23.6,
23.7, 26.9, 32.0, 66.4, 78.9, 126.3, 128.0, 130.3, 131.5, 135.6,
140.7 ppm. HRMS (ESI-TOF): calcd. for C14H20O2Na [M + Na]+
243.1361; found 243.1361. C14H20O2 (220.31): calcd. C 76.33, H
9.15; found C 76.08, H 9.16.
column chromatography (hexane/ethyl acetate, 9:1) to give 11a
(75 mg, 95%) as a colourless oil. [α]3D0 = +58.2 (c 1.0, CHCl3). IR
(KBr): ν = 3100–2800 (br), 1453, 1377, 1364, 1201, 1079, 1042,
˜
1
991, 886, 848, 733, 572 cm–1. H NMR (400.0 MHz, CDCl3): δ =
1.23 (d, J = 6.4 Hz, 3 H, Me), 1.3–2.0 (m, 6 H, 3-H, 3Ј-H, 4-H, 4Ј-
H, 5-H, 5Ј-H), 2.22 (s, 3 H, ArMe), 2.40 (s, 6 H, 2 ArMe), 3.5–3.6
(m, 1 H, 6-H), 4.75 (dd, J = 11.6, 2.4 Hz, 1 H, 2-H), 6.80 (s, 2 H,
2 ArH) ppm. 13C NMR (100.4 MHz, CDCl3): δ = 20.7, 20.8, 22.2,
24.3, 28.9, 33.1, 74.4, 130.0, 135.8, 135.8, 136.2 ppm. HRMS (ESI-
TOF): calcd. for C15H22ONa [M + Na]+ 241.1568; found 241.1568.
(2R,6S)-6-(Hydroxymethyl)-2-(p-tolyl)oxacyclohexane (9c): Tri-
methylsilyl chloride (253 μL, 4.0 mmol) was added to a mixture of
the diol 6c (111 mg, 0.5 mmol), sodium iodide (300 mg, 2.0 mmol),
and MeCN (1.0 mL). The mixture was stirred for 24 h, then the
reaction was quenched by addition of Na2S2O3 (satd. aq.). The
mixture was extracted with ethyl acetate. The combined organic
extracts were washed with NaHCO3 (satd. aq.) and brine, and dried
with Na2SO4, and the solvents were evaporated. The residue was
purified by silica gel column chromatography (hexane/ethyl acetate,
3:1) to give 9c (30 mg, 29%) as a colourless oil. [α]2D5 = +59.6 (c
Synthesis of (2R,6R)-6-Methyl-2-mesityloxacyclohexane (11a) via
Glucal β-3a (Route B)
(2S,3S,6S)-6-(Acetoxymethyl)-3-hydroxy-2-mesityloxacyclohexane
(β-3aa), (2S,3R,6S)-6-(Acetoxymethyl)-3-hydroxy-2-mesityloxacy-
clohexane (β-3ab), (2S,3S,6S)-6-Hydroxymethyl-3-hydroxy-2-mes-
ityloxacyclohexane (12aa), and (2S,3R,6S)-6-Hydroxymethyl-3-
hydroxy-2-mesityloxacyclohexane (12ab): NaBH4 (138 mg,
3.6 mmol) was added slowly to a solution of alcohol β-3a (350 mg,
1.2 mmol) in EtOH (5.0 mL) at 0 °C. The mixture was stirred for
1 h to give alcohols β-3aa and β-3ab. After that, NaOMe (50 mg,
0.93 mmol) was added to the reaction mixture. The mixture was
stirred for 12 h, then the reaction was quenched by the addition of
HCl (1 n aq.) at 0 °C. The mixture was evaporated to remove the
MeOH. The residue was extracted with ethyl acetate. The combined
organic extracts were washed with HCl (1 n aq.) and brine, and
dried with Na2SO4, and the solvents were evaporated. The residue
was purified by silica gel column chromatography (hexane/ethyl
acetate, 5:1 then 3:1) to give diols 12aa and 12ab (200 mg, 67%,
52:48 ratio).
1.0, CHCl ). IR (KBr): ν = 3600–3100 (br), 3000–2800 (br), 1516,
˜
3
1439, 1363, 1307, 1277, 1207, 1192, 1077, 1038, 984, 947, 921, 890,
806, 767, 755 cm–1. 1H NMR (400.0 MHz, CDCl3): δ = 1.3–1.4 (m,
1 H, 5-H), 1.5–1.6 (m, 2 H, 3-H, 5Ј-H), 1.6–1.8 (m, 2 H, 3Ј-H, 4-
H), 1.9–2.0 (m, 1 H, 4Ј-H), 2.29 (br. s, 1 H, OH), 2.34 (s, 3 H,
ArMe), 3.5–3.7 (m, 3 H, 6-H, 7-H, 7Ј-H), 4.36 (dd, J = 11.2,
2.0 Hz, 1 H, 2-H), 7.15 (d, J = 8.2 Hz, 2 H, 2 ArH), 7.24 (d, J =
8.2 Hz, 2 H, 2 ArH) ppm. 13C NMR (100.4 MHz, CDCl3): δ =
21.00, 23.3, 26.7, 33.4, 66.2, 78.5, 79.6, 125.9, 128.9, 137.1,
140.0 ppm. HRMS (ESI-TOF): calcd. for C13H18O2Na [M + Na]+
229.1205; found 229.1203. C13H18O2 (206.28): calcd. C 75.69, H
8.80; found C 75.98, H 8.77.
Confirmation of the Structure of 9a
Synthesis of (2R,6R)-6-Methyl-2-mesityloxacyclohexane (11a) Data for β-3aa: Colourless syrup. [α]2D7 = +42.0 (c 2.6, CHCl3). IR
(Route A)
(KBr): ν = 3600–3300 (br), 3100–2800 (br), 1736, 1611, 1446, 1373,
˜
1
1232, 1094, 1048, 945, 899, 803, 756, 720, 648, 605, 575 cm–1. H
(2R,6S)-6-(tosyloxymethyl)-2-mesityloxacyclohexane (10a): p-Tolu-
enesulfonyl chloride (144 mg, 0.76 mmol) was added to a solution
of alcohol 9a (118 mg, 0.50 mmol) in pyridine (1.0 mL). The mix-
ture was stirred for 2 h, then the reaction was quenched by the
addition of HCl (1 n aq.). The mixture was extracted with dichloro-
methane. The combined organic extracts were washed with
NaHCO3 (satd. aq.) and brine, and dried with Na2SO4, and the
solvents were evaporated. The residue was purified by silica gel
column chromatography (hexane/ethyl acetate, 20:1 then 9:1) to
NMR (400.0 MHz, CDCl3): δ = 1.4–1.5 (m, 1 H, 5-H), 1.8–1.9 (m,
2 H, 4-H, 5Ј-H), 2.07 (s, 3 H, CH3CO2), 2.1–2.2 (m, 1 H, 4Ј-H),
2.25 (s, 3 H, ArMe), 2.41 (s, 6 H, 2 ArMe), 3.7–3.8 (m, 1 H, 6-H),
3.83 (s, 1 H, 3-H), 4.17 (d, J = 4.8 Hz, 2 H, 7-H, 7Ј-H), 4.87 (s, 1
H, 2-H), 6.84 (s, 2 H, 2 ArH) ppm. 13C NMR (100.4 MHz, CDCl3):
δ = 20.6, 20.8, 21.5, 29.7, 66.5, 67.0, 75.8, 80.3, 130.5, 131.7, 136.4,
136.8, 171.1 ppm. HRMS (ESI-TOF): calcd. for C17H24O4Na [M
+ Na]+ 315.1572; found 315.1572.
give 15a (140 mg, 72%) as a white solid; m.p. 86–87 °C. [α]2D5
+45.9 (c 1.1, CHCl ). IR (KBr): ν = 3000–2800 (br), 1353, 1189,
=
Data for β-3ab: Colourless syrup. [α]2D5 = +42.0 (c 0.5, CHCl3). IR
(KBr): ν = 3600–3200 (br), 3100–2800 (br), 1732, 1611, 1436, 1387,
˜
˜
3
1177, 1040, 980, 942, 850, 811, 791, 664 cm–1
.
1 H NMR 1361, 1237, 1118, 1083, 1043, 961, 856, 848, 628, 603, 571 cm–1. 1H
NMR (400.0 MHz, CDCl3): δ = 1.5–1.7 (m, 2 H, 4-H, 5-H), 1.7–
(400.0 MHz, CDCl3): δ = 1.2–2.0 (m, 6 H, 3-H, 3Ј-H, 4-H, 4Ј-H,
Eur. J. Org. Chem. 2014, 244–253
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
251

K. Michigami, A. Shimazaki, M. Hayashi
FULL PAPER
1.9 (m, 1 H, 5Ј-H), 2.04 (s, 3 H, CH3CO2), 2.1–2.2 (m, 4 H, 4Ј-H,
ArMe), 2.36 (s, 3 H, ArMe), 2.46 (s, 3 H, ArMe), 3.6–3.7 (m, 1 H,
6-H), 3.8–4.0 (m, 1 H, 3-H), 4.08 (dd, J = 11.6, 4.4 Hz, 1 H, 7-H),
H, 5-H, 5Ј-H), 2.20 (s, 3 H, ArMe), 2.3–2.5 (m, 13 H, 2 ArMe, 2
CS2Me, 4Ј-H), 3.9–4.0 (m, 1 H, 6-H), 4.63 (dd, J = 11.3, 4.2 Hz, 1
H, 7-H), 4.69 (dd, J = 11.3, 4.8 Hz, 1 H, 7Ј-H), 4.63 (d, J = 9.6 Hz,
4.12 (dd, J = 11.6, 6.4 Hz, 1 H, 7Ј-H), 4.53 (d, J = 9.2 Hz, 1 H, 2- 1 H, 2-H), 6.0–6.1 (m, 1 H, 3-H), 6.76 (s, 2 H, 2 ArH) ppm. 13C
H), 6.81 (s, 2 H, 2 ArH) ppm. 13C NMR (100.4 MHz, CDCl3): δ
NMR (100.4 MHz, CDCl3): δ = 18.79, 18.84, 20.6, 26.8, 28.6, 74.8,
= 20.8, 20.9, 21.6, 27.5, 31.6, 66.7, 68.3, 75.4, 81.3, 129.1, 130.6, 75.1, 130.3, 137.3, 214.8, 215.9 ppm. HRMS (ESI-TOF): calcd. for
131.5, 137.5, 171.2 ppm. HRMS (ESI-TOF): calcd. for
C19H26O3S4Na [M + Na]+ 453.0663; found 453.0662. C19H26O3S4
(430.65): calcd. C 52.99, H 6.09; found C 52.83, H 6.18.
C17H24O4Na [M + Na]+ 315.1572; found 315.1572.
Data for 12aa: Colourless syrup. [α]2D7 = +58.5 (c 1.0, CHCl3). IR
Synthesis of (2R,6R)-6-Methyl-2-mesityloxacyclohexane (11a) from
13aa and 13ab: A mixture of tri-n-butyltin hydride (185 μL,
0.70 mmol) and AIBN (3.8 mg, 0.02 mmol) in toluene (1.5 mL) was
added dropwise to a solution of xanthates 13aa and 13ab (100 mg,
0.23 mmol; 52:48 ratio) in toluene (4.5 mL) at 100 °C. The mixture
was stirred for 1 h at 100 °C, then the reaction mixture was evapo-
rated. The residue was purified by silica gel column chromatog-
raphy (hexane/ethyl acetate, 300:1) to give 11a (19 mg, 37%).
(KBr): ν = 3600–3300 (br), 3100–2800 (br), 1736, 1611, 1446, 1373,
˜
1232, 1212, 1094, 1047, 945, 899, 852, 803, 756, 720, 647, 605,
1
574 cm–1. H NMR (400.0 MHz, CDCl3): δ = 1.4–1.5 (m, 1 H, 5-
H), 1.7–2.0 (m, 2 H, 4-H, 5Ј-H), 2.0–2.2 (m, 1 H, 4Ј-H), 2.25 (s, 3
H, ArMe), 2.42 (s, 6 H, 2 ArMe), 3.6–3.7 (m, 3 H, 6-H, 7-H, 7Ј-
H), 3.84 (s, 1 H, 3-H), 4.88 (s, 1 H, 3Ј-H), 6.85 (s, 2 H, 2 ArH)
ppm. 13C NMR (100.4 MHz, CDCl3): δ = 20.6, 21.1, 21.6, 29.9,
66.2, 66.8, 78.9, 80.4, 130.6, 131.9, 136.4, 136.9 ppm. HRMS (ESI-
TOF): calcd. for C15H22O3Na [M + Na]+ 273.1467; found
273.1466.
Synthesis of (2R,3S,6R)-6-Methyl-3-hydroxy-2-mesityloxacyclohex-
ane (15a)
Data for 12ab: Colourless syrup. [α]2D9 = +64.7 (c 1.5, CHCl3). IR
(2S,3R,6S)-6-Tosyloxymethyl-3-hydroxy-2-mesityloxacyclohexane
(16a): p-Toluenesulfonyl chloride (197 mg, 1.0 mmol) was added to
a solution of diol 12ab (215 mg, 0.86 mmol) in pyridine (1.0 mL).
The mixture was stirred for 12 h, then the reaction was quenched
by the addition of HCl (1 n aq.). The mixture was extracted with
ethyl acetate. The combined organic extracts were washed with
NaHCO3 (satd. aq.) and brine, and dried with Na2SO4, and the
solvents were evaporated. The residue was purified by silica gel
column chromatography (hexane/ethyl acetate, 9:1 then 3:1) to give
16a (363 mg, 87%) as a white solid; m.p. 106–107 °C. [α]2D5 = +9.7
(KBr): ν = 3600–3100 (br), 3100–2800 (br), 1610, 1453, 1374, 1207,
˜
1085, 1045, 965, 941, 904, 850, 731, 571 cm–1 1 H NMR
.
(400.0 MHz, CDCl3): δ = 1.5–1.7 (m, 3 H, 4-H, 5-H, 5Ј-H), 2.0–
2.1 (br. s, 1 H, OH), 2.1–2.2 (m, 4 H, 3 ArH, 4Ј-H), 2.34 (s, 3 H,
ArMe), 2.46 (s, 3 H, ArMe), 3.5–3.7 (m, 3 H, 6-H, 7-H, 7Ј-H), 3.9–
4.0 (m, 1 H, 3-H), 4.55 (d, J = 10.8 Hz, 1 H, 2-H), 6.82 (s, 2 H,
ArH) ppm. 13C NMR (100.4 MHz, CDCl3): δ = 20.7, 20.9, 21.3,
26.7, 31.6, 65.8, 68.4, 78.3, 81.2, 129.1, 130.5, 131.4, 131.5,
137.6 ppm. HRMS (ESI-TOF): calcd. for C15H22O3Na [M + Na]+
273.1467; found 273.1466. C15H22O3 (250.34): calcd. C 71.97, H
8.86; found C 72.37, H 8.73.
(c 1.0, CHCl ). IR (KBr): ν = 3600–3300 (br), 3100–2800 (br),
˜
3
1598, 1450, 1353, 1188, 1173, 1111, 1096, 977, 927, 833, 813, 790,
1
732, 718, 666, 574, 554 cm–1. H NMR (400.0 MHz, CDCl3): δ =
(2S,3S,6S)-3-O-(S-Methylxanthate)-6-O-(S-methylxanthatemethyl)-
2-mesityloxacyclohexane (13aa) and (2S,3R,6S)-3-O-(S-Methylxan-
thate)-6-O-(S-methylxanthatemethyl)-2-mesityloxacyclohexane
(13ab): NaH (50% in oil; 182 mg, 3.8 mmol) was added slowly to
a solution of diols 12aa and 12ab (190 mg, 0.76 mmol; 52:48 ratio)
in THF (2.0 mL) at 0 °C, and the mixture was stirred for 30 min
at room temperature. After that, CS2 (230 μL, 3.8 mmol) was added
at 0 °C, and the reaction mixture was stirred for 30 min at room
temperature. Finally, MeI (238 μL, 3.8 mmol) was added to the re-
action mixture at 0 °C. The mixture was stirred for 12 h at room
temperature, then the reaction was quenched by the addition of
H2O and HCl (1 n aq.) at 0 °C. The mixture was extracted with
ethyl acetate. The combined organic extracts were washed with
brine, and dried with Na2SO4, and the solvents were evaporated.
The residue was purified by silica gel column chromatography (hex-
ane/ethyl acetate, 30:1) to give xanthates 13aa and 13ab (320 mg,
98%; 58:42 ratio).
1.4–1.5 (m, 1 H, 4-H), 1.60 (s, 1 H, OH), 1.8–2.0 (m, 2 H, 4Ј-H, 5-
H), 2.1–2.3 (m, 1 H, 5Ј-H), 2.24 (s, 3 H, ArMe), 2.29 (s, 6 H, 2
ArMe), 2.37 (s, 3 H, ArMe), 3.7–3.8 (m, 1 H, 3-H), 4.15 (dd, J =
10.3, 4.8 Hz, 1 H, 7-H), 4.3–4.4 (m, 1 H, 6-H), 4.40 (dd, J = 10.3,
7.4 Hz, 1 H, 7Ј-H), 4.90 (d, J = 1.2 Hz, 1 H, 2-H), 6.80 (s, 2 H, 2
ArH), 7.15 (d, J = 8.4 Hz, 2 H, 2 ArH), 7.70 (d, J = 8.4 Hz, 2 H,
2 ArH) ppm. 13C NMR (100.4 MHz, CDCl3): δ = 18.9, 20.6, 21.4,
21.5, 25.6, 66.7, 68.6, 69.9, 73.4, 127.7, 130.0, 130.4, 131.2, 133.0,
136.8, 144.7 ppm. HRMS (ESI-TOF): calcd. for C22H28O5S2Na [M
+ Na]+ 427.1555; found 427.1555.
(2S,3R,6R)-6-Methyl-3-hydroxy-2-mesityloxacyclohexane (15a): Li-
AlH4 (85 mg, 2.2 mmol) was added to a solution of 16a (300 mg,
0.74 mmol) in THF (2.0 mL) at 0 °C. The mixture was stirred for
12 h at room temperature, then the reaction was quenched by the
addition of HCl (1 n aq.). The mixture was extracted with ethyl
acetate. The combined organic extracts were washed with H2SO4
(10% aq.), NaHCO3 (satd. aq.), and brine, and dried with Na2SO4,
and the solvents were evaporated. The residue was purified by silica
gel column chromatography (hexane/ethyl acetate, 9:1) to give 15a
(160 mg, 53%) as a colourless syrup. [α]2D5 –27.8 (c 1.1, CHCl3). IR
Data for 13aa: Yellow syrup. [α]2D8 = +5.4 (c 1.0, CHCl3). IR (KBr):
1
ν = 3000–2800 (br), 1422, 1202, 1051, 965, 852, 818, 715 cm–1. H
˜
NMR (400.0 MHz, CDCl3): δ = 1.6–1.7 (m, 1 H, 5-H), 1.8–2.1 (m,
2 H, 4-H, 5Ј-H), 2.22 (s, 3 H, ArMe), 2.4–2.5 (m, 10 H, 2 ArMe,
CS2Me, 4Ј-H), 2.58 (s, 3 H, CS2Me), 3.9–4.1 (m, 1 H, 6-H), 4.7–
4.8 (m, 2 H, 7-H, 7Ј-H), 5.04 (s, 1 H, 2-H), 5.86 (s, 1 H, 3-H), 6.78
(s, 2 H, 2 ArH) ppm. 13C NMR (100.4 MHz, CDCl3): δ = 19.0,
19.2, 20.7, 21.6, 22.5, 27.4, 75.4, 75.6, 79.2, 130.2, 130.8, 136.4,
136.8, 216.0, 216.1 ppm. HRMS (ESI-TOF): calcd. for
C19H26O3S4Na [M + Na]+ 453.0663; found 453.0662. C19H26O3S4
(430.65): calcd. C 52.99, H 6.09; found C 52.59, H 6.27.
(KBr): ν = 3600–3300 (br), 3100–2800 (br), 1727, 1611, 1482, 1447,
˜
1376, 1338, 1255, 1215, 1131, 1063, 1022, 971, 955, 906, 852, 803,
1
740, 716, 630, 574, 564 cm–1. H NMR (400.0 MHz, CDCl3): δ =
1.2–1.3 (m, 1 H, 4-H), 1.34 (d, J = 8.4 Hz, 3 H, Me), 1.67 (d, J =
3.2 Hz, 1 H, OH), 1.88 (ddd, J = 11.6, 7.2, 3.8 Hz, 1 H, 5-H), 2.07
(dddd, J = 13.7, 13.7, 3.6, 3.6 Hz, 1 H, 4Ј-H), 2.24 (s, 3 H, ArMe),
2.2–2.3 (m, 1 H, 5Ј-H), 2.43 (s, 6 H, 2 ArMe), 3.8–3.9 (m, 1 H, 3-
H), 4.3–4.4 (m, 1 H, 6-H), 3.8–3.9 (m, 1 H, 3-H), 5.12 (d, J =
Data for 13ab: Yellow syrup. [α]2D8 = +12.0 (c 2.7, CHCl3). IR
(KBr): ν = 3100–2800 (br), 1423, 1204, 1051, 967, 905, 850, 1.6 Hz, 1 H, 2-H), 6.83 (s, 2 H, ArH) ppm. 13C NMR (100.4 MHz,
˜
1
731 cm–1. H NMR (400.0 MHz, CDCl3): δ = 1.7–2.0 (m, 3 H, 4-
CDCl3): δ = 16.0, 20.7, 21.6, 23.3, 25.1, 67.4, 68.6, 71.6, 130.6,
252
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Eur. J. Org. Chem. 2014, 244–253

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Acknowledgments
This work was supported by the Ministry of Education, Culture,
Sports, Science and Technology, Japan (Grants-in-Aid for Scientific
Research on Priority Areas “Advanced Molecular Transformations
of Carbon Resources” and grant number B17340020) and by Spe-
cial Coordination Funds for Promoting Science and Technology,
Creation of Innovation Centers for Advanced Interdisciplinary Re-
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Received: September 11, 2013
Published Online: November 15, 2013
Eur. J. Org. Chem. 2014, 244–253
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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