Asymmetric synthesis of (+)-dihydrokawain-5-ol

Full text of DOI:10.1021/jo991307n

258
J . Org. Chem. 2000, 65, 258-262
Sch em e 1a
Asym m etr ic Syn th esis of
(+)-Dih yd r ok a w a in -5-ol
Yoshitsugu Arai,*,† Tsutomu Masuda,† Shinya Yoneda,†
Yukio Masaki,† and Motoo Shiro‡
Gifu Pharmaceutical University, 5-6-1 Mitahora-Higashi,
Gifu 502-8585, J apan, and Rigaku Corporation,
3-9-12 Matsubara, Akishima, Tokyo 196-0003, J apan
Received August 17, 1999
(+)-Kawain (1) and (+)-methysticin (2) were isolated
from the extracts of the kava plant (Piper methysticum
Forst.), a Polynesian shrub of the pepper family,1 and
the extracts of the roots and stem of the plant are utilized
as a folk medicine and a ceremonial drink in the South
Pacific. Because of its anxiolytic and analgesic properties,
(()-kawain is prepared in multigram scale and is mar-
keted as a drug.2 The absolute stereochemistry of 2 was
established by chemical degradation to (+)-malic acid.3
J udging from the positive Cotton effect of 2 as well as 1
in circular dichroism, the chiral center of C-6 of 1 was
assigned to be the R configuration.4
a
Reagents and conditions: (a) DIBALH (4 equiv), CH2Cl2, -78
°C, 1.5 h, 74%; (b) Sml2 (4 equiv), THF, HMPA-MeOH (25:1), 25
°C, 0.5 h, 65%; (c) TsCl (1.5 equiv), pyridine, 0 °C, 3 h; (d) Ph2CuLi
(3 equiv), Et2O, -30 f 0 °C, 1.5 h, 63% from 10; (e) NBS (1.1
equiv), KOAc, THF-H2O, 0 °C, 100%; (f) CH(OMe)3, PPTS, MeOH
0 °C, 22 h, 85%.
3 by degradation of the furan ring in the furyl alcohol.
Herein we wish to report the first asymmetric synthesis
of (+)-dihydrokawain-5-ol (3) based upon this strategy.
Chirally functionalized furylpropanoate 7 was easily
obtained by Mukaiyama aldol reaction of 5 and 6 with
90% diastereoisomeric excess in 91% combined yield.
Isomerically pure 7 was separated from the minor
diastereoisomer 8 by simple crystallization of the reaction
mixture. The absolute stereochemistry of 7 was unequivo-
cally established by single-crystal X-ray analysis.10 In-
troduction of the phenyl group was accomplished as
illustrated in Scheme 1. Reduction of the ester 7 with
diisobutylaluminum hydride (DIBALH) proceeded smooth-
ly to give the diol 9, accompanied by a small amount of
the over-reduction product 10. Deoxygenation of the
sulfinyl group in 9 with Sm(II)I2-hexamethylphosphor-
amide (HMPA)11 produced the sulfanyl diol 10 in 65%
yield. Attempts at deoxygenation of 7 by means of other
reducing agents such as trichlorosilane12 or TiCl4/Zn13
(+)-Dihydrokawain-5-ol (3) was also isolated5 and its
5R absolute configuration was suggested by identical
transformation through SeO2 allylic oxidation of (+)-
dihydrokawain (4) derived from 1.6 Although 3 was thus
prepared from (+)-1 or (()-17 by oxidation followed by
hydrogenation, the oxidation step proceeds in a nonste-
reoselective manner and affords a poor yield of 3. It does
not seem to be suitable from synthetic viewpoint. Re-
cently, an elegant synthesis of racemic 3 has been
reported by Friesen;8 however, no asymmetric synthesis
has appeared to date.
As part of our ongoing program aimed at asymmetric
reactions using chiral sulfoxides, we recently reported
that the aldol reaction of sulfinyl furaldehyde 5 with
1-phenoxy-1-trimethylsilyloxyethene (6) proceeds smoothly
to give the aldol product 7 with high diastereoselectivity.9
High stereochemical control of the reaction led us to
exploit an efficient route to a chiral pyranone moiety in
(10) Crystal data for 7: MW ) 370.42, C20H18O5S, crystal dimen-
sions 0.30 × 0.30 × 0.20 mm, monoclinic, space group P21/c (No.14),
a ) 10.733(2) Å, b ) 9.571(5) Å, c ) 18.714(3) Å, V ) 1884(1) Å3, Z )
4, Dcalc ) 1.306 g cm-3, 2θmax ) 50.0°, Mo KR radiation (λ ) 0.71069
Å), T ) 296 K. Data were collected using the Rigaku AFC7R system,
and the structure was solved by direct methods, SIR92 (Altomare, A.;
Burla, M. C.; Camalli, M.; Cascarano, M.; Giacovazzo, C.; Guagliardi,
A.; Polidori, G. J . Appl. Crystallogr. 1994, 27, 435). Full-matrix least-
squares refinement using the DIRDIF94 program system converged
with final R ) 0.066 and Rw ) 0.105 for 1598 independent reflections
with I > 3.00σ(Ι) and 236 variable parameters.
(11) (a) Girard, P.; Namy, J . L.; Kagan, H. B. J . Am. Chem. Soc.
1980, 102, 2693. (b) Inanaga, J .; Ishikawa, M.; Yamaguchi, M. Chem.
Lett. 1987, 1485.
(12) (a) Chan, T. H.; Melnyk, A. J . Am. Chem. Soc. 1970, 92, 3718.
(b) Kricheldorf, H. R. Synthesis 1972, 695. (c) Segall, Y.; Granoth, I.;
Kalir, A. J . Chem. Soc., Chem. Commun. 1974, 501.
* To whom correspondence should be addressed. E-mail: araiy@gifu-
pu.ac.jp. Fax: +81-58-237-5979.
† Gifu Pharmaceutical University.
‡ Rigaku Corp.
(1) Ha¨nsel, R.; Weiss, D.; Schmidt, B. Planta Med. 1966, 14, 1.
(2) Spezialchemie G.m.b. H. und Co. Patent DE 661220; Chem.
Abstr. 1969, 71, 3275v.
(3) Achenbach, H.; Theobald, N. Chem. Ber. 1974, 107, 735.
(4) Snatzke, G.; Ha¨nsel, R. Tetrahedron Lett. 1968, 1797.
(5) For isolation: Achenbach, H.; Wittmann, G. Tetrahedron Lett.
1970, 3259. For asymmetric synthesis of 4: Spino, C.; Mayes, N.;
Desfosse´s, H.; Sotheeswaran, S. Tetrahedron Lett. 1996, 37, 6503.
(6) Achenbach, H.; Huth, H. Tetrahedron Lett. 1974, 119.
(7) Ha¨nsel, R.; Schulz, J . Chem. Ber. 1973, 106, 570.
(8) Friesen, R. W.; Vanderwal, C. J . Org. Chem. 1996, 61, 9103.
(9) Arai, Y.; Masuda, T.; Masaki, Y. Synlett 1997, 1459.
(13) Drabowicz, J .; Mikołajczyk, M. Synthesis 1978, 138.
10.1021/jo991307n CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/16/1999

Notes
J . Org. Chem., Vol. 65, No. 1, 2000 259
Sch em e 2a
Ta ble 1. Red u ction of P yr a n on e 14
temp time yield ratio
reducing agent
solvent
(°C)
(h)
(%)a 15:16b
NaBH4-CeCl3
DIBALH
L-Selectride
LiBH3Bu
CH2Cl2-MeOH
CH2Cl2
CH2Cl2
THF
0
-78
-78
-78
0.2
3
0.75
0.3
69
47
0
0
<1
78
2:3
1:1
i-Bu3Al
Et2O
-78 28
-78
DIBALH-BHTc toluene
1
15:1
a
b
Yield of combined isomers. Ratio determined from the inte-
grated value in the 1H NMR spectrum of the crude reaction
mixture. c BHT ) 2,6-di-tert-butyl-4-methylphenol.
Our attention was then focused on the stereoselective
reduction of the carbonyl group in pyranone 14 (Scheme
2). Of the several methods available, the use of the
combination of DIBALH and 2,6-di-tert-butyl-4-meth-
ylphenol18 was found to be most effective, giving the axial
alcohol 15 and the equatorial alcohol 16 in a 15:1 ratio
in 78% yield. With a â-anomer enriched pyranone 14 (3.7:
1), R-anomeric alcohol of 15 was not obtained in sub-
stantial yield. Attempts at reduction of 14 by the use of
other reducing agents were not fruitful (Table 1). For the
reduction of 14, NaBH4/CeCl319 or DIBALH had no effect
in increasing the yield of desired alcohol 15. The stereo-
chemistry of the newly formed hydroxyl group in 15 and
1
16 was determined on the basis of H NMR analysis of
the acetates 17 and 18 derived from 15 and 16, respec-
tively. Particularly informative are the large coupling
constant between the H-5 proton and the H-6 proton
(J 5,6 ) 9.0 Hz, axial-axial coupling) of 18 in the 1H NMR
a
Reagents and conditions: (a) DIBALH (3 equiv), 2,6-di-tert-
butyl-4-methylphenol (6 equiv), toluene, -78 °C, 1 h, 78%; (b)
MPMCl (1.2 equiv), NaH, DMF, 25 °C, 2 h, 86%; (c) TsOH (cat.),
THF-H2O, 0 °C f 25 °C, 6.5 h; TPAP (cat.), N-methylmorphorine
N-oxide, molecular sieve 4A (powder), CH2Cl2, 25 °C, 2 h, 56%;
(d) m-CPBA (2.5 equiv), CH2Cl2, 25 °C, 2.5 h, 89%; (e) K2CO3 (1.5
equiv), MeOH, 0 °C, 0.5 h, 100%; (f) DDQ (1.5 equiv), CH2Cl2-
H2O (20:1), 25 °C, 4 h, 68%.
gave no better results. After selective monotosylation14
of 10 with TsCl in pyridine at 0 °C, the subsequent
replacement of the unstable tosylate 11 with diphenyl-
copperlithium gave the alcohol 12 in 63% yield from 10.
Although several methods for the conversion of furyl
alcohols into the pyranones have been reported,15 the
procedure involving oxidation with N-bromosuccinimide
(NBS) gave the best results. Namely, exposure of 12 to
NBS in THF-H2O16 afforded the pyrane acetal 13, as a
7:3 anomeric mixture, which was successively protected
as the methyl acetal 14 obtained as an anomeric mixture
ranging from 3:1 to 4.4:1. On the other hand, with the
corresponding sulfinyl and sulfonyl derivatives of 12,
attempts at a similar oxidative degradation gave no
successful results, accompanied by mass recovery of
starting material, and in no cases were substantial
amounts of desired product detected. The lower reactivity
is consistent with the fact that furans with electron-
withdrawing substituents are generally resistant to
attack by protic acids.17
spectrum and the small coupling constant (J 5,6 ) 2.2 or
1.8 Hz) of anomeric 17 which indicates a cis relationship
due to the H-5 equatorial hydrogen and the H-6 axial
hydrogen. Protection of the resulting hydroxyl group in
15 as the p-methoxyphenylmethyl (MPM) ether20 19 and
subsequent deprotection of the acetal moiety followed by
oxidation with tetrapropylammonium perruthenate(VII)
(TPAP)21 produced the pyranone 20 in good yield. Expo-
sure of 20 to m-chloroperoxybenzoic acid (m-CPBA)
afforded the sulfonyl derivative 21 in 89% yield.
Transformation of 21 into 22 was readily effected using
K2CO3 in MeOH22 to provide the pyranone 22. Finally,
removal of the MPM protecting group in 22 furnished
(+)-dihydrokawain-5-ol (3) {mp 89.5-90 °C (Et2O) (lit.5
mp 92 °C, lit.6 mp 91-92 °C); [R]20D +72.6 (c 0.22, CHCl3)
for >99% ee by chiral HPLC {lit.5 [R]20 +73 (CHCl3);
D
lit.6 [R]20 +69 (c 0.001, CHCl3)}.
D
In summary, we succeeded in the asymmetric synthesis
of (+)-dihydrokawain-5-ol 3 using the highly selective
aldol condensation of sulfinyl-substituted furaldehyde 5
(14) (a) J ohnson, W. S.; Collins, J . C.; Pappo, R.; Rubin, M. B.; Kropp,
P. J .; J ohns, W. F.; Pike, J . E.; Bartmann, W. J . Am. Chem. Soc. 1963,
85, 1409. (b) Slates, H. L.; Zelawski, Z. S.; Taub, D.; Wendler, N. L.
Tetrahedron 1974, 30, 819.
(15) (a) Lefebvre, Y. Tetrahedron Lett. 1972, 133. (b) Shono, T.;
Matsumura, Y. Tetrahedron Lett. 1976, 1363. (c) Piancatelli, G.; Scettri,
A.; D’Auria, M. Tetrahedron Lett. 1977, 2199. (d) Bromidge, S. M.;
Sammes, P. G.; Street, L. J . J . Chem. Soc., Perkin Trans. 1 1985, 1725.
(e) Achmatowicz, O.; Bukowski, P.; Szechner, B.; Zwierzchowska, Z.;
Zamojski, A. Tetrahedron 1971, 27, 1973.
(18) Iguchi, S.; Nakai, H.; Hayashi, M.; Yamamoto, H. J . Org. Chem.
1979, 44, 1363.
(19) Luche, J . L. J . Am. Chem. Soc. 1978, 100, 2226.
(20) (a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett.
1982, 23, 885. (b) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.;
Yonemitsu, O. Tetrahedron 1986, 42, 3021.
(21) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
(16) Georgiadis, M. P.; Couladouros, E. A. J . Org. Chem. 1986, 51,
2725.
(17) Piancatelli, G.; D’Auria, M.; D’Onofrio, F. Synthesis 1994, 867.
(22) Masaki, Y.; Nagata, K.; Serizawa, Y.; Kaji, K. Tetrahedron Lett.
1984, 25, 95.

260 J . Org. Chem., Vol. 65, No. 1, 2000
Notes
J ) 2.0 Hz), 7.07 (ABq, 4H, J ) 3.0 Hz, ∆ν ) 4.4 Hz), 7.44 (d,
1H, J ) 2.0 Hz); 13C NMR (CDCl3) δ 20.9, 37.1, 60.8, 65.2, 110.7,
115.3, 127.6 (2C), 129.8 (2C), 133.3, 135.9, 142.5, 157.8; Anal.
Calcd for C14H16O3S: C, 63.61; H, 6.10. Found: C, 63.45; H, 6.12.
Further elutions with ethyl acetate afforded diol 9 (3.10 g, 66%)
with silyl ketene acetal 6 and the highly selective
reduction of the carbonyl group in pyranone 14 as key
steps.
Exp er im en ta l Section 23
as a crystalline solid: mp 110-112 °C (CH2Cl2-Et2O); [R]20
D
+17.1 (c 1.2, CHCl3); IR (CHCl3) 3340, 1025 cm-1; 1H NMR (270
MHz, CDCl3) δ 2.0-2.3 (m, 2H), 2.40 (s, 3H), 2.75 (dd, 1H, J )
6.0, 4.9 Hz), 3.7-3.95 (m, 2H), 4.42 (d, 1H, J ) 5.5 Hz), 5.29
(dt, 1H, J ) 8.6, 5.5 Hz), 6.17 (d, 1H, J ) 2.0 Hz), 7.31 (d × 2,
total 3H, J ) 7.9 and 2.0 Hz), 7.57 (d, 2H, J ) 7.9 Hz); 13C NMR
(CDCl3) δ 21.4, 37.7, 59.8, 65.6, 107.9, 124.8 (2C), 125.1, 130.0
(2C), 140.0, 141.6, 142.6, 158.7. Anal. Calcd for C14H16O4S: C,
59.98; H, 5.75. Found: C, 59.82; H, 5.76.
(1S)-3-H yd r oxy-1-[3-(p -t olylsu lfa n yl)-2-fu r yl]p r op a n -1-
ol (10). To a well-sonicated solution of sulfoxide 9 (566 mg, 2.01
mmol) in degassed dry hexamethylphosphoramide (10 mL) and
degassed dry methanol (0.4 mL) was added dropwise SmI2 (80.4
mL of 0.1 M in THF, 8.04 mmol, 4 equiv) at room temperature
under a stream of argon. After being stirred for 0.5 h, the purple
mixture was then treated with water (5 mL). After removal of
the solvents under reduced pressure, 3% hydrochloric acid was
added until a clear solution was obtained. The aqueous phase
was extracted with AcOEt. The combined extracts were washed
with 3% hydrochloric acid and brine, dried, and concentrated.
Purification of the residue by column chromatography on silica
(hexane/AcOEt 1:1) provided diol 10 (345 mg, 65%) as a solid,
which was identified with the minor product obtained by
DIBALH reduction of 7.
(1S)-3-P h en yl-1-[3-(p-tolylsu lfa n yl)-2-fu r yl]p r op a n -1-ol
(12). To a solution of diol 10 (373 mg, 1.41 mmol) in pyridine (2
mL) was added p-toluenesulfonyl chloride (404 mg, 1.5 equiv)
in portions at 0 °C. The mixture was stirred at the same
temperature for 3 h and partitioned between Et2O (20 mL) and
1% hydrochloric acid (15 mL). The aqueous layer was extracted
with Et2O. The combined organic phases were washed with
brine, dried, and concentrated. Purification of the residue by
flash chromatography on silica (hexane/AcOEt 5:1 to 3:1) af-
forded tosylate 11 (494 mg, 84%) as an unstable oil, which was
immediately used in the next step without further purification.
Tosylate 11: 1H NMR (270 MHz, CDCl3) δ 2.07-2.3 (m, 3H),
2.30 (s, 3H), 2.43 (s, 3H), 4.11 (dt, 1H, J ) 10.1, 5.5 Hz), 4.26
(ddd, 1H, J ) 10.1, 5.3, 5.1 Hz), 5.04 (br, 1H), 6.35 (d, 1H, J )
2.0 Hz), 7.07 (s, 4H), 7.31 (d, 2H, J ) 8.2 Hz), 7.39 (d, 1H, J )
2.0 Hz), 7.78 (d, 2H, J ) 8.2 Hz).
IR spectra were recorded on a FT-IR spectrometer in CHCl3
solution or in liquid film. H NMR spectra were measured with
1
a 400 and 270 MHz spectrometer, and 13C NMR spectra were
obtained with 100 MHz. Extracts were dried over anhydrous
MgSO4 before evaporation of solvents on a rotary evaporator
under reduced pressure. Dry tetrahydrofuran (THF) and diethyl
ether were freshly distilled from sodium benzophenone ketyl
prior to use. Dry dichloromethane was distilled from CaH2 prior
to use. m-CPBA was used after purification by washing with
pH 7.5 phosphate buffer, according to the literature method.24
P h en yl (3S,Ss)-3-Hyd r oxy-3-[3-(p-tolylsu lfin yl)-2-fu r yl]-
p r op a n oa te (7).25 To a suspension of Nd(OTf)3 (0.607 g, 1.03
mmol) in dry THF (60 mL) was added a solution of aldehyde 59
(4.81 g, 20.5 mmol) in dry THF (20 mL) at 0 °C. After being
stirred at the same temperature for 15 min, silyl ketene acetal
626 (8.55 g, 41.1 mmol) in dry THF (20 mL) was added dropwise
and the solution was stirred for 5 h. The reaction mixture was
then treated with 3% hydrochloric acid (50 mL) and stirred for
0.5 h. The organic phase was separated and the aqueous phase
was extracted with AcOEt. The combined extracts were washed
with brine, dried, and concentrated. The residue was purified
by column chromatography on silica (hexane/EtOAc 4:1 to 1:1)
to give a mixture of 7 and 8 (6.94 g, 91%) as a semisolid, which
was recrystallized from benzene to afford isomerically pure 7
(6.16 g, 81%) as a crystalline solid: mp 45-48 °C (benzene);
[R]20 -83.9 (c 1.0, acetone) for >99% ee by chiral HPLC
D
[Chiralcel OD, hexane-2-propanol, 7:1, flow rate, 1.0 mL min-1
,
retention time (+)-7, 55.8 min; (-)-7, 28.7 min]; IR (CHCl3) 3280,
1
1750 cm-1; H NMR (270 MHz, CDCl3) δ 2.38 (s, 3H), 3.12 (dd,
1H, J ) 16.1, 5.1 Hz), 3.25 (dd, 1H, J ) 16.1, 8.3 Hz), 4.69 (d,
1H, J ) 6.3 Hz), 5.55 (ddd, 1H, J ) 8.3, 6.3, 5.1 Hz), 6.30 (d,
1H, J ) 2.2 Hz), 7.09 (d, 2H, J ) 8.3 Hz), 7.2-7.4 (m, 5H), 7.33
(d, 1H, J ) 2.2 Hz), 7.59 (d, 2H, J ) 8.3 Hz); 13C NMR (CDCl3)
δ 21.4, 40.3, 63.7, 108.4, 121.5 (2C), 124.9 (2C), 126.0 (2C), 128.3
(2C), 130.1 (2C), 140.4, 141.9, 142.5, 150.4, 156.5, 169.5. Anal.
Calcd for C20H18O5S: C, 64.85; H, 4.90. Found: C, 64.84; H, 4.91.
The minor product 8 (7:8 ) 95:5) was inseparable from 7, but
was characterized from the 1H NMR analysis of the crude
product. 8: δ 2.40 (s, 3 H), 3.23 (dd, 1 H, J ) 16.2, 6.5 Hz), 3.29
(dd, 1 H, J ) 16.2, 7.3 Hz), 4.7 (br, 1 H), 5.59 (dd, 1 H, J ) 7.3,
6.5 Hz), 6.20 (d, 1 H, J ) 2.0 Hz), 7.10 (d, 2 H, J ) 8.3 Hz),
7.2-7.45 (m, 6 H), 7.60 (d, 2 H, J ) 8.3 Hz).
To a gray suspension of CuI (672 mg, 3.53 mmol) in dry Et2O
(20 mL) was added phenyllithium (7.5 mL of 0.94 M solution in
cyclohexane/Et2O, 6 equiv) at -30 °C, and the resulting black
suspension was stirred at the same temperature for 10 min.
Essentially pure tosylate 11 (494 mg), obtained previously in
the reaction, in dry Et2O (5 mL) was then added slowly and the
mixture was allowed to warm to 0 °C over 1.5 h. The mixture
was quenched with saturated NH4Cl (30 mL) and the organic
layer was separated. The aqueous layer was extracted with Et2O
and the extracts were washed brine, dried, and concentrated.
Purification of the residue by flash chromatography on silica
(hexane/AcOEt 7:1) gave 12 (286 mg, 75%) as a colorless oil:
For determination of the enantiomeric excess of (-)-7, a
racemic sample (()-7 was prepared by reaction of (()-5 with the
ketene acetal 6.
(1S,Ss)-3-Hyd r oxy-1-[3-(p-tolylsu fin yl)-2-fu r yl]p r op a n -1-
ol (9). To a stirred solution of the phenyl ester 7 (6.16 g, 16.6
mmol) in dry dichloromethane (150 mL) was added dropwise
diisobutylaluminum hydride (DIBALH, 65.9 mL of 1.01 M
solution in toluene, 66.5 mmol) over 10 min at -78 °C. The
mixture was stirred at the same temperature for 1.5 h and then
quenched by slow addition of MeOH (10 mL). The reaction
mixture was warmed to room temperature and treated with
saturated aqueous Rochelle’s salt (200 mL) and then 3%
hydrochloric acid (100 mL). After being stirred vigorously for 3
h, the mixture was extracted with dichloromethane. The com-
bined extracts were washed with brine, dried, and concentrated.
The residue was purified by column chromatography on silica.
Early fractions eluted with hexane/EtOAc (1:1) afforded sulfide
10 (347 mg, 8%) as a crystalline solid: mp 104-105 °C (hexane/
[R]21 -29.5 (c 1.2, CHCl3) for >99% ee determined by chiral
D
HPLC [Chiralpak AS, hexane-2-propanol, 100:1, flow rate, 1.0
mL min-1, retention time (+)-12, 26.2 min; (-)-12, 22.2 min];
IR (CHCl3) 3520 cm-1 1H NMR (270 MHz, CDCl3) δ 2.0-2.3
;
(m, 3H), 2.29 (s, 3H), 2.5-2.75 (m, 2H), 4.96 (dt, 1H. J ) 6.7,
5.9 Hz), 6.38 (d, 1H, J ) 2.0 Hz), 7.05-7.3 (m, 9H), 7.43 (d, 1H,
J ) 2.0 Hz); 13C NMR (CDCl3) δ 20.9, 31.7, 37.0, 65.4, 111.1,
115.4, 125.9, 127.7 (2C), 128.4 (4C), 129.8 (2C), 133.4, 135.9,
141.3, 142.3, 158.0; HRMS calcd for C20H20O2S 324.1184. found,
324.1178.
AcOEt); [R]22 -8.55 (c 1.03, CHCl3); IR (CHCl3) 3400, 1500,
D
For determination of the enantiomeric excess of (-)-12, a
racemic sample (()-12 was prepared starting with (()-5 and the
ketene acetal 6.
1045, 995 cm-1
;
1H NMR (CDCl3) δ 1.9-2.3 (m, 3H), 2.29 (s,
3H), 2.80 (br, 1H), 3.7-3.95 (m, 2H), 5.20 (m, 1H), 6.38 (d, 1H,
(2S,6S/6R)-6-Meth oxy-2-(1-p h en yleth yl)-4-(p-tolylsu lfa n -
yl)-2H-p yr a n -3(6H)-on e (14). To a stirred solution of furyl
alcohol 12 (1.967 g, 6.06 mmol) and potassium acetate (655 mg,
6.67 mmol) in THF (64 mL) and H2O (16 mL) was added in
portions N-bromosuccinimide (NBS, 1.187 g, 6.67 mmol) at 0
°C. After being stirred at the same temperature for 20 min, the
reaction mixture was partitioned between Et2O (120 mL) and
(23) General experimental procedures and instrumentation are
described in the following: Arai, Y.; Suzuki, A.; Masuda, T.; Masaki,
Y.; Shiro, M. J . Chem. Soc., Perkin Trans. 1 1995, 2913.
(24) Schwartz, N. N.; Blumbergs, J . H. J . Org. Chem. 1964, 29, 1976.
(25) The symbol Ss given in this text expresses that the sulfinyl
center is the S configuration.
(26) Slougui, N.; Rousseau, G. Synth. Commun. 1987, 17, 1.

Notes
J . Org. Chem., Vol. 65, No. 1, 2000 261
10% potassium iodide (80 mL). The organic layer was separated
and the aqueous layer was extracted with Et2O. The combined
extracts were washed with 15% sodium thiosulfate and satu-
rated sodium hydrogen carbonate and brine, dried, and concen-
trated. Purification of the residue by column chromatography
on silica (hexane/AcOEt 9:1 to 4:1) yielded pyranone 13 (2.07 g,
100%) of a ca. 7:3 anomeric mixture, which was used in the next
step without further purification. 13: colorless oil; 1H NMR (400
MHz, CDCl3, 7:3 anomeric mixture) δ 2.0-2.2 (m, 1H), 2.25-
2.4 (m, 1H), 2.38 (s, 3H), 2.65-2.9 (m, 2.7H), 3.0 (br, 0.3H), 4.06
(ddd, 0.3H, J ) 8.5, 3.9, 1.2 Hz), 4.62 (dd, 0.7H, J ) 8.2, 3.8
Hz), 5.54 (br s, 0.3H), 5.57 (d, 0.7H, J ) 3.9 Hz), 5.92 (d, 0.7H,
J ) 3.9 Hz), 5.95 (d, 0.3H, J ) 1.7 Hz), 7.05-7.45 (m, 9H); 13C
NMR (CDCl3, major anomer) δ 21.3, 31.0, 31.5, 73.2, 88.9, 92.0,
125.1, 126.0, 128.4 (2C), 128.6 (2C), 130.7 (2C), 133.1, 135.6 (2C),
139.9, 141.2, 192.9.
submitted to column chromatography on silica (hexane/AcOEt
50:1 to 9:1) to afford a 15:1 mixture of 17 and 18 (18 mg, 78%),27
which was separated by preparative TLC (hexane/AcOEt 7:1,
two developments). Acetate 17 (7:3 anomeric mixture): mp 86-
88 °C (for â-anomer); IR (CHCl3) 1730 cm-1; 1H NMR (270 MHz,
CDCl3, 7:3 anomeric mixture) δ 1.7-2.1 (m, 2H), 2.10, 2.11 (each
s, total 3H), 2.35 (s, 3H), 2.6-2.75 (m, 1H), 2.75-2.95 (m, 1H),
3.44, 3.50 (each s, total 3H), 3.55 (ddd, 0.3H, J ) 9.5, 3.7, 1.8
Hz), 4.07 (ddd, 0.7H, J ) 9.2, 3.7, 2.2 Hz), 4.94 (d, 0.3H, J ) 1.5
Hz), 4.95 (d, 0.7H, J ) 3.3 Hz), 5.16 (d, 0.7H, J ) 2.2 Hz), 5.20
(t, 0.3H, J ) 1.8 Hz), 5.55 (d, 0.3H, J ) 1.5 Hz), 5.65 (d, 0.7H,
J ) 3.3 Hz), 7.14-7.34 (m, 5H), 7.26 (d, 0.6H, J ) 8.3 Hz), 7.27
(d, 1.4H, J ) 8.3 Hz), 7.32 (d, 2H, J ) 8.3 Hz); HRMS calcd for
C23H26O4S 398.1552, found 398.1542. Anal. Calcd for C23H26O4-
S: C, 69.32; H, 6.58. Found: C, 69.16; H, 6.69. Acetate 18 (single
â-anomer): [R]20 -61.9 (c 1.0, CHCl3); IR (film) 1749 cm-1; 1H
D
To a solution of 13 (2.618 g, 7.69 mmol) and trimethyl
orthoformate (4.21 mL, 38.5 mmol) in dry methanol (40 mL) was
added pyridinium p-toluenesulfonate (387 mg, 1.54 mmol) at 0
°C. The reaction mixture was stirred at the same temperature
for 22 h and concentrated. Purification of the residue by column
chromatography on silica (hexane/AcOEt 30:1 to 15:1) provided
acetal 14 (2.31 g, 85%) as a colorless oil in a ratio of a ca. 3:1
NMR (270 MHz, CDCl3) δ 1.7-1.9 (m, 2H), 2.06 (s, 3H), 2.35 (s,
3H), 2.55-2.65 (m, 1H), 2.85-3.0 (m, 1H), 3.41 (s, 3H), 3.95 (dt,
1H, J ) 9.0, 3.7 Hz), 4.86 (d, 1H, J ) 3.2 Hz), 5.27 (dd, 1H, J )
3.2, 1.6 Hz), 5.48 (dt, 1H, J ) 9.0, 1.6 Hz), 7.2-7.4 (m, 5H), 7.17
(d, 2H, J ) 7.9 Hz), 7.35 (d, 2H, J ) 7.9 Hz); HRMS calcd for
C23H26O4S 398.1552, found 398.1547.
(2S,3R,6R)-6-Meth oxy-3-(4-m eth oxyben zyloxy)-2-(1-ph en -
yleth yl)-4-(p-tolylsu lfa n yl)-3,6-d ih yd r o-2H-p yr a n (19). To
a suspension of NaH (18 mg, 0.45 mmol, 60% oil dispersion) in
dry DMF (2.5 mL) was added 15 (80 mg, 0.22 mmol) in dry DMF
(2 mL) at 0 °C. After being stirred for 10 min, p-methoxybenzyl
chloride (40 µL, 0.29 mmol) was added and the mixture was
stirred at room temperature for 2 h. The mixture was poured
into a pH 7.5 phosphate buffer solution (10 mL), and the aqueous
layer was extracted with AcOEt. The combined extracts were
washed with water and brine, dried, and concentrated. Purifica-
tion of the residue by column chromatography on silica (hexane/
AcOEt 8:1) yielded 19 (92 mg, 86%) as a single â-anomer 19:
anomeric mixture: [R]20 -7.78 (c 1.35, CHCl3) (3:1 anomeric
D
mixture); IR (CHCl3) 1680, 1600 cm-1
;
1H NMR (270 MHz,
CDCl3, anomeric mixture) δ 2.0-2.3 (m, 2H), 2.37 (s, 3H), 2.7-
2.95 (m, 2H), 3.41 (s, 2.1H), 3.50 (s, 0.9H), 4.04 (ddd, 0.3H, J )
8.8, 4.0, 0.9 Hz), 4.47 (dd, 0.7H, J ) 8.4, 3.5 Hz), 5.01 (d, 0.7H,
J ) 3.9 Hz), 5.13 (dd, 0.3H, J ) 2.2, 0.9 Hz), 5.87 (d, 0.7H, J )
3.9 Hz), 5.91 (d, 0.3H, J ) 2.2 Hz), 7.2-7.5 (m, 9H). 13C NMR
(CDCl3, for major anomer) δ 21.3, 31.2, 31.5, 56.3, 73.2, 95.3,
98.0, 125.2, 126.0, 128.4 (2C), 128.5 (2C), 130.7 (2C), 132.2 (2C),
135.7, 139.9, 141.2, 193.0; HRMS calcd for C21H22O3S 354.1290,
found 354.1281.
[R]26 +131.5 (c 1.0, CHCl3); IR (CHCl3) 3016, 1515 cm-1 1H
;
(2S,3R/3S,6R/6S)-3-Hydr oxy-6-m eth oxy-2-(1-ph en yleth yl)-
4-(p-tolylsu lfa n yl)-3,6-d ih yd r o-2H-p yr a n (15 a n d 16). To a
solution of 2,6-di-tert-butyl-4-methylphenol (2.63 g, 11.9 mmol)
in dry toluene (30 mL) was added DIBALH (5.9 mL of 1.01 M
in toluene, 5.97 mmol) at 0 °C. The mixture was stirred for 10
min and cooled to -78 °C. Pyranone 14 (705 mg, 1.99 mmol,
3.7:1 anomeric mixture) in dry toluene (10 mL) was then added
and stirred at the same temperature for 0.5 h. The reaction
mixture was quenched with saturated Rochelle’s salt (150 mL)
and diluted with AcOEt (100 mL). The mixture was stirred
vigorously at room temperature for 2 h. The organic layer was
separated and the aqueous layer was extracted with AcOEt. The
combined extracts were washed with brine, dried, and concen-
trated. The product ratio (15:16 ) 15:1) was estimated by the
olefinic signals in the 1H NMR spectrum of the crude product.
Purification of the residue was carried out by column chroma-
tography on silica (hexane/AcOEt 9:1 to 3:1). Initial fractions
contained 16 (57 mg, 8%) as an unstable oil, contaminated with
15. Later fractions gave pure 15 (497 mg, 70%) as an almost
single â-anomer. By using a g3.7:1 anomeric mixture 14 for this
reduction, R-anomer of 15 was not obtained in substantial yield.
D
NMR (270 MHz, CDCl3) δ 1.75-1.9 (m, 1H), 2.05-2.2 (m, 1H),
2.36 (s, 3H), 2.63 (ddd, 1H, J ) 13.9, 9.6, 6.4 Hz), 2.86 (ddd, 1H,
J ) 13.9, 10.0, 5.2 Hz), 3.41 (s, 3H), 3.61 (d, 1H, J ) 2.5 Hz),
3.78 (s, 3H), 3.96 (ddd, 1H, J ) 9.1, 4.0, 2.5 Hz), 4.63 (AB q, 2H,
J ) 10.8 Hz, ∆ν ) 38 Hz), 4.92 (d, 1H, J ) 3.2 Hz), 5.55 (d, 1H,
J ) 3.2 Hz), 6.85 (d, 2H, J ) 8.5 Hz), 7.1-7.35 (m, 9H), 7.37 (d,
2H, J ) 8.1 Hz); 13C NMR (CDCl3) δ 21.2, 32.1, 32.5, 55.2, 55.4,
71.2, 71.3, 71.4, 96.3, 113.7 (2C), 123.4, 125.8, 127.1, 128.3 (4C),
129.9 (2C), 130.3 (2C), 130.5, 134.3 (2C), 138.9, 139.1, 141.8,
159.2; HRMS calcd for C29H32O4S 476.2022, found 476.2028.
Isolative workup for acid-sensitive 19 often resulted in produc-
tion of variable amounts of the corresponding hemiacetal, which
was used in TPAP oxidation.
(5R,6S)-5-(4-Meth oxyben zyloxy)-6-(1-p h en yleth yl)-4-(p-
tolylsu lfa n yl)-5,6-d ih yd r o-2H-p yr a n -2-on e (20). To an ice-
cooled solution of 19 (85.5 mg, 0.18 mmol) in THF-H2O (4:1,
7.5 mL) was added p-TsOH‚H2O (6.8 mg). The reaction mixture
was then allowed to warm to room temperature. After being
stirred for 6.5 h, the resulting mixture was extracted with CHCl3.
The combined extracts were washed with saturated sodium
hydrogen carbonate and brine, dried, and concentrated. Since
the hemiacetal was labile to silica gel and could not be separated
from small amounts of unidentified byproducts by silica gel
column chromatography, the purification was achieved in the
subsequent step.
To a stirred suspension of N-methylmorphorine N-oxide (105
mg, 0.9 mmol) and molecular sieve 4A powder (90 mg) in dry
dichloromethane (2.5 mL) was added the above hemiacetal in
dry dichloromethane (2.5 mL) at 0 °C. After being stirred at the
same temperature for 10 min, tetrapropylammonium perruth-
enate (TPAP, 3.2 mg) was added to the suspension. The mixture
was stirred at room temperature for 1 h and filtered with the
aid of a short pad of Celite. The filtrate was concentrated and
the residue was purified by column chromatography on silica
(hexane/AcOEt 6:1) to afford 20 (46.1 mg, 56% from 19) as a
crystalline solid: mp 109-110 °C (hexane/AcOEt); [R]28D +159.6
(c 1.0, CHCl3); IR (CDCl3) 1702 cm-1; 1H NMR (270 MHz, CDCl3)
δ 1.8-2.0 (m, 1H), 2.3-2.4 (m, 1H), 2.40 (s, 3H), 2.68 (dt, 1H,
15: mp 111-113 °C (â-anomer, hexane/AcOEt); [R]20 +83.4 (c
D
1.03, CHCl3); IR (CHCl3) 3400 cm-1; 1H NMR (400 MHz, CDCl3)
δ 1.85-1.95 (m, 1H), 1.98 (d, 1H, J ) 8.8 Hz), 2.05-2.15 (m,
1H), 2.35 (s, 3H), 2.65-2.75 (m, 1H), 2.8-2.9 (m, 1H), 3.42 (s,
3H), 3.55 (dd, 1H, J ) 8.8, 1.8 Hz), 3.95 (ddd, 1H, J ) 8.8, 4.4,
1.8 Hz), 4.87 (d, 1H, J ) 3.1 Hz), 5.47 (d, 1H, J ) 3.1 Hz), 7.14-
7.3 (m, 7H), 7.37 (d, 2H, J ) 8.1 Hz); 13C NMR (CDCl3) δ 21.2,
31.9, 32.2, 55.5, 65.8, 70.6, 96.2, 121.7, 125.9, 126.6, 127.6, 128.3
(2C), 128.4, 129.8, 130.2 (2C), 134.4 (2C), 139.1, 141.7. Anal.
Calcd for C21H24O3S: C, 70.76; H, 6.79. Found: C, 70.53; H, 6.82.
16: 1H NMR (270 MHz, CDCl3, ca.. 6:1 anomeric mixture) δ
1.75-1.9 (m, 1H), 2.05 (br, 1H), 2.2-2.3 (m, 1H), 2.35 (s, 3H),
2.65-2.8 (m, 1H), 2.85-3.0 (m, 1H), 3.41 (s, 2.55H), 3.47 (s,
0.45H), 3.75 (dt, 0.85H, J ) 9.3, 2.2 Hz), 3.95 (br, 1.15H), 4.85
(d, 0.85H, J ) 3.2 Hz), 4.95 (t, 0.15H, J ) 1.7 Hz), 5.36 (dd,
0.85H, J ) 3.2, 1.7 Hz), 5.48 (dd, 0.15H, J ) 1.5, 1.0 Hz), 7.17
(d, 2H, J ) 7.9 Hz), 7.1-7.3 (m, 5H), 7.36 (d, 2H, J ) 7.9 Hz).
(2S,3R/3S,6R/6S)-3-Acetoxy-6-m eth oxy-2-(1-ph en yleth yl)-
4-(p-tolylsu lfa n yl)-3,6-d ih yd r o-2H-p yr a n (17 a n d 18). A
crude mixture of 15 and 16, obtained by stereoselective reduction
of 14 (3:1 ratio, 21 mg, 0.059 mmol), was treated with acetic
anhydride and pyridine in the usual manner. The product was
(27) The product ratio was determined by the peak intensities in
the 1H NMR spectrum: 5.16 and 5.20 ppm for the H-5 protons of 17;
5.48 ppm for the H-3 proton of 18.

262 J . Org. Chem., Vol. 65, No. 1, 2000
Notes
J ) 14.0, 7.9 Hz), 2.84 (ddd, 1H, J ) 14.0, 8.6, 5.3 Hz), 3.81 (s,
3H), 3.91 (d, 1H, J ) 2.8 Hz), 4.25 (ddd, 1H, J ) 9.2, 4.1, 2.8
Hz), 4.70 (AB q, 2H, J ) 11.3 Hz, ∆ν ) 47 Hz), 5.28 (s, 1H), 6.89
(d, 2H, J ) 8.7 Hz), 7.1-7.4 (m, 11H); 13C NMR (CDCl3) δ 21.4,
31.0, 31.5, 55.3, 71.7, 72.2, 78.7, 111.5, 114.0 (2C), 123.4, 126.1,
128.5 (2C), 128.6 (2C), 129.1, 129.9 (2C), 131.0 (2C), 135.2 (2C),
140.8, 141.2, 159.6, 160.6, 162.8. Anal. Calcd for C28H28O4S: C,
73.02; H, 6.13. Found: C, 72.76; H, 6.15.
δ 1.88 (dddd, 1H, J ) 13.9, 8.7, 8.1, 4.9 Hz), 2.32 (dddd, 1H,
J ) 13.9, 8.7, 8.1, 5.7 Hz), 2.66 (dt, 1H, J ) 13.9, 8.1 Hz), 2.78
(ddd, 1H, J ) 13.9, 8.7, 5.7 Hz), 3.70 (dd, 1H, J ) 2.5, 1.2 Hz),
3.75 (s, 3H), 3.80 (s, 3H), 4.18 (ddd, 1H, J ) 8.7, 4.9, 2.5 Hz),
4.57 (AB q, 2H, J ) 11.6 Hz, ∆ν ) 79 Hz), 5.20 (d, 1H, J ) 1.2
Hz), 6.86 (d, 2H, J ) 8.8 Hz), 7.05-7.4 (m, 7H); 13C NMR (CDCl3)
δ 30.9, 31.3, 55.3, 56.1, 70.8, 72.0, 77.6, 78.0, 92.4, 113.8 (2C),
126.1, 128.5 (3C), 129.2, 129.7 (2C), 140.9, 159.5, 166.1, 171.8,
HRMS calcd for C22H24O5 368.1624, found 368.1621.
(5R,6S)-5-(4-Meth oxyben zyloxy)-6-(1-p h en yleth yl)-4-(p-
tolylsu lfon yl)-5,6-d ih yd r o-2H-p yr a n -2-on e (21). To a solu-
tion of 20 (76 mg, 0.16 mmol) in dry dichloromethane (3 mL)
was added dropwise m-CPBA (71 mg, 0.41 mmol) in dry
dichloromethane (5 mL) at room temperature. The mixture was
stirred for 2.5 h and diluted with Et2O (20 mL). The organic
phase was washed with 1% NaOH and brine, dried, and
concentrated to yield essentially pure 21 (72 mg, 89%) as a
(+)-Dih yd r ok a w a in -5-ol (3). To a solution of 22 (14.8 mg,
0.04 mmol) was added DDQ (14 mg, 0.06 mmol) in CH2Cl2-
H2O (20:1, 2.1 mL) at room temperature. The mixture was
stirred vigorously for 4 h and quenched with an aqueous
saturated sodium hydrogen carbonate (5 mL). The aqueous layer
was extracted with CHCl3, and the extracts were washed with
brine, dried, and concentrated. The residue was purified by
column chromatography on silica (hexane/AcOEt 1:1) to afford
(+)-3 (6.8 mg, 68%), whose NMR spectrum was in good agree-
ment with that reported in the literature by Friesen et al.:8 mp
89.5-90 °C (Et2O) (lit.5 mp 92 °C, lit.6 mp 91-92 °C); [R]20D +72.6
(c 0.22, CHCl3) for >99% ee determined by chiral HPLC
crystalline solid: mp 132-134.5 °C (hexane/AcOEt); [R]26
D
+105.2 (c 1.03, CHCl3); IR (CHCl3) 1728 cm-1
;
1H NMR (270
MHz, CDCl3) δ 1.8-1.96 (m, 1H), 2.2-2.4 (m, 1H), 2.44 (s, 3H),
2.68 (dt, 1H, J ) 14.0, 8.0 Hz), 2.82 (ddd, 1H, J ) 14.0, 8.5, 5.6
Hz), 3.79 (s, 3H), 4.18 (ddd, 1H, J ) 9.2, 4.3, 2.2 Hz), 4.41 (d,
1H, J ) 2.2 Hz), 4.43 (AB q, 2H, J ) 10.6 Hz, ∆ν ) 46 Hz), 6.60
(s, 1H), 6.81 (d, 2H, J ) 8.7 Hz), 7.05 (d, 2H, J ) 8.7 Hz), 7.1-
7.35 (m, 5H), 7.34 (d, 2H, J ) 8.3 Hz), 7.80 (d, 2H, J ) 8.3 Hz);
13C NMR (CDCl3) δ 21.7, 30.8, 31.7, 55.2, 67.3, 72.3, 81.2, 113.7
(2C), 126.0, 126.3, 128.4 (2C), 128.6 (3C), 128.9 (2C), 129.7 (2C),
130.3 (2C), 134.1, 140.1, 146.3, 155.2, 159.5, 161.7; Anal. Calcd
for C28H28O6S: C, 68.27; H, 5.73. Found: C, 68.23; H, 5.80.
(5R,6S)-4-Meth oxy-5-(4-m eth oxyben zyloxy)-6-(1-p h en yl-
eth yl)-5,6-d ih yd r o-2H-p yr a n -2-on e (22). A mixture of 21 (49.2
mg, 0.10 mmol) and anhydrous potassium carbonate (21 mg) in
dry MeOH (8 mL) was stirred at 0 °C for 0.5 h and then was
treated with saturated NH4Cl solution (10 mL). The mixture was
extracted with AcOEt and the extracts were washed with brine,
dried, and concentrated to produce 22 (36.6 mg, 100%) as a
[Chiralcel OD, hexane-2-propanol, 10:1, flow rate, 1.0 mL min-1
,
retention time (+)-3, 33.3 min; (-)-3, 42.8 min][lit.5 [R]20 +73
D
(CHCl3); lit.6 [R]20 +69 (c 0.001, CHCl3)].
D
Ack n ow led gm en t. We thank Dr. R. W. Friesen
(Merck Frosst Centre, Canada) for suppling a copy of
the NMR spectrum of (()-3. This work was supported
by a Grant-in-Aid for Scientific Research from the
Ministry of Education, Science, Sports and Culture
(J apan) and the Fund of Specially Promoted Research
Project (GPU), to which we are grateful.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 7-22 and X-ray crystallographic data for com-
pound 7. This material is available free of charge via the
Internet at http://pubs.acs.org.
colorless oil; [R]21 +161.0 (c 1.01, CHCl3) for >99% ee deter-
D
mined by chiral HPLC [Chiralpak AS, hexane-2-propanol, 5:1,
flow rate, 1.0 mL min-1, retention time (+)-22, 47.4 min; (-)-
22, 73.4 min]; IR (CDCl3) 1704 cm-1; 1H NMR (400 MHz, CDCl3)
J O991307N