Efficient stereoselective synthesis of enantiopure 2-substituted paraconic acids

Article abstract of DOI:10.1016/j.tetasy.2008.02.031

Eight enantiopure (2S,3S)-2-aryl-5-oxotetrahydrofuran-3-carboxylic acids have been synthesized. The key step was a highly stereoselective aldol reaction between an N-acyl oxazolidinone and a corresponding aldehyde.

Full text of DOI:10.1016/j.tetasy.2008.02.031

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 896–899
Efficient stereoselective synthesis of enantiopure 2-substituted
paraconic acids
Hyun-Chul Kim and Oee-Sook Park*
Department of Chemistry, Institute for Basic Sciences, College of Natural Sciences, Chungbuk National University,
Cheong ju 361-763, Chungbuk, South Korea
Received 17 January 2008; accepted 29 February 2008
Abstract—Eight enantiopure (2S,3S)-2-aryl-5-oxotetrahydrofuran-3-carboxylic acids have been synthesized. The key step was a highly
stereoselective aldol reaction between an N-acyl oxazolidinone and a corresponding aldehyde.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
2-substituted paraconic acid 2 is a key starting material
(Scheme 1). Lawlor and McNamee8 reported the synthesis
of trans 2-substituted paraconic acid, together with its cis-
isomer (3:2 overall 75%).
Paraconic acids are a family of chiral c-butyrolactones with
a carboxylic acid at the b-position, isolated from various
species of mosses, lichens, and fungus. They possess impor-
tant biological activities, such as antitumor, antibiotic,
antifungal, and antibacterial.1 Racemic, as well as enantio-
selective syntheses of several paraconic acids have already
been reported.2 However, many of these suffer from poor
overall yields, large number of steps, and a lack of general-
ity. Furofurans, one of the major subclasses of the lignan
family, exhibit a wide variety of biological activities, such
as antitumor, antihypertensive, antioxidant, inhibition of
plate-activating factor (PAF), phosphodiesterase inhibitory
activity on microsomal monooxygenase in insects, and pyr-
enthrins insecticidal.3
In connection with our synthetic studies for unsymmetri-
cally substituted furofurans, we herein report an efficient
stereoselective synthesis of enantiopure 2-substituted
O
Ar2
HO2C
H
H
Ar1
O
Ar1
O
O
2
1
Ar2
Due to the important biological activities of paraconic
acids, many publications have represented interesting
methods for their stereoselective syntheses,4 including the
ring-closing methathesis of two electron deficient olefins,5
free radical-mediated conjugate additions,6 and aldol
reactions of dioxones derived from tartaric acid.7 Of the
furofurans, unsymmetrically substituted furofurans 1, such
as (+)-fargesin, (+)-epimagnolin, and (+)-kobusin have
generated considerable and continued interest due to their
unique structural characteristics and stereochemical diver-
sity. For the synthesis of those compounds, enantiopure
Ar2
H
HO
O
HO
HO
O
O
HO
Ar2
H
H
H
H
H
H
H
Ar1
Ar1
Ar1
O
O
1
OH
HO2C
Ar1
O
Ar1
O
O
O
2
*
Corresponding author. Tel.: +82 43 261 2283; fax: +82 43 267 2279;
e-mail: ospark@cbnu.ac.kr
Scheme 1. Retrosynthetic analysis of 1.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.02.031

H.-C. Kim, O.-S. Park / Tetrahedron: Asymmetry 19 (2008) 896–899
897
O
Bn
NH
Bn
Bn
O
H
a
b
Ar1
OBR
O
O
N
O
N
O
O
O
O
O
O
3
4
5
O
O
Bn
HO2C
Ar1
H
c
O
N
O
O
O
Ar1
O
2
6
Scheme 2. Reagents and conditions: (a) n-BuLi, b-carbomethoxypropionyl chloride/THF, ꢀ78 °C to rt, 3 h; (b) Bu2BOTf, DIPEA/CH2Cl2, ꢀ78 °C,
Ar1CHO, 20 min; (c) LiOH, H2O2/THF:H2O, 0 °C to rt, 3 h.
Table 1. Physical and spectroscopic data of 2-substituted paraconic acids
Entry Products
Yielda
IR (neat, cmꢀ1
)
HRMS
NMR
physicochemical
properties
1
Yield: 65%
3428, 1782,
1736, 1170
Calcd for C12H11O6 1H NMR (300 MHz, CD3OD):
HO2C
mp (°C): 160–161
251.0556 [M+H]+,
found 251.0567
d 2.97 (m, 2H), 3.41 (m, 1H), 5.56
(d, J = 7.79 Hz, 1H), 5.97 (s, 2H),
6.72–6.92 (m, 3H). 13C NMR
(75 MHz, CD3OD): d 177.1,
174.0, 149.6, 133.4, 121.3, 109.1,
107.4, 102.7, 84.5, 49.6, 33.5
25
½aꢁD ¼ ꢀ44:2 (c 1.0, MeOH)
O
O
O
O
HO2C
2
Yield: 48%
3479, 1778,
1735, 1126
Calcd for C14H16O7 1H NMR (300 MHz, CD3OD):
MeO
mp (°C): 143–145
296.0896 [M+H]+,
found 296.0998
d 2.70 (m, 2H), 3.33 (m, 1H), 3.77
(s, 9H), 5.56 (d, J = 6.70 Hz, 1H),
6.53 (s, 2H). 13C NMR (75 MHz,
CD3OD): d 177.1, 174.1, 154.8,
135.8, 104.4, 104.3, 84.4, 61.1,
56.7, 56.6, 49.7, 33.4
O
25
O
½aꢁD ¼ ꢀ36:2 (c 1.0, MeOH)
MeO
MeO
HO2C
3
Yield: 67%
3386, 1743,
1643, 1176
Calcd for C13H15O6 1H NMR (300 MHz, CDCl3):
mp (°C): 178–179
267.0869 [M+H]+,
found 267.0775
d 3.02 (m, 2H), 3.44 (m, 1H), 3.81
(d, J = 1.10 Hz, 6H), 5.60 (d,
J = 7.26 Hz, 1H), 6.80 (m, 3H).
13C NMR (75 MHz, CDCl3):
d 177.1, 173.8, 149.8, 129.9, 118.2,
111.1, 108.4, 82.1, 56.0,
O
25
O
½aꢁD ¼ ꢀ29:4 (c 1.0, MeOH)
MeO
MeO
48.1, 32.3
HO2C
4
5
Yield: 57%
3413, 1747,
1643, 1191
Calcd for C11H11O4 1H NMR (300 MHz, CD3OD):
mp (°C): 119–123
207.0657 [M+H]+,
found 207.0676
d 2.80 (m, 2H), 3.41 (m, 1H), 5.60
(d, J = 7.41 Hz, 1H), 7.30–7.391
(m, 5H). 13C NMR (75 MHz,
CD3OD): d 177.2, 174.1, 139.9,
129.9, 129.8, 127.1, 84.4, 49.7, 33.3
25
½aꢁD ¼ ꢀ37:4 (c 1.6, MeOH)
O
O
Calcd for C12H13O5 1H NMR (300 MHz, CDCl3):
HO2C
Yield: 69%
3490, 1785,
1731, 1173
mp (°C): 138–139
237.0763 [M+H]+,
found 237.0884
d 3.02 (m, 2H), 3.41 (m, 1H),
3.80 (s, 3H), 5.60 (d, J = 7.35 Hz),
6.90 (m, 2H), 7.32 (m, 2H).
13C NMR (75 MHz, CDCl3):
d 174.1, 173.9, 132.4, 127.1, 114.3,
113.8, 82.1, 55.4, 48.2, 32.3
25
½aꢁD ¼ ꢀ56:0 (c 1.6, MeOH)
O
O
MeO
(continued on next page)

898
H.-C. Kim, O.-S. Park / Tetrahedron: Asymmetry 19 (2008) 896–899
Table 1 (continued)
Entry Products
Yielda
IR (neat, cmꢀ1
)
HRMS
NMR
physicochemical
properties
6
Yield: 52%
3394, 1747,
1670, 1191
Calcd for C12H13O4 1H NMR (300 MHz, CDCl3):
HO2C
mp (°C): 110–113
221.0814 [M+H]+,
found 221.0768
d 2.40 (s, 3H), 3.05 (m, 2H),
3.30–3.44 (m, 1H), 5.60 (d,
J = 6.60 Hz, 1H), 7.06–7.30
(m, 4H). 13C NMR (75 MHz,
CDCl3): d 175.8, 174.3, 138.8,
137.6, 129.8, 128.8, 125.9, 122.5,
82.0, 48.2, 31.8, 21.4
25
½aꢁD ¼ ꢀ61:1 (c 1.0, MeOH)
O
O
HO2C
7
Yield: 60%
3428, 1747,
1673, 1195
Calcd for C12H13O4 1H NMR (300 MHz, CDCl3):
mp (°C): 103–106
221.0814 [M+H]+,
found 221.0772
d 2.36 (s, 3H), 2.95 (m, 2H), 3.35
(m, 1H), 5.60 (d, J = 6.87 Hz,
1H), 7.12–7.26 (m, 5H).
13C NMR (75 MHz, CDCl3):
d 175.1, 174.1, 139.1, 134.7,
129.6, 125.4, 82.1, 48.2, 32.0, 21.8
25
½aꢁD ¼ ꢀ31:3 (c 1.0, MeOH)
O
O
HO2C
8
Yield: 46%
3390, 1778,
1735, 1167
Calcd for C13H13O4 1H NMR (300 MHz, CDCl3):
mp (°C): 145–146
233.0814 [M+H]+,
found 233.0746
d 2.70 (dd, J = 8.60, 17.7 Hz, 1H),
3.03 (dd, J = 7.20, 17.7 Hz, 1H),
3.69 (m, 1H), 5.45 (m, 1H), 6.20
(m, 1H), 6.79 (d, J = 15.8 Hz,
1H), 7.2–7.3 (m, 5H). 13C NMR
(75 MHz, CDCl3): d 177.0, 174.5,
135.3, 134.9, 128.7, 126.9, 121.5,
79.8, 31.0, 29.7
O
25
O
½aꢁD ¼ þ15:0 (c 1.6, MeOH)
a Isolated yield based on compound 4.
paraconic acids 2. The key reaction is a highly stereoselec-
tive aldol reaction between an N-acyl oxazolidinone and a
suitable aldehyde.
3. Conclusion
In conclusion, we have presented a short, general, and effi-
cient approach to the synthesis of enantiopure 2-substi-
tuted paraconic acids. By using this methodology, (+)-
fargesin and (+)-epimagnolin were synthesized.14
2. Results and discussion
The synthesis of (2S,3S)-2-aryl-5-oxotetrahydrofuran-3-
carboxylic acids 2 was accomplished as depicted in Scheme
Acknowledgment
2.
This work was supported by a Chungbuk National Univer-
sity Grant in 2007.
b-Carbomethoxypropionyl chloride was treated with
freshly prepared (S)-(ꢀ)-4-benzyl-2-oxazolidinone
3
(reduction of (S)-phenylalanine with sodium borohydride
gave (S)-phenylalaninol, which upon treatment with
anhydrous sodium carbonate in diethyl carbonate gave
an oxazolidinone, 80% yield over two steps9), in the pres-
ence of n-BuLi to afford 1-(4S-benzyl-2-oxazolidin-3-yl)-
4-methoxybutane-1,4-dione 4 in 95% yield. Aldol conden-
sation of a boron (Z)-enolate10 (generated by the treatment
of N-acyl oxazolidinone 4 with dibutylboron triflate11 and
DIPEA in CH2Cl2 at ꢀ78 °C), followed by treatment with
the corresponding aldehyde, afforded the addition product
5 as an unstable key intermediate, which was not isolated
but instead subjected to intramolecular ring cyclization to
give c-lactone 6 with 95:5 diastereomeric selectivity, which
was determined on the basis of HPLC analysis.12 The
chiral auxiliary was removed using lithium peroxide13 to
afford (2S,3S)-2-aryl-5-oxotetrahydrofuran-3-carboxylic
acids 2. Eight (2S,3S)-2-aryl-5-oxotetrahydrofuran-3-carb-
oxylic acids were prepared. Their physical and spectral
data are given in Table 1.
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