A concise synthesis of paraconic acids: (-)-methylenolactocin and (-)-phaseolinic acid

Article abstract of DOI:10.1016/j.tetasy.2011.05.007

A concise synthesis of (-)-methylenolactocin and (-)-phaseolinic acid, the common members of the paraconic acids, is described. The synthesis is based on regioselective asymmetric dihydroxylation and the orthoester Johnson-Claisen rearrangement of allyl alcohol with a vicinal diol functionality as the key steps. The synthesis was completed in 10 steps with overall yields of 4.1% for (-)-methylenolactocin and 4.3% for (-)-phaseolinic acid.

Full text of DOI:10.1016/j.tetasy.2011.05.007

Tetrahedron: Asymmetry 22 (2011) 1114–1119
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A concise synthesis of paraconic acids: (ꢀ)-methylenolactocin
and (ꢀ)-phaseolinic acid
⇑
Rodney A. Fernandes , Asim K. Chowdhury
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Maharashtra, Mumbai 400076, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise synthesis of (ꢀ)-methylenolactocin and (ꢀ)-phaseolinic acid, the common members of the
paraconic acids, is described. The synthesis is based on regioselective asymmetric dihydroxylation and
the orthoester Johnson–Claisen rearrangement of allyl alcohol with a vicinal diol functionality as the
key steps. The synthesis was completed in 10 steps with overall yields of 4.1% for (ꢀ)-methylenolactocin
and 4.3% for (ꢀ)-phaseolinic acid.
Received 5 May 2011
Accepted 17 May 2011
Available online 14 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1
. Introduction
O
Paraconic acids are a class of highly substituted
c-butyrolactones
O
R = n-C11H23: (+)-nephrosteranic acid 1
R = n-C13H27: (+)-roccellaric acid 2
with a b-COOH group and -methyl or methylene group and display
a
HO
a range of stereochemical relationship of substituents on adjacent
carbon centers (Fig. 1). They are isolated from various species of li-
chen, moss and fungus and possess important biological activities
including antitumor, antifungal, antibacterial and antibiotic. These
interesting biological activities have prompted many researchers to
devise synthetic routes toward these natural products. A number of
R
O
O
R = n-C5H11: (-)-methylenolactocin 3
R = n-C11H23: (-)-nephrosterinic acid 4
R = n-C13H27: (-)-protolichesterinic acid 5
1
O
HO
R
O
2
–6
7
O
total
and formal syntheses have been reported for this class of
2
3–6
compounds in racemic and enantiopure
forms. (ꢀ)-Methyleno-
R = n-C11H23: (+)-nephrosterinic acid ent-4
R = n-C : (+)-protolichesterinic acid ent-5
O
lactocin 3 was isolated by Nakayama et al. from the culture filtrate
of the fungus Penicillium sp.1 Its structure was determined to be 3-
carboxy-2-methylene-4-nonanolide by spectroscopic data. It is ac-
tive againstsomegram-positivebacteriaand it prolongsthelifespan
13 27
H
HO
c
R
O
O
R = n-C5H11: (-)-phaseolinic acid 6
1c
of mice inoculated with Ehrlich carcinoma. It has been synthesized
O
R = n-C13H27: (-)-nephromopsinic acid 7
2c,d,h,m
HO
by several research groups in both racemic
and as enantiome-
(ꢀ)-Phaseolinic acid 6 was
isolated from the culture filtrate of the phytotoxic fungus
R = n-C13
H
COCH : (-)-dihydropertusaric acid 8
26
3
3
b,4a,b,h,5a,b,i,m,n,6i,k,l
R
rically pure forms.
O
O
1d
Macrophomina phaseolina. It differs from methylenolactocin in
R = n-C13H27: (+)-lichesterinic acid 9
having an
ment of b,
enantiomerically pure forms.
a
-methyl substituent and more importantly the cis-place-
O
12 24
R = n-C H COOH: (+)-praesorediosic acid 10
2
a,e
HO
c
-substituents. It has been synthesized in racemic
and
R = n-C12H24CH2OAc: (-)-13-acetoxylichesterinic acid 11
3d,e,4a,e,5a,k,6e,i
Over the course of studies
R
O
directed toward the enantioselective synthesis of bioactive natural
products employing the orthoester Johnson–Claisen rearrangement
Figure 1. Paraconic acids.
8
of allyl alcohols with a chiral vicinal diol functionality, we became
interested in the synthesis of (ꢀ)-methylenolactocin
ꢀ)-phaseolinic acid 6 employing asymmetric dihydroxylation of a
,d-olefinic bond of an ,b, ,d-unsaturated ester and the orthoester
Johnson–Claisen rearrangement as the key steps.
3
and
2. Results and discussion
(
c
a
c
The retrosynthetic route to 3 and 6 is shown in Scheme 1.
Removal of the free hydroxyl group in 12a, the conversion of the
b-vinyl bond to a carboxylic acid group and the stereoselective
⇑
Corresponding author. Fax: +91 22 25767152.
E-mail address: rfernand@chem.iitb.ac.in (R.A. Fernandes).
a
-methylene group introduction would give title compound 3.
Similarly, the introduction of an -methyl group in the b-COOH
a
0
957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.05.007

R. A. Fernandes, A. K. Chowdhury / Tetrahedron: Asymmetry 22 (2011) 1114–1119
1115
O
O
HO
O
cleave/oxidise to acid
LiHMDS, THF
H
-
78 C, 1.5 h
o
EtO
OH
+
OHC
remove
86%
H
O
16
17
introduce =CH2
O
O
1
2a
(
-)-methylenolactocin 3
O
EtO
Ph3P, PhH, rt, 6h
0%
O
cleave/oxidise to acid
OH
7
HO
H
OH
remove
Me
1
5
K3Fe(CN)6, K2CO3
MeSO2NH2
H
O
introduce CH3
O
O
O
K2OsO4.2H2O
O
1
2b
O
EtO
EtO
HO
(
-)-phaseolinic acid 6
(DHQD)2-PHAL
Johnson-Claisen
rearangement
t-BuOH/H2O (1:1)
o
0
C, 12 h, 61%
14
asymmetric
O
O
(
i) Me2C(OMe)2, Me2CO
p-TSOH (cat), rt
12 h, 98%
dihydroxylation
OH
EtO
EtO
HO
14
O
OH
(
ii) DIBAL-H, CH2Cl2
1
3
0
o
C, 2.5 h, 95%
1
8
O
(
MeO)3CMe, toluene
EtCO2H (cat), reflux
4 h, then rt, 4M HCl
MeOH, 12 h, 12a (59%)
2b (22%)
O
O
2
EtO
+
OHC
1
OH
O
1
5
16
17
1
3
or
(MeO)3CMe, xylene
EtCO2H (cat), reflux
Scheme 1. Retrosynthetic analysis of 3 and 6.
4
h, then rt, 4M HCl
MeOH, 12 h, 12a (46%)
2b (42%)
1
containing intermediate from 12b would give (ꢀ)-phaseolinic acid
. The b, -disubstituted- -lactones 12a and 12b were the products
6
c
c
OH
OH
of orthoester Johnson–Claisen rearrangement of allyl alcohol 13
which had a vicinal chiral diol functionality. Compound 13 could
be obtained via the regioselective asymmetric dihydroxylation
+
O
O
of the distant olefinic bond of
lowed by usual acetonide formation and ester group reduction.
Dienenoate 14 can be obtained from the ethyl propiolate 16 addi-
a,b,c,d-unsaturated ester 14 fol-
O
O
12a
12b
c-lactones 12a and 12b.
Scheme 2. Synthesis of separable diastereomeric
3
tion to aldehyde 17, followed by PPh mediated ‘allene’ type rear-
9
rangement of 15. Thus, from the common intermediate allyl
alcohol 13, both 3 and 6 can be synthesized.
The hydroxyl group in 12a was converted into a xanthate to give
9a in 71% yield. Similarly, 12b afforded 19b (70%). Next, the
AIBN/nBu SnH mediated removal of the xanthate group from 19a
gave b-vinyl- -lactone 20a in quantitative yield. Compound 19b
upon similar removal of the xanthate group gave 20b. The ozono-
lytic cleavage of the vinyl bond in 20a and further oxidation effi-
ciently placed the desired b-carboxylic acid group to provide 21a
in good yields of 95%. Similarly, 20b provided 21b in 92% yield.
1
The synthesis was initiated by assembling the precursor b,
disubstituted- -lactones 12a and 12b as shown in Scheme 2. The
addition of lithiated ethyl propiolate 16 to aldehyde 17 produced
the hydroxy alkynoate 15 (86%). The Ph P mediated ‘allene’ type
rearrangement of 15 gave the all trans-dienoate 14 in good yields
70%). The enantio- and regioselective asymmetric dihydroxyla-
c-
c
3
c
3
9
(
1
0
11
tion of 14 afforded diol 18 (61%, 97% ee ). The acetonide protec-
tion of diol 18 (98%) and subsequent DIBAL-H reduction of the
ester group gave 13 in 95% yield. The orthoester Johnson–Claisen
rearrangement of the allyl alcohol 13 with a chiral vicinal diol
functionality with trimethylorthoacetate in the presence of a cata-
lytic amount of propionic acid in toluene solvent over 24 h and the
same-pot hydrolysis provided a mixture of 12a/12b in a 2.5:1 ratio.
The
a-methylene group was introduced following the literature
4
h
12
procedure. The treatment of 21a with methoxy magnesiumm-
1
3
ethylcarbonate followed by formaldehyde and N-methylaniline
2
5
gave (ꢀ)-methylenolactocin 3 in 64% yield, ½
aꢁ
¼ ꢀ7 (c 0.12,
¼ ꢀ6:8 (c 0.5,
D
5
a
20
D
4h
20
D
MeOH), lit.
½
a
ꢁ
¼ ꢀ10 (c 0.5, MeOH), lit.
½
a
ꢁ
MeOH). The stereoselective introduction of
a
-methyl group in
2
1b using NaHMDS/MeI gave (ꢀ)-phaseolinic acid 6 in quantitative
The same reaction in xylene solvent over 4 h gave a mixture of 12a/
2
D
5
6g
25
D
2b in a 1.1:1 ratio.8 From the toluene reaction, the mixture was
b
yield, ½
a
ꢁ
¼ ꢀ117 (c 0.10, CHCl
3
), lit.
½
a
ꢁ
¼ ꢀ112 (c 0.26,
1
3
CHCl ). The spectroscopic data for 3 and 6 were in full agreement
easily separated by silica gel flash column chromatography to give
2a in 59% and 12b in 22% yields. From the xylene reaction 12b
5
a
with the literature data.
1
8b
was obtained in 42% and 12a in 46% yields. Lactone 12a has the re-
quired functionality to set the b, -stereocenters of the target mole-
cule 3 while the free hydroxyl group in the side chain needs to be
removed. Similarly 12b with cis-b, -substituents is a precursor for 6.
c
3. Conclusions
c
In conclusion, we have efficiently synthesized (ꢀ)-methyleno-
lactocin and (ꢀ)-phaseolinic acid in 10 steps and overall yields of
4.1% and 4.3%, respectively. The synthesis features the regioselective
The final stage leading to the completion of the synthesis of (ꢀ)-
methylenolactocin and (ꢀ)-phaseolinic acid is shown in Scheme 3.

1
116
R. A. Fernandes, A. K. Chowdhury / Tetrahedron: Asymmetry 22 (2011) 1114–1119
R'
R
OH
H
Mercury Plus, AS400 spectrometer and Bruker, AVANCE III 400
spectrometer. The chemical shifts are based on TMS peak at
CS2, NaH, THF, 0 oC, 1 h
o
then MeI, 0 C to rt, 2 h
1
3
d = 0.00 pm for H NMR and the CDCl peak at d = 77.00 ppm (t)
1
3
O
in C NMR. The IR spectra were obtained on Perkin Elmer Spec-
trum One FT-IR spectrometer. Optical rotations were measured
with Jasco DIP-370 digital polarimeter. HRMS was recorded using
a Micromass: Q-Tof micro (YA-105) spectrometer. HPLC was per-
formed with JASCO-(PU-2080PLUS Pump with UV-2075PLUS
Detector.
O
R = H, R' = -CH=CH2, 12a
R = -CH=CH2, R' = H, 12b
S
R'
R
O
S
Bu3SnH, AIBN (cat), toluene
reflux, 6 h
4
.1.1. Ethyl 4-hydroxynon-2-ynoate 15
To solution of ethylpropiolate 16 (2.15 g, 21.96 mmol,
a
quantitative
H
O
1.1 equiv) in dry THF (60 mL) at ꢀ78 °C was added LiHMDS
(23.3 mL, 27.96 mmol, 1.2 M solution in THF, 1.4 equiv), and the
mixture was stirred at ꢀ78 °C for 1.5 h. Aldehyde 17 (2.0 g,
19.97 mmol) in THF (15 mL) was added at ꢀ78 °C and stirring
was continued for 30 min. The reaction mixture was quenched
O
R = H, R' = -CH=CH2, 19a, 71%
R = -CH=CH2, R' = H, 19b, 70%
R'
R
(i) O3, CH2Cl2, -78 oC, 0.5 h
4
with a satd aq NH Cl solution and warmed to room temperature.
o
then Me2S, -78 C, 1 h, rt, 2 h
It was diluted with water and extracted with EtOAc (4 ꢂ 50 mL).
H
(ii) CrO3, H2SO4, acetone, 0 o
The combined organic layers were washed with water, brine, dried
O
C
(
2 4
Na SO ) and concentrated. The residue was purified by silica gel
2
0 min
O
column chromatography (petroleum ether/EtOAc, 9:1) to give 15
R = H, R' = -CH=CH2, 20a
R = -CH=CH2, R' = H, 20b
(3.4 g, 86%) as a colorless oil. IR (CHCl
):
m
max 3419, 2958, 2934,
3
ꢀ1
2
863, 2238, 1715, 1467, 1368, 1248, 1020, 861, 752, 636 cm
.
1
O
H NMR (400 MHz, CDCl
.40 (m, 7H, CH
m, 2H, H-5), 1.91 (brs, 1H, –OH), 4.24 (q, J = 7.2 Hz, 2H, OCH
3 3
): d 0.89 (t, J = 6.7 Hz, 3H, CH ), 1.10–
O
HO
O
HO
H
1
(
3
, H-8, H-7), 1.40–1.60 (m, 2H, H-6), 1.70–1.90
),
3
.48 (t, J = 6.7 Hz, 1H, H-4). C NMR (100 MHz, CDCl ): d 13.9
H
2
1
3
4
H
H
O
O
(2C), 22.4, 24.6, 31.3, 36.8, 62.1, 62.2, 76.5, 87.9, 153.5. HRMS
+
O
18 3
(ESI ): Calcd for [C11H O + H] 199.1334. Found: 199.1340.
21a 95%
21b 92%
4
.1.2. (2E,4E)-Ethyl nona-2,4-dienoate 14
To a solution of 15 (4.1 g, 20.68 mmol) in benzene (30 mL) was
added PPh (6.51 g, 24.82 mmol, 1.2 equiv) at room temperature
(
i) MeOMgOCO2Me
DMF, 135 oC, 60h
NaHMDS
THF, -78 °C
3
(
ii) CH2O,
1
2
.5 h, MeI, -78 °C
h, quant.
N-methylaniline
AcOH, NaOAc
and the resulting mixture was stirred for 6 h. It was then diluted
with petroleum ether/EtOAc (95:5, 80 mL) and filtered through a
pad of silica gel. The filtrate was concentrated and the residue puri-
fied by silica gel column chromatography (petroleum ether/EtOAc,
rt, 2.5 h, 64% (two steps)
O
H
O
9
5:5) to give 14 (2.64 g, 70%) as a colorless oil. IR (CHCl
3 max
): m
HO
O
HO
H
2959, 2934, 2873, 1724, 1467, 1370, 1304, 1270, 1179, 1121,
ꢀ
1 1
Me
1030, 981, 861, 725, 696, 544 cm
0.89 (t, J = 7.1 Hz, 3H, CH ), 1.10–1.50 (m, 7H, CH
.10–2.30 (m, 2H, H-6), 4.18 (q, J = 7.1 Hz, 2H, OCH
J = 15.3 Hz, 1H, H-olefin), 6.07–6.20 (m, 2H, H-olefin), 7.25 (dd,
.
H NMR (400 MHz, CDCl
, H-8, H-7),
), 5.77 (d,
3
): d
H
O
H
3
3
O
2
2
O
1
3
(
-)-phaseolinic acid 6
J = 15.3, 9.8 Hz, 1H, H-olefin). C NMR (100 MHz, CDCl
3
): d 13.8,
(
-)-methylenolactocin 3
1
4.2, 22.2, 30.8, 32.6, 60.1, 119.1, 128.3, 144.7, 145.1, 167.3. HRMS
Scheme 3. Synthesis of (ꢀ)-methylenolactocin and (ꢀ)-phaseolinic acid.
+
(
18 2
ESI ): Calcd for [C11H O + H] 183.1385. Found: 183.1391.
4
.1.3. (4R,5R,E)-Ethyl 4,5-dihydroxynon-2-enoate 18
To a mixture of K Fe(CN) (13.39 g, 40.66 mmol, 3.0 equiv),
CO (5.62 g, 40.66 mmol, 3.0 equiv), MeSO NH (1.29 g,
PHAL (106 mg, 0.136 mmol,
O (20 mg, 0.0542 mmol, 0.4 mol %) in
O (1:1, 136 mL) at 0 °C was added olefin 14 (2.47 g,
3.55 mmol) in one portion. The reaction mixture was stirred at
°C for 12 h and then quenched with solid Na SO (5.0 g). The stir-
asymmetric dihydroxylation and the orthoester Johnson–Claisen
rearrangement of the allyl alcohol with a chiral vicinal diol func-
tionality as the key steps. Both diastereomers obtained in the latter
reaction were separately converted into the desired target mole-
cules exhibiting a versatile strategy that has significant potential
for further extension to the synthesis of other paraconic acids.
3
6
K
1
1
2
3
2
2
3.55 mmol, 1.0 equiv), (DHQD)
.0 mol %) and K OsO
ꢃ2H
2
2
4
2
t-BuOH–H
1
0
2
2
3
4
4
. Experimental
ring was continued for an additional 45 min and the solution ex-
tracted with EtOAc (5 ꢂ 50 mL). The combined organic layers
.1. General
2 4
were washed with 10% aqueous KOH, water, brine, dried (Na SO )
and concentrated. Silica gel column chromatography of the crude
Flasks were oven or flame dried and cooled in a desiccator. Dry
product (petroleum ether/EtOAc, 6:4) as eluent gave 18 (1.79 g,
2
5
reactions were carried out under an atmosphere of Ar or N
2
. Sol-
61%) as a colorless oil. ½
a
ꢁ
¼ þ38:2 (c 0.22, CHCl
3 3 max
). IR (CHCl ): m
D
vents and reagents were purified by standard methods. Thin-layer
chromatography was performed on EM 250 Kieselgel 60 F254 silica
3434, 2958, 2935, 2873, 1710, 1659, 1467, 1395, 1370, 1307, 1281,
ꢀ
1 1
1217, 1180, 1131, 1093, 1040, 981, 871, 757, 668 cm
(400 MHz, CDCl ): 0.91 (t, J = 7.0 Hz, 3H, CH ), 1.05–1.60
(m, 9H, CH , H-8, H-7, H-6), 2.09 (bs, 2H, -OH), 3.45–3.60 (m, 1H,
. H NMR
gel plates. The spots were visualized by staining with KMnO
UV lamp. The H NMR and C NMR were recorded on Varian
4
or by
3
d
3
1
13
3

R. A. Fernandes, A. K. Chowdhury / Tetrahedron: Asymmetry 22 (2011) 1114–1119
1117
H-5), 4.08–4.16 (m, 1H, H-4), 4.21 (q, J = 7.0 Hz, 2H, OCH
2
), 6.12
4.1.7. S-Methyl O-(R)-1-[(2R,3S)-5-oxo-3-vinyltetrahydrofuran-
(
dd, J = 15.7, 1.7 Hz, 1H, H-2), 6.94 (dd, J = 15.7, 5.0 Hz, 1H, H-3).
2-yl]pentyl carbonodithioate 19a
1
3
C NMR (100 MHz, CDCl
4.0, 74.1, 122.3, 147.1, 166.5. HRMS (ESI ): Calcd for [C11
Na] 239.1259. Found: 239.1264.
3
): d 14.0, 14.1, 22.6, 27.7, 32.7, 60.6,
2
To a mixture of lactone 12a (0.21 g, 1.06 mmol) and CS (0.9 ml,
+
7
H
20
O
4
+
14.83 mmol, 14.0 equiv) in THF (8 mL) was added in portions NaH
(31 mg, 1.27 mmol, 1.2 equiv) at 0 °C and the reaction mixture was
stirred at 0 °C for 1 h. Next, MeI (0.93 ml, 2.1 g, 14.83 mmol,
14 equiv) was added and stirred at room temperature for 2 h.
The reaction was quenched with a saturated aq NH Cl solution
4
and diluted with EtOAc (15 mL). The solution was extracted with
4
.1.4. (4R,5R,E)-4,5-(Isopropylidenedioxy)nona-2-ene-1-ol 13
To a solution of diol 18 (1.06 g, 4.90 mmol) in acetone (30 mL)
were added p-TsOH (catalytic) and 2,2-dimethoxypropane
1.51 mL, 1.28 g, 12.25 mmol, 2.5 equiv) and the reaction mixture
stirred at room temperature for 12 h. Next, NaHCO (0.2 g) was
(
EtOAc (4 ꢂ 30 mL) and the combined organic layers were washed
3
2 4
with brine, dried (Na SO ) and concentrated. The residue was puri-
added and the mixture stirred for an additional 30 min and then
filtered through a pad of silica gel. The filtrate was concentrated
to give virtually pure acetonide ester (1.23 g, 98%) as a colorless
oil. This was used directly for the next reaction without further
fied by silica gel flash column chromatography (petroleum ether/
EtOAc, 95:5) to give xanthate 19a (0.217 g, 71%) as a colorless oil.
2
D
5
½
aꢁ
¼ þ58:2 (c 0.14, CHCl
3
). IR (CHCl
3
): mmax 3081, 2956, 2928,
2860, 1787, 1645, 1459, 1420, 1379, 1217, 1163, 1059, 976, 926,
861, 759, 677 cm
J = 7.0 Hz, 3H, CH
1H, H-2 ), 1.86–2.0 (m, 1H, H-2 ), 2.44 (dd, J = 17.7, 8.6 Hz, 1H,
2
5
ꢀ1
1
purification. ½
a
ꢁ
¼ þ6:2 (c 0.22, CHCl
3
). IR (CHCl
3
):
m
max 2986,
.
3
H NMR (400 MHz, CDCl ): d 0.89 (t,
D
0
0
2
1
960, 2935, 2873, 1725, 1662, 1459, 1380, 1371, 1302, 1258,
3
), 1.1–1.51 (m, 4H, H-4 , H-3 ), 1.71–1.85 (m,
ꢀ
1
1
0
0
167, 1113, 1098, 1051, 979, 875, 857, 812, 758, 625 cm
): d 0.90 (t, J = 7.1 Hz, 3H, CH ), 1.0–1.80
, H-8, H-7, H-6), 1.41 (s, 3H, CH ), 1.44 (s, 3H, CH ),
.71–3.77 (m, 1H, H-5), 4.12–4.17 (m, 1H, H-4), 4.21 (q,
J = 7.1 Hz, 2H, OCH ), 6.11 (dd, J = 15.6, 1.5 Hz, 1H, H-2), 6.86 (dd,
J = 15.6, 5.8 Hz, 1H, H-3). C NMR (100 MHz, CDCl
.
H
NMR (400 MHz, CDCl
m, 9H, CH
3
3
A 3 B
H -4), 2.58 (s, 3H, S–CH ), 2.76 (dd, J = 17.7, 8.9 Hz, 1H, H -4),
(
3
3
3
2.94–3.10 (m, 1H, H-3), 4.36 (dd, J = 7.0, 2.1 Hz, 1H, H-2), 5.15–
5.25 (m, 2H, H-vinyl), 5.72–5.85 (m, 1H, H-vinyl), 5.94–5.99 (m,
3
0
13
2
1H, H-1 ). C NMR (100 MHz, CDCl
3
): d 13.8, 19.2, 22.5, 27.2,
13
3
): d 13.8, 14.1,
2.6, 26.6, 27.2, 28.0, 31.7, 60.5, 80.2, 80.6, 109.2, 122.6, 144.1,
66.0. HRMS (ESI ): Calcd for [C14
57.1762. To a solution of the above acetonide ester (1.23 g,
.8 mmol) in CH Cl (40 mL) was added DIBAL-H (10.6 mL,
0.6 mmol, 1 M solution in hexane, 2.2 equiv) dropwise at 0 °C
30.6, 34.6, 41.0, 80.8, 84.0, 118.4, 135.6, 175.2, 216.3. HRMS
+
2
1
2
4
1
20 3 2
(ESI ): Calcd for [C13H O S + H] 289.0933. Found: 289.0938.
+
24 4
H O + H] 257.1753. Found:
4.1.8. S-Methyl O-(R)-1-[(2R,3R)-5-oxo-3-vinyltetrahydrofuran-
2-yl]pentyl carbonodithioate 19b
The title compound was prepared from 12b (0.13 g,
0.656 mmol) by a procedure similar to that described for the con-
version of 12a to 19a to afford 19b (0.132 g, 70%) as a colorless oil.
2
2
and the reaction mixture stirred for 2.5 h. It was then quenched
by adding a saturated aq solution of potassium-sodium tartrate
and stirred vigorously at room temperature for 1 h. The solution
2
D
5
½
a
ꢁ
¼ ꢀ34:7 (c 0.12, CHCl
3
). IR (CHCl
3
): mmax 3021, 2960, 2928,
was extracted with CH
extracts were washed with brine, dried (Na
2
Cl
2
(4 ꢂ 40 mL) and the combined organic
2873, 1783, 1643, 1467, 1418, 1217, 1164, 1063, 969, 931, 758,
ꢀ1
1
2
SO ) and concentrated.
4
668 cm
CH
(s, 3H, S-CH
3), 4.73 (dd, J = 8.3, 2.2 Hz, 1H, H-2), 5.18–5.26 (m, 2H, H-vinyl),
.
H NMR (400 MHz, CDCl
3
): d 0.90 (t, J = 7.1 Hz, 3H,
0
0
0
The residue was purified by silica gel flash column chromatogra-
3
), 1.31–1.35 (m, 4H, H-4 , H-3 ), 1.81–1.88 (m, 2H, H-2 ), 2.57
phy (petroleum ether/EtOAc, 4:1) to provide the allyl alcohol 13
3
), 2.6 (d, J = 10.0 Hz, 2H, H-4), 3.35–3.46 (m, 1H, H-
2
D
5
(
0.977 g, 95%) as a colorless oil. ½
a
ꢁ
¼ þ22:8 (c 0.22, CHCl
3
). Other
0
13
spectroscopic data and analysis were the same as reported
5.60–5.67 (m, 1H, H-vinyl), 5.67–5.72 (m, 1H, H-1 ). C NMR
(100 MHz, CDCl ): d 13.9, 19.3, 22.5, 27.1, 29.5, 33.8, 42.4, 81.3,
1.8, 119.8, 133.0, 175.8, 214.5. HRMS (ESI ): Calcd for
+ H] 289.0933. Found: 289.0941.
8
b
earlier.
3
+
8
4
.1.5. (4S,5R)-5-[(R)-1-Hydroxypentyl]-4-vinyl-4,5-
20 3 2
[C13H O S
dihydrofuran-2(3H)-one 12a and (4R,5R)-5-[(R)-1-
hydroxypentyl]-4-vinyl-4,5-dihydrofuran-2(3H)-one 12b
To a solution of allyl alcohol 13 (0.60 g, 2.80 mmol) in toluene
4.1.9. (4S,5S)-5-Pentyl-4-vinyl-4,5-dihydrofuran-2(3H)-one 20a
A mixture of 19a (0.230 g, 0.797 mmol), Bu SnH (3.22 mL,
3
(
1
2
15 mL) were added trimethylorthoacetate (3.36 g, 28.0 mmol,
3.48 g, 11.96 mmol, 15.0 equiv) and AIBN (catalytic amount) in tol-
uene (15 mL) was stirred at reflux for 6 h. It was then concentrated
and the residue purified by silica gel flash column chromatography
(petroleum ether/EtOAc, 95:5) to provide 20a (0.145 g, quant.) as a
0.0 equiv) and EtCO
2
H (catalytic) and the solution refluxed for
4 h. After cooling to room temperature, the volatile material
was removed under reduced pressure and the residue (0.77 g)
was used directly for the next reaction without any further purifi-
cation. Analysis of the crude methyl ester by H NMR indicated a
diastereomer mixture (2.5:1). To a solution of crude methyl ester
in MeOH (30 mL) was added 4 M HCl (5 mL), and stirred for 12 h
at room temperature. It was then quenched with powdered NaH-
2
5
colorless oil. ½
a
ꢁ
¼ ꢀ79:6 (c 0.4, CHCl
3 3
). IR (CHCl ): mmax 3083,
D
1
2932, 2861, 1782, 1645, 1466, 1380, 1264, 1208, 1168, 996, 946,
ꢀ1
1
922, 758, 682, 527 cm
J = 6.8 Hz, 3H, CH ), 1.15–1.78 (m, 8H, H-4 , H-3 , H-2 , H-1 ), 2.45
B
(dd, J = 17.2, 10.3 Hz, 1H, H -3), 2.69 (dd, J = 17.2, 8.1 Hz, 1H, H -
3
. H NMR (400 MHz, CDCl ): d 0.89 (t,
0
0
0
0
3
A
CO
idue purified by silica gel flash column chromatography
petroleum ether/EtOAc, 9:1) to provide 12b (0.122 g, 22%) as a
colorless oil. Further elution gave 12a (0.327 g, 59%) as a colorless
3
(1.0 g) and filtered. The filtrate was concentrated and the res-
3), 2.73–2.89 (m, 1H, H-4), 4.15 (dt, J = 8.4, 3.7 Hz, 1H, H-5),
5.15–5.21 (m, 2H, H-vinyl), 5.67–5.77 (m, 1H, H-vinyl). 13C NMR
(
3
(100 MHz, CDCl ): d 13.9, 22.4, 25.4, 31.5, 33.6, 35.5, 46.3, 84.8,
+
118.0, 135.7, 175.9. HRMS (ESI ): Calcd for [C11
18 2
H O + H]
25
oil. Data for 12a: ½
a
ꢁ
¼ ꢀ48:9 (c 0.12, CHCl
3
). Data for 12b:
183.1385. Found: 183.1391.
D
2
D
5
½aꢁ
¼ ꢀ50:5 (c 0.8, CHCl
3
). Other spectroscopic data and analysis
8b
for 12a and 12b were the same as reported earlier.
4.1.10. (4R,5S)-5-Pentyl-4-vinyl-4,5-dihydrofuran-2(3H)-one
0b
The title compound was prepared from 19b (0.230 g,
2
4
.1.6. (4S,5R)-5-[(R)-1-Hydroxypentyl]-4-vinyl-4,5-
dihydrofuran-2(3H)-one 12a and (4R,5R)-5-[(R)-1-
0.797 mmol) by a procedure similar to that described for the con-
hydroxypentyl]-4-vinyl-4,5-dihydrofuran-2(3H)-one 12b
The orthoester Johnson–Claisen rearrangement reaction of 13 in
xylene solvent over 4 h was performed in a manner similar to that
version of 19a to 20a to provide 20b (0.145 g, quant.) as a colorless
2
5
oil. ½
a
ꢁ
¼ ꢀ35:6 (c 0.24, CHCl
3 3
). IR (CHCl ): mmax 3020, 2957, 2931,
D
2861, 1778, 1466, 1420, 1351, 1217, 1171, 1140, 1025, 946, 926,
8
b
ꢀ1
1
reported earlier to give 12a (46%) and 12b (42%).
3
758, 670 cm . H NMR (400 MHz, CDCl ): d 0.89 (t, J = 6.7 Hz,

1
118
R. A. Fernandes, A. K. Chowdhury / Tetrahedron: Asymmetry 22 (2011) 1114–1119
0
0
0
3
1
H
H, CH
3
), 1.23–1.43 (m, 6H, H-4 , H-3 , H-2 ), 1.44–1.66 (m, 2H, H-
-3), 2.71 (dd, J = 17.3, 8.1 Hz, 1H,
-3), 3.11–3.21 (m, 1H, H-4), 4.50 (ddd, J = 9.2, 6.4, 4.3 Hz, 1H, H-
(40 mL, containing 4 mL concd HCl) was added and the aqueous
layer extracted with Et
O (5 ꢂ 30 mL). The combined organic lay-
ers were washed with brine, dried (Na SO ) and concentrated.
The residue was purified by silica gel flash column chromatogra-
0
), 2.44 (dd, J = 17.3, 5.6 Hz, 1H, H
A
2
B
2
4
5
), 5.12–5.23 (m, 2H, H-vinyl), 5.76 (ddd, J = 17.0, 10.3, 8.7 Hz, 1H,
1
3
H-vinyl). C NMR (100 MHz, CDCl
4.7, 43.1, 83.3, 118.0, 134.0, 176.3. HRMS (ESI ): Calcd for
+ H] 183.1385. Found: 183.1389.
3
): d 13.9, 22.4, 25.3, 30.8, 31.5,
phy (CH
2
Cl
2
/EtOAc, 95:5) to provide 3 (61 mg, 64%) as a white so-
+
3a
25
D
5a
3
lid. Mp 81–83 °C, lit. 82–84 °C. ½
a
ꢁ
¼ ꢀ7:0 (c 0.12, CH
3
OH). lit.
¼ ꢀ6:8 (c 0.5, MeOH). IR
2
D
0
4h
20
D
[
C
11
H
18
O
2
½
a
(
ꢁ
¼ ꢀ10 (c 0.5, MeOH), lit.
½
aꢁ
CHCl
3
):
mmax 3352, 3020, 2930, 1763, 1720, 1216, 1115, 1025,
ꢀ
1
1
4
.1.11. (2S,3R)-5-Oxo-2-pentyltetrahydrofuran-3-carboxylic
929, 760, 669 cm
J = 6.7 Hz, 3H, CH
.
H
NMR (400 MHz, CDCl
3
):
d
0.89 (t,
0
0
0
acid 21a
A solution of vinyl lactone 20a (0.145 g, 0.8 mmol) in CH
25 mL) was cooled to –78 °C and a stream of O /O was bubbled
through the reaction mixture for 30 min. The reaction was
quenched with Me S (0.5 mL) and stirred for 1 h at –78 °C and
for a further 2 h at room temperature. The mixture was concen-
trated to give the crude aldehyde (0.147 g), which was used di-
rectly for the next reaction. To a solution of the crude aldehyde
in acetone (10 mL) at 0 °C was dropwise added Jones’ reagent
3
), 1.11–1.58 (m, 6H, H-4 , H-3 , H-2 ), 1.65–1.81
0
2
Cl
2
(m, 2H, H-1 ), 3.62–3.64 (m, 1H, H-3), 4.78–4.83 (m, 1H, H-2),
6.02 (d, J = 2.8 Hz, 1H, H-methylene), 6.47 (d, J = 2.8 Hz, 1H, H-meth-
(
3
2
1
3
ylene). C NMR (CDCl
49.4, 78.8, 125.8, 132.4, 168.2, 173.8. HRMS (ESI ): Calcd for
+ H] 213.1127. Found: 213.1135.
3
, 100 MHz): d 13.9, 22.4, 24.4, 31.3, 35.7,
+
2
16 4
[C11H O
4.1.14. (2S,3S,4S)-4-Methyl-5-oxo-2-pentyltetrahydrofuran-3-
carboxylic acid/(–)-phaseolinic acid 6
[
0.5 mL; (Jones reagent: CrO
this solution was added conc. H
O (1 mL) to give a transparent orange solution]. The reaction
3
(1.33 g) dissolved in H
2
O (3 mL). To
To a solution of 21b (20 mg, 0.10 mmol) in THF (4 mL) at –78 °C
was added NaHMDS (0.22 mL, 0.22 mmol, 1.0 M solution in THF,
2.2 equiv) and stirred for 1.5 h. Next, MeI (0.063 mL, 0.142 g,
1.0 mmol, 10.0 equiv) was added and the mixture stirred at –
78 °C for 2 h and then allowed to warm to –20 °C. Next, 2 M HCl
(1.0 mL) was added and the mixture extracted with EtOAc
2
SO (1.2 mL) at 0 °C, and finally
4
H
2
mixture was stirred at 0 °C for 20 min and then excess Jones’ re-
agent was destroyed by adding isopropanol (1 mL). The volatiles
were removed under reduced pressure, and a brine solution
(
5 mL) was added after which the reaction mixture was extracted
with EtOAc (5 ꢂ 30 mL). The combined organic layers were dried
Na SO ) and concentrated. The residue was purified by silica gel
flash column chromatography (petroleum ether/EtOAc, 1:1) to pro-
vide 21a (0.151 g, 95%) as white solid. Mp 103–105 °C.
). IR (CHCl ): max 3467, 3020, 2930,
856, 1779, 1746, 1461, 1217, 1021, 910, 770, 669 cm . H NMR
400 MHz, CDCl ): d 0.90 (t, J = 6.6 Hz, 3H, CH ), 1.11–1.56 (m,
H, H-4 , H-3 , H-2 ), 1.65–1.85 (m, 2H, H-1 ), 2.81 (dd, J = 18.0,
.6 Hz, 1H, H -4), 2.94 (dd, J = 18.0, 8.6 Hz, 1H, H -4), 3.05–3.15
):
d 13.9, 22.4, 24.8, 31.3, 31.9, 35.3, 45.4, 81.8, 174.4, 176.0. HRMS
(5 ꢂ 15 mL). The combined organic layers were dried (Na
2 4
SO )
and concentrated. The residue was purified by silica gel flash col-
umn chromatography (petroleum ether/EtOAc, 1:1) as eluent to
provide 6 (21.4 mg, quantitative) as a white solid. Mp 138–
(
2
4
1
d
25
D
6g
a
140 °C, lit.
139–140 °C.
½
a
ꢁ
¼ ꢀ117 (c 0.10, CHCl
): max 3021, 2959, 2930,
2861, 1775, 1717, 1524, 1459, 1420, 1382, 1216, 1017, 984, 759,
3
), lit.
2
D
5
25
½
a
2
ꢁ
¼ ꢀ39:6 (c 0.16, CHCl
3
3
m
½
aꢁ
¼ ꢀ112 (c 0.26, CHCl
3
). IR (CHCl
3
m
D
ꢀ
1 1
ꢀ
1 1
(
6
9
3
3
3
669, 625 cm . H NMR (400 MHz, CDCl ): d 0.89 (t, J = 7.0 3H,
0
0
0
0
0
0
0
CH
CH
3
), 1.21–1.57 (m, 6H, H-4 , H-3 , H-2 ), 1.33 (d, J = 7.1 Hz, 3H,
), 1.57–1.67 (m, 2H, H-1 ), 3.0–3.09 (m, 1H, H-4), 3.22 (dd,
J = 9.6, 8.2, 1H, H-3), 4.69–4.73 (m, 1 H, H-2). C NMR (100 MHz,
0
A
B
3
13
13
(
m, 1H, H-3), 4.57–4.65 (m, 1H, H-2). C NMR (100 MHz, CDCl
3
3
CDCl ): d = 13.9, 14.4, 22.4, 25.3, 31.0, 31.3, 36.4, 51.6, 77.4,
+
+
(
ESI ): Calcd for [C10
H
16
O
4
+ H] 201.1127. Found: 201.1132.
174.8, 177.5. HRMS (ESI ): Calcd for [C11
Found: 215.1289.
18 4
H O + H] 215.1283.
4
2
.1.12. (2S,3S)-5-Oxo-2-pentyltetrahydrofuran-3-carboxylic acid
1b
The title compound was prepared from 20b (0.145 g, 0.8 mmol)
Acknowledgements
by a procedure similar to that described for the conversion of 20a
to 21a to provide 21b (0.147 g, 92%) as a white solid. Mp 102–
The authors are indebted to IRCC, IIT-Bombay and the Depart-
ment of Science and Technology, New Delhi (Grant No. SR/S1/OC-
25/2008) for financial support. A.K.C. is grateful to Council of Scien-
tific and Industrial Research (CSIR) New Delhi for a research
fellowship.
2
5
1
2
04 °C. ½
931, 1781, 1718, 1441, 1217, 1025, 911, 769, 669 cm . H NMR
): d 0.89 (t, J = 7.1 Hz, 3H, CH ), 1.25–1.75 (m,
H, H-4 , H-3 , H-2 , H-1 ), 2.71 (dd, J = 17.7, 8.5 Hz, 1H, H -4),
.90 (dd, J = 17.7, 5.1 Hz, 1H, H -4), 3.42–3.52 (m, 1H, H-3), 4.67
): d 13.9,
a
ꢁ
¼ ꢀ44:1 (c 0.16, CHCl
3 3
). IR (CHCl ): mmax 3465, 3020,
D
ꢀ1 1
(
400 MHz, CDCl
3
3
0
0
0
0
8
2
(
A
B
dd, J = 13.7, 7.1 Hz, 1H, H-2). 13C NMR (100 MHz, CDCl
3
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8
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5
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a,b,c,d-unsaturated esters see: (a) Zhang, Y.; O’Doherty, G. A. Tetrahedron
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11. Enantiomeric excess was determined by chiral HPLC.
(
f) Bohm, C.; Reiser, O. Org. Lett. 2001, 3, 1315; (g) Ariza, X.; Garcia, J.; Lopez, M.;
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a
,b,-unsaturated ester and further chain elongation by Wittig reaction. Herein
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a
c
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1
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1
6
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(a) Jongkol, R.; Choommongkol, R.; Tarnchompoo, B.; Nimmanpipug, P.;
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