Enantio- and regioselective baeyer-villiger oxidations of 2- and 3-substituted cyclopentanones using engineered bakers' yeast

Full text of DOI:10.1021/jo980737v

J . Org. Chem. 1998, 63, 7103-7106
7103
Sch em e 1
En a n tio- a n d Regioselective
Ba eyer -Villiger Oxid a tion s of 2- a n d
3-Su bstitu ted Cyclop en ta n on es Usin g
En gin eer ed Ba k er s’ Yea st
Margaret M. Kayser,*,† Gang Chen,‡ and
J on D. Stewart*,§
Departments of Chemistry, University of New Brunswick,
Saint J ohn, NB, Canada, and University of Florida,
Gainesville, Florida 32611
Received April 20, 1998
In tr od u ction
We have reported the construction and evaluation of
a new strain of bakers’ yeast (Saccharomyces cerevisiae)
that performs asymmetric Baeyer-Villiger oxidations on
a variety of cyclohexanones.1 This strain represents the
first example of our engineered yeast strategy that allows
nonspecialists to easily apply enzymes to asymmetric
organic synthesis. The Baeyer-Villiger reaction is car-
ried out by cyclohexanone monooxygenase, cloned from
the bacterium Acinetobacter sp. NCIB 9871.2 This en-
zyme was chosen because of its broad substrate tolerance
and its high enantioselectivity (reviewed in ref 3). Our
previous studies have focused on a complete series of
alkyl-substituted cyclohexanones, and we found that the
engineered yeast strain oxidized these compounds with
high regio- and enantioselectivities.1,4 Under the opti-
mized conditions, no byproducts were formed and car-
bonyl reduction and lactone hydrolysis by yeast enzymes
were not significant.
We also found that the same yeast oxidized cyclopen-
tanone to δ-valerolactone in 67% yield.1 Moreover, the
work of Furstoss and co-workers suggested that cyclo-
hexanone monooxygenase might also be useful for oxida-
tions of substituted cyclopentanones.5 Chiral substituted
δ-valerolactones are valuable intermediates in organic
synthesis6-9 and Baeyer-Villiger oxidations of substi-
tuted cyclopentanones are an attractive route to these
lactones. We therefore examined the oxidations of a
series of 2- and 3-alkyl-substituted cyclopentanones using
our engineered yeast strain. The results roughly parallel
those previously observed for cyclohexanones: the en-
zyme selectively oxidizes (S)-2-alkyl-substituted cyclo-
pentanones and displays useful regioselectivities in the
oxidations of 3-alkyl-substituted cyclopentanones.
Resu lts a n d Discu ssion
2-Alkyl-substituted cyclopentanones (1b,c,e-h ; Scheme
1) were prepared by alkylation and decarboxylation of
methyl cyclopentanone-2-carboxylate. 2-Allylcyclopen-
tanone 1d was prepared by direct alkylation of cylopen-
tanone. An analogous series of 3-substituted cyclopen-
tanones (3b-h ; Scheme 1) was synthesized by Michael
addition of the appropriate alkyl Grignard reagents to
2-cyclopenten-1-one in the presence of cuprous iodide.10
Yeast-mediated oxidations were carried out essentially
as described previously,1 and the results are summarized
in Table 1. One equivalent of â-cyclodextrin (relative to
the ketone) was included during the oxidations of 1g and
1h to overcome problems with substrate solubility.11 In
the case of 3-substituted cyclopentanones 3a -h , this
strategy was not useful: addition of either â- or γ-cyclo-
dextrin to the reaction mixture resulted in substrate
precipitation and the yields were inferior to those ob-
tained from the reactions carried out in the absence of
cyclodextrins. The reactions were sampled periodically
and analyzed by chiral-phase GC. We were able to
achieve baseline resolution of all enantiomers except
lactones 4e-h . Absolute configurations of 1c-h and
2c-h were deduced by comparing the signs of the optical
rotations with literature values.5,12-14 Optical rotation
data for 1f and 2f were unavailable, and we have
† University of New Brunswick. Phone (506) 648-5576, fax (506)
648-5650, e-mail kayser@unbsj.ca.
‡ University of New Brunswick.
§ University of Florida. Phone (352) 846-0743, fax (352) 846-2095,
e-mail jds2@chem.ufl.edu.
(1) Engineered yeast strain: 15C(pKR001); its construction is
described in Stewart, J . D.; Reed, K. W.; Kayser, M. M. J . Chem. Soc.,
Perkin Trans. 1 1996, 755-757.
(2) Chen, Y.-C. J .; Peoples, O. P.; Walsh, C. T. J . Bacteriol. 1988,
170, 781-789.
(3) Stewart, J . D. Curr. Org. Chem. 1998, 2, 211-232.
(4) (a) Stewart, J . D.; Reed, K. W.; Zhu, J .; Chen, G.; Kayser, M. M.
J . Org. Chem. 1996, 61, 7652-7653. (b) Stewart, J . D.; Reed, K. W.;
Martinez, C. A.; Zhu, J .; Chen, G.; Kayser, M. M. J . Am. Chem. Soc.
1998, 120, 3541-3548.
(5) Alphand, V.; Archelas, A.; Furstoss, R. J . Org. Chem. 1990, 55,
347-350.
(6) Smith, C. D.; Zhang, X. Q.; Mooberry, S. L.; Patterson, G. M. L.;
Moore, R. E. Cancer Res. 1994, 54, 3779-3784.
(7) Golakoti, T.; Ogino, J .; Heltzel, C. E.; Lehusebo, T.; J ensen, C.
M.; Larsen, L. K.; Patterson, G. M. L.; Moore, R. E.; Mooberry, S. L.;
Corbett, T. H.; Valeriote, F. A. J . Am. Chem. Soc. 1995, 117, 12030-
12049.
(8) Harris, L.; J arowicki, K.; Kocienski, P. Synlett 1996, 903.
(9) Schabbert, S.; Tiedemann, R.; Schaumann, E. Liebigs Ann.-Rec.
1997, 879-880.
(10) Horiguchi, Y.; Komatsu, M.; Kuwajima, I. Tetrahedron Lett.
1989, 7087-7080.
(11) Bar, R. Trends Biotechnol. 1989, 7, 2-4.
(12) Utaka, M.; Watabu, H.; Takeda, A. J . Org. Chem. 1987, 52,
4363-4368.
(13) Posner, G. H.; Hulce, M. Tetrahedron Lett. 1984, 379-382.
(14) Hashimoto, S.; Miyazaki, Y.; Ikegami, S. Synth. Commun. 1992,
22, 2717-2722.
S0022-3263(98)00737-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/09/1998

7104 J . Org. Chem., Vol. 63, No. 20, 1998
Ta ble 1. Oxid a tion s of Su bstitu ted Cyclop en ta n on es by En gin eer ed Ba k er s’ Yea st
Notes
a
b
Yields refer to chromatographically purified samples unless otherwise indicated. Yields determined by gas chromatography using
an internal standard. c Values of enantiomeric excess were determined by chiral-phase GC analysis. Optical rotations were measured
d
from CHCl3 solutions at ambient temperature. e Not determined. f Enantioselectivity values were calculated from plots of ee(substrate)
g
h
versus fractional conversion. This isomer was not detected by capillary GC analysis. Regioisomeric composition of reactions that had
proceeded to the indicated fractional conversion.
therefore assigned these absolute configurations by anal-
ogy with our other results. Enantioselectivity values for
the oxidations of 1a -h were determined by nonlinear
least-squares fitting as described previously.4,15
purities were determined by chiral-phase GC analysis
using conditions that allowed baseline resolution of all
components.
In contrast to the above results, 3-alkyl-substituted
cyclopentanones 3e-f were oxidized to single regioiso-
mers according to GC and 2-D NMR analyses of the crude
reaction mixtures. Since it was not possible to resolve
the enantiomeric δ-valerolactones by chiral-phase GC,
these compounds were reduced by LiAlH4 to diols that
could be resolved (eq 1). This reduction also confirmed
Cyclohexanone monooxygenase exhibits virtually com-
plete enantioselectivity for the (S)-enantiomer of 2-alkyl-
substituted cyclohexanones, provided that the substitu-
ent is larger than methyl.4a This enantioselectivity
allows for efficient kinetic resolutions in these systems.
The same general trend was observed for 2-alkyl-
substituted cyclopentanones, although high enantiose-
lectivities required at least a four-carbon substituent
(Table 1). In the cases of 1e-h , optically pure ketone
and lactone could be isolated from a single biotransfor-
mation starting from the racemic ketone.
The yeast-mediated oxidations of racemic 3a -d pro-
duced both possible lactone regioisomers (4 and 5; Table
1). Similar behavior had been previously observed in the
enzymatic oxidations of 3-methyl- and 3-ethylcyclohex-
anone, although the optical purities of the lactone re-
gioisomers were higher in these cases.3 Unfortunately,
the regioisomeric δ-valerolactones could not be separated
chromatographically; however, the structures of the
lactone regioisomers in the product mixtures were con-
clusively established from 2-D NMR spectra. Optical
the regiochemistry of lactones 4e-h .16 Because of the
low enantioselectivities of these reactions, we did not
attempt to assign absolute configurations to the isolated
ketones and lactones. The major utility of these reactions
lies in their ability to produce exclusively 5-alkyltetrahy-
(16) Reduction of the alternate regioisomer would have produced a
meso diol. 13C NMR data were not consistent with a symmetrical
molecule.
(15) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J . J . Am. Chem.
Soc. 1982, 104, 7294-7299.

Notes
J . Org. Chem., Vol. 63, No. 20, 1998 7105
enantioselectivities observed for 3-subsituted cyclopen-
tanones are also likely to be due to the near-equivalence
of pseudoaxial and pseudoequatorial conformations. As
in the case of cyclohexanones, the regioselectivities
observed for compounds with long side chains probably
reflects specific contacts between the protein and these
substrates.
Compared to analogous cyclohexanones, cyclohexanone
monooxygenase displays relatively less regio- and enan-
tioselectivities for substituted cyclopentanones. How-
ever, for certain specific cases, our designer yeast meth-
odology makes important chiral building blocks easily
available in high optical (1e-h ; 2e-h ) and regiochemical
purities (4e-h ). For example, lactone 2h is a pheromone
isolated from the oriental hornet Vespa orientalis,19 and
our methodology makes it easily available in optically
pure form. To show that this methodology can accom-
modate larger quantities of substrates, the oxidation of
ketone 1f was carried out on a 0.45 g scale and the (R)-
ketone and (S)-lactone were isolated in 78% and 88%
yields, respectively.
F igu r e 1. Active site models for cyclohexanone monooxyge-
nase. A. Diamond lattice model of the tetrahedral intermediate
derived from studies of substituted cyclohexanones.17 The
migrating carbon-carbon bond is indicated by a heavy line.
The locations of substituents tolerated by the enzyme are
illustrated by solid lines. The dotted line indicates that an axial
methyl group is partially tolerated in this position. B. Analo-
gous conformation for the tetrahedral intermediates involved
in oxidations of 2- and 3-substituted cyclopentanones. Allowed
positions of substituents are depicted in cartoon form, and the
lengths of the side chains tolerated at these positions are
indicated by the compound numbers of the corresponding
ketones. Note the good overall similarity between the size of
allowed cyclopentanone substituents and the dimensions of the
active site as determined by the diamond lattice model.
dropyran-2-ones in a transformation that cannot be
duplicated by organic peracids. Moreover, preliminary
experiments indicate that yields can be significantly
improved by the use of lower ketone concentrations
during the biotransformations.
Exp er im en ta l Section
Gen er a l. Packed column gas chromatography was performed
using a 5% OV-101 on 100/120 Supelcoport (1/8 in. × 1 m)
column with helium as carrier gas. Capillary gas chromatog-
raphy separations utilized a 0.32 mm × 30 m × 0.25 µm column
using helium as the carrier gas. The injector and detector
temperatures were maintained at 225 °C. Thin-layer chroma-
tography was performed on precoated silica gel 60 plates.
Reaction products were purified by flash chromatography using
200-425 mesh silica gel.20 Tetrahydrofuran and diethyl ether
were distilled from K-Na alloy in the presence of benzophenone.
Potassium carbonate was dried at 80 °C and cooled to room
temperature in a desiccator prior to use. Acetone was dried over
CaSO4 and distilled from KMnO4. Methylene chloride was dried
over anhydrous K2CO3, distilled and stored over 3 Å molecular
sieves. All solvents were purified by fractional distillation.
Other reagents were obtained from commercial suppliers and
used as received.
P r ep a r a tion of Yea st Cells. A 200 mL portion of YPD (1%
Bacto-Yeast Extract, 2% Bacto-Peptone, 2% glucose) in a 500
mL baffled conical flask was inoculated with a single colony of
yeast. The flask was agitated on a rotatory shaker at 30 °C.
When the OD600 of the culture reached 4.0, the cells were
harvested by centrifuging at 3000g for 10 min at 20 °C. The
yeast pellet was transferred to a second 500 mL conical flask
containing 200 mL of YP-Gal (1% Bacto-Yeast Extract, 2% Bacto-
Peptone, 2% galactose). Cyclopentanone (20 µL) was added, and
the reaction was allowed to proceed for 3-4 h until the OD600
reached 6-8.21 The yeast was harvested by centrifugation as
above, and the pellet was washed 3 times with TE (10 mM Tris-
Cl, pH 7.5, 1 mM EDTA). After this, the yeast cells were
resuspended in 10 mM Tris-Cl, pH 7.5, 1 mM EDTA, 15%
glycerol at a concentration of 0.2 g/mL. This was divided into 1
mL aliquots and frozen at -80 °C prior to use in biotransfor-
mations. These frozen stocks did not show significant loss of
activity for at least 1 month.
The behavior of 2- and 3-substituted cyclopentanones
can be rationalized by considering the conformational
behavior of the substrates and the active site structure
of the enzyme. The principal differences between the
behavior of cyclopentanones and cyclohexanones can be
ascribed to the low-energy barriers between alternate
cyclopentane conformations and the accessibility of half-
chair structures in this ring system. The results from
the present study have been summarized in Figure 1,
which also depicts our diamond lattice model of the
enzyme active site based on studies of cyclohexanones.17
Both enantiomers of 2-substituted cyclopentanones were
oxidized to the same regioisomer, which meant that the
substituted carbon was always located in the same
position. For the (S)-enantiomer, the substituent can
occupy a pseudoequatorial position; however, the sub-
stituent in the (R)-enantiomer must be located in a
pseudoaxial position. For cyclohexanones, this confor-
mational difference provides a large fraction of the
observed selectivity for the (S)-ketones.4b By contrast,
the energy differences between substituents in pseudo-
axial and pseudoequatorial positions of cyclopentanes in
the twist boat conformation are minimal,18 so that this
reinforcement is largely absent for all of the 2-substituted
cyclopentanones (1a -h ). The high enantioselectivities
observed for 1e-h must therefore result from additional
favorable interactions between the long side chain and
the active site of the enzyme. The relatively small
Gen er a l P r oced u r e for Yea st Med ia ted Ba eyer -Villiger
Oxid a tion s. The ketone substrate (100 µL) was added to YP-
Gal (100 mL) in a 250 mL baffled conical flask. When necessary,
1 equiv of â- or γ-cyclodextrin (relative to the ketone) was
included. The mixture was then shaken at 30 °C at 250 rpm
for 5-10 min to obtain a uniform dispersion. A 1 mL portion of
yeast cells was added to the reaction flask; then the culture was
(17) While other models for the active site of cyclohexanone mo-
nooxygenase have been constructed independently, the close structural
relationship between the cyclopentanones and the cyclohexanones used
to construct this model make it especially convenient for the present
purpose. Other cyclohexanone monooxygenase active site models:
Taschner, M. J .; Peddada, L.; Cyr, P.; Chen, Q. Z.; Black, D. J . NATO
ASI Ser., Ser. C 1992, 381, 347-360; Alphand, V.; Furstoss, R. J . Org.
Chem. 1992, 57, 1306-1309; Kelly, D. R. Tetrahedron: Asymmetry
1996, 7, 1149-1152; Ottolina, G.; Pasta, P.; Carrea, G.; Colonna, S.;
Dallavalle, S.; Holland, H. L. Tetrahedron: Asymmetry 1995, 6, 1375-
1386; Ottolina, G.; Carrea, G.; Colonna, S.; Ru¨ckemann, A. Tetrahe-
dron: Asymmetry 1996, 7, 1123-1136.
(19) Ikan, R.; Gottlieb, R.; Bergman, E. D.; Ishay, J . J . Insect Physiol.
1969, 15, 1709-1712.
(20) Still, W. C.; Kahn, M.; Mitra., A. J . Org. Chem. 1978, 15, 2923-
2925.
(21) The inclusion of cyclopentanone during this step was empiri-
cally found to increase the efficiency of the yeast cells during the
subsequent Baeyer-Villiger oxidations.
(18) Carey, F. A.; Sundberg, R. J . Advanced Organic Chemistry. Part
B: Reactions and Synthesis; 2nd ed.; Plenum: New York, 1983.

7106 J . Org. Chem., Vol. 63, No. 20, 1998
Notes
was shaken at 30 °C at 250 rpm and the reaction was monitored
by GC. Once the conversion reached approximately 50% (or
when the ratio of products remained constant), the yeast cells
were removed by centrifugation. The yeast cell pellet was
suspended in 50 mL of distilled water; then this was extracted
with ethyl acetate (2 × 100 mL). The aqueous growth medium
was extracted with ethyl acetate (3 × 100 mL). The combined
organic extracts were washed once with brine, dried over
anhydrous Na2SO4 or MgSO4, and concentrated by rotary
evaporation. Pure products were isolated by flash chromatog-
raphy. For reaction mixtures derived from 1a -h , 3:1 hexane:
diethyl ether followed by 1:1 hexane:diethyl ether was used for
chromatographic purifications. For reaction mixtures derived
from 3-substituted cyclopentanones, petroleum ether:acetone (5:
1) was used for 3a and 3b and a 10:1 ratio of these solvents was
used for 3c-h . After the ketones had been completely eluted,
chromatography was continued with petroleum ether:acetone (3:
1) until the lactones had been eluted.
La r ger -Sca le Oxid a tion of 2-n -Hexylcyclop en ta n on e 1f.
γ-Cyclodextrin (2.3 mmol, 3.0 g) and 2-n-hexylcyclopentanone
1f (2.7 mmol, 0.45 g) were added to a 2 L Erlenmeyer flask
containing 1 L of YP-Gal. The resulting mixture was shaken
at 200 rpm for 24 h at 30 °C to obtain a uniform suspension;
then 1 g of frozen yeast cells was added. The culture was shaken
at 200 rpm for 60 h at 30 °C; then the yeast cells were removed
by centrifugation. The supernatant was extracted with petro-
leum ether (4 × 250 mL). The cell pellet was suspended in 100
mL of water; then it was extracted with petroleum ether (4 ×
75 mL). The combined organic extracts were washed with brine,
dried with MgSO4, and concentrated in vacuo. Chromatographic
purification using 10:1 petroleum ether-acetone afforded ketone
1f (0.18 g, 78% yield) and lactone 2f (0.22 g, 88% yield, 96% ee).
Hz), 0.91 (3H, t, J ) 7.3 Hz) ppm. 13C NMR: δ 171.5, 68.5, 36.3,
33.1, 28.9, 28.5, 10.9 ppm.
5- a n d 4-P r op yltetr a h yd r op yr a n -2-on es 4c a n d 5c (83:
17 r a tio). Spectral data were obtained from the inseparable
mixture. Many spectral signals overlapped, and only those that
were distinct are reported. IR (neat) ν: 1743 cm-1
.
4c. 1H
NMR: δ 4.30(1 H, m), 3.91 (1H, m) ppm. 13C NMR: δ 171.62,
73.6, 33.6, 32.5, 29.0, 25.4, 19.9, 14.0 ppm. MS: m/e 142 (M+,
5), 84 (100), 70 (33), 69 (32), 56 (51), 55 (74). 5c. 1H NMR: δ
4.37 (1H, m), 4.21 (1H, m) ppm. 13C NMR: δ 171.57, 68.5, 38.3,
36.5, 31.1, 19.5, 18.7, 13.9 ppm. MS: m/e 99 (M+ - 43, 82), 84
(34), 70 (57), 69 (68), 56 (100), 55 (95).
5- a n d 4-Allyltetr a h yd r op yr a n -2-on es 4d a n d 5d (44:56
r a tio). Spectral data were obtained from the inseparable
mixture. IR (neat) ν: 1726 cm-1. 5d . 1H NMR: δ 4.39 (1H, m),
4.24 (1H, m), 2.64 (1H, m), 2.50 (1H, dd, J ) 9.6 Hz, J ) 7.0 Hz)
ppm (all other 1H NMR signals overlap). 13C NMR: δ 171.2,
134.5, 117.8, 68.4, 40.2, 36.1, 31.2, 28.4 ppm. 4d . 1H NMR δ
4.32 (1H, m), 3.96 (1H, dd, J ) 11.3 Hz, J ) 9.1 Hz), 2.68 (1H,
dd, J ) 5.5 Hz, J ) 1.4 Hz), 2.59 (1H, dd, J ) 6.8 Hz, J ) 4.4
1
Hz) ppm (all other H NMR signals overlap). 13C NMR: δ 171.4,
134.6, 117.6, 73.1, 35.9, 32.4, 29.0, 25.1 ppm.
5-n -Bu tyltetr a h yd r op yr a n -2-on e 4e. IR (neat) ν: 1740
cm-1 1H NMR: δ 4.30 (1H, ddd, J ) 11.1 Hz, J ) 4.6 Hz, J )
.
2.1 Hz), 3.93 (1H, dd, J ) 10.9 Hz, J ) 9.7 Hz), 2.59 (1H, m),
2.46 (1H, m), 1.98 (1H, m), 1.87 (1H, m), 1.50 (1H, m), 1.28
(6H,m), 0.87 (3H, t, J ) 6.8 Hz) ppm. 13C NMR: δ 171.6, 73.7,
32.8, 31.2, 29.0, 28.9, 25.5, 22.7, 13.9 ppm. MS: m/e 156 (M+,
2), 98 (100), 84 (33), 70 (65), 69 (56), 56 (72), 55 (79).
5-n -Hexyltetr a h yd r op yr a n -2-on e 4f. IR (neat) ν: 1743
cm-1 1H NMR: δ 4.31 (1H, ddd, J ) 11.1 Hz, J ) 4.4 Hz, J )
.
1.9 Hz), 3.92 (1H, dd, J ) 11.1 Hz, J ) 9.7 Hz), 2.59 (1H, m),
2.47 (1H, m), 1.98 (1H, m), 1.86 (1H,m), 1.50 (1H, m), 1.20-
1.36 (10H, m), 0.86 (3H, t, J ) 7.2 Hz) ppm. 13C NMR: δ 171.5,
73.7, 32.8, 31.6, 31.5, 29.3, 29.1, 26.7, 25.5, 22.6, 14.0 ppm.
MS: m/e 154 (M+ - 30, 1), 128 (23), 98 (100), 84 (30), 70 (50),
69 (50), 56 (38), 55 (71).
Sp ectr a l Da ta for New Com p ou n d s. 6-n -P r op yltetr a h y-
d r op yr a n -2-on e 2c. IR (neat) ν: 1732 cm-1 1H NMR: δ 4.27
.
(1H, m), 2.34 (1H, m), 2.40 (1H, m), 1.92-1.74 (3H, m), 1.66 (1H,
m), 1.50 (3H, m), 1.39 (1H, m), 0.90 (3H, t, J ) 7.2 Hz) ppm. 13
C
NMR δ 171.9, 80.3, 37.8, 29.4, 27.7, 18.4, 18.1, 13.8 ppm. MS:
5-n -Octyltetr a h yd r op yr a n -2-on e 4g. IR (neat) ν: 1742
m/e 142 (M+, 1.4), 99 (100), 71 (50), 70 (35), 55 (26).
cm-1 1H NMR: δ 4.32 (1H, ddd, J ) 11.1 Hz, J ) 4.6 Hz, J )
.
6-Allyltetr a h yd r op yr a n -2-on e 2d . IR (neat) ν: 1734 cm-1
.
2.0 Hz), 3.93 (1H, dd, J ) 11.1 Hz, J ) 9.7 Hz), 2.60 (1H, m),
2.48 (1H, m), 1.99 (1H, m), 1.87 (1H, m), 1.49 (1H, m), 1.25 (14H,
m) 0.86 (3H, t, J ) 6.7 Hz) ppm. 13C NMR: δ 171.6, 73.7, 32.8,
31.8, 31.5, 29.6, 29.4, 29.2, 26.8, 25.5, 22.7, 22.4, 14.1 ppm.
MS: m/e 212 (M+, 1), 150 (33), 128 (22), 98 (100), 97 (48), 83
(47), 70 (43), 69 (48), 55 (72).
1H NMR: δ 5.78 (1H, m), 5.14 (2H, m), 4.32 (1H, m), 2.55 (1H,
m), 2.50-2.40 (2H, m), 2.36 (1H, m), 1.89 (2H, m), 1.80 (1H, m),
1.51 (1H, m) ppm. 13C NMR δ 171.6, 132.6, 118.5, 79.7, 40.0,
29.4, 27.1, 18.4 ppm. MS: m/e 99 (M+ - 45, 100), 71 (66), 55
(29).
6-n -Bu tyltetr a h yd r op yr a n -2-on e 2e. IR (neat) ν: 1731
5-n -Un d ecyltetr a h yd r op yr a n -2-on e 4h . IR (neat) ν: 1742
cm-1
.
1H NMR: δ 4.26 (1H, m), 2.55 (1H, m), 2.42 (1H, m),
cm-1 1H NMR δ 4.32 (1H, ddd, J ) 11.1 Hz, J ) 4.6 Hz, J )
.
1.94-1.76 (3H, m), 1.67 (1H, m), 1.60-1.40 (3H, m), 1.32 (3H,
m), 0.88 (3H, t, J ) 7.2 Hz) ppm. 13C: NMR δ 172.0, 80.6, 35.5,
29.4, 27.8, 27.0, 22.5, 18.5, 13.9 ppm. MS: m/e 156 (M+, 1), 99
(100), 71 (46), 70 (27), 55 (27).
1.9 Hz), 3.93 (1H, dd, J ) 11.1 Hz, J ) 9.7 Hz), 2.60 (1H, m),
2.48 (1H, m), 1.98 (1H, m), 1.87 (1H, m), 1.48 (1H, m), 1.27 (20H,
m), 0.86 (3H, t, J ) 6.7 Hz) ppm. 13C NMR: δ 171.7, 73.7, 40.2,
36.9, 32.8, 31.9, 31.7, 31.5, 31.0, 29.9, 29.7, 29.6, 29.4, 26.7, 22.7,
14.1 ppm. MS: m/e 254 (M+, 3), 192 (100), 141 (38), 111 (57),
98 (89), 83 (73), 69 (66), 55 (95).
6-n -Octyltetr a h yd r op yr a n -2-on e 2g. IR (neat) ν: 1743
cm-1 1H NMR δ 4.26 (1H, m), 2.55 (1H, m), 2.42 (1H, m), 1.92-
.
1.75 (3H, m), 1.68 (1H, m), 1.50 (3H, m), 1.26 (11H, m), 0.86
(3H, t, J ) 7.2 Hz) ppm. 13C NMR: δ 172.0, 80.6, 35.8, 31.8,
29.5, 29.44, 29.41, 29.2, 27.8, 24.9, 22.6, 18.5, 14.1 ppm. MS:
m/e 194 (M+ - 18, 1), 99 (100), 71 (36), 70 (29), 55 (31).
LiAlH4 Red u ction of La cton es 4e-h . A 5 mL round-
bottomed flask containing LiAlH4 (20 mg) was flushed with
nitrogen. THF (1 mL) was added via syringe, and the suspen-
sion was stirred at 0 °C for 10 min. The lactone (5 mg) dissolved
in CDCl3 (100 µL) was added slowly to the reaction flask, and
the mixture was stirred for another 30 min at this temperature.
The reaction was quenched by injecting 1 mL of saturated
aqueous tartaric acid; then the product was extracted with 15
mL of CHCl3. The organic extract was dried over anhydrous
5- a n d 4-Meth yltetr a h yd r op yr a n -2-on es 4a a n d 5a (13:
87 r a tio). Spectral data were obtained from the inseparable
mixture. Many spectral signals overlapped and only those that
were distinct are reported. IR (neat) ν: 1745, 1731 cm-1
. 4a .
1H NMR: δ 4.32 (1H, dd, J ) 4.6 Hz, J ) 2.2 Hz), 3.91 (1H, t,
J ) 10.1 Hz), 3.86 (1H, t, J ) 6.7 Hz), 1.01 (3H, d, J ) 6.7 Hz)
ppm. 13C NMR: δ 171.2, 74.8, 39.1, 29.0, 27.4, 16.4 ppm. MS:
m/e 114 (M+, 15), 84 (25), 70 (31), 56 (100), 55 (45). 5a . 1H
NMR: δ 4.43 (1H, m), 4.27 (1H, m), 1.07 (3H, d, J ) 6.2 Hz)
ppm. 13C NMR: δ 171.2, 68.5, 38.1, 30.5, 26.4, 21.3 ppm. MS:
m/e 114 (M+, 31), 70 (24), 56 (56), 55 (100).
Na2SO4, and the solution was concentrated on
a rotatory
evaporator. Chiral-phase GC analysis of the product afforded
the enantiomeric composition of the original lactone sample.
Ack n ow led gm en t. This work was supported finan-
cially by the National Science Foundation (CHE-
9513349; J .D.S.) and by the Natural Sciences and
Engineering Research Council and the University of
New Brunswick (M.M.K.). We would like to thank
Cerestar, Inc., for supplying the cyclodextrins used in
this study, Kieth W. Reed and Elise R. Manning for
preliminary studies in this area and Marko D. Mi-
hovilovic for helpful discussions.
5- a n d 4-Eth yltetr a h yd r op yr a n -2-on es 4b a n d 5b (80:20
r a tio). Spectral data were obtained from the inseparable
mixture. Many spectral signals overlapped, and only those that
were distinct are reported. IR (neat) ν: 1743 cm-1
. MS: m/e
128 (M+, 4), 99 (100),71 (71), 70 (31), 56 (30), 55 (33). 4b. 1H
NMR: δ 4.33 (1H, ddd, J ) 11.2 Hz, J ) 8.8 Hz, J ) 2.0 Hz),
3.93 (1H, dd, J ) 11.1 Hz, J ) 9.7 Hz), 0.87 (3H, t, J ) 7.3 Hz)
ppm. 13C NMR: δ 171.5, 73.4, 34.4, 25.1, 24.5, 22.4, 11.3 ppm.
5b. 1H NMR: δ 4.39 (1H, m), 4.22 (1H, td, J ) 10.4 Hz, J ) 3.6
J O980737V