Total synthesis of (S)-(+)-curcudiol, and (S)-(+)- and (R)-(-)-curcuphenol1)

Article abstract of DOI:10.1248/cpb.49.1581

A highly enantioselective synthesis of the versatile chiral synthons possessing one stereogenic center, (S)-and (R)-4-aryl-5-hydroxy-(2E)-pentenoate (3) was achieved based on the enzymatic reaction of (±)-3 with commercially available lipases MY-30 or OF-360 from Candida rugosa. Application of (S)-3 and (R)-3 to the total syntheses of (S)-curcuphenol (1), (S)-curcudiol (2), and (R)-curcuphenol (1), respectively, is described.

Full text of DOI:10.1248/cpb.49.1581

December 2001
Chem. Pharm. Bull. 49(12) 1581—1585 (2001)
1581
Total Synthesis of (S)-(؉)-Curcudiol, and (S)-(؉)- and
(R)-(؊)-Curcuphenol1)
Machiko ONO, Yuuko OGURA, Kazumi HATOGAI, and Hiroyuki AKITA*
School of Pharmaceutical Sciences, Toho University, 2–2–1 Miyama, Funabashi, Chiba 274–8510, Japan.
Received July 30, 2001; accepted September 12, 2001
A highly enantioselective synthesis of the versatile chiral synthons possessing one stereogenic center, (S)-
and (R)-4-aryl-5-hydroxy-(2E)-pentenoate (3) was achieved based on the enzymatic reaction of (؎)-3 with com-
mercially available lipases MY-30 or OF-360 from Candida rugosa. Application of (S)-3 and (R)-3 to the total
syntheses of (S)-curcuphenol (1), (S)-curcudiol (2), and (R)-curcuphenol (1), respectively, is described.
Key words bisabolane sesquiterpene; enantioselective hydrolysis; lipase; total synthesis
The phenolic sesquiterpenes of the bisabolane family have using several types of commercially available lipases.
been isolated from many different natural sources.2) Among Among them, the two lipases MY-30 and OF-360 from Can-
them, (S)-(ϩ)-curcuphenol (1), isolated from the marine dida rugosa were found to be effective. When (Ϯ)-4 was
sponge Epipolasis sp. strongly inhibits the activity of gastric subjected to enantioselective hydrolysis using MY-30 in
H, K-ATPase,3) while (R)-(Ϫ)-curcuphenol (1), isolated from water-saturated isopropyl ether, the alcohol (S)-3 (27%,
the Caribbean gorgonians Pseudopterogorgia rigida and 80% ee) and unchanged (R)-4 (69%, 36% ee) were obtained.
Lasianthaea podocephala, exhibits antibacterial activities On the other hand, asymmetric hydrolysis of (Ϯ)-4 using OF-
against Staphylcoccus aureus and Vibrio anguillarum.4) Ac- 360 gave (S)-3 (60%, 51% ee) and (R)-4 (38%, 83% ee). The
cordingly, the establishment of an efficient and general syn- desired stereochemistry of 3 was found to be governed by the
thetic route to both enantiomers of these sesquiterpenoids is selection of lipase. Then immobilized lipases MY-30 and
of significance. Although racemic syntheses of bisabolane OF-360 were obtained by illumination of a mixture consist-
sesquiterpenes have been developed,5) useful asymmetric ing of the photo-crosslinkable resin prepolymer ENTP-
synthesis bearing a benzylic asymmetric center have not 4000,8) a photosensitizer such as benzoin ethyl ether and the
been reported except for a few examples.6) We now report crude lipases MY-30 and OF-360, respectively. Using the im-
that (S)-1, (R)-1, and (S)-curcudiol (2) have been synthesized mobilized lipases afforded much better results, as shown in
based on enzymatic resolution using immobilized lipase in Table 1 [entry 2, (S)-3, 85% ee; entry 4, (R)-4, 90% ee]. The
organic solvent.
alcohol (S)-3 with 80% enantiomeric excess was subjected to
The most intriguing point of the present synthesis is the enantioselective acetylation using OF-360 in the presence of
preparation of the optically active primary alcohols possess- isopropenyl acetate in isopropyl ether to afford (S)-4 [74%,
ing one stereogenic center of (S)- and (R)-4-aryl-5-hydroxy- 90% ee [a]D Ϫ7.2° (cϭ0.46, MeOH)] and (S)-3 (16%,
(2E)-pentenoate (3). This was successfully achieved by car- 30% ee).
rying out enantioselective hydrolysis of the reported (Ϯ)-ac-
Treatment of (S)-4 and (R)-4 (entry 4, 90% ee) with
etate 47) using immobilized lipase. The desired racemic (Ϯ)- MeONa in MeOH produced (S)-3 [90% ee, [a]D Ϫ15.1°
3 had previously been obtained by us in the reaction of (cϭ0.67, MeOH)] and (R)-3 (90% ee), respectively. The
methyl (4,5)-epoxy-(2E)-pentenoate and m-methoxytoluene enantiomeric purity of the obtained chiral compounds was
in the presence of BF3·Et2O.7)
determined by HPLC on a Chiralcel OD (250ϫ4.6 mm) col-
Initially, (Ϯ)-4 was subjected to screening experiments umn. To confirm the absolute configuration of the present
Table 1
Chart 1
Substrate
Entry
Lipase
Products (%, % ee)
(g)
1
(Ϯ)-4 (1)
(Ϯ)-4 (1)
(Ϯ)-4 (1)
(Ϯ)-4 (1)
(S)-3 (0.4)
MY-30 (Candida rugosa)
Immobilized lipase (MY-30)
OF-360 (Candida rugosa)
Immobilized lipase (OF-360)
OF-360
(R)-4 69 (36) (S)-3 27 (80)
(R)-4 77 (24) (S)-3 22 (85)
(R)-4 38 (83) (S)-3 60 (51)
(R)-4 40 (90) (S)-3 52 (58)
(S)-4 74 (90) (S)-3 16 (30)
2
3
4
5a)
Chart 2
a) Optically active (S)-3 (80% ee) was employed.
To whom correspondence should be addressed. e-mail: akita@phar.toho-u.ac.jp
© 2001 Pharmaceutical Society of Japan

1582
Vol. 49, No. 12
Chart 3
Chart 4
dure. The alcohol (S)-9 was treated with iodine in the pres-
ence of triphenylphosphine (Ph3P) to give an iodide (S)-12
[[a]D ϩ5.8° (cϭ0.78, MeOH)] in 48% yield, which was re-
acted with NaCN in dimethylformamide (DMF) to provide a
cyanide (S)-13 [[a]D Ϫ0.9° (cϭ1.22, MeOH)] in 99% yield.
Alkaline hydrolysis of (S)-13 followed by successive esterifi-
cation gave the methyl ester (S)-14 [[a]D ϩ6.2° (cϭ1.15,
MeOH)] in 54% overall yield from (S)-13. Demethylation of
(S)-14 with a combination of AlCl3 and EtSH provided the
phenol (S)-15, which was treated with Grignard reagent to
afford (S)-curcudiol (2) [[a]D ϩ9.9° (cϭ4.96, CHCl3) corre-
sponding to 90% ee] in 91% overall yield from (S)-14. The
(Ϫ)-3, (Ϫ)-3 was successfully converted to the reported acid
(S)-(ϩ)-4-( p-tolyl)pentanoic acid 5.9) Catalytic hydrogena-
tion of (S)-3 gave (S)-6, followed by treatment with tosyl
chloride (TsCl) to afford the tosylate (S)-7 [[a]D ϩ16.9°
(cϭ0.99, MeOH)] in 83% overall yield from (S)-3. NaBH4
reduction of (S)-7 provided the 4-arylpentanoate (S)-8 [42%
yield, [a]D ϩ7.1° (cϭ1.32, MeOH)] and the corresponding
alcohol (S)-9 [40% yield, [a]D ϩ4.5° (cϭ1.68, MeOH)].
Demethylation of (S)-8 with a combination of AlCl3 and
ethanethiol (EtSH),9) followed by the treatment with trifluo-
romethanesulfonic anhydride (Tf2O) gave the triflate (S)-10,
which was subjected to catalytic hydrogenolysis to afford
the (ϩ)-( p-tolyl)pentanoate (S)-11 [[a]D ϩ29.1° (cϭ0.89,
MeOH)] in 48% overall yield from (S)-8. An alkaline hy-
drolysis of (S)-11 provided a carboxylic acid (S)-5 [92%
yield, [a]D ϩ25.1° (cϭ0.55, MeOH) corresponding to 90%
ee], of which the spectral data ([a]D) were identical to those
[[a]D ϩ29.1° (cϭ0.99, MeOH)] of the reported (S)-5.10)
Thus the absolute configuration of the present (Ϫ)-3 was de-
termined to be S. Then total synthses of (S)-curcudiol (2),
(R)- and (S)-curcuphenol (1) formally derived from (S)-2,3b)
were achieved from (S)-3 (90% ee) and (R)-3 (90% ee), re-
spectively. Conversion of (S)-9 into the one-carbon homolo-
gation product (S)-13 was achieved by the standard proce-
1
spectral data ([a]D, H- and 13C-NMR) of the synthesized
(S)-2 were identical to those [[a]D ϩ9.2° (cϭ10.8, CHCl3)]3b)
of natural product (S)-2, which is reported to convert into
(S)-curcuphenol (1) in the literature.3)
The synthesis of (R)-curcuphenol (1) from (R)-3 (90% ee)
was carried out in basically by the same way as for (S)-3.
Conversion of (R)-3 into the alcohol (R)-9 was achieved by
the same route [(R)-7, 83% overall yield from (R)-3, (R)-8
(47% yield), and (R)-9 (26% yield)] as in the previous case.
Acetylation of (R)-9 gave the corresponding acetate (R)-16
[90% yield, [a]D Ϫ2.6° (cϭ2.31, CHCl3)], which was sub-
jected to demethylation to afford the phenol (R)-17. The

December 2001
1583
Methyl (4S)-(2-Methoxy-4-methylphenyl)-5-hydroxypentanoate (3)
To a solution of (S)-4 (90% ee, 0.346 g, 1.18 mmol) in MeOH (10 ml) was
added 0.5 M MeONa/MeOH (3 ml) at 0 °C and the whole mixture was stirred
at the same temperature for 1 h. After 7% aqueous NaHCO3 and ether were
added to the reaction mixture, the organic layer was washed with saturated
phenol (R)-17 was treated with methoxymethyl chloride
(MOMCl) to give the MOM ether (R)-18 [[a]D Ϫ3.1°
(cϭ1.88, CHCl3)] in 94% overall yield from (R)-16. Hydrol-
ysis of (R)-18 gave an alcohol (R)-19 [[a]D Ϫ3.9° (cϭ1.47,
CHCl3)] in 98% yield, which was subjected to pyridinium brine and dried over MgSO4. The organic layer was evaporated to give a
residue that was chromatographed on silica gel (15 g, n-hexane : AcOEtϭ
chlorochromate (PCC) oxidation to provide an aldehyde (R)-
20. The Wittig reaction of (R)-20 afforded an olefin (R)-21
4 : 1) to afford (S)-3 (0.293 g, 99%) as a homogeneous oil. (S)-3: [a]D24
Ϫ15.1° (cϭ0.67, MeOH). The NMR data of (S)-3 were identical to those of
[[a]D Ϫ9.8° (cϭ1.01, CHCl3)] in 62% overall yield from
(R)-19. Deprotection of (R)-21 gave (R)-curcuphenol (1)
[62% yield, [a]D Ϫ20.9° (cϭ1.73, CHCl3) corresponding to
the reported (Ϯ)-3.5c)
Methyl (4R)-(2-Methoxy-4-methylphenyl)-5-hydroxypentanoate (3)
To a solution of (R)-4 (90% ee, 0.852 g, 2.92 mmol) in MeOH (20 ml) was
added 0.5 M MeONa/MeOH (6 ml) at 0 °C and the whole mixture was stirred
at the same temperature for 1 h. After 7% aqueous NaHCO3 and ether were
added to the reaction mixture, the organic layer was washed with saturated
brine and dried over MgSO4. The organic layer was evaporated to give a
residue that was chromatographed on silica gel (20 g, n-hexane : AcOEtϭ
4 : 1) to afford (R)-3 (0.722 g, 99%) as a homogeneous oil. (R)-3: [a]D24
1
90% ee], for which the spectral data [[a]D, H-, 13C-NMR,
and high-resolution mass spectra (HR-MS)] were identical
with those [[a]D Ϫ23.6° (CHCl3)]3c) of natural product (R)-1.
Experimental
1H- and 13C-NMR spectra were recorded on JEOL EX-400 (400 MHz) or ϩ13.6° (cϭ0.65, MeOH). The NMR data of (R)-3 were identical to those of
a JEOL a-500 (500 MHz) spectrometers with tetramethylsilane (TMS) as an the reported (Ϯ)-3.5c)
internal standard in CDCl3. The following abbreviations are used: singlet (s),
Methyl (4S)-(2-Methoxy-4-methylphenyl)-5-tosyloxypentanoate (7)
doublet (d), triplet (t), quartet (q), double doublet (dd), multiplet (m), and A solution of (S)-3 (90% ee, 0.558 g, 2.3 mmol) in AcOEt (10 ml) was hy-
broad (br). Carbon substitution degrees were established by distortionless drogenated over 20% Pd–C (50 mg) at room temperature under atmospheric
enhancement by polarization transfer (DEPT) pulse sequence. HR-MS were pressure of hydrogen. After removal of the catalyst by filtration, the filtrate
obtained with a JEOL JMS-DX 303 spectrometer. IR spectra were recorded was evaporated quantitatively to give (S)-6 as a colorless oil. Crude (S)-6
on a Hitachi 260-30 spectrometer. Optical rotations were measured with a was dissolved in pyridine (5 ml), then TsCl (0.56 g, 2.95 mmol) was added to
JASCO DIP-370 digital polarimeter. All evaporations were performed under the solution, and the whole mixture was allowed to stand for 12 h at room
reduced pressure. For column chromatography, silica gel (Kieselgel 60) was temperature. Ether and 7% aqueous NaHCO3 were added to the reaction
employed.
mixture, and the organic layer was washed with saturated brine and dried
Immobilization of Lipase on Photo-Crosslinkable Resin Prepolymer over MgSO4. The organic layer was evaporated to give a residue that was
(ENTP-4000) Typical immobilization procedures with photocross-linkable chromatographed on silica gel (15 g, n-hexane : AcOEtϭ7 : 1) to afford (S)-7
resin prepolymer are as follows. One gram of ENTP-4000 is mixed with [0.75 g, 83% yield from (4S)-3)] as a homogeneous oil. (S)-7: [a]D24 ϩ16.9°
10 mg of the photosensitizer benzoin ethyl ether. The mixture is melted com- (cϭ0.99, MeOH). The NMR data of (S)-7 were identical to those of the re-
pletely at 60 °C. The powdered lipase (100 mg) is added to the molten mix- ported (Ϯ)-7.5c)
ture under continuous mixing. The prepolymer–lipase mixture is layered on
Methyl (4S)-(2-Methoxy-4-methylphenyl)pentanoate (8) and (4S)-(2-
a sheet of transparent polyester film (thickness, ca. 0.5 mm). The layer is Methoxy-4-methylphenyl)pentanol (9) A solution of (S)-7 (0.931 g, 2.29
covered with transparent thin film and then illuminated with chemical lamps mmol) and NaBH4 (0.43 g, 2.29 mmol) in dimethyl sulfoxide (DMSO) (10
(wavelength range, 300—400 nm) for 3 min. The gel film thus formed is cut ml) was warmed for 2 h at 80 °C, then allowed to cool. Small amounts of
into small pieces (0.5ϫ0.5ϫ0.5 mm) and used for the bioconversion reac- acetone, ether, and 7% aqueous NaHCO3 were added to the reaction mixture
tion.
Enzymatic Resolution of (؎)-4 i) Table 1, Entry 1: A suspension of urated brine and dried over MgSO4. The organic layer was evaporated to
(Ϯ)-4 (0.2 g), lipase MY-30 (0.1 g) in H2O-saturated isopropyl ether (10 ml) give
residue that was chromatographed on silica gel (10 g, n-
and the organic layer was separated. The organic layer was washed with sat-
a
was incubated at 33 °C for 3 d. This scale experiment was carried out five hexane : AcOEtϭ7 : 1) to afford (S)-8 (0.227 g, 42% yield) as a homoge-
times simultaneously (total amount of (Ϯ)-4 was 1 g). After the reaction neous oil from n-hexane : AcOEtϭ20 : 1 eluate and (S)-9 (0.191 g, 40%
mixture was filtered, the precipitate was washed with diisopropyl ether. The yield) as a homogeneous oil from n-hexane : AcOEtϭ10 : 1 eluate. (S)-8:
combined organic layer was dried over MgSO4 and evaporated. The residue [a]D26 ϩ7.1° (cϭ1.32, MeOH), (S)-9: [a]D27 ϩ4.5° (cϭ1.68, MeOH). The
was chromatographed on silica gel (50 g) to give (R)-4 (0.69 g, 69%, NMR data of (S)-8 and (S)-9 were identical to those of the reported (Ϯ)-85c)
36% ee) from n-hexane : AcOEtϭ10 : 1 eluate and (S)-3 (0.231 g, 27%,
80% ee) as a homogeneous oil from n-hexane : AcOEtϭ4 : 1 eluate. The
NMR data of (S)-3 were identical to those of the reported (Ϯ)-3.7)
and (Ϯ)-9,5c) respectively.
Methyl (4S)-(4-Methylphenyl)pentanoate (11) i) To a solution of (S)-
8 (0.203 g, 0.86 mmol) in EtSH (1 ml) was added a mixture of AlCl3 (0.57 g,
ii) Table 1, Entry 2: A suspension of (Ϯ)-4 (0.25 g), immobilized lipase 4.2 mmol) in EtSH (3 ml) at 0 °C, and the whole mixture was stirred for 1 h
MY-30 (0.1 g) in H2O-saturated isopropyl ether (10 ml) was incubated at at the same temperature. After ether and 0.2 M aqueous HCl were added to
33 °C for 3 d. This scale experiment was carried out four times simultane- the reaction mixture, the organic layer was washed with saturated brine ether
ously (total amount of (Ϯ)-4 was 1 g). The reaction mixture was worked up and dried over MgSO4. Evaporation of the organic solvent gave a crude oil.
in the same way as for i) to give (R)-4 (0.77 g, 77%, 24% ee) and (S)-3
(0.188 g, 22%, 85% ee).
ii) To a solution of the above oil and Et3N (0.26 g, 2.6 mmol) in CH2Cl2 (2
ml) was added a solution of Tf2O (0.37 g, 1.3 mmol) in CH2Cl2 (0.5 ml) at 0
iii) Table 1, Entry 3: A suspension of (Ϯ)-4 (0.2 g), lipase OF-360 (0.1 g) °C and the whole mixture was stirred at the same temperature. The reaction
in H2O-saturated isopropyl ether (10 ml) was incubated at 33 °C for 3 d. This
mixture was diluted with ice-water and the organic layer was washed with
scale experiment was carried out five times simultaneously (total amount of 7% aqueous NaHCO3, and saturated brine. The organic layer was dried over
(Ϯ)-4 was 1 g). The reaction mixture was worked up in the same way as for MgSO4 and evaporated to give a crude oil that was chromatographed on sil-
i) to give (R)-4 (0.38 g, 38%, 83% ee) and (S)-3 (0.514 g, 60%, 51% ee).
ica gel (10 g, n-hexane : AcOEtϭ20 : 1) to afford (S)-10 (0.226 g). iii) A so-
iv) Table 1, Entry 4: A suspension of (Ϯ)-4 (0.2 g), immobilized lipase lution of (S)-10 (0.226 g) and Hünig base [(iso-Pr)2NEt, 0.087 g, 0.7 mmol]
OF-360 (0.1 g) in H2O-saturated isopropyl ether (10 ml) was incubated at in MeOH (10 ml) was hydrogenated over 20% Pd–C (30 mg) at room tem-
33 °C for 3 d. This scale experiment was carried out five times simultane- perature under atmospheric pressure of hydrogen. After removal of the cata-
ously (total amount of (Ϯ)-4 was 1 g). The reaction mixture was worked up lyst by filtration, the filtrate was evaporated to give a residue. After ether and
in the same way as for i) to give (R)-4 (0.4 g, 40%, 90% ee) and (S)-3 (0.445
g, 52%, 58% ee).
0.2 M aqueous HCl were added to the residue, the organic layer was washed
with saturated brine and dried over MgSO4. Evaporation of the organic sol-
v) Table 1, Entry 5: A suspension of (S)-3 (80% ee, 0.2 g), lipase OF-360 vent gave a crude oil that was chromatographed on silica gel (10 g, n-
(0.1 g) and isopropenyl acetate (0.2 g) in isopropyl ether (10 ml) was incu- hexane : AcOEtϭ30 : 1) to afford (S)-11 [0.085 g, 48% overall yield from
bated at 33 °C for 3 d. This scale experiment was carried out two times si- (S)-8]. (S)-11: [a]D22 ϩ29.1° (cϭ0.89, MeOH); NMR: d: 1.25 (3H, d,
multaneously (total amount of (S)-3 was 0.4 g). The reaction mixture was Jϭ7 Hz), 1.81—1.96 (2H, m), 2.14—2.22 (2H, m), 2.31 (3H, s), 2.67 (1H,
worked up in the same way as for i) to give (S)-4 [0.346 g, 74%, [a]D26 Ϫ7.2° q, Jϭ10 Hz), 3.61 (3H, s), 7.06 (2H, d, Jϭ8 Hz), 7.10 (2H, d, Jϭ8 Hz).
(cϭ0.46, MeOH) corresponding to 90% ee] and (S)-3 (0.064 g, 16%, 30% FAB-MS Calcd for C13H18O2 (Mϩ, m/z): 206. Found: 206. Anal. Found: C,
ee).
75.40; H, 8.75. Calcd for C13H18O2: C, 75.69; H, 8.80%.

1584
Vol. 49, No. 12
(4S)-(4-Methylphenyl)pentanoic Acid (5) A solution of (S)-11 (0.064
g, 0.31 mmol) and 2 M aqueous NaOH (1 ml) in MeOH (2 ml) was stirred at
(4R)-(2-Methoxymethyloxy-4-methylphenyl)pentyl Acetate (18) i) To
a solution of (R)-16 (0.173 g, 0.69 mmol) in EtSH (1 ml) was added a mix-
50 °C for 1 h. After the reaction mixture was diluted with H2O and ether, the ture of AlCl3 (0.46 g, 3.5 mmol) in EtSH (2 ml) at 0 °C, and the whole mix-
water layer was acidified with 2 M aqueous HCl and extracted with ether. The ture was stirred for 30 min at the same temperature. After ether and 0.2 M
organic layer was washed with saturated brine and dried over MgSO4. Evap- aqueous HCl were added to the reaction mixture, the organic layer was
oration of the organic solvent gave an acid (S)-5 (0.055 g, 92%) as a homo- washed with saturated brine ether and dried over MgSO4. Evaporation of the
geneous oil. (S)-5: [a]D21 ϩ25.1° (cϭ0.55, MeOH; corresponding to 90%
ee); NMR: d: 1.25 (3H, d, Jϭ7 Hz), 1.81—1.96 (2H, m), 2.17—2.25 (2H,
organic solvent gave crude (R)-17. The NMR data of (R)-17 were identical
to those of the reported (Ϯ)-17.2) ii) To a stirred solution of (R)-17 in MeCN
m), 2.30 (3H, s), 2.69 (1H, q, Jϭ13 Hz), 7.05 (2H, d, Jϭ8 Hz), 7.10 (2H, d, (2 ml) at 0 °C, 55% NaH (0.09 g, 2.1 mmol), 18-crown-16 (0.024 g, 0.07
Jϭ8 Hz). HR-MS (EI) Calcd for C12H16O2 (Mϩ, m/z): 192.1150. Found: mmol), MOMCl (0.11 g, 1.38 mmol) were added, and the whole mixture was
192.1129.
1-Iodo-(4S)-(2-methoxy-4-methylphenyl)pentane (12) Triphenyl
phosphine (Ph3P, 0.79 g, 3 mmol), imidazole (0.26 g, 3.7 mmol) and iodine
stirred for 1 h at 0 °C. After ether and aqueous NH4Cl were added to the re-
action mixture, the ether layer was washed with saturated brine and dried
over MgSO4. The organic layer was evaporated to give a residue that was
chromatographed on silica gel (10 g, n-hexane : AcOEtϭ9 : 1) to afford (R)-
(0.9 g, 3.7 mmol) were added to a solution of (S)-9 (0.312 g, 1.5 mmol) in
Et2O (5 ml) and MeCN (5 ml) at 0 °C and the whole mixture was stirred for 18 (0.183 g, 94% overall yield from (R)-16) as a homogeneous oil. (R)-18:
0.5 h at room temperature. The reaction mixture was filtered with the aid of [a]D23 Ϫ3.1° (cϭ1.88, CHCl3). The NMR data of (R)-18 were identical to
Celite and the filtrate was evaporated to give a residue that was chromato- those of the reported (Ϯ)-18.5c)
graphed on silica gel (10 g, n-hexane : AcOEtϭ100 : 1) to afford (S)-12
(0.229 g, 48%) as a homogeneous oil. (S)-12: [a]D24 ϩ5.8° (cϭ0.78, MeOH).
The NMR data of (S)-12 were identical to those of the reported (Ϯ)-12.5c)
(4R)-(2-Methoxymethyloxy-4-methylphenyl)pentanol (19) A solution
of (R)-18 (0.164 g, 0.58 mmol) in MeOH (1 ml) was treated with 2 M aque-
ous NaOH (0.5 ml), and the whole mixture was warmed at 50 °C for 10 min,
(4S)-(2-Methoxy-4-methylphenyl)hexanenitrile (13)
A solution of and then allowed to cool. After ether was added to the reaction mixture, the
(S)-12 (0.229 g, 0.85 mmol) in DMF (1 ml) was treated with NaCN (0.06 g, ether layer was washed with saturated brine and dried over MgSO4. The or-
1.3 mmol), and the whole mixture was stirred for 12 h at room temperature. ganic layer was evaporated to give a residue that was chromatographed on
After ether and 7% aqueous NaHCO3 were added to the reaction mixture, silica gel (10 g, n-hexane : AcOEtϭ5 : 1) to afford (R)-19 (0.136 g, 98%) as a
the organic layer was washed with saturated brine and dried over MgSO4.
homogeneous oil. (R)-19: [a]D22 Ϫ3.9° (cϭ1.47, CHCl3). The NMR data of
Evaporation of organic solvent gave a residue that was chromatographed on (R)-19 were identical to those of the reported (Ϯ)-19.5c)
silica gel (10 g, n-hexane : AcOEtϭ30 : 1) to afford (S)-13 (0.155 g, 99%) as
Protected (4R)-curcuphenol (21) i) PCC (0.67 g, 3.1 mmol) was added
a homogeneous oil. (S)-13: [a]D25 Ϫ0.9° (cϭ1.22, MeOH). The NMR data of to a mixture of (R)-19 (0.147 g, 0.62 mmol) and Celite 545 (2 g) in CH2Cl2
(S)-13 were identical with those of the reported (Ϯ)-13.5c)
(5 ml) at 0 °C. The reaction mixture was stirred for 1 h at room temperature
Methyl (5S)-(2-Methoxy-4-methylphenyl)hexanoate (14) A solution and filtered. The filtrate was subjected to short column chromatography to
of (S)-13 (0.155 g, 0.7 mmol) in EtOH (5 ml) was treated with 2 M aqueous give the aldehyde (R)-20. ii) This was added to a solution of triphenyliso-
NaOH (1 ml) and the whole mixture was refluxed for 12 h. After cooling, the propylphosphonium iodide (0.54 g, 1.24 mmol) and 1.6 M n-BuLi in hexane
reaction mixture was acidified with 2 M aqueous HCl, and extracted with (0.78 ml, 1.24 mmol) in tetrahydrofuran (THF, 10 ml) under stirring and the
ether, then treated with CH2N2. The ether layer was dried over MgSO4 and whole mixture was stirred for 2 d at room temperature. After ether and aque-
evaporated to give a residue. It was chromatographed on silica gel (10 g, n- ous NH4Cl were added to the reaction mixture, the ether layer was washed
hexane : AcOEtϭ30 : 1) to afford (S)-14 (0.096 g, 54% overall yield from with saturated brine and dried over MgSO4. The organic layer was evapo-
(S)-13) as a homogeneous oil. (S)-14: [a]D24 ϩ6.2° (cϭ1.15, MeOH). The rated to give a residue that was chromatographed on silica gel (10 g, n-
NMR data of (S)-14 were identical to those of the reported (Ϯ)-14.5c)
hexane : AcOEtϭ50 : 1) to afford (R)-21 (0.10 g, 62% overall yield) as a ho-
(S)-Curcudiol (2) i) To a solution of (S)-14 (0.096 g, 0.38 mmol) in mogeneous oil. (R)-21: [a]D26 Ϫ9.8 ° (cϭ1.01, CHCl3). The NMR data of
EtSH (1 ml) was added a mixture of AlCl3 (0.31 g, 2.3 mmol) in EtSH (1 ml) (R)-21 were identical to those of the reported (Ϯ)-21.5c)
at 0 °C, and the whole mixture was stirred for 1 h at the same temperature.
After ether and 0.2 M aqueous HCl were added to the reaction mixture, the
organic layer was washed with saturated brine ether and dried over MgSO4.
Evaporation of the organic solvent gave a crude oil. ii) A 2 M MeMgI ether
(R)-Curcuphenol (1) A mixture of 2 M aqueous HCl (1 ml) and iso-
propanol (1 ml) was added to a solution of (R)-21 (0.1 g, 0.38 mmol) in iso-
propanol (0.5 ml). The whole reaction mixture was warmed at 60 °C for 30
min. After ether was added to the reaction mixture, the ether layer was
solution (0.6 ml) was added to a solution of the above crude oil in ether (1 washed with saturated brine and dried over MgSO4. The organic layer was
ml) and the whole mixture was stirred for 2 d at room temperature. Under evaporated to give a residue that was chromatographed on silica gel (10 g, n-
ice-cooling, 2 M aqueous HCl was added to the reaction mixture and it was hexane : AcOEtϭ5 : 1) to afford (R)-1 (0.052 g, 62%) as a homogeneous oil.
extracted with ether. The organic layer was washed with saturated brine and (R)-1: [a]D23 Ϫ20.9° (cϭ1.73, CHCl3). HR-MS Calcd for C15H22O (Mϩ,
dried over MgSO4. Evaporation of the organic solvent gave a residue that m/z): 218.1617. Found: 218.1689. The spectral data (1H-, 13C-NMR, IR, HR-
was chromatographed on silica gel (10 g, n-hexane : AcOEtϭ4 : 1) to afford MS) were identical with those of the reported (Ϯ)-1.5c)
(S)-2 (0.083 g, 91% yield from (S)-14) as a homogeneous oil. (S)-2: [a]D24
ϩ9.9° (cϭ4.96, CHCl3). FAB-MS Calcd for C15H24O2 (Mϩ, m/z): 236.
Acknowledgments The authors are grateful to Meito Sangyo Co., Ltd.,
Found: 236. The spectral data (1H-, 13C-NMR, IR, and FAB-MS) were iden- Japan, for providing the lipases MY-30 and OF-360.
tical to those of the reported (Ϯ)-2.5c)
Methyl (4R)-(2-Methoxy-4-methylphenyl)-5-tosyloxypentanoate (7) References and Notes
Compound (R)-3 (90% ee, 1.563 g, 6,2 mmol) was converted into (R)-7
(2.103 g, 83% overall yield from (R)-3) by the same way as for the prepara-
tion of (S)-7 from (S)-3. (R)-7: [a]D26 Ϫ14.3° (cϭ1.26, MeOH). The NMR
data of (R)-7 were identical with those of the reported (Ϯ)-7.5c)
1) A part of this work was published as a preliminary communication:
Ono M., Ogura Y., Hatogai K., Akita H., Tetrahedron: Asymmetry, 6,
1829—1832 (1995).
2) ApSimon J. (ed.), “The Total Synthesis of Natural Product,” Vol. 5,
John Wiley and Sons, New York, 1983, pp. 35—45.
Methyl (4R)-(2-Methoxy-4-methylphenyl)pentanoate (8) and (4R)-(2-
Methoxy-4-methylphenyl)pentanol (9) NaBH4 reduction of (R)-7 (2.102
g, 5.2 mmol) in the same way as for the preparation of (S)-8 and (S)-9 from
(S)-7 gave (R)-8 (0.574 g, 47% yield) and (R)-9 (0.28 g, 26% yield). (R)-8:
[a]D24 Ϫ10.0 (cϭ1.91, MeOH), (R)-9: [a]D25 Ϫ4.8° (cϭ1.84, MeOH). The
NMR data of (R)-8 and (R)-9 were identical to those of the reported (Ϯ)-8.5c)
(4R)-(2-Methoxy-4-methylphenyl)pentyl Acetate (16) A solution of
(R)-9 (0.265 g, 1.3 mmol) and Ac2O (0.2 g, 2 mmol) in pyridine (1 ml) was
allowed to stand for 1 d at room temperature. The reaction mixture was di-
luted with H2O and extracted with ether. The organic layer was washed with
2 M aqueous HCl, 7% aqueous NaHCO3, and saturated brine and dried over
MgSO4. The organic layer was evaporated to give a residue that was chro-
matographed on silica gel (10 g, n-hexane : AcOEtϭ10 : 1) to afford (R)-16
(0.287 g, 90%) as a homogeneous oil. (R)-16: [a]D29 Ϫ2.6° (cϭ2.31, CHCl3).
The NMR data of (R)-16 were identical to those of the reported (Ϯ)-16.5c)
3) a) Fusetani N., Sugano M., Matsunaga S., Hashimoto K., Experientia,
43, 1234—1235 (1987); b) Wright A. E., Pomponi S. A., McConnell
O. J., Kohmoto S., McCarthy P., J. Nat. Prod., 50, 976—978 (1987); c)
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1627—1630 (1979).
4) McEnroe F. J., Fenical W., Tetrahedron, 34, 1661—1664 (1978).
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Nippon Kagakukaishi, 1988, 1065—1073; b) Shama M. L., Chand T.,
Indian J. Chem., 36B, 553—556 (1997); Synthesis of (Ϯ)-curcuphenol
and (Ϯ)-curcudiol; c) Ono M., Yamamoto Y., Akita H., Chem. Pharm.
Bull., 43, 553—558 (1995).
6) a) Sugawara T., Ogasawara K., Tetrahedron: Asymmetry, 9, 2215—
2217 (1998); b) Fuganti C., Serra S., Synlett, 1998, 1252—1254; c)
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(1984).