δ-Lactone formation from δ-hydroxy-trans-α,β-unsaturated carboxylic acids accompanied by trans-cis isomerization: synthesis of (-)-tetra-O-acetylosmundalin

Article abstract of DOI:10.1016/j.tet.2007.07.106

(±)-(4,5-anti)-4-Benzyloxy-5-hydroxy-(2E)-hexenoic acid 6 was subjected to δ-lactonization in the presence of 2,4,6-trichlorobenzoyl chloride and pyridine to give the α,β-unsaturated-δ-lactone congener (±)-7 (87% yield) accompanied by trans-cis isomerizat

Full text of DOI:10.1016/j.tet.2007.07.106

Tetrahedron 63 (2007) 10140–10148
d-Lactone formation from d-hydroxy-trans-a,b-unsaturated
carboxylic acids accompanied by trans–cis isomerization:
synthesis of (L)-tetra-O-acetylosmundalin
Machiko Ono,a Xi Ying Zhao,b Yuki Shidab and Hiroyuki Akitab,
*
aSchool of Pharmaceutical Sciences, International University of Health and Welfare, 2600-1, Kitakanemaru, Ohtawara,
Tochigi 324-8501, Japan
bSchool of Pharmaceutical Sciences, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan
Received 14 July 2007; revised 27 July 2007; accepted 28 July 2007
Available online 3 August 2007
Abstract—(ꢀ)-(4,5-anti)-4-Benzyloxy-5-hydroxy-(2E)-hexenoic acid 6 was subjected to d-lactonization in the presence of 2,4,6-trichloro-
benzoyl chloride and pyridine to give the a,b-unsaturated-d-lactone congener (ꢀ)-7 (87% yield) accompanied by trans–cis isomerization.
This d-lactonization procedure was applied to the chiral synthesis of (+)-(4S,5R)-7 or (ꢁ)-(4R,5S)-7 from the chiral starting material (+)-
(4S,5R)-6 or (ꢁ)-(4R,5S)-6. Deprotection of the benzyl group in (+)-(4S,5R)-7 or (ꢁ)-(4R,5S)-7 by the AlCl3/m-xylene system gave the
natural osmundalactone (+)-(4S,5R)-5 or (ꢁ)-(4R,5S)-5 in good yield, respectively. Condensation of (ꢁ)-(4R,5S)-5 and tetraacetyl-b-D-
glucosyltrichloroimidate 22 in the presence of BF3$Et2O afforded the condensation product (ꢁ)-8 (97% yield), which was identical to
tetra-O-acetylosmundalin (ꢁ)-8 derived from natural osmundalin 9.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
by applying the modified Horner–Emmons reaction of a-
or b-O-protected aldehyde C and methoxycarbonylmethyl-
entrialkoxyphosphorane D.7 Ring-closing metatheses using
Grubbs reagent have recently been reported to be a useful
method to construct a,b-unsaturated lactone structures8
(Scheme 1).
a,b-Unsaturated-d-lactones are found as structural subunits
in a wide variety of natural products possessing diverse bio-
logical activities. Furthermore, simple lactones have been
used as intermediates for the synthesis of biologically active
compounds. We previously reported the enantioselective hy-
drolysis of (ꢀ)-(4,5-anti)-5-acetoxy-4-benzyloxy-(2E)-hex-
enoate 1 using the lipase ‘Amano P’ from Pseudomonas sp.
in phosphate buffer solution to give the (4R,5S)-5-acetoxy
ester 1 (>99% ee, 48% yield) and the (4S,5R)-5-hydroxy es-
ter 2 (>99% ee, 44% yield). The subsequent methanolysis of
(4R,5S)-1 provided (4R,5S)-2 in 84% yield.1 The E-value2 of
this enzymatic reaction was estimated to be 1060. The syn-
theses of biologically active natural products such as (+)-
asperlin 33 or (+)-anamarine 44 from (4S,5R)-2 or (4R,5S)-2
required practical routes to the chiral oxygen-substituted
a,b-unsaturated-d-lactone. The synthesis of (4S,5R)-osmun-
dalactone 55 or (4R,5S)-osmundalactone 56 from (4S,5R)-2
or (4R,5S)-2, respectively, would serve as an excellent model
experiment. In general, the syntheses of a,b-unsaturated lac-
tones A are achieved based on the direct lactonization of the
corresponding g- or d-hydroxy-a,b-unsaturated esters B. To
achieve efficient syntheses of molecules A, it is necessary
to obtain the Z-isomer of the a,b-unsaturated esters B in
a stereoselective manner. This problem could be overcome
We now report the efficient synthesis of a,b-unsaturated-d-
lactone (ꢀ)-7 from (ꢀ)-(4,5-anti)-5-hydroxy-4-benzyloxy-
(2E)-hexenoic acid 6 accompanied by trans–cis isomerization.
Moreover, the syntheses of (4S,5R)- or (4R,5S)-osumunda-
lactone 5 from (4S,5R)- or (4R,5S)-2, respectively, and appli-
cation to the first synthesis of tetra-O-acetylosmundalin
86 (Scheme 1) derived from natural osmundalin 96 will be
described.
2. Results and discussion
When the reported methyl ester (ꢀ)-21 was individually sub-
jected to heating in the presence of 10-camphorsulfonic acid
(CSA) or 4-dimethylaminopyridine (DMAP), the starting
(ꢀ)-2 was recovered. The reaction of carboxylic acid (ꢀ)-
6 with CSA and DMAP gave a,b-unsaturated d-lactone
(ꢀ)-7 in 46% yield, while (ꢀ)-6 in the presence of CSA
alone afforded the starting (ꢀ)-6. Surprisingly, the reaction
of (ꢀ)-6 with DMAP gave (ꢀ)-7 in 30% yield (Scheme 2).
These results indicate that CSA did not serve any purpose
* Corresponding author. E-mail: akita@phar.toho-u.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.106

M. Ono et al. / Tetrahedron 63 (2007) 10140–10148
10141
OCH2Ph
COOMe
OCH2Ph
OCH2Ph
COOMe
lipase
Me
Me
Me
+
COOMe
OAc
( )-1
OR1
OH
R1 = Ac: (4R,5S)-1 (>99% ee, 48%)
R1 = H: (4R,5S)-2 (>99% ee)
(4S,5R)-2 (>99% ee, 44%)
NaOMe / MeOH
OAc
OAc OAc
H
O
H
O
Me
Me
OAc OAc
O
O
O
(+)-3
(+)-4
OR1
OH
O
OH
Me
O
R1O
R1O
O
Me
Me
O
O
O
O
OR1
O
R
1 = Ac Tetra-O-acetylosmundalin 8
R1 = H Osmundalin 9
(4S,5R)-Osmundalactone 5
(4R,5S)-5
R2
O
R2
R2
OH
OP
R3
O
R3
COOR3
R3
(R4O)3P=CHCOOR5
+
CHO
C
A
B
D
P: protecting group
Scheme 1.
in the reaction, while DMAP worked against the isomeriza-
tion of the double bond. The formation of (ꢀ)-7 could be
explained by thermal d-lactonization after DMAP-assisted
double bond isomerization. DMAP is reported to function
as a nucleophilic catalyst as well as a Brønsted base.9 Mor-
ita–Baylis–Hillman reactions10 and isomerization of nitro-
alkenes11 are typical examples of nucleophile-assisted
reactions, where nucleophiles function as nucleophilic cata-
lyst in the reactions of a,b-unsaturated esters or nitro-
alkenes. In order to promote smooth d-lactonization in this
reaction, the carboxylic acid group in (ꢀ)-6 must be acti-
vated. To investigate conditions for effective a,b-unsatu-
rated d-lactonization from (ꢀ)-6 in conjunction with
double bond isomerization, the reaction of (ꢀ)-6 using var-
ious kinds of nucleophiles and activating reagents was exam-
ined, and the results are shown in Table 1.
and triphenylphosphine (Ph3P) as an additional nucleophile
(entry 2) gave 59% and 69% of (ꢀ)-7, respectively. For the
purpose of finding a more effective additive, other nucleo-
philes were examined. Addition of morpholine instead of
Ph3P afforded the corresponding morpholine-amide 10 in
62% yield (entry 3). The reaction of (ꢀ)-6 with 2,4,6-tri-
chlorobenzoyl chloride and 1,4-diazabicyclo[2,2,2]octane
(DABCO) (entry 4) gave the unexpected 12-membered dio-
lide 1113 in 4.4% yield, though the major product recovered
was (ꢀ)-6. When pyridine was used as the nucleophile, the
usage of 2,4,6-trichlorobenzoyl chloride (entry 5), 2-chloro-
benzoyl chloride (entry 6), methyl chloroformate (entry 7),
isobutyl chloroformate (entry 9), methanesulfonyl chloride
(MsCl) (entry 10) provided yields of (ꢀ)-7 of 87%, 65%,
50%, 77% and 41%, respectively. The combination of methyl
chloroformate and DMAP (entry 8) gave (ꢀ)-7 (38%) and
methyl ester 2 (18%). The combination of 2,20-dipyridyl
disulfide and Ph3P14 (entry 11) yielded (ꢀ)-7 (12%) and
the thiopyridine adduct 12 (31%). The combination of
The reaction of (ꢀ)-6 with 2,4,6-trichlorobenzoyl chloride12/
DMAP (entry 1) or 2,4,6-trichlorobenzoyl chloride/DMAP
OCH2Ph
1) CSA / toluene, 100 °C, 16 h
or 2) DMAP / toluene, 100 °C, 16 h
Me
Me
( )-2 (recovery)
COOMe
OH
( )-2
1) OH-, 2) H+
CSA / toluene, 100 °C, 16 h
( )-6 (recovery)
OCH2Ph
COOH
OH
( )-6
OCH2Ph
Me
1) CSA / DMAP toluene, 100 °C, 16 h 46% yield
or 2) DMAP / toluene, 100 °C, 16 h 30% yield
O
O
( )-7
Scheme 2.

10142
M. Ono et al. / Tetrahedron 63 (2007) 10140–10148
Table 1
OCH2Ph
O
Me
OCH2Ph
COOH
O
nucleophile, activating reagent
CH2Cl2 r .t.
Me
OH
( )-6
( )-7
Entry
Activating reagent (1.1 equiv)
Nucleophile
Reaction time (h)
Yield of (ꢀ)-7 (%)
59
69
0, Morpholine-amide 10 (62%)
0, 12-Membered diolide 11 (2.2%)
1
2
3
4
2,4,6-Trichlorobenzoyl chloride/DMAP
2,4,6-Trichlorobenzoyl chloride/DMAP
2,4,6-Trichlorobenzoyl chloride/DMAP
2,4,6-Trichlorobenzoyl chloride/
1,4-diazabicyclo[2,2,2]octane
DMAP
Ph3P
6
6
4
3
Morpholine
1,4-Diazabicyclo[2,2,2]octane
5
6
7
8
2,4,6-Trichlorobenzoyl chloride/pyridinea
2-Chlorobenzoyl chloride/pyridinea
Methyl chloroformate/pyridinea
Pyridine
Pyridine
Pyridine
DMAP
1
3
3
1
87
65
50
38, Methyl
Methyl chloroformate/DMAP
ester 2 (18%)
77
41
12, Thiopyridine
adduct 12 (31%)
34, DCC-adduct 13 (44%)
60, DCC-adduct 13 (11%)
0, DCC-adduct 13 (40%)
45, DIPC-adduct 14 (14%)
9
10
11
Isobutyl chloroformate/pyridinea
Methanesulfonyl chloride/pyridinea
2,20-Dipyridyl disulfide/Ph3Pb
Pyridine
Pyridine
Ph3P
3
3
1
12
13
14
15
Dicyclohexylcarbodiimide
Dicyclohexylcarbodiimide
Dicyclohexylcarbodiimide
Diisopropylcarbodiimide
Ph3P
DMAP
2,4,6-Collidine
Pyridine
2
12
9
24
OCH2Ph
O
Me
OCH2Ph
Me
OCH2Ph
COOMe
Me
Me
C
O
N
O
O
O
OH
OH
10
2
Me
OCH2Ph
O
11
=
OCH2Ph
S
OCH2Ph
OCH2Ph
cyclohexyl
isopropyl
Me
Me
C
O
N
C
N
N
O
O
O
OH
OH
O
HN
HN
O
cyclohexyl
isopropyl
12
13
14
a
Reaction solvent: pyridine.
Reaction solvent: MeCN, CF3SO3Ag was added.
b
dicyclohexylcarbodiimide (DCC) and Ph3P (entry 12) or
DCC and DMAP (entry 13) gave (ꢀ)-7 (34% or 60%) along
with DCC-adduct 13 (44% or 11%), respectively. In the case
of DCC and 2,4,6-collidine (entry 14), only the DCC-adduct
13 (40%) was obtained. The combination of diisopropylcar-
bodiimide (DIPC) and pyridine (entry 15) afforded (ꢀ)-7
(45%) and the DIPC-adduct 14 (14%). From a synthetic point
of view, the combination of 2,4,6-trichlorobenzoyl chloride
and pyridine (entry 5) was found to be the most practical pro-
cedure for the preparation of a,b-unsaturated d-lactone (ꢀ)-7
from (ꢀ)-6 accompanied by trans–cis isomerization. The use
of isobutyl chloroformate (entry 9), however, is more practi-
cal due to the lower price ofisobutylchloroformate compared
to that of 2,4,6-trichlorobenzoyl chloride.
OCH2Ph
path a
Me
OCH2Ph
COOH
OCH2Ph
-
+ Nu
- Nu
Me
Me
Me
HO
C
COOH
E
Nu+
HO
( )-6
OH
OH
15
O
activating
reagent
activating
reagent
path b
: activated group
OCH2Ph
OCH2Ph
OCH2Ph
Me
HO
Me
OCH2Ph
-
- Nu
+ Nu
Me
O
C
O
O
Nu+
O
OH
OH
H
F
G
O
( )-7
Scheme 3.

M. Ono et al. / Tetrahedron 63 (2007) 10140–10148
10143
There are two plausible mechanistic routes for a,b-unsatu-
rated d-lactonization accompanied by trans–cis isomeriza-
tion [(ꢀ)-6 to (ꢀ)-7] as shown in Scheme 3. One is the
Michael addition (intermediate E) of the nucleophile to the
a,b-unsaturated double bond in (ꢀ)-6 followed by consecu-
tive cis isomerization (intermediate 15) along with the elim-
ination of nucleophile, followed by activation (intermediate
F) of the carboxylic acid group in 15 and d-lactonization
(path a). The other possible route is the activation (interme-
diate G) of the carboxylic acid group followed by consecu-
tive Michael addition (intermediate H) of the nucleophile,
formation of the cis-isomer (intermediate F) along with
the elimination of the nucleophile and d-lactonization
(path b). Pyridine-assisted addition–elimination reaction
on 6 did not occur because carboxylic acid (ꢀ)-6 exists as
a pyridinium carboxylate in pyridine. When (ꢀ)-6 and
(ꢀ)-7 were subjected to exchange reaction using a 4:1 mix-
ture of deuterated pyridine and deuterated methanol
(C5D5N/CD3OD¼4:1) in an NMR tube for 25 h at 25 ꢂC,
formation of C(2)-deuterium exchange products [(ꢀ)-6
and (ꢀ)-7] was not observed in either case. This result indi-
cates that pyridine-assisted addition–elimination reaction
does not occur via path a. No observation of C(2)-deuterium
exchange reaction in the course of path b might be explained
from the fact that conversion rates from G to H, from H to F,
and from F to (ꢀ)-7 are extremely high. Therefore, the
formation of (ꢀ)-7 from (ꢀ)-6 might occur via path b. The
present reaction was completed within several hours in com-
parison to Morita–Baylis–Hillman reactions’ case. The
faster rate of d-lactonization from intermediate G might be
due to the pyridine-assisted addition–elimination reaction.
The scope and limitation of this reaction should be examined
and two examples are shown in Scheme 4. Alkaline hydro-
lysis of (ꢀ)-1615 or (ꢀ)-1916 gave quantitatively carboxylic
acid (ꢀ)-17 (99%) or (ꢀ)-20 (99%), respectively, which was
separately subjected to d-lactonization using 2,4,6-trichloro-
benzoyl chloride and pyridine to afford (ꢀ)-18 (90% yield)
or (ꢀ)-21 (81% yield), respectively.
Application of this reaction to natural product synthesis was
examined. The syntheses of (+)-(4S,5R)-osmundalactone 5
and (ꢁ)-(4R,5S)-osmundalactone 5, and tetra-O-acetyl-
osmundalin 8 are shown in Scheme 4. (+)-Osmundalactone
5 was isolated from the fungus Paxillus atrotomentosus. The
structure was established by spectroscopic methods and X-
ray analysis.5 From the Japanese foodstuff Akaboshi zenmai,
consisting of dried leaves of Osmunda japonica Thunberg
and from the Vermont royal fern Osmunda regalis var. spec-
tabilis (Wilid.) Gray a new hydroxypentenolide glucoside,
osmundalin 9, was isolated.6 Osmundalin 9 was character-
ized as its crystalline tetra-O-acetylosmundalin 8 and the
structure and absolute stereochemistry of 9 were established
by spectroscopic and degradation methods and its aglycone,
(ꢁ)-osmundalactone 5, was synthesized.6 Alkaline hydroly-
sis of the reported (4S,5R)-21 with 2 M NaOH solution in i-
PrOH gave carboxylic acid (+)-(4S,5R)-6 (99%), which was
subjected to d-lactonization using 2,4,6-trichlorobenzoyl
chloride and pyridine to afford (+)-(4S,5R)-7 in 85% yield.
Benzyl ether (+)-(4S,5R)-7 was deprotected using the
reported AlCl3/m-xylene system1 to provide alcohol (+)-
OCH2Ph
OCH2Ph
OCH2Ph
COOH
OH
( )-17
a
b
COOMe
COOMe
O
O
99%
90%
OH
( )-16
O
( )-18
Me
Me
a
b
Me
Me
Me
Me
COOH
COOH
81%
99%
OH
OH
O
( )-19
( )-20
( )-21
OCH2Ph
OH
O
OCH2Ph
OCH2Ph
Me
a
b
c
COOMe
O
O
85%
85%
99%
OH
OH
O
(4S,5R)-2
(4S,5R)-6
(4S,5R)-7
OCH2Ph
(4S,5R)-5
OH
OCH2Ph
OCH2Ph
COOH
Me
Me
a
b
c
Me
Me
COOMe
O
O
85%
91%
94%
OH
OH
O
O
(4R,5S)-2
(4R,5S)-6
(4R,5S)-5
(4R,5S)-7
OAc
OAc
O
OH
6'
Me
O
O
Me
AcO
AcO
AcO
AcO
d
O
O
+
O
CCl3
O
97%
1'
OAc
OAc
2
NH
O
22
8
(4R,5S)-5
Scheme 4. Reagents and conditions: (a) (1) 2 M NaOH/i-PrOH, rt; (2) 2 M HCl; (b) 2,4,6-trichlorobenzoyl chloride/pyridine, rt; (c) AlCl3/m-xylene, CH2Cl2,
0 ꢂC; (d) BF3$Et2O, CH2Cl2, rt.

10144
M. Ono et al. / Tetrahedron 63 (2007) 10140–10148
(4S,5R)-5 {[a]2D6 +69.1 (c 0.53, H2O)} in 85% yield. NMR
data of (+)-(4S,5R)-5 were identical to those of the natural
osmundalactone (+)-(4S,5R)-55 as was the specific rotation
{[a]2D2 +70.9 (c 1.27, H2O)}. The synthesis of (ꢁ)-osmunda-
lactone (4R,5S)-5 was achieved in the same way as the syn-
thesis of (+)-(4S,5R)-5 from (4S,5R)-2. Alkaline hydrolysis
of the reported (4R,5S)-21 gave carboxylic acid (ꢁ)-
(4R,5S)-6 (94%), which was subjected to d-lactonization to
afford (ꢁ)-(4R,5S)-7 in 85% yield. Deprotection of the ben-
zyl group in (ꢁ)-(4R,5S)-7 provided alcohol (ꢁ)-(4R,5S)-5
{[a]2D8 ꢁ68.4 (c 0.41, H2O)}. NMR data of (ꢁ)-(4R,5S)-5
were identical to those of the natural osmundalactone (ꢁ)-
(4R,5S)-56 as was the specific rotation {[a]2D2 ꢁ70.6 (c 2.0,
H2O)}. The reaction of (ꢁ)-(4R,5S)-5 and tetraacetyl-b-D-
glucosyltrichloroimidate 2217 in the presence of BF3$Et2O
afforded the condensation product (ꢁ)-8 {[a]2D5 ꢁ40.4 (c
1.0, CHCl3)} in 97% yield. NMR data of (ꢁ)-8 were identical
to those of the reported tetra-O-acetylosmundalin 86,18 de-
rived from natural osmundalin 9 as was the specific rotation
{[a]2D0 ꢁ40.9 (c 1.0, CHCl3)}.
a residue. Then it was acidified with 2 M HCl solution and
extracted with Et2O. The organic layer was washed with
brine and dried over MgSO4. Evaporation of the organic sol-
vent gave a residue, which was chromatographed on silica
gel (300 g, CHCl3/MeOH¼10:1) to afford (ꢀ)-6 (12.34 g,
95%) as a colorless oil. (ꢀ)-6: IR (CHCl3): 3450,
1
1702 cmꢁ1; H NMR: d 1.15 (3H, d, J¼6.0 Hz), 2.38 (1H,
d, J¼4.4 Hz, OH), 3.94 (1H, ddd, J¼6.0, 4.0, 1.2 Hz), 3.97
(1H, qd, J¼6.0, 4.0 Hz), 4.42, 4.64 (each 1H, d,
J¼12.0 Hz), 6.07 (1H, dd, J¼16.0, 1.2 Hz), 7.02 (1H, dd,
J¼16.0, 6.0 Hz), 7.10–7.40 (5H, m). Anal. Calcd for
C13H16O4: C, 66.09; H, 6.83%. Found: C, 65.94; H, 6.84.
FABMS m/z: 237 (M++1).
4.3. d-Lactonization from ( )-6 (synthesis of ( )-7)
(Scheme 2)
A mixture of (ꢀ)-6 (0.085 g, 0.36 mmol), CSA (0.10 g,
0.43 mmol), and DMAP (0.053 g, 0.43 mmol) in toluene
(5 mL) was stirred for 16 h at 100 ꢂC, and the reaction mix-
ture was diluted with Et2O. The organic layer was washed
with 2 M NaOH solution and dried over MgSO4. Evapora-
tion of the organic solvent gave a residue, which was chro-
matographed on silica gel (5 g, n-hexane/AcOEt¼8:1) to
afford (ꢀ)-7 (0.037 g, 46%) as a colorless oil. The alkaline
layer was acidified with 2 M HCl solution and extracted
with Et2O. The organic layer was washed with brine and
dried over MgSO4. Evaporation of the organic solvent
gave crude (ꢀ)-6 (0.029 g, 34%) as a colorless oil. Com-
3. Conclusion
(ꢀ)-(4,5-anti)-4-benzyloxy-5-hydroxy-(2E)-hexenoic acid 6
was subjected to d-lactonization in the presence of 2,4,6-tri-
chlorobenzoyl chloride and pyridine to give the a,b-unsatu-
rated-d-lactone congener (ꢀ)-7 (87% yield) accompanied
by trans–cis isomerization. The mechanism of this d-lactoni-
zation was discussed. This d-lactonization procedure was ap-
plied to the chiral synthesis of (+)-(4S,5R)-7 or (ꢁ)-(4R,5S)-7
from the chiral starting (+)-(4S,5R)-2 or (ꢁ)-(4R,5S)-2, re-
spectively. Deprotection of the benzyl group in (+)-(4S,5R)-
7 or (ꢁ)-(4R,5S)-7 by the AlCl3/m-xylene system gave natu-
ral osmundalactone (+)-(4S,5R)-5 or (ꢁ)-(4R,5S)-5 in good
yield, respectively. Condensation of (ꢁ)-(4R,5S)-5 and tetra-
acetyl-b-D-glucosyltrichloroimidate 22 in the presence of
BF3$Et2O afforded the condensation product (ꢁ)-8 in 97%
yield, which was identical to tetra-O-acetylosmundalin 8
derived from natural osmundalin 9.
1
pound (ꢀ)-7: IR (neat): 1732 cmꢁ1; H NMR: d 1.42 (3H,
d, J¼6.0 Hz), 3.97 (1H, ddd, J¼8.0, 2.0, 2.0 Hz), 4.45
(1H, qd, J¼8.0, 2.0 Hz), 4.60, 4.69 (each 1H, d,
J¼12.0 Hz), 5.98 (1H, dd, J¼10.0, 0.2 Hz), 6.85 (1H, dd,
J¼10.0, 4.0 Hz), 7.28–7.39 (5H, m). 13C NMR: d 18.5 (q),
70.0 (t), 73.9 (d), 77.2 (d), 120.8 (d), 127.9 (2C, d), 128.3
(d), 128.5 (2C, d), 136.7 (s), 145.8 (d), 162.7 (s). Anal. Calcd
for C13H14O3: C, 71.54; H, 6.47%. Found: C, 71.24; H, 6.64.
FABMS m/z: 219 (M++1).
4.4. d-Lactonization from ( )-6 (synthesis of ( )-7)
(Scheme 2)
4. Experimental
4.1. General
A mixture of (ꢀ)-6 (0.130 g, 0.55 mmol) and DMAP
(0.08 g, 0.66 mmol) in toluene (5 mL) was stirred for 16 h
at 100 ꢂC. The reaction mixture was worked up in the
same way as described in Section 2.3 to afford (ꢀ)-6
(0.037 g, 30%) as a colorless oil. 1H NMR data of the present
(ꢀ)-7 were identical to those of the previous (ꢀ)-7.
1H NMR and 13C NMR spectra were recorded on Jeol AL
400 spectrometer in CDCl3. Carbon substitution degrees
were established by DEPT pulse sequence. High-resolution
mass spectra (HRMS) and fast atom bombardment mass
spectra (FABMS) were obtained with a 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 evaporations were
performed under reduced pressure. For column chromato-
graphy, silica gel (Kieselgel 60) was employed.
4.5. d-Lactonization from ( )-6 (synthesis of ( )-7)
(Table 1, entry 1)
To a solution of (ꢀ)-6 (0.688 g, 2.9 mmol) in CH2Cl2
(15 mL) were added 2,4,6-trichlorobenzoyl chloride
(0.78 g, 3.19 mmol) and DMAP (0.71 g, 5.8 mmol) and
the reaction mixture was stirred for 6 h at rt. The reaction
mixture was diluted with Et2O. The organic layer was
washed with 7% aqueous NaHCO3 solution and dried over
MgSO4. Evaporation of the organic solvent gave a residue,
which was chromatographed on silica gel (5 g, n-hexane/
AcOEt¼8:1) to afford (ꢀ)-7 (0.374 g, 59%) as a colorless
oil. 1H NMR data of the present (ꢀ)-7 were identical to those
of the previous (ꢀ)-7.
4.2. ( )-(4,5-anti)-4-Benzyloxy-5-hydroxy-(2E)-hexenoic
acid (6)
A mixture of the reported (ꢀ)-21 (13.68 g, 54.5 mmol) and
2 M NaOH solution (55 mL) in i-PrOH (110 mL) was stirred
for 1 h at rt and the reaction mixture was evaporated to give

M. Ono et al. / Tetrahedron 63 (2007) 10140–10148
10145
4.6. d-Lactonization from ( )-6 (synthesis of ( )-7)
(Table 1, entry 2)
(0.44 g, 2.59 mmol) in CH2Cl2 (1 mL) at 0 ꢂC and the reac-
tion mixture was stirred for 3 h at rt. The reaction mixture
was worked up in the same way as described in Section
1
Toasolutionof(ꢀ)-6(0.512 g,2.2 mmol)andDMAP(0.32 g,
2.6 mmol) in CH2Cl2 (15 mL) was added 2,4,6-trichloroben-
zoyl chloride (0.59 g, 2.4 mmol) at 0 ꢂC and then Ph3P
(1.15 g, 4.4 mmol) was added. The whole reaction mixture
was stirred for 6 h at rt. The reaction mixture was worked
up in the same way as described in Section 2.5 to afford
(ꢀ)-7 (0.326 g, 69%) as a colorless oil. 1H NMR data of the
present (ꢀ)-6 were identical to those of the previous (ꢀ)-7.
2.5 to afford (ꢀ)-7 (0.325 g, 65%) as a colorless oil. H
NMR data of the present (ꢀ)-7 were identical to those of
the previous (ꢀ)-7.
4.11. d-Lactonization from ( )-6 (synthesis of ( )-7)
(Table 1, entry 7)
To a solution of (ꢀ)-6 (0.20 g, 0.85 mmol) in pyridine
(2 mL) was added a solution of methyl chloroformate
(0.09 g, 0.95 mmol) in CH2Cl2 (1 mL) at 0 ꢂC and the reac-
tion mixture was stirred for 3 h at rt. The reaction mixture
was worked up in the same way as described in Section
4.7. d-Lactonization from ( )-6 (synthesis of ( )-10)
(Table 1, entry 3)
1
To a solution of (ꢀ)-7 (0.503 g, 2.1 mmol) and DMAP
(0.31 g, 2.5 mmol) in CH2Cl2 (15 mL) was added 2,4,6-tri-
chlorobenzoyl chloride (0.59 g, 2.4 mmol) at 0 ꢂC and
then morpholine (0.37 g, 4.2 mmol) was added. The whole
reaction mixture was stirred for 4 h at rt. The reaction mix-
ture was diluted with Et2O. The organic layer was washed
with 7% aqueous NaHCO3 solution and dried over
MgSO4. Evaporation of the organic solvent gave a residue,
which was chromatographed on silica gel (10 g, n-hexane/
AcOEt¼1:1) to afford (ꢀ)-10 (0.403 g, 62%). Compound
(ꢀ)-10: 1H NMR: d 1.16 (3H, d, J¼6.0 Hz), 2.20–3.68
(8H, m), 3.94 (2H, m), 4.45, 4.62 (each 1H, d,
J¼12.0 Hz), 6.43 (1H, dd, J¼10.0, 0.2 Hz), 6.82 (1H, dd,
J¼10.0, 4.0 Hz), 7.20–7.40 (5H, m). Anal. Calcd for
C17H23NO4: C, 66.86; H, 7.59; N, 4.59%. Found: C,
66.33; H, 7.43; N, 4.35. FABMS m/z: 306 (M++1).
2.5 to afford (ꢀ)-7 (0.092 g, 50%) as a colorless oil. H
NMR data of the present (ꢀ)-7 were identical to those of
the previous (ꢀ)-7.
4.12. d-Lactonization from ( )-6 (synthesis of ( )-7)
(Table 1, entry 8)
To a solution of (ꢀ)-6 (0.20 g, 0.85 mmol) in CH2Cl2 (2 mL)
was added DMAP (0.31 g, 2.5 mmol) and then a solution of
methyl chloroformate (0.09 g, 0.95 mmol) in CH2Cl2 (1 mL)
at 0 ꢂC was added. The reaction mixture was stirred for 1 h at
rt. The reaction mixture was worked up in the same way as
described in Section 2.5 to afford (ꢀ)-7 (0.070 g, 38%) as
a colorless oil and (ꢀ)-2 (0.037 g, 18%) as a colorless oil.
1H NMR data of the present (ꢀ)-7 and (ꢀ)-2 were identical
to those of the previous (ꢀ)-7 and (ꢀ)-2, respectively.
4.8. d-Lactonization from ( )-6 (synthesis of ( )-11)
(Table 1, entry 4)
4.13. d-Lactonization from ( )-6 (synthesis of ( )-7)
(Table 1, entry 9)
To a solution of (ꢀ)-6 (0.500 g, 2.1 mmol) in CH2Cl2
(15 mL) was added 2,4,6-trichlorobenzoyl chloride
(0.56 g, 2.3 mmol) at 0 ꢂC and then 1,4-diazabicyclo[2.2.2]-
octane (DABCO, 0.75 g, 6.7 mmol) was added. The whole
reaction mixture was stirred for 3 h at rt. The reaction mix-
ture was diluted with Et2O. The organic layer was washed
with 7% aqueous NaHCO3 solution and dried over
MgSO4. Evaporation of the organic solvent gave a residue,
which was chromatographed on silica gel (10 g, n-hexane/
To a solution of (ꢀ)-6 (0.504 g, 2.1 mmol) in pyridine (4 mL)
was added a solution of isobutyl chloroformate (0.32 g,
2.3 mmol) in CHCl3 (1 mL) at 0 ꢂC and the reaction mixture
was stirred for 3 h at rt. The reaction mixture was worked up
in the same way as described in Section 2.5 to afford (ꢀ)-7
(0.358 g, 77%) as a colorless oil. 1H NMR data of the present
(ꢀ)-7 were identical to those of the previous (ꢀ)-7.
4.14. d-Lactonization from ( )-6 (synthesis of ( )-7)
(Table 1, entry 10)
1
AcOEt¼12:1) to afford (ꢀ)-11 (0.02 g, 2.2%). H NMR
data of the present (ꢀ)-11 were identical to those of the
reported (ꢀ)-11.3 FABMS m/z: 437 (M++1).
4.9. d-Lactonization from ( )-6 (synthesis of ( )-7)
(Table 1, entry 5)
To a solution of (ꢀ)-6 (0.457 g, 1.9 mmol) in pyridine
(4 mL) was added a solution of methanesulfonyl chloride
(MsCl, 0.24 g, 2.1 mmol) in CHCl3 (1 mL) at 0 ꢂC and the
reaction mixture was stirred for 3 h at rt. The reaction mix-
ture was worked up in the same way as described in Section
To a solution of (ꢀ)-6 (1.79 g, 7.6 mmol) in pyridine
(15 mL) was added 2,4,6-trichlorobenzoyl chloride
(2.04 g, 8.3 mmol) at 0 ꢂC and the reaction mixture was
stirred for 1 h at rt. The reaction mixture was worked up in
the same way as described in Section 2.5 to afford (ꢀ)-7
(1.437 g, 87%) as a colorless oil. 1H NMR data of the present
(ꢀ)-7 were identical to those of the previous (ꢀ)-7.
1
2.5 to afford (ꢀ)-7 (0.172 g, 41%) as a colorless oil. H
NMR data of the present (ꢀ)-7 were identical to those of
the previous (ꢀ)-7.
4.15. d-Lactonization from ( )-6 (syntheses of ( )-7 and
12a,b) (Table 1, entry 11)
4.10. d-Lactonization from ( )-6 (synthesis of ( )-7)
(Table 1, entry 6)
To a mixture of (ꢀ)-6 (0.506 g, 2.4 mmol), 2,20-dipyridyl
disulfide (0.47 g, 2.1 mmol), and Ph3P (0.56 g, 2.1 mmol) in
benzene (2 mL) was added a solution of 0.4 M silver trifluo-
romethanesulfonate (CF3SO3Ag)/toluene solution (15 mL) in
MeCN (10 mL) and the reaction mixture was allowed to
To a solution of (ꢀ)-6 (0.537 g, 2.2 mmol) in pyridine
(4 mL) was added a solution of 2-chlorobenzoyl chloride

10146
M. Ono et al. / Tetrahedron 63 (2007) 10140–10148
stand for 1 h at rt. The reaction mixture was filtered off and
the filtrate was evaporated to give a residue. It was diluted
with benzene and the organic layer was washed with
0.5 M NaOH, brine and dried over MgSO4. Evaporation of
the organic solvent gave a residue, which was chromato-
graphed on silica gel (30 g, n-hexane/AcOEt¼5:1) to afford
(ꢀ)-7 (0.058 g, 12%) and 12a (0.11 g) and 12b (0.112 g), to-
tal (0.222 g, 31%) in elution order. 1H NMR data of the pres-
ent (ꢀ)-7 were identical to those of the previous (ꢀ)-7.
4.18. d-Lactonization from ( )-6 (synthesis of 13)
(Table 1, entry 14)
To a solution of (ꢀ)-6 (1.02 g, 4.3 mmol) and 2,4,6-collidine
(1.05 g, 8.6 mmol) in CH2Cl2 (10 mL) was added DCC
(0.89 g, 4.3 mmol) and the mixture was stirred for 9 h at rt.
The reaction mixture was worked up in the same way as de-
scribed in Section 2.17 to afford 13 (0.722 g, 38%). 1H NMR
dataofthepresent13wereidenticaltothoseoftheprevious13.
1
Compound 12a: IR (CHCl3): 1749 cmꢁ1; H NMR: d 1.40
(3H, d, J¼6.0 Hz), 2.91 (1H, s), 2.93 (1H, d, J¼1.0 Hz),
3.70 (1H, t, J¼3.0 Hz), 4.60 (2H, s), 4.67 (2H, m), 6.91
(1H, ddd, J¼8.0, 5.0, 1.0 Hz), 7.09 (1H, dt, J¼8.0, 1.0 Hz),
7.19–7.31 (5H, m), 7.40 (1H, ddd, J¼10.0, 7.0, 2.0 Hz),
8.30 (1H, ddd, J¼5.0, 2.0, 1.0 Hz). Anal. Calcd
for C18H19O3NS: C, 65.63; H, 5.81; N, 4.25%. Found:
C, 65.64; H, 5.86; N, 4.25. FABMS m/z: 330 (M++1).
4.19. d-Lactonization from ( )-6 (syntheses of ( )-7 and
14) (Table 1, entry 15)
To a solution of (ꢀ)-6 (0.289 g, 1.2 mmol) in CH2Cl2
(18 mL) was added pyridine (0.97 g, 12.3 mmol) and a
solution of 1,3-diisopropylcarbodiimide (DIPC, 0.17 g,
1.3 mmol) in CH2Cl2 (2 mL) was added to the above reac-
tion mixture at 0 ꢂC. The whole reaction mixture was stirred
for 24 h at rt. The reaction mixture was worked up in the
same way as described in Section 2.17 to afford (ꢀ)-7
1
Compound 12b: IR (neat): 1733 cmꢁ1; H NMR: d 1.43
(3H, d, J¼6.0 Hz), 2.84 (1H, dd, J¼16.0, 4.0 Hz), 3.21
(1H, dd, J¼16.0, 6.0 Hz), 3.63 (1H, dd, J¼8.0, 5.0 Hz),
4.30 (1H, qd, J¼6.0, 6.0 Hz), 4.47 (1H, dt, J¼6.0, 5.0 Hz),
4.60, 4.85 (each 1H, J¼12.0 Hz), 7.16 (1H, dt, J¼8.0,
1.0 Hz), 7.20 (1H, ddd, J¼8.0, 5.0, 1.0 Hz), 7.23–7.39 (5H,
m), 7.49 (1H, ddd, J¼9.0, 7.0, 2.0 Hz), 8.42 (1H, d,
J¼5.0 Hz). Anal. Calcd for C18H19NO3S: C, 65.63; H,
5.81; N, 4.25%. Found: C, 65.49; H, 5.95; N, 4.23. FABMS
m/z: 330 (M++1).
1
(0.120 g, 45%) and 14 (0.063 g, 14%) in elution order. H
NMR data of the present (ꢀ)-7 were identical to those of
1
the previous (ꢀ)-7. Compound 14: H NMR: d 1.16 (3H,
d, J¼7.0 Hz), 1.17 (6H, d, J¼7.0 Hz), 1.39 (6H, d,
J¼7.0 Hz), 2.27–2.40 (1H, br s), 3.94 (1H, dd, J¼6.0,
7.0 Hz), 3.96 (2H, sextet, J¼7.0 Hz), 4.42 (1H, dq, J¼7.0,
7.0 Hz), 4.40, 4.62 (each 1H, d, J¼12.0 Hz), 6.44 (1H, d,
J¼16.0 Hz), 6.86 (1H, dd, J¼16.0, 6.0 Hz), 7.28–7.35
(5H, m), 7.42 (1H, br s). Anal. Calcd for C20H30N2O4: C,
66.27; H, 8.34; N, 7.73%. Found: C, 66.40; H, 8.58; N,
7.40. FABMS m/z: 363 (M++1).
4.16. d-Lactonization from ( )-6 (syntheses of ( )-7 and
13) (Table 1, entry 12)
To a solution of (ꢀ)-6 (0.455 g, 1.9 mmol) in CH2Cl2 (8 mL)
were added DMAP (0.24 g, 1.9 mmol) and 1,3-dicyclohex-
ylcarbodiimide (DCC, 0.40 g, 1.9 mmol) at 0 ꢂC and then
Ph3P (1.01 g, 3.86 mmol) was added. The whole reaction
mixture was stirred for 2 h at rt. The reaction mixture
was worked up in the same way as described in Section
2.5 to afford (ꢀ)-7 (0.143 g, 34%) and 13 (0.375 g, 44%)
4.20. d-Lactonization from ( )-3-benzyloxy-4-hydroxy-
(2E)-pentenoate 16 (synthesis of ( )-18)
(1) A mixture of (ꢀ)-1615 (0.186 g, 0.79 mmol) and 2 M
NaOH solution (2 mL) in i-PrOH (3 mL) was stirred for
12 h at rt. The reaction mixture was worked up in the same
way as for (ꢀ)-6 to give (ꢀ)-17 (0.175 g, 99%). Compound
1
in elution order. H NMR data of the present (ꢀ)-7 were
1
identical to those of the previous (ꢀ)-7. Compound 13:
1H NMR: d 1.15 (3H, d, J¼6.0 Hz), 1.09–1.95 (10H, m),
2.31 (1H, br s), 3.60–3.70 (1H, m), 3.98–4.07 (1H, m),
3.90–3.96 (2H, m), 4.42, 4.62 (each 1H, d, J¼12.0 Hz),
6.41 (1H, d, J¼16.0 Hz), 6.85 (1H, d, J¼16.0, 6.0 Hz),
7.02 (1H, br s), 7.26–7.36 (5H, m). FABMS m/z: 443
(M++1).
(ꢀ)-17: H NMR: d 3.62 (1H, dd, J¼12.0, 6.0 Hz), 3.71
(1H, dd, J¼12.0, 4.0 Hz, OH), 4.17 (1H, dddd, J¼6.0, 6.0,
4.0, 2.0 Hz), 4.45 (1H, d, J¼12.0 Hz), 4.66 (1H, d, J¼
12.0 Hz), 6.13 (1H, dd, J¼16.0, 10.0 Hz), 6.97 (1H, d,
J¼16.0, 6.0 Hz), 7.27–7.40 (5H, m). The crude (ꢀ)-17
was used for the next reaction without further purification.
(2) To a solution of (ꢀ)-17 (0.175 g, 0.79 mmol) in pyridine
(2 mL) was added a solution of 2,4,6-trichlorobenzoyl chlo-
ride (0.21 g, 0.87 mmol) in CH2Cl2 (0.2 mL) at 0 ꢂC and the
reaction mixture was stirred for 2 h at rt. The reaction mix-
ture was worked up in the same way as described in Section
2.5 to afford (ꢀ)-18 (0.145 g, 90%) as a colorless oil. Com-
pound (ꢀ)-18: IR (neat): 1730, 1629 cmꢁ1; 1H NMR: d 4.17
(1H, dddd, J¼5.0, 5.0, 4.0, 1.0 Hz), 4.39 (1H, dd, J¼10.0,
5.0 Hz), 4.41 (1H, dd, J¼10.0, 5.0 Hz), 4.61 (2H, s), 6.05
(1H, dd, J¼10.0, 1.0 Hz), 6.89 (1H, dd, J¼10.0, 4.0 Hz).
Anal. Calcd for C12H12O3: C, 70.57; H, 5.92%. Found: C,
70.74; H, 6.00. FABMS m/z: 205 (M++1).
4.17. d-Lactonization from ( )-6 (syntheses of ( )-7 and
13) (Table 1, entry 13)
To a solution of (ꢀ)-6 (1.718 g, 7.3 mmol) in CH2Cl2
(20 mL) was added DMAP (1.78 g, 14.6 mmol) and the reac-
tion mixture was stirred for 1 h at rt. 1,3-Dicyclohexylcarbo-
diimide (DCC, 1.81 g, 8.7 mmol) was added to the above
reaction mixture and the whole mixture was stirred for 12 h
at rt. The reaction mixture was filtered off and filtrate was
washed with 2 M NaOH solution and dried over MgSO4.
Evaporation of the organic solvent gave a residue, which
was chromatographed on silica gel (50 g, n-hexane/
AcOEt¼5:1) to afford (ꢀ)-7 (0.961 g, 60%) and 13 (0.35 g,
11%) in elution order. 1H NMR data of the present
(ꢀ)-7 and 13 were identical to those of the previous (ꢀ)-7
and 13.
4.21. d-Lactonization from ( )-5-hydroxy-(2E)-
hexenoate 19 (synthesis of ( )-21)
(1) To a solution of (ꢀ)-1916 (0.163 g, 1.13 mmol) in THF
(2 mL) was added 2 M NaOH solution (1.5 mL) and the

M. Ono et al. / Tetrahedron 63 (2007) 10140–10148
10147
reaction mixture was stirred for 2.5 h at rt. The reaction mix-
ture was worked up in the same way as for (ꢀ)-6 to give (ꢀ)-
20 (0.147 g, 99%). Compound (ꢀ)-20: 1H NMR: d 1.20 (3H,
d, J¼6.0 Hz), 2.35 (2H, dd, J¼7.0, 7.0 Hz), 3.96 (1H, ddq,
J¼7.0, 7.0, 6.0 Hz), 5.85 (1H, d, J¼16.0 Hz), 6.43–6.70
(1H, m), 7.02 (1H, dt, J¼16.0, 7.0 Hz). The crude (ꢀ)-20
was used for the next reaction without further purification.
(2) To a solution of (ꢀ)-20 (0.147 g, 1.13 mmol) in
CH2Cl2 (3 mL) were added pyridine (0.159 g, 2.26 mmol)
and pyridinium chloride (0.232 g, 2.26 mmol). To the above
reaction mixture was added a solution of 2,4,6-trichloroben-
zoyl chloride (0.268 g, 2.26 mmol) in CH2Cl2 (0.5 mL) at
0 ꢂC and the reaction mixture was stirred for 1 h at rt. The
reaction mixture was worked up in the same way as de-
scribed in Section 2.5 to afford (ꢀ)-21 (0.193 g, 81%) as
a colorless oil. Compound (ꢀ)-21: IR (neat): 1724,
d-Lactonization from (ꢁ)-(4R,5S)-6 (3.00 g, 12.7 mmol) in
the same way as for (+)-(4S,5R)-6 afforded (4R,5S)-7
{2.342 g, 85%, [a]2D5 ꢁ97.8 (c 0.32, CHCl3)}. (3) Deprotec-
tion of benzyl group of (ꢁ)-(4R,5S)-7 (0.352 g, 1.6 mmol) in
the same way as for (+)-(4S,5R)-7 gave (ꢁ)-(4R,5S)-5
{0.189 g, 91%, [a]2D8 ꢁ68.4 (c 0.41, H2O)}.
4.24. Tetra-O-acetylosmundalin 8
To a solution of (ꢁ)-(4R,5S)-5 (0.028 g, 0.22 mmol) and
tetraacetyl-b-D-glucosyltrichloroimidate 2215 (0.218 g,
0.44 mmol) in CH2Cl2 (6 mL) was added BF3$Et2O
(0.013 g, 0.09 mmol) at 0 ꢂC and the reaction mixture was
stirred for 3.5 h at rt. The reaction mixture was diluted with
7%aqueousNaHCO3 andextractedwithCH2Cl2. Theorganic
layer was washed with brine and dried over MgSO4. Evapora-
tion of the organic solvent gave a residue, which was chroma-
tographed on silica gel (10 g, n-hexane/AcOEt¼1:1) to afford
(ꢁ)-8 (0.099 g, 97%) as a colorless oil. Compound (ꢁ)-8:
1
1390 cmꢁ1; H NMR: d 1.39 (3H, d, J¼7.0 Hz), 2.25 (1H,
dddd, J¼18.0, 11.0, 2.0, 2.0 Hz), 2.32 (1H, dddd, J¼18.0,
6.0, 3.0, 1.0 Hz), 4.52 (1H, ddq, J¼11.0, 7.0, 3.0 Hz), 5.96
(1H, ddd, J¼10.0, 2.0, 1.0 Hz), 6.83 (1H, ddd, J¼10.0,
6.0, 1.0 Hz). Anal. Calcd for C6H8O2: C, 62.27; H, 7.19%.
Found: C, 61.99; H, 7.35. FABMS m/z: 113 (M++1).
1
[a]D25 ꢁ40.4 (c 1.0, CHCl3). IR (CHCl3): 1756 cmꢁ1; H
NMR: d 1.42 (3H, d, J¼6.0 Hz, 5-Me), 4.27 (1H, ddd,
J¼8.0, 2.4, 2.0 Hz, 4-H), 4.42 (1H, qd, J¼8.0, 6.0 Hz, 5-H),
6.02 (1H, dd, J¼10.0, 1.8 Hz, 2-H), 6.71 (1H, dd, J¼10.0,
2.4 Hz, 3-H), 1.98, 2.00, 2.02, 2.06 (each 3H, s, OAc), 3.69
(1H, ddd, J¼10.0, 4.4, 2.4 Hz, 50-H), 4.14 (1H, dd, J¼12.0,
2.4 Hz, 60a-H), 4.20 (1H, dd, J¼12.0, 4.4 Hz, 60b-H), 4.67
(1H, d, J¼8.0 Hz, 10-H), 4.95 (1H, dd, J¼10.0, 8.0 Hz, 20-
H), 5.05 (1H, dd, J¼10.0, 10.0 Hz, 40-H), 5.18 (1H, dd,
J¼10.0, 10.0 Hz, 30-H). 13C NMR: d 18.27 (q, 6), 77.10 (d,
5), 73.00 (d, 4), 121.80 (d, 2), 144.20 (d, 3), 162.07 (s, 1),
20.67, 20.67, 20.73, 20.79 (each q, MeCOO–), 61.84 (t, 60),
68.25 (d, 40), 71.13 (d, 20), 72.15 (d, 50), 72.57 (d, 30), 98.84
(d, 10), 168.86, 169.06, 169.92, 170.19 (each s, MeCOO–).
Anal. Calcd for C20H26O12: C, 52.40; H, 5.72%. Found: C,
52.11; H, 5.89. FABMS m/z: 459 (M++1).
4.22. d-Lactonization from (D)-(4S,5R)-6 (synthesis of
(4S,5R)-osmundalactone 5)
(1) A mixture of the reported (4S,5R)-21 (6.30 g, 25 mmol)
and 2 M NaOH solution (25 mL) in i-PrOH (50 mL) was
stirred for 90 min at rt. The reaction mixture was worked
up in the same way as for (ꢀ)-6 to give (+)-(4S,5R)-6
(5.90 g, 99%). Compound (+)-(4S,5R)-6: [a]2D5 +69.51 (c
0.33, CHCl3). 1H NMR data of (+)-(4S,5R)-6 were identical
to those of (ꢀ)-6. (2) To a solution of (+)-(4S,5R)-6 (0.225 g,
0.95 mmol) in pyridine (2 mL) was added 2,4,6-trichloro-
benzoyl chloride (0.26 g, 1.05 mmol) at 0 ꢂC and the reaction
mixture was stirred for 1 h at rt. The reaction mixture was
worked up in the same way as described in Section 2.5 to af-
1
References and notes
ford (4S,5R)-7 (0.177 g, 85%) as a colorless oil. H NMR
data of (4S,5R)-7 were identical to those of (ꢀ)-7. Compound
(+)-(4S,5R)-7: [a]2D5 +97.4 (c 0.35, CHCl3). (3) To a suspen-
sion of AlCl3 (5.06 g, 38.0 mmol) in CH2Cl2 (75 mL) was
added a solution of (+)-(4S,5R)-7 (3.310 g,1.6 mmol) in m-
xylene (12 mL) at 0 ꢂC and the reaction mixture was stirred
for 1 h at 0 ꢂC. The reaction mixture was poured into ice-
water and extracted with Et2O. The Et2O layer was washed
with brine and dried over MgSO4. Evaporation of the organic
solvent gave a residue, which was chromatographed on silica
gel (300 g, n-hexane/AcOEt¼1:1) to afford (+)-(4S,5R)-5
(1.654 g, 85%). Compound (+)-(4S,5R)-5: [a]2D6 +69.1 (c
1. Ono, M.; Saotome, C.; Akita, H. Tetrahedron: Asymmetry
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1969–1973.
ꢀ
ꢀ
4. Alemany, A.; Marquez, C.; Pascual, C.; Valverde, S.; Martınez-
Ripoll, M.; Fayos, J.; Perales, A. Tetrahedron Lett. 1979, 20,
3583–3586.
5. Buchanan, M. S.; Hashimoto, T.; Takaoka, S.; Asakawa, Y.
Phytochemistry 1995, 40, 1251–1257.
0.53, H2O). IR (CHCl3): 3422, 1727 cmꢁ1 1H NMR:
;
d 1.44 (3H, d, J¼6.0 Hz), 2.85 (1H, d, J¼7.0 Hz, OH), 4.20
(1H, ddd, J¼8.0, 2.0, 2.0 Hz), 4.34 (1H, qd, J¼8.0,
6.0 Hz), 5.91 (1H, dd, J¼8.0, 2.0 Hz), 6.83 (1H, dd, J¼8.0,
2.0 Hz). 13C NMR: d 18.2 (q), 67.5 (d), 79.2 (d), 120.0 (d),
149.0 (d), 163.5 (s). Anal. Calcd for C6H8O3: C, 56.24; H,
6.29%. Found: C, 56.07; H, 6.37. FABMS m/z: 129 (M++1).
6. Hollenbeak, K. H.; Kuehne, M. E. Tetrahedron 1974, 30, 2307–
2316.
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J. Am. Chem. Soc. 2000, 122, 3783–3784.
€
€
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4.23. d-Lactonization from (L)-(4R,5S)-6 (synthesis of
(4R,5S)-osmundalactone 5)
11. Stanetty, P.; Kremslehner, M. Tetrahedron Lett. 1998, 39, 811–
812.
12. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993.
(1)The reported (4R,5S)-21 (1.449 g, 58 mmol) was con-
verted to (ꢁ)-(4R,5S)-6 {1.288 g, 94%, [a]2D5 ꢁ69.97 (c
0.37, CHCl3)} in the same way as for (+)-(4S,5R)-6. (2)

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M. Ono et al. / Tetrahedron 63 (2007) 10140–10148
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15. Compound (ꢀ)-18 was synthesized by applying the following
reference: Ono, M.; Suzuki, K.; Akita, H. Tetrahedron Lett.
1999, 40, 8223–8226.
16. Compound (ꢀ)-19 was synthesized by applying the following
reference: Nakamura, H.; Ono, M.; Shida, Y.; Akita, H.
Tetrahedron: Asymmetry 2002, 13, 705–713.
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Takemura, T. Chem. Pharm. Bull. 1990, 38, 2862–2865.