5-(Acyloxy)-2(5H)-furanone and Pyrrolinone Synthons
J. Am. Chem. Soc., Vol. 118, No. 16, 1996 3803
stirred at room temperature for the time indicated (Table 1). At given
intervals samples of 0.3 mL were taken and filtered over Celite (1.0
cm in a Pasteur pipet). The Celite was washed with 0.5 mL of acetone,
and the crude mixture was analyzed by GC for conversion and ee.
General Procedure for the Lipase-Catalyzed Esterifications. A
typical procedure is as follows: 66 mg of immobilized lipase (or 20
mg of immobilized CAL) was added to 3 mL of a solution of the
appropriate solvent containing 20 mg of substrate and 8 mg of the
internal standard. To this mixture was added the appropriate vinyl ester
(0.5 mL). The mixture was stirred at room temperature (only for
compound 2 was it refluxed). At given intervals samples of 0.2 mL
were taken and filtered over Celite (1.0 cm in a Pasteur pipet). The
Celite was washed with CH2Cl2 or acetone, and the crude mixture was
analyzed by GC for conversion and ee.
(2)
Transesterification of Acetic Acid 1-Acetyl-5-oxo-2,5-dihydro-
1H-pyrrol-2-yl Ester (2). A solution of 2 (10.0 g, 54.6 mmol) in
1-butanol (100 mL) was added to 1 L of n-hexane-1-butanol (3:1).
Immobilized CAL (1.82 g) was added, and the mixture was shaken at
20 °C for 40 h. The mixture was filtered over a glass filter (P3), and
the enzyme was washed with acetone (it could be used again). The
solution was concentrated in vacuo, the temperature not exceeding 25
°C. The white solid product mixture was separated by column
chromatography (silica gel, ethyl acetate-n-hexane (1:1)). Pure 2 was
obtained in 50% yield (5.02 g, 27.4 mmol) as almost white crystals:
Rf 0.38; [R]D +199° (c 1.00, CHCl3); ee > 99% as estimated by chiral
GC. 1H NMR and 13C NMR (CDCl3) were identical to those of the
racemate (see the supporting information). 1-Acetyl-5-hydroxy-1,5-
dihydropyrrol-2-one (6) was obtained in 47% yield (3.61 g, 25.6 mmol),
as almost white crystals: mp 90-91 °C; Rf 0.17; 1H NMR (CDCl3) δ
2.50 (s, 3H, NCOCH3), 4.58 (br s, 1H, OH), 6.11 (d, J ) 0.9 Hz, 1H,
OCHN), 6.16 (d, J ) 6.0 Hz, 1H, CHdCHCO), 7.12 (dd, J ) 2.0, 6.0
Hz, 1H, CHdCHCO); 13C NMR (CDCl3) δ 24.29 (q, NCOCH3), 81.63
(d), 128.16 (d), 147.48 (d), 167.79 (s), 171.31 (s); exact mass calcd
for C6H7NO3 141.043, found 141.043. An analytical sample was
sublimed (0.1 mmHg, 50 °C). Anal. Calcd for C6H7NO3: C, 51.06;
H, 5.00; N, 9.92. Found: C, 51.14; H, 5.06; N, 9.90.
Transesterification of Acetic Acid 5-Oxo-2,5-dihydrofuran-2-yl
Ester (1b). To a solution of 1b (8.00 g, 56.3 mmol) in 1.5 L of
n-hexane-1-butanol (3:1) was added immobilized (at pH 7 in a
phosphate buffer)10 lipase PS (3.0 g, 30% w/w). The mixture was
stirred vigorously at room temperature and was monitored by capillary
GC. After 4 h, the ee of (+)-1b was >99% and the stirrer was stopped.
After standing for 15 min, the solution was decanted from the enzyme
slurry and filtered through Celite. The solvent was removed by vacuum
distillation at 10-15 °C, leaving a yellow oil (4.1 g), which was purified
by flash chromatography (silica gel, ethyl acetate-n-hexane (1:3)) to
give 2.6 g (64% yield based on 50% conversion) of a slightly yellow
oil (1b), [R]D + 25.4° (c 1.00, CHCl3), which was pure as determined
by NMR and GC.
variations in acyl substituents at C5 are tolerated (see Table 1,
entries 4-8).
The 5-hydroxy derivative 6, also formed in 50% yield,
partially racemized during the transesterification. Esterification
of 6 (Table 1, entry 9) in n-hexane-vinyl acetate (1:1) at 69
°C (the higher temperature is needed to speed the rate of
racemization relative to the rate of acylation) again with C.
antarctica provides (-)-2 within 18 h in 99% conversion and
>99% ee!
By use of lipases in organic solvents, it is now possible to
prepare in excellent yield and enantiomeric excess either
enantiomer of the investigated butenolides or pyrrolinones either
by transesterification ((+)-enantiomer) or by esterification of
the 5-hydroxy derivatives ((-)-enantiomer) as is illustrated in
Scheme 1. Complete transformation into either enantiomer is
now achievable by (a) in situ racemization of the 5-hydroxy
butenolide and 5-hydroxypyrrolinone followed by esterification
with the appropriate anhydride combined with the enzymatic
transesterification and (b) second-order asymmetric transforma-
tion.
To our knowledge this is the first description of a procedure
to obtain directlysat reasonable rates of conversionsboth
enantiomers with a single enzyme simply by variation of the
procedure. Useful synthons are now available via this approach,
and the potential for application to other heterocyclic systems
is most appealing.
Acknowledgment. A.v.O. and R.P.H. have been supported
by the Dutch National Science Foundation administered through
the Office for Chemical Research. A.D.C. is supported by the
program Innovative Research in Catalysis, an activity of the
Dutch Ministry of Economic Affairs. Prof. B. Zwanenburg
(Nijmegen) kindly provided information on applications of 3
to strigol synthesis.
Experimental Section
Immobilization of Lipases on Hyflo Super Cell. Lipases were
immobilized following a literature procedure.13 Lipase (1.5 g) and
Hyflo Super Cell (5 g) were mixed. After adding 5 mL of a phosphate
buffer of pH 7, the mixture was stirred well for 15 min. The enzyme
slurry was spread on a Petri dish and allowed to dry in the air for 2
days.
General Procedure for the Lipase-Catalyzed Transesterifications
of Pyrrolinones. A typical procedure is as follows: 10 mg of
immobilized enzyme (CAL) was added to 3 mL of a solution of
hexane-n-BuOH (3:1) containing 0.15 mmol of substrate and 8 mg
of tridecane or n-decane (internal standard). Dichloromethane was
added until the solution was clear (0-0.3 mL). The suspension was
Supporting Information Available: Experimental proce-
dures for the synthesis and characterization of 1a, 1b, acetic
acid 1-methyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl ester (7), 5-hy-
droxy-1,5-dihydropyrrol-2-one (12), 2, 8, 9, and 10 (6 pages).
This material is contained in many libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, can be ordered from the ACS, and can be downloaded
from the Internet: see any current masthead page for ordering
information and Internet access instructions.
(14) The absolute configuration is indicated as analogous to 1; this
remains to be proven.
JA953812H