Stereoselective synthesis and characterization of (Z)-(-)-4-(1′- Alkoxyl-1′-alkyloxycarbonyl-methylidene)-5(R)-[(1R)-menthyloxy] - Butyrolactones

Article abstract of DOI:10.1080/00397911003611760

A series of enantiomerically pure (Z)-(-)-4-(1′-alkyloxy-1′- alkyloxycarbonylmethylidene)- 5(R)-[(1R)-menthyloxy]-c-butyrolactones were synthesized and characterized in good to excellent yields via O-alkylation of (4R,5R)-(-)-4-ethoxyoxalyl-5-[(1R)- menthyloxy]-γ-butyrolactone with alkyl halides in the presence of K2CO3 in acetone at room temperature.

Full text of DOI:10.1080/00397911003611760

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Stereoselective Synthesis and
Characterization of (Z)-(-)-4-(1′-
Alkoxyl-1′-alkyloxycarbonyl-
methylidene)-5(R)-[(1R)-menthyloxy]-γ-
butyrolactones
Zhiqiang Feng a & Chenglie Yin b
a Institute of Materia Medica, Chinese Academy of Medical Sciences ,
Beijing, China
b Department of Chemistry , Beijing Normal University , Beijing,
China
Published online: 02 Feb 2011.
To cite this article: Zhiqiang Feng & Chenglie Yin (2011) Stereoselective Synthesis and
Characterization of (Z)-(-)-4-(1′-Alkoxyl-1′-alkyloxycarbonyl-methylidene)-5(R)-[(1R)-menthyloxy]-γ-
butyrolactones, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 41:4, 507-515, DOI: 10.1080/00397911003611760
To link to this article: http://dx.doi.org/10.1080/00397911003611760
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Synthetic Communications1, 41: 507–515, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911003611760
STEREOSELECTIVE SYNTHESIS AND
CHARACTERIZATION OF (Z)-(ꢀ)-4-(1’-ALKOXYL-
1’-ALKYLOXYCARBONYL-METHYLIDENE)-
5(R)-[(1R)-MENTHYLOXY]-c-BUTYROLACTONES
Zhiqiang Feng1 and Chenglie Yin2
1Institute of Materia Medica, Chinese Academy of Medical Sciences,
Beijing, China
2Department of Chemistry, Beijing Normal University, Beijing, China
Abstract A series of enantiomerically pure (Z)-(ꢀ)-4-(10-alkyloxy-10-alkyloxycarbonyl-
methylidene)-5(R)-[(1R)-menthyloxy]-c-butyrolactones were synthesized and character-
ized in good to excellent yields via O-alkylation of (4R,5R)-(ꢀ)-4-ethoxyoxalyl-5-[(1R)-
menthyloxy]-c-butyrolactone with alkyl halides in the presence of K2CO3 in acetone at
room temperature.
Keywords O-Alkylation; 4-methylidene-c-butyrolactone; stereoselective synthesis
Many natural and unnatural molecules with the c-butyrolactone moiety have been
known to display a wide range of biological activities.[1–4] The methylidene-c-
butyrolactone fragment has also been found in many natural compounds.[5–8] There
are three types of methylidene-c-butyrolactones: 3-methylidene-, 4-methylidene-,
and 5-methylidene-c-butyrolactone. Among them, a large number of compounds
possessing the 3-methylidene-c-butyrolactone moiety are known to have various bio-
logical activities (e.g., antitumor,[9] antiplatelet,[10] insecticidal,[11] cardiovascular,[12]
plant growth,[13] anti-inflammatary,[14] leishmanicidal,[15] and fungicidal,[16] activi-
ties), which have attracted considerable synthetic attention. However, little has been
described about compounds possessing the 4-methylidene-butyrolactone moiety. In
this article, the synthesis and characterization of compounds with the 4-methylidene
c-butyrolactone structural unit are reported.
Received May 24, 2009.
Address correspondence to Zhiqiang Feng, Institute of Materia Medica, Chinese Academy of
Medical Sciences, Beijing 100050, China. E-mail: fengzhq@imm.ac.cn
507

508
Z. FENG AND C. YIN
Scheme 1. Synthesis of 4-methylene-c-butyrolactones 3a–n.
A 4-methylidene-c-butyrolactone structural unit is present in some furanoid
terpenes[8] and sesquiterpenes.[17] The homogynolides A1 and B2 containing a novel
3-spiro-4-methylidene butyrolactone were found to possess antifeedant activity
against certain types of beetle adults (Sitophilus granarius, Tribolium confusum)
and larvae (Trogoderma granarium, Tribolium confusum).[18] A few methods of
synthesizing the unit have been reported. One method involves the reaction of an
enol ether with a carbene derived from diazomalonate as a key step.[19] The second
method utilizes the thermally induced cyclization of a b,c-epoxy ester.[20] The third
method involves the [2,3]-sigmatropic rearrangement of the carbazate derivative
for the total synthesis of (ꢁ)-bakkenolide, a furanoid terpenes.[21] The fourth method
utilized the reductive cyclization of 2-bromoalkanal acetals.[22] Recently, in the
study of an asymmetric synthesis of a natural product, we synthesized a key inter-
mediate, the a-keto ester linked to c-butyrolactone (2b),[23] which was obtained
by a four-step procedure starting from furfural.[24] When we treated 2b with
iodoethane in the presence of K2CO3, the only product, the enantiomerically pure
(Z)-(ꢀ)-4-ethoxycarbonyl-methylidene-5-(R)-[(1R)-menthyloxy]-c-butyrolactone (3m)
(Scheme 1), was obtained, which apparently involves a number of stereoselective
transformation in one pot. It appeared to be the first example of a stereoselective
synthesis of optically pure 4-alkoxylcarbonyl-methylidene-c-butyrolactone. We
determined the configuration of this new compound based on NMR analysis.
RESULTS AND DISCUSSION
The nitronic acid 1a or 1b was synthesized via Michael addition to 5-(1R)-
menthyloxy-3,4-unsaturated-c-butyrolactone by methyl nitroacetate or ethyl nitroa-
cetate.[24] The key intermediate (4R,5R)-(ꢀ)-4-ethoxyoxalyl-5-[(1R)-menthyloxy]-c-
butyrolactone (2b) was obtained via Nef reaction by treating 1b with O3 at 0 ꢂC in
methanol in the presence of KOH,[23] in which (4R,5R)-(ꢀ)-4-methoxyoxalyl-5[(1-
R)-menthyloxy]-c-butyrolactone (2a) was obtained as a by-product, resulting from
the reaction of ester exchange with methanol. Use of ethanol as the solvent led to
the formation of the only product 2b and the acceleration of Nef reaction. The struc-
ture of 2a was confirmed by 1H NMR and 13C NMR spectral and elemental analysis.
In the presence of K2CO3, 2b was treated with iodoethane, generating the
4-(10-ethoxy-10-ethoxycarbonyl-methylidene)-5(R)-menthyloxy-c-butyrolactone (3m)
as a single isomer. Its infrared (IR) spectrum showed very strong absorption at

4-METHYLIDENE-c-BUTYROLACTONE DERIVATIVES
509
ꢀ1
1615 cmꢀ1(C C) and 1735 cm (C O), which are the characteristic absorptions of
an enol ether. Its 1H NMR spectrum showed an H3 signal at d 3.34 ppm and an H5
signal at d 7.99 ppm, while those of 2b emerged at 2.90 ppm and 5.80 ppm. Its
13C NMR spectrum showed a C4 signal at d 162.3 ppm and a C6 signal at d
182.5 ppm, while those of 2b emerged at 50.4 ppm and 189.5 ppm. Results of the
elemental analysis were consistent with its structure.
=
=
In principle, the alkylation of a-keto ester 2 could produce four stereoisomers
either from R=S C-alkylations at C4 or E=Z O-alkylations of the enolized a-keto.
However, during the course of the reaction and after the workup, we obtained only
a single O-alkylated product, which suggested a highly stereoselective O-alkylation
of 2. The configuration of the enol ether 3 was assigned to be Z on the basis of
the nuclear Overhauser effect spectroscopy (NOESY) 1D spectrum in which strong
NOEs among C5-H, C8-H, and C9-H (OCH2 in OR2) were observed.
This stereoselective O-alkylation reaction might result from the steric effect
between the menthyloxy group and carbethoxy group and the formation of the eno-
late under basic conditions. In the presence of K2CO3, the enolization of a-keto
ester 2 might readily occur as a result of the conjugation effect of the olefin and ester
group; therefore, O-alkylation is preferred relative to C-alkylation. Because the
carbethoxy group is much bigger than the hydroxy group after enolization, the car-
bethoxy group should be trans to the bulky menthyloxy group as a result of the steric
effect, and therefore the Z-configuration is favored compared to the E-configuration.
Subsequently, we prepared a series of enantiomerically pure (Z)-(ꢀ)-4-(10-
alkoxy-10-alkoxycarbonyl-methylidene)-5(R)-[(1R)-menthyloxy]-c-butyrolactones in
65–89% yields (Table 1). We found that the a-keto ethyl ester was almost as reactive
as the a-keto methyl ester in the alkylation reaction. Acetone and dimethylformanide
(DMF) are both effective solvents, but the former is easier to remove than the latter
during reaction workup. It is interesting to note that no reaction was observed when
secondary or tertiary alkyl halides were used under similar reaction conditions, and
it is not surprising that the ease of the alkylation of 2 seems to follow the usual order:
RCH2I > RCH2Br > RCH2Cl.
Table 1. Synthesis of 4-methylidene-c-butyrolactones 3a–n
25
½aꢃ589 (acetone)
No.
R1
R2X
Time (d)
Yield (%)
Config.
3a
3b
3c
3d
3e
3f
CH3CH2
CH3
CH3I
CH3I
1
1
80
80
72
68
66
89
87
67
87
85
86
65
75
86
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
ꢀ25.90 (c ¼ 2.57)
ꢀ28.30 (c ¼ 2.51)
ꢀ30.20 (c ¼ 4.30)
ꢀ25.46 (c ¼ 2.96)
ꢀ24.77 (c ¼ 2.16)
ꢀ27.10 (c ¼ 1.09)
ꢀ27.30 (c ¼ 6.90)
ꢀ21.25 (c ¼ 1.48)
ꢀ26.00 (c ¼ 1.71)
ꢀ21.10 (c ¼ 6.54)
ꢀ30.75 (c ¼ 3.61)
ꢀ20.06 (c ¼ 1.24)
ꢀ26.16 (c ¼ 1.15)
ꢀ23.26 (c ¼ 3.30)
CH3CH2
CH3
CH3CH2CH2Br
CH3(CH2)3Br
CH3(CH2)4 Br
CH2¼CHCH2Br
CH2¼CHCH2Br
CH3(CH2)4Br
PhCH2Br
2
2
CH3CH2
CH3CH2
CH3
2
1
3g
3h
3i
1
CH3
CH3CH2
CH3
2
1.5
1.5
1.5
3
3j
BrCH2COOEt
BrCH2COOEt
CH3(CH2)15Br
CH3CH2Br
3k
3l
CH3CH2
CH3CH2
CH3CH2
CH3CH2
3m
3n
2
O2NC6H4CH2Br
1

510
Z. FENG AND C. YIN
In summary, a series of optically pure (Z)-(ꢀ)-4-(10-alkoxy-10-alkyloxycarbo-
nyl-methylidene)-5(R)-[(1R)-menthyloxy]-c-butyrolactones were synthesized in good
yields under mild conditions via stereoselective O-alkylation of (5R,4R)-(ꢀ)-4-
alkoxyoxalyl-5-[(1R)-menthyloxy]-c-butyrolactone with primary alkyl halides. All
new compounds were characterized by IR, 1H NMR, 13C NMR, elemental analysis,
and NOESY 1D experiments. The biological activities of the new compounds
obtained herein are currently under investigation.
EXPERIMENTAL
Unless otherwise indicated, all reagents and solvents were the best commercial
grades available and were not purified further. 1H NMR and 13C NMR spectra were
recorded on a DMX 300-MHz spectrometer using CDCl3 as the solvent and tetra-
methylsilane (TMS) as the internal standard with coupling constant (J) in hertz.
IR spectra were performed on a Hitachi 260-50 spectrometer. Ultraviolet (UV)
spectra were recorded on a Shimadzu UV-240 spectrometer.
Nitronic acid (1a and 1b) and a-keto ester 2 were prepared by Kang’s
methods.[23,24]
(4R,5R)-(ꢀ)-4-Ethoxyoxalyl-5-[(1R)-menthyloxy]-c-butyrolactone (2b)
O3 from an ozone generator was bubbled into a stirred solution of compound
1b (6.0 g, 16.2 mmol) and KOH (1.0 g, 17.8 mmol) in 90 mL of ethanol at 0 ꢂC. After
3 h, the reaction mixture was filtered, and the solvent was removed in vacuo. The
residue was dissolved in 150 mL of ether and was washed with water (3 ꢄ 20 mL)
and brine (2 ꢄ 30 mL). The solution was dried with anhydrous Na2SO4. Removal
of solvent furnished the crude product, which was purified by flash chromatography
on silica gel using 50% AcOEt–light petroleum ether, giving 4.3 g (80%) of 2b as a
colorless oil.
(4R,5R)-(ꢀ)-4-Methoxyoxalyl-5-[(1R)-menthyloxy]-c-butyrolactone (2a)
Compound 2a was prepared from nitronic acid 1a in methanol using the same
20
procedure as 2b. Colorless oil; ½aꢃ589 ¼ ꢀ138:1 (c ¼ 1.16, CHCl3); IR (neat) 1792,
1761, 1750, 1732 cmꢀ1 1H NMR (CDCl3, 300 MHz) d 0.68–1.30 (m, 14H),
;
1.55–1.75 (m, 2H), 2.01–2.22 (m, 2H), 2.79 (dd, 1H, J ¼ 18.0, 4.8), 2.87 (dd, 1H,
J ¼ 18.0, 9.4), 3.45–3.65 (m, 1H), 3.82–4.02 (m, 1H), 3.89 (s, 3H), 5.87 (d, 1H,
J ¼ 2.2); 13C NMR (CDCl3, 75 MHz) d15.6, 20.9, 22.3, 23.2, 25.4, 29.5, 31.7, 34.3,
39.2, 47.7, 50.6, 63.2, 77.9, 99.1, 159.7, 173.6, 188.3. Anal. calcd. for C17H26O6: C,
62.58; H, 7.98. Found: C, 62.55; H, 7.96.
General Procedure for Preparation of (Z)-(ꢀ)-4-(1’-Alkoxyl-
1’-alkoxycarbonyl-methylidene)-5(R)-[(1R)-menthyloxy]-c-
butyrolactone (3)
Compound 2 (2.9 mmol) and finely ground anhydrous K2CO3 (0.5 g, 3.6 mmol)
were mixed in acetone (20 mL) at room temperature. To this well-stirred suspension
was added an alkyl halide (3 mmol). The progress of the reaction was monitored by

4-METHYLIDENE-c-BUTYROLACTONE DERIVATIVES
511
TLC. After being stirred at room temperature for the indicated time, ether (30 mL)
was added. Then the mixture was filtered, and the solvent was removed from the
filtrate in vacuo to give the crude product, which was further purified by flash chro-
matography on silica gel using a mixture of light petroleum ether and ethyl acetate
(5:1), affording the compound 3.
(Z)-(ꢀ)-4-(1’-Methoxy-1’-ethoxycarbonyl-
methylidene)-5(R)-[(1R)-menthyloxy]-c-butyrolactone (3a)
25
A colorless liquid; ½aꢃ589 ¼ ꢀ25:9 (c ¼ 2.57, acetone); IR (neat) 1750, 1623 cmꢀ1
;
1
UV kmax ¼ 326.5 nm (acetone); H NMR (CDCl3, 300 MHz) d 0.77–1.21 (m, 12H),
1.38 (t, 3H, J ¼ 7.2), 1.42–1.58 (m, 2H), 1.65–1.80 (m, 2H), 1.89–2.10 (m, 2H), 3.35
(s, 2H), 3.65 (s, 3H), 3.79–3.92 (m, 1H), 4.32 (q, 2H, J ¼ 7.2), 8.01 (s, 1H); 13C
NMR (CDCl3, 75 MHz) d 13.5, 15.7, 20.1, 21.4, 22.8, 25.3, 27.6, 31.0, 33.3, 41.2,
47.0, 51.3, 61.5, 86.5, 111.9, 162.9, 166.0, 170.3, 183.1. Anal. calcd. for C19H30O6:
C, 64.41; H, 8.47. Found: C, 63.95; H, 8.65.
(Z)-(ꢀ)-4-(1’-Methoxy-1’-methoxycarbonyl-
methylidene)-5(R)-[(1R)-menthyloxy]-c-butyrolactone (3b)
25
A colorless liquid; ½aꢃ589 ¼ ꢀ28:3 (c ¼ 2.51, acetone); IR (neat) 1740, 1620 cmꢀ1
;
1
UV kmax ¼ 268.4 nm (EtOH); H NMR (CDCl3, 300 MHz) d 0.78–1.22 (m, 12H),
1.42–1.58 (m, 2H), 1.65–1.80 (m, 2H), 1.88–2.11 (m, 2H), 3.35 (s, 2H), 3.65 (s, 3H),
3.88 (s, 3H), 3.79–3.93 (m, 1H), 8.04 (s, 1H); 13C NMR (CDCl3, 75 MHz) d 16.1,
20.6, 21.8, 23.2, 25.7, 28.0, 31.4, 33.7, 41.6, 47.4, 51.7, 52.5, 85.9, 112.5, 163.4, 166.5,
170.8, 182.0. Anal. calcd. for C18H28O6: C, 63.53; H, 8.23. Found: C, 63.15; H, 8.53.
(Z)-(ꢀ)-4-(1’-Propyloxy-1’-ethoxycarbonyl-methylidene)–5(R)-
[(1R)-menthyloxy]-c-butyrolactone (3c)
25
A colorless liquid; ½aꢃ589 ¼ ꢀ30:2 (c ¼ 4.30, acetone); IR (neat): 1740,
1
1720 cmꢀ1; UV kmax ¼ 267.5 nm (EtOH); H NMR (CDCl3, 300 MHz) d 0.77–1.18
(m, 16H), 1.38 (t, 3H, J ¼ 7.2), 1.59–1.72 (m, 5H), 1.89–2.12 (m, 2H), 3.34 (s, 2H),
3.76–3.95 (m, 1H), 4.01 (t, 2H, J ¼ 6.6), 4.33 (q, 2H, J ¼ 7.2), 7.98 (s, 1H); 13C
NMR (CDCl3, 75 MHz) d 9.1, 12.8, 15.0, 19.4, 20.7, 22.1, 24.6, 27.1, 30.3, 32.6,
40.5, 46.3, 60.8, 65.0, 75.5, 85.7, 111.4, 162.2, 165.1, 169.3, 182.4. Anal. calcd. for
C21H34O6: C, 65.97; H, 8.90. Found: C, 65.95; H, 9.25.
(Z)-(ꢀ)-4-(1’-Butoxy-1’-methoxycarbonyl-methylidene)-
5(R)-[(1R)-menthyloxy]-c-butyrolactone (3d)
25
A colorless liquid; ½aꢃ589 ¼ ꢀ25:46 (c ¼ 2.96, acetone); IR (neat): 1730,
1
1610 cmꢀ1; UV kmax ¼ 268.6 nm (EtOH); H NMR (CDCl3, 300 MHz) d 0.75–1.23
(m, 15H), 1.38–1.58 (m, 4H), 1.61–1.80 (m, 4H), 1.90–2.12 (m, 2H), 3.32 (s, 2H),
3.66 (s, 3H), 3.76–3.92 (m, 1H), 4.25–4.33 (m, 2H), 7.99 (s, 1H); 13C NMR (CDCl3,
75 MHz) d 13.6, 16.1, 19.1, 20.5, 21.8, 23.2, 25.7, 28.0, 30.5, 31.4, 33.7, 41.6, 47.4,

512
Z. FENG AND C. YIN
51.7, 65.6, 86.8, 112.4, 163.3, 166.1, 170.7, 183.2. Anal. calcd. for C21H34O6: C,
65.97, H, 8.90. Found: C, 65.48, H, 9.25.
(Z)-(ꢀ)-4-(1’-Pentyloxy-1’-ethoxycarbonyl-methylidene)-
5(R)-[(1R)-menthyloxy]-c-butyrolactone (3e)
25
A colorless liquid; ½aꢃ589 ¼ ꢀ24:77 (c ¼ 2.16, acetone); IR (neat): 1740,
1
1620 cmꢀ1; UV kmax ¼ 268.2 nm (EtOH); H NMR (CDCl3, 300 MHz) d 0.77–1.22
(m, 15H), 1.31–1.40 (m, 9H), 1.50–1.72 (m, 4H), 1.87–2.12 (m, 2H), 3.34 (s, 2H),
3.80–3.89 (m, 1H), 4.04 (t, 2H, J ¼ 6.7), 4.33 (q, 2H, J ¼ 7.2), 7.98 (s, 1H); 13C
NMR (CDCl3, 75 MHz) d 12.8, 13.7, 15.9, 20.3, 21.6, 21.9, 22.9, 25.4, 27.6, 27.9,
28.0, 31.1, 33.5, 41.4, 47.1, 61.7, 64.5, 86.6, 112.3, 163.0, 167.4, 170.3, 183.2. Anal.
calcd. for C23H38O6: C, 67.31; H, 9.27. Found: C, 66.8; H, 9.78.
(Z)-(ꢀ)-4-(1’-Allyloxy-1’-ethoxycarbonyl-methylidene)-
5(R)-[(1R)-menthyloxy]-c-butyrolactone (3f)
25
A colorless liquid; ½aꢃ589 ¼ ꢀ27:1 (c ¼ 1.09, acetone); IR (neat) 1740,
1
1622 cmꢀ1; UV kmax ¼ 268.9 nm (EtOH); H NMR (CDCl3, 300 MHz) d 0.76–1.18
(m, 12H), 1.37 (t, 3H, J ¼ 7.1), 1.32–1.50 (m, 2H), 1.52–1.72 (m, 2H), 1.90–2.10
(m, 2H), 3.38 (s, 2H), 3.81–3.88 (m, 1H), 4.33 (q, 2H, J ¼ 7.1), 4.56 (d, 2H,
J ¼ 5.5), 5.80–5.96 (m, 1H), 5.19–5.33 (m, 2H), 8.01 (s, 1H); 13C NMR (CDCl3,
75 MHz) d 13.67, 15.8, 20.3, 21.5, 22.9, 25.4, 27.8, 31.1, 33.5, 41.3, 47.1, 61.5,
64.8, 86.5, 112.0, 117.3, 131.8, 162.9, 166.0, 169.6, 183.1. Anal. calcd. for
C21H32O6: C, 66.32; H, 8.42. Found: C, 66.71; H, 8.15.
(Z)-(ꢀ)-4-(1’-Allyloxy-1’-methoxycarbonyl-methylidene)-
5(R)-[(1R)-menthyloxy]-c-butyrolactone (3g)
25
A colorless liquid; ½aꢃ589 ¼ ꢀ27:30 (c ¼ 6.90, acetone); IR (neat): 1742,
1
1619 cmꢀ1; UV kmax ¼ 269.2 nm (EtOH); H NMR (CDCl3, 300 MHz) d 0.77–1.18
(m, 12H), 1.40–1.48 (m, 2H), 1.62–1.72 (m, 2H), 1.97–2.05 (m, 2H), 3.38 (s, 2H),
3.82–3.89 (m, 1H), 3.87 (s, 3H), 4.57 (q, 2H, J ¼ 5.1), 5.15–5.33 (m, 2H), 5.80–6.00
(m, 1H), 8.06 (s, 1H); 13C NMR (CDCl3, 75 MHz) d 15.8, 20.8, 22.0, 23.0, 25.6,
28.1, 31.3, 33.6, 41.5, 47.2, 52.5, 65.1, 86.9, 112.3, 117.7, 131.9, 163.3, 166.6, 170.0,
182.8. Anal. calcd. for C20H30O6: C, 65.57; H, 8.19. Found: C, 65.25; H, 8.41.
(Z)-(ꢀ)-4-(1’-Pentyloxy-1’-methoxycarbonyl-methylidene)-
5(R)-[(1R)-menthyloxy]-c-butyrolactone (3h)
25
A colorless liquid; ½aꢃ589 ¼ ꢀ21:25 (c ¼ 1.48, acetone); IR (neat): 1742,
1
1625 cmꢀ1; UV kmax ¼ 268.5 nm (EtOH); H NMR (CDCl3, 300 MHz) d 0.77–1.20
(m, 15H), 1.31–1.42 (m, 6H), 1.51–1.72 (m, 4H), 1.87–2.11 (m, 2H), 3.34 (s, 2H),
3.86 (s, 3H), 3.81–3.88 (m, 1H), 4.04 (t, 2H, J ¼ 6.7), 8.03 (s, 1H); 13C NMR (CDCl3,
75 MHz) d 14.0, 16.2, 20.6, 21.9, 22.3, 23.2, 25.8, 28.0, 28.2, 28.4, 31.6, 33.8, 41.7,
47.6, 52.7, 64.9, 87.0, 112.7, 163.6, 166.6, 170.6, 183.1. Anal calcd. for C22H36O6:
C, 66.67; H, 9.09. Found: C, 66.18; H, 9.45.

4-METHYLIDENE-c-BUTYROLACTONE DERIVATIVES
513
(Z)-(ꢀ)-4-(1’-Benzyloxy-1’-ethoxylcarbonyl-methylidene)-
5(R)-[(1R)-menthyloxy]-c-butyrolactone (3i)
25
A colorless liquid; ½aꢃ589 ¼ ꢀ26:0 (c ¼ 1.71, acetone); IR (neat): 1740,
1620 cmꢀ1; UV kmax ¼ 326.4 nm (acetone); 1H NMR (CDCl3, 300 MHz) d 0.75–
1.21 (m, 10H), 1.31–1.50 (m, 7H), 1.60–1.75 (m, 2H), 1.86–2.23 (m, 2H), 3.4 (s,
2H), 3.75–3.95 (m, 1H), 4.2–4.4 (m, 2H), 5.1 (s, 2H), 7.3 (s, 5H), 8.0 (s, 1H); 13C
NMR (CDCl3, 75 MHz) d 13.8, 15.8, 20.2, 21.5, 22.8, 25.4, 27.9, 31.0, 33.4, 41.2,
47.0, 61.5, 65.8, 88.5, 111.9, 127.4 ꢄ 2, 127.5, 128.0 ꢄ 2, 135.6, 162.9, 166.0, 169.8,
183.2. Anal. calcd. for C25H34O5: C, 69.77; H, 7.91. Found: C, 69.58; H, 7.79.
(Z)-(ꢀ)-4-(1’-Ethoxycarbonylmethyl-1’-methoxycarbonyl-
methylidene)-5(R)-[(1R)-menthyloxy]-c-butyrolactone (3j)
25
A colorless liquid; ½aꢃ589 ¼ ꢀ21:1 (c ¼ 6.54, acetone); IR (neat): 1750,
1620 cmꢀ1; UV kmax ¼ 326.1 nm (acetone); 1H NMR (CDCl3, 300 MHz) d 0.75–
1.18 (m, 12H), 1.30 (t, 3H, J ¼ 7.2), 1.21–1.55 (m, 2H), 1.61–1.80 (m, 2H),
1.85–2.1 (m, 2H), 3.43 (s, 2H), 3.84 (s, 3H), 3.80–3.95 (m, 1H), 4.2 (q, 2H,
J ¼ 7.2), 4.60 (s, 2H), 8.10 (s, 1H); 13C NMR (CDCl3, 75 MHz) d 13.8, 15.9, 20.5,
21.6, 22.9, 25.5, 27.6, 31.2, 33.5, 41.4, 47.1, 52.4, 60.7, 60.9, 86.9, 111.7, 163.2,
166.5, 167.3, 169.6, 182.8. Anal calcd. for C21H32O8: C, 61.16; H, 7.76. Found: C,
61.05; H, 8.10.
(Z)-(ꢀ)-4-(1’-Ethoxycarbonylmethyl-1’-ethoxycarbonyl-
methylidene)-5(R)-[(1R)-menthyloxy]-c-butyrolactone (3k)
25
A colorless oil; ½aꢃ589 ¼ ꢀ30:75 (c ¼ 3.61, acetone); IR (meat): 1750, 1620 cmꢀ1
;
1
UV kmax ¼ 325.9 nm (acetone); H NMR (CDCl3, 300 MHz) d 0.75–1.18 (m, 12H),
1.29 (t, 3H, J ¼ 7.2), 1.38 (t, 3H, J ¼ 7.2), 1.22–1.55 (m, 2H), 1.62–1.80 (m, 2H),
1.86–2.11 (m, 2H), 3.43 (s, 2H), 3.80–3.95 (m, 1H), 4.2 (q, 2H, J ¼ 7.2), 4.3 (q,
2H, J ¼ 7.2), 4.6 (s, 2H), 8.05 (s, 1H); 13C NMR (CDCl3, 75 MHz) d 13.5, 15.7,
20.2, 21.4, 22.7, 25.3, 27.3, 29.2, 31.0, 33.4, 41.2, 47.0, 60.4, 60.7, 61.5, 86.6, 111.4,
162.6, 166.2, 167.1, 169.9, 182.9. Anal. calcd. for C22H34O8: C, 61.97; H, 7.98;
Found: C, 61.81; H, 7.89.
(Z)-(ꢀ)-4-(1’-Hexadecyloxy-1’-ethoxycarbonyl-methylidene)-
5(R)-[(1R)-menthyloxy]-c-butyrolactone (3l)
25
A colorless oil; ½aꢃ589 ¼ ꢀ20:06 (c ¼ 1.24, acetone); IR (neat): 1740 (s),
1
1622 cmꢀ1; UV kmax ¼ 267.7 nm (EtOH); H NMR (CDCl3, 300 MHz) d 0.75–1.18
(m,16H), 1.18–1.50 (m, 30H), 1.52–1.82 (m, 4H), 1.86–2.20 (m, 2H), 3.33 (s, 2H),
3.80–3.94 (m, 1H), 4.04 (t, 2H, J ¼ 6.6), 4.32 (q, 2H, J ¼ 7.2), 7.99 (s, 1H); 13C
NMR (CDCl3, 75 MHz) d 14.8, 14.9, 17.0, 21.4, 22.6, 23.5, 26.6, 26.7, 29.4, 29.5,
30.1, 30.2, 30.3, 30.4, 30.5, 30.6 ꢄ 6, 32.2, 32.7, 34.8, 42.5, 48.3, 62.7, 65.6, 87.6,
113.4, 164.1, 167.1, 171.2, 184.3. Anal. calcd. for C34H60O6: C, 72.34; H, 10.64.
Found: C, 71.89; H, 11.05.

514
Z. FENG AND C. YIN
(Z)-(ꢀ)-4-(1’-Ethoxy-1’-ethoxycarbonyl-methylidene)-
5(R)-[(1R)-menthyloxy]-c-butyrolactone (3m)
25
A colorless liquid; ½aꢃ589 ¼ ꢀ26:16 (c ¼ 1.15, acetone); IR (neat): 1735,
1
1615 cmꢀ1; UV kmax ¼ 268.4 nm (EtOH); H NMR (CDCl3, 300 MHz) d 0.78–1.18
(m, 12H), 1.23 (t, 3H, J ¼ 7.2), 1.37 (t, 3H, J ¼ 7.2), 1.32–1.45 (m, 2H), 1.55–1.82
(m, 2H), 1.85–2.11 (m, 2H), 3.34 (s, 2H), 3.80–3.93 (m, 1H), 4.10 (q, 2H, J ¼ 7.2),
4.32 (q, 2H, J ¼ 7.2), 7.99 (s, 1H); 13C NMR (CDCl3, 75 MHz) d 12.8, 13.0, 15.1,
19.4, 20.7, 22.1, 24.7, 27.1, 30.3, 32.7, 40.6, 46.4, 59.4, 60.8, 85.7, 111.4, 162.3,
165.2, 169.2, 182.5. Anal. calcd. for C20H32O6: C, 65.22; H, 8.70. Found: C, 65.12;
H, 8.90.
(Z)-(ꢀ)-4-(1’-p-Nitrobenzyloxy-1’-ethoxycarbonyl-
methylidene)-5(R)-[(1R)-menthyloxy]-c-butyrolactone (3n)
25
A colorless oil; ½aꢃ589 ¼ ꢀ23:26 (c ¼ 3.30, acetone); IR (neat): 1750, 1620,
1
1521 cmꢀ1; UV kmax ¼ 268 nm (EtOH); H NMR (CDCl3, 300 MHz) d 0.74–1.18
(m, 12H), 1.41 (t, 3H, J ¼ 7.2), 1.32–1.45 (m, 2H), 1.60–1.82 (m, 2H), 1.88–2.11
(m, 2H), 3.44 (s, 2H), 3.80–3.95 (m, 1H), 4.34 (q, 2H, J ¼ 7.2), 5.21 (s, 2H), 7.51
(d, 2H, J ¼ 8.5), 8.19 (d, 2H, J ¼ 8.5), 8.03 (s, 1H) ; 13C NMR (CDCl3, 75 MHz) d
13.71, 15.9, 20.2, 21.5, 22.9, 25.6, 27.9, 31.1, 33.4, 41.3, 47.1, 61.7, 64.4, 86.8,
111.7, 123.3 ꢄ 2, 127.7 ꢄ 2, 143.2, 147.1, 162.9, 166.3, 169.6, 183.3; MS (FAB,
m=z): 476 (M þ 1). Anal. calcd. for C25H33O8N: C, 63.16; H, 6.95; N, 2.95. Found:
C, 62.95; H, 7.16; N, 2.78.
ACKNOWLEDGMENT
Financial support provided by the National Natural Science Foundation of
China, the Doctoral Program Foundation of the State Education Commission, is
gratefully acknowledged.
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