Synthesis of (R)-curcumene and (R)-xanthorrizol based on 1,2-aryl migration via phenonium ion

Article abstract of DOI:10.1248/cpb.55.1361

Solvolysis reaction of methyl (4S,5S)-4-(4′-methoxyphenyl)-5- tosyloxy-2(E)-hexenoate 5 in water-saturated MeNO₂ gave the 1,2-migration product, (4S,5S)-5-hydroxy-4-(4′-methoxyphenyl)-2-(E)- hexenoate 6 (55% yield), which was converted to methyl (R)-(4′- methylphenyl)hexanoate 11 in 25% overall yield (5 steps). Treatment of (R)-11 with MeLi gave tertiary alcohol congener 12, which was subjected to dehydration to afford (R)-(-)-curcumene 1. An introduction of hydroxyl group at meta-position of the aromatic ring in (R)-11 was achieved based on consecutive treatment [1) selective iodination, 2) conversion of aryl iodide to aryl boronate, 3) conversion of aryl boronate to phenol]. Thus obtained phenol (R)-16 was treated with MeLi to give tertiary alcohol congener 17, which was subjected to dehydration to afford (R)-(-)-xanthorrizol 2.

Full text of DOI:10.1248/cpb.55.1361

September 2007
Chem. Pharm. Bull. 55(9) 1361—1364 (2007)
1361
Synthesis of (R)-Curcumene and (R)-Xanthorrizol Based on 1,2-Aryl
Migration via Phenonium Ion
a,b
a
c
,a
Takeru EHARA, Shin TANIKAWA, Machiko ONO, and Hiroyuki AKITA*
a
b
School of Pharmaceutical Sciences, Toho University; 2–2–1 Miyama, Funabashi, Chiba 274–8510, Japan: Tsukuba
c
Research Institute, Novartis Pharma K.K.; 8 Ohkubo, Tsukuba, Ibaraki 300–2611, Japan: and School of Pharmaceutical
Sciences, International University of Health and Welfare; 2600–1 Kitakanemaru, Ohtawara, Tochigi 324–8501, Japan.
Received June 1, 2007; accepted July 2, 2007; published online July 3, 2007
Solvolysis reaction of methyl (4S,5S)-4-(4ꢀ-methoxyphenyl)-5-tosyloxy-2(E)-hexenoate 5 in water-saturated
MeNO gave the 1,2-migration product, (4S,5S)-5-hydroxy-4-(4ꢀ-methoxyphenyl)-2-(E)-hexenoate 6 (55% yield),
2
which was converted to methyl (R)-(4ꢀ-methylphenyl)hexanoate 11 in 25% overall yield (5 steps). Treatment of
(R)-11 with MeLi gave tertiary alcohol congener 12, which was subjected to dehydration to afford (R)-(ꢁ)-cur-
cumene 1. An introduction of hydroxyl group at meta-position of the aromatic ring in (R)-11 was achieved based
on consecutive treatment [1) selective iodination, 2) conversion of aryl iodide to aryl boronate, 3) conversion of
aryl boronate to phenol]. Thus obtained phenol (R)-16 was treated with MeLi to give tertiary alcohol congener
17, which was subjected to dehydration to afford (R)-(ꢁ)-xanthorrizol 2.
Key words (R)-(ꢀ)-curcumene; (R)-(ꢀ)-xanthorrizol; solvolysis; 1,2-aryl migration; phenonium ion
8)
In the several important classes of natural products, bis- version in good yield. We now report that (R)-curcumene 1
abolane family compounds are characterized by a benzylic and (R)-xanthorrizol 2 have been synthesized based on 1,2-
chiral center bearing a methyl group. (R)-(ꢀ)-curcumene 1 is aryl migration via phenonium ion.
the constituent of a large number of essential oil, and used
We previously reported that the BF ·Et O-assisted reac-
3 2
for the syntheses of a number of other bisabolane family and tion of (4,5)-epoxy-2(E)-hexenoate (3) with benzene analog
1)
other related terpene. Xanthorrizol 2 was first extracted bearing electron-donating group gave (4,5-anti)-4-aryl-5-hy-
9
—11)
from Curcuma xanthorrhiza, which is used in traditional droxy-(2E)-hexenoate A.
Moreover, solvolysis of (4,5-
2)
medicine in Indonesia. Afterward, xanthorrizol 2 was also anti)-4-aryl-5-tosyloxy-(2E)-hexenoate B derived from A in
water-saturated MeNO gave 1,2-aryl migration product D
2
Moreover, xanthorrizol 2 was identified as a principle pro- along with complete inversion in good yield. In the case of
3)
isolated from the same plant as an antitumor constituent.
8)
longing pentobarbital-induced sleeping time, of which effect this reaction, an intermolecular attack of the nucleophile
was indicated to be due to inhibition of cytochrome P-450 (H O) to the s-bridged phenonium ion C proceeded selec-
2
4)
activity. Despite their rather simple structures, the stereo- tively at the C(4)-position to provide the (4,5-anti)-5-aryl-4-
center at the benzylic position poses a significant challenge hydroxy-(2E)-hexenoate D. If this reaction were applied for
in the asymmetric synthesis of even the simplest of these the chiral synthesis of (R)-1 or (R)-2, solvolysis of (4S,5S)-4-
molecules. Judging from the publications dealing with the (4ꢂ-methoxyphenyl)-5-tosyloxy-(2E)-hexenoate 5 seems to
synthesis of curcumene 1, this molecule has evolved as a test be promising, because solvolysis of (ꢃ)-5 gives the type D
8)
target for indicating new asymmetric methodology and nine compound with a 7 : 1 selectivity (D : Aꢄ7 : 1). Methoxyl
5)
synthesis of (ꢀ)-1 were reported. Although nine syntheses group of the type D compound (6) could be convertible to
of xanthorrizol 2 have been reported, the first asymmetric methyl group. Then the BF ·Et O-assisted reaction of
3
2
6
)
7)
synthesis of unnatural (ꢁ)-2 and natural (ꢀ)-2 based on (4S,5S)-4-epoxy-(2E)-hexenoate 3 and anisole was carried
chemoenzymatic transformation were reported. On the other out. The synthesis of (R)-(ꢀ)-curcumene (2) from (4S,5S)-3
hand, we reported construction of the stereocenter at the ben- is shown in Chart 2.
12)
zylic position based on solvolysis of (4,5-anti)-4-aryl-5-tosyl-
The reaction of (4S,5S)-3 and anisole gave (4S,5S)-4
oxy-(2E)-hexenoate congeners in water-saturated MeNO af- (72% yield), of which structure was confirmed by the direct
2
10)
fording 1,2-aryl migration products along with complete in- comparison of the reported (ꢃ)-3. Treatment of (4S,5S)-4
Chart 1
∗
To whom correspondence should be addressed. e-mail: akita@phar.toho-u.ac.jp
© 2007 Pharmaceutical Society of Japan

1
362
Vol. 55, No. 9
Chart 2
Chart 3
with tosyl chloride (TsCl) afforded the corresponding tosy- aryl boronate, 3) conversion of aryl boronate to phenol. Re-
late (4S,5S)-5 (87% yield), which was subjected to solvolysis cently, benzene derivatives, bearing at least one bulky, alkyl
in water-saturated MeNO to provide the 1,2-migration prod- group (iso-Pr, tert-Bu) were reported to give effectively the
2
uct (4S,5S)-6 (55% yield). Treatment of (4S,5S)-6 with N- iodinated compounds using elemental iodine activated by 1-
chlorosuccinimide (NCS) and triphenylphosphine (Ph P) (chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
3
TM
15)
gave a single isomer (5S)-7 (82% yield), which was sub- bis(tetrafluoroborate) (Selectfluor , F-TEDA-BF4).
By
jected to hydrogenolysis to afford the saturated ester (R)-8 applying this procedure, (R)-11 was treated with iodine (I )
2
TM
(
65% yield). Demethylation of (R)-8 with a combination in the presence of Selectfluor to give the desired iodide 14
of AlCl and 1-dodecanethiol (C H SH) provided the in 65% yield. Substitution pattern of the aromatic ring of 14
phenol (R)-9 (82% yield), which was treated with trifluoro- was confirmed by H-NMR analysis. The reaction of 14 with
methanesufonic anhydride (Tf O) to afford the correspond- bis(pinacolato)diboron [B (pin) ] in the presence of [1,1ꢂ-
13)
3
12 25
1
16)
2
2
2
ing trifluoromethanesufonate (R)-10 (86% yield). The reac- bis(diphenylphosphino)ferrocene]dichloropalladium(II) com-
tion of (R)-10 with tetramethyltin (Me Sn) in the presence of plex with dichloromethane [PdCl (dppf)·CH Cl ] afforded
4
2
2
2
tetrakis(triphenylphosphine)palladium(0) (Pd(PPh ) ) gave 4- the corresponding aryl boronate congener 15 (87%), which
3
4
substituted toluene congener (R)-11 (67% yield). Treatment was treated with 30% H O to provide the desired phenol 16
2
2
of (R)-11 with MeLi followed by dehydration afforded a 9 : 1 in 75% yield. Treatment of (R)-16 with MeLi gave tertiary
mixture (1 : 13ꢄ9 : 1) of dehydration products in 87% yield. alcohol congener 17 (88%), which was subjected to dehydra-
For the purpose of exclusion of the undesired isomer 13, this tion to provide a 10 : 1 mixture of 2 and 18 (2 : 18ꢄ10 : 1). A
mixture was treated with Grubb’s reagent (2nd generation) to part of this mixture was subjected to preparative TLC to
2
3
24
provide (R)-curcumene 1 ([a] ꢀ45.0° (cꢄ0.75, CHCl )) in afford a synthetic (R)-xanthorrizol 2 ([a] ꢀ53.5° (cꢄ0.75,
D
3
D
1
13
1
13
3
2% yield. Spectral data ( H-, C-NMR) were identical with CHCl )). Spectral data ( H-, C-NMR) of the synthetic
3
those of the reported sample 1 including a specific rotation (R)-xanthorrizol 2 were identical with those of the reported
2
3
14)
(
(
[a] ꢀ46.2° (cꢄ0.95, CHCl )). Then, the synthesis of sample 2 including a specific rotation ([a] ꢀ54° (cꢄ0.13,
D
3
D
7)
R)-(ꢀ)-xanthorrizol (2) from (5R)-11 is shown in Chart 3.
The most intriguing point in the synthesis of (R)-2 from
CHCl )).
3
(R)-11 is introduction of hydroxyl group at meta-position of Conclusion
the aromatic ring. This problem was solved by the following
Solvolysis reaction of methyl (4S,5S)-4-(4ꢂ-methoxyphen-
steps: 1) selective iodination, 2) conversion of aryl iodide to yl)-5-tosyloxy-2(E)-hexenoate 5 in water-saturated MeNO2

September 2007
1363
); IR (neat): 1738 cm . NMR: d 1.21 (3H, d, Jꢄ
ꢀ
1
gave the 1,2-migration product, (4S,5S)-5-hydroxy-4-(4ꢂ- ꢀ11.0° (cꢄ2.50, CHCl
methoxyphenyl)-2-(E)-hexenoate 6 (55% yield), which was
converted to methyl (R)-(4ꢂ-methylphenyl)hexanoate 11 in
3
6
6
8
1
.8 Hz), 1.45—1.61 (4H, m), 2.26 (2H, t, Jꢄ7 Hz), 2.65 (1H, sixtet, Jꢄ
.8 Hz), 3.64 (3H, s), 3.79 (3H, s), 6.83 (2H, d, Jꢄ8.7 Hz), 7.09 (2H, d, Jꢄ
1
3
.7 Hz). C-NMR: d 22.6, 23.3, 34.2, 38.1, 39.0, 51.6, 55.4, 113.9 (2C),
25% overall yield (5 steps). Treatment of (R)-11 with MeLi
27.9 (2C), 139.4, 158.0, 174.2. HR-MS (EI) Calcd for C H O : 236.1413.
1
4
20
3
followed by dehydration afforded (R)-(ꢀ)-1. An introduction Found: 236.1415.
of hydroxyl group at meta-position of the aromatic ring in
R)-11 was achieved based on consecutive treatment [1) se-
lective iodination, 2) conversion of aryl iodide to aryl
boronate, 3) conversion of aryl boronate to phenol]. Thus ob-
Methyl (R)-(4ꢀ-Hydroxyphenyl)hexanoate 9 To a suspension of (R)-8
(
1
1.57 g, 6.6 mmol) and AlCl (2.66 g, 20 mmol) in CH Cl (33 ml) was added
(
3
2
2
-dodecanethiol (C H SH, 4.1 g, 20 mmol) at 0 °C and the whole mixture
12 25
was stirred for 12 h at r.t. The reaction mixture was poured into ice and ex-
tracted with CH Cl . The organic layer was washed with brine and dried
2
2
tained phenol (R)-16 was treated with MeLi followed by de- over MgSO . Evaporation of the organic solvent gave a crude oil which was
4
hydration to afford (R)-(ꢀ)-2.
chromatographed on silica gel (60 g, n-hexane : AcOEtꢄ6 : 1) to afford (5R)-
2
5
9
(1.21 g, 82%) as a colorless oil. (R)-9: [a] ꢀ17.8° (cꢄ1.0, CHCl ); IR
D 3
ꢀ1
Experimental
(neat): 3404, 1713 cm . NMR: d 1.21 (3H, d, Jꢄ7.1 Hz), 1.43—1.59 (4H,
All melting points were measured on a Mettler FP-62 melting point appa- m), 2.26 (2H, t, Jꢄ7.2 Hz), 2.63 (1H, sixtet, Jꢄ7.1 Hz), 3.64 (3H, s), 4.75
1
13
ratus and are uncorrected. H-NMR spectra were recorded by a Bruker (1H, s), 6.76 (2H, d, Jꢄ8.5 Hz), 7.04 (2H, d, Jꢄ8.5 Hz). C-NMR: d 22.6,
AV400M digital NMR. Spectra were taken with 5—10% (w/v) solution in
CDCl with Me Si as an internal reference. Mass spectra and the fast atom
23.3, 34.2, 38.1, 39.0, 51.6, 115.3 (2C), 128.1 (2C), 139.6, 153.8, 174.4.
HR-MS (EI) Calcd for C H O : 222.1256. Found: 222.1265.
3
4
13 18
3
bombardment mass spectra (FAB-MS) were obtained with a JEOL JMS-
00H (matrix; glycerol, m-nitrobenzyl alcohol) spectrometer. IR spectra a solution of (R)-9 (1.18 g, 5.3 mmol) and pyridine (1.64 g, 21 mmol) in
were recorded on a JASCO FT/IR-300 spectrometer. All evaporations were CH Cl (27 ml) was added trifluoromethanesufonic anhydride (Tf O, 1.95 g,
Methyl (R)-(4ꢀ-Trifluoromethanesufonyloxyphenyl)hexanoate 10 To
6
2
2
2
performed under reduced pressure. For column chromatography, silica gel 6.9 mmol) at 0 °C and the whole mixture was stirred for 2 h at r.t. The reac-
(Kieselgel 60) was employed.
tion mixture was diluted with H O and extracted with CH Cl . The organic
2
2
2
Methyl (4S,5S)-anti-4-(4ꢀ-Methoxyphenyl)-5-hydroxy-2(E)-hexenoate layer was washed with brine and dried over MgSO . Evaporation of the or-
4
4
To a solution of (4S,5S)-3 (3.0 g, 21.1 mmol) and anisole (4.577 g,
ganic solvent gave a crude oil which was chromatographed on silica gel
4
ꢀ
2.3 mmol) in CH Cl2 (42 ml) was added BF ·Et O (3.5 ml, 28 mmol) at
20 °C, and the whole mixture was stirred for 2 h at ꢀ20 °C. The reaction
(40 g, n-hexane : AcOEtꢄ20 : 1) to afford (R)-10 (1.61 g, 86%) as a colorless
oil. (R)-10: [a] ꢀ10.2° (cꢄ1.57, CHCl ); IR (neat): 1739, 1422, 1141
D 3
ꢀ1
2
3
2
2
3
mixture was diluted with brine and extracted with CH Cl . The organic layer cm . NMR: d 1.24 (3H, d, Jꢄ7.1 Hz), 1.41—1.64 (4H, m), 2.28 (2H, t, Jꢄ
was dried over Na SO and evaporated to provide a residue, which was chro- 6.8 Hz), 2.74 (1H, sixtet, Jꢄ7.1 Hz), 3.65 (3H, s), 7.19 (2H, d, Jꢄ8.8 Hz),
matographed on silica gel (700 g, n-hexane : AcOEtꢄ4 : 1—2 : 1) to afford
2
2
2
4
1
3
7.24 (2H, d, Jꢄ8.8 Hz). C-NMR: d 22.3, 23.1, 34.1, 37.7, 39.5, 51.6,
2
5
(
4S,5S)-4 (3.8 g, 72%) as a colorless oil. (4S,5S)-4: [a] ꢁ21.3° (cꢄ2.12, 117.3, 120.5, 121.3 (2C), 128.8 (2C), 147.9, 174.0. HR-MS (EI) Calcd for
D
1
CHCl ). H-NMR data of (4S,5S)-4 was identical with those of the reported
C F H O S: 354.0749. Found: 354.0744.
14 3 17 5
Methyl (R)-(4ꢀ-Methylphenyl)hexanoate 11 To a solution of (R)-10
3
1
0)
(ꢃ)-4.
Methyl (4S,5S)-anti-4-(4ꢀ-Methoxyphenyl)-5-tosyloxy-2(E)-hexenoate (1.58 g, 4.5 mmol) and tetramethyltin (Me Sn, 1.20 g, 6.7 mmol) in DMF
4
5
A mixture of (4S,5S)-4 (3.7 g, 14 mmol), p-toluenesulfonyl chloride (18 ml) was added tetrakis(triphenylphosphine)palladium(0) (Pd(PPh ) ,
3
4
(TsCl, 5.6 g, 29 mmol), pyridine (30 ml) was stirred for 1 d at r.t. The reac- 0.12 g, 0.1 mmol) under nitrogen atmosphere at 0 °C and the whole mixture
tion mixture was diluted with H O, which was extracted with AcOEt. The was stirred for 13 h at 80 °C. The reaction mixture was quenched with H O
2
2
organic layer was washed with 1 M aqueous HCl and 7% aqueous NaHCO3.
and extracted with Et O. The organic layer was washed with brine and dried
2
The organic layer was dried over Na SO and evaporated to give a residue, over MgSO . Evaporation of the organic solvent gave a crude oil which was
2
4
4
which was chromatographed on silica gel (200 g, n-hexane : AcOEtꢄ5 : 1) chromatographed on silica gel (90 g, n-hexane : AcOEtꢄ20 : 1) to afford (R)-
2
2
to afford (4S,5S)-5 (5.2 g, 87%). Crystallization of (4S,5S)-5 from a mixed 11 (0.655 g, 67%) as a colorless oil. (R)-11: [a] ꢀ22.9° (cꢄ1.35, CHCl3);
D
ꢀ1
solvent (n-hexane : AcOEtꢄ1 : 1) gave amorphous precipitate (4S,5S)-5. IR (neat): 1740 cm . NMR: d 1.22 (3H, d, Jꢄ7.1 Hz), 1.46—1.61 (4H, m),
2
2
1
(
(
4S,5S)-5: mp 105 °C, [a]D +41.4° (cꢄ1.00, CHCl ). H-NMR data of
2.23—2.28 (2H, m), 2.31 (3H, s), 2.66 (1H, sixtet, Jꢄ7.1 Hz), 3.64 (3H, s),
7.07 (2H, d, Jꢄ8.2 Hz), 7.09 (2H, d, Jꢄ8.2 Hz). C-NMR: d 21.1, 22.5,
23.3, 34.3, 37.9, 39.5, 51.6, 127.0 (2C), 129.2 (2C), 135.5, 144.3, 174.3.
3
8)
13
4S,5S)-5 was identical with those of the reported (ꢃ)-5.
Solvolysis of (4S,5S)-5 A solution of (4S,5S)-5 (10.0 g, 24.7 mmol) in
water-saturated nitromethane (500 ml) was stirred for 4 d at 50 °C. The reac- HR-MS (EI) Calcd for C H O : 220.1463. Found: 220.1479.
1
4
20
2
tion mixture was diluted with water and extracted with AcOEt. The organic
(6R)-2-Hydroxy-2-methyl-6-(4ꢀ-methylphenyl)heptane 12 To a solu-
tion of (5R)-11 (0.185 g, 0.84 mmol) in THF (1.5 ml) was added 1 M MeLi
layer was washed with 5% aqueous NaHCO and dried over Na SO . Evapo-
3
2
4
ration of the organic solvent gave a residue, which was chromatographed on solution in Et O (2.52 ml, 2.52 mmol) at 0 °C and the whole mixture was
2
silica gel (700 g, n-hexane : AcOEtꢄ7 : 1—4 : 1) to afford (4S,5S)-6 (3.4 g,
stirred for 2 h at 0 °C. Under ice-cooling, to the reaction mixture was added
2
0
1
5
5%) as a colorless oil. (4S,5S)-6: [a]D ꢀ14.7° (cꢄ1.00, CHCl ). H-NMR 5% aqueous KHSO and it was extracted with ether. The organic layer was
3
4
8
)
data of (4S,5S)-6 was identical with those of the reported (ꢃ)-6.
washed with brine and dried over Na SO . Evaporation of the organic sol-
2
4
Methyl (5S)-4-Chloro-5-(4ꢀ-Methoxyphenyl)-2(E)-hexenoate 7 To a
vent gave a residue which was chromatographed on silica gel (4 g, n-
hexane : AcOEtꢄ20 : 1—9 : 1) to afford (6R)-12 (0.157 g, 85%) as a color-
solution of (4S,5S)-6 (3.3 g, 13.2 mmol) and Ph P (5.19 g, 19.8 mmol) in
3
2
3
ꢀ1
CH Cl2 (160 ml) was added a solution of NCS (2.64 g, 19.8 mmol) in
less oil. (6R)-12: [a]D ꢀ29.8° (cꢄ1.13, CHCl ). IR (neat): 3366 cm .
2
3
CH Cl (100 ml) at ꢀ20 °C, and the whole mixture was stirred for 2 h at
NMR: d1.16 (6H, s), 1.22 (3H, d, Jꢄ6.8 Hz), 1.25—1.63 (6H, m), 2.32
(3H, s), 2.66 (1H, sixtet, Jꢄ6.8 Hz), 7.08 (2H, d, Jꢄ8.3 Hz), 7.09 (2H, d,
2
2
0
°C. The reaction mixture was diluted with 5% aqueous NaHCO and dried
3
1
3
over Na SO . Evaporation of the organic solvent gave a residue, which was
Jꢄ8.3 Hz). C-NMR: d 21.1, 22.5, 22.6, 29.4 (2C), 39.1, 39.6, 44.1, 71.2,
2
4
ꢁ
chromatographed on silica gel (500 g, n-hexane : AcOEtꢄ20 : 1) to afford
127.0 (2C), 129.2 (2C), 135.4, 144.8. MS (EI) m/z: 219 (M ꢀ1).
2
3
(
ꢀ
5R)-7 (2.90 g, 82%) as amorphous precipitate (R)-7: mp 55 °C, [a]
(R)-(ꢁ)-Curcumene 1 A mixture of (6R)-12 (0.135 g, 6 mmol), TsOH·
D
ꢀ1
1
57.4° (cꢄ1.09, CHCl ). IR (neat): 1725 cm . H-NMR: d 1.42 (3H, d, H O (0.058 g, 0.3 mmol) and MgSO (0.148 g, 1.2 mmol) in toluene (2 ml)
Jꢄ7 Hz), 3.10 (1H, dq, Jꢄ6.8, 7.1 Hz), 3.71 (3H, s), 3.79 (3H, s), 4.52 (1H, was stirred for 12 h at 60 °C. The reaction mixture was evaporated to give a
dt, Jꢄ1.3, 8.0 Hz), 5.89 (1H, dd, Jꢄ1.3, 15.4 Hz), 6.82 (1H, dd, Jꢄ8.0, residue, which was chromatographed on silica gel (2 g, n-hexane) to a 9 : 1
5.4 Hz), 6.84 (2H, d, Jꢄ8.6 Hz), 7.11 (2H, d, Jꢄ8.6 Hz). C-NMR: d 18.0, mixture (1 : 13ꢄ9 : 1) of dehydration products (0.108 g, 87%) as a colorless
5.6, 51.9, 55.4, 65.9, 114.1 (2C), 122.9, 129.0 (2C), 133.9, 145.5, 158.9, oil. A mixture of this mixture (0.09 g, 0.45 mmol) and Grubb’s reagent (2nd
3
2
4
1
3
1
4
1
3
5
66.3. HR-MS (EI) Calcd for C H Cl O : 268.0866. Found: 268.0864. generation, 0.038 g, 0.31 mmol) in ClCH CH Cl (0.5 ml) was stirred for 12 h
1
4
17
3
2
2
37
Calcd for C H Cl O : 270.0837. Found: 270.0841.
at 60 °C. The reaction mixture was evaporated to give a residue, which was
14
17
3
Methyl (R)-(4ꢀ-Methoxyphenyl)hexanoate
2.84 g, 10.6 mmol) in MeOH (50 ml) was hydrogenated over 20% Pd(OH)2–
C (0.28 g) at room temperature under atmospheric pressure of hydrogen. NMR:d1.21 (3H, d, Jꢄ6.8 Hz), 1.52 (3H, s), 1.52—1.64 (2H, m), 1.67 (3H,
After removal of the catalyst by filtration, the filtrate was evaporated to give s), 1.82—1.93 (2H, m), 2.32 (3H, s), 2.61—2.70 (1H, m), 5.06—5.11 (1H,
a crude oil which was chromatographed on silica gel (60 g, n-hexane : m), 7.07 (2H, d, Jꢄ8.2 Hz), 7.09 (2H, d, Jꢄ8.2 Hz). C-NMR: d 17.8, 21.1,
AcOEtꢄ9 : 1) to afford (R)-8 (1.62 g, 65%) as a colorless oil. (R)-8: [a]D
8
A
solution of (R)-7
subjected to the preparative TLC (silicagel, n-hexane) to afford (R)-1
2
3
1
(
(0.029 g, 32%) as a colorless oil. (R)-1: [a]D ꢀ45.0° (cꢄ0.75, CHCl ). H-
3
1
3
2
3
22.6, 25.9, 26.3, 38.6, 39.2, 124.7, 127.0 (2C), 129.1 (2C), 131.5, 135.3,

1
1
364
Vol. 55, No. 9
25
ꢀ1
44.8. HR-MS (EI) Calcd for C H : 202.1722. Found: 202.1722.
(6R)-17: [a]D ꢀ30.2° (cꢄ1.50, CHCl ). IR (neat): 3366 cm . NMR: d 1.16
(6H, s), 1.21 (3H, d, Jꢄ6.8 Hz), 1.37—1.62 (6H, m), 2.21 (3H, s), 2.62 (1H,
sixtet, Jꢄ6.8 Hz), 4.65 (1H, s), 6.61 (1H, d, Jꢄ1.5 Hz), 6.67 (1H, dd, Jꢄ1.5,
1
5
22
3
Methyl (R)-(3ꢀ-Iodo-4ꢀ-methylphenyl)hexanoate 14 To a solution of
R)-11 (0.408 g, 1.85 mmol) in MeCN (20 ml) were added iodine (I2,
.258 g, 1.02 mmol) and F-TEDA-BF (0.361 g, 1.02 mmol) at r.t. and the
(
0
1
3
7.7 Hz), 7.02 (2H, d, Jꢄ7.7 Hz). C-NMR: d 15.6, 22.5 (2C), 29.3 (2C),
4
whole mixture was stirred for 2 h at 55 °C. Evaporation of the organic sol- 38.9, 39.5, 43.9, 71.6, 113.7, 119.2, 121.3, 130.9, 147.1, 154.0. HR-MS (EI)
vent gave a crude oil which was chromatographed on silica gel (70 g, n- Calcd for C H O : 236.1776. Found: 236.1775.
1
5
24
2
hexane : AcOEtꢄ20 : 1) to afford (R)-14 (0.415 g, 65%) as a colorless oil.
(R)-(ꢁ)-Xanthorrizol 2 A mixture of (6R)-17 (0.079 g, 0.33 mmol),
20
ꢀ1
(
R)-14: [a] ꢀ10.7° (cꢄ0.45, CHCl ); IR (neat): 1738 cm . NMR: d 1.20
TsOH·H O (0.032 g, 0.17 mmol) and MgSO (0.079 g, 0.66 mmol) in
D
3
2
4
(
2
3H, d, Jꢄ6.8 Hz), 1.43—1.61 (4H, m), 2.24—2.29 (2H, m), 2.39 (3H, s), toluene (1 ml) was stirred for 6 h at 60 °C. The reaction mixture was evapo-
.56—2.65 (1H, m), 3.65 (3H, s), 7.05 (1H, dd, Jꢄ1.9, 7.6 Hz), 7.14 (1H, d, rated to give a residue, which was chromatographed on silica gel (2 g, n-
1
3
Jꢄ7.6 Hz), 7.61 (1H, d, Jꢄ1.9 Hz). C-NMR: d 17.8, 21.1, 22.6, 25.9, 26.3,
8.6, 39.2, 124.7, 127.0, 129.1, 131.5, 135.3, 144.8, 174.1. MS (EI) m/z: 346
hexane : AcOEtꢄ9 : 1) to a 10 : 1 mixture (2 : 18ꢄ10 : 1) of dehydration
products (0.064 g, 88%) as a colorless oil. A part of this mixture was sub-
jected to the preparative TLC (silicagel, n-hexane : AcOEtꢄ6 : 1) to afford
3
ꢁ
(M ).
2
4
Methyl (R)-(3ꢀ-4,4,5,5-Tetramethyl-1,3,2-dioxoborolanyl-4ꢀ-methyl- (R)-2 (0.016 g) as a colorless oil. (R)-2: [a] ꢀ53.5° (cꢄ0.75, CHCl ). IR
D
3
ꢀ1 1
phenyl)hexanoate 15 A flask charged with PdCl (dppf)·CH Cl (0.045 g, (neat): 3387 cm . H-NMR: d 1.20 (3H, d, Jꢄ7.1 Hz), 1.53 (3H, s), 1.49—
2
2
2
0.06 mmol), AcOK (0.324 g, 3.3 mmol) and Bis(pinacolato)diboron
1.64 (2H, m), 1.67 (3H, s), 1.82—1.93 (2H, m), 2.21 (3H, s), 2.61 (1H, six-
[
(
B (pin) , 0.363 g, 1.4 mmol] was flushed with nitrogen. A solution of (R)-14
0.38 g, 1.1 mmol) in DMSO (10 ml) was added to the above flask and the 6.67 (1H, dd, Jꢄ1.5, 7.8 Hz), 7.02 (1H, d, Jꢄ7.8 Hz). C-NMR: d 15.5,
tet, Jꢄ7.1 Hz), 4.54 (1H, s), 5.06—5.10 (1H, m), 6.61 (1H, d, Jꢄ1.5 Hz),
2
2
1
3
whole mixture was stirred for 4 h at 80 °C. The reaction mixture was 17.8, 22.5, 25.8, 26.3, 38.5, 39.2, 113.7, 119.6, 120.9, 124.7, 130.9, 131.6,
quenched with H O and extracted with Et O. The organic layer was washed 147.4, 153.8. HR-MS (EI) Calcd for C H O: 218.1671. Found: 218.1687.
2
2
15 22
with brine and dried over MgSO . Evaporation of the organic solvent gave a
4
crude oil which was chromatographed on silica gel (30 g, n-hexane : References and Notes
AcOEtꢄ20 : 1) to afford (R)-15 (0.331 g, 87%) as a colorless oil. (R)-15:
1) For recent references, see the following cited therein. Hagiwara H.,
Okabe T., Ono H., Kamat V. P., Hoshi T., Suzuki T., Ando M., J. Chem.
Soc., Perkin Trans. I, 2002, 895—900 (2002).
2) Rimpler H., Hansel R., Kochendoerfer L., Z. Naturforsch, 25b, 995
(1970).
20
ꢀ1
[
a] ꢀ7.9° (cꢄ1.35, CHCl ); IR (neat): 1740 cm . NMR: d 1.22 (3H, d,
D
3
Jꢄ7.1 Hz), 1.34 (12H, s), 1.44—1.65 (4H, m), 2.25—2.28 (2H, m), 2.50
3H, s), 2.65—2.70 (1H, m), 3.64 (3H, s), 7.09 (1H, d, Jꢄ7.8 Hz), 7.13 (1H,
(
1
3
dd, Jꢄ1.9, 7.8 Hz), 7.54 (1H, d, Jꢄ1.9 Hz). C-NMR: d 21.9, 22.5, 23.4,
2
5.0 (2C or 4C), 25.1 (4C or 2C), 34.3, 37.9, 39.4, 51.6, 83.5, 129.2, 130.1,
34.7, 142.6, 143.5, 174.3. HR-MS (EI) Calcd for C BH O : 346.2315.
3) Itokawa H., Hirayama F., Funakoshi K., Takeya K., Chem. Pharm.
Bull., 33, 3488—3491 (1985).
1
2
0
31
2
Found: 346.2312.
4) Yamazaki M., Maebayashi Y., Iwase N., Kaneko T., Chem. Pharm.
Bull., 36, 2070—2074 (1988).
5) For recent references, see the following cited therein. Zhang A., Rajan-
Babu T. V., Org. Lett., 6, 3159—3161 (2004).
6) Meyers A. I., Stoianova D., J. Org. Chem., 62, 5219—5221 (1997).
7) Sato K., Bando T., Shindo M., Shishido K., Heterocycles, 50, 11—15
(1999).
Methyl (R)-(3ꢀ-Hydroxy-4ꢀ-methylphenyl)hexanoate 16 To a solution
of (R)-15 (0.29 g, 0.84 mmol) in MeOH (1 ml) was added 30% H O (1 ml)
at 0 °C and the whole mixture was stirred for 2 h at 0 °C. The reaction mix-
ture was poured into a suspension of Et O and 5% aqueous Na S O and
2
2
2
2
2
3
stirred for 30 min at 0 °C. The organic layer was washed with brine and dried
over Na SO . Evaporation of the organic solvent gave a crude oil which was
2
4
chromatographed on silica gel (20 g, n-hexane : AcOEtꢄ4 : 1) to afford (R)-
8) Ono M., Ehara T., Yokoyama H., Ohtani N., Hoshino Y., Akita H.,
Chem. Pharm. Bull., 53, 1259—1265 (2005).
9) Akita H., Umezawa I., Takano M., Matsukura H., Oishi T., Chem.
Pharm. Bull., 39, 3094—3096 (1991).
2
0
1
6 (0.148 g, 75%) as a colorless oil. (R)-16: [a] ꢀ25.1° (cꢄ0.25, CHCl3);
D
ꢀ1
IR (neat): 3417, 1714 cm . NMR: d 1.21 (3H, d, Jꢄ7.1 Hz), 1.46—1.58
(4H, m), 2.21 (3H, s), 2.25—2.28 (2H, m), 2.61 (1H, sixtet, Jꢄ7.1 Hz), 3.64
(
7
1
3H, s), 4.68 (1H, s), 6.60 (1H, d, Jꢄ1.6 Hz), 6.66 (1H, dd, Jꢄ1.6, 7.6 Hz),
.02 (1H, d, Jꢄ7.6 Hz). C-NMR: d 15.4, 22.5, 23.3, 34.2, 37.8, 39.5, 51.6,
13.6, 119.5, 121.2, 131.0, 146.8, 153.9, 174.3. HR-MS (EI) Calcd for 11) Akita H., Umezawa I., Takano M., Oishi T., Chem. Pharm. Bull., 41,
10) Akita H., Umezawa I., Takano M., Ohyama C., Matsukura H., Oishi
13
T., Chem. Pharm. Bull., 41, 55—63 (1993).
C H O : 236.1413. Found: 236.1410.
680—684 (1993).
6R)-2-Hydroxy-2-methyl-6-(3ꢀ-hydroxy-4ꢀ-methylphenyl)heptane 17 12) Ono M., Saotome C., Akita H., Tetrahedron: Asymmetry, 7, 2595—
1
4
20
3
(
To a solution of (R)-16 (0.119 g, 0.5 mmol) in THF (2 ml) was added 1 M
2602 (1996).
MeLi solution in Et O (2.02 ml, 2.02 mmol) at 0 °C and the whole mixture
was stirred for 2 h at 0 °C. Under ice-cooling, to the reaction mixture was
13) Nishide K., Ohsugi S., Miyamoto T., Kumar K., Node M., Monatsh.
Chem., 135, 189—200 (2004).
2
added 5% aqueous KHSO and it was extracted with ether. The organic layer 14) Honda Y., Sakai M., Tsuchihashi G., Chem. Lett., 1985, 1153—1156
4
was washed with brine and dried over MgSO . Evaporation of the organic
(1985).
solvent gave a residue which was chromatographed on silica gel (2 g, n- 15) Stavber S., Kralj P., Zupan M., Synthesis, 2002, 1513—1518 (2002).
hexane : AcOEtꢄ4 : 1) to afford (6R)-17 (0.105 g, 88%) as a colorless oil.
16) Liu X., Synlett, 2003, 2442—2443 (2003).
4