The asymmetric syntheses of methyl D-digitoxoside, L-oleandrose and L-cymarose from methyl sorbate, an achiral precursor

Article abstract of DOI:10.1248/cpb.c12-00308

The addition of 4 eq of chloral to osmundalactone (4S,5R)-4 gave quantitative formation of the hemiacetal derivative (4S,5R)-8, which was treated with methane sulfonic acid to afford the intramolecular Micheal addition product (+)-(3S,4S,5R)-9 possessing a 3,4-cis-dihydroxy-d-lactone in 78% overall yield from (4S,5R)-4. The obtained (+)-(3S,4S,5R)-9 was subsequently converted to methyl D-digitoxoside (pyranoside) (12) in 13% overall yield and methyl D-digitoxoside (furanoside) (12) in 20% overall yield. The reaction of benzyl-osmundalactone (4R,5S)-3 and MeOH in the presence of Amberlyst A-26 as a basic catalyst gave 3,4-trans-δ-lactone (-)-(3S,4R,5S)-20 in 28% yield and 3,4-cis-d-lactone (-)-(3R,4R,5S)-21 in 45% yield. Dibal-H reduction of (-)-(3S,4R,5S)-20 followed by catalytic hydrogenation gave L-oleandrose (6) in 86% overall yield, while Dibal-H reduction of (-)-(3R,4R,5S)-21 followed by catalytic hydrogenation provided L-cymarose (7) in 85% overall yield.

Full text of DOI:10.1248/cpb.c12-00308

1076
Note
Chem. Pharm. Bull. 60(8) 1076–1082 (2012)
Vol. 60, No. 8
The Asymmetric Syntheses of Methyl D-Digitoxoside, L-Oleandrose and
L-Cymarose from Methyl Sorbate, an Achiral Precursor
,b,†
Machiko Ono,a Xi Ying Zhao,b Keisuke Kato,b and Hiroyuki Akita*
a School of Pharmaceutical Sciences, International University of Health and Welfare; 2600–1 Kitakanemaru,
b
Ohtawara, Tochigi 324–8501, Japan: and Faculty of Pharmaceutical Sciences, Toho University; 2–2–1 Miyama,
Funabashi, Chiba 274–8510, Japan. Received April 5, 2012; accepted May 28, 2012
The addition of 4eq of chloral to osmundalactone (4S,5R)-4 gave quantitative formation of the hemi-
acetal derivative (4S,5R)-8, which was treated with methane sulfonic acid to afford the intramolecular Mi-
cheal addition product (+)-(3S,4S,5R)-9 possessing a 3,4-cis-dihydroxy-δ-lactone in 78% overall yield from
(4S,5R)-4. The obtained (+)-(3S,4S,5R)-9 was subsequently converted to methyl D-digitoxoside (pyranoside)
(12) in 13% overall yield and methyl D-digitoxoside (furanoside) (12) in 20% overall yield. The reaction of
benzyl-osmundalactone (4R,5S)-3 and MeOH in the presence of Amberlyst A-26 as a basic catalyst gave
3,4-trans-δ-lactone (ꢀ)-(3S,4R,5S)-20 in 28% yield and 3,4-cis-δ-lactone (ꢀ)-(3R,4R,5S)-21 in 45% yield.
Dibal-H reduction of (ꢀ)-(3S,4R,5S)-20 followed by catalytic hydrogenation gave L-oleandrose (6) in 86%
overall yield, while Dibal-H reduction of (ꢀ)-(3R,4R,5S)-21 followed by catalytic hydrogenation provided L-
cymarose (7) in 85% overall yield.
Key words osmundalactone; methyl D-digitoxoside; L-oleandrose; L-cymarose
We previously reported the syntheses of (4S,5R)- and possessing three contiguous chiral centers as shown in Chart
(4R,5S)-4-benzyloxy-5-hydroxyhexen-2(E)-oates (2) based on 1. D-Digitoxose (5) is an important structural component of
a chemoenzymatic method from methyl sorbate (1).1) Hy- cardiac glycoside, digoxin,3–5) while L-oleandrose (6) is a com-
drolysis of (4S,5R)- and (4R,5S)-2 gave the corresponding ponent of several antibiotics such as oleandomycin6–8) and the
δ-hydroxy-trans-α,β-unsaturated carboxylic acids, which were avermectin series.9–11) L-Cymarose (7) is a glycosidic compo-
converted to osmundalactones (4S,5R)- and (4R,5S)-4 via the nent of a number of cardiac glycosides. Several syntheses of
formation of δ-lactones (4S,5R)- and (4R,5S)-3 accompanied methyl D-digitoxoside (12) (Chart 2) and L-oleandrose (6) have
by trans–cis isomerization, respectively.2)
been reported,12) but the synthesis of L-cymrose (7) has scarce-
Introduction of an oxygen functional group at C-3 position ly been reported. Herein we report the asymmetric syntheses
of (4S,5R)- and (4R,5S)-4 may enable the synthesis of D-gigi- of methyl D-digitoxoside (12), L-oleandrose (6) and L-cymarose
toxose (5) and L-oleandrose (6), L-cymarose (7), respectively, (7) from methyl sorbate, an achiral precursor.
Chart 1
The authors declare no conflict of interest.
† Present address: Nihon Pharmaceutical University; 10281 Komuro,
Inamachi, Kitaadachigun, Saitama 362–0806, Japan.
*To whom correspondence should be addressed. e-mail: hiroakita@nichiyaku.ac.jp
© 2012 The Pharmaceutical Society of Japan

August 2012
1077
Chart 2
Synthesis of Methyl D-Digitoxoside (12) For the synthe-
sis methyl D-digitoxoside (12), the construction of a 3,4-cis-
dihydroxy-δ-lactone moiety is required from (4S,5R)-4. The
oxymercuration–demercuration reaction of a trichloroacetalde-
hyde hemiacetal derivative derived from an unsaturated cyclic
alcohol possessing an allylic alcohol moiety for a neighboring
carbon–carbon double bond was reported to give an acetal
possessing a 1,2-cis-dihydroxy-structure.13) Owing to its high
tendency for formation of hemiacetal, trichloroacetaldehyde
(chloral) was selected for this study. The addition of 4eq of
chloral to (4S,5R)-4 resulted in quantitative formation of the
hemiacetal derivative (4S,5R)-8 as shown in Chart 2. Hemiac-
Fig. 1. NOE Correlation of (+)-(3S,4S,5R)-9
etal formation was easily monitored by observing the appear- reported pure α-epimer (pyranoside)-12 {[α]D20 +174 (c=1.0,
14)
ance of the characteristic singlet (δ 5.53ppm) of the methine CHCl3)} and β-epimer (pyranoside)-12 {[α]D20 −36 (c=1.0,
hydrogen attached to the trichloromethyl-bearing carbone in CHCl3)} using the following equation.
14)
nuclear magnetic resonance (NMR) spectrum. To promote
the Micheal addition of the hemiacetal hydroxyl group to
the neighboring α,β-unsaturated double bond, methane sul-
calculated value ([α]D )
=+174×0.37+(36)×0.63=+41.7
fonic acid (MsOH) was added and the intramolecular Micheal
The [α]D value of the 1.0:1.27 mixture of α- and β-epimers
addition product (+)-(3S,4S,5R)-9 possessing the 3,4-cis- (furanoside)-12 {[α]D25 +1.4 (c=0.44, CHCl3)} was consistent
dihydroxy-structure was obtained in 78% overall yield from with the calculated one {[α]D +2.24 (CHCl3)}. The calculated
(4S,5R)-4. The structure of (+)-(3S,4S,5R)-9 was confirmed value was obtained based on the reported pure α-isomer (fu-
14)
by nuclear Overhauser effect (NOE) spectroscopy as shown ranoside)-12 {[α]D20 +140 (c=1.0, CHCl3)} and β-isomer (fu-
in Fig. 1.
14)
ranoside)-12 {[α]D20 −106 (c=1.0, CHCl3)} as follows.
Treatment of (+)-(3S,4S,5R)-9 with tributyltin hydride
calculated value ([α]D )
(Bu3SnH) in the presence of azoisobutyronitrile (AIBN)
=+140×0.44+(106)×0.56=+2.24
gave an acetal (+)-(3S,4S,5R)-10 in 78% yield. Treatment of
(+)-(3S,4S,5R)-10 with diisobutylaluminum hydride (Dibal- Thus the structure of the synthetic methyl D-digitoxoside (12)
H) gave a 1.0:1.6 mixture of α- and β-epimers of lactol was unequivocally confirmed.
(3S,4R,5R)-11 in 81% yield. Acid treatment of this mixture
Synthesis of L-Oleandrose (6) and L-Cymarose (7) For
with Dowex 50W (H+) in MeOH followed by addition of the synthesis of L-oleandrose (6) and L-cymarose (7), the
camphor sulfonic acid (CSA) in MeOH afforded a 1.0:1.67 construction of a 3,4-trans-dihydroxy-δ-lactone moiety is re-
mixture of α- and β-epimers of methyl D-digitoxoside (py- quired from (4R,5S)-4. The reaction of ( )-4 and mercury(II)
ranoside)-12 (20% yield) and a 1.0:1.27 mixture of α- and trifluoroacetate [Hg(OCOCF3)2] followed by addition of an
β-epimers of methyl D-digitoxoside (furanoside)-12 (31% oxygen nucleophile such as water or methanol could give
1
yield). H-NMR data of both epimers of (pyranoside)-12 and compound ( )-14, which could be reduced with sodium bo-
both epimers of (furanoside)-12 were identical with those of rohydride (NaBH4) to afford compound ( )-15 possessing the
the reported compounds.14) The [α]D value of the 1.0:1.67 mix- 3,4-trans-dihydroxy-δ-lactone moiety as shown in Chart 3. In
ture of α- and β-epimers (pyranoside)-12 {[α]D20 +35.4 (c=0.85, this case, the structure of intermediary ( )-13 could be either
CHCl3)} were consistent with the calculated value {[α]D +41.7 2,3-cis- and 3,4-cis because of the chelation between hydroxyl
(CHCl3)}. The calculated value was obtained based on the group and mercury ion.

1078
Vol. 60, No. 8
Chart 3
Chart 4
Chart 5

August 2012
1079
In order to examine this working hypothesis, the reaction aldehyde group formations based on MeOH elimination could
of ( )-4 and Hg(OCOCF3)2 in the presence of 70% HClO4 afford α,β-unsaturated aldehyde 25, which could be accompa-
solution followed by the reduction with alkaline NaBH4 was nied by Micheal addition of MeOH and hemiaetal formation
carried out to afford compound ( )-16 in 26% overall yield to afford (3S,4R,5S)-22 possessing more stable all equatorial
as shown in Chart 4. In this case, no other products were ob- configurations.
tained.
The synthetic ( )-16 was identical with the authentic ( )-
16, which was obtained by treatment of previously mentioned
Conclusion
The addition of 4eq of chloral to osmundalactone (4S,5R)-
( )-10 (Chart 2) with aqueous 1M H2SO4 in 83% overall yield. 4 gave quantitative formation of the hemiacetal derivative
The reaction of ( )-4, Hg(OCOCF3)2 and MeOH in the pres- (4S,5R)-8, which was treated with methane sulfonic acid
ence of 70% HClO4 solution followed by the reduction with (MsOH) to afford the intramolecular Micheal addition
alkaline NaBH4 was carried out to give compound ( )-18 in product (+)-(3S,4S,5R)-9 possessing a 3,4-cis-dihydroxy-δ-
32% overall yield (Chart 4). In this case, no other products lactone moiety in 78% overall yield from (4S,5R)-4. Thus
were obtained. AlCl3-assisted demethylation of ( )-18 in obtained (+)-(3S,4S,5R)-9 was converted to actal-δ-lactone (+
ethane thiol (EtSH) afforded ( )-16 (13%) and a mixture of )-(3S,4S,5R)-10, which was reduced with Dibal-H to provide
α- and β-isomers of ( )-19a,b (31%). Consequently, the struc- lactol (3S,4R,5R)-11 in 81% yield. Deprotection of the acetal in
ture of ( )-18 was confirmed. From these fact, the structure (3S,4R,5R)-11 followed by acid treatment in MeOH gave meth-
of intermediary ( )-13 could be either 2,3-cis- and 3,4-trans yl D-digitoxoside (pyranoside) (12) in 20% yield and methyl
because stereic repulsion of between hydroxyl group and mer- D-digitoxoside (furanoside) (12) in 31% yield.
cury ion could be larger than the above mentioned chelation
The reaction of benzyl-osmundalactone (4R,5S)-3 and
effect. Consequently, water could attack at C(3)-position from MeOH in the presence of Amberlyst A-26 as a basic catalyst
β-side to give 3,4-cis ( )-17, which could be immediately con- gave 3,4-trans-δ-lactone (−)-(3S,4R,5S)-20 in 28% yield and
verted to ( )-16.
3,4-cis-δ-lactone (−)-(3R,4R,5S)-21 in 45% yield. Dibal-H re-
Due to the low yield of ( )-16 and ( )-18, the introduc- duction of (−)-(3S,4R,5S)-20 followed by catalytic hydrogena-
tion of methoxyl group at the 3-position of the benzyl ether tion gave L-oleandrose (6) in 86% overall yield, while Dibal-H
(4R,5S)-3 via the Michael addition was examined. The reaction reduction of (−)-(3R,4R,5S)-21 followed by catalytic hydroge-
of (4R,5S)-3 and MeOH in the presence of Amberlyst A-26 as nation provided L-cymarose (7) in 85% overall yield.
a basic catalyst gave 3,4-trans-δ-lactone (−)-(3S,4R,5S)-20
{[α]D22 −112 (c=1.73, CHCl3)} in 28% yield and 3,4-cis-δ-
Experimental
lactone (−)-(3R,4R,5S)-21 {[α]D24 −72 (c=1.5, CHCl3)} in 45%
1H- and 13C-NMR spectra were recorded on JEOL AL 400
yield. The structures of both products were confirmed by the spectrometer in CDCl3. Carbon substitution degrees were
fact that (−)-(3S,4R,5S)-20 and (−)-(3R,4R,5S)-21 were con- established by distortionless enhancement by polarization
verted to natural products L-oleandrose (6) and L-cymarose transfer (DEPT) pulse sequence. The fast atom bombardment-
(7), respectively, as shown in Chart 5.
mass spectra (FAB-MS) were obtained with a JEOL JMS
Dibal-H reduction of (−)-(3S,4R,5S)-20 provided a 1.8:1.0 600H spectrometer. IR spectra were recorded with a JASCO
mixture of α- and β-epimers (3S,4R,5S)-22 {[α]D23 −73 (c=0.55, FT/IR-300 spectrometer. Optical rotations were measured with
CHCl3)} in 91% yield, which was subjected to catalytic hydro- a JASCO DIP-370 digital polarimeter. All evaporations were
genation to give a 1.7:1.0 mixture of α- and β-L-oleandroses performed under reduced pressure. For column chromatogra-
(6) in 95% yield. The specific rotation of the synthetic L-ole- phy, silica gel (Kieselgel 60) was employed.
androse (6) {[α]D23 +10 (c=0.51, H2O)} was consistent with the
Synthesis of Methyl D-Digitoxoside (11) i) A mixture of
reported data {[α]D23 +11.2 (c=1.0, H2O)}.9) 1H-NMR data and (4S,5R)-4 (0.601g, 4.7mmol) and CCl3CHO (3.46g 23.5mmol)
13C-NMR data of the synthetic L-oleandrose (6) were identical was stood for 24h at rt and a solution of MsOH (1.36g,
with those of the reported data.15)
14.1mmol) in CH2Cl2 (10mL) was added to the above reac-
Dibal-H reduction of (−)-(3R,4R,5S)-21 provided a 3.1:1.0 tion mixture. All reaction mixture was stirred for 8h at rt.
mixture of α- and β-epimers (3R,4R,5S)-23 {[α]D24 −87.7 The reaction mixture was diluted with Et2O and the organic
(c=1.46, CHCl3)} in 98% yield, which was subjected to cata- layer was washed with brine. The organic layer was dried
lytic hydrogenation to give a 3:2 mixture of L-cymarose (py- over MgSO4 and evaporated to give a crude oil, which was
ranose) (7) and L-cymarose (furanose) (7) in 87% yield and chromatographed on silica gel (35g, n-hexane–AcOEt=1:3)
(3R,4R,5S)-24 in 8% yield. The specific rotation of the syn- to give (+)-(3S,4S,5R)-9 (1.010g, 78%) as a colorless oil.
thetic mixture L-cymarose (7) {[α]D24 −52 (c=0.42, H2O)} was (+)-(3S,4S,5R)-9: IR (CHCl3): 1755cm−1; [α]D30 +58.7 (c=0.34,
1
consistent with the reported data {[α]D23 −50 (c=1.0, H2O)}.16) CHCl3), H-NMR δ: 1.51 (3H, d, J=6Hz), 2.81 (1H, dd, J=16,
1H-NMR data and 13C-NMR data of the synthetic L-cymarose 6Hz), 3.02 (1H, dd, J=16, 6Hz), 4.42 (1H, qd, J=6, 6Hz), 4.52
(7) were identical with those of the reported data.16)
(1H, dd, J=6, 6Hz), 5.07 (1H, ddd, J=6, 6, 6Hz), 5.55 (1H, s).
The reaction of the 3.1:1.0 mixture of α- and β-epimers Anal. Calcd for C8H9O4Cl3: C, 34.88; H, 3.27. Found: C, 34.59;
(3R,4R,5S)-23 and MeOH in the presence of Amberlyst A-26 H, 3.26. MS (FAB) m/z: 276 (M++1).
gave a 1.8:1.0 mixture of α- and β-epimers (3S,4R,5S)-22 in
ii) To a solution of (+)-(3S,4S,5R)-9 (0.453g, 1.64mmol)
55% yield and the recovery of (3R,4R,5S)-23 in 21% yield. It and AIBN (70mg, 0.43mmol) in benzene (40mL) under ar-
was found that an equilibrium relationship was established gon atmosphere were added n-Bu3SnH (2.16g, 7.42mmol)
between (3R,4R,5S)-23 and (3S,4R,5S)-22 via the aldehyde and the reaction mixture was stirred for 2.5h at 90°C. The
intermediate (25). This process could be explained in the reaction mixture was evaporated to give a residue, which was
following manner. Acid-promoted trans double bond and chromatographed on silica gel (55g, n-hexane–AcOEt=1:3)

1080
Vol. 60, No. 8
to give (+)-(3S,4S,5R)-10 (0.222g, 78%) as a colorless oil. and 13C-NMR of each epimer were assigned by comparison of
1
(+)-(3S,4S,5R)-10: IR (neat): 1756cm−1; [α]D26 +105.9 (c=0.43, the reported data. α-Epimer, H-NMR δ: 1.22 (3H, d, J=6Hz),
CHCl3), 1H-NMR δ: 1.34 (3H, d, J=5Hz), 1.47 (3H, d, 1.96 (1H, dd, J=14, 2Hz), 2.07 (1H, ddd, J=14, 7, 2Hz),
J=6Hz), 2.72 (1H, dd, J=16, 8Hz), 2.93 (1H, dd, J=16, 6Hz), 3.35 (3H, s), 3.80–3.90 (2H, m), 4.22 (1H, brs), 5.06 (1H, d,
4.08 (1H, dd, J=8.4, 8Hz), 4.33 (1H, qd, J=8.4, 6Hz), 4.59 J=4Hz). 13C-NMR δ: 105.20 (d), 90.80 (d), 71.16 (d), 67.64 (d),
(1H, ddd, J=8.4, 8, 6Hz), 5.30 (1H, q, J=5Hz). Anal. Calcd 54.80 (s), 42.05 (t), 18.72 (s). β-Epimer δ: 1.21 (3H, d, J=6Hz),
for C8H12O4·0.25H2O: C, 54.37; H, 7.08. Found: C, 54.49; H, 2.04–2.14 (1H, m), 2.24 (1H, ddd, J=14, 7, 2Hz), 3.34 (3H, s),
7.25. MS (FAB) m/z: 173 (M++1).
3.75–3.85 (2H, m), 4.56 (1H, brs), 5.04 (1H, d, J=6Hz). 13C-
iii) To a solution of (+)-(3S,4S,5R)-10 (0.173g, 1.0mmol) NMR δ: 105.40 (d), 91.00 (d), 70.97 (d), 68.58 (d), 55.40 (s),
in toluene (15mL) was added 1M Dibal-H toluene solution 42.74 (t), 18.98 (s).
(2.7mL, 2.7mmol) under argon atmosphere at −20°C and
(ꢁ)-(3S′,4R′,5R′)-3,5-Dihydroxyhexano-4-lactone
(16)
the reaction mixture was stirred for 1h at −20°C. The reac- To a solution of ( )-4 (0.069g, 0.54mmol) in tetrahydro-
tion mixture was diluted with 2M HCl solution and extracted furan (THF) (3mL) at 0°C were added Hg(OCOCF3)2 (0.69g,
with Et2O. The organic layer was washed with brine and 1.62mmol) and 70% HClO4 solution (0.15mL, 0.97mmol),
dried over MgSO4. Evaporation of the organic solvent gave and the reaction mixture was stirred for 2h at 0°C. To the
a crude oil, which was chromatographed on silica gel (10g, reaction mixture were added 7% NaHCO3 solution (7mL) and
n-hexane–AcOEt=5:1) to give a 1:1.6 mixture of α- and NaBH4 (0.06g, 1.59mmol) at 0°C, and the reaction mixture
β-epimers of (+)-(3S,4R,5R)-11 (0.141g, 81%) as a colorless was stirred for 1h. The reaction mixture was filtered and the
oil. (+)-(3S,4R,5R)-11: IR (neat): 3432cm−1; [α]D24 +82.03 filtrate was acidified with AcOH. The reaction mixture was
(c=0.79, CHCl3), Anal. Calcd for C8H14O4·0.25H2O: C, 53.75; condensed to afford a residue, which was chromatographed on
H, 8.12. Found: C, 53.76; H, 8.19. MS (FAB) m/z: 175 (M++1). silica gel (25g, n-hexane–AcOEt=1:1) to give ( )-16 (0.020g,
1
1H-NMR of each epimer was analyzed based on NOE and 26%) as a colorless oil. ( )-16: IR (neat): 1732, 3444cm−1; H-
proton–proton decoupling (homo decoupling) analysis tech- NMR (CD3OD) δ: 1.22 (3H, d, J=6Hz), 2.34 (1H, dd, J=18,
nique. α-Epimer δ: 1.26 (3H, d, J=6Hz), 1.32 (3H, d, J=6Hz), 2Hz), 2.89 (1H, dd, J=18, 8Hz), 3.89 (1H, qd, J=6, 4Hz), 4.18
1.80 (1H, ddd, J=14, 9, 4Hz), 2.32 (1H, ddd, J=14, 4, 3Hz), (1H, dd, J=4, 2Hz), 4.50 (1H, dt, J=8, 2, 2Hz). 13C-NMR
3.15 (1H, d, J=5.8Hz), 3.53 (1H, qd, J=9, 6Hz), 3.78 (1H, dd, (CD3OD) δ: 178.33 (s), 93.27 (d), 67.89 (d), 67.63 (d), 39.27 (t),
J=10, 4Hz), 4.25–4.35 (1H, m), 5.03 (1H, ddd, J=9, 5.8, 2Hz), 19.02 (q). Anal. Calcd for C6H10O4·0.25H2O: C, 47.84; H, 7.03.
5.38 (1H, q, J=5.2Hz). β-epimer δ: 1.26 (3H, d, J=6Hz), 1.32 Found: C, 47.56; H, 7.08. MS (FAB) m/z: 147 (M++1).
(3H, d, J=6Hz), 2.06–2.20 (2H, m), 3.75 (1H, dd, J=10, 5Hz),
3.97 (1H, qd, J=9, 6Hz), 4.25–4.35 (1H, m), 5.15 (1H, ddd, To a solution of ( )-10 (0.166g, 0.96mmol) in THF (4mL) was
J=8, 4, 4Hz), 5.42 (1H, q, J=5.2Hz). added 1M H2SO4 solution (2.5mL) and the reaction mixture
Conversion of (ꢁ)-(3S′,4R′,5R′)-10 to (ꢁ)-(3S′,4R′,5R′)-16
iv) To a solution of a 1:1.6 mixture of α- and β-epimers was stirred for 2h at 80°C. The reaction mixture was diluted
of (+)-(3S,4R,5R)-11 (0.107g, 0.61mmol) in MeOH (0.5mL) with 7% NaHCO3 solution (7mL) and extracted with AcOEt.
was added H2O (3.6mL) and Dowex 50W(H+) (0.4g), and the The organic layer was dried over Na2SO4 and evaporated to
reaction mixture was stirred for 1.5h at 70°C. The reaction afford a residue which was chromatographed on silica gel
mixture was filtered and the filtrate was evaporated to give (20g, n-hexane–AcOEt=1:2) to give ( )-16 (0.117g, 83%) as
1
a crude oil. To a solution of the above oil in MeOH (2mL) a colorless oil. H- and 13C-NMR data of ( )-12 were identical
was added CSA (0.12g, 0.52mmol) and the reaction mixture with those of the previous ( )-16.
was stood for 1h at rt. The reaction mixture was condensed
(ꢁ)-(3S′,4R′,5R′)-5-Hydroxy-3-methoxyhexano-4-lactone
to give a crude oil, which was chromatographed on silica gel (18) To a solution of ( )-4 (0.081g, 0.63mmol) in MeOH
(10g, n-hexane–AcOEt=1:1) to give a 1:1.67 mixture of α- (5mL) was added Hg(OCOCF3)2 (0.82g, 1.92mmol) and
and β-epimers of (+)-methyl D-digitoxoside (12) (pyranoside, the reaction mixture was stirred for 2h at rt. To the reac-
0.020g, 20%) as a colorless oil and a 1:1.27 mixture of α- tion mixture were added 7% NaHCO3 solution (7mL) and
and β-epimers of (+)-methyl D-digitoxoside (12) (furanoside, NaBH4 (0.07g, 1.85mmol) at 0°C, and the reaction mixture
0.031g, 31%) as a colorless oil in elution order: D-digitoxoside was stirred for 1h. The reaction mixture was worked up in
(12) (pyranoside): IR (neat): 3445cm−1; [α]D24 +35.4 (c=0.85, the same way of ( )-12 to give ( )-18 (0.033g, 32%) as a
1
CHCl3), Anal. Calcd for C7H14O4·0.25H2O: C, 50.44; H, 8.77. colorless oil. ( )-18: IR (neat): 1775, 3448cm−1; H-NMR δ:
1
Found: C, 50.65; H, 8.84. MS (FAB) m/z: 163 (M++1). H- and 1.24 (3H, d, J=6Hz), 2.50 (1H, dd, J=18, 2Hz), 2.82 (1H, dd,
13C-NMR of each epimer were assigned by comparison of the J=18, 7Hz), 3.30 (3H, s), 4.04 (1H, qd, J=6, 4Hz), 4.12 (1H,
1
reported data. α-Epimer, H-NMR δ: 1.31 (3H, d, J=6Hz), dt, J=7, 3Hz), 4.26 (1H, dd, J=4, 3Hz). 13C-NMR δ: 175.85
1.89 (1H, ddd, J=14.5, 3.4, 3.4Hz), 2.15 (1H, ddd, J=14.5, (s), 88.56 (d), 75.76 (d), 66.74 (d), 56.51 (q), 35.40 (t), 18.34 (q).
5.3, 1Hz), 3.12 (1H, d, J=7Hz), 3.35 (3H, s), 3.69 (1H, qd, Anal. Calcd for C7H12O4: C, 52.49; H, 7.55. Found: C, 52.51;
J=10, 6Hz), 3.92 (1H, brs), 4.75 (1H, d, J=3.4Hz). 13C-NMR H, 7.29. MS (FAB) m/z: 161 (M++1).
δ: 98.21 (d), 72.51 (d), 67.54 (d), 64.29 (d), 55.20 (s), 35.20 (t),
17.90 (s). β-Epimer δ: 1.29 (3H, d, J=6Hz), 1.68 (1H, ddd, To a mixture of AlCl3 (0.120g, 0.9mmol) in EtSH (2mL,
J=14, 10, 3Hz), 2.08 (1H, ddd, J=14, 4, 2Hz), 3.28 (1H, d, 0.03mmol) was added solution of ( )-18 (0.047g,
Conversion of (ꢁ)-(3S′,4R′,5R′)-18 to (ꢁ)-(3S′,4R′,5R′)-16
a
J=9Hz), 3.45 (3H, s), 3.71 (1H, qd, J=9, 6Hz), 4.08 (1H, dd, 0.29mmol) in EtSH (1mL) at 0°C and the reaction mixture
J=5, 3Hz), 4.69 (1H, dd, J=10, 2Hz). 13C-NMR δ: 98.71 (d), was stirred for 4h at rt. The reaction mixture was diluted with
73.00 (d), 69.52 (d), 68.00 (d), 56.49 (s), 37.70 (t), 18.22 (s). H2O and extracted with Et2O. The organic layer was dried
D-digitoxoside (12) (furanoside): IR (neat): 3445cm−1; [α]D24 over Na2SO4 and evaporated to afford a residue which was
1
+1.37 (c=0.44, CHCl3), MS (FAB) m/z: 163 (M++1). H-NMR chromatographed on silica gel (10g) to give a 3:2 mixture

August 2012
1081
of ( )-19a,b (0.017g, 31%) as a colorless oil from n-hexane– J=10, 9Hz), 3.44 (3H, s), 3.72 (1H, ddd, J=14, 9, 5Hz), 3.94
AcOEt=2:1 elution, recovery of ( )-18 (0.020g, 42%) from (1H, qd, J=10, 6Hz), 4.63, 4.89 (each 1H, d, J=11Hz), 5.31
1
n-hexane–AcOEt=1:1 elution and ( )-16 (0.006g, 13%) from (1H, brs), 7.23–7.40 (5H, m). β-Epimer: H-NMR δ: 1.30 (3H,
1
n-hexane–AcOEt=1:3 elution. H- and 13C-NMR data of ( )- d, J=6Hz), 1.43 (1H, ddd, J=12, 12, 10Hz), 2.40 (1H, ddd,
16 were identical with those of the previous ( )-16. ( )-19a,b: J=12, 5, 2Hz), 3.00 (1H, dd, J=6, 3Hz), 3.33–3.43 (2H, m),
IR (neat): 1732, 3414cm−1; Anal. Calcd for C8H14O3S: C, 3.42 (3H, s), 4.62, 4.88 (each 1H, d, J=11Hz), 5.05 (1H, brs),
50.50; H, 7.42. Found: C, 50.26; H, 7.35. MS (FAB) m/z: 191 7.23–7.40 (5H, m).
1
(M++1). H-NMR of each isomer was analyzed based on the
iii) A mixture of (−)-(3S,4R,5S)-22 (1.8:1 mixture of α- and
proton–proton decoupling (homo decoupling) analysis tech- β-epimers) (0.207g, 0.82mmol) and 20% Pd(OH)2–C (0.16g)
nique. 19a, H-NMR (CD3OD) δ: 1.21 (3H, d, J=6Hz), 1.28 in AcOEt (20mL) was subjected to a catalytic hydrogenation
1
(3H, d, J=7Hz), 2.44 (1H, dd, J=18, 4Hz), 2.50–2.74 (2H, m), under ordinary pressure for 12h at rt. The reaction mixture
3.09–3.19 (1H, m), 3.68 (1H, ddd, J=9, 4, 4Hz), 3.94 (1H, qd, was filtered and the filtrate was condensed to give a crude
1
J=6, 4Hz), 4.22 (1H, dd, J=7, 3Hz). 19b, H-NMR (CD3OD) oil, which was chromatographed on silica gel (10g, n-hexane–
δ: 1.25 (3H, d, J=7Hz), 1.40 (3H, d, J=6Hz), 2.50–2.74 (2H, AcOEt=1:2) to give a 1.7:1 mixture of α- and β-L-oleandrose
m), 3.05–3.18 (3H, m), 3.35 (1H, dd, J=9, 7Hz), 4.19 (1H, qd, (6) (0.153g, 95%) as a colorless oil. L-Oleandrose (6): IR
J=6, 5Hz).
(neat): 3443cm−1; [α]D23 +10.0 (c=0.51, H2O), Anal. Calcd for
Synthesis of L-Oleandrose (6) i) To a mixture of (4R,5S)- C7H14O4: C, 51.84; H, 8.70. Found: C, 51.58; H, 8.98. MS
3 (0.866g, 3.97mmol) and molecular sieve (MS) 3A (1.0g) in (FAB) m/z: 145 (M++1−H2O). H-NMR of each epimer was
MeOH (20mL) was added Amberlyst A-26 (hydroxide form) analyzed based on NOE and proton–proton decoupling (homo
(0.6g) and the reaction mixture was stirred for 3h at rt. The decoupling) analysis technique. α-Pyranose (6): H-NMR δ:
1
1
reaction mixture was filtered and the filtrate was condensed to 1.26 (3H, d, J=6Hz), 1.47 (1H, ddd, J=14, 12, 4Hz), 2.28 (1H,
give a crude oil. To a solution of the above oil in THF (20mL) ddd, J=14, 4.4, 1.6Hz), 3.13 (1H, dd, J=9, 9Hz), 3.37 (3H, s),
was added aqueous 2M NaOH (6mL) and the reaction mixture 3.55 (1H, ddd, J=14, 9, 5Hz), 3.91 (1H, qd, J=9, 6Hz), 5.32
was stirred for 1h at rt. The reaction mixture was acidified (1H, brs, J=3Hz). 13C-NMR δ: 91.89 (d), 77.85 (d), 76.10 (d),
1
with aqueous 2M HCl and condensed to give a crude product, 67.65 (d), 56.45 (q), 34.15 (t), 18.00 (q). β-Pyranose (6): H-
which was diluted with AcOEt. The AcOEt layer was filtered NMR δ: 1.32 (3H, d, J=6Hz), 1.35–1.37 (1H, m), 2.39 (1H,
and the filtrate was condensed to give a crude oil, which was ddd, J=12, 4, 2Hz), 3.08–3.44 (3H, m), 3.35 (3H, s), 4.79 (1H,
chromatographed on silica gel (30g) to give (−)-(3S,4R,5S)-20 dd, J=10, 2Hz). 13C-NMR δ: 93.90 (d), 80.50 (d), 75.15 (d),
(0.284g, 28%) as a colorless oil from n-hexane–AcOEt=5:1 71.75 (d), 56.38 (q), 36.50 (t), 17.95 (q).
eluent and (−)-(3R,4R,5S)-21 (0.453g, 45%) as a colorless oil
Synthesis of L-Cymarose (7) i) To a solution of
from n-hexane–AcOEt=2:1 eluent. (−)-(3S,4R,5S)-20: [α]D22 (−)-(3R,4R,5S)-21 (0.313g, 1.25mmol) in toluene (13mL) was
1
−111.5 (c=1.73, CHCl3), IR (neat): 1758cm−1; H-NMR δ: 1.41 added 1M Dibal-H toluene solution (2.5mL, 2.5mmol) under
(3H, d, J=6Hz), 2.74 (1H, ddd, J=16, 4, 1Hz), 2.79 (1H, dd, argon atmosphere at −20°C and the reaction mixture was
J=16, 5Hz), 3.36 (3H, s), 3.39 (1H, ddd, J=8, 3, 1Hz), 3.74 stirred for 1h at −20°C. The reaction mixture was diluted
(1H, dd, J=8, 4Hz), 4.19 (1H, qd, J=6, 4Hz), 4.58, 4.72 (each with 2M HCl solution (2.5mL) and extracted with Et2O. The
1H, d, J=12Hz), 7.28–7.38 (5H, m). Anal. Calcd for C14H18O4: organic layer was washed with brine and dried over MgSO4.
C, 67.18; H, 7.25. Found: C, 66.98; H, 7.41. MS (FAB) m/z: Evaporation of the organic solvent gave a crude oil, which was
251 (M++1). (−)-(3R,4R,5S)-21: [α]D24 −71.9 (c=1.5, CHCl3), IR chromatographed on silica gel (15g, n-hexane–AcOEt=2:1) to
1
(neat): 1733cm−1; H-NMR δ: 1.37 (3H, d, J=6Hz), 2.58 (1H, give a 3.1:1 mixture of α- and β-epimers of (−)-(3R,4R,5S)-23
dd, J=18, 4Hz), 2.90 (1H, dd, J=18, 5.6Hz), 3.41 (3H, s), 3.46 (0.308g, 98%) as a colorless oil. (−)-(3R,4R,5S)-23: IR (neat):
(1H, dd, J=7, 2Hz), 3.75 (1H, ddd, J=5.8, 4, 2Hz), 4.70 (1H, 3420cm−1; [α]D24 −87.7 (c=1.46, CHCl3), Anal. Calcd for
qd, J=7, 6Hz), 4.61, 4.72 (each 1H, d, J=12Hz), 7.26–7.38 C14H20O4·0.25H2O: C, 65.42; H, 7.98. Found: C, 65.22; H,
1
(5H, m). Anal. Calcd for C14H18O4: C, 67.18; H, 7.25. Found: C, 7.94. MS (FAB) m/z: 253 (M++1). H-NMR of each epimer
66.89; H, 7.31. MS (FAB) m/z: 251 (M++1).
was analyzed based on NOE and proton–proton decoupling
1
ii) To a solution of (−)-(3S,4R,5S)-20 (0.246g, 0.98mmol) (homo decoupling) analysis technique. α-Epimer: H-NMR δ:
in toluene (12mL) was added 1M Dibal-H toluene solution 1.29 (3H, d, J=6Hz), 1.70 (1H, ddd, J=14, 6, 2Hz), 2.19 (1H,
(2mL, 2mmol) under argon atmosphere at −20°C and the ddd, J=14, 4, 1.8Hz), 3.10 (1H, dd, J=10, 3Hz), 3.52 (3H, s),
reaction mixture was stirred for 1h at −20°C. The reaction 3.83 (1H, brs), 4.21 (1H, qd, J=10, 6Hz), 4.55, 4.65 (each 1H,
1
mixture was diluted with 2M HCl solution (2mL) and ex- d, J=12Hz), 5.17 (1H, brs), 7.24–7.40 (5H, m). β-Epimer: H-
tracted with Et2O. The organic layer was washed with brine NMR δ: 1.26 (3H, d, J=6Hz), 1.42 (1H, ddd, J=14, 10, 2Hz),
and dried over MgSO4. Evaporation of the organic solvent 2.27 (1H, ddd, J=14, 4, 2Hz), 3.10 (1H, dd, J=10, 3Hz), 3.42
gave a crude oil, which was chromatographed on silica gel (3H, s), 3.72 (1H, brs), 3.96 (1H, qd, J=10, 6Hz), 4.51, 4.63
(10g, n-hexane–AcOEt=2:1) to give a 1.8:1 mixture of α- (each 1H, d, J=12Hz), 5.05 (1H, brs), 7.24–7.40 (5H, m).
and β-epimers of (−)-(3S,4R,5S)-22 (0.226g, 91%) as a color-
ii) A mixture of (−)-(3R,4R,5S)-23 (3.1:1 mixture of α- and
less oil. (−)-(3S,4R,5S)-22: IR (neat): 3440cm−1; [α]D23 −72.5 β-epimers) (0.142g, 0.56mmol) and 20% Pd(OH)2-C (0.16g)
(c=0.55, CHCl3), Anal. Calcd for C14H20O4: C, 66.65; H, 7.99. in AcOEt (20mL) was subjected to a catalytic hydrogenation
1
Found: C, 66.57; H, 8.25. MS (FAB) m/z: 253 (M++1). H- under ordinary pressure for 12h at rt. The reaction mixture
NMR of each epimer was analyzed based on NOE and pro- was filtered and the filtrate was condensed to give a crude
ton–proton decoupling (homo decoupling) analysis technique. oil, which was chromatographed on silica gel (10g) to give
1
α-Epimer: H-NMR δ: 1.25 (3H, d, J=6Hz), 1.54 (1H, ddd, (3R,4R,5S)-24 (0.007g, 8%) as a colorless oil from n-hexane–
J=14, 14, 3Hz), 2.27 (1H, ddd, J=14, 5, 2Hz), 3.02 (1H, dd, AcOEt=1:1 eluent and a 3:2 mixture of pyranose type and

1082
Vol. 60, No. 8
1
furanose type of L-cymarose (7) (0.079g, 87%) as a color- (3R,4R,5S)-23 (0.007g, 21%) as a colorless oil. H-NMR data
less oil from n-hexane–AcOEt=1:2 eluent. (3R,4R,5S)-24: of both compounds were identical with those of the previous
IR (neat): 3450cm−1; Anal. Calcd for C7H14O3: C, 57.51; H, (3S,4R,5S)-22 and (3R,4R,5S)-23, respectively.
9.65. Found: C, 57.23; H, 9.73. MS (FAB) m/z: 147 (M++1).
1H-NMR δ: 1.18 (3H, d, J=6Hz), 1.80–1.97 (2H, m), 2.22 (1H,
References
1) Ono M., Saotome C., Akita H., Tetrahedron Asymmetry, 7, 2595–
brs), 3.29 (3H, s), 3.58 (1H, dd, J=4, 4Hz), 3.78–3.98 (3H, m).
13C-NMR δ: 88.09 (d), 80.85 (d), 67.50 (d), 67.35 (t), 56.80 (q),
2602 (1996).
32.65 (t), 18.60 (q). L-Cymarose (7) IR (neat): 3418cm−1; [α]D23
2) Ono M., Zhao X. Y., Shida Y., Akita H., Tetrahedron, 63, 10140–
10148 (2007).
3) Reichstein T., Angew. Chem., 63, 412–421 (1951).
−51.6 (c=0.42, H2O), Anal. Calcd for C7H14O4: C, 51.84; H,
8.70. Found: C, 51.54; H, 8.87. MS (FAB) m/z: 145 (M++1−
4) Tschesche R., Wirtz S., Snatzke G., Chem. Ber., 88, 1619–1624
1
H2O). H-NMR of each epimer was analyzed based on NOE
(1955).
and proton–proton decoupling (homo decoupling) analysis
5) Lichti H., Tamm C., Reichstein T., Helv. Chim. Acta, 39, 1914–1932
1
technique. α-Pyranose (7): H-NMR δ: 1.17 (3H, d, J=6Hz),
(1956).
1.73 (1H, ddd, J=15, 4, 3Hz), 2.02–2.17 (1H, m), 3.32 (3H, s),
6) Jäger H., Schindler O., Reichstein T., Helv. Chim. Acta, 42, 977–
3.33–3.43 (1H, m), 3.57–3.66 (1H, m), 3.89–3.90 (1H, m), 5.06
1013 (1959).
1
7) Korte F., Ripphahn J., Liebigs Ann. Chem., 621, 58–71 (1959).
8) Hochstein F. A., Els H., Celmer W. D., Shapiro B. L., Woodward R.
B., J. Am. Chem. Soc., 82, 3225–3227 (1960).
9) Tsukamoto S., Hayashi K., Mitsuhashi H., Chem. Pharm. Bull., 33,
2294–2304 (1985).
10) Tsukamoto S., Hayashi K., Mitsuhashi H., Snykers F. O., Fourie T.
G., Chem. Pharm. Bull., 33, 4807–4814 (1985).
11) Tsukamoto S., Hayashi K., Mitsuhashi H., Tetrahedron, 41, 927–
934 (1985).
12) Ley S. V., Armstrong A., Diez-Martin D., Ford M. J., Grice P.,
Knight J. G., Kolb H. C., Madin A., Marby C. A., Mukherjee S.,
Shaw A. N., Slawin A. M. Z., Vile S., White A. D., Williams D.,
Woods M., J. Chem. Soc., Perkin Trans. I, 1991, 667–692 (1991).
13) Overman L. E., Campbell C. B., J. Org. Chem., 39, 1474–1481
(1974).
14) Zeeck A., Liebigs Ann. Chem., 11, 2079–2088 (1975).
15) Bredenkamp M. W., Holzapfel C. W., Toerien F., Synth. Commun.,
22, 2459–2477 (1992).
(1H, brs). β-Pyranose (7): H-NMR δ: 1.25 (3H, d, J=6Hz),
1.49 (1H, ddd, J=14, 10, 3Hz), 2.26 (1H, ddd, J=14, 4, 2Hz),
3.19 (1H, ddd, J=10, 10, 3Hz), 3.39 (3H, s), 3.57–3.66 (1H,
m), 3.86–3.98 (1H, m), 4.97 (1H, dd, J=10, 2Hz). A mixture
1
of furanose (7): H-NMR δ: 1.19, 1.25 (each 3H, d, J=6Hz),
1.98, 2.30 (each 1H, ddd, J=15, 4, 3Hz and ddd, J=14, 4,
2Hz), 2.18, 2.30 (each 1H, ddd, J=14, 7, 2Hz and ddd, J=14,
4, 2Hz), 3.26, 3.49 (each 3H, s), 4.04, 4.13 (each 1H, dd, J=4,
2Hz and ddd, J=8, 5, 4Hz), 5.44, 5.56 (each 1H, d, J=5Hz
and dd, J=6, 2.8Hz).
Conversion of (3R,4R,5S)-23 to (3S,4R,5S)-22 To a
solution of a mixture of (−)-(3R,4R,5S)-23 (3.1:1 mixture of
α- and β-epimers) (0.035g, 0.14mmol) in MeOH (2mL) was
added Amberlyst A-26 (hydroxide form) (0.1g) and the reac-
tion mixture was stirred for 2h at 35°C. The reaction mixture
was filtered and the filtrate was condensed to give a crude
oil, which was chromatographed on silica gel (10g, n-hexane–
AcOEt=2:1) to give a 1.7:1 mixture of α- and β-epimers of
(3S,4R,5S)-22 (0.019g, 55%) as a colorless oil and starting
16) Nakagawa T., Hayashi K., Wada K., Mitsuhashi H., Tetrahedron,
39, 607–612 (1983).