Synthesis of γ- and δ-lactone natural products by employing a trans-cis isomerization/lactonization strategy

Article abstract of DOI:10.1248/cpb.c12-01026

Alkaline hydrolysis of 4-hydroxy- or/and 5-hydroxy-(2E)-alkenoate followed by acid treatment gave the corresponding (2E)-alkenoic acids which were subjected to lactone formation reaction without further purification. The crude acids were treated with 2,4,6-trichlorobenzoyl chloride in pyridine to afford ?-lactone or d-lactone, respectively, accompanied by trans-cis isomerization. By this procedure, (±)-(4,5)-trans-5-benzyloxy- 2-hexen-4-olide (90% overall yield), (S)-5-hydroxy-2-penten-4-olide (86% overall yield), (4S,5R)-5- hydroxy-2-hexen-4-olide (86% overall yield), (4R,5S)-5-hydroxy-2-hexen-4-olide (82% overall yield), (S)- parasorbic acid (58% overall yield) and natural product, (5R,7S)-7-hydroxy-2-octen-5-olide (euscapholide: 20% overall yield) were synthesized.

Full text of DOI:10.1248/cpb.c12-01026

464
Note
Chem. Pharm. Bull. 61(4) 464–470 (2013)
Vol. 61, No. 4
Synthesis of γ- and δ-Lactone Natural Products by Employing a
trans–cis Isomerization/Lactonization Strategy
,b,†
Machiko Ono,a 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 November 27, 2012; accepted January 24, 2013
Alkaline hydrolysis of 4-hydroxy- or/and 5-hydroxy-(2E)-alkenoate followed by acid treatment gave the
corresponding (2E)-alkenoic acids which were subjected to lactone formation reaction without further pu-
rification. The crude acids were treated with 2,4,6-trichlorobenzoyl chloride in pyridine to afford γ-lactone
or δ-lactone, respectively, accompanied by trans–cis isomerization. By this procedure, (±)-(4,5)-trans-5-ben-
zyloxy-2-hexen-4-olide (90% overall yield), (S)-5-hydroxy-2-penten-4-olide (86% overall yield), (4S,5R)-5-
hydroxy-2-hexen-4-olide (86% overall yield), (4R,5S)-5-hydroxy-2-hexen-4-olide (82% overall yield), (S)-
parasorbic acid (58% overall yield) and natural product, (5R,7S)-7-hydroxy-2-octen-5-olide (euscapholide:
20% overall yield) were synthesized.
Key words lactone formation; trans–cis isomerization; euscapholide
The α,β-unsaturated lactones are found as structural sub- a stereoselective manner. This problem could be overcome
units in a wide variety of natural products possessing diverse by applying the modified Horner–Emmons reaction1) Ring-
biological activities as shown in Chart 1. Furthermore, simple closing metatheses using Grubbs reagent have recently been
lactones have been used as intermediates for the synthesis reported to be a useful method to construct α,β-unsaturated
of biologically active compounds. The structure of typical lactone structures.2)
natural products such as (S)-parasorbic acid (1), (4R,5S)-
We previously reported the syntheses of (4S,5R)- and
osmundalactone (2), (4R,5S)-5-hydroxy-2-hexen-4-olide (3), (4R,5S)-4-benzyloxy-5-hydroxy-(2E)-hexenoates (11) based
(5R,7S)-euscapholide (4), (+)-asperlin (5), (+)-anamarine (6), on a chemoenzymatic method from methyl sorbate (9).3) Hy-
(−)-tarchonanthuslactone (7), and fostriecin (8) are shown in drolysis of (4S,5R)- and (4R,5S)-11 gave the corresponding
Chart 1.
5-hydroxy-(2E)-unsaturated carboxylic acids, which were
In general, the syntheses of α,β-unsaturated lactones are converted to osmundalactones (4S,5R)- and (4R,5S)-2 via the
achieved based on the direct lactonization of the correspond- formation of δ-lactones (4S,5R)- and (4R,5S)-12 accompanied
ing 4- or 5-hydroxy-(2Z)-unsaturated esters. To achieve by trans–cis isomerization, respectively as shown in Chart 2.
efficient syntheses of α,β-unsaturated lactones, it is neces- In this paper, a reaction mechanism of isomerization from E-
sary to obtain the Z-isomer of the α,β-unsaturated esters in isomer to Z-isomer is described.4)
Chart 1
The authors declare no conflict of interest.
† Present address: Nihon Pharmaceutical University; 10281 Komuro,
Inamachi, Kitaadachigun, Saitama 362–0806, Japan.
© 2013 The Pharmaceutical Society of Japan
*To whom correspondence should be addressed. e-mail: hiroakita@nichiyaku.ac.jp

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465
Chart 2
Chart 3
We now report the scope and limitation of the synthesis of by acid treatment provided the desired acid (±)-17, which
α,β-unsaturated lactone using the above mentioned lactone was subjected to γ-lactone formation reaction without further
formation method accompanied by trans–cis isomerization purification. The trans-structure of (±)-17 was confirmed by
from 4- or/and 5-hydroxy-2(E)-unsaturated ester and applica- 1H-NMR analysis. The crude acid (±)-17 was treated with
tion to the first synthesis of (5R,7S)-euscapholide (4) will be 2,4,6-trichlorobenzoyl chloride in pyridine to give the desired
described.
γ-lactone (±)-18 in 90% overall yield from (±)-16. The AlCl3
γ-Lactonization from (±)-(4,5-anti)-5-Benzyloxy-4-hy- mediated debenzylation of (±)-18 in m-xylene afforded the
droxy-(2E)-hexenoic acid (17) (Synthesis of (±)-18) (Chart racemic natural product (±)-3 in 82% yield. The NMR data of
3) The (4R,5S)-5-hydroxy-2-hexen-4-olide (3) having anti- the synthetic (±)-18 and (±)-3 were identical with those of the
feeding activites for the larvae of the yellow butterfly, Eurema reported (+)-187) and (+)-3,7) respectively.
hecabe mandarina de L’orza, was isolated from Osmunda
γ-Lactonization from (S)-4,5-Dihydroxy-(2E)-pentenoic
japonica Thunb.5) The asymmetric synthesis of (4R,5S)-3 was Acid (21) (Synthesis of (S)-22) (Chart 4) The (S)-5-hy-
reported based on the baker’s yeast mediated asymmetric re- droxy-2-penten-4-olide (22) was obtained as an aglycone from
duction of 1-phenylthio-2,3-butandiones.6) In order to examine a glycoside, ranunculin, which was isolated from Pulsatilla
the above mentioned methodology for γ-lactone formation, the vulgaris MiLL.8) It is much interested to reveal whether the
synthesis of (±)-(4,5)-trans-5-benzyloxy-2-hexen-4-olide (18) formation of the γ-lactone formation or δ-lactone formation
from (±)-(4,5-anti)-5-benzyloxy-4-hydroxy-(2E)-hexenoic acid from a (S)-4,5-dihydroxy-(2E)-pentenoic acid (21) may occur.
(17) was selected as shown in Chart 3.
The synthesis of (S)-22 from the commercial available methyl
The compound (±)-17 was synthesized from the re- (S)-(+)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-trans-2-propenoate
ported (±)-113) as shown in Chart 3. The AlCl3 mediated (19) was carried out as shown in Chart 4.
debenzylation3) of (±)-11 in m-xylene gave (±)-(4,5-anti)-4,5-
Deprotection of (S)-19 with Dowex 50W (H+) gave (S)-4,5-
dihydroxy- (2E)-hexenoate (13) in 66% yield, which was dihydroxy-(2E)-pentenoate (20) in 91% yield. Alkakine hydro-
treated with benzaldehyde in the presence of p-toluenesul- lysis of (S)-20 followed by acid treatment provided the desired
fonic acid (p-TsOH) to afford a mixture of acetals [(±)-14 acid (S)-21, which was subjected to lactone formation reaction
and (±)-15] in 83% yield. Treatment of this mixture with without further purification. The trans-structure of (S)-21
1
sodium cyanoborohydride [Na(CN)BH3] gave (±)-(4,5-anti)- was confirmed by H-NMR analysis. The crude acid (S)-21
5-benzyloxy-4-hydroxy-(2E)-hexenoate (16) (78% yield) and was treated with 2,4,6-trichlorobenzoyl chloride in pyridine
(±)-11 (13% yield). Alkakine hydrolysis of (±)-16 followed to give the desired γ-lactone (S)-22 in 86% overall yield from

466
Vol. 61, No. 4
Chart 4
Chart 5
(S)-20. The specific rotation of (S)-22 ([α]D26 −142 (c=0.332, selective formation of (4S,5R)- and (4R,5S)-3 from (4S,5R)-
H2O)) was consistent with those of the reported (S)-22 ([α]D25 and (4R,5S)-23, respectively will be discussed at late.
−145 (c=0.126, H2O).8) The NMR data of the synthetic (S)-22
δ-Lactonization from (S)-5-Hydroxy-(2E)-hexenoic Acid
were identical with those of the reported (S)-22.8) This result (25) (Synthesis of (S)-Parasorbic Acid (1)) (Chart 6) By
is particularly surprising in view of the fact that the γ-lactone applying the reported procedure, the starting material (S)-
formation from (S)-21 occurred in spite of the presence of two 5-hydroxy-(2E)-hexenoate (24) was obtained from the report-
hydroxyl groups at C(4)- and C(5)-positions in substrate.
ed (4R,5S)-13.9) The synthesis of (S)-parasorbic acid (1) from
γ-Lactonization from (4S,5R)- and (4R,5S)-4,5-Dihy- (S)-24 was shown in Chart 6 (see Chapter ‘δ-Lactonization
droxy-(2E)-hexenoic Acid (23) (Synthesis of (4S,5R)- and from (5R,7S)-5,7-Dihydroxy-(2E)-octenoic Acid (29) (Syn-
(4R,5S)-3) (Chart 5) From the result mentioned at Chapter thesis of (5R,7S)-Euscapholide (4)’)). Alkakine hydrolysis of
‘γ-Lactonization from (S)-4,5-Dihydroxy-(2E)-pentenoic Acid (S)-24 followed by acid treatment provided the desired acid
(21) (Synthesis of (S)-22),’ lactone formation of (4S,5R)- and (S)-25 which was subjected to lactone formation reaction
(4R,5S)-4,5-dihydroxy-(2E)-hexenoic acids (23) has aroused without further purification. The trans-structures of (S)-25
1
our interest as shown in Chart 5.
was confirmed by H-NMR analysis. The crude acid (S)-25
Deprotection of the reported (4S,5R)- and (4R,5S)-113) by was treated with 2,4,6-trichlorobenzoyl chloride in pyridine to
the same way as the preparation of (±)-13 from (±)-11 gave give the desired δ-lactone (S)-parasorbic acid (1; [α]D21 +134.9
(4S,5R)-13 (86% yield) and (4R,5S)-13 (74% yield), respec- (c=0.44, EtOH), 70% overall yield from (S)-24). The NMR
tively. Alkakine hydrolysis of (4S,5R)-13 and (4R,5S)-13 fol- data of the synthetic (S)-1 were identical with those of the
lowed by acid treatment provided the desired acids (4S,5R)-23 reported (±)-1.10)
and (4R,5S)-23, respectively, which were subjected to lactone
δ-Lactonization from (5R,7S)-5,7-Dihydroxy-(2E)-oc-
formation reaction without further purification. The trans- tenoic Acid (29) (Synthesis of (5R,7S)-Euscapholide (4))
structures of (4S,5R)-23 and (4R,5S)-23 were separately con- (Chart 6) The (+)-euscapholide (4) was isolated from the
1
firmed by H-NMR analysis. The crude acids (4S,5R)-23 and leaves of Euscaphis japonica and the absolute structure of
(4R,5S)-23 were separately treated with 2,4,6-trichlorobenzoyl 4 was deduced to possess 5R,7S-configurations by means of
chloride in pyridine to give the desired γ-lactones (4S,5R)-5- spectroscopic and chemical analysis.11) The first total synthesis
hydroxy-2-hexen-4-olide (3; [α]D24 −176.2 (c=0.47, CHCl3), of (−)-tarchonanthuslactone (7) (see Chart 1) having antipodal
73% overall yield from (4S,5R)-13) and (4R,5S)-5-hydroxy-2- stereochemistry of (+)-4 as a partial structure was achieved
hexen-4-olide (3; [α]D23 +167.2 (c=0.34, CHCl3), 82% overall based on the synthetic strategy of 1,3-syn-polyol system12)
yield from (4R,5S)-13), respectively. The specific rotation of but the asymmetric synthesis of (+)-4 was not achieved. The
(4R,5S)-3 was consistent with those of the reported (4R,5S)- asymmetric synthesis of (5R,7S)-4 from the above mentioned
3 ([α]D +177 (c=1.5, CHCl3).5) The NMR data (1H- and (S)-24 was shown in Chart 6.
13C-NMR) of the synthetic (4S,5R)- and (4R,5S)-3 were identi-
cal with those of the reported (4R,5S)-3,5) respectively. The dihydroxy-(2E)-octenoic acid (29) from (S)-24 is necessary. To
For the synthesis of (5R,7S)-4, the synthesis of (5R,7S)-5,7-

April 2013
467
Chart 6
construct the 1,3-syn-structure of (5R,7S)-29, (S)-24 was con-
verted into the acetal (3S,5S)-26 by applying Evans method.13)
Chiral alcohol (S)-24 was treated with benzaldehyde (PhCHO)
in the presence of tert-BuOK to give the acetal (3S,5S)-26 in
67% yield. The 1,3-syn-structure of (3S,5S)-26 was confirmed
by nuclear Overhauser effect (NOE) measurement as shown
in Fig. 1. Diisobutylaluminum hydride (Dibal-H) reduction of
(3S,5S)-26 followed by treatment of trimethylphosphonoace-
tate ((MeO)2P(O)CH2COOM) in the presence of base [LiCl/
DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)] afforded the Horner
Fig. 1. NOE Correlation of (3S,5S)-26
In conclusion, alkaline hydrolysis of both (±)-(4,5-anti)-
Emmons reaction product (5R,7S)-27 in 67% overall yield. 5-benzyloxy-4-hydroxy-(2E)-hexenoate (16) and (S)-5-hy-
Alkakine hydrolysis of (5R,7S)-27 followed by acid treatment droxy-(2E)-hexenoate (24) followed by acid treatment gave
provided the acid (5R,7S)-28 which were subjected to depro- the corresponding (2E)-hexenoic acids (±)-17 and (S)-25,
tection of benzyl group without further purification to afford which were subjected to lactone formation reaction with-
the trans acid (5R,7S)-29. The trans-structure of (5R,7S)- out further purification. Both crude acids were treated with
29 was confirmed by 1H-NMR analysis. The crude acid 2,4,6-trichlorobenzoyl chloride in pyridine to afford γ-lactone
(5R,7S)-29 was treated with 2,4,6-trichlorobenzoyl chloride in [(±)-(4,5)-trans-5-benzyloxy-2-hexen-4-olide (18; 90% over-
pyridine to give the desired δ-lactone (5R,7S)-4 ([α]D22 113.5 all yield from (±)-16)] and δ-lactone [(S)-parasorbic acid (1;
(c=0.10, MeOH)) in 45% overall yield from (5R,7S)-27. The 70% overall yield from (S)-24)], respectively, accompanied
spectral data (1H- and 13C-NMR) of synthetic (5R,7S)-4 were by trans–cis isomerization. Meanwhile (S)-4,5-dihydroxy-
identical with those of the reported (5R,7S)-4.11) The specific (2E)-pentenoate (20) was selectively converted to γ-lactone
rotation of synthetic (5R,7S)-4 was consistent with those of the [(S)-5-hydroxy-2-penten-4-olide (22; 86% overall yield from
reported (5R,7S)-4 ([α]D30 +115.5 (c=1.52, MeOH).11) Thus the (S)-20)] by the above mentioned procedure. The (4S,5R)- and
absolute stereochemistry of (+)-euscapholide (4) was deter- (4R,5S)-4,5-dihydroxy-(2E)-hexenoates (13) were also selec-
mined unequivocally to possess 5R,7S-configurations.
tively converted to δ-lactone [(4S,5R)-5-hydroxy-2-hexen-4-
olide (3; 73% overall yield from (4S,5R)-13) and (4R,5S)-5-hy-
droxy-2-hexen-4-olide (3; 82% overall yield from (4R,5S)-13),
Discussion and Conclusion
As above mentioned in Chapters ‘γ-Lactonization from respectively, by the above mentioned procedure. The (S)-24
(S)-4,5-Dihydroxy-(2E)-pentenoic Acid (21) (Synthesis of was converted to (5R,7S)-5,7-dihydroxy-(2E)-octenoic acid
(S)-22)’ and ‘γ-Lactonization from (4S,5R)- and (4R,5S)-4,5- (29), which was subjected to δ-lactone formation reaction by
Dihydroxy-(2E)-hexenoic Acid (23) (Synthesis of (4S,5R)- and the above mentioned procedure to afford (5R,7S)-euscapholide
(4R,5S-3),’ the selective γ-lactone formation [(S)-22, (4S,5R)- (4). By the asymmetric synthesis of (5R,7S)-4, the absolute
and (4R,5S)-3] from 4,5-dihydroxy-2(E)-alkenic acid [(S)-21, stereochemistry of euscapholide (4) was unequivocally deter-
(4S,5R)- and (4R,5S)-23], respectively was occurred. These mined to possess (5R,7S)-configurations.
phenomena could be explained by the fact that the heat of
formation of γ-lactones [(4S,5R)- and (4R,5S)-3] is 4.35kcal/
mol stability than that of δ-lactones [(4S,5R)- and (4R,5S)-2]
Experimental
1H- and 13C-NMR spectra were recorded on JEOL AL
by SPARTAN Hartree–Fock method Molecular Orbital calcu- 400 spectrometer in CDCl3. Carbon substitution degrees
lation.
were established by DEPT pulse sequence. The fast atom

468
Vol. 61, No. 4
bombardment mass spectra (FAB MS) were obtained with a MS (FAB) m/z: 251 (M++1). NMR data of (±)-11 were consis-
JEOL JMS 600H spectrometer. IR spectra were recorded with tent with the authentic (±)-11.
a JASCO FT/IR-300 spectrometer. Optical rotations were mea-
iv) To a solution of (±)-16 (0.985g, 3.9mmol) in tetrahydro-
sured with a JASCO DIP-370 digital polarimeter. All evapo- furan (THF; 20mL) was added 2M NaOH solution (6mL) and
rations were performed under reduced pressure. For column the reaction mixture was stirred for 24h at rt. The reaction
chromatography, silica gel (Kieselgel 60) was employed.
mixture was acidified with 2M HCl solution and extracted
γ-Lactonization from (±)-(4,5-anti)-5-Benzyloxy-4-hy- with Et2O. The organic layer was washed with brine and.
droxy-(2E)-hexenoic Acid (17) (Synthesis of (±)-18) (Chart dried over MgSO4. Evaporation of organic solvent gave a
3) i) To a mixture of AlCl3 (20.8g, 156mmol) in CH2Cl2 crude oil (±)-17 (0.893g, 96%) as a colorless oil. A part of
(200mL) was added a solution of (±)-11 (13.0g, 52mmol) in crude oil (±)-17 was purified by preparative thin-layer chro-
1
m-xylene (20mL) at 0°C and the reaction mixture was stirred matography technique to afford pure (±)-17. (±)-17: H-NMR
for 15min at the same temperature. The reaction mixture was δ: 1.14 (3H, d, J=6Hz), 3.68 (1H, qd, J=6.0, 4.0Hz), 4.47 (1H,
diluted with H2O and extracted with Et2O. The organic layer m), 4.51, 4.63 (each 1H, d, J=12.0Hz), 6.13 (1H, dd, J=16.0,
was washed with brine and dried over MgSO4. Evaporation 2.0Hz), 6.99 (1H, dd, J=16.0, 5.0Hz), 7.25–7.38 (5H, m). Anal.
of the organic solvent gave a residue, which was chromato- Calcd for C13H16O4: C, 66.09; H, 6.83. Found: C, 65.80; H,
graphed on silica gel (300g, n-hexane–AcOEt=1:3) to afford 6.92. MS (FAB) m/z: 237 (M++1).
(±)-13 (5.52g, 66%) as a colorless oil. (±)-13: IR (neat): 3410,
v) To a solution of (±)-17 (0.101g, 0.4mmol) in pyridine
1
1709 cm−1; H-NMR δ: 1.12 (3H, d, J=6.0Hz), 2.85, 3.21 (each (2mL) were added 2,4,6-trichlorobenzoyl chloride (0.11g,
1H, brs), 3.72 (3H, s), 3.92 (1H, brt), 4.72 (1H, m), 6.09 (1H, 0.47mmol) and the reaction mixture was stirred for 1h at
dd, J=16.0, 2.0Hz), 6.92 (1H, dd, J=16.0, 5.0Hz). Anal. Calcd rt. The reaction mixture was diluted with H2O and extracted
for C7H12O4: C, 56.24; H, 6.29%. Found: C, 56.07; H, 6.37. with Et2O. The organic layer was washed with 7% aqueous
FAB-MS m/z: 161 (M++1).
NaHCO3 solution and dried over MgSO4. Evaporation of the
ii) A mixture of (±)-13 (2.133g, 13.3mmol), p-toluene- organic solvent gave a residue, which was chromatographed
sulfonic acid 0.25g, 1.3mmol) and benzaldehyde (1.62g, on silica gel (10g, n-hexane–AcOEt=10:1) to afford (±)-18
21.3mmol) in benzene (30mL) was refluxed using Dean– (0.085g, 90% overall yield from (±)-16) as a colorless oil.
1
Stark apparatus for 4h. The reaction mixture was diluted (±)-18: H-NMR δ: 1.33 (3H, d, J=6Hz), 3.68 (1H, qd, J=6.0,
with brine and extracted with Et2O. The organic layer was 4.0Hz), 4.43, 4.55 (each 1H, d, J=12.0Hz), 4.91 (1H, m), 6.15
dried over MgSO4. Evaporation of the organic solvent gave (1H, dd, J=16.0, 2.0Hz), 7.19–7.32 (5H, m), 7.55 (1H, dd,
a residue, which was chromatographed on silica gel (80g, J=6.0, 2.0Hz). 13C-NMR δ: 172.8 (s), 153.8 (d), 137.6 (1C, s),
n-hexane–AcOEt=50:1) to afford a less polar part (±)-14 128.4 (2C, d), 128.0 (2C, d), 127.6 (1C, d), 122.3 (d), 85.7 (d),
(0.982g, 30%) as a colorless oil and a more polar part. (±)- 74.9 (d), 16.6 (q). Anal. Calcd for C13H14O3: C, 71.54; H, 6.47.
15 (1.746g, 53%) as a colorless oil in elution order: (±)-14: Found: C, 71.25; H, 6.67. MS (FAB) m/z: 219 (M++1).
IR (neat): 1724cm−1;1H-NMR: δ: 1.23 (3H, d, J=6.0Hz), 3.76
vi) To a suspension of AlCl3 (0.160g, 1.2mmol) in CH2Cl2
(3H, s), 4.47 (1H, qd, J=6.0, 6.0Hz), 4.80 (1H, ddd, J=6.0, (2mL) was added a solution of (±)-18 (0.065g,0.3mmol) in m-
6.0, 1.8Hz), 6.19 (1H, s, benzylidene H), 6.19 (1H, dd, J=16.0, xylene (1.0mL) at 0°C and the reaction mixture was stirred for
1.8Hz), 6.90 (1H, dd, J=16.0, 6.0Hz), 7.30–7.47 (5H, m) Anal. 45min at 0°C. The reaction mixture was poured into ice-H2O
Calcd for C14H16O4: C, 67.73; H, 6.50%. Found: C, 67.26; H, and extracted with Et2O. The Et2O layer was washed with
6.50. FAB-MS m/z: 249 (M++1). (±)-15: IR (neat): 1726cm−1; brine and dried over MgSO4. Evaporation of the organic sol-
1H-NMR δ: 1.26 (3H, d, J=6.0Hz), 3.73 (3H, s), 4.45 (1H, vent gave a residue, which was chromatographed on silica gel
qd, J=6.0, 6.0Hz), 4.74 (1H, ddd, J=6.0, 6.0, 1.8Hz), 5.84 (20g, n-hexane–AcOEt=1:1) to afford (±)-3 (0.031g, 82%).
1
(1H, s, benzylidene H), 6.11 (1H, dd, J=16.0, 1.8Hz), 6.88 (±)-3; H-NMR δ: 1.28 (3Η, d, J=6.0Hz), 1.70–1.90 (1H, brs),
(1H, dd, J=16.0, 6.0Hz), 7.33–7.53 (5H, m). Anal. Calcd for 4.02 (1H, m), 4.91 (1H, m), 6.16 (1H, dd, J=6.0, 2.0Hz), 7.54
C14H16O4·0.5H2O: C, 65.36; H, 6.66%. Found: C, 65.65; H, (1H, dd, J=6.0, 2.0Hz). 13C-NMR δ: 173.0 (s), 153.5 (d), 122.5
6.30. FAB-MS m/z: 249 (M++1).
(d), 87.0 (d), 67.6 (d), 18.4 (q). Anal. Calcd for C6H8O3: C,
iii) NaBH3(CN) (1.95g, 30.8mmol) was added to a 1:1.76 56.24; H, 6.29. Found: C, 56.51; H, 6.18. MS (FAB) m/z: 129
mixture (7.647g, 30.8mmol) of (±)-14 and (±)-15 in MeCN (M++1).
(210mL) at −20°C and additional NaBH3(CN) (1.95g,
γ-Lactonization from (S)-4,5-Dihydroxy-(2E)-pentenoic
30.8mmol) and TiCl4 (3.39mL, 30.8mmol) were added to the Acid (21) (Synthesis of (S)-22) (Chart 4) i) To a solution of
above reaction mixture. The reaction mixture was stirred for commercially available (S)-19 (0.367g, 2.0mmol) in dioxane
40min at the same temperature. The reaction mixture was (10mL) and H2O (10mL) was added Dowex 50W (H+) (2.0g),
diluted with 7% NaHCO3 solution at 0°C and extracted with and the reaction mixture was stirred for 12h at 50°C. The
Et2O. The organic layer was washed with brine and. dried reaction mixture was filtered and the filtrate was evaporated
over MgSO4. Evaporation of organic solvent gave a crude oil, to give a crude oil. (S)-20 (0.261g, 91%) as a colorless oil. (S)-
1
which was chromatographed on silica gel (160g, n-hexane– 20: H-NMR δ: 2.50 (2Η, brs), 3.54 (1H, dd, J=11.0, 7.0Hz),
AcOEt=10:1) to give (±)-16 (6.039g, 78%) as a colorless oil 3.73 (1H, dd, J=11.0, 3.5Hz), 3.72 (3H, s), 4.41 (1H, dddd,
and (±)-11 (1.006g, 13%) in elution order. (±)-16: IR (neat): J=7.0, 4.5, 3.5, 2.0Hz), 6.13 (1H, dd, J=16.0, 2.0Hz), 6.89 (1H,
1726 cm−1; 1H-NMR δ: 1.13 (3H, d, J=6Hz), 2.38 (1H, d, dd, J=16.0, 4.5Hz).
J=4.4Hz), 3.66 (1H, qd, J=6.0, 3.0Hz), 3.73 (3H, s), 4.42 (1H,
ii) To a solution of crude (S)-20 (0.261g) in isopropyl
m), 4.51, 4.62 (each 1H, d, J=12.0Hz), 6.12 (1H, dd, J=16.0, alcohol (6.0mL) was added 2M NaOH solution (3mL) and
2.0Hz), 6.90 (1H, dd, J=16.0, 5.0Hz), 7.25–7.38 (5H, m). Anal. the reaction mixture was stirred for 12h at rt. The reaction
Calcd for C14H18O4: C, 67.18; H, 7.25. Found: C, 66.93; H, 7.35. mixture was treated with Et2O and water layer was acidified

April 2013
469
with 2M HCl solution. The water layer was evaporated to give n-hexane–AcOEt=1:3) to give (4S,5R)-3 (0.280g, 80% over-
a crude solid, which was dissolved with MeOH. Evaporation all yield from (4S,5R)-13). (4S,5R)-3: [α]D24 −176.2 (c=0.47,
of MeOH afforded (S)-21 (0.237g, quantitative yield). (S)-21: CHCl3), The spectral data (1H- and 13C-NMR) of (4S,5R)-3
1
IR (KBr): 3342, 1687, 1638cm−1; H-NMR δ: 3.52 (1H, dd, were identical with those of (±)-3. The antipode (4R,5S)-3
J=11.0, 6.0Hz), 3.56 (1H, dd, J=11.0, 5.5Hz), 4.29 (1H, ddd, (0.060g, 82% overall yield from (4R,5S)-13) was also obtained
J=6.0, 5.5, 2.0Hz), 6.06 (1H, dd, J=16.0, 2.0Hz), 6.97 (1H, from (4R,5S)-12 (0.091g). (4R,5S)-3: [α]D23 +167.2 (c=0.34,
dd, J=16.0, 5Hz). Anal. Calcd for C5H8O4: C, 45.46; H, 6.10. CHCl3). The spectral data (1H-NMR) of (4R,5S)-3 were identi-
Found: C, 45.29; H, 5.97. MS (FAB) m/z: 155 (M++Na).
iii) To a solution of (S)-21 (0.237g, 1.8mmol) in pyridine
cal with those of (±)-3.
δ-Lactonization from (S)-5-Hydroxy-(2E)-hexenoic Acid
(5mL) were added a solution of 2,4,6-trichlorobenzoyl chloride (25) (Synthesis of (S)-Parasorbic Acid (1)) (Chart 6) i) To
(0.44g, 1.8mmol) in CH2Cl2 (0.3mL) at 0°C and the reaction a solution of (S)-24 (0.173g, 1.2mmol) in THF (2.0mL) was
mixture was stirred for 2h at 0°C. The reaction mixture was added 2M NaOH solution (1.6mL) and the reaction mixture
treated with 7% aqueous NaHCO3 solution (5mL) and stirred was stirred for 2.5h at rt. The reaction mixture was acidified
for 20min. The reaction mixture was evaporated to give a with 2M H2SO4 solution (3.0mL) and extracted with Et2O.
residue, which was dissolved with Et2O. The Et2O soluble part The organic layer was dried over MgSO4 and evaporated to
by filtration was dried over MgSO4 and evaporated to afford give a crude (S)-25 (0.157g, quantitative yield), which was
a residue, which was chromatographed on silica gel (20g, n- used for next reaction without further purification. (S)-25;
hexane–AcOEt=1:1) to give (S)-22 (0.177g, 86% overall yield 1H-NMR (CDCl3) δ: 1.20 (3H, dd, J=6.0Hz), 2.35 (2H, dd,
from (S)-20). (S)-22: IR (neat): 3419, 1730, 1579cm−1; [α]D26 J=7.0, 7.0Hz), 3.96 (1H, dq, J=7.0, 7.0, 6.0Hz), 5.85 (1H, d,
1
−142 (c=0.332, H2O), H-NMR δ: 2.45 (1Η, brs), 3.78 (1H, dd, J=16.0Hz), 6.43–7.71 (1H, brs), 7.02 (1H, dt, J=16.0, 7.0Hz).
J=12.0, 5.0Hz), 3.98 (1H, dd, J=12.0, 4.0Hz), 5.14 (1H, dddd,
ii) To a solution of (S)-25 (0.157g, 2.7mmol) in CH2Cl2
J=5.0, 4.0, 2.0, 2.0Hz), 6.19 (1H, dd, J=6.0, 2.0Hz), 7.46 (1H, (2.0mL) were added 4-dimethylaminopyridine (DMAP,
1
dd, J=6.0, 2.0Hz). H-NMR (CD3OD) δ: 3.72 (1H, dd, J=10.0, 0.22g, 1.8mmol) and 2,4,6-trichlorobenzoyl chloride (0.35g,
5.0Hz), 3.88 (1H, dd, J=10.0, 4.0Hz), 5.16 (1H, dddd, J=5.0, 1.4mmol) at rt and the reaction mixture was stirred for 2h at
4.0, 2.0, 2.0Hz), 6.19 (1H, dd, J=6.0, 2.0Hz), 7.65 (1H, dd, rt. Additional DMAP (0.4g, 1.4mmol) was added to the above
J=6.0, 2.0Hz). Anal. Calcd for C5H6O3: C, 52.63; H, 5.30. reaction mixture and the reaction mixture was stirred for 2h
Found: C, 52.40; H, 5.42. MS (FAB) m/z: 115 (M++1).
at rt. The reaction mixture was diluted with brine and extract-
γ-Lactonization from (4S,5R)- and (4S,5R)-4,5-Dihy- ed with Et2O. The organic layer was washed with 7% NaHCO3
droxy-(2E)-hexenoic Acid (23) (Synthesis of (4S,5R)- and solution and dried over MgSO4.The organic solvent was evap-
(4R,5S)-3) (Chart 5) i) To a mixture of AlCl3 (2.05g, orated to give a residue, which was chromatographed on silica
15.2mmol) in CH2Cl2 (15mL) was added a solution of (4S,5R)- gel (20g, n-hexane–AcOEt=5:1) to give (S)-1 (0.078g, 58%
11 (0.961g, 3.8mmol) in m-xylene (2mL) at 0°C and the reac- overall yield from (S)-24). (S)-1: [α]D21 +134.9 (c=0.44, EtOH),
1
tion mixture was stirred for 15min at the same temperature. IR (neat): 1724, 1390cm−1; H-NMR δ: 1.39 (3H, d, J=7.0Hz),
The reaction mixture was worked up in the same way as for 2.25 (1H, dddd, J=18.0, 11.0, 2.0, 2.0Hz), 2.32 (1H, dddd,
(±)-13 to give (4S,5R)-13 (0.530g, 86%). (4S,5R)-13: [α]D25 J=18.0, 6.0, 3.0, 1.0Hz), 4.52 (1H, ddq, J=11.0, 7.0, 3.0Hz),
1
−19.9 (c=0.58, CHCl3). The spectral data (IR and H-NMR) 5.96 (1H, ddd, J=10.0, 2.0, 1.0Hz), 6.83 (1H, ddd, J=10.0, 6.0,
of (4S,5R)-13 were identical with those of (±)-13. The anti- 1.0Hz). Anal. Calcd for C6H8O2: C, 62.27; H, 7.19. Found: C,
pode (4R,5S)-13 (0.397g) was also obtained from (4R,5S)-11 61.99; H, 7.35. MS (FAB) m/z: 112 (M++1).
(0.835g, 3.3mmol) in 74% yield. (4R,5S)-13: [α]D25 +20.1
δ-Lactonization from (5R,7S)-5,7-Dihydroxy-(2E)-oc-
(c=0.47, CHCl3). The spectral data (1H-NMR) of (4R,5S)-13 tenoic Acid (29) (Synthesis of (5R,7S)-Euscapholide (4))
were identical with those of (±)-13. (Chart 6) i) To a solution of (S)-24 (0.969g, 6.7mmol) in
ii) To a solution of (4S,5R)-13 (0.480g, 3.0mmol) in THF anhydrous THF (50.0mL) was added benzaldehyde (0.71g,
(6.0mL) was added 2M NaOH solution (3mL) and the reaction 6.7mmol) and tert-BuOK (0.075g, 0.67mmol) for 15min
mixture was stirred for 1h at rt. The reaction mixture was at 20°C. This procedure was totally carried out three times
acidified with 2M HCl solution and extracted with Et2O. The and the reaction mixture was stirred for 2h at the same tem-
organic layer was dried over MgSO4 and evaporated to give perature. To the reaction mixture was added phosphate buffer
a crude (4S,5R)-23 (0.442g, quantitative yield), which was (pH=7) solution (80mL) and the reaction mixture was stirred
used for next reaction without further purification. (4S,5R)-23; for 10min. The reaction mixture was condensed to half vol-
1
[α]D26 −33.9 (c=0.49, CHCl3), H-NMR (CD3OD) δ: 1.17 (3H, ume and extracted with Et2O. The organic layer was dried
dd, J=6.0Hz), 3.70 (1H, qt, J=6.0, 6.0Hz), 4.06 (1H, ddd, over MgSO4 and evaporated to give a residue, which was
J=6.0, 6.0, 2.0Hz), 6.04 (1H, dd, J=16.0, 2.0Hz), 7.04 (1H, chromatographed on silica gel (30g, n-hexane–AcOEt=25:1)
dd, J=16.0, 6.0Hz). MS (FAB) m/z: 145 (M++1). The anti- to afford (3S,5S)-26 (1.124g, 67%) as a colorless oil. (3S,5S)-
pode (4R,5S)-23 (0.075g) was also obtained from (4R,5S)-13 26; IR (neat): 1724, 1659cm−1; [α]D25 +37.5 (c=0.46, MeOH);
(0.091g, 0.6mmol). (4R,5S)-23: [α]D29 +30.3 (c=0.31, CHCl3). 1H-NMR (CDCl3) δ: 1.32 (3H, d, J=7.0Hz), 1.42 (1H, ddd,
The spectral data (1H-NMR) of (4R,5S)-23 were identical with J=12.0, 12.0, 13.0Hz), 1.71 (1H, ddd, J=12.0, 3.0, 3.0Hz), 2.50
those of (4S,5R)-23.
(1H, dd, J=6.0, 6.0Hz), 2.73 (1H, dd, J=6.0, 6.0Hz), 3.68 (3H,
iii) To a solution of (4S,5R)-23 (0.399g, 2.7mmol) in s), 3.97 (1H, ddq, J=13.0, 7.0, 3.0Hz), 4.30 (1H, dddd, J=12.0,
pyridine (10mL) were added 2,4,6-trichlorobenzoyl chloride 6.0, 6.0, 3.0Hz), 5.55 (1H, s), 7.28–7.37 (3H, m), 7.46–7.51 (2H,
(0.72g, 3.0mmol) at 0°C and the reaction mixture was stirred m). Anal. Calcd for C14H18O4: C, 67.18; H, 7.25. Found: C,
for 1h at rt. The reaction mixture was evaporated to give 66.98; H, 7.46. MS (FAB) m/z: 251 (M++1).
a residue, which was chromatographed on silica gel (50g,
ii) To a solution of (3S,5S)-26 (1.001g, 4.0mmol) in

470
Vol. 61, No. 4
anhydrous toluene (50.0mL) under argon atmosphere was 6.99 (1H, dt, J=16.0, 7.0Hz).
added a solution of 1M diisobutylaluminum hydride (Dibal-H)
iv) To a solution of (5R,7S)-29 (0.082g, 0.5mmol) in pyri-
in toluene solution (5.0mL) at −78°C and the reaction mixture dine (10mL) were added a solution of 2,4,6-trichlorobenzoyl
was stirred for 1h at the same temperature. The reaction mix- chloride (0.16g, 0.7mmol) in CH2C2 (0.3mL) and the reaction
ture was diluted with H2O (5mL) and Et2O (50mL) at 0°C and mixture was stirred for 2.5h at rt. The reaction mixture was
stirred for 30min. To the above reaction mixture was added treated with 7% aqueous NaHCO3 solution (3mL) and stirred
2M HCl solution (20mL) and reaction mixture was stirred for 20min. The reaction mixture was evaporated to give a res-
for 40min. The reaction mixture was extracted with Et2O. idue, which was dissolved with a mixed solvent (Et2O (5.0mL)
The organic layer was dried over MgSO4 and evaporated to and AcOEt (2mL)). The organic solvent soluble part by filtra-
give a crude aldehyde (0.849g), which was used for the next tion was dried over MgSO4 and evaporated to afford a resi-
reaction without further purification. To a mixture of LiCl due, which was chromatographed on silica gel (20g, CHCl3–
(0.17g, 4mmol) in CH3CN (20mL) at 0°C was added a solu- MeOH=25:1) to provide (5R,7S)-4 (0.041g, 45% overall yield
tion of trimethylphosphonoacetate ((MeO)2P(O)CH2COOMe; from (5R,7S)-27) as a homogeneous oil. (5R,7S)-4: [α]D22 113.5
0.73g, 4.0mmol) in CH3CN (20mL) at 0°C and the reaction (c=0.10, MeOH), IR (CHCl3): 3420, 1700, 1230, 1200cm−1;
mixture was stirred for 15min. To the above reaction mixture 1H-NMR (CDCl3) δ: 1.24 (3H, d, J=6.0Hz), 1.74 (1H, ddd,
was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 0.91g, J=15.0, 5.0, 4.0Hz), 1.99 (1H, dt, J=15.0, 8.0Hz), 2.39 (2H,
6.0mmol) in CH3CN (20mL) and the reaction mixture was m), 4.07 (1H, m), 4.63 (1H, m), 6.00 (1H, dt, J=10.0, 2.0Hz),
stirred for 15min. To the above reaction mixture was added 6.88 (1H, ddd, J=10.0, 5.5, 3.5Hz). 13C-NMR (CD3OD) δ:
a solution of the above aldehyde (0.849g) in CH3CN (25mL) 166.4 (s), 148.3 (d), 121.3 (d), 77.5 (d), 64.8 (d), 44.7 (t), 30.2
at 0°C and the reaction mixture was stirred for 12h at rt. The (t), 23.6 (q). Anal. Calcd for C8H12O3: C, 61.52; H, 7.74. Found:
reaction mixture was diluted with saturated NH4Cl solution C, 61.77; H, 7.44. MS (FAB) m/z: 157 (M++1). The spectral
(40mL) and a whole mixture was condensed to half volume. data (1H- and 13C-NMR) of synthetic (5R,7S)-4 were identical
It was extracted with Et2O. The organic layer was dried over with those of the reported (5R,7S)-4.
MgSO4 and evaporated to give a residue, which was chro-
matographed on silica gel (20g, n-hexane–AcOEt=10:1) to
Acknowledgement The authors are grateful to Profes-
afford (5R,7S)-27 (0.744g, 67%) as a colorless oil. (5R,7S)-27; sor Shigeo Yamamura, Josai International University for the
1
IR (KBr): 1736cm−1; [α]D26 +45.7 (c=0.52, MeOH); H-NMR calculations of the heat of formation of γ-lactones (±)-3 and
(CDCl3) δ: 1.30 (3H, d, J=7.0Hz), 1.42 (1H, ddd, J=13.0, 13.0, δ-lactones (±)-2.
11.0Hz), 1.61 (1H, ddd, J=13.0, 3.0, 3.0Hz), 2.40–2.47 (1H,
m), 2.51–2.61 (1H, m), 3.72 (3H, s), 3.89–3.98 (2H, m), 5.50
(1H, s), 5.91 (1H, dt, J=16.0, 12.0Hz), 7.00 (1H, dd, J=16.0,
7.0Hz), 7.32–7.50 (5H, m). Anal. Calcd for C16H20O4: C, 69.54;
H, 7.30. Found: C, 69.17; H, 7.53. MS (FAB) m/z: 277 (M++1).
iii) To a solution of (5R,7S)-27 (0.162g, 0.6mmol) in iso-
PrOH (10.0mL) was added 2M NaOH solution (2.0mL) at
0°C and the reaction mixture was stirred for 12h at rt. The
reaction mixture was condensed to half volume and acidi-
fied with 2M HCl solution (5.0mL) and extracted with Et2O.
The organic layer was dried over MgSO4 and evaporated to
give a crude (5R,7S)-28 (0.154g, quantitative yield), which
was used for next reaction without further purification. To a
solution of (5R,7S)-28 (0.154g) in H2O (8.0mL) and dioxane
(8.0mL) was added Dowex 50W (H+) (1.0g) and the reaction
mixture was stirred for 1.5h at 130°C. The reaction mixture
was filtered and the filtrate was evaporated to afford a crude
(5R,7S)-29 (0.082g, 80% yield from (5R,7S)-27), which was
used for the next reaction without further purification. (5R,7S)-
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1
29; H-NMR (CDCl3) δ: 1.16 (3H, d, J=7.0Hz), 1.52 (1H, ddd,
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J=14.0, 5.0, 5.0Hz), 1.62 (1H, ddd, J=14.0, 8.0, 8.0Hz), 2.34
(1H, dddd, J=14.0, 7.0, 7.0, 2.0Hz), 2.43 (1H, dddd, J=14.0,
7.0, 5.0, 2.0Hz), 3.88 (1H, dddd, J=8.0, 7.0, 5.0, 5.0Hz), 3.93
(1H, ddq, J=8.0, 7.0, 6.0Hz), 5.86 (1H, dt, J=16.0, 2.0Hz),