Total synthesis of (+)-asperlin

Article abstract of DOI:10.1016/j.tetasy.2008.04.011

Syntheses of (+)-asperlin 1 were achieved via two different synthetic routes. 1,2-Addition of α-furyl anion to (2R,3S)-2-^tbutyldimethylsilyloxy-3-chlorobutanal 6 gave (1S,2R,3S)-1-(2-furyl)-2-^tbutyldimethylsilyloxy-3-chlorobutanol 7, which was converted to the chiral intermediate, (1S,2R,3R)-1-(2-furyl)-2,3-epoxybutanol 8 (37% overall yield from 6) for the synthesis of (+)-1. The second synthesis of (+)-asperlin 1 from (2R,3S)-6 was achieved in 8% overall yield, based on a combination of the indium-assisted stereoselective addition of 3-bromopropenyl acetate 9 to (2R,3S)-6 and the ring closing metathesis (RCM) using Grubbs catalyst.

Full text of DOI:10.1016/j.tetasy.2008.04.011

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 1100–1105
Total synthesis of (+)-asperlin
Hideaki Akaike, Hidekazu Horie, Keisuke Kato and Hiroyuki Akita*
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan
Received 13 March 2008; accepted 2 April 2008
Abstract—Syntheses of (+)-asperlin 1 were achieved via two different synthetic routes. 1,2-Addition of a-furyl anion to (2R,3S)-2-tbutyl-
dimethylsilyloxy-3-chlorobutanal 6 gave (1S,2R,3S)-1-(2-furyl)-2-tbutyldimethylsilyloxy-3-chlorobutanol 7, which was converted to the
chiral intermediate, (1S,2R,3R)-1-(2-furyl)-2,3-epoxybutanol 8 (37% overall yield from 6) for the synthesis of (+)-1. The second synthesis
of (+)-asperlin 1 from (2R,3S)-6 was achieved in 8% overall yield, based on a combination of the indium-assisted stereoselective addition
of 3-bromopropenyl acetate 9 to (2R,3S)-6 and the ring closing metathesis (RCM) using Grubbs catalyst.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
tion was estimated to be 16.2. Repeated lipase-assisted res-
olution of both (2R,3S)-3 (89% ee) and (2S,3R)-2 (87% ee)
gave enantiomerically pure (2R,3S)-3 (>99% ee) and
(2S,3R)-2 (>99% ee), respectively, as shown in Scheme 1.
Herein, we report two concise syntheses of (+)-asperlin 1
based on the stereoselective addition of carbon-nucleophile
to the chiral a-silyloxy aldehyde, (2R,3S)-3-chloro-2-tert-
butyldimethylsilyloxybutanal 6, derived from (2R,3S)-3 as
shown in Schemes 2 and 4.
(+)-Asperlin 1, isolated from Aspergillus nidulans and
Aspergillus caespiyosus, has been shown to exhibit antitu-
mor and antibacterial activity. Its structure, including the
absolute configuration, was determined by spectroscopic
and chemical studies,1–3 as shown in Figure 1. Due to its
interesting bioactivity, the synthesis of the natural product
1 and the related compounds has already been reported by
several groups.4 Syntheses of (+)-1 from natural products
such as L-rhamnose,5 (S,S)-tartaric acid,6 and D-glucose7
have been reported. Recently, the convenient synthesis of
(+)-1 based on the Sharpless asymmetric epoxidation of
unsymmetrical divinylmethanol congeners has been
reported.8 On the other hand, we reported the lipase-
assisted resolution of racemic a-acetoxy ester ( )-2, a key
intermediate in the synthesis of (+)-asperlin, to give
(2R,3S)-a-hydroxy ester 3 (40%, 89% ee) and (2S,3R)-a-
acetoxy ester 2 (45%, 87% ee).9 The E-value of this resolu-
2. Results and discussion
2.1. Formal synthesis of (+)-asperlin 1
The formal synthesis of (+)-asperlin 1 from (2R,3S)-3 is
t
shown in Scheme 2. Silylation of (2R,3S)-3 with butyl-
dimethylsilyl chloride (TBDMSCl) gave the corresponding
silyl ether (2R,3S)-4 (92%), which was reduced with di-
isobutylaluminum hydride (Dibal-H) to afford alcohol
(2R,3S)-5 in 88% yield. Pyridinium chlorochromate
(PCC) oxidation of (2R,3S)-5 gave the desired aldehyde
(2R,3S)-6 (69%), which was reacted with a-furyl anion to
afford the (1S,2R,3S)-secondary alcohol 7 stereoselectively
in 72% yield. To confirm the stereochemistry of
(1S,2R,3S)-7, it was converted to the known chiral interme-
diate, epoxy-alcohol (ꢀ)-(1S,2R,3S)-7,8a,b for the synthesis
of (+)-1. Protection of the secondary alcohol group of
(1S,2R,3S)-7 as a tetrahydropyranyl (THP) group, fol-
lowed by consecutive desilylation and K2CO3 treatment
gave an epoxide, which was subjected to deprotection of
the THP group to provide the desired epoxy-alcohol 8 in
O
O
Me
O
OAc
(+)-Asperlin 1
Figure 1.
*
Corresponding author. Tel.: +81 047 472 1805; fax: +81 047 476 6195;
e-mail: akita@phar.toho-u.ac.jp
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.04.011

H. Akaike et al. / Tetrahedron: Asymmetry 19 (2008) 1100–1105
1101
Cl
Cl
lipase "Amano P"
COOMe
COOMe
( )-2
+
Me
Me
H2O saturated i-Pr2O
OH
OAc
(2R,3S)-3 (>99% ee)
(2S,3R)-2 (>99% ee)
Scheme 1.
Cl
Cl
Cl
a
92%
b
88%
c
69%
COOMe
CHO
CH2OH
(2R,3S)-3
Me
Me
Me
OTBDMS
(2R,3S)-4
OTBDMS
OTBDMS
(2R,3S)-6
(2R,3S)-5
Cl
OH
1
OH
O
ref. 8a
d
72%
e
83%
O
(+)-1
Me
TBDMSO
(1S,2R,3S)-7
Me
O
(-)-(1S,2R,3R)-8
Scheme 2. Reagents: (a) TBDMSCl/imidazole/DMF; (b) Dibal-H; (c) PCC; (d) furan/n-BuLi; (e) (1) ethyl vinyl ether/PPTS; (2) TBAF; (3) K2CO3; (4)
AcOH/H2O/THF.
83% overall yield from 7. Spectral data (1H and 13C NMR)
of the synthetic 8 were identical with those of the reported
addition of 3-bromopropenyl acetate 910 to the a-silyloxy
aldehyde, (2R,3S)-6 and the ring closing metathesis
(RCM) using Grubbs catalyst,11 is shown in Scheme 4. Re-
cently, Lombardo et al. reported that the a-hydroxyallyla-
tion reaction of Garner aldehyde 10 using 9 in the presence
of indium gave predominantly a C(4)–C(10)-anti-C(10)–
C(20)-anti-diol 12 via 11 as shown in Scheme 3.12 This strat-
egy could be promising for the construction of the four
contiguous stereogenic centers in asperlin 1.
(ꢀ)-(1S,2R,3R)-8.8a The specific rotation of the synthetic 8
24
f½aꢁD ¼ ꢀ42:2 (c 0.67, CHCl3)} was in accord with that of
the reported (ꢀ)-(1S,2R,3R)-88a {[a]D = ꢀ43 (CHCl3)},
including the sign of the specific rotation. The synthesis
of (+)-1 from (ꢀ)-(1S,2R,3R)-8 was already achieved by
Honda et al.8a
The stereoselective formation of (ꢀ)-(1S,2R,3S)-7 from
(2R,3S)-6 could be explained by a Felkin–Anh model as
shown in Figure 2.
The reaction of (2R,3S)-6 with 3-bromopropenyl acetate 9
in the presence of indium gave predominantly alcohol 13 in
75% yield, which was converted to epoxyalcohol 14. Pro-
tection of the secondary alcohol group of 13 as a THP
group followed by consecutive desilylation and K2CO3
treatment gave an epoxide, which was subjected to depro-
tection of the THP group to provide the desired epoxyalco-
hol 14 in 83% overall yield from 13. Treatment of 14 and
acryloyl chloride gave the corresponding acrylate 15 in
71% yield, which was subjected to the RCM reaction using
Grubbs catalyst 2nd generation13 to afford (ꢀ)-epi-asperlin
16 in 49% yield. Spectral data (1H and 13C NMR) of the
synthetic (ꢀ)-16 were identical with those of the reported
R
O
R
OH
H
H
TBDMSO
Cl
O
TBDMSO
H
H
Furan
R=
(1S,2R,3S)-7
Me
Figure 2. Felkin–Anh model for the preparation of anti, anti-7.
(ꢀ)-16.4b The specific rotation of the synthetic (ꢀ)-16
24
2.2. Concise synthesis of (+)-asperlin 1
f½aꢁD ¼ ꢀ181:9 (c 0.13, EtOH)} was in accord with the re-
20
ported value for (ꢀ)-164b f½aꢁD ¼ ꢀ185 (c 0.50, EtOH)},
A concise synthesis of (+)-asperlin 1 from (2R, 3S)-6 based
including the sign of the specific rotation. Based on the
on a combination of the indium-assisted stereoselective
conversion of 13 to (ꢀ)-16, the stereochemistry of 13 was
Boc
Boc
Boc
AcO
Br
N
OAc
N
N
OH
K2CO3
9
O
O
O
1'
2'
4
CHO
In / THF-H2O
10
OH 11
OH 12
95% (85% purity)
Scheme 3.

1102
H. Akaike et al. / Tetrahedron: Asymmetry 19 (2008) 1100–1105
OH
Cl
OH
c
a
75%
b
83%
(2R,3S)-6
3
Me
Me
TBDMSO
(3R,4R,5R,6S)-13
71%
O
OAc
OAc
(3R,4R,5S,6R)-14
O
O
O
2
O
O
O
d
e
50% Me
f
6
(+)-1
Me
O
49% Me
O
72%
1'
O
OAc
OAc
OH
(5R,6R,1'S,2'R)-17
(-)-epi-Asperlin 16
(3R,4R,5S,6R)-15
Scheme 4. Reagents: (a) In/3-bromopropenyl acetate 9/THF/H2O (1:1); (b) (1) ethyl vinyl ether/PPPTS; (2) TBAF; (3) K2CO3; (4) AcOH/H2O/THF;
(c) acryloyl chloride/(i-Pr)2NEt; (d) Grubbs catalyst (2nd)/CH2Cl2; (e) lipase PL/H2O saturated (i-Pr)2O; (f) Ph3P/AcOH/DEAD/THF.
Table 1. Ring closing metathesis of (3R,4R,5S,6R)-11
Entry
Grubbs reagent
Condition
Time (h)
Concentration (mol/L)
Product
1
2
3
4
5
6
1st (0.08 equiv)
2nd (0.2 equiv)
2nd (0.08 equiv)
2nd (0.08 equiv)
2nd (0.08 equiv)
2nd (0.1 equiv)
CH2Cl2 (40 °C)
Toluene (110 °C)
Toluene (110 °C)
Toluene (110 °C)
CH2Cl2 (40 °C)
CH2Cl2 (40 °C)
10
32
31
22.5
21
0.013
0.064
0.009
0.023
0.0079
0.0095
No reaction
Complex mixture
Complex mixture
16 (11%), S.M. (39%)
16 (38%), S.M. (49%)
16 (49%), S.M. (17%)
5.5
20
determined to be (3R,4R,5R,6S). The yield of (ꢀ)-16 was
found to be governed by the substrate concentration and
the reaction temperature as shown in Table 1.
with that of the reported (+)-18d f½aꢁD ¼ þ330 (c 0.3,
EtOH)}, including the sign of the specific rotation.
The stereoselective formation of 13 from (2R,3S)-6 can be
explained by insights reviewed by Lombardo et al.14
Among the four possible twist-boat transition states
(TSs), TS-A, -B, -C, and -D as shown in Figure 3, TS-C
(or TS-D) might be more favored than TS-A (or TS-B) be-
cause steric repulsion between the aldehyde substituent (R)
and the acetoxyl group appears to be small. This insight
might imply the formation of C(3)–C(4)-anti-13. On the
other hand, the C(4)–C(5)-anti-stereoselection of 13 could
be explained by Paquette et al.15 who showed that the
1,2-addition of the allylindium reagents to a-oxygenated
aldehydes gave the non-chelation-controlled product,
which corresponds to the 1,2-anti product by the Felkin–
Anh model.
When the hydrolysis of the acetyl group in (ꢀ)-16 was car-
ried out using K2CO3 in MeOH, the desired product 17
was not obtained. The lipase PL (from Alcaligenesis sp.)-
assisted hydrolysis of (ꢀ)-16 in H2O saturated (i-Pr)2O
gave the desired alcohol 17 (50%) along with the starting
material (ꢀ)-16 (32% recovery). Finally, alcohol 17 was
treated with AcOH in the presence of triphenylphosphine
(Ph3P) and diethyl azodicarboxylate (DEAD) to provide
(+)-asperlin 1 in 72% yield. Spectral data (1H and 13C
NMR) of the synthetic (+)-1 were identical with those of
the reported (+)-1.8a The specific rotation of the synthetic
25
(+)-1 f½aꢁD ¼ þ328:0 (c 0.54, EtOH)} was in accordance
CH3
CH3
3. Conclusion
O
O
OH
O
O
R
L
H
In
3
The syntheses of (+)-asperlin 1 were achieved by two differ-
ent routes. One is the formal synthesis of (+)-1 based on
the 1,2-addition of an a-furyl anion to 2-silyloxygenated
aldehyde (2R,3S)-6 giving the 1-(2-furyl)-2-silyloxybutanol
congener 7 and the conversion of 7 to the chiral intermedi-
ate, 1-(2-furyl)-2,3-epoxybutanol 8 (37% overall yield from
6) for the synthesis of (+)-1. The other is the concise syn-
thesis of (+)-asperlin 1 from (2R,3S)-6 in 8% overall yield,
which was achieved based on a combination of the indium
(In)-assisted stereoselective addition of 3-bromopropenyl
acetate 9 to a-silyloxy aldehyde, (2R,3S)-6 and the ring
closing metathesis (RCM) using Grubbs catalyst. Indium-
mediated a-hydroxyallylation reaction of (2R,3S)-6 with
In
4
R
H
R
H
L
O
O
OAc
H
H
H
syn-13
Cl
H
O
H
TS-A
TS-B
H
H
=
R
L
Me
TBDMSO
CH3
CH3
O
OH
O
O
H
L
H
3
In
In
R 4
H
O
H
H
O
OAc
H
H
anti-13
R
H
H
H
TS-D
TS-C
R
Figure 3. Chelation model for the preparation of anti-13.

H. Akaike et al. / Tetrahedron: Asymmetry 19 (2008) 1100–1105
1103
3-bromopropenyl acetate 9 gave selectively (3,4)-anti-(4,5)-
anti product 13 (75%), which was subjected to consecutive
epoxy formation and acrylation to provide epoxy-acrylate
16. The RCM reaction of 16 afforded (ꢀ)-epi-asperlin 16,
which was subjected to consecutive hydrolysis and Mitsun-
obu inversion to give (+)-asperlin 1.
graphed on silica gel (50 g, n-hexane/AcOEt = 50:1) to give
(2R,3S)-6 (1.38 g, 69%) as a colorless oil. (2R,3S)-6:
29
½aꢁD ¼ ꢀ24:4 (c 0.41, CHCl3); IR (neat): 1738 cmꢀ1; H
NMR: d 0.12 (3H, s), 0.15 (3H, s), 0.94 (9H, s), 1.49 (3H,
d, J = 6.8 Hz), 4.05 (1H, dd, J = 1.6, 4.4 Hz), 4.20–4.28
(1H, m), 9.54 (1H, d, J = 1.6 Hz). 13C NMR: d ꢀ4.9 (q),
ꢀ4.6 (q), 18.2 (s), 19.8 (3C, q), 25.7 (q), 56.7 (d), 81.0 (d),
201.1 (d). HR-MS (CI+): calcd for C10H22O2ClSi
(M++1): 237.1078, found: 237.1048.
1
4. Experimental
1H and 13C NMR spectra were recorded on JEOL AL 400
spectrometer in CDCl3. Carbon substitution degrees were
established by DEPT pulse sequence. The fast atom bom-
bardment mass spectra (FAB MS) were obtained with
JEOL JMS 600H spectrometer. IR spectra were recorded
with a JASCO FT/IR-300 spectrometer. Optical rotations
were measured with a JASCO DIP-370 digital polarimeter.
All the evaporations were performed under reduced pres-
sure. For column chromatography, silica gel (Kieselgel
60) was employed.
4.2. (1S,2R,3S)-1-(2-Furyl)-2-tbutyldimethylsilyloxy-3-
chlorobutanol 7
To a solution of furan (1.16 g, 17 mmol) in THF (10 mL)
was added 1.5 M solution of n-butyllithium in pentane
(5 mL, 12 mmol) under an argon atmosphere at ꢀ78 °C
and the reaction mixture was stirred for 1.5 h at the same
temperature. A solution of (2R,3S)-6 (1.34 g, 5.7 mmol)
in THF (5 mL) was added to the above mixture and the
whole mixture was stirred for 40 min at rt. The reaction
mixture was diluted with a saturated NH4Cl solution and
extracted with AcOEt. The organic layer was washed with
brine and dried over MgSO4. Evaporation of the organic
solvent gave a residue, which was chromatographed on sil-
ica gel (30 g, n-hexane/AcOEt = 100:1) to give (1S,2R,3S)-
4.1. (2R,3S)-2-tButyldimethylsiloxy-3-chlorobutanal 6
(i) To a solution of (2R,3S)-3 (3.13 g, 20.5 mmol) in DMF
(50 mL) were added imidazole (2.79 g, 41 mmol) and tert-
butyldimethylsilyl chloride (TBDMSCl; 5.57 g, 37 mmol)
and the reaction mixture was stirred for 15 h at rt. The
reaction mixture was diluted with brine and extracted with
AcOEt. The organic layer was dried over MgSO4 and evap-
orated to give a crude oil, which was chromatographed on
7
(1.24 g, 72%) as
a
colorless oil. (1S,2R,3S)-7:
26
½aꢁD ¼ ꢀ3:51 (c 0.94, CHCl3); IR (neat): 3484 cmꢀ1; H
NMR: d ꢀ0.09 (3H, s), 0.15 (3H, s), 0.15 (3H, s), 0.86
(9H, s), 1.51 (3H, d, J = 5.9 Hz), 4.20–4.26 (2H, m), 4.72
(1H, t, J = 5.4 Hz), 6.34–6.36 (2H, m), 7.39 (1H, t,
J = 0.8, 1.2 Hz). 13C NMR: d ꢀ4.8 (q), ꢀ4.1 (q), 18.4 (s),
19.4 (q), 26.0 (3C, q), 58.4 (d), 69.8 (d), 78.2 (d), 108.3
(d), 110.4 (d), 142.0 (d), 153.1 (s). HR-MS (CI+): calcd
for C14H24O3ClSi (M+ꢀ1): 303.1183, found: 303.1170.
1
silica gel (150 g, n-hexane/AcOEt = 20:1) to give (2R,3S)-4
24
(5.03 g, 92%) as a colorless oil. (2R,3S)-4: ½aꢁD ¼ ꢀ25:0 (c
0.34, CHCl3); IR (neat): 1758 cmꢀ1 1H NMR: d 0.10
;
(3H, s), 0.11 (3H, s), 0.92 (9H, s), 1.47 (3H, d,
J = 6.6 Hz), 3.75 (3H, s), 4.26–4.32 (2H, m). 13C NMR: d
ꢀ5.3 (q), ꢀ5.1 (q), 18.2 (s), 19.5 (q), 25.6 (3C, q), 52.1
(q), 57.4 (d), 76.9 (d), 171.2 (s). HR-MS (FAB): calcd for
C11H24O3ClSi (M++1): 267.1183, found: 267.1194. (ii) To
a solution of (2R,3S)-4 (3.50 g, 13.5 mmol) in dry toluene
(50 mL) were added 1 M solution of diisobutylaluminum
hydride (Dibal-H) in toluene (31 mL, 31 mmol) under ice
cooling and the reaction mixture was stirred for 1 h at
the same temperature. The reaction mixture was diluted
with H2O and filtered off with the aid of Celite. The filtrate
was extracted with AcOEt. The organic layer was dried
over MgSO4 and evaporated to give a crude oil, which
was chromatographed on silica gel (90 g, n-hexane/
4.3. (1S,2R,3R)-1-(2-Furyl)-2,3-epoxybutanol 8
To a solution of (1S,2R,3S)-7 (150 mg, 0.49 mmol) in
CH2Cl2 (5 mL) were added ethyl vinyl ether (70 mg,
0.97 mmol) and a catalytic amount of pyridinum p-toluene-
sulfonate (PPTS) at rt and the reaction mixture was stirred
for 1 h at the same temperature. The reaction mixture was
diluted with H2O and extracted with AcOEt. The organic
layer was washed with brine and dried over MgSO4. Evap-
oration of the organic solvent gave a crude THP ether. To
a solution of THP ether in THF (4 mL) was added a 1 M
solution of tetrabutylammonium fluoride (TBAF) in
THF (2 mL, 2 mmol) at rt and the reaction mixture was
stirred for 12 h at the same temperature. The reaction mix-
ture was evaporated to give a residue. A mixture of the
above residue in MeOH (5 mL) and K2CO3 (135 mg,
0.98 mmol) was stirred for 12 h at rt and the reaction mix-
ture was diluted with H2 O and extracted with AcOEt. The
organic layer was washed with brine and dried over
MgSO4. Evaporation of the organic solvent gave a crude
oil. A solution of the crude oil in THF (1 mL)/H2O
(1 mL) and AcOH (2 mL) was stirred for 2 h at rt and
the reaction mixture was stirred for 2 h at the same temper-
ature. The reaction mixture was diluted with a saturated
NaHCO3 solution and extracted with AcOEt. The organic
layer was washed with brine and dried over MgSO4. Evap-
oration of the organic solvent gave a residue, which was
AcOEt = 40:1) to give (2R,3S)-5 (2.75 g, 88%) as a color-
24
less oil. (2R,3S)-5: ½aꢁD ¼ ꢀ5:2 (c 0.6, CHCl3); IR (neat):
1
3389 cmꢀ1; H NMR: d 0.12 (3H, s), 0.14 (3H, s), 0.92
(9H, s), 1.50 (3H, d, J = 6.6 Hz), 1.76 (1H, br s), 3.64
(1H, dd, J = 3.8, 11.4 Hz), 3.74 (1H, dd, J = 3.8, 6.6 Hz),
3.82 (1H, dd, J = 3.8, 11.4 Hz), 4.12 (1H, quintet,
J = 6.6 Hz). 13C NMR: d ꢀ4.6 (q), ꢀ4.4 (q), 18.1 (s),
20.9 (q), 25.8 (3C, q), 57.0 (d), 63.8 (t), 76.8 (d). HR-MS
(FAB): calcd for C10H24O2ClSi (M++1): 239.1235, found:
239.1236. (iii) To a solution of (2R,3S)-5 (2.02 g, 8.5 mmol)
in CH2Cl2 (50 mL) was added pyridinium chlorochromate
(PCC; 3.6 g, 16.7 mmol) at rt and the reaction mixture was
stirred for 12 h at the same temperature. The reaction mix-
ture was filtered off with the aid of Celite. The filtrate was
concentrated to give a residue, which was chromato-

1104
H. Akaike et al. / Tetrahedron: Asymmetry 19 (2008) 1100–1105
chromatographed on silica gel (10 g, n-hexane/
silica gel (10 g, n-hexane/AcOEt = 3:1) to give
AcOEt = 6:1) to give (1S,2R,3R)-8 (63 mg, 83%) as a color-
(3R,4R,5R,6R)-14 (812 mg, 83%) as a pale yellow oil.
24
26
less oil. (1S,2R,3R)-8: ½aꢁD ¼ ꢀ42:2 (c 0.67, CHCl3); IR
(3R,4R,5S,6R)-14: ½aꢁD ¼ þ16:3 (c 0.52, EtOH); IR
1
(neat): 3401 cmꢀ1; H NMR: d 1.38 (3H, d, J = 5.2 Hz),
(neat): 3448, 1739 cmꢀ1 1H NMR: d 1.32 (3H, d,
;
2.34 (1H, br s), 3.05 (1H, dd, J = 2.4, 3.6 Hz), 3.25 (1H,
dq, J = 2.4, 5.2 Hz), 4.87 (1H, d, J = 3.6 Hz), 6.35–6.38
(2H, m), 7.42 (1H, dd, J = 0.8, 1.8 Hz). 13C NMR: d 17.1
(q), 51.7 (d), 59.8 (d), 65.2 (d), 107.7 (d), 110.2 (d), 142.5
(d), 152.4 (s). HR-MS (FAB): calcd for C8H11O3
(M++1): 155.0708, found: 155.0706.
J = 5.3 Hz), 2.12 (3H, s), 2.8 (1H, dd, J = 2.3, 4.0 Hz),
3. 8 (1H, dd, J = 2.3, 5.3 Hz), 3.88 (1H, dd, J = 4.0,
6.0 Hz), 5.30–5.42 (3H, m), 5.89–5.97 (1H, m). 13C
NMR: d 17.0 (q), 21.1 (q), 51.6 (d), 58.3 (d), 70.8 (d),
75.8 (d), 119.4 (t), 132.0 (d), 170.1 (s). HR-MS (CI+):
calcd for C9H15O4 (M++1): 187.0970, found: 187.0983.
4.4. (3R,4R,5R,6S)-3-Acetoxy-5-tbutyldimethylsilyloxy-6-
chloro-4-hydroxy-1-heptene 13
4.6. (3R,4R,5S,6R)-3-Acetoxy-4-acryloyloxy-5,6-epoxy-1-
heptene 15
To a mixture of (2R,3S)-6 (843 mg, 3.56 mmol) in THF
(5 mL)/H2O (5 mL) were added In powder (1.23 g,
10.7 mmol) and 3-bromopropenyl acetate (1.91 g,
10.7 mmol) at 0 °C and the reaction mixture was stirred
for 1.5 h at rt. The reaction mixture was diluted with
H2O and extracted with AcOEt. The organic layer was
washed with brine and dried over MgSO4. Evaporation
of the organic solvent gave a residue, which was chromato-
graphed on silica gel (40 g, n-hexane/AcOEt = 30:1) to give
To a solution of (3R,4R,5R,6R)-14 (812 mg, 4.3 mmol) in
CH2Cl2 (10 mL) were added diisopropylethylamine
(2.81 g, 27.6 mmol) and acryloyl chloride (680 mg,
7.5 mmol) under an argon atmosphere at ꢀ20°C and the
reaction mixture was stirred for 3 h at the same tempera-
ture. The reaction mixture was diluted with H2O and
extracted with CH2Cl2. The organic layer was washed with
brine and dried over MgSO4. Evaporation of the organic
solvent gave a residue, which was chromatographed on
silica gel (50 g, n-hexane/AcOEt = 30:1) to give
(3R,4R,5R,6S)-9 (920 mg, 77%) as
a colorless oil.
25
(3R,4R,5R,6S)-13: ½aꢁD ¼ þ16:0 (c 0.4, CHCl3); IR (neat):
(3R,4R,5R,6R)-15 (740 mg, 71%) as a pale yellow oil.
25
1
3481, 1744 cmꢀ1; H NMR: d 0.16 (3H, s), 0.20 (3H, s),
(3R,4R,5S,6R)-15: ½aꢁD ¼ þ19:1 (c 0.54, EtOH); IR (neat):
0.94 (9H, s), 1.49 (3H, d, J = 6.8 Hz), 2.09 (3H, s), 3.82
(1H, d, J = 2.8 Hz), 3.89 (1H, dd, J = 2.8, 6.4 Hz), 4.38
(1H, dq, J = 3.2, 6.8 Hz), 5.26–5.55 (2H, m), 5.53 (1H, t,
J = 5.2 Hz), 5.89–5.97 (1H, m). 13C NMR: d ꢀ4.6 (q),
ꢀ3.9 (q), 18.3 (s), 19.0 (q), 20.9 (q), 25.9 (3C, q), 58.2 (d),
74.0 (d), 74.1 (d), 76.7 (d), 119.8 (t), 131.5 (d), 169.4 (s).
HR-MS (CI+): calcd for C15H30O4ClSi (M++1):
337.1602, found: 337.1609.
1730 cmꢀ1; 1H NMR: d 1.30 (3H, d, J = 5.2 Hz), 2.10 (3H,
s), 2.83 (1H, dd, J = 2.2, 6.0 Hz), 3.04 (1H, dq, J = 2.2,
5.2 Hz), 4.92 (1H, dd, J = 3.7, 6.0 Hz), 5.35–5.45 (2H,
m), 5.55–5.58 (1H, m), 5.87–5.97 (2H, m), 6.09–6.19 (1H,
m), 6.40–6.47 (1H, m). 13C NMR: d 17.1 (q), 21.0 (q),
53.1 (d), 55.9 (d), 73.1 (d), 74.0 (d), 120.0 (t), 127.8 (t),
131.3 (d), 131.8 (d), 164.9 (s), 169.8 (s). HR-MS (CI+):
calcd for C12H17O5 (M++1): 241.1076, found: 241.1097.
4.5. (3R,4R,5S,6R)-3-Acetoxy-5,6-epoxy-4-hydroxy-1-
heptene 14
4.7. (ꢀ)-epi-Asperlin 16
To a solution of (3R,4R,5R,6R)-15 (227 mg, 0.95 mmol) in
CH2Cl2 (95 mL) was added a solution of Crubbs catalyst
2nd generation (80 mg, 0.095 mmol) in CH2Cl2 (5 mL) un-
der an argon atmosphere at rt and the reaction mixture was
stirred for 5.5 h at 40 °C. The reaction mixture was evapo-
rated to give a residue, which was chromatographed on sil-
ica gel (20 g) to afford the starting (3R,4R,5R,6R)-15
(46 mg, 20% recovery) from n-hexane/AcOEt = 30:1 elu-
tion and (ꢀ)-epi-Asperlin (16; 98 mg, 49%) as a pale yellow
To a solution of (3R,4R,5R,6S)-13 (1.77 g, 5.3 mmol) in
CH2Cl2 (20 mL) were added ethyl vinyl ether (1.13 g,
15.7 mmol) and a catalytic amount of pyridinum p-tolu-
enesulfonate (PPTS) at rt and the reaction mixture was
stirred for 3 h at the same temperature. The reaction mix-
ture was diluted with a saturated NaHCO3 solution and
extracted with CHCl3. The organic layer was washed with
brine and dried over MgSO4. Evaporation of the organic
solvent gave a crude THP ether. To a solution of THP
ether in THF (10 mL) was added 1 M solution of tetrabut-
ylammonium fluoride (TBAF) in THF (11 mL, 11 mmol)
at rt and the reaction mixture was stirred for 3 h at the
same temperature. To the reaction mixture was added
K2CO3 (2.18 g, 15.8 mmol) at rt and the whole mixture
was stirred for 7 h at rt. The reaction mixture was diluted
with H2O and extracted with CHCl3. The organic layer
was washed with brine and dried over MgSO4. Evapora-
tion of the organic solvent gave a crude oil. A solution
of the crude oil in THF (2 mL)/H2O (2 mL) and AcOH
(8 mL) was stirred for 20 h at rt. The reaction mixture
was diluted with a saturated NaHCO3 solution and
extracted with CHCl3. The organic layer was washed with
brine and dried over MgSO4. Evaporation of the organic
solvent gave a residue, which was chromatographed on
oil
from
n-hexane/AcOEt = 4:1
elution. (ꢀ)-16:
24
1
½aꢁD ¼ ꢀ181:9 (c 0.13, EtOH); IR (neat): 1731 cmꢀ1; H
NMR: d 1.35 (3H, d, J = 5.2 Hz), 2.13 (3H, s), 2.85 (1H,
dd, J = 2.0, 6.6 Hz), 3.05 (1H, dq, J = 2.0, 5.2 Hz), 4.21
(1H, t, J = 6.0 Hz), 5.51 (1H, ddd, J = 1.1, 3.8, 5.2 Hz),
6.18 (1H, dd, J = 1.1, 9.9 Hz), 6.87 (1H, dd, J = 4.0,
9.9 Hz). 13C NMR: d 17.0 (q), 20.7 (q), 53.9 (d), 57.0 (d),
64.0 (d), 80.1 (d), 123.4 (d), 141.9 (d), 160.9 (s), 169.8 (s).
HR-MS (CI+): calcd for C10H13O5 (M++1): 213.0763,
found: 213.0784.
4.8. (5R,6R,10S,20R)-5,6-Dihydro-5-hydroxy-6-(10,20-epoxy-
propyl)-2H-pyran-2-one 17
A mixture of (ꢀ)-16 (47 mg, 0.22 mmol) and lipase PL
(50 mg) in H2O saturated (i-Pr)2O (8 mL) was incubated

H. Akaike et al. / Tetrahedron: Asymmetry 19 (2008) 1100–1105
1105
for 5 h at 33 °C. The reaction mixture was dried over
References
MgSO4 and evaporated to give a residue, which was chro-
matographed on silica gel (5 g) to afford the starting (ꢀ)-16
(15 mg, 32% recovery) from n-hexane/AcOEt = 8:1 elution
and (5R,6R,10S,20R)-17 (19 mg, 50%) as a colorless oil from
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n-hexane/AcOEt = 1:1 elution. (ꢀ)-(5R,6R,10S,20R)-17:
24
½aꢁD ¼ ꢀ32:4 (c 0.33, EtOH); IR (neat): 3410, 1710 cmꢀ1
;
1H NMR: d 1.38 (3H, d, J = 5.1 Hz), 3.00 (1H, dd,
J = 2.0, 6.5 Hz), 3.12 (1H, dq, J = 2.0, 5.1 Hz), 4.04–4.07
(1H, m), 4.62–4.64 (1H, m), 6.01 (1H, dd, J = 1.7,
10.0 Hz), 6.86 (1H, dd, J = 5.2, 10.0 Hz). 13C NMR: d
17.1 (q), 54.3 (d), 58.4 (d), 64.7 (d), 81.0 (d), 120.1 (d),
148.0 (d), 161.8 (s). HR-MS (FAB): calcd for C8H11O4
(M++1): 171.0657, found: 171.0671.
5. Ramesh, S.; Franck, R. W. Tetrahedron: Asymmetry 1990, 1,
137–140.
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4.9. (+)-Asperlin 1
To
a
solution of (ꢀ)-(5R,6R,10S,20R)-17 (40 mg,
0.24 mmol) in THF (2 mL) were added AcOH (72 mg,
1.2 mmol) and triphenylphosphine (Ph3P; 105 mg,
0.4 mmol) at rt. To the above reaction mixture was added
diethyl azodicarboxylate (DEAD; 40% in toluene, 0.19 mL,
0.4 mmol) under an argon atmosphere at ꢀ78 °C and the
reaction mixture was stirred for 1 h at ꢀ78 °C. The reac-
tion mixture was diluted with a saturated NaHCO3 solu-
tion and extracted with AcOEt. The organic layer was
dried over MgSO4 and evaporated to give a residue, which
was chromatographed on silica gel (8 g, n-hexane/
AcOEt = 5:1) to afford (+)-1 (37 mg, 73%) as a colorless
25
oil. (+)-1: ½aꢁD ¼ þ328:0 (c 0.54, EtOH); IR (neat):
1727 cmꢀ1 1H NMR: d 1.38 (3H, d, J = 5.2 Hz), 2.14
;
(3H, s), 3.05–3.10 (2H, m), 4.11 (1H, dd, J = 2.8, 7.2 Hz),
5.32 (1H, dd, J = 2.8, 5.6 Hz), 6.22 (1H, d, J = 9.6 Hz),
7.07 (1H, dd, J = 5.6, 9.6 Hz). 13C NMR: d 17.0 (q), 20.5
(q), 54.6 (d), 54.9 (d), 62.1 (d), 78.9 (d), 124.9(d), 140.4
(d), 161.5 (s), 169.8 (s). HR-MS (EI): calcd for C10H12O5
(M+): 212.0685, found: 212.0678.
15. Paquette, L. A.; Mitzel, T. M. J. Am. Chem. Soc. 1996, 118,
1931–1937.