Synthesis of both enantiomers of methylenolactocin, nephrosterinic acid and protolichesterinic acid via tandem aldol-lactonization reactions

Article abstract of DOI:10.1016/S0957-4166(01)00345-7

Both forms of the enantiomerically pure methylenolactocin, nephrosterinic and protolichesterinic acid have been synthesized via tandem aldol-lactonization reactions from corresponding optically active itaconate-anthracene adducts.

Full text of DOI:10.1016/S0957-4166(01)00345-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1913–1922
Synthesis of both enantiomers of methylenolactocin,
nephrosterinic acid and protolichesterinic acid via tandem
aldol–lactonization reactions
Palangpon Kongsaeree,a Puttinan Meepowpana and Yodhathai Thebtaranontha,b,
*
aDepartment of Chemistry, Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand
bNational Center for Genetic Engineering and Biotechnology (BIOTEC)/National Science and Technology Development Agency
(NSTDA), Rama 6 Road, Bangkok 10400, Thailand
Received 3 July 2001; accepted 1 August 2001
Abstract—Both forms of the enantiomerically pure methylenolactocin, nephrosterinic and protolichesterinic acid have been
synthesized via tandem aldol–lactonization reactions from corresponding optically active itaconate–anthracene adducts. © 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
reported the synthesis of racemic 1a–1c employing
tandem aldol–lactonization reactions of dimethyl ita-
conate–anthracene adduct, ( )-2,8 as the starting mate-
rial and the process is outlined in Scheme 1. We now
report the synthesis of both (−)-1a–1c and (+)-1%a–1%c
by using optically pure (+)-2 and (−)-2% as starting
blocks.
Methylene-g-butyrolactone moiety is a core skeleton in
many structurally complex natural products.1 Disubsti-
tuted a-methylene-g-butyrolactones, for examples
methylenolactocin 1a,2,3 nephrosterinic acid 1b,4 and
protolichesterinic acid 1c,5,6 (Fig. 1) are noted for their
biological activities, being antibacterial,7a–h antifun-
gal,7b antitumor,7h and, in certain cases, growth regulat-
ing agents.7i
2. Results and discussion
Although there is a report describing the isolation of
(+)-protolichesterinic acid from Cetraria islandica and
Parmelia sinodensis, the absolute stereochemistry of
compounds in this class was later proved by synthesis
to be (2S,3R) as shown in (−)-1. We have recently
Enantiomerically pure (+)-2 and (−)-2% were prepared
by partial hydrolysis of ( )-2 with KOH (1.3 equiv.) in
MeOH:H2O (2:1) followed by treatment of the resulting
monoacid with (−)-(1R,2S,5R)-menthol in the presence
of a catalytic amount of dimethylformamide in thionyl
Figure 1.
* Corresponding author. Tel.: +66-2-246-0063 ext. 1306; fax: +66-2-245-8332; e-mail: scytr@mucc.mahidol.ac.th
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00345-7

1914
P. Kongsaeree et al. / Tetrahedron: Asymmetry 12 (2001) 1913–1922
Scheme 1. Reagents and conditions: (i) (a) 1.2 equiv. LDA, THF, −78 to 0°C 2 h; (ii) (a) 1.2 equiv. RCHO, 0°C to rt 3 h, (b) aq.
NH4Cl, 30% HCl; (iii) 0.5 equiv. NaOMe, THF:MeOH (2:1), rt 6 days; (iv) FVP; (v) 2-butanone, 6N HCl, reflux 2 h.
chloride solution to provide the crude diastereomeric
mixture which upon purification by column chromatog-
raphy (silica gel, using EtOAc:acetone:hexane=
0.5:0.3:9.2 as eluent) yielded almost pure (−)-6 and (−)-7.
Crystallization of (−)-6 and (−)-7, respectively, from ethyl
acetate–hexane and methanol gave pure (−)-6 (34%), as a
white powder (mp 185–187°C, >99% d.e.,9 [h]D30=−109.0
(c, 1.29, CHCl3)) and (−)-7 (34%), as white crystals (mp
101–103°C, >99% d.e.,9 [h]D30=−51.4 (c, 1.20, CHCl3))
(Scheme 2). The absolute stereochemistry at the C(11)
stereogenic center of (11R)-7 (and hence (−)-2%) was
determined by X-ray crystallographic analysis and its
PLATON drawing is shown in Fig. 2.10
Due to the low yield of the lactone 8 obtained from the
tandem aldol–lactonization reactions of 6 as compared to
that previously observed when the corresponding
dimethyl ester ( )-2 was employed, the mixed esters 6 and
7 were converted to their corresponding dimethyl ester
adducts, (+)-2 and (−)-2%, respectively.
Transmethylation of (−)-6 and (−)-7 was effected by
refluxing their methanol solutions in the presence of
catalytic sulfuric acid, followed by flash column chro-
matographic purification to yield, respectively homo-
chiral (+)-2 and (−)-2%, in 95% (>99% e.e.,11 [h]D29=+38.7
(c, 1.06, CHCl3)) and 89% (>99% e.e.,11 [h]D29=−39.0 (c,
1.18, CHCl3)), respectively (Scheme 2). The enantio-
meric excesses of (+)-(11S)-2 and (−)-(11R)-2% were deter-
Due to the failure to obtain good quality crystals for X-
ray analysis, (−)-6 was converted to the corresponding
lactone 8 via the tandem aldol–lactonization with
capronaldehyde under the conditions previously
reported.8e The spiro–lactone product, (−)-8, obtained as
white crystals (mp 205–206°C (from dichloro-
methane/hexane), [h]D31=−179.5 (c, 0.40, CHCl3), 34%
purified yield), was subjected to X-ray analysis and its
absolute configuration was determined (Scheme 3, Fig.
3).10 The X-ray result unequivocally established the (S)-
absolute configuration at C(11) for (−)-6, and thus (+)-2.
1
mined by H NMR using the chiral lanthanide shift
reagent, tris[3-(heptafluoropropylhydroxymethylene)-d-
camphorato]praseodymium(III), (Pr(hfc)3).
The tandem aldol–lactonization of (+)-2 with 1.2 equiv.
of capronaldehyde was then carried out according to the
published procedure8e to produce enantiomerically pure
spiro–lactones, 4a-i–4a-iv, in 19, 65, 7 and 2%, respec-
tively. Also, (+)-2 was allowed to react with
Scheme 2. Reagents and conditions: (i) 1.3 equiv. KOH, MeOH:H2O (2:1), reflux 2 h, (97%); (ii) (a) 5.0 equiv. SOCl2, DMF (cat.),
N2, reflux 2 h, (b) 1.3 equiv. (−)-(1R,2S,5R)-menthol, 1.3 equiv. NEt3, benzene, reflux 2 h ((−)-6, 34%; (−)-7, 34%); (iii) excess
anhydrous MeOH, H2SO4 (cat.), reflux 6 days ((+)-2, 95%; (−)-2%, 89%).

P. Kongsaeree et al. / Tetrahedron: Asymmetry 12 (2001) 1913–1922
1915
Figure 2. PLATON plot of (−)-(11R)-7.
Scheme 3.
n-dodecanal and n-tetradecanal to give 4b-i–4b-iv (in
20, 63, 7 and 1%) and 4c-i–4c-iv (in 18, 62, 7 and 2%),
respectively whose results are shown in Table 1. Similar
experiments were conducted with (−)-2% and results are
summarized in Table 2.
4a-iv, (+)-4b-iv and (+)-4c-iv (Table 4). Under the same
conditions, (2R,3S)-5%a, (2R,3S)-5%b and (2R,3S)-5%c
were obtained from (−)-4%a-iv, (−)-4%b-iv and (−)-4%c-iv
(Table 4).
Subsequent hydrolysis of (2S,3R)-5a by refluxing in
2-butanone with a catalytic amount of conc. HCl
afforded (−)-methylenolactocin, 1a in 69% yield (mp
82–83°C, [h]D29=−11.6 (c, 0.31 in CHCl3) and [h]3D2=
−8.5 (c, 0.31 in MeOH)). Hence, (−)-nephrosterinic
acid, 1b, (79%, mp 86–88°C, [h]3D2=−10.9 (c, 0.68 in
CHCl3) and [h]3D2=−7.2 (c, 0.39 in MeOH)) and (−)-
protolichesterinic acid, 1c, (70%, mp 101–103°C, [h]3D2=
−10.4 (c, 0.46 in CHCl3) and [h]3D1=−8.9 (c, 0.18 in
MeOH)) were obtained (Table 5).
The isomerization of the major products, cis-isomers,
(−)-4a-ii–(−)-4c-ii, was affected by treatment with
NaOMe (0.5 equiv.) in the solution of THF:MeOH
(5:1) to furnish the required trans-(+)-4a-iv–(+)-4c-iv in
good yields (Table 3). Similarly, (+)-4%a-ii, (+)-4%b-ii and
(+)-4%c-ii gave (−)-4%a-iv, (−)-4%b-iv and (−)-4%c-iv, respec-
tively and the results are displayed in Table 3.
Methyl esters of methylenolactocin, (2S,3R)-5a,
nephrosterinic acid, (2S,3R)-5b, and protolichesterinic
acid, (2S,3R)-5c, were obtained in 89, 77 and 75%
yields, respectively upon flash vacuum pyrolysis of (+)-
The syntheses of (+)-1%a, (+)-1%b and (+)-1%c were also
achieved in the same manner (Table 5).

1916
P. Kongsaeree et al. / Tetrahedron: Asymmetry 12 (2001) 1913–1922
Figure 3. PLATON plot of (−)-(11S)-8.
Table 1. Yields of products, 4-i–4-i6, from tandem aldol–lactonization reactions of (+)-2
Entry
R
Enantiomeric spiro–lactone adducts, 4-i–4-i6
i (%)
19
[h]a
ii (%)
65
[h]a
iii (%)
[h]a
i6 (%)
[h]a
1
2
3
a
+94.2
+78.5
+73.1
–136.7
–115.4
–103.2
7
7
7
+61.2
+53.8
+48.5
2
1
2
+4.6
+1.8
+0.8
n-C5H11
b
n-C11H23
c
20
63
18
62
n-C13H27
a The specific rotations were measured in CHCl3.
3. Conclusion
4. Experimental
Enantiomerically pure dimethyl itaconate–anthracene
adducts, (+)-(11S)-2 and (−)-(11R)-2%, were obtained
from resolution of the racemates which involved forma-
tion and separation of the mixed ester, 6 and 7.
Tandem aldol–lactonization reactions of (+)-(11S)-2
and (−)-(11R)-2% gave corresponding lactone–anthra-
cene adducts, 4, which upon pyrolysis provided 1a–1c
in enantiomerically pure form.
4.1. General methods
Melting points were determined using an Electrother-
1
mal Melting Point apparatus and are uncorrected. H
NMR and 13C NMR spectra were recorded on Bruker
DPX 300 and 400 MHz spectrometers. All NMR spec-
tra were measured in CDCl3, and chemical shift are
expressed in ppm relative to internal TMS. Infrared

P. Kongsaeree et al. / Tetrahedron: Asymmetry 12 (2001) 1913–1922
1917
Table 2. Yields of products, ent-(4%-i–4%-i6), from tandem aldol–lactonization reactions of (−)-2%
Entry
R
Enantiomeric spiro–lactone adducts, ent-(4%-i–4%-i6)
i (%)
20
[h]a
ii (%)
72
[h]a
iii (%)
[h]a
i6 (%)
[h]a
1
2
3
a
−88.6
−76.1
−72.2
+134.9
+117.1
+107.3
6
4
7
−57.5
−50.1
−49.3
2
1
2
−4.3
−1.5
−0.5
n-C5H11
b
n-C11H23
c
16
57
27
76
n-C13H27
a The specific rotations were measured in CHCl3.
Table 3. Yields of products, (+)-(4%R,5%S,11R)-4-i6 and (−)-(4%S,5%R,11S)-4%-i6, from isomerization
Entry
R
(+)-(4%R,5%S,11R)-4-i6 (%)
(−)-(4%S,5%R,11S)-4%-i6 (%)
1
2
3
a: n-C5H11
b: n-C11H23
c: n-C13H27
84
75
79
65
89
83
Table 4. Yields of products, (2S,3R)-5 and (2R,3S)-5%,
from flash vacuum pyrolysis
chiral lanthanide shift reagent, tris[3-(heptafluoro-
propylhydroxymethylene) - d - camphorato]praseody-
mium(III), Pr(hfc)3.
4.2. Resolution of optically active dimethyl itaconate–
anthracene adduct, 2
4.2.1.
(−)-11-Carbomethoxy-11-[(−)-menthoxyacetyl]-
9,10-dihydro-9,10-ethanoanthracenes, (11S)-6 and (11R)-
7. A solution of KOH (0.111 g, 1.98 mmol) in H2O (15
mL) was added to a solution of ( )-dimethyl itaconate–
anthracene adduct, 2 (0.555 g, 1.65 mmol), in MeOH
(30 mL) and heated under reflux for 2 h. The cooled
reaction mixture was diluted with water (15 mL) and
acidified to pH 2–3 by 30% HCl, then extracted with
CH2Cl2, dried over MgSO4, filtered and evaporated to
dryness. The crude product was crystallized from
CH2Cl2–hexane to give the corresponding ( )-monoacid
(0.516 g, 97%) as white crystals; mp 207–208°C. A
mixture of the monoacid (0.516 g, 1.60 mmol), thionyl
chloride (0.7 mL, 9.60 mmol) and dimethyl formamide
(as catalyst) was heated under reflux for 2 h and the
solvent was removed under reduced pressure. The mix-
ture of the acid chloride obtained, benzene (20 mL),
triethylamine (0.3 mL, 1.92 mmol) and (−)-menthol
(0.3002 g, 1.92 mmol) was heated under reflux for 2 h,
filtered through Celite 545, diluted with H2O and
extracted with CH2Cl2. The solution was washed with
H2O, saturated NaCl solution, dried over MgSO4,
filtered and evaporated to dryness. The crude product
was purified by flash column chromatography (silica
gel) using EtOAc:acetone:hexane=0.5:0.3:9.2 as eluent
to give two diastereoisomers, (−)-6 (0.252 g, 34%, >99%
d.e.) as a white powder; mp 185–187°C and (−)-7 (0.250
g, 34%, >99% d.e.) as a white crystalline solid; mp
101–103°C.
Entry
R
(2S,3R)-5 (%)
(2R,3S)-5% (%)
1
2
3
a: n-C5H11
b: n-C11H23
c: n-C13H27
89
77
75
79
78
74
spectra were recorded on a FT-IR system 2000 (Perkin–
Elmer) spectrometer. Elemental analyses were per-
formed on a Perkin–Elmer Elemental Analyzer 2400
CHN and mass spectra were recorded on Bruker
Esquire and Finnigan MAT INCOS 50 mass spectrom-
eters. The electrospray-ion trap mass spectra were
recorded on Bruker mass spectrometer and the electro-
spray-time of flight mass spectra was recorded on
Perkin–Elmer (Mariner) mass spectrometer. Merck sil-
ica gel 60 PF254 was used for PLC, Merck silica gel 60
and Merck silica gel 60H were employed for the flash
column chromatography. Solvents were distilled before
use. Dried, oxygen-free THF (distilled from sodium/
benzophenone) was used in all experiments. Lithium
diisopropylamide (LDA) was prepared by the conven-
tional method using n-butyllithium (purchased from
Metallgesellschaft AG, molarity was determined by
titration with 2,5-dimethoxybenzyl alcohol) and diiso-
propylamine in THF solution. Enantiomeric excesses
1
were determined by H NMR spectroscopy using the

1918
P. Kongsaeree et al. / Tetrahedron: Asymmetry 12 (2001) 1913–1922
Table 5. Yields of products, (−)-(2S,3R)-1 and (+)-(2R,3S)-1%, from hydrolysis
Entry
R
(−)-(2S,3R)-1
[h]
(+)-(2R,3S)-1%
[h]
(%)
69
(%)
66
1
2
3
a: n-C5H11
b: n-C11H23
c: n-C13H27
[h]2D9=−11.6
[h]3D0=+16.6
(c, 0.31, in CHCl3)
(c, 0.33, in CHCl3)
[h]3D2=−8.5
[h]3D2=+7.4
(c, 0.31, in MeOH)
[h]3D2=−10.9
(c, 0.33, in MeOH)
[h]3D2=+13.0
79
70
81
72
(c, 0.68, in CHCl3)
(c, 0.66, in CHCl3)
[h]3D2=−7.2
[h]3D2=+7.5
(c, 0.39, in MeOH)
[h]3D2=−10.4
(c, 0.43, in MeOH)
[h]3D2=+11.2
(c, 0.46, in CHCl3)
(c, 0.50, in CHCl3)
[h]3D1=−8.9
[h]3D1=+10.0
(c, 0.18, in MeOH)
(c, 0.24, in MeOH)
Compound (11S)-6: White powder, mp 185–187°C
(from EtOAc/hexane); [h]3D0=−109.0 (c, 1.29, CHCl3).
IR (KBr-pellet), wmax 3072, 3038, 2949, 2866, 1729,
added, and the mixture neutralized with aqueous
NaHCO3 solution, then extracted with CH2Cl2, washed
with H2O, dried over MgSO4, filtered and evaporated
to dryness. The crude product was recrystallized from
EtOAc/hexane to give optically active adduct, (+)-2
(0.1210 g, 95% yield, >99% e.e.) as white crystals; mp
154–155°C; [h]2D9=+38.7 (c, 1.06, CHCl3) whose IR, 1H,
13C NMR and mass spectral data are identical to those
previously published.8a
1
1460, 1432, 1371, 1220, 1198, 1167, 764, 751 cm−1. H
NMR (400 MHz, CDCl3): l 0.73 (d, J 7.0 Hz, 3H),
0.76–1.93 (m, 9H), 0.88 (d, J 6.5 Hz, 1H), 0.89 (d, J 7.0
Hz, 3H), 1.51, 2.84, 4.35 (ABX system, J 13.0, 3.0, 2.4
Hz, 3H), 1.96 (d, J 16.2 Hz, 1H), 2.94 (d, J 16.2 Hz,
1H), 3.49 (s, 3H), 4.37 (s, 1H), 4.62 (ddd, J 10.9, 10.9,
4.4 Hz, 1H), 7.05–7.34 (m, 8H). 13C NMR (100 MHz,
CDCl3): l 16.1, 20.8, 22.0, 23.2, 34.2, 40.9, 26.0, 31.4,
37.1, 44.2, 45.0, 50.3, 52.1, 53.0, 74.7, 123.4, 123.6, 14.3,
125.8, 126.5, 126.6, 139.8, 140.2, 142.9, 143.8, 170.7,
174.8. m/z (EIMS) 460 (M+, 0.1%), 322 (0.2), 215 (2),
202 (2), 178 (100), 322 (1). m/z (ESITOF-MS) 461.2686
(M+H)+, calcd for C30H36O4 461.2692.
4.2.3. (11R)-11-Carbomethoxy-11-methoxyacetyl-9,10-
dihydro-9,10-ethanoanthracene, (−)-2%. Under the same
conditions, the adduct (−)-7 provided (−)-2% (89% yield,
>99% e.e.) as white crystals; mp 154–155°C; [h]2D9=
1
−39.0 (c, 1.18, CHCl3) whose IR, H, 13C NMR and
mass spectral data are identical to those previously
published.8a
Compound (11R)-7: White crystals; mp 101–103°C
(from methanol); [h]3D0=−51.4 (c, 1.20, CHCl3). IR
(CHCl3), wmax 3068, 3040, 3025, 2943, 2868, 1748, 1732,
1468, 1457, 1389, 1370, 1235, 1218, 1185, 766, 749
4.3. Preparation of optically pure tetrahydro-4%-carbo-
methoxy-5%-n-alkyl-2%-furanone-3%-spiro-11-9,10-dihydro-
9,10-ethanoanthracenes, 4-i–4-iv, from (+)-2
1
cm−1. H NMR (400 MHz, CDCl3): l 0.70 (d, J 7.0 Hz,
Typical procedure
3H), 0.77–1.94 (m, 9H), 0.86 (d, J 7.0 Hz, 3H), 0.90 (d,
J 6.6 Hz, 3H), 1.47, 2.83, 4.34 (ABX system, J 13.0, 3.1,
2.3 Hz, 3H), 1.96 (d, J 15.8 Hz, 1H), 2.98 (d, J 15.8 Hz,
1H), 3.50 (s, 3H), 4.37 (s, 1H), 4.62 (ddd, J 10.9, 10.9,
4.4 Hz, 1H), 7.06–7.34 (m, 8H). 13C NMR (100 MHz,
CDCl3): l 16.0, 20.8, 22.0, 23.1, 34.2, 44.9, 25.9, 30.4,
36.7, 40.7, 44.2, 46.8, 50.5, 52.1, 53.0, 74.7, 123.3, 123.6,
124.2, 125.78, 125.82, 126.5, 126.7, 139.7, 140.3, 142.8,
143.8, 170.5, 174.8. m/z (EIMS) 460 (M+, 1%), 215 (3),
202 (4), 178 (100). m/z (ESITOF-MS) 461.2697 (M+H)+,
calcd for C30H36O4 461.2692.
4.3.1. Tetrahydro-4%-carbomethoxy-5%-n-pentyl-2%-fura-
none-3%-spiro-11-9,10-dihydro-9,10-ethanoanthracenes,
4a-i–4a-iv. A solution of (11S)-dimethyl itaconate–
anthracene adduct, (+)-2 (0.549 g, 1.63 mmol) in THF
(15 mL) was introduced to the LDA solution (1.96
mmol in THF 5 mL, prepared by the standard method)
at −78°C, then stirred at 0°C for 2 h. Freshly distilled
capronaldehyde (0.24 mL, 1.96 mmol) was added to the
anion solution at −78°C after which the reaction mix-
ture was stirred at room temperature for 3 h. The
reaction mixture was quenched with saturated aqueous
ammonium chloride solution at 0°C and the crude
mixture was extracted several times with CH2Cl2. The
dichloromethane solution was washed with H2O, satu-
rated NaCl solution, then dried over MgSO4, filtered
and evaporated to dryness.
4.2.2. (11S)-11-Carbomethoxy-11-methoxyacetyl-9,10-
dihydro-9,10-ethanoanthracene, (+)-2. To a solution of
(−)-6 (0.174 g, 0.38 mmol) in excess anhydrous MeOH
(60 mL) was added conc. H2SO4 (1 mL) and the
mixture was heated under reflux for 7 days. H2O was

P. Kongsaeree et al. / Tetrahedron: Asymmetry 12 (2001) 1913–1922
1919
The crude product was purified by flash column chro-
matography (silica gel) using EtOAc:acetone:hexane=
1:0.5:8.5 as eluent to give enantiomeric spiro–lactones,
tetrahydro-4%-carbomethoxy-5%-n-pentyl-2%-furanone-3%-
spiro-11-9,10-dihydro-9,10-ethanoanthracenes, 4a-i–4a-
iv in 19% (0.120 g), 65% (0.420 g), 7% (0.047 g) and 2%
(0.011 g), respectively.
Compound (4%S,5%S,11R)-4c-ii (62%): White crystals,
mp 165–166°C (from CH2Cl2–hexane); [h]3D0=−103.2 (c,
1
1.12, CHCl3) whose IR, H, 13C NMR and mass spec-
tral data are identical to those previously published.8e
Compound (4%S,5%R,11R)-4c-iii (7%): White crystals,
mp 84–85°C (from hexane); [h]2D9=+48.5 (c, 1.08,
CHCl3) whose IR, 1H, 13C NMR and mass spectral
data are identical to those previously published.8e
Compound (4%R,5%R,11R)-4a-i: White crystals, mp 144–
146°C (from hexane); [h]3D1=+94.2 (c, 0.86, CHCl3)
1
whose IR, H, 13C NMR and mass spectral data are
Compound (4%R,5%S,11R)-4c-iv (2%): White crystals,
mp 86–87°C (from hexane); [h]3D0=+0.8 (c, 0.77, CHCl3)
identical to those previously published.8e
1
whose IR, H, 13C NMR and mass spectral data are
Compound (4%S,5%S,11R)-4a-ii: White crystals, mp 210–
212°C (from CH2Cl2–hexane); [h]2D8=−136.7 (c, 1.16,
CHCl3) whose IR, 1H, 13C NMR and mass spectral
data are identical to those previously published.8e
identical to those previously published.8e
4.4. Preparation of optically pure tetrahydro-4%-carbo-
methoxy-5%-n-alkyl-2%-furanone-3%-spiro-11-9,10-dihydro-
9,10-ethanoanthracenes, 4%-i–4%-iv, from (−)-2%
Compound (4%S,5%R,11R)-4a-iii: White crystals, mp
118–119°C (from hexane); [h]3D0=+61.2 (c, 0.92, CHCl3)
1
whose IR, H, 13C NMR and mass spectral data are
4.4.1. Tetrahydro-4%-carbomethoxy-5%-n-pentyl-2%-fura-
none-3%-spiro-11-9,10-dihydro-9,10-ethanoanthracenes,
4%a-i–4%a-iv. Enantiomeric isomers, 4%a-i–4%a-iv were
obtained when capronaldehyde and (11R)-dimethyl ita-
conate–anthracene adduct, (−)-2% were employed as in
the typical procedure in Section 4.3.1.
identical to those previously published.8e
Compound (4%R,5%S,11R)-4a-iv: White crystals, mp 83–
85°C (from hexane); [h]3D0=+4.6 (c, 1.12, CHCl3) whose
1
IR, H, 13C NMR and mass spectral data are identical
to those previously published.8e
Compound (4%S,5%S,11S)-4%a-i (20%): White crystals;
mp 144–146°C (from hexane); [h]3D2=−88.6 (c, 0.88,
CHCl3) whose IR, 1H, 13C NMR and mass spectral
data are identical to those previously published.8e
4.3.2. Tetrahydro-4%-carbomethoxy-5%-n-undecyl-2%-fura-
none-3%-spiro-11-9,10-dihydro-9,10-ethanoanthracenes,
4b-i–4b-iv. Compounds 4b-i–4b-iv were obtained when
laurinaldehyde was employed as in the typical procedure
in Section 4.3.1.
Compound (4%R,5%R,11S)-4%a-ii (72%): White crystals;
mp 210–212°C (from CH2Cl2–hexane); [h]2D9=+134.9 (c,
Compound (4%R,5%R,11R)-4b-i (20%): White crystals,
mp 94–95°C (from hexane); [h]3D1=+78.5 (c, 0.79,
CHCl3) whose IR, 1H, 13C NMR and mass spectral
data are identical to those previously published.8e
1
1.09, CHCl3) whose IR, H, 13C NMR and mass spec-
tral data are identical to those previously published.8e
Compound (4%R,5%S,11S)-4%a-iii (6%): White crystals;
mp 118–119°C (from hexane); [h]3D0=−57.5 (c, 1.03,
CHCl3) whose IR, 1H, 13C NMR and mass spectral
data are identical to those previously published.8e
Compound (4%S,5%S,11R)-4b-ii (63%): White crystals,
mp 159–160°C (from CH2Cl2–hexane); [h]2D9=−115.4 (c,
1
0.66, CHCl3) whose IR, H, 13C NMR and mass spec-
tral data are identical to those previously published.8e
Compound (4%S,5%R,11S)-4%a-iv (2%): White crystals;
mp 83–85°C (from hexane); [h]3D0=−4.3 (c, 1.20, CHCl3)
Compound (4%S,5%R,11R)-4b-iii (7%): White crystals,
mp 78–79°C (from hexane); [h]3D0=+53.8 (c, 0.71,
CHCl3) whose IR, 1H, 13C NMR and mass spectral
data are identical to those previously published.8e
1
whose IR, H, 13C NMR and mass spectral data are
identical to those previously published.8e
4.4.2. Tetrahydro-4%-carbomethoxy-5%-n-undecyl-2%-fura-
none-3%-spiro-11-9,10-dihydro-9,10-ethanoanthracenes,
4%b-i–4%b-iv. Compounds 4%b-i–4%b-iv were obtained
when laurinaldehyde was employed as in the typical
procedure in Section 4.3.1.
Compound (4%R,5%S,11R)-4b-iv (1%): White crystals,
mp 71–73°C (from hexane); [h]3D0=+1.8 (c, 0.66, CHCl3)
1
whose IR, H, 13C NMR and mass spectral data are
identical to those previously published.8e
4.3.3. Tetrahydro-4%-carbomethoxy-5%-n-tridecyl-2%-fura-
none-3%-spiro-11-9,10-dihydro-9,10-ethanoanthracenes,
4c-i–4c-iv. Four enantiomeric isomers, 4c-i–4c-iv were
obtained when n-tetradecanal was employed in the
reaction mentioned above.
Compound (4%S,5%S,11S)-4%b-i (16%): White crystals;
mp 94–95°C (from hexane); [h]3D0=−76.1 (c, 0.62,
CHCl3) whose IR, 1H, 13C NMR and mass spectral
data are identical to those previously published.8e
Compound (4%R,5%R,11R)-4c-i (18%): white crystals, mp
67–69°C (from hexane); [h]2D8=+73.1 (c, 1.20, CHCl3)
Compound (4%R,5%R,11S)-4%b-ii (57%): White crystals;
mp 159–160°C (from CH2Cl2–hexane); [h]3D0=+117.1 (c,
1
1
whose IR, H, 13C NMR and mass spectral data are
0.61, CHCl3) whose IR, H, 13C NMR and mass spec-
identical to those previously published.8e
tral data are identical to those previously published.8e

1920
P. Kongsaeree et al. / Tetrahedron: Asymmetry 12 (2001) 1913–1922
Compound (4%R,5%S,11S)-4%b-iii (4%): White crystals;
mp 78–79°C (from hexane); [h]3D0=−50.1 (c, 0.76,
CHCl3) whose IR, 1H, 13C NMR and mass spectral
data are identical to those previously published.8e
4.6. Flash vacuum pyrolysis of optically pure tetra-
hydro-4%-carbomethoxy-5%-n-pentyl-2%-furanone-3%-spiro-
11-9,10-dihydro-9,10-ethanoanthracenes, (+)-4a-iv
Flash vacuum pyrolysis of (+)-4a-iv (trans-isomers) by
the method previously described8c induced the retro
Diels–Alder reaction to provide methylenolactocin
methyl ester, (2S,3R)-5a ((0.377 g, 89% yield) as a
Compound (4%S,5%R,11S)-4%b-iv (1%): White crystals,
mp 71–73°C (from hexane); [h]3D0=−1.5 (c, 0.66, CHCl3)
1
whose IR, H, 13C NMR and mass spectral data are
identical to those previously published.8e
colorless oil whose IR, H, 13C NMR and mass spectral
1
data are identical to those previously published).8e
Flash vacuum pyrolysis of (+)-4b-iv and (+)-4c-iv pro-
vided the corresponding a-methylene-g-butyrolactone,
(2S,3R)-5b (77%) and (2S,3R)-5c (75%), respectively,
and, under the same reaction conditions, (2R,3S)-5%a,
(2R,3S)-5%b and (2R,3S)-5%c were obtained from (+)-4%a-
iv, (+)-4%b-iv and (+)-4%c-iv in 79, 78 and 74% yields,
respectively.
4.4.3. Tetrahydro-4%-carbomethoxy-5%-n-tridecyl-2%-fura-
none-3%-spiro-11-9,10-dihydro-9,10-ethanoanthracenes,
4%c-i–4%c-iv. Four enantiomeric isomers, 4%c-i–4%c-iv were
obtained when n-tetradecanal was employed in the
reaction mentioned above.
Compound (4%S,5%S,11S)-4%c-i (27%): White crystals,
mp 67–69°C (from hexane); [h]2D9=−72.2 (c, 1.97,
CHCl3) whose IR, 1H, 13C NMR and mass spectral
data are identical to those previously published.8e
4.7. Hydrolysis of optically pure methyl tetrahydro-4-
methylene-5-oxo-2-n-alkyl-3-furancarboxylates,
(2S,3R)-5a–c and (2R,3S)-5%a–c
Compound (4%R,5%R,11S)-4%c-ii (76%): White crystals,
mp 165–166°C (from CH2Cl2–hexane); [h]3D0=+107.3 (c,
Typical procedure
1
1.06, CHCl3) whose IR, H, 13C NMR and mass spec-
4.7.1. (2S,3R)-Tetrahydro-4-methylene-5-oxo-2-n-pen-
tyl-3-furancarboxylic acid [(−)-methylenolactocin], (−)-
1a. Acid-catalyzed hydrolysis of (2S,3R)-5a (0.101 g,
0.45 mmol), performed according to the reported
method3d using 6 M aqueous HCl in 2-butanone, pro-
vided methylenolactocin, (−)-1a (0.065 g, 69%), as white
crystals, mp 82–83°C (from EtOAc/hexane); (lit.3d mp
82–83°C (EtOAc/hexane)); [h]3D2=−8.5 (c, 0.31,
MeOH), [h]2D9=−11.6 (c, 0.31, CHCl3); (lit. [h]2D5=−2.4
(c, 3.0, MeOH),2b [h]D25=−6.8 (c, 0.5, MeOH),2b [h]D25=
−6.8 (c, 0.52, MeOH),3g [h]DT =−12.4 (c, 0.5, MeOH)3d).
1H NMR (400 MHz, CDCl3): l 0.91 (t, J 6.9 Hz, 3H),
1.28–1.60 (m, 6H), 1.67–1.85 (m, 2H), 3.65 (ddd, J 5.6,
3.0, 2.7 Hz, 1H), 4.83 (ddd, J 7.2, 7.2, 5.6 Hz, 1H), 6.04
(d, J 2.7 Hz, 1H), 6.48 (d, J 3.0 Hz, 1H), 8.66 (broad
peak, 1H), whose spectroscopic data are identical in all
respects to those reported.8e
tral data are identical to those previously published.8e
Compound (4%R,5%S,11S)-4%c-iii (7%): White crystals,
mp 84–85°C (from hexane); [h]2D9=−49.3 (c, 1.06,
CHCl3) whose IR, 1H, 13C NMR and mass spectral
data are identical to those previously published.8e
Compound (4%S,5%R,11S)-4%c-iv (2%): White crystals,
mp 86–87°C (from hexane); [h]3D1=−0.5 (c, 0.75, CHCl3)
1
whose IR, H, 13C NMR and mass spectral data are
identical to those previously published.8e
4.5. Base induced isomerization reactions of optically
pure (4%S,5%S,11R)-tetrahydro-4%-carbomethoxy-5%-n-pen-
tyl-2%-furanone-3%-spiro-11-9,10-dihydro-9,10-ethanoan-
thracenes, (−)-4a-ii
4.7.2. (2S,3R)-Tetrahydro-4-methylene-5-oxo-2-n-unde-
cyl-3-furancarboxylic acid [(−)-nephrosterinic acid], (−)-
To a solution of the cis-adduct, (−)-4a-ii (2.9786 g, 7.36
mmol) in THF (200 mL) and MeOH (40 mL) was
added at 0°C sodium methoxide solution (1.45N in
anhydrous MeOH, 2.54 mL, 3.68 mmol) and the mix-
ture was stirred at room temperature for 2 days. The
reaction mixture was quenched with saturated NH4Cl
solution and extracted several times with CH2Cl2. The
combined organic layer was washed with H2O, satu-
rated NaCl solution, then dried over MgSO4, filtered
and evaporated to dryness. Purification by PLC (silica
gel, using EtOAc:acetone:hexane=1:0.5:8.5 as eluent)
followed by crystallization from hexane provided trans-
isomer, (+)-4a-iv (2.01 g, 84% yield).
1b. Obtained as
a
white crystalline solid
(EtOAc/hexane): mp 86–88°C; [h]3D2=−7.2 (c, 0.39,
1
MeOH), [h]3D2=−10.9 (c, 0.68, CHCl3). H NMR (400
MHz, CDCl3): l 0.90 (t, J 7.1 Hz 3H), 1.20–1.68 (m,
18H), 1.68–1.85 (m, 2H), 3.65 (ddd, J 5.5, 2.9, 2.5 Hz,
1H), 4.83 (ddd, J 6.9, 5.8, 5.5 Hz, 1H), 6.05 (d, J 2.5
Hz, 1H), 6.49 (d, J 2.9 Hz, 1H), 6.90 (broad peak, 1H),
whose spectroscopic data are identical in all respects to
those reported.8e
4.7.3. (2S,3R)-Tetrahydro-4-methylene-5-oxo-2-n-tride-
cyl-3-furancarboxylic acid [(−)-protolichesterinic acid],
(−)-1c. Obtained as a white crystalline solid (EtOAc/
hexane): mp 101–103°C (lit.6a mp 103–105°C (EtOAc/
hexane)); [h]3D1=−8.9 (c, 0.18, MeOH), [h]3D2=−10.4 (c,
0.46, CHCl3), (lit.6a [h]D25=−15 (c, 1.0, CHCl3)). 1H
NMR (300 MHz, CDCl3): l 0.89 (t, J 6.4 Hz, 3H),
1.20–1.65 (m, 22H), 1.65–1.85 (m, 2H), 3.65 (ddd, J 5.4,
Isomerization of (−)-4b-ii and (−)-4c-ii furnished (+)-4b-
iv (75%) and (+)-4c-iv (79%), respectively, and, under
the same reaction conditions, (+)-4%a-ii, (+)-4%b-ii and
(+)-4%c-ii gave (−)-4%a-ii, (−)-4%b-iv and (−)-4%c-iv, in 65,
89 and 83% yields, respectively.

P. Kongsaeree et al. / Tetrahedron: Asymmetry 12 (2001) 1913–1922
1921
2.9, 2.4 Hz, 1H), 4.83 (ddd, J 6.8, 5.9, 5.4 Hz, 1H), 6.04
(d, J 2.4 Hz, 1H), 6.49 (d, J 2.9 Hz, 1H), 7.15 (broad
peak, 1H), whose spectroscopic data are identical in all
respects to those reported.8e
from the Nation Center for Genetic Engineering and
Biotechnology (BIOTEC)/Nation Science and Technol-
ogy Development Agency (NSTDA).
4.7.4. (2R,3S)-Tetrahydro-4-methylene-5-oxo-2-n-pen-
tyl-3-furancarboxylic acid [(+)-methylenolactocin], (+)-
References
1%a. Obtained as
a
white crystalline solid
1. For reviews on the occurrence, biological properties, and
synthesis a-methylene-g-butyrolactones, see: (a) Cavillto,
C. J.; Haskell, T. H. J. Chem. Soc. 1946, 68, 2332–2334;
(b) Yoshioka, H.; Mabry, T. J.; Timmermann, B. N.
Sesquiterpene Lactones; University of Tokyo Press:
Tokyo, 1973; (c) Grieco, P.A. Synthesis 1975, 67–82; (d)
Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed.
Engl. 1985, 24, 94–110; (e) Petragnani, N.; Ferraz, H. M.
C.; Silva, G. V. L. Synthesis, 1986, 157–183.
2. (a) Park, B. K.; Nakagawa, M.; Hirota, A.; Nakayama,
M. Agric. Biol. Chem. 1987, 51, 3443; (b) Park, B. K.;
Nakagawa, M.; Hirota, A.; Nakayama, M. J. Antibiot.
1988, 44, 751–758; (c) Nakayama, M.; Nakagawa, S.;
Boku, T.; Hirota, A.; Shima, S.; Nakanishi, O.; Yamada,
Y. Jpn. Kokai Tokkyo Koho 1989, 1 (16), 776; Chem.
Abstr. 1990, 112, 34404f.
3. Enantiomeric syntheses of methylenolactocin: (a) de
Azevedo, M. B. M.; Murta, M. M.; Greene, A. E. J. Org.
Chem. 1992, 57, 4567–4569; (b) Takahata, H.; Uchida,
Y.; Momose, T. J. Org. Chem. 1995, 60, 5628–5633; (c)
Vaupel, A.; Knochel, P. Tetrahedron Lett. 1995, 36,
231–232; (d) Mawson, S. D.; Weavers, R. T. Tetrahedron
1995, 51, 11257–11270; (e) Zhu, G.; Lu, X. Tetrahedron
Asymmetry 1995, 6, 885–892; (f) Drioli, S.; Felluga, F.;
Forzata, C.; Nitti, P.; Pitacco, G. Chem. Commun. 1996,
1289–1290; (g) Chandrasekharam, M.; Liu, R. S. J. Org.
Chem. 1998, 63, 9122–9124; (h) Masaki, Y.; Arasaki, H.;
Itoh, A. Tetrahedron Lett. 1999, 40, 4829–4832.
4. Asahina, Y.; Yanagita, M.; Sakurai, Y. Ber. Chem. 1937,
70B, 227–235.
5. (a) Zopf, W. Liebigs Ann. Chem. 1902, 324, 39–78; (b)
Asahina, Y.; Asano, M. J. Pharm. Sci. Jpn. 1927, 539,
1–17; (c) Asahina, Y.; Yanagita, M. Chem. Ber. 1936,
69B, 120–125.
6. Enantiomeric syntheses of protolichesterinic acid: (a)
Murta, M. M.; de Azevedo, M. B. M.; Greene, A. E. J.
Org. Chem. 1993, 58, 7537–7541; (b) Martin, T.;
Rodriguez, C. M.; Martin, V. S. J. Org. Chem. 1996, 61,
6450–6453.
7. (a) Be´rdy, J. Handbook of Antibiotic Compounds; CRC
Press: Boca Raton, FL, 1982; Vol. IX and references
cited therein; (b) Cavallito, C. J.; Fruehuauf, M. D.;
Bailey, J. N. J. Am. Chem. Soc. 1948, 70, 3724–3726; (c)
Shibata, S.; Miura, Y.; Sugimura, H.; Toyoizumi, Y. J.
Pharm. Soc. Jpn. 1948, 68, 300–303; Chem. Abstr. 1951,
45, 6691i; (d) Fujikawa, F.; Hitosa, Y.; Yamaoka, M.;
Fujiwara, Y.; Nakazawa, S.; Omatsu, T.; Toyoda, T. J.
Org. Chem. 1953, 73, 135–138; Chem. Abstr. 1954, 48,
230a; (e) Borkawski, B.; Wozniak, W.; Gertig, H.; Wer-
akso, B. Diss. Pharm. 1964, 16, 189–194; Chem. Abstr.
1965, 62, 1995b; (f) Sticker, O. Pharm. Acta Helv. 1965,
40, 183–195; Chem. Abstr. 1965, 63, 8778d; (g) Sticker, O.
Pharm. Acta Helv. 1965, 40, 385–394; Chem. Abstr. 1965,
63, 12026c; (h) Hirayama, T.; Fujikawa, F.; Kasahara,
(EtOAc/hexane): mp 82–83°C (lit.3d mp 82–83°C
(EtOAc/hexane)); [h]3D2=+7.4 (c, 0.33, MeOH), [h]3D0=
+16.6 (c, 0.33, CHCl3); (lit.3e [h]D25=+6.8 (c, 0.51,
MeOH) whose spectroscopic data are identical in all
respects to those reported.8e
4.7.5. (2R,3S)-Tetrahydro-4-methylene-5-oxo-2-n-unde-
cyl-3-furancarboxylic acid [(+)-nephrosterinic acid],
(+)-1%b. Obtained as a white crystalline solid (EtOAc/
hexane): mp 86–88°C; [h]3D2=+7.5 (c, 0.43, MeOH),
[h]D32=+13.0 (c, 0.66, CHCl3); (lit.4 [h]TD=+10.8) whose
spectroscopic data are identical in all respects to those
reported.8e
4.7.6. (2R,3S)-Tetrahydro-4-methylene-5-oxo-2-n-tride-
cyl-3-furancarboxylic acid [(+)-protolichesterinic acid],
(+)-1%c. Obtained as a white crystalline solid (EtOAc/
hexane): mp 101–103°C (lit.6a mp 103–105°C (EtOAc/
hexane)); [h]D31=+10.0 (c, 0.24, CH3OH), [h]3D2=+11.2
(c, 0.50, CHCl3); (lit.6b [h]D25=+14.2 (c, 0.95, CHCl3))
whose spectroscopic data are identical in all respects to
those reported.8e
4.7.7. (11S)-Tetrahydro-4%-carbomenthoxy-5%-n-pentyl-
2%-furanone -3%-spiro -11 -9,10 -dihydro -9,10 -ethanoan-
thracenes, (−)-8. Using the typical procedure described
in Section 4.7.1, capronaldehyde (0.28 mL, 2.27 mmol)
was reacted with menthyl methyl itaconate–anthracene
adduct, (−)-6 (1.0011 g, 1.89 mmol) to give enan-
tiomeric spiro–lactoness, (4%R,5%R,11R)-tetrahydro-4%-
carbomenthoxy-5%-n-pentyl-2%-furanone-3%-spiro-11-9,10-
dihydro-9,10-ethanoanthracenes, (−)-8 (0.346 g, 34%).
Compound (4%R,5%R,11R)-8: White crystals; mp 205–
206°C (from hexane); [h]3D1=−179.5 (c, 0.40, CHCl3).
IR (KBr-pellet), wmax 2989, 2931, 2872, 1783, 1722,
1460, 1371, 1176, 1137 cm−1. 1H NMR (400 MHz,
CDCl3): l 0.88 (t, J 6.9 Hz, 3H), 0.92 (d, J 7.0 Hz, 3H),
0.96 (d, J 7.0 Hz, 3H), 0.99 (d, J 6.5 Hz, 3H), 1.00–1.81
(m, 15H), 1.98, 2.13, 4.40 (ABX system, J 12.4, 3.0, 2.4
Hz, 3H), 2.01 (m, 1H), 2.25 (d, J 4.9 Hz, 1H), 2.38 (m,
1H), 4.33 (m, 1H), 4.80 (s, 1H), 4.84 (ddd, J 10.8, 4.9,
4.4 Hz, 1H), 7.05–7.35 (m, 8H). 13C NMR (100 MHz,
CDCl3): l 13.9, 15.9, 21.1, 22.1, 22.4, 22.7, 25.1, 25.6,
31.2, 31.4, 31.5, 34.1, 40.6, 41.2, 43.8, 46.4, 46.7, 50.7,
58.1, 76.4, 77.0, 122.5, 123.8, 124.5, 125.85, 125.93,
126.1, 126.7, 127.5, 140.0, 140.9, 142.5, 143.1, 169.6,
176.8. m/z (ESITOF-MS) 529.3317 (M+H)+, calcd for
C30H36O4 529.3318.
Acknowledgements
This work was supported by post-graduate study grant
(to P.M.) and a senior Fellowship Award (to Y.T.)

1922
P. Kongsaeree et al. / Tetrahedron: Asymmetry 12 (2001) 1913–1922
T.; Otsuka, M.; Nishida, N.; Mizuno, D. Yakugaku
10. Structures of compounds 6 and 8 have been confirmed by
X-ray crystallography whose data have been deposited
with the Cambridge Crystallographic Data Center and
allocated the deposition numbers CCDC 163247 and
CCDC 163248, respectively. Copies of the data can be
obtained free of charge on application to The Director,
Cambridge Crystallographic Data Center, 12 Union
Road, Cambridge CB2 1EZ, UK. (Fax: +44(0)-1223-
336033; e-mail: deposit@ccdc.cam.ac.uk; Web site: http://
www.ccdc.cam.ac.uk)
Zasshi 1980, 100, 755–759; Chem. Abstr. 1980, 93,
179563f; (i) Huneck, S.; Schreiber, K. Phytochemistry
1972, 11, 2429–2434.
8. (a) Golfiler, M.; Prange, T. Bull. Soc. Chim. Fr. 1974,
1159–1160; (b) Thebtaranonth, Y. Pure Appl. Chem.
1997, 69, 609–614; (c) Kodpinid, M.; Siwapinyoyos, T.;
Thebtaranonth, Y. J. Am. Chem. Soc. 1984, 106, 4862–
4865; (d) Mahidol, C.; Thebtaranonth, C.; Thebtara-
nonth, Y.; Yenjai, C. Tetrahedron Lett. 1984, 30,
3857–3860; (e) Lertvorachon, J.; Meepowpan, P.; Theb-
taranonth, Y. Tetrahedron 1998, 54, 14341–14358.
11. The enantiomeric excesses of (+)-2 and (−)-2% were deter-
1
mined by H NMR using chiral lanthanide shift reagent,
9. The diastereomeric excesses of (−)-6 and (−)-7 was deter-
tris[3-(heptafluoropropylhydroxymethylene)-d-camphor-
ato]praseodym(III), (Pr(hfc)3).
1
mined by H NMR spectroscopy.