Solvolysis of (4,5)-anti-4-Aryl-5-tosyloxy-2(E)-hexenoate derivatives

Article abstract of DOI:10.1248/cpb.53.1259

The solvolysis reaction of (4,5)-anti-4-aryl-5-tosyloxy-2(E)-hexenoates 4a-k gave (4,5)-anti-4-aryl-5-hydroxy-2(E)-hexenoates 2a-k and (4,5)-anti-5-aryl-4-hydroxy-2(E)-hexenoates 5a-k along with the complete inversion. This 1,2-aryl migration was induced

Full text of DOI:10.1248/cpb.53.1259

October 2005
Chem. Pharm. Bull. 53(10) 1259—1265 (2005)
1259
Solvolysis of (4,5)-anti-4-Aryl-5-tosyloxy-2(E)-hexenoate Derivatives
a
a,b
a
a
a
Machiko ONO, Takeru EHARA, Hirofumi YOKOYAMA, Nobuyoshi OHTANI, Youko HOSHINO, and
,a
Hiroyuki AKITA*
a
b
School of Pharmaceutical Sciences, Toho University; 2–2–1 Miyama, Funabashi, Chiba 274–8510, Japan: and Tsukuba
Research Institute, Novartis Pharma K.K.; 8 Ohkubo, Tsukuba, Ibaraki 300–2611, Japan.
Received May 11, 2005; accepted July 19, 2005
The solvolysis reaction of (4,5)-anti-4-aryl-5-tosyloxy-2(E)-hexenoates 4a—k gave (4,5)-anti-4-aryl-5-hy-
droxy-2(E)-hexenoates 2a—k and (4,5)-anti-5-aryl-4-hydroxy-2(E)-hexenoates 5a—k along with the complete in-
version. This 1,2-aryl migration was induced by treatment with heating in water-saturated nitromethane. On the
basis of the substituent effect on the aromatic ring, this 1,2-aryl migration is thought to proceed via the s-
bridged phenonium ion. The product selectivity between 2a—k and 5a—k was found to be subtly governed by
the substituent and substitution pattern in the aromatic ring of the substrates 4a—k.
Key words solvolysis; 1,2-aryl migration; phenonium ion
We previously reported that solvolysis of 4-aryl-5-tosyl- yields of 2a, 2f and 2g were improved in comparison to the
4)
oxy-2(E)-pentenoate A in water-saturated MeNO gave 1,2- reported data. The substitution pattern in the aromatic ring
2
aryl migration product C along with complete inversion in of the products was determined by a nuclear Overhauser ef-
1,2)
good yield. In the case of this reaction, an intermolecular fect (NOE) experiment as shown in Chart 2.
attack of the nucleophile (H O) to the s-bridged phenonium
1,2-Aryl Migration Under Solvolysis Condition At
2
ion B proceeded selectively at the C(4)-position to provide first, 1,2-aryl migration along with the intermolecular nucle-
the 4-hydroxy-5-aryl-2(E)-pentenoate C. If the (4,5)-anti-4- ophilic substitution at the C(4)-position using 4a and 6a was
aryl-5-tosyloxy-2(E)-hexenoate D is subjected to solvolysis examined. The substrate 2a was treated with TsCl in pyridine
in the presence of a nucleophile, 1,2-aryl migration followed to give the corresponding tosylate 4a, which was subjected to
by intermolecular nucleophilic substitution along with inver- solvolysis in water-saturated MeNO to provide 2a (10%)
2
sion at the C(4)-position should occur to afford the (4,5)- and 5a (70%). Meanwhile, the corresponding mesylate 6a
anti-5-aryl-4-substituted-2(E)-hexenoate derivatives E. How- was exposed to the same reaction condition to give 2a (12%)
ever, this type of reaction has not been reported so far. In this and 5a (42%). It was apparent that 1,2-migration ability of
paper, we wish to report both the possibility of the above- the aromatic group of the tosylate 4a is higher than that of
mentioned reaction and its stereochemical course based on the mesylate 6a (Chart 3).
the substituent effect in the aromatic ring.
Consequently, the residual ten kinds of the (4,5)-anti-5-hy-
Synthesis of Substrates In our previous paper, we re- droxy-4-aryl-2(E)-hexenoates 2b—k were converted into the
ported that the reaction of (4,5)-trans-epoxy-2(E)-hexenoate corresponding tosylates 4b—k in good yield as shown in
1
with aromatic nucleophiles having electron-donating group Chart 2. The reaction product 2a was identical with the syn-
in the presence of BF ·Et O gave the (4,5)-anti-5-hydroxy-4- thesized 2a. Structure elucidation of 5a was carried out as
3
2
aryl-2(E)-hexenoate 2 and (2,5)-anti-5-hydroxy-2-aryl-3(E)- follows. Acetylation of 5a gave the corresponding acetate 8a
3—5)
hexenoate 3.
This reaction was carried out using other whose NMR spectrum showed the presence of an acetoxyl
nine kinds of aromatic compounds. The reaction of 1 and group at the C -position, because the signal due to C -H was
4
4
4)
anisole gave 2a (53%) and 2b (3%). The reaction of 1 and a triple doublet at d 5.46 with three coupling constants (Jꢀ7,
m-methoxytoluene gave 2c (51%) and 2d (28%). Moreover, 6, 2 Hz). Moreover, the chemical shift (d 5.46) due to C -H
4
the reaction of 1 and o-methoxytoluene, 1,2-dimethoxy- of 8a appeared to the lower field in comparison to that (d
benzene, p-methoxytoluene, 2,5-dimethoxytoluene, 2,5-di- 5.16, dq, Jꢀ7, 9 Hz) due to C -H of an acetate 7a derived
5
methylanisole, m-xylene, 1,2,3,4-tetramethylbenzene pro- from 2a. The 4,5-anti-configuration of 5a was determined
vided 2e (70%), 2f (90%), 2g (51%), 2h (63%), 2i (84%), 2j using the same type compound 5c as 5a at late in this text. To
(55%), and 2k (94%), respectively, as shown in Chart 2. The investigate the solvent effect, usage of the residual ni-
Chart 1
∗
To whom correspondence should be addressed. e-mail: akita@toho-u.ac.jp
© 2005 Pharmaceutical Society of Japan

1
260
Vol. 53, No. 10
Chart 2. NOE Experiments Were Carried Out in the Substrates 2c—j
Chart 3
troalkane such as nitroethane, 2-nitropropane, and nitroben- The dielectric constant of nitromethane (eꢀ35.9) is similar
zene was found to be less reactive than nitromethane by to that of DMF (eꢀ36.7), while solvent effect on solvolysis
NMR analysis of the reaction mixture. Moreover, water-satu- reaction was not explained by only dielectric constant. Then,
rated solvents such as n-butyronitrile, cyclohexanone, DMF, solvolysis of ten kinds of substrates was carried out under the
isopropyl ether, ethyl acetate, 1,2-dichloroethane, and ben- same reaction condition as 4a and the results were shown in
zene did not promote the 1,2-rearrangement reaction for 5d Table 1. To investigate the influence of the substituent in the
at 50 °C. It was apparent that nitromethane was the best sol- aromatic ring, solvolysis of three groups of substrates was
vent for 1,2-migration reaction using substrate 4a. Ni- carried out. In the case of the same type substrate 4e, f with-
tromethane or dimethylsulfoxide (DMSO) is reported to be out substituent at ortho-position as 4a, solvolysis reaction
6)
the best solvent for solvolysis reaction by Winstein et al.
smoothly occurred to afford 2e, f and 5e, f in moderate yield.

October 2005
1261
Table 1. Solvolysis of (4,5)-anti-4-Aryl-5-tosyloxy-2(E)-hexenoate Derivatives
3
4
5
6
Entry
Tosylate (g)
R
R
R
R
Time (d) Recovered 4 (%) 2 (yield, %)
5 (yield, %) Ratio (2 : 5)
1
2
3
4
5
6
7
8
9
4a (0.939)
4e (1.01)
4f (1.00)
4b (0.671)
4d (1.723)
4g (1.01)
4h (1.19)
4c (1.00)
4i (1.148)
4j (1.01)
4k (1.148)
H
H
H
OMe
OMe
OMe
OMe
Me
H
OMe
OMe
OMe
H
Me
H
H
5
3
4
7
3
7
4
3
5
8
18
3
16
0
10
6
70
51
52
21
47
19
15
17
28
25
21
1 : 7
1 : 8.5
1 : 4.3
Me
OMe
H
H
H
H
H
H
H
H
H
H
H
Me
OMe
H
Me
H
Me
12
31
38
28
19
55
46
29
69
1.5 : 1
1 : 1.2
1.5 : 1
1.3 : 1
3.2 : 1
1.6 : 1
1.2 : 1
3.3 : 1
7
Me
11
10
5
7
3
OMe
OMe
Me
Me
Me
Me
1
1
0
1
12
5
Me
Me
The 1,2-migration products 5e, f were predominantly ob-
tained (entries 2, 3). The second group substrates 4b, d, g, h
possessing the methoxyl group at ortho-position were sub-
jected to solvolysis reaction to provide 2b, d, g, h and
5b, d, g, h in moderate yield (entries 4—7). In these cases,
the product selectivity was not observed. The third group
substrates 4c, i—k possessing the methyl group at ortho-po-
sition were subjected to solvolysis reaction to yield 2c, i—k
Chart 4
and 5c, i—k in moderate yield (entries 8—11). The reaction phenonium ion intermediate I, H O as nucleophile attacks at
2
products 2b—k were identical with the synthesized 2b—k, both C(4)- and C(5)-positions along with inversion to afford
respectively. To confirm the 4,5-anti-configuration of the 1,2- 5a as a major product and 2a as a minor product. This prod-
migration products 5a—k, the substrate 5c was selected for uct selectivity can be rationalized by considering that the re-
the structure elucidation. Catalytic hydrogenation of 5c fol- activity of C(4)-carbenium ion corresponding to the allyl car-
lowed by the consecutive alkaline hydrolysis and g-lactone benium ion is higher than that of C(5)-carbenium ion as
formation using dicyclohexyl carbodiimide (DCC) gave g- shown in Chart 5.
lactone 9c in 70% overall yield, which was identical with the
In the case of the solvolysis of 4b possessing the methoxyl
authentic sample 9c (Chart 4). The structures of the residual group at ortho-position, two possible intermediates II and III
a, b, d—k were deduced by the similarity of the NMR spec- are considered as shown in Chart 5. The formation of 2b and
7)
5
trum of 5c.
5b is explained by way of the phenonium ion intermediate II,
and 2b is presumed to be also formed via an oxonium ion in-
termediate III which is corresponded to the methoxyl oxygen
Disscussion
It was apparent that the solvolysis reaction of (4,5)-anti-4- participation at the C(5)-position. Consequently, product se-
aryl-5-tosyloxy-2(E)-hexenoates 4a—k gave 2a—k and 1,2- lectivity might be not observed. Ramsey et al. reported the
migration products 5a—k along with the complete inversion. presence of such an oxonium ion 10 and the s-bridged
The product selectivity between 2a—k and 5a—k was found phenonium ion 11 based on the ionization of o-anisylethyl
to be subtly governed by the substituent and substitution pat- chloride 12 in SbF ·SO at ꢁ70 °C and SbF ·SO ·BF at
5
2
5
2
3
1
tern in the aromatic ring of the substrates 4a—k. When both ꢁ20 °C, respectively, by means of H-NMR measurement of
a and 5a were individually exposed to the solvolysis condi- the resulting reaction mixture as shown in Chart 5. In the
8
)
2
tion (TsOH in H O-saturated MeNO at 50 °C for 5 d), both case of the solvolysis of 4c, i—k possessing the methyl
2
2
substrates were intact, respectively. This experiment indicates group at ortho-position, two possible intermediates IV and V
that the reaction is kinetically controlled and the rate-deter- are considered as shown in Chart 6. The formation of 2c, k
mining stage might be until the formation of the reaction in- and 5c, k is explained by way of the phenonium ion interme-
termediate. Both substrates 2a and 5a could be formed from diate IV, and the preferential formation of 2c, k could be
the common intermediate which is corresponding to the s- considered an alternative pathway. Although such an alterna-
bridged phenonium ion F as shown in Table 1. We already tive pathway should be present in literature, the detailed
9)
reported that treatment of (4,5)-anti-4-aryl-5-tosyloxy-hexa- structure of the intermediate has not yet been determined.
noates under a solvolytic condition afforded a G-lactoniza-
tion product along with the complete 1,2-aryl migration via Conclusion
1)
the s-bridged phenonium ion intermediate. In the case of
a without substituent at ortho-position, the plausible reac- 2(E)-hexenoates 4a—k gave (4,5)-anti-4-aryl-5-hydroxy-
tion course is considered as follow. After the formation of 2(E)-hexenoates 2a—k and (4,5)-anti-5-aryl-4-hydroxy-
The solvolysis reaction of (4,5)-anti-4-aryl-5-tosyloxy-
4

1
262
Vol. 53, No. 10
Chart 5
product selectivity between 2a—k and 5a—k was found to
be governed by the substituent and substitution pattern in the
aromatic ring of the substrates 4a—k.
Experimental
1
H-NMR spectra were recorded by a JEOL EX 400 spectrometer (Tokyo,
Japan). Spectra were taken with 5—10% (w/v) solution in CDCl3 with
Me Si as an internal reference. Mass spectra and the fast atom bombardment
4
mass spectra (FAB-MS) were obtained with a JEOL JMS-600H (matrix;
glycerol, m-nitrobenzyl alcohol) spectrometer. IR spectra were recorded on a
JASCO FT/IR-300 spectrometer. All evaporations were performed under re-
duced pressure. For column chromatography, silica gel (Kieselgel 60) was
employed.
Methyl (4,5)-anti-4-(4ꢀ-Methoxyphenyl)-5-hydroxy-2(E)-hexenoate 2a
and Methyl (4,5)-anti-4-(2ꢀ-Methoxyphenyl)-5-hydroxy-2(E)-hexenoate
2b
To a solution of 1 (5.83 g, 0.041 mol) and anisole (6.93 g, 0.082 mol) in
CH Cl (30 ml) was added BF ·Et O (5.1 ml, 0.041 mol) at ꢁ78 °C, and the
2
2
3
2
whole mixture was stirred for 1 h at ꢁ78 °C, and for 1 h at ꢁ20 °C. The re-
action mixture was diluted with brine and extracted with CH Cl . The or-
2
2
ganic layer was dried over MgSO4 and evaporated to provide a residue,
which was chromatographed on silica gel (200 g, n-hexane : AcOEtꢀ85 : 15)
to afford 2b (0.229 g, 3%) and 2a (4.908 g, 53%) as a colorless oil, respec-
4
)
tively, in elution order. Compound 2a was identical with the reported 2a.
2
ꢁ1 1
b: IR (neat): 3444, 1720 cm ; H-NMR: d 1.11 (3H, d, Jꢀ6 Hz), 1.84 (1H,
d, Jꢀ4 Hz), 3.72 (3H, s), 3.79 (1H, t, Jꢀ8 Hz), 3.82 (3H, s), 4.19 (1H, ddq,
Jꢀ4, 8, 8 Hz), 5.91 (1H, d, Jꢀ15.6 Hz), 6.88 (1H, d, Jꢀ8 Hz), 6.93 (1H, t,
Jꢀ8 Hz), 7.15 (1H, d, Jꢀ8 Hz), 7.23 (1H, t, Jꢀ8 Hz), 7.34 (1H, dd, Jꢀ8,
Chart 6
1
5.6 Hz). Anal. Calcd for C H O ·H O: C, 66.00; H, 7.32. Found: C,
14 18 4 2
6
6.03; H, 7.63.
Methyl (4,5)-anti-4-(2ꢀ-Methyl-4ꢀ-methoxyphenyl)-5-hydroxy-2(E)-
2
(E)-hexenoates 5a—k along with the complete inversion.
hexenoate 2c and Methyl (4,5)-anti-4-(4ꢀ-Methyl-2ꢀ-methoxyphenyl)-5-
hydroxy-2(E)-hexenoate 2d To a solution of 1 (6.05 g, 0.043 mol) and m-
methoxytoluene (4.68 g, 0.12 mol) in CH Cl (80 ml) was added BF ·Et O
This 1,2-aryl migration was induced by treatment with heat-
ing in water-saturated nitromethane. On the basis of the sub-
stituent effect on the aromatic ring, this 1,2-aryl migration is
2
2
3
2
(5.3 ml, 0.043 mol) at ꢁ78 °C, and the whole mixture was stirred for 1 h at
thought to proceed via the s-bridged phenonium ion. The ꢁ78 °C, and for 1 h at –20 °C. The reaction mixture was worked up in the

October 2005
1263
same way as 2a to afford 2d (3.18 g, 28%) and 2c (5.75 g, 51%) as a color-
less oil, respectively, in elution order. 2c: IR (neat): 3443, 1720 cm ; H-
NMR: d 1.12 (3H, d, Jꢀ6.5 Hz), 1.74 (1H, br s), 2.31 (3H, s), 3.58 (1H, ddd, 2.25 (3H, s), 2.27 (3H, s), 2.35 (1H, br s), 3.58 (1H, ddd, Jꢀ2, 8, 8 Hz), 3.66
Jꢀ2, 7.5, 8 Hz), 3.71 (3H, s), 3.78 (3H, s), 4.10 (1H, dq, Jꢀ6.5, 7.5 Hz), (3H, s), 4.09 (1H, dq, Jꢀ8, 6 Hz), 5.82 (1H, dd, Jꢀ2, 16 Hz), 6.93—6.99
action mixture was worked up in the same way as 2a to afford 2j (4.09 g,
55%). 2j: IR (neat): 3443, 1723 cm ; H-NMR: d 1.08 (3H, d, Jꢀ6 Hz),
ꢁ1
1
ꢁ1
1
5
.86 (1H, dd, Jꢀ2, 15.5 Hz), 6.73 (1H, s), 6.75 (1H, d, Jꢀ7.5 Hz), 7.08 (1H,
(2H, m), 7.02 (1H, d, Jꢀ8 Hz), 7.23 (1H, dd, Jꢀ8, 16 Hz). Anal. Calcd for
d, Jꢀ1, 7.5 Hz), 7.23 (1H, dd, Jꢀ8, 15.5 Hz). Anal. Calcd for C H O : C, C H O : C, 72.55; H, 8.12. Found: C, 72.10; H, 8.39. MS (FAB) m/z: 249
1
5
20
4
15 20
3
ꢂ
ꢂ
6
8.16; H, 7. 63. Found: C, 67.86; H, 7.74. MS (FAB) m/z: 265 (M ꢂ1). 2d: (M ꢂ1).
ꢁ
1
1
IR (neat): 3444, 1695 cm ; H-NMR: d 1.10 (3H, d, Jꢀ6 Hz), 1.74 (1H,
br s), 2.33 (3H, s), 3.71 (3H, s), 3.77 (1H, ddd, Jꢀ1, 7, 8.5 Hz), 3.80 (3H, s),
Methyl (4,5)-anti-4-(2ꢀ,3ꢀ,4ꢀ,5ꢀ-Tetramethylphenyl)-5-hydroxy-2(E)-
hexenoate 2k To a solution of 1 (4.26 g, 0.03 mol) and 1,2,3,4-tetra-
4
.17 (1H, dq, Jꢀ7, 6 Hz), 5.89 (1H, dd, Jꢀ1, 15.6 Hz), 6.69 (1H, s), 6.74 methylbenzene (12.08 g, 0.09 mol) in CH Cl (50 ml) was added BF ·Et O
2
2
3
2
(1H, d, Jꢀ7.5 Hz), 7.01 (1H, d, Jꢀ7.5 Hz), 7.33 (1H, dd, Jꢀ8.5, 15.6 Hz). (3.78 ml, 0.03 mol) at ꢁ78 °C, and the whole mixture was stirred for 1 h at
Anal. Calcd for C H O : C, 68.16; H, 7.63. Found: C, 67.72; H, 7.69. MS ꢁ78 °C, and for 1 h at ꢁ20 °C. The reaction mixture was worked up in the
1
5
20
4
ꢂ
ꢁ1
(
FAB) m/z: 265 (M ꢂ1).
Methyl (4,5)-anti-4-(3ꢀ-Methyl-4ꢀ-methoxyphenyl)-5-hydroxy-2(E)-
hexenoate 2e To a solution of 1 (11.38 g, 0.08 mol) and o-methoxytoluene s), 2.24 (3H, s), 3.68 (1H, ddd, Jꢀ2, 9, 9 Hz), 3.69 (3H, s), 4.11 (1H, dq,
same way as 2a to afford 2k (6.89 g, 94%). 2k: IR (neat): 3435, 1719 cm ;
1
H-NMR: d 1.10 (3H, d, Jꢀ6.5 Hz), 1.91 (1H, br s), 2.16 (3H, s), 2.20 (6H,
(
19.53 g, 0.16 mol) in CH Cl (150 ml) was added BF ·Et O (10 ml,
Jꢀ9, 6.5 Hz), 5.86 (1H, dd, Jꢀ2, 16 Hz), 6.80 (1H, s), 7.26 (1H, dd, Jꢀ9,
2
2
3
2
0
.08 mol) at ꢁ78 °C, and the whole mixture was stirred for 1 h at ꢁ78 °C, 16 Hz). Anal. Calcd for C H O : C, 73.88; H, 8.75. Found: C, 73.87; H,
1
7
24
3
ꢂ
and for 1 h at ꢁ20 °C. The reaction mixture was worked up in the same way 8.76. MS (FAB) m/z: 299 (M ꢂNa).
as 2a to afford 2e (14.7 g, 70%) as a colorless oil. 2e: IR (neat): 3444, Methyl (4,5)-anti-4-(4ꢀ-Methoxyphenyl)-5-tosyloxy-2(E)-hexenoate 4a
ꢁ1 1
1
3
6
714 cm ; H-NMR: d 1.08 (3H, d, Jꢀ6 Hz), 2.12 (1H, br s), 2.18 (3H, s),
A mixture of 2a (2.773 g, 0.011 mol), p-toluenesulfonyl chloride (TsCl,
.25 (1H, ddd, Jꢀ2, 6, 8 Hz), 3.69 (3H, s), 3.78 (3H, s), 4.02 (1H, dq, Jꢀ6,
3.14 g, 0.016 mol), pyridine (8 ml) was stirred for 1 d at rt. The reaction mix-
Hz), 5.87 (1H, dd, Jꢀ2, 16 Hz), 6.74 (1H, d, Jꢀ8 Hz), 6.93 (1H, d, ture was diluted with H O, which was extracted with ether. The organic layer
2
Jꢀ2 Hz), 6.95 (1H, dd, Jꢀ2, 8 Hz), 7.24 (1H, d, Jꢀ8, 16 Hz). Anal. Calcd
was washed with 1 M aqueous HCl and 7% aqueous NaHCO . The organic
3
for C H O : C, 68.16; H, 7.63. Found: C, 67.88; H, 7.84. MS (FAB) m/z: layer was dried over MgSO and evaporated to give a residue, which was
1
5
20
4
4
ꢂ
2
65 (M ꢂ1).
chromatographed on silica gel (80 g, n-hexane : AcOEtꢀ5 : 1) to afford 4a
ꢁ1 1
Methyl (4,5)-anti-4-(3ꢀ,4ꢀ-Dimethoxyphenyl)-5-hydroxy-2(E)-hexeno- (2.02 g, 73%) as a colorless oil. 4a: IR (neat): 1730, 1376 cm ; H-NMR: d
ate 2f To a solution of 1 (4.26 g, 0.03 mol) and 1,2-dimethoxybenzene
8.29 g, 0.06 mol) in CH Cl (60 ml) was added BF ·Et O (3.75 ml,
.03 mol) at ꢁ78 °C, and the whole mixture was stirred for 1 h at ꢁ78 °C,
1.24 (3H, d, Jꢀ6 Hz), 2.44 (3H, s), 3.48 (1H, t, Jꢀ8 Hz), 3.70 (3H, s), 3.77
(3H, s), 4.83 (1H, dq, Jꢀ8, 6 Hz), 5.75 (1H, d, Jꢀ16 Hz), 6.80 (2H, d,
Jꢀ9 Hz), 6.94 (1H, dd, Jꢀ8, 16 Hz), 7.00 (2H, d, Jꢀ9 Hz), 7.28 (2H, d,
(
0
2
2
3
2
and for 1 h at ꢁ20 °C. The reaction mixture was worked up in the same way Jꢀ9 Hz), 7.70 (2H, d, Jꢀ9 Hz). Anal. Calcd for C H SO : C, 62.36; H,
2
1
24
6
ꢂ
as 2a to afford 2f (8.40 g, 90%) as a colorless oil. 2f: IR (CCl ): 3560,
5.98. Found: C, 62.57; H, 6.08. MS (FAB) m/z: 405 (M ꢂ1).
Methyl (4,5)-anti-4-(4ꢀ-Methoxyphenyl)-5-mesyloxy-2(E)-hexenoate 6a
4
ꢁ1
1
1715 cm ; H-NMR: d 1.07 (3H, d, Jꢀ6 Hz), 2.12 (1H, br s), 3.24 (1H,
ddd, Jꢀ2, 6, 8 Hz), 3.66 (3H, s), 3.80 (3H, s), 3.82 (3H, s), 4.01 (1H, dq, A mixture of 2a (1.9 g, 0.0076 mol), methanesulfonyl chloride (MsCl, 1.4 g,
Jꢀ6, 6 Hz), 5.86 (1H, dd, Jꢀ2, 16 Hz), 6.66 (1H, d, Jꢀ2 Hz), 6.70 (1H, dd, 0.012 mol), pyridine (8 ml) was stirred for 1 d at rt. The reaction mixture was
Jꢀ2, 8 Hz), 6.78 (1H, d, Jꢀ8 Hz), 7.22 (1H, d, Jꢀ8, 16 Hz). Anal. Calcd for
C H O : C, 64.27; H, 7.19. Found: C, 64.10; H, 7.43. MS (FAB) m/z: 265
worked up in the same way as 4a to afford 6a (1.775 g, 93%) as a colorless
oil. 6a: IR (neat): 1721, 1655 cm ; H-NMR: d 1.38 (3H, d, Jꢀ7 Hz), 2.82
(3H, s), 3.57 (1H, t, Jꢀ8 Hz), 3.74 (3H, s), 3.79 (3H, s), 4.97(1H, dq, Jꢀ8,
ꢁ1 1
15
20
5
ꢂ
(M ꢂ1).
Methyl (4,5)-anti-4-(5ꢀ-Methyl-2ꢀ-methoxyphenyl)-5-hydroxy-2(E)- 7 Hz), 5.91 (1H, d, Jꢀ16 Hz), 6.89 (2H, d, Jꢀ9 Hz), 7.13 (2H, d, Jꢀ9 Hz),
hexenoate 2g To a solution of 1 (11.38 g, 0.08 mol) and 4-methoxytoluene 7.20 (1H, dd, Jꢀ8, 16 Hz). Anal. Calcd for C H SO : C, 54.86; H, 6.14.
1
5
20
6
ꢂ
(
19.54 g, 0.16 mol) in CH Cl (150 ml) was added BF ·Et O (10 ml, Found: C, 54.91; H, 6.13. MS (FAB) m/z: 329 (M ꢂ1).
2
2
3
2
0.08 mol) at ꢁ78 °C, and the whole mixture was stirred for 1 h at ꢁ78 °C,
Methyl (4,5)-anti-4-(2ꢀ-Methoxyphenyl)-5-tosyloxy-2(E)-hexenoate 4b
and for 1 h at ꢁ20 °C. The reaction mixture was worked up in the same way A mixture of 2b (0.63 g, 0.0025 mol), p-toluenesulfonic anhydride (Ts O,
2
as 2a to afford 2g (10.72 g, 51%) as a colorless oil. 2g: IR (CCl ): 3570,
0.99 g, 0.003 mol), pyridine (3 ml) was stirred for 1 d at rt. The reaction mix-
4
ꢁ1 1
1
3
6
720 cm ; H-NMR: d 1.10 (3H, d, Jꢀ6 Hz), 2.15 (1H, br s), 2.26 (3H, s),
ture was worked up in the same way as 4a to afford 4b (0.723 g, 71%) as a
ꢁ1 1
.70 (3H, s), 3.76 (1H, ddd, Jꢀ2, 6, 8 Hz), 3.78 (3H, s), 4.17 (1H, dq, Jꢀ6,
colorless oil. 4b: IR (KBr): 1721 cm ; H-NMR: d 1.28 (3H, d, Jꢀ6.3 Hz),
Hz), 5.90 (1H, dd, Jꢀ2, 16 Hz), 6.77 (1H, d, Jꢀ8 Hz), 6.94 (1H, d, 2.39 (3H, s), 3.69 (3H, s), 3.76 (3H, s), 3.83 (1H, dd, Jꢀ7.3, 9.3 Hz), 5.05
Jꢀ2 Hz), 7.34 (1H, dd, Jꢀ8, 16 Hz). Anal. Calcd for C H O : C, 68.14; H, (1H, dq, Jꢀ7.3, 6.3 Hz), 5.75 (1H, d, Jꢀ16.1 Hz), 6.77 (1H, d, Jꢀ8.3 Hz),
1
5
20
4
ꢂ
7
.63. Found: C, 67.74; H, 7.82. MS (FAB) m/z: 265 (M ꢂ1).
Methyl (4,5)-anti-4-(4 -Methyl-2 ,5 -dimethoxyphenyl)-5-hydroxy-2(E)-
6.84 (1H, t, Jꢀ7.3 Hz), 7.00 (1H, dd, Jꢀ9.3, 16.1 Hz), 7.00 (1H, d,
Jꢀ7.3 Hz), 7.19 (1H, t, Jꢀ7.3 Hz), 7.24 (2H, d, Jꢀ8.3 Hz), 7.65 (2H, d,
Jꢀ8.3 Hz). Anal. Calcd for C H SO : C, 62.36; H, 5.98. Found: C, 62.60;
ꢀ
ꢀ ꢀ
hexenoate 2h To a solution of 1 (4.26 g, 0.03 mol) and 2,5-dimethoxy-
2
1
24
6
ꢂ
toluene (9.13 g, 0.06 mol) in CH Cl (60 ml) was added BF ·Et O (3.75 ml,
H, 5.87. MS (FAB) m/z: 405 (M ꢂ1).
Methyl (4,5)-anti-4-(2ꢀ-Methyl-4ꢀ-methoxyphenyl)-5-tosyloxy-2(E)-
and for 1 h at ꢁ20 °C. The reaction mixture was worked up in the same way hexenoate 4c A mixture of 2c (1.464 g, 0.0054 mol), p-toluenesulfonyl
2
2
3
2
0.03 mol) at ꢁ78 °C, and the whole mixture was stirred for 1 h at ꢁ78 °C,
as 2a to afford 2h (5.55 g, 63%) as a colorless oil. 2h: IR (neat): 3443,
chloride (TsCl, 1.55 g, 0.0083 mol), pyridine (4 ml) was stirred for 1 d at rt.
ꢁ1 1
1
714 cm ; H-NMR: d 1.09 (3H, d, Jꢀ6 Hz), 2.12 (1H, br s), 2.17 (3H, s),
The reaction mixture was worked up in the same way as 4a to afford
ꢁ1
1
3
.68 (3H, s), 3.72 (1H, ddd, Jꢀ2, 6, 8 Hz), 3.74 (3H, s), 3.75 (3H, s), 4.15 4c (2.034 g, 89%). 4c: IR (neat): 1714 cm
; H-NMR: d 1.25 (3H, d,
(
1H, dq, Jꢀ6, 6 Hz), 5.88 (1H, dd, Jꢀ2, 16 Hz), 6.60 (1H, s), 6.68 (1H, s),
Jꢀ6.4 Hz), 2.23 (3H, s), 2.44 (3H, s), 3.67 (3H, s), 3.74 (1H, t, Jꢀ8.4 Hz),
7
.31 (1H, dd, Jꢀ8, 16 Hz). Anal. Calcd for C H O : C, 65.29; H, 7.53. 3.75 (3H, s), 4.78 (1H, dq, Jꢀ8.4, 6.4 Hz), 5.68 (1H, d, Jꢀ15.6 Hz), 6.66
16 22 5
ꢂ
Found: C, 65.01; H, 7.72. MS (FAB) m/z: 295 (M ꢂ1).
Methyl (4,5)-anti-4-(2 ,5 -Dimethyl-4 -methoxyphenyl)-5-hydroxy-2(E)-
hexenoate 2i To a solution of 1 (4.26 g, 0.03 mol) and 1,4-dimethyl-2-
(1H, br s), 6.67 (1H, br d, Jꢀ8.4 Hz), 6.88 (1H, dd, Jꢀ8.4, 15.6 Hz), 6.91
(1H, d, Jꢀ8.4 Hz), 7.29 (2H, d, Jꢀ8.4 Hz), 7.73 (2H, d, Jꢀ8.4 Hz). Anal.
Calcd for C H SO : C, 63.14; H, 6.23. Found: C, 62.74; H, 6.34. MS
ꢀ
ꢀ
ꢀ
2
2
26
6
ꢂ
methoxybenzene (12.17 g, 0.09 mol) in CH Cl (50 ml) was added BF ·Et O (FAB) m/z: 419 (M ꢂ1).
2
2
3
2
(
ꢁ
3.78 ml, 0.03 mol) at ꢁ78 °C, and the whole mixture was stirred for 1 h at
78 °C, and for 1 h at ꢁ20 °C. The reaction mixture was worked up in the hexenoate 4d A mixture of 2d (0.488 g, 0.0018 mol), p-toluenesulfonyl
same way as 2a to afford 2i (6.89 g, 84%) as a colorless oil. 2i: IR (neat): chloride (TsCl, 0.718 g, 0.0037 mol), pyridine (2 ml) was stirred for 1 d at rt.
Methyl (4,5)-anti-4-(4ꢀ-Methyl-2ꢀ-methoxyphenyl)-5-tosyloxy-2(E)-
ꢁ1 1
3
422, 1719 cm ; H-NMR: d 1.07 (3H, d, Jꢀ7 Hz), 2.13 (3H, s), 2.23 (1H,
br s), 2.27 (3H, s), 3.53 (1H, dd, Jꢀ8.5, 8.5 Hz), 3.66 (3H, s), 3.77 (3H, s),
.06 (1H, dq, Jꢀ8.5, 7 Hz), 5.82 (1H, d, Jꢀ16 Hz), 6.59 (1H, s), 6.87 (1H,
s), 7.21 (1H, dd, Jꢀ8.5, 16 Hz). Anal. Calcd for C H O : C, 69.04; H, 7.97. (1H, t, Jꢀ8.4 Hz), 5.02 (1H, dq, Jꢀ8.4, 6.4 Hz), 5.67 (1H, br s), 5.73 (1H, d,
The reaction mixture was worked up in the same way as 4a to afford 4d
ꢁ
1
1
(0.773 g, quantitative yield). 4d: IR (neat): 1715 cm
; H-NMR: d 1.28
4
(3H, d, Jꢀ6.4 Hz), 2.30 (3H, s), 2.43 (3H, s), 3.69 (3H, s), 3.72 (3H, s), 3.78
1
6
22
4
ꢂ
Found: C, 68.78; H, 8.05. MS (FAB) m/z: 301 (M ꢂNa).
Methyl (4,5)-anti-4-(2ꢀ,4ꢀ-Dimethylphenyl)-5-hydroxy-2(E)-hexenoate dd, Jꢀ8.4, 15.8 Hz), 7.24 (2H, d, Jꢀ8.2 Hz), 7.66 (2H, d, Jꢀ8.2 Hz). Anal.
To a solution of 1 (4.26 g, 0.03 mol) and m-xylene (6.37 g, 0.06 mol) in Calcd for C H SO ·1/4H O; C, 62.47; H, 6.31. Found: C, 62.35; H, 6.36.
CH Cl (60 ml) was added BF ·Et O (3.75 ml, 0.03 mol) at ꢁ78 °C, and the
Jꢀ15.8 Hz), 6.64 (1H, br d, Jꢀ7.5 Hz), 6.86 (1H, d, Jꢀ7.5 Hz), 6.99 (1H,
2
j
2
2
26
6
2
ꢂ
MS (FAB) m/z: 419 (M ꢂ1).
2
2
3
2
whole mixture was stirred for 1 h at ꢁ78 °C, and for 1 h at ꢁ20 °C. The re-
Methyl (4,5)-anti-4-(3ꢀ-Methyl-4ꢀ-methoxyphenyl)-5-tosyloxy-2(E)-

1
264
Vol. 53, No. 10
hexenoate 4e A mixture of 2e (1.28 g, 0.0048 mol), p-toluenesulfonic an- washed with 7% aqueous NaHCO and dried over MgSO . Evaporation of
3
4
hydride (Ts O, 2.49 g, 0.0072 mmol), pyridine (10 ml) was stirred for 1 d at
the organic solvent gave a residue, which was chromatographed on silica gel
2
rt. The reaction mixture was worked up in the same way as 4a to afford 4e (20 g) to afford 4a (0.076 g, 8% recovery) from n-hexane : AcOEtꢀ50 : 1
ꢁ
1 1
(
2
(
1.59 g, 78%). 4e: IR (neat): 1725 cm ; H-NMR: d 1.22 (3H, d, Jꢀ6 Hz),
elution, 5a (0.405 g, 70%) from n-hexane : AcOEtꢀ30 : 1 elution and 2a
.11 (3H, s), 2.40 (3H, s), 3.40 (1H, ddd, Jꢀ2, 6, 8 Hz), 3.67 (3H, s), 3.75 (0.057 g, 10%) from n-hexane : AcOEtꢀ5 : 1 elution. Compound 2a was
3H, s), 4.80 (1H, dq, Jꢀ6, 6 Hz), 5.72 (1H, dd, Jꢀ2, 16 Hz), 6.67 (1H, d,
ꢁ1 1
identical with the above-mentioned 2a. 5a: IR (neat): 3472, 1716 cm ; H-
Jꢀ8 Hz), 6.78 (1H, d, Jꢀ2 Hz), 6.83 (1H, dd, Jꢀ2, 8 Hz), 6.91 (1H, dd, NMR: d 1.28 (3H, d, Jꢀ7 Hz), 2.92 (1H, dq, Jꢀ7, 7 Hz), 3.71 (3H, s), 3.78
Jꢀ8, 16 Hz), 7.23 (2H, d, Jꢀ8 Hz), 7.66 (2H, d, Jꢀ8 Hz). Anal. Calcd for (3H, s), 4.35 (1H, ddd, Jꢀ2, 5, 7 Hz), 5.99 (1H, dd, Jꢀ2, 15 Hz), 6.85 (2H,
C H SO ; C, 63.14; H, 6.26. Found: C, 63.15; H, 6.38. MS (FAB) m/z: 419 d, Jꢀ9 Hz), 6.90 (1H, dd, Jꢀ5, 15 Hz), 7.13 (2H, d, Jꢀ9 Hz). Anal. Calcd
22
26
6
ꢂ
(
M ꢂ1).
Methyl (4,5)-anti-4-(3
A mixture of 2f (1.67 g, 0.006 mol), p-toluenesulfonic anhydride (Ts O,
for C H O : C, 67.18; H, 7.25. Found: C, 67.64; H, 7.29. MS (FAB) m/z:
14 18 4
ꢂ
ꢀ,4ꢀ
-Dimethoxyphenyl)-5-tosyloxy-2(E)-hexenoate
251 (M ꢂ1).
4
3
f
Solvolysis of 6a A solution of 6a (0.749 g, 0.0023 mol) in water-satu-
rated nitromethane (120 ml) was stirred for 8 d at 50 °C. The reaction mix-
2
.11 g, 0.0091 mmol), pyridine (15 ml) was stirred for 1 d at rt. The reaction
mixture was worked up in the same way as 4a to afford 4f (2.47 g, 94%). 4f: ture was worked up in the same way as 4a to afford 6a (0.034 g, 5%), 5a
ꢁ1 1
IR (neat): 1725 cm ; H-NMR: d 1.21 (3H, d, Jꢀ6 Hz), 2.36 (3H, s), 3.42 (0.242 g, 42%) and 2a (0.065 g, 12%).
(
1H, ddd, Jꢀ2, 6, 8 Hz), 3.65 (3H, s), 3.76 (3H, s), 3.79 (3H, s), 4.80 (1H,
Acetylation of 2a A solution of 2a (0.518 g, 0.002 mol) and Ac O
2
dq, Jꢀ6, 6 Hz), 5.73 (1H, dd, Jꢀ2, 16 Hz), 6.51 (1H, d, Jꢀ2 Hz), 6.59 (1H,
dd, Jꢀ2, 8 Hz), 6.71 (1H, d, Jꢀ8 Hz), 6.94 (1H, ddd, Jꢀ2, 6, 8 Hz), 7.21
(0.42 g, 0.0041 mol) in pyridine (2 ml) was stirred for 1 d at rt. The reaction
mixture was diluted with H O and extracted with ether. The organic layer
2
(
6
2H, d, Jꢀ8 Hz), 7.62 (2H, d, Jꢀ8 Hz). Anal. Calcd for C H SO ; C,
0.81; H, 6.03. Found: C, 60.75; H, 6.10. MS (FAB) m/z: 434 (M ).
Methyl (4,5)-anti-4-(5ꢀ-Methyl-2ꢀ-methoxyphenyl)-5-tosyloxy-2(E)-
was washed with 1 M aqueous HCl, 7% aqueous NaHCO and dried over
2
2
26
7
3
ꢂ
MgSO . Evaporation of the organic solvent gave a residue, which was chro-
4
matographed on silica gel (20 g, n-hexane : AcOEtꢀ10 : 1) to afford 7a
ꢁ1
1
hexenoate 4g A mixture of 2g (1.58 g, 0.006 mol), p-toluenesulfonic anhy- (0.545 g, 90%). 7a: IR (neat): 1730, 1657 cm ; H-NMR: d 1.19 (3H, d,
dride (Ts O, 3.07 g, 0.009 mmol), pyridine (12 ml) was stirred for 1 d at rt.
The reaction mixture was worked up in the same way as 4a to afford 4g
Jꢀ7 Hz), 2.00 (3H, s), 3.44 (1H, ddd, Jꢀ1, 9, 9 Hz), 3.67 (3H, s), 3.76 (3H,
s), 5.16 (1H, dq, Jꢀ9, 7 Hz), 5.79 (1H, dd, Jꢀ1, 16 Hz), 6.83 (2H, d,
Jꢀ8 Hz), 7.08 (2H, d, Jꢀ8 Hz), 7.09 (1H, dd, Jꢀ9, 16 Hz). Anal. Calcd for
C H O : C, 65.74; H, 6.90. Found: C, 65.34; H, 6.88. MS (FAB) m/z: 293
2
ꢁ1 1
(
2
2.12 g, 85%). 4g: IR (neat): 1715 cm ; H-NMR: d 1.26 (3H, d, Jꢀ6 Hz),
.18 (3H, s), 2.40 (3H, s), 3.67 (3H, s), 3.69 (3H, s), 3.76 (1H, ddd, Jꢀ2, 6,
Hz), 5.04 (1H, dq, Jꢀ6, 6 Hz), 5.73 (1H, dd, Jꢀ2, 16 Hz), 6.63 (1H, d, (M ꢂ1).
1
6
20
5
ꢂ
8
Jꢀ8 Hz), 6.75 (1H, d, Jꢀ2 Hz), 6.94 (1H, dd, Jꢀ2, 8 Hz), 6.97 (1H, dd,
Jꢀ6, 16 Hz), 7.21 (2H, d, Jꢀ8 Hz), 7.62 (2H, d, Jꢀ8 Hz). Anal. Calcd for
Acetylation of 5a A solution of 5a (0.169 g, 0.0007 mol) and Ac O
(0.14 g, 0.0014 mol) in pyridine (2 ml) was stirred for 1 d at rt. The reaction
2
C H SO ; C, 63.14; H, 6.26. Found: C, 62.92; H, 6.38. MS (FAB) m/z: 419 mixture was worked up in the same way as 2a to afford 8a (0.176 g, 89%).
2
2
26
6
ꢂ
ꢁ1 1
(
M ꢂ1).
8a: IR (neat): 1726, 1662 cm ; H-NMR: d 1.27 (3H, d, Jꢀ7 Hz), 2.06 (3H,
s), 2.98 (1H, dq, Jꢀ7, 7 Hz), 3.66 (3H, s), 3.77 (3H, s), 5.46 (1H, ddd, Jꢀ2,
Methyl (4,5)-anti-4-(4
ꢀ-Methyl-2ꢀ,5ꢀ-dimethoxyphenyl)-5-tosyloxy-2(E)-
hexenoate 4h A mixture of 2h (1.48 g, 0.005 mol), p-toluenesulfonic anhy- 6, 7 Hz), 5.78 (1H, dd, Jꢀ2, 16 Hz), 6.71 (1H, dd, Jꢀ6, 16 Hz), 6.81 (2H, d,
dride (Ts O, 2.58 g, 0.0075 mmol), pyridine (12 ml) was stirred for 1 d at rt.
Jꢀ8 Hz), 7.07 (2H, d, Jꢀ8 Hz). Anal. Calcd for C H O : C, 65.74; H, 6.90.
16 20 5
ꢂ
2
The reaction mixture was worked up in the same way as 4a to afford 4h
Found: C, 65.50; H, 6.90. MS (FAB) m/z: 293 (M ꢂ1).
Solvolysis of 4e A solution of 4e (1.01 g, 0.0024 mol) in water-saturated
.14 (3H, s), 2.39 (3H, s), 3.65 (3H, s), 3.66 (3H, s), 3.68 (3H, s), 3.75 (1H, nitromethane (120 ml) was stirred for 3 d at 50 °C. The reaction mixture was
ꢁ1 1
(
2
1.42 g, 79%). 4h: IR (neat): 1715 cm ; H-NMR: d 1.27 (3H, d, Jꢀ6 Hz),
ddd, Jꢀ2, 6, 8 Hz), 5.02 (1H, dq, Jꢀ6, 6 Hz), 5.75 (1H, dd, Jꢀ2, 16 Hz),
worked up in the same way as 4a to afford 4e (0.18 g, 18% recovery), 5e
(0.32 g, 51%) and 2e (0.04 g, 6%). Compound 2e was identical with the
6
.41 (1H, s), 6.55 (1H, s), 7.00 (1H, dd, Jꢀ8, 16 Hz), 7.20 (2H, d, Jꢀ8 Hz),
ꢁ1 1
7
.61 (2H, d, Jꢀ8 Hz). Anal. Calcd for C H SO ; C, 61.59; H, 6.29. Found: above-mentioned 2e. 5e: IR (neat): 3462, 1724 cm ; H-NMR: d 1.25 (3H,
2
3
28
7
ꢂ
C, 61.38; H, 6.58. MS (FAB) m/z: 449 (M ꢂ1).
Methyl (4,5)-anti-4-(2 ,5 -Dimethyl-4 -methoxyphenyl)-5-tosyloxy-2(E)-
d, Jꢀ8 Hz), 2.18 (3H, s), 2.55 (1H, br s), 2.83 (1H, dq, Jꢀ4, 8 Hz), 3.68 (3H,
s), 3.77 (3H, s), 4.31 (1H, ddd, Jꢀ2, 4, 4 Hz), 5.98 (1H, dd, Jꢀ2, 16 Hz),
6.73 (1H, d, Jꢀ8 Hz), 6.88 (1H, dd, Jꢀ4, 16 Hz), 6.96 (1H, d, Jꢀ2 Hz), 6.97
(1H, dd, Jꢀ2, 8 Hz). Anal. Calcd for C H O : C, 68.16; H, 7.63. Found: C,
ꢀ
ꢀ
ꢀ
hexenoate 4i A mixture of 2i (2.766 g, 0.0099 mol), p-toluenesulfonic an-
hydride (Ts O, 4.9 g, 0.015 mmol), pyridine (20 ml) was stirred for 1 d at rt.
2
15 20
4
ꢂ
The reaction mixture was worked up in the same way as 4a to afford 4i
68.46; H, 7.73. MS (FAB) m/z: 287 (M ꢂNa).
ꢁ
1
1
(
3.153 g, 73%). 4i: IR (neat): 1715 cm
;
H-NMR: d 1.23 (3H, d,
Solvolysis of 4f A solution of 4f (1.00 g, 0.0023 mol) in water-saturated
Jꢀ6.5 Hz), 2.09 (3H, s), 2.21 (3H, s), 2.42 (3H, s), 3.66 (3H, s), 3.69 (1H, nitromethane (120 ml) was stirred for 4 d at 50 °C. The reaction mixture was
ddd, Jꢀ2, 8, 8 Hz), 4.87 (1H, dq, Jꢀ8, 6.5 Hz), 5.66 (1H, dd, Jꢀ2, 16 Hz),
worked up in the same way as 4a to afford 4f (0.03 g, 3% recovery), 5f
(0.34 g, 52%) and 2f (0.076 g, 12%). Compound 2f was identical with the
6
.53 (1H, s), 6.69 (1H, s), 6.86 (1H, dd, Jꢀ8, 16 Hz), 7.27 (2H, d, Jꢀ8 Hz),
ꢁ1 1
7
.70 (2H, d, Jꢀ8 Hz). Anal. Calcd for C H SO ; C, 63.87; H, 6.53. Found: above-mentioned 2f. 5f: IR (neat): 3500, 1714 cm ; H-NMR: d 1.27 (3H,
2
3
28
6
ꢂ
C, 63.66; H, 6.58. MS (FAB) m/z: 433 (M ꢂ1).
d, Jꢀ8 Hz), 1.92 (1H, br s), 2.90 (1H, dq, Jꢀ4, 8 Hz), 3.68 (3H, s), 3.82 (3H,
Methyl (4,5)-anti-4-(2ꢀ,4ꢀ-Dimethylphenyl)-5-tosyloxy-2(E)-hexenoate s), 3.83 (3H, s), 4.35 (1H, ddd, Jꢀ2, 4, 4 Hz), 5.97 (1H, dd, Jꢀ2, 16 Hz),
4
j
A mixture of 2j (1.51 g, 0.006 mol), p-toluenesulfonic anhydride (Ts O,
6.69 (1H, d, Jꢀ2 Hz), 6.73 (1H, dd, Jꢀ2, 8 Hz), 6.79 (1H, d, Jꢀ8 Hz), 6.89
(1H, dd, Jꢀ4, 16 Hz). Anal. Calcd for C H O : C, 64.27; H, 7.19. Found:
2
4.09 g, 0.012 mmol), pyridine (15 ml) was stirred for 1 d at rt. The reaction
1
5
20
5
ꢂ
mixture was worked up in the same way as 4a to afford 4j (2.02 g, 82%). 4j: C, 64.11; H, 7.38. MS (FAB) m/z: 303 (M ꢂNa).
ꢁ1 1
IR (neat): 1714 cm ; H-NMR: d 1.23 (3H, d, Jꢀ7 Hz), 2.20 (3H, s), 2.24
3H, s), 2.43 (3H, s), 3.66 (3H, s), 3.75 (1H, ddd, Jꢀ2, 8, 8 Hz), 4.87 (1H,
dq, Jꢀ8, 7 Hz), 5.66 (1H, dd, Jꢀ2, 16 Hz), 6.85 (1H, dd, Jꢀ8, 16 Hz), 6.86
1H, d, Jꢀ8 Hz), 6.90—6.94 (2H, m), 7.27 (2H, d, Jꢀ8 Hz), 7.71 (2H, d,
Solvolysis of 4b A solution of 4b (0.671 g, 0.0017 mol) in water-satu-
rated nitromethane (100 ml) was stirred for 7 d at 50 °C. The reaction mix-
ture was worked up in the same way as 4a to afford 4b (0.106 g, 16% recov-
ery), 5b (0.085 g, 21%) and 2b (0.127 g, 31%). Compound 2b was identical
(
(
ꢁ1 1
Jꢀ8 Hz). Anal. Calcd for C H SO ; C, 65.65; H, 6.51. Found: C, 65.37; H, with the above-mentioned 2b. 5b: IR (neat): 3454, 1716 cm ; H-NMR: d
2
2
26
5
ꢂ
6
.74. MS (FAB) m/z: 403 (M ꢂ1).
Methyl (4,5)-anti-4-(2ꢀ,3ꢀ,4ꢀ,5ꢀ-Tetramethylphenyl)-5-tosyloxy-2(E)- (3H, s), 3.82 (3H, s), 4.49 (1H, ddd, Jꢀ2, 4, 5 Hz), 6.02 (1H, dd, Jꢀ2,
hexenoate 4k A mixture of 2k (2.644 g, 0.01 mol), p-toluenesulfonic an- 16 Hz), 6.87 (1H, d, Jꢀ8 Hz), 6.93 (1H, t, Jꢀ7 Hz), 6.94 (1H, dd, Jꢀ5,
1.25 (3H, d, Jꢀ7 Hz), 2.34—2.48 (1H, m), 3.47 (1H, dq, Jꢀ4, 7 Hz), 3.71
hydride (Ts O, 4.89 g, 0.015 mmol), pyridine (20 ml) was stirred for 1 d at rt.
16 Hz), 7.15—7.23 (2H, m). Anal. Calcd for C H O : C, 67.18; H, 7.25.
2
14 18
4
ꢂ
The reaction mixture was worked up in the same way as 4a to afford Found: C, 67.59; H, 7.49. MS (FAB) m/z: 251 (M ꢂ1).
ꢁ
1
1
4
k (3.016 g, 70%). 4k: IR (neat): 1715 cm
;
H-NMR: d 1.25 (3H, d,
Solvolysis of 4d A solution of 4d (1.723 g, 0.0041 mol) in water-satu-
Jꢀ6.5 Hz), 2.11 (3H, s), 2.13 (3H, s), 2.14 (3H, s), 2.19 (3H, s), 2.42 (3H, rated nitromethane (200 ml) was stirred for 3 d at 50 °C. The reaction mix-
s), 3.67 (3H, s), 3.82 (1H, ddd, Jꢀ2, 9, 9 Hz), 4.90 (1H, dq, Jꢀ9, 6.5 Hz),
.68 (1H, dd, Jꢀ2, 16 Hz), 6.62 (1H, s), 6.92 (1H, dd, Jꢀ9, 16 Hz), 7.25
2H, d, Jꢀ8 Hz), 7.69 (2H, d, Jꢀ8 Hz). Anal. Calcd for C H SO ; C,
ture was worked up in the same way as 4a to afford 5d (0.508 g, 47%) and
2d (0.411 g, 38%). Compound 2d was identical with the above-mentioned
2d. 5d: IR (neat): 3474, 1719 cm ; H-NMR: d 1.24 (3H, d, Jꢀ7 Hz), 2.34
(3H, s), 3.45 (1H, dq, Jꢀ4, 7 Hz), 3.72 (3H, s), 3.82 (3H, s), 4.47—4.52
5
(
ꢁ1 1
2
4
30
5
ꢂ
6
6.95; H, 7.02. Found: C, 66.76; H, 7.07. MS (FAB) m/z: 431 (M ꢂ1).
Solvolysis of 4a A solution of 4a (0.939 g, 0.0023 mol) in water-satu- (1H, m), 6.03 (1H, dd, Jꢀ2, 16 Hz), 6.70 (1H, s), 6.76 (1H, d, Jꢀ8 Hz), 6.94
rated nitromethane (120 ml) was stirred for 5 d at 50 °C. The reaction mix- (1H, dd, Jꢀ4, 16 Hz), 7.05 (1H, d, Jꢀ8 Hz). Anal. Calcd for C H O : C,
ture was diluted with water and extracted with ether. The organic layer was 68.16; H, 7.63. Found: C, 68.32; H, 7.61. MS (FAB) m/z: 265 (M ꢂ1).
1
5
20
4
ꢂ

October 2005
Solvolysis of 4g A solution of 4g (1.01 g, 0.0024 mol) in water-saturated C, 72.25; H, 8.25. MS (FAB) m/z: 271 (M ꢂNa).
1265
ꢂ
nitromethane (120 ml) was stirred for 7 d at 50 °C. The reaction mixture was
Solvolysis of 4k A solution of 4k (1.148 g, 0.0027 mol) in water-satu-
worked up in the same way as 4a to afford 4g (0.071 g, 7% recovery), 5g
rated nitromethane (200 ml) was stirred for 5 d at 50 °C. The reaction mix-
(
0.12 g, 19%) and 2g (0.18 g, 28%). Compound 2g was identical with the ture was worked up in the same way as 4a to afford 4k (0.034 g, 3% recov-
ꢁ1 1
above-mentioned 2g. 5g: IR (neat): 3458, 1714 cm ; H-NMR: d 1.22 (3H, ery), 5k (0.152 g, 21%) and 2k (0.507 g, 69%). Compound 2k was identical
d, Jꢀ8 Hz), 2.26 (3H, s), 2.38 (1H, br s), 3.40 (1H, dq, Jꢀ4, 8 Hz), 3.69 (3H,
s), 3.77 (3H, s), 4.46 (1H, ddd, Jꢀ2, 4, 4 Hz), 6.01 (1H, dd, Jꢀ2, 16 Hz),
ꢁ1
1
with the above-mentioned 2j. 5j: IR (neat): 3472, 1693 cm ; H-NMR: d
1.26 (3H, d, Jꢀ6 Hz), 1.77 (1H, br s), 2.19 (3H, s), 2.21 (3H, s), 2.22 (3H,
s), 2.27 (3H, s), 3.31 (1H, dq, Jꢀ7, 6 Hz), 3.73 (3H, s), 4.38 (1H, ddd, Jꢀ2,
6
.74 (1H, d, Jꢀ8 Hz), 6.92 (1H, dd, Jꢀ4, 16 Hz), 6.97 (1H, d, Jꢀ2 Hz), 6.98
(
6
1H, dd, Jꢀ2, 8 Hz). Anal. Calcd for C H O : C, 68.16; H, 7.63. Found: C, 5, 7 Hz), 6.08 (1H, dd, Jꢀ2, 16 Hz), 6.91 (1H, s), 6.95 (1H, d, Jꢀ5, 16 Hz).
1
5
20
4
ꢂ
8.07; H, 7.70. MS (FAB) m/z: 287 (M ꢂNa).
Solvolysis of 4h A solution of 4h (1.19 g, 0.0026 mol) in water-satu- (FAB) m/z: 299 (M ꢂNa).
Anal. Calcd for C H O : C, 73.88; H, 8.75. Found: C, 73.68; H, 8.78. MS
17 24 3
ꢂ
rated nitromethane (120 ml) was stirred for 4 d at 50 °C. The reaction mix-
ture was worked up in the same way as 4a to afford 4h (0.13 g, 11% recov-
ery), 5h (0.12 g, 15%) and 2h (0.15 g, 19%). Compound 2h was identical
Conversion of 5c into g-Lactone 9c A solution of 5c (0.21 g,
0.0008 mol) in AcOEt (10 ml) was subjected to a catalytic hydrogenation in
the presence of 20% Pd(OH) –C at rt and the reaction mixture was filtered
2
ꢁ1 1
with the above-mentioned 2h. 5h: IR (neat): 3470, 1714 cm ; H-NMR: d
off. The filtrate was condensed to give a residue, which was treated with 2 M
aqueous NaOH (1 ml) and stirred for 1 h at rt. Acidification of the reaction
mixture with 2 M aqueous HCl gave a crude carboxylic acid. A mixture of a
crude carboxylic acid and DCC (0.15 g, 0.0007 mol) in CH Cl (5 ml) was
1
3
.23 (3H, d, Jꢀ8 Hz), 2.18 (3H, s), 2.28 (1H, br s), 3.42 (1H, dq, Jꢀ4, 8 Hz),
.69 (3H, s), 3.75 (3H, s), 3.76 (3H, s), 4.47 (1H, ddd, Jꢀ2, 4, 4 Hz), 6.00
(
1H, dd, Jꢀ2, 16 Hz), 6.64 (1H, s), 6.68 (1H, s), 6.92 (1H, dd, Jꢀ4, 16 Hz).
2
2
Anal. Calcd for C H O : C, 65.29; H, 7.53. Found: C, 64.99; H, 7.69. MS stirred for 1 d at rt. The whole mixture was condensed to give a residue,
1
6
22
5
ꢂ
(
FAB) m/z: 317 (M ꢂNa).
Solvolysis of 4c A solution of 4c (1.00 g, 0.0024 mol) in water-saturated afford 9c (0.13 g, 70%). 9c: IR (neat): 1769 cm ; H-NMR: d 1.19 (3H, d,
nitromethane (120 ml) was stirred for 3 d at 50 °C. The reaction mixture was
Jꢀ6.3 Hz), 1.99—2.05 (2H, m), 2.34 (3H, s), 2.62 (1H, dt, Jꢀ17.5, 8.5 Hz),
worked up in the same way as 4a to afford 4c (0.10 g, 10% recovery), 5c 2.80 (1H, dt, Jꢀ17.5, 5.5 Hz), 3.00 (1H, dq, Jꢀ10.3, 6.3 Hz), 3.78 (3H, s),
0.11 g, 17%) and 2c (0.35 g, 55%). Compound 2c was identical with the 4.58 (1H, ddd, Jꢀ6.8, 9.8, 10.3 Hz), 6.74 (1H, s), 6.75 (1H, d, Jꢀ6.8 Hz),
which was chromatographed on silica gel (20 g, benzene : AcOEtꢀ10 : 1) to
ꢁ1 1
(
ꢁ1 1
above-mentioned 2c. 5c: IR (neat): 3472, 1715 cm ; H-NMR: d 1.27 (3H, 7.01 (1H, d, Jꢀ6.8 Hz). Anal. Calcd for C H O : C, 71.77; H, 7.74. Found:
d, Jꢀ7 Hz), 2.29 (3H, s), 3.18 (1H, dq, Jꢀ5, 7 Hz), 3.73 (3H, s), 3.78 (3H,
s), 4.32—4.37 (1H, m), 6.05 (1H, dd, Jꢀ2, 16 Hz), 6.73 (1H, d, Jꢀ3 Hz),
1
4
18
3
ꢂ
C, 71.23; H, 7.99. MS (FAB) m/z: 235 (M ꢂ1). The NMR data of 9c were
identical with those of the authentic sample 9c prepared by the reported
7
6
.74 (1H, dd, Jꢀ3, 8 Hz), 6.92 (1H, dd, Jꢀ4, 16 Hz), 7.15 (1H, d, Jꢀ8 Hz).
method.
Anal. Calcd for C H O : C, 68.16; H, 7.63. Found: C, 67.74; H, 8.05. MS
1
5
20
4
ꢂ
(
FAB) m/z: 265 (M ꢂ1).
References
Solvolysis of 4i A solution of 4i (1.148 g, 0.0023 mol) in water-saturated
nitromethane (200 ml) was stirred for 5 d at 50 °C. The reaction mixture was
1) Ono M., Suzuki K., Akita H., Tetrahedron Lett., 40, 8223—8226
(1999).
worked up in the same way as 4a to afford 4i (0.054 g, 5% recovery), 5i
2) Ono M., Tanikawa S., Suzuki K., Akita H., Tetrahedron, 60, 10187—
10195 (2004).
3) Akita H., Umezawa I., Takano M., Matsukura H., Oishi T., Chem.
Pharm. Bull., 39, 3094—3096 (1991).
4) Akita H., Umezawa I., Takano M., Ohyama C., Matsukura H., Oishi
T., Chem. Pharm. Bull., 41, 55—63 (1993).
(
0.208 g, 28%) and 2i (0.337 g, 46%). Compound 2i was identical with the
ꢁ1 1
above-mentioned 2i. 5i: IR (neat): 3419, 1725 cm ; H-NMR: d 1.24 (3H,
d, Jꢀ6.5 Hz), 2.00 (1H, br s), 2.16 (3H, s), 2.26 (3H, s), 3.11 (1H, dq,
Jꢀ6.5, 6.5 Hz), 3.69 (3H, s), 3.78 (3H, s), 4.33 (1H, ddd, Jꢀ2, 5, 6.5 Hz),
6
.03 (1H, dd, Jꢀ2, 15 Hz), 6.61 (1H, s), 6.88 (1H, dd, Jꢀ5, 16 Hz), 6.96
(
8
1H, s). Anal. Calcd for C H O : C, 69.04; H, 7.97. Found: C, 68.98; H,
.15. MS (FAB) m/z: 301 (M ꢂNa).
5) Akita H., Umezawa I., Takano M., Oishi T., Chem. Pharm. Bull., 41,
680—684 (1993).
1
6
22
4
ꢂ
Solvolysis of 4j A solution of 4j (1.01 g, 0.0024 mol) in water-saturated
nitromethane (120 ml) was stirred for 12 d at 50 °C. The reaction mixture
6) Winstein S., Brown M., Schreiber C., Schleinger A. H., J. Am. Chem.
Soc., 74, 1140—1147 (1952).
was worked up in the same way as 4a to afford 4j (0.07 g, 7% recovery), 5j
7) Nagumo S., Hisano T., Kakimoto Y., Kawahara N., Ono M., Furukawa
T., Takeda S., Akita H., Tetrahedron Lett., 39, 8109—8112 (1998).
8) Manner J. A., Cook J. A., Ramsey B. G., J. Org. Chem., 39, 1199—
1203 (1974).
(
0.15 g, 25%) and 2j (0.18 g, 29%). Compound 2j was identical with the
ꢁ1 1
above-mentioned 2j. 5j: IR (neat): 3455, 1724 cm ; H-NMR: d 1.26 (3H,
d, Jꢀ8 Hz), 1.98 (1H, br s), 2.26 (3H, s), 2.28 (3H, s), 3.17 (1H, dq, Jꢀ4,
8
6
7
Hz), 3.71 (3H, s), 4.37 (1H, ddd, Jꢀ2, 4, 4 Hz), 6.04 (1H, dd, Jꢀ2, 16 Hz),
.90 (1H, dd, Jꢀ4, 16 Hz), 6.98 (1H, d, Jꢀ2 Hz), 6.99 (1H, dd, Jꢀ2, 8 Hz),
.11 (1H, d, Jꢀ8 Hz). Anal. Calcd for C H O : C, 72.55; H, 8.12. Found:
9) Nagumo S., Ono M., Kakimoto Y., Furukawa T., Hisano T., Mizukami
M., Kawahara N., Akita H., J. Org. Chem., 67, 6618—6622 (2002).
1
5
20
3