Chemoenzymatic approach to optically active 4-hydroxy-5-alkylcyclopent-2- en-1-one derivatives: An application of a combined circular dichroism spectroscopy and DFT calculations to assignment of absolute configuration

Article abstract of DOI:10.1002/chir.22322

A series of representative optically active derivatives of 4-hydroxy-5-alkylcyclopent-2-en-1-one were prepared from the respective 2-furyl methyl carbinols via the Piancatelli rearrangement followed by the enzymatic kinetic resolution of racemates. Applicability of chiroptical methods (experimental and calculated electronic circular dichroism [ECD] and vibrational circular dichroism [VCD] spectra) to determine the absolute configuration of both stereogenic centers in 4-hydroxy-5-methylcyclopent-2-en-1-one was demonstrated. It was also demonstrated that the concurrent application of ECD and VCD spectroscopy can be used for the determination of the configuration of two stereogenic centers. Chirality 26:300-306, 2014. 2014 Wiley Periodicals, Inc.

Full text of DOI:10.1002/chir.22322

CHIRALITY 26:300–306 (2014)
Chemoenzymatic Approach to Optically Active 4-Hydroxy-5-
alkylcyclopent-2-en-1-one Derivatives: An Application of a Combined
Circular Dichroism Spectroscopy and DFT Calculations to Assignment
of Absolute Configuration
JADWIGA FRELEK,* MICHAŁ KARCHIER, DARIA MADEJ, KAROL MICHALAK, PAWEŁ RÓŻAŃSKI, AND JERZY WICHA*
Institute of Organic Chemistry of the Polish Academy of Sciences, Warsaw, Poland
ABSTRACT
A series of representative optically active derivatives of 4-hydroxy-5-alkylcyclopent-2-
en-1-one were prepared from the respective 2-furyl methyl carbinols via the Piancatelli rearrangement
followed by the enzymatic kinetic resolution of racemates. Applicability of chiroptical methods (exper-
imental and calculated electronic circular dichroism [ECD] and vibrational circular dichroism [VCD]
spectra) to determine the absolute configuration of both stereogenic centers in 4-hydroxy-5-
methylcyclopent-2-en-1-one was demonstrated. It was also demonstrated that the concurrent applica-
tion of ECD and VCD spectroscopy can be used for the determination of the configuration of two
stereogenic centers. Chirality 26:300–306, 2014. © 2014 Wiley Periodicals, Inc.
KEY WORDS: chiral cyclopentenones; Piancatelli rearrangement; kinetic resolution; Candida
antarctica lipase; density functional theory; electronic circular dichroism;
vibrational circular dichroism
INTRODUCTION
assignment.14 Moreover, a combination of theoretical and
experimental studies enhances the prospects for the safe use
of chiroptical spectroscopy since it enables the direct mutual
verification of the results.
Diverse optically active cyclopentenone derivatives are
required as starting materials in the natural product synthesis,
most notably prostaglandins and terpenoids. In this context
a great deal of attention was devoted to the preparation and
chemoenzymatic kinetic resolution of racemic 4-hydroxy-2-
alkylcyclopent-2-en-1-one derivatives (1, Fig. 1). Several repre-
sentatives of this group of compounds have been successfully
resolved using various lipases and acylating reagents. How-
ever, to the best of our knowledge no reports on the
preparation of closely related optically active 4-hydroxy-5-
alkylcyclopent-2-en-1-ones (2, Fig. 1), are available in the litera-
ture. One could expect that the application of enzyme-mediated
acylation to hydroxy-enones 2 would be methodologically
more demanding due to their propensity to isomerization into
and their possible epimerization at C-5.
The determination of absolute configuration of products of
kinetic resolution of 2 with two stereogenic centers could be
considered as a challenge by itself. Although the preference
of lipases to catalyze acylation of (R)-enantiomers of aliphatic
secondary alcohols has been established, the application of
1
–3
MATERIALS AND METHODS
Synthesis
4
–9
Melting points were determined on a hot-stage apparatus and are
uncorrected. Optical rotations were measured on a Jasco P-2000 polar-
imeter using 1 mL capacity cell (10 cm path length) in CHCl
magnetic resonance (NMR) spectra were recorded in CDCl
3
. Nuclear
3
solutions
1
13
on a Varian (Palo Alto CA) VNMRS spectrometer for H at 500 MHz/ C
1
13
at 125 MHz, Varian Mercury 400 for H at 400 MHz/ C at 100 MHz, or
1
13
Varian Gemini H at 200 MHz and C at 50 MHz. Chemical shifts are
1
0
quoted using δ scale and taking the solvent signal as the internal standard
1
13
1
(CHCl
3
,
H NMR 7.26 ppm; CDCl
3
,
C NMR 77.00 ppm). High-perfor-
mance liquid chromatography (HPLC) analyses were conducted using a
Daicel (Tokyo, Japan) Chiralcel AD-H or OD-H columns, flow 1 mL/min,
on a Knauer (Germany) analytical instrument equipped with a UV detector
(
220 nm). Column chromatography was performed on Merck silica gel 60,
30–400 mesh and thin-layer chromatography (TLC) on aluminum sheets,
Merck 60F 254. Organic extracts were dried over anhydrous Na SO
and solvents were evaporated using a rotary evaporator. Sigma-Aldrich
St. Louis, MO) lipase from Candida antarctica (recombinant expressed
2
1
1–13
2
4
the empirical rules to cyclic alcohols requires a caution.
In the given case, it was anticipated that the determination
of absolute configuration (AC) of the resolution products will
be achieved employing a set of modern chiroptical methods.
We now present the results of our studies on the pre-
paration and kinetic resolution of racemic hydroxy enones
(
in Aspargilus niger) on acrylic resin was used and is further referred to
as lipase. Kinetic resolution experiments were carried out at ambient
4
a–4c (Scheme 1), and on the determination of the AC of
Contract grant sponsor: National Science Centre
the resolved representative compound 4a applying combina-
Contract grant number: UMO-2011/01/B/ST5/00827.
Contract grant sponsor: Interdisciplinary Center for Mathematical and Com-
putational Modeling (ICM) of the University of Warsaw
Contract grant number: G50-5.
tion of electronic (ECD) and vibrational circular dichroism
(
VCD) spectroscopy. Such a combined approach has been
made possible due to the recent progress in ab initio simula-
tion of the CD spectra and availability of commercial instru-
ments dedicated to the VCD spectroscopy. Currently, the
application of multiple (usually not less than two) chiroptical
techniques is recommended by many authors since it
greatly enhances the confidence level of stereochemical
*Correspondence to: Jadwiga Frelek (structure determination) and Jerzy Wicha,
Institute of Organic Chemistry of the Polish Academy of Sciences, ul.
Kasprzaka 44/52, 01-224 Warsaw, Poland. E-mail: jadwiga.frelek@icho.edu.
pl; jerzy.wicha@icho.edu.pl
Received for publication 28 November 2013; Accepted 27 February 2014
DOI: 10.1002/chir.22322
Published online 1 May 2014 in Wiley Online Library
(wileyonlinelibrary.com).
©
2014 Wiley Periodicals, Inc.

OPTICALLY ACTIVE 4-HYDROXY-5-ALKYLCYCLOPENT-2-EN-1-ONES
301
transition according to the procedure described by Diedrich and
1
8
Grimme. The populations of conformers derived from the Gibbs free
energies were used to obtain the population-weighted ECD spectra.
The IR and VCD spectra were simulated with Lorentzian band shapes
ꢀ1
of 6 cm half-width at half-peak height. Populations of conformers derived
from Gibbs free energies were used to obtain the population-weighted
VCD spectra.
Fig. 1. Chiral hydroxycyclopentenones.
The computed ECD and VCD spectra (the UV and IR spectra as well)
were determined as the sum of the individual conformer spectra, each
one weighted by the fractional equilibrium population of the corres-
ponding conformer.
(± ±-trans-4-Hydroxy-5-methylcyclopent-2-en-1-one [(± ±-4aꢀ] (± ±-
cis-4-hydroxy-5-methylcyclopent-2-en-1-one [(±±-5aꢀ and (±±-4-hy-
droxy-2-methylcyclopent-2-en-1-one [(± ±-1aꢀ. (a) Distilled water
(1L) was placed in a 2 L round-bottomed flask equipped with a reflux con-
denser and a magnetic stirring device. Water was stirred, brought to boiling,
and then (±)-3a (10 g, 89.25mmol) was added. The addition was repeated 3
more times every 20min (40g in total). The mixture was heated for addi-
tional 3 h and allowed to cool to ambient temperature. The aqueous solution
was decanted from polymeric material and was washed with a mixture of
hexane and tert-butyl methyl ether (MTBE) (1:1, 2 × 40mL). The organic
extract was discarded. The aqueous solution was subsequently salted out
with NaCl and extracted with EtOAc (450 mL and then 4 × 300 mL). The
combined extracts were dried and the solvent was removed on a rotary
evaporator. The residue (20.5 g) was distilled under reduced pressure
collecting a fraction with bp 82–84°C/2 mm Hg. Product (16.3 g, 41% yield)
composition was estimated by HPLC analysis as: (±)-4a (91%), (±)-5a (4%),
(±)-1a (3%) and (±)-3a (2%). Column chromatography of the above
described product [2 g of mixture, 200g of silica gel, 1% acetone in
methyl-tert-butyl ether (1.2L)] gave 550 mg of (±)-4a free from (±)-5a; all
our attempts to isolate sample of pure (±)-5a failed.
Scheme 1. Synthesis of hydroxy-cyclopentenone derivatives.
temperature using a rotary shaker. Isopropenyl acetate was used as
purchased (Aldrich). Triethylamine was distilled prior to the use.
Spectroscopy
The UV spectra were measured using a Jasco V-670 spectrometer in
acetonitrile solutions. The ECD spectra were recorded between 185 and
4
00 nm at room temperature with a Jasco J-815 spectrometer in acetoni-
.
trile solutions. The solutions with concentrations of 0.00143 mol L were
examined in cells with a pathlength of 0.1 or 1 cm. The IR and VCD spec-
tra were measured on a ChiralIR-2X (DualPEM) spectrometer (BioTools,
Jupiter, FL). Spectra were obtained using the following two conditions:
ꢀ1
1
(
a) for measurements in the 1650–1050 cm region (fingerprint region,
FP) 19.02 mg of sample was dissolved in 120 μL of CD CN (~1.30 M)
and the spectrum was collected for 3.3 h (10,204 scans); (b) for measure-
(±)-4a, H NMR (500 MHz):7.50 (dd, J = 5.8, 2.2 Hz, 1H), 6.21 (dd,
3
J = 5.8, 1.3 Hz, 1H), 4.57 (dd, J = 3.6, 2.4 Hz, 1H), 2.27 (dq, J = 2.6, 7.4 Hz,
1
3
1H), 1.25 (d, J = 7.4 Hz, 3H). C NMR (125 MHz): 208.1, 161.4, 134.0,
ꢀ1
9
ments in the 1800–1650 cm region (carbonyl region, CO) 1.57 mg of
sample was dissolved in 120 μL of CD CN (~0.117 M) and spectrum was
collected for 7 h (21,504 scans). In both cases the photoelastic modulators
78.4, 50.5, 12.5; in agreement with reported data.
1
3
(±)-5a (from the mixture): H NMR (500 MHz): 7.55 (dd, J = 5.8, 2.5 Hz,
1H), 6.21 (dd, J = 5.8, 1.3 Hz, 1H), 5.04-4.97 (m, 1H), 2.52 (dq, J = 6.1,
7.7 Hz, 1H), 1.14 (d, J = 7.7 Hz, 3H).
ꢀ1
ꢀ1
(
PEM) were set to 1400 cm and the spectral resolution was 4 cm . A
demountable cuvette SL-4 Heavy Duty (ICL) with BaF windows (each
.5 mm thick) with 102 μm Teflon spacer was used and rotation 11 rpm was ap-
plied. Baseline correction was performed with the spectra of CD CN using the
2
6
(b) Distilled water (67 mL), dioxane (134 mL) and (±)-3a (7.509 g) were
placed in a thick-wall ampoule equipped with a magnetic stirring bar. The
ampoule was sealed and immersed in an oil bath preheated to 160°C
(placed behind a protective shield), and the mixture was vigorously
stirred for 18 h. After cooling, the mixture was transferred into a flask
and concentrated using rotary evaporator to a residual volume of ca.
40 mL. The solution was decanted from an oily polymer into a separatory
funnel containing TBME (2 mL) and hexane (4 mL). The content of the
separatory funnel was vigorously agitated and allowed to settle. The or-
ganic layer was separated, washed with water previously used for
washing the ampoule and the flask (4 mL), and discarded. The combined
aqueous solution was extracted with EtOAc (30 mL and then 4 × 20 mL).
The combined organic extracts were dried and the solvent was evapo-
rated. The crude product thus obtained (6.542 g) was distilled using a
Kugelrohr apparatus at 140°C/1.7 mm Hg to give the product (5.820 g,
78% yield) consisting of (±)-4a, (±)-5a and (±)-1a in a ratio of 87:10:3 by
3
same measurement setup, cuvette, and time acquisition as for solution of
sample.
Computation
All possible diastereoisomers of 4-hydroxy-5-methylcyclopent-2-en-1-
one were the subject of conformational analysis. The molecular mechan-
ics-based conformational search program HyperChem0815 was used for
conducting the preliminary conformational search. The identified con-
formers were subsequently subjected to the quantum chemical geometry
optimization using B3LYP density functional and 6-31G(d) basis set. The
optimized geometries at the B3LYP/6-31G(d) level were subjected to
further geometry optimizations at the B3LYP/TZVP level with PCM
model for acetonitrile solvent. For all Density Functional Theory (DFT)
1
6
calculations, Gaussian 09 was used. Populations were calculated based
on ΔG, assuming Boltzmann statistics at 298.15 K.
1
H NMR.
The UV, IR, ECD, and VCD spectra were computed for the fully opti-
mized geometries using B3LYP functional and TZVP basis sets with the
PCM model for acetonitrile solvent. The UV and ECD spectra were sim-
ulated from the first 15 singlet singlet electronic transitions by applying
Gaussian band shapes with 0.35 eV exponential half bandwidth at 1/e
peak height using the program SpecDis v. 1.53. The rotatory strengths
were calculated using both the length and the velocity representations.
The differences between the length and the velocity calculated values of
the rotatory strengths were quite small and for this reason, only the veloc-
ity rotatory strengths were taken into further consideration. The ECD and
UV spectra were simulated by overlapping Gaussian functions for each
(c) Acetone (60 mL), distilled water (2.5 mL, 139 mmol), 2 (1.547 g,
13.8 mmol), and ZnCl (1.194 g, 8.8 mmol) were placed in a thick-wall
2
ampoule equipped with a magnetic stirring bar. The ampoule was sealed
and immersed in an oil bath preheated to 70°C (placed behind a protec-
tive shield), and the mixture was stirred for 8 d. After cooling, the mixture
was transferred into a flask and the solvent was evaporated. The water-
17
2 4
soluble residue was transferred using 10% aq Na SO (30 mL) into a
separatory funnel containing MTBE (2 mL) and hexane (2 mL) (the
polymeric material remaining in the ampoule was discarded). The
mixture was agitated and allowed to settle and the organic layer was
Chirality DOI 10.1002/chir

3
02
FRELEK ET AL.
separated and discarded. The aqueous layer was extracted with EtOAc
1 × 30 mL and then 4 × 20 mL). The organic extracts were combined
and the solvent was evaporated. The crude product (1.02 g) was purified
diluted with water (400 mL) and extracted with EtOAc (3 × 100 mL). The
combined organic extracts were washed with brine, dried, and the sol-
vent was evaporated. The residue was distilled collecting fraction with
bp 79–82°C/12 mmHg to give carbinol (±)-3c (8.85 g, 69% yield from
(
by column chromatography on silica gel [20 g, hexane:EtOAc, 7:3
1
(
9
200 mL) and then 4:6 (200 mL)] to give mixture of (±)-4a and (±)-5a,
7:3 by H NMR (775 mg, 50% yield).
the ketone): H NMR (200 MHz) 7.35 (dd, J = 2.0, 1.0 Hz, 1H), 6.33
1
(ddd, J = 3.2, 1.8, 0.2 Hz, 1H), 6.21 (ddd, J = 3.2, 0.6, 0.4 Hz, 1H), 3.09
13
(
d, J = 5.0 Hz, 1H), 1.95 (d, J = 5.0 Hz, 1H), 0.96 (s, 9H); C NMR
(
50 MHz) 155.7, 141.3, 109.9, 107.0, 76.4, 35.8, 25.8 in agreement with
2
-Furyl isopropyl carbinol [(± ±-3bꢀ. A stirred solution of isopropyl-
magnesium bromide, prepared from magnesium turnings (21.9 g;
.90 mol) and 2-bromopropane (97.6 g; 0.80 mol; 74.5 mL) in Et
600 mL) was cooled to –78°C (a thick suspension has formed). Furfural
48.0 g; 0.5 mol, 41.5 mL) in Et O (200 mL) was then added dropwise over
1 h, maintaining the temperature below -60°C. The mixture was stirred
at –78°C for an additional 15 min and allowed to warm to room tempera-
ture. Sat. aq. NH Cl (170 mL) was carefully added. The mixture was
briefly stirred and left to settle. The organic layer was decanted from a
semisolid mass and the residue was washed with Et O (1 × 100 mL;
× 50 mL). The combined ethereal solutions were dried (Na SO ) and
the solvent was evaporated. The residue was distilled at 76°C/10 mmHg
2
3
reported data.
0
(
(
2
O
(± ±-5-tert-Butyl-4-hydroxycyclopent-2-en-1-one [(± ±-4cꢀ. Carbi-
nol (±)-3c (2.5 g) was added portionwise to distilled water (250 mL)
heated under reflux and stirred. The mixture was maintained at the reflux
temperature for 24 h, cooled, and the solution was decanted from a poly-
meric material. The residue was washed with water (15 mL) and the com-
bined aqueous solution was washed with MTBE-hexane (1:2, 10 mL).
Organic washings were discarded. Aqueous solution was saturated with
NaCl and extracted with EtOAc (100 mL and then 3 × 50 mL). The com-
bined organic extracts were dried and the solvent was evaporated. The
residue was distilled (Kügelrohr apparatus) at 150°C/2.5 mmHg to give
2
~
4
2
2
2
4
1
1
to give (±)-3b: (oil; 36.6 g, 51 % yield, >99% pure by H NMR): H NMR
400 MHz) 7.36 (dd, J = 2.0, 0.8 Hz, 1H), 6.33 (dd, J = 3.2, 2.0 Hz, 1H),
.22 (dd, J = 3.2, 0.8 Hz, 1H), 4.37 (dd, J = 6.8, 5.1 Hz, 1H), 2.10 (oct,
J = 6.8 Hz, 1H), 1.88 (d, 5.1 Hz, 1H, OH), 1.02 (d, J = 6.8 Hz, 3H), 0.86
(±)-4c, as s colorless oil, solidifying on standing, (1.93 g, 77% yield), An an-
(
6
1
alytical sample was recrystallized from hexane: mp 40–41°C, H NMR
(400 MHz) 7.46 (dd, J = 6.0, 2.4 Hz, 1H), 6.12 (dd, J = 5.6, 1.2 Hz, 1H), 4.80
13
1
3
(s, 1H), 2.25 (brs, 1H, OH), 2.00 (d, J = 2.4 Hz, 1H), 1.06 (s, 9H);
NMR (100 MHz) 207.5, 160.9, 135.4, 74.0, 64.0, 32.7, 27.8. Anal. Calcd.
for C (MW 154.21): C, 70.10; H, 9.15; found: C, 69.97, H, 9.03%.
C
(
d, J = 6.8 Hz, 3H); C NMR (100 MHz) 156.1, 141.7, 110.0, 106.5,
3.5, 33.3, 18.7 and 18.2; in agreement with reported data.1
9,20
7
9
14 2
H O
Product of the analogous reaction carried out at room temperature was
contaminated with ~5% of (2-furyl)methanol.
Kinetic resolution of (± ±-4a. Isopropenyl acetate (1.52 mL,
3.79 mmol, 3 equiv.) and Candida antarctica lipase (5.75 mg, 5% w/w)
1
(
±±-trans-4-Hydroxy-5-isopropylcyclopent-2-en-1-one [(±±-4bꢀ.
mixture of 3b (970mg; 6.9 mmol), PPTS (100mg), and distilled water
31 mL) was heated at the reflux for 3.5 h. After cooling, the solution was
A
were consecutively added to a solution of (±)-4a (515 mg, 4.60 mmol;
1
9
9% pure by H NMR) in MTBE (15.5 mL) shaken at room tempera-
ture (rt). The reaction was conducted until the residual alcohol reached
95% enantiomeric excess (ee) (30 h). The solid was then filtered off and
(
decanted from the polymeric material and the residue was washed with wa-
ter (2 mL). The combined aqueous solution was washed with MTBE
2× 2.5 mL), saturated with NaCl, and extracted with AcOEt (1× 12mL;
× 6 mL). The organic extracts were combined and solvent was evaporated.
The residue was purified by column chromatography on silica gel (10 g,
hexane:AcOEt, 6:4) to give (±)-4b containing ~1% of 5b (406mg, 42% yield):
H NMR (400 MHz) 7.51 (dd, J = 5.6, 2.4 Hz, 1H), 6.16 (dd, J = 5.6, 1.2 Hz,
H), 4.80-4.79 (m, 1H), 2.39 (brs, 1H, OH), 2.32-2.24 (m, 1H), 2.19 (dd,
J = 4.4, 2.4 Hz, 1H), 1.09 (d, J = 6.8 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H);
~
the filtrate was evaporated. The residue was purified by column chromatogra-
phy on silica gel (9 g, hexane:EtOAc, 9:1 (150 mL) and then 6:4 (125 mL) to
give consecutively: (1) (4R,5S)-6a, (oil, 548.4 mg, 28% ee, 77% yield), (2)
(
3
23
D
(4S, 5R)-4a] (oil, 107.2 mg, 99% ee, 21% yield), [α]
= +95.9 (c = 1.29, CHCl
3
);
ECD (Δε, λmax): -12.9 (197 nm), +19.3 (221.5 nm), -2.2 (329.6 nm). HPLC,
AD-H column, n-hexane:isopropanol, 90:10; the following t were recorded:
4R,5S)-6a, 6.3 min, its enantiomer 6.0 min; (4S,5R)-4a, 7.5min, its
enantiomer 8.1 min.
1
R
1
(
13
C
NMR (100 MHz): 208.2, 162.2, 134.9, 72.8, 60.8, 27.1, 20.7 and 20.2, in
The separate analogous experiment, using the distilled rearrangement
product (2 g), isopropenyl acetate (5.89 mL, 53.6 mmol), lipase (100 mg,
5
(
9
agreement with reported data.7
,21,22
An analogous experiment carried out over an extended reaction time
afforded (±)-4b contaminated with a side product to which the structure
of (±)-5b was tentatively assigned, H NMR (400 MHz)(from the mixture)
% w/w) and in MTBE (60 mL) afforded: (1) acetate fraction, 1.693 g
65%) and (2) alcohol fraction 0.667 g (35%) consisting of: (4S,5R)-4a,
0% and ca. 10% of isomers (by HPLC).
1
7
.57 (dd, J = 5.6, 2.4 Hz, 1H), 6.20 (dd, J = 5.6, 1.2 Hz, 1H), 5.03-5.00 (m, 1H).
± ±-2-Furyl tert-butyl carbinol [(± ±-3cꢀ.Dry THF (63 mL) and furan
10.71 g; 0.16 mol; 1.25 equiv) were placed, under argon, in a 250 mL
(
Kinetic resolution of (± ±-4b. Isopropenyl acetate (217 mg;
(
2
.17 mmol; 238 μL) and Candida antarctica lipase, (15.2 mg, 15% w/w)
1
round-bottomed flask. The stirred mixture was cooled to –78°C and
n-butyllithium (2.32 M in hexane, 54 mL, 0.13 mol; 1 equiv) was added
dropwise maintaining the temperature below –65°C. After completed
addition, the mixture was allowed to warm to 0°C (a white cloudy precipi-
tate appeared). Thus prepared furyllithium slurry was cooled to –78°C. In
parallel, a solution of pivaloyl chloride (19.58 g; 0.16 mol; 20 mL; 1.3 equiv)
in dry THF (63 mL), under argon, was prepared and cooled to –78°C. The
furyllithium slurry was then added dropwise via a cannula the cold pivaloyl
chloride solution maintaining the temperature below –65°C. After the
addition was completed (~1 h) the mixture was allowed to warm to room
temperature and the solvent was evaporated. The residue was taken up
in hexane (100 mL) and washed consecutively with a mixture of sat. aq.
were consecutively added to a solution of (±)-4b (99% pure by H NMR,
1
action was monitored by HPLC. After 46 h the solid was filtered off and
the solvent was evaporated. The residue was purified by column chroma-
tography on silica gel (2 g, hexane) to give: (1) (4R,5S)-6b (oil, 54.4 mg,
01.3 mg, 9.72 mmol) in MTBE (2.3 mL) shaken at rt. The progress of re-
9
D
6% ee, 41% yield), (2) (4S,5R)-4b (oil, 46.4 mg, (99% ee, 46% yield); [α]
23
3
= +65.2 (c = 2.18, CHCl ). Retention times, OJ-H column, n-hexane:
isopropanol, 98:2): (4R,5S)-6b - 9.5 min, its enantiomer - 11.5 min;
(4S,5R)-4b - 22.7 min, its enantiomer - 26.0 min.
Kinetic resolution of (± ±-4c. Isopropenyl acetate (202 mg; 0.22 mL,
2.02 mmol) and Candida antarctica lipase (41 mg; 50% w/w) were added
to a solution of (±)-4c (104 mg, 0.68 mmol) in MTBE (2 mL). The prog-
ress of reaction was monitored by HPLC. After 71 h the solid was filtered
off and the solvent was evaporated. The residue was purified by column
chromatography on silica gel (3 g, hexane–isopropanol, 90:10 and then
70:30) to give: (1) (4R,5S)-6c (oil, 69 mg, >95% ee, 52% yield), (2)
3
NaHCO and water (1:1, 100 mL) and water (100 mL). The organic
solution was then dried and the solvent was evaporated. The residue was
distilled collecting fraction 88–92°C/14 mmHg to give the intermediary
tert-butyl 2-furyl ketone (13.0 g, 68% yield from n-BuLi). The latter product
13.0 g) was dissolved in MeOH (250 mL) and the solution was cooled to
0°C. The solid NaBH (9.75 g) was then added in portions to a stirred
(
2
2
1
4
(4S,5R)-4c (oil, 50 mg, 98% ee, 48% yield) [α]
D
+ 96.3 (c = 2.51, CHCl
3
).
solution maintaining the temperature below 20°C. After the addition was
completed, the mixture was stirred for an additional 1 h at room tempera-
ture and then the bulk of the solvent was evaporated. The residue was
HPLC, OJ-H column, n-hexane:isopropanol, 96:4 the following t
recorded: (4R,5S)-6c - 6.7 min, its enantiomer - 7.5 min; (4S,5R)-4c -
12.4 min, its enantiomer - 14.6 min.
R
were
Chirality DOI 10.1002/chir

OPTICALLY ACTIVE 4-HYDROXY-5-ALKYLCYCLOPENT-2-EN-1-ONES
303
TABLE 1. Rearrangement of 2-furyl alkyl carbinols
a
1
Substrate
Conditions
Product composition (%) (by H NMR)
Yield (%, distilled product)
b
1
2
3
4
5
(±)-3a
(±)-3a
(±)-3a
(±)-3b
(±)-3c
Water, reflux, 4 h
Water-dioxane, 1:2, 160°, 18 h
ZnCl , aq acetone, 70°, 8 days
2
Water, PPTS, reflux, 3.5 h
Water, reflux 24 h
(±)-4a (91), (±)-5a (4), (±)-1a (3), (±)-3a (2)
41
78
50
42
77
(±)-4a (87±] (±)-5a (10), (±)-1a (3)
(±)-4a (97), (±)-5a (3)
(±)-4b (99), (±)-5b (1)
c
(±)-4c
a
Distilled products.
The product of 99% purity was prepared by column chromatography.
b
c
The product was purified by crystallization.
RESULTS AND DISCUSSION
reactions were carried out in tert-butyl methyl ether (MTBE)
at ambient temperature using a rotary shaker. The composi-
tion of the mixture was determined by HPLC equipped with
a Daicel Chiralcel AD-H or OJ-H column and a UV detector.
The results are presented in Scheme 2 and Table 2.
Synthesis
The carbinol (±)-3a (Scheme 1) was prepared by NaBH –
MeOH reduction of 2-acylfuran following the reported proce-
4
2
4
7,25
dure. For the preparation of carbinols (±)-3b
and (±)-
2
3
3c
with purity over 99%, some modifications of the reported
Determination of Absolute Configuration of 4a
procedures proved necessary: (±)-3b was prepared in reac-
tion of isopropylmagnesium bromide and furfural in diethyl
ether at –78°C [at higher temperatures (2-furyl)methanol
was formed as a by-product], (±)-3c was obtained by coupling
of 2-lithiofuran with pivalic chloride followed by NaBH reduc-
tion of the intermediate 2-furyl tert-butyl ketone.
To determine the absolute configuration of alcohol
obtained as described above by the kinetic optical resolution
of (±)-4 a simultaneous use of experimental and theoretical
ECD and VCD spectroscopy was applied. Nowadays, such a
combined approach of more than one chiroptical method is
widely recognized as leading to confident assignment of abso-
4
The preparation of 4-hydroxy-5-alkylcyclopent-2-en-1-ones
from respective 2-furyl alkyl carbinols via the Piancatelli
14
lute configuration. Moreover, the comparison of experimen-
tal and theoretical circular dichroism spectra has already
proven efficient and reliable for the assignment of the abso-
2
6,27
rearrangement is well documented.
The challenge of the
present work was to prepare the trans-isomers (±)-4a–4c, free
of the accompanying isomerization and rearrangement
byproducts. Since the starting carbinols are available at low
cost, we focused on the development of operationally conve-
nient procedures with the yield of product being of secondary
importance.
33–36
lute configuration of various chiral organic molecules.
A fundamental prerequisite for the computational calcula-
tion of CD spectra is the knowledge of all CD-relevant confor-
mational species of the respective molecule. In our case, the
conformational analysis performed within the 5 kcal/mol
energy window revealed three conformers for each diastereo-
isomer. These conformers were in fact rotamers of hydroxy
2
8,29
Heating of (±)-3a in water
(1 g/100 mL) until the
starting material was consumed afforded (±)-4a contaminated
with the double bond migration product (±)-1a and the diffi-
cult to remove isomer to which the structure (±)-5a was
assigned (5–10%). It was convenient to carry out the reaction
until ~60% of the carbinol (±)-3a was consumed and then re-
move the remaining starting material by distillation. In this
9
way (±)-4a, contaminated with (±)-5a, (±)-1a and some
unchanged (±)-3a, was prepared (Table 1, entry 1). A sample
of (±)-4a with purity over 99% was prepared by column chro-
matography. Other examined methods of affecting the
rearrangements of (±)-3a such as heating in aqueous dioxane
at 160°C, or in acetone (or dioxane) in the presence of zinc
6,7,30
chloride
similarly afforded mixtures of isomers (Table 1,
Scheme 2. Kinetic resolution of rac-2-alkyl-4-hydroxycyclopent-2-en-1-ones
using Candida antarctica lipase.
entries 2 and 3).
The rearrangement of the isopropyl derivative (±)-3b in
boiling water afforded (±)-4b contaminated with 5–10% (±)-5b.
Addition of catalytic amount of pyridinium p-toluenesulfonate
TABLE 2. Kinetic optical resolution of alcohols (± ±-4 according
to Scheme 2
(PPTS) and reduction of the reaction time resulted in (±)-4b
contaminated with ~1% of (±)-5b (Table 1, entry 4). Rearrange-
ment of (±)-3c was markedly slower affording crystalline (±)-
Acetate, yield
(%), ee
(4R,5S)-6
Residual alcohol
yield (%) , ee
a
a
Lipase
w/w%
Time
(h)
4
c, which was purified by recrystallization (Table 1, entry 5).
Substrate
(4S,5R)-4
The results are compiled in Table 1.
(
(
±)-4ab
±)-4a
5
5
15
50
30
30
32
71
77, 28
65, 32
41, 96
52, >95
21, 99b
35, 90
47, 99
48, 98
Kinetic Resolution
(±)-4b
(
±)-4c
Irreversible trans-esterification of alcohols was conducted
using the immobilized Candida antarctica lipase (Sigma-
a
Isolated yields.
3
1,32
b
Aldrich) and an excess of isopropenyl acetate.
The
The product containing ~10% of isomers (by HPLC).
Chirality DOI 10.1002/chir

3
04
FRELEK ET AL.
group at carbon C-4. Attempts to obtain the ring conformers
by manually changing ring torsion C3-C4-C5-C1 followed by
the time-dependent density functional theory (TD-DFT) opti-
mization was fruitless, indicating the restricted conforma-
tional freedom for the ring. In cis-diastereoisomers, i.e.,
parameters reported in Tables 1 and 2, respectively, can be
found in Supplemental Information section.
From a set of four isomers only two diastereoisomers
[(4S,5R)-4a and (4S,5S)-5a] were selected for further struc-
tural analysis. The structures of all conformers of 4a and 5a
found within the 5 kcal/mol energy window are shown in Fig. 2.
The molar ratio of conformers in conformational equilibrium
recalculated at a higher level of theory (B3LYP/TZVP/PCM)
using Gibbs free energy were found to be 0.34, 0.34, 0.32 for
(4S,5R)-4a and 0.37, 0.39, 0.24 for (4S,5S)-5a. In the subse-
quent calculations of the chiroptical properties the above popu-
lation molar ratios of conformers were taken into account.
In the Boltzmann-averaged ECD spectra comprising, by
definition, the sum of contributions from all populated
(
4R,5R) and (4S,5S), the five-membered ring is almost planar,
whereas in the case of trans-diastereoisomers, i.e., (4R,5S)
and (4S,5R), it is slightly skewed. Based on the increasing
free Gibbs energy, the distribution of conformers of cis-
diastereoisomers was 0.72, 0.23, and 0.05, respectively, and
the distribution for one of trans-diastereoisomers was 0.57,
0
.26, and 0.17, respectively. The relative electronic free
energies with corresponding fractional populations for the
DFT conformers of all diastereoisomers and the geometric
3
Fig. 2. B3LYP/TZVP/PCM (CH CN) structures of conformers (rotamers) of (4S,5R)-4a (top) and (4S,5S)-5a (bottom).
Fig. 3. Comparison of experimental spectra to the conformationally averaged B3LYP/TZVP/PCM spectra of (4S,5S)-5a and (4S,5R)-4a; left: ECD (top) and UV
bottom); right: VCD (top) and IR (bottom).
(
Chirality DOI 10.1002/chir

OPTICALLY ACTIVE 4-HYDROXY-5-ALKYLCYCLOPENT-2-EN-1-ONES
305
conformers, three ECD bands in the 190–400 nm spectral
SUPPORTING INFORMATION
range are visible (Fig. 3, left). The simulated spectra show a
very satisfactory agreement between experiment and theory,
especially in the range of nπ* enone transition, i.e., at around
Additional supporting information may be found in the
online version of this article at the publisher’s web-site.
3
30 nm. Since for both diastereoisomers the absolute configu-
LITERATURE CITED
ration at C-4 carbon atom was arbitrarily chosen as the S, this
result unambiguously identifies the AC in 4a as 4S. This fur-
ther means that the ECD is mainly governed by the AC at C-4.
Based on the presented ECD results, however, the proper
assignment of the absolute configuration of the methyl group
at C-5 was not unequivocal. Both diastereoisomers under
study exhibit quite good consistency of the simulated spectra
with the experimental spectrum throughout the whole spec-
tral range. Although the calculated spectrum of (4S,5R) dia-
stereoisomer, in particular in the 220 nm region, shows a
better compatibility with the experiment, even then the
ECD spectrum is not uniquely conclusive for the confident
assignment of absolute configuration at C-5. The comparison
of experimental and simulated VCD spectra for both diaste-
reoisomers should bring the solution to this problem.
In Fig. 3, right, the averaged B3LYP/TZVP/PCM VCD
spectra of both (4S,5R) and (4S,5S) diastereoisomers are
compared with the experimental VCD spectrum of optical
resolution product of (±)-4a. As can be seen in Fig. 3, only
for the diastereoisomer (4S,5R) is there a sufficiently good
correlation for relatively large number of bands in experi-
mental and simulated VCD spectrum to conclude that the
1
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