Synthesis of N-butanoylhomoserine lactone

Article abstract of DOI:10.1002/jccs.200700116

Synthesis of N-butanoylhomoserine lactone has been achieved from trans-(2S,4R)-4-hydroxyproline via the key regioselective Baeyer-Villiger reaction.

Full text of DOI:10.1002/jccs.200700116

Journal of the Chinese Chemical Society, 2007, 54, 803-806
803
Note
Synthesis of N-Butanoylhomoserine Lactone
Meng-Yang Chang* (
Department of Applied Chemistry, National University of Kaohsiung, Kaohsiung 811, Taiwan, R.O.C.
), Yung-Hua Kung (
) and Tsun-Cheng Wu (
)
Synthesis of N-butanoylhomoserine lactone has been achieved from trans-(2S,4R)-4-hydroxyproline
via the key regioselective Baeyer-Villiger reaction.
Keywords: trans-(2S,4R)-4-Hydroxyproline; N-Butanoylhomoserine lactone; Regioselective
Baeyer-Villiger reaction.
INTRODUCTION
and its analogs, one-step acylation reaction of commer-
cially available L-homoserine lactone4f,5 with acid chloride
has been generally employed. Therefore, we envisioned
that there is a continuing need for other chiral materials to
synthesize C4-HSL (2) and related derivatives. In continu-
ing the previous investigations and building upon these ob-
servations on trans-(2S,4R)-4-hydroxyproline (1) as the
chiral material, we are interested in developing a new
method to C4-HSL (2) via the key regioselective Baeyer-
Villiger reaction.
The structural framework of trans-(2S,4R)-4-hydroxy-
proline shows that it possesses three functional groups that
can be easily modified, and these are 1-amino, 2-carboxy-
late and 4-hydroxy groups.1 The skeleton represents a sig-
nificant feature for producing a series of different carbon
frameworks using an efficient modification technique.2 Re-
cently we have introduced a straightforward approach to-
ward anisomycin,2h epibatidine,2i pancracine,2j and strepto-
rubin B core2k employing trans-(2S,4R)-4-hydroxyproline
(1) as the starting material. To explore a new application,
synthetic studies toward N-butanoylhomoserine lactone (2)
were investigated.
RESULTS AND DISCUSSION
As shown in Scheme I, compound 3 was prepared by
the standard protocol operation via esterification with
thionyl chloride and methanol at -78 °C and acylation with
triethylamine and n-butanoyl chloride in dichloromethane
at 0 °C. Oxidation of compound 3 was treated with pyri-
dinium chlorochromate and Celite to yield ketone 4 in di-
chloromethane at rt. Regioselective Baeyer-Villiger reac-
tion of ketone 4 with m-chloroperoxybenzoic acid6 yielded
sole tetrahydro-1,3-oxazin-6-one 5. During the process,
other ring-expanded frameworks were not observed. While
poring over the related literature of Baeyer-Villiger ring ex-
pansion reactions, we found that Young and co-workers
had developed a copper(II) acetate-mediated ring expan-
sion of 4-ketoprolines with m-chloroperoxybenzoic acid in
modest yield. The most likely explanation would be that it
is controlled by involvement of the nitrogen lone pair on
substituted pyrrolidin-4-one.6
HO
O
HN
CO H
2
N
H
O
O
N-butanoylhomoserine lactone (2)
trans-(2S,4R)-4-hydroxyproline (1)
Pseudomonas aeruginosa is an opportunistic patho-
gen that causes a wide range of acute and chronic infec-
tions, including sepsis and wound and pulmonary infec-
tions.3a-b It predominately produces two small diffusible
autoinducers, N-3-oxododecanoylhomoserine lactone (3-
oxo-C12-HSL) and N-butanoylhomoserine lactone (C4-
HSL).3c-d Bioassays revealed that L-isomers were essential
as the autoinducers in quorum sensing, while no effect was
observed with D-isomers. The scaffold of N-acyl homo-
serine lactones is common in certain biological analogs
including anti-allergy, asthma, immunosuppressant, and
antineoplastic agents.4 For the preparation of C4-HSL (2)
Finally, C4-HSL (2) was afforded by the regioselec-
tive reduction with diisobutylaluminum hydride and fol-

804 J. Chin. Chem. Soc., Vol. 54, No. 3, 2007
Chang et al.
Scheme I Synthesis of N-butanoylhomoserine lactone (C4-HSL, 2)
HO
HO
1) SOCl , MeOH
2
PCC
CO H
2
CO Me
2
N
H
N
2) C H COCl, Et N
3
(82%)
4
(two steps 90%)
9
O
1
3
O
O
MCPBA
DIBALH, THF
O
O
O
O
HN
CO Me
2
Na CO
2
(62%)
then 6N HCl
(65%)
N
N
CO Me
2
3
O
O
4
5
2
lowed acidification.7 Although the synthetic efficiency of
C4-HSL (2) is decreased in comparison with the literature
reports, we believe the rather lengthy route will be valuable
to report and the present work is complementary to existing
methodology. In summary, we succeeded in accomplishing
the synthesis of C4-HSL (2) from the chiral starting mate-
rial trans-(2S,4R)-4-hydroxyproline (1) via the key regio-
selective Baeyer-Villiger reaction. Currently studies are in
progress in this direction.
afford crude product. Recrystallization from hexane and
ethyl acetate (approx. 4:1) yielded compound 3 (1.94 g,
90%). [a]D22 -81.12° (c 0.04, CHCl3); IR (CHCl3) 3400,
2961, 1742, 1655, 1436, 1200, 1084 cm-1; HRMS (ESI,
M++1) calcd for C10H18NO4 216.1236, found 216.1240; 1H
NMR (500 MHz, CDCl3) d 4.58-4.55 (m, 2H), 3.77-3.72
(m, 1H), 3.73 (s, 3H), 3.53 (d, J = 10.5 Hz, 1H), 2.83 (br s,
1H), 2.32-2.26 (m, 1H), 2.28 (t, J = 7.5 Hz, 2H), 2.10-2.04
(m, 1H), 1.70-1.62 (m, 2H), 0.96 (t, J = 7.5 Hz, 3H); 13
C
NMR (125 MHz, CDCl3) d 172.99, 172.53, 70.27, 57.47,
55.12, 52.27, 37.74, 36.33, 18.05, 13.75; Anal. Calcd for
C10H17NO4: C, 55.80; H, 7.96; N, 6.51. Found: C, 55.98; H,
8.21; N, 6.72.
EXPERIMENTAL SECTION
(2S,4R)-1-Butyryl-4-hydroxy-pyrrolidine-2-carboxylic
acid methyl ester (3)
(2S)-1-Butyryl-4-oxo-pyrrolidine-2-carboxylic acid
methyl ester (4)
Thionyl chloride (2.5 g, 21.0 mmol) was added to a
stirred solution of trans-4-hydroxyproline (1) (1.31 g, 10.0
mmol) in methanol (20 mL) at -78 °C for 10 min. The mix-
ture was stirred in an ice bath for 30 min then at rt for 30
min, followed by reflux for 3 h. Concentration in vacuo fol-
lowed by azotropic removal of water using benzene (50
mL) gave methyl 4-hydroxyproline hydrochloride (1.81 g,
100%). Triethylamine (3.1 g, 30.6 mmol) and n-butanoyl
chloride (1.07 g, 10.0 mmol) were added to a solution of the
resulting product in dichloromethane (40 mL) at 0 °C. Af-
ter stirring at the same temperature for 10 h, the reaction
mixture was concentrated. Ethyl acetate (40 mL) was added
to the residue, and the solution was washed with hydrogen
chloride solution (0.1 N, 10 mL), saturated sodium bicar-
bonate solution and brine, dried, filtered and evaporated to
A solution of compound 3 (1.1 g, 5.1 mmol) in di-
chloromethane (10 mL) was added to a mixture of pyri-
dinium chlorochromate (2.2 g, 10.2 mmol) and Celite (2.0
g) in dichloromethane (20 mL) at rt. After being stirred at rt
for 10 h, the mixture was filtered through a short silica gel
column. The filtrate was dried, filtered and evaporated. Pu-
rification on silica gel (hexane/ethyl acetate = 5/1) yielded
compound 4 (900 mg, 82%). [a]D22 +8.33° (c 0.04, CHCl3);
IR (CHCl3) 1750, 1656, 1651, 1435, 1418, 1196 cm-1;
HRMS (ESI, M++1) calcd for C10H16NO4 214.1079, found
214.1081; 1H NMR (300 MHz, CDCl3) d 5.04 (dd, J = 2.7,
10.5 Hz, 1H), 4.50 (d, J = 17.7 Hz, 1H), 3.97 (d, J = 17.7
Hz, 1H), 3.76 (s, 3H), 2.92 (dd, J = 10.5, 18.9 Hz, 1H), 2.61
(dd, J = 2.7, 18.9 Hz, 1H), 2.28 (t, J = 7.5 Hz, 2H), 1.74-

Synthesis of N-Butanoylhomoserine Lactone
J. Chin. Chem. Soc., Vol. 54, No. 3, 2007 805
1.67 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 207.53, 172.99, 172.13, 55.32, 53.21, 52.93,
40.36, 36.82, 18.06, 13.94; Anal. Calcd for C10H15NO4: C,
56.33; H, 7.09; N, 6.57. Found: C, 56.69; H, 6.77; N, 6.96.
ACKNOWLEDGMENT
The authors would like to thank the National Science
Council (NSC-95-2113-M-390-003-MY2) of the Republic
of China for financial support.
(2S)-3-Butyryl-6-oxo-[1,3]oxazinane-4-carboxylic acid
methyl ester (5)
To a solution of m-chloroperoxybenzoic acid (6.0 g,
75%, 26.1 mmol) in dichloromethane (30 mL) was added a
solution of compound 4 (2.2 g, 10.3 mmol) and sodium car-
bonate (4.3 g, 40.6 mmol) in dichloromethane (30 mL) at 0
°C. The reaction mixture was stirred at rt for 20 h. Saturated
sodium carbonate solution (10 mL) was added to the reac-
tion mixture and the solvent was concentrated. The residue
was extracted with ethyl acetate (3 ´ 50 mL). The com-
bined organic layers were washed with brine, dried, filtered
and evaporated to afford crude product. Purification on sil-
ica gel (hexane/ethyl acetate = 4/1~2/1) afforded lactone
compound 5 (1.47 g, 62%) as the rotamers. HRMS (ESI,
M++1) calcd for C10H16NO5 230.1029, found 230.1026; 1H
NMR (300 MHz, CDCl3) d 5.60 (d, J = 10.5 Hz, 1H), 5.38
(d, J = 10.5 Hz, 1H), 4.91-4.82 (m, 1H), 3.74 (s, 3H), 3.09
(dd, J = 10.5, 18.9 Hz, 1H), 2.64 (dd, J = 2.7, 18.9 Hz, 1H),
2.25 (t, J = 7.5 Hz, 2H), 1.76-1.61 (m, 2H), 0.99 (t, J = 7.5
Hz, 3H); Anal. Calcd for C10H15NO5: C, 52.40; H, 6.60; N,
6.11. Found: C, 52.69; H, 6.72; N, 6.36.
Received September 4, 2006.
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N-Butanoylhomoserine lactone (C4-HSL, 2)
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