A stereoselective approach to optically active butenolides by Horner-Wadsworth-Emmons olefination reaction of α-hydroxy ketones

Article abstract of DOI:10.1016/j.tetasy.2007.07.027

Di- and trisubstituted butenolides and tricyclic unsaturated lactones, of high enantiomeric excess were prepared via the efficient sequential esterification Horner-Wadsworth-Emmons reaction of enantiomerically enriched 2-hydroxy-substituted phenones and a

Full text of DOI:10.1016/j.tetasy.2007.07.027

Tetrahedron: Asymmetry 18 (2007) 1780–1787
A stereoselective approach to optically active butenolides by
Horner–Wadsworth–Emmons olefination reaction
of a-hydroxy ketones
Ewa Krawczyk,* Marek Koprowski and Jerzy Łuczak
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Ło´dz´, Poland
Received 22 May 2007; accepted 30 July 2007
Abstract—Di- and trisubstituted butenolides and tricyclic unsaturated lactones, of high enantiomeric excess were prepared via the effi-
cient sequential esterification Horner–Wadsworth–Emmons reaction of enantiomerically enriched 2-hydroxy-substituted phenones and
aromatic cyclic a-hydroxy ketones in good yield.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
asymmetric catalytic oxidation of readily available enol
phosphates by a chiral oxomanganese(III) salen complex.
We have shown that the sense of asymmetric induction in
this oxidation reaction depends on the substitution pattern
of starting enol phosphates. Using this methodology both
enantiomers of acyclic and cyclic a-hydroxy ketones 1 were
obtained with high enantioselectivity up to 96% (Scheme
1).
Polysubstituted butenolides constitute as a class of com-
pounds of high current interest due to their potential broad
range of biological activities.1 They can serve as the precur-
sors for the synthesis of various natural products, including
those bearing a chiral c-lactone moiety.2 As a consequence
of butenolides importance, many methods have been de-
vised for the butenolide unit preparation.3 Among them,
methodologies based on the intermediate hydroxy-substi-
tuted carbonyl compounds, such as the reactions of lacton-
ization,4 base catalyzed intramolecular condensation,5 or
Wittig olefination6 have been applied with success. For
the stereoselective synthesis of these target com-
pounds1c,2d,e,7 the asymmetric nucleophilic addition of tri-
alkylsilyloxy furans to various electrophiles has been
widely used.7a,g,h Also, approach to the optically active,
c-hydroxy-substituted butenolides, namely tetronic acids
by intramolecular condensation reactions of accessible
asymmetric a-hydroxy esters is well recognized in the liter-
ature.2a,8 Nevertheless, the development of novel methods
for the preparation of enantiomerically pure, or at least
enantiomerically enriched butenolides is still an important
goal in synthetic chemistry.
So far only one synthesis of structures containing optically
active butenolide moiety, where olefination step was
accomplished by Horner–Wadsworth–Emmons (HWE)
reaction of chiral a-hydroxy aldehydes, has been repor-
ted.2c Therefore, we decided to apply optically active
a-hydroxy ketones 1, easily obtained by our methodology,
in the HWE reaction, with the purpose of the elaboration
of general synthesis of chiral butenolides.
Herein, we report a stereoselective entry to enantiomeri-
cally enriched butenolides via a two-step procedure
involving esterification of ketones 1 followed by an intra-
molecular-HWE reaction.
2. Results and discussion
Recently, we elaborated the enantioselective synthesis of
a-hydroxy ketones.9 Our approach was based on the
Our initial investigations were conducted with enantiomeri-
cally enriched (S)-(ꢀ) and (R)-(+)-2-alkyl-2-hydroxy-phen-
ones 1a–c (see Table 1). Ketones 1a–c were subjected to
esterification with diethyl phosphonoacetic acid 3a. Using
*
Corresponding author. Tel.: +48 42 680 32 16; fax: +48 42 684 71 26;
e-mail: ewakrsoj@bilbo.cbmm.lodz.pl
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.07.027

E. Krawczyk et al. / Tetrahedron: Asymmetry 18 (2007) 1780–1787
1781
O
R1
H
OP(OAr)2
O
Ar
O
O
O
NaOCl
H3O
R1
H
OP(OR)2
R1
R1
0 °C
or
Ar
Ar
(R,R)-salen
PPNO
O
OH
(S)-1
OH
(R)-1
Ar
R1
H
OP(OAlk)2
R1=Ar, Alk
R,
Ar
O
Scheme 1.
Table 1. Synthesis of optically active furanones 2 from a-hydroxy ketones 1 and phosphonates 3 or 5a
Entry
R1
R2
Substrates
(S)-(ꢀ)-1a
eeb (%) of 1
Routea
Product
eeb (%)
>99
94.0
83.7
67.3
76.5
88.8
74.0
63.3
76.0
Yieldc (%)
1
2
3
4
5
6
7
8
9
Me
Et
Pr
Pr
Pr
H
H
H
H
H
H
H
H
H
H
Me
Me
3a
3a
3a
3a
5
96
93
88
68
88
93
83
83
83
83
83
83
A
A
A
A
(S)-(+)-2a
(S)-(+)-2b
(S)-(+)-2c
(R)-(ꢀ)-2c
(S)-(+)-2c
(S)-(+)-2b
(S)-(+)-2d
(S)-(+)-2d
(S)-(+)-2d
6
76
75
67
61
35
60
50
89
25
30
40
36
(S)-(ꢀ)-1b
(S)-(ꢀ)-1c
(R)-(+)-1c
(S)-(ꢀ)-1c
(S)-(ꢀ)-1b
(S)-(+)-1d
(S)-(+)-1d
(S)-(+)-1d
(S)-(+)-1d
(S)-(+)-1d
(S)-(+)-1d
B
Et
5
Bd
Ae
Af
Ag
Bh
A
Ph
Ph
Ph
Ph
Ph
Ph
3a
3a
3a
5
10
11
12
—
59.0
77.6
3e
3e
(S)-(+)-2e
(S)-(+)-2e
Ai
a
˚
Conditions: route A: base—K2CO3, 18-crown-6, 0 ꢁC to +5 ꢁC, 24 h; route B: base—LiOHÆH2O, molecular sieves 4 A, rt, 24 h.
b Determined by HPLC analysis (see Section 4) using racemic compounds as references.
c Isolated yield (not optimized).
d Conditions: 5 ꢁC, 48 h.
e Conditions: ꢀ20 ꢁC, 24 h.
f Base—LiN(cyclohexyl)2, ꢀ100 ꢁC, 1 h, warming to rt, 4 h.
g Base—LiN(cyclohexyl)2, ꢀ100 ꢁC, 2 h, quenching, warming to rt.
h Base—DBU/LiCl, ꢀ20 ꢁC, 2 h; 5 ꢁC, 7 h.
i Base—Et3N/LiCl, ꢀ30 ꢁC, 36 h.
R2
water soluble carbodiimide (WSC) as a condensing agent in
the presence of pyridine and catalytic amounts of
DMAP,6g full conversion of 1a–c into the desired esters
4a–c was achieved. The next step of this synthesis involved
an intramolecular-HWE reaction of 4a–c in the presence of
potassium carbonate and 18-crown-6 in toluene.6g,10 Opti-
cally active 4-phenyl-5-alkylfuran-2-(5H)-ones 2a–c, not
reported in the literature, were obtained in good yields
(Scheme 2, Table 1). The enantiomeric purity of 2a–c was
determined using HPLC chiral separation (Table 1, entries
1–4). According to HPLC analysis, these compounds were
formed without the loss of enantiomeric purity. In the case
of 4-phenyl-5-methylfuran-2-(5H)-one 2a only one enantio-
mer was detected by chiral HPLC.
O
Py, WSC, DMAP cat.
R1
O
+
P(OEt)2
O
Ph
O
OH
OH
1a-d
3a, e
R2
O
R2
Ph
(a)
P(O)OEt)2
O
O
O
R1
R1
Ph
2a-e
4a-e
R1 R2
a
Me
Et
Pr
Ph
Ph Me
H
H
H
H
(a) = K2CO3/18-crown-6
or Et3N/LiCl or (Cy)2NLi
WSC = water soluble carbodiimide
b
c
d
e
These promising results prompted us to apply the same
procedure for the synthesis of optically active di- and tri-
substituted 5-phenylfuranones 2d and 2e.
Scheme 2.
Ester 4d, easily prepared from (S)-(+)-benzoin 1d (83% ee)
and phosphonoacetic acid 3a, underwent an intramole-
cular-Horner–Wadsworth–Emmons reaction to give 4,5-
diphenylfuran-2-(5H)-one 2d in moderate yield. Due to
the increased lability of the carbon stereogenic center of
4d during 2d formation, this reaction was carried out at
lower temperature (ꢀ20 ꢁC). However, even under such
mild conditions, 2d was formed with partial racemization

1782
E. Krawczyk et al. / Tetrahedron: Asymmetry 18 (2007) 1780–1787
(74% ee) (Table 1, entry 7). To improve the enantiomeric
reaction of ketone 1b (93% ee) with 5, carried out under
slightly different conditions (5 ꢁC, 48 h), provided the
desired furanone 2b with 88.8% ee in good yield (60%)
(Table 1, entry 6). The other olefination procedure (LiCl,
DBU, ꢀ20 ꢁC up to 5 ꢁC, 9 h), recommended for use with
base-sensitive carbonyl compounds (mainly aldehydes),11
was applied to the reaction of (S)-(+)-benzoin 1d with
phosphonate 5. Unexpectedly, the desired furanone 2d
was not formed. Among the unidentified products c-keto-
a,b-unsaturated ester 6 (Fig. 1) and recovered benzoin 1d
were found, probably as a result of the disproportionation
reaction of benzoin and consecutive reactions that occurred
under the reaction condition.12
excess and yield of 2d, the modified reaction conditions
8b
were used. Use of the excess of LiN(Cy)2 under kineti-
cally controlled conditions: ꢀ100 ꢁC, 2 h, provided fura-
none 2d with 76% ee and 25% yield and unreacted ester
4d in 60% yield with 75% ee. The same reaction was carried
out under thermodynamically controlled conditions, which
means generation of an anion at ꢀ100 ꢁC, and then warm-
ing the mixture to room temperature, afforded 2d in high
yield of 89% with 63.3% ee (Table 1, entries 8 and 9).
Methyl-substituted phosphonoacetic acid 3e was used as a
reagent for the synthesis of trisubstituted furanone. Since
over the course of the esterification of (S)-(+) a-hydroxy
ketone 1d with acid 3e, a new stereogenic center is formed,
this reaction afforded a mixture of two diastereoisomers of
ester 4e inseparable by chromatography. However, this
additional center is not important as it disappears after
the HWE reaction. The conversion of 4e to 3-methyl-4,5-
diphenylfuran-2-(5H)-one 2e was accomplished by this
reaction performed in the presence of K2CO3/18-crown-6
or Et3N/LiCl6f,11 base systems. Furanone 2e was formed
in moderate yields and with moderate to good enantio-
meric excess (Scheme 2, Table 1, entries 11 and 12). An at-
tempt to use LiN(Cy)2 for the synthesis of trisubstituted
furanone 2e from the corresponding ester 4e failed. Start-
ing ester 4e was recovered with partial racemization as indi-
cated by the measurement of the value of its optical
rotation.
COOEt
Ph
6
Ph
O
Figure 1.
To determine the scope of intramolecular-Horner–Wads-
worth–Emmons reaction in the synthesis of optically active
substituted butenolides, we studied the conversion of
several other a-hydroxy ketones into the corresponding
butenolides. Since the presence of a lactone functionality
fused to a carbocyclic framework is common in biologically
active natural products, for example, in the novel heritol
family of the cadinane sesquiterpenes class,13 we applied
structurally related, optically active a-hydroxy ketones:
2-hydroxy benzosuberone 7a and 2-hydroxy-2-methyl
indanone 7b, previously prepared by us.9b The preliminary
results obtained are presented in Scheme 4.
The enantiomeric excess values of the starting esters 4d and
4e, determined by chiral HPLC, were the same as those of
benzoin 1d used for their synthesis. It seems that partial
racemization of esters 4d and 4e occurring under HWE
reaction conditions is responsible for the loss of enantio-
meric purity of products 2d and 2e.
P(OEt)2
O
O
It was of interest to compare the results of the synthesis of
optically active butenolides 2 (Scheme 2) with those ob-
tained by a ‘reversed’ procedure, in which the lactonization
is preceded by HWE reaction of optically active a-hydroxy
ketones 1 with stabilized lithium phosphonate 5 (Scheme 3).
O
O
O
O
(S)
O
(S)
OH
HO
P(OEt)2
3
O
8a
O
7a: 93.0%ee
.
LiOH H2O
O
P(O)(OEt)2
+
Ph
molecular
sieves 4Å
EtO
(S)
OH
Ph
O
K2CO3/18-crown-6
1b, c
9a: 83%ee
5
yield: 40%
O
COOEt
Ph
R1
P(OEt)2
O
O
R1=Et, Pr
(R)
O
P(OEt)2
O
O
O
O
HO
OH
R1
OH
O
2b, c
3
Scheme 3.
7b: 69%ee
8b
(R)
O
Therefore, we performed the reaction of 1c (88% ee) with 5
˚
at room temperature using LiOH and activated 4 A mole-
K2CO3/18-crown-6
9b: 94%ee
O
cular sieves, according to Bonadies–Scettri6d (rt, 24 h) and
obtained furanone 2c in moderate yield with the partial
racemization (76.5% ee) (Table 1, entry 5, route B). The
yield: 32%
Scheme 4.

E. Krawczyk et al. / Tetrahedron: Asymmetry 18 (2007) 1780–1787
1783
16
˚
Intramolecular Horner–Emmons reactions of esters 8a and
8b, obtained from ketones 7a and 7b by standard proce-
dure, proceed cleanly but afford tricyclic unsaturated c-lac-
tones 9a and 9b in moderate to poor yields together with
recovered starting esters 8. The enantiomeric excesses of
7 and 9 are presented in Scheme 4. As indicated by chiral
HPLC, compound 9a was formed with good enantiomeric
excess and indanone derivative 9b in high enantiomeric
excess with regard to that of substrate 7b. This is probably
the result of the recrystallization.
sieves 4 A were prepared as reported. Chromatographic
purification was performed on silica gel columns (Merck,
Kieselgel 70–230 mesh) with indicated eluent. All racemic
and optically active a-hydroxy ketones 1 and 7 were pre-
pared as described.9 Racemic esters 4a–e, 8a,b, and fura-
nones 2a–e and tricyclic unsaturated lactones 9a,b were
prepared according to the procedure described for enantio-
merically enriched compounds 2, 4, 8, and 9. Products 2, 4,
8, and 9 were characterized by the comparison of their data
with those of known racemic samples or by their spectral
data.
Further investigation concerning the scope of our
approach in the synthesis of naturally occurred tricyclic
lactones will be continued.
4.1. Esterification of a-hydroxy ketones 1 and 7 by
phosphonoacetic acid 3a or phosphonopropionic acid 3e.
Synthesis of 4a as a general procedure
3. Conclusion
4.1.1. (S)-(ꢀ)-1-Methyl-2-oxo-2-phenylethyl(diethoxyphos-
phoryl)acetate 4a.6f To a cooled (0 ꢁC) solution of (S)-
20
In conclusion, we have demonstrated that the intramole-
cular-Horner–Wadsworth–Emmons reaction can be suc-
cessfully employed in the synthesis of enantiomerically
enriched di- and trisubstituted butenolides as well as tri-
cyclic ones starting from the corresponding a-hydroxy
ketones of known enantiomeric purity. Presented by us
procedure for the preparation of these target compounds,
where the esterification of a-hydroxy ketones precedes the
HWE step and seems to be more effective in terms of the
enantiomeric purity and yield than an alternative route.
Therefore, the conversion of chiral a-hydroxy ketones to
optically active butenolides of known absolute configura-
tion via intramolecular-HWE reaction can be supplemen-
tary to the previously reported methods using
intramolecular Claisen condensation.8
(ꢀ)-2-hydroxy-1-phenyl-1-propan-1-one 1a ½aꢁD ¼ ꢀ82:7
(c 3.6, CHCl3), 96% ee (0.04 g, 0.26 mmol) in dichloro-
methane (2.5 mL) were added pyridine (21 lL, 0.26 mmol),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydro-
chloride (WSC) (0.1 g, 0.53 mmol), 4-dimethylaminopyri-
dine (DMAP) (0.0096 g, 0.078 mmol). Then, a solution of
diethylphosphonoacetic acid 3a (0.104 g, 0.53 mmol) in
CH2Cl2 (1 mL) was added by syringe. The mixture was stir-
red for 24 h at 5 ꢁC and diluted with CH2Cl2 (5 mL). Next,
the solution was washed with 0.1 M aqueous HCl to pH
5–6, extracted with additional CH2Cl2 (3 · 5 mL), organic
extracts were washed with brine, dried (MgSO4), and
evaporated in vacuo to afford crude 4a as a colorless oil
20
(0.0818 g, 96%), ½aꢁD ¼ ꢀ30:1 (c 2.8, CHCl3), Rf = 0.29
(hexane/EtOAc = 1.5:1); 1H NMR (CDCl3): d 1.32 (t,
J = 7.0 Hz, 6H, OCH2CH3), 1.54 (d, J = 7.0 Hz, 3H,
2
2
CH3), 3.06 (d(AB), JHP = 21.6 Hz, JAB = 14.5 Hz, 2H,
3
3
4. Experimental
CH2P), 4.16 (quint, JHP = 7.1 Hz, JHH = 7.1 Hz, 4H,
OCH2CH3), 6.01 (q, J = 7.0 Hz, 1H, OCH), 7.43–7.62
(m, 3H, C6H5), 7.93 (d, J = 7.0 Hz, 2H, C6H5); 13C
NMR (CDCl3): d 11.5 (CH3), 15.3 (OCH2CH3), 35.9 (d,
1JCP = 135.2 Hz, CH2P), 62.9 (OCH2CH3), 76.5 (CHO),
127.3 (C6H5), 128.4 (C6H5), 129.5 (C6H5), 134.1 (C-ipso),
1H, 13C, and 31P NMR spectra were recorded on a Bruker
AC 200 Spectrometer at 200.13, 50.32, and 81.02 MHz,
respectively (using deuterochloroform as solvent), unless
otherwise noted. IR spectra were measured on an Ati Matt-
son Infinity FTIR 60. MS spectra (CI and HRMS) were
recorded on a Finnigan MAT 95 spectrometer. Melting
points were measured with PHMK Boetius (VEB Analytik
Dresden) apparatus. Optical rotation values were measured
in 100 mm cell on Perkin–Elmer 241 MC under Na lamp
radiation. The enantiomer ratios were determined by
HPLC analysis on the commercially available column
Chiracel OD, Chiralpak AS, or Chirobiotic T under condi-
tion specified.
2
168.3 (d, JCP = 6.2 Hz, OC(O)), 188.5 (C6H5CO); 31P
NMR (CDCl3): d 19.1; MS (CI): m/z % 329 [M+H] (100)
(lit.6f 1H NMR, IR, elemental analysis).
4.1.2. (S)-(ꢀ)-1-Benzoylpropyl(diethoxyphosphoryl)acetate
4b. From (S)-(ꢀ)-2-hydroxy-1-phenyl-1-butan-1-one 1b
20
½aꢁD ¼ ꢀ29:3 (c 1.1, CHCl3) (93% ee) (0.047 g, 0.29 mmol),
ester 4b was obtained as a light yellow oil (0.088 g, 90%),
20
½aꢁD ¼ ꢀ16:6 (c 0.2, CHCl3), Rf = 0.35 (hexane/
EtOAc = 1.2:1); IR (film) mmax (cmꢀ1) 2971, 2906, 2870,
1
All the reactions were carried out using anhydrous condi-
tions and under an atmosphere of dry argon. Chemicals
and solvents were obtained from commercial sources.
Solvents and some of the chemicals were dried (drying
reagents in brackets) and distilled prior to use: tetrahydro-
furan and toluene (Na/benzophenone ketyl), acetonitrile
(NaH), dichloromethane (P2O5), triethylamine (CaH2),
dicyclohexylamine (CaH2). LiCl was dried in vacuo
(0.5 torr, 24 h). Diethyl carboxymethanephosphonate 3a14
and diethyl carboxyethane phosphonate 3e15 were prepared
according to the reported procedure. Activated molecular
1722, 1595, 1512, 1449, 1230, 1212, 1118, 1027, 786; H
NMR (CDCl3): d 1.02 (t, J = 7.4 Hz, 3H, CH3), 1.32 (t,
J = 7.0 Hz, 6H, OCH2CH3), 1.78–2.00 (m, 2H, CH2),
2
3.07 (d(AB), JHP = 21.5 Hz, JAB = 14.5 Hz, 2H, CH2P),
4.17
(quint,
3JHP = 7.1 Hz,
3JHH = 7.1 Hz,
4H,
OCH2CH3), 6.01 (ddd, J = 5.9, 4.4, 1.3 Hz, 1H, OCH),
7.31–7.61 (m, 3H, C6H5), 7.91 (d, J = 6.8 Hz, 2H, C6H5);
13C NMR (CDCl3): d 9.9 (CH3), 15.4 (OCH2CH3), 28.3
(CH2), 35.5 (d, 1JCP = 135.2 Hz, CH2P), 62.8 (OCH2CH3),
78.2 (CHO), 127.7, 128.8, 129.8, (C6H5), 133.6 (C-ipso),
2
167.3 (d, JCP = 5.9 Hz, OC(O)), 191.8 (C6H5C@O); 31P

1784
E. Krawczyk et al. / Tetrahedron: Asymmetry 18 (2007) 1780–1787
NMR (CDCl3): d 19.2; MS (CI): m/z % 343 [M+H] (100);
HRMS m/z calcd for C16H23O6P 342.1232; found
342.1230. HPLC analysis: Chiracel OD, 7% (i-PrOH/EtOH
4:1) in hexane, 0.5 mL/min; tR[min] 19.6 (R), tR[min] 25.6
(S), ee = 93%.
1:1.4) was obtained as light yellow crystals, mp 171–
20
173 ꢁC, (0.058 g, 96%). ½aꢁD ¼ þ78:2 (c 1.28, CHCl3);
Rf = 0.48 (hexane/EtOAc = 1.1:1); IR (film) mmax (cmꢀ1
)
1
2962, 2857, 1740, 1696, 1260, 1093, 1044, 1022, 800; H
NMR (CDCl3): d 1.19, 1.22, 1.27 (3 · t, J = 7.1 Hz, 6H,
OCH2CH3), 1.47, 1.56 (2 · t, J = 6.9 Hz, 3H, CH3), 3.14,
2
3
4.1.3. (S)-(ꢀ)-1-Benzoylbutyl(diethoxyphosphoryl)acetate
3.25 (2 · dq, JHP = 22.6 Hz, JHH = 7.2 Hz, 1H, CHP),
4.08, 4.09 (2 · dq, 3JHP = 9.5 Hz, 3JHP = 6.8 Hz,
3JHH = 7.2 Hz, 4H, OCH2CH3), 6.88, 6.89 (2 · s, 1H,
OCH), 7.30–7.55 (m, 8H, C6H5), 7.91 (d, J = 7.2 Hz, 2H,
C6H5); 13C NMR (CDCl3): d 11.6 (major isomer, d,
2JCP = 6.1 Hz, CH3), 11.8 (minor isomer, d, 2JCP = 6.0 Hz,
4c. From (S)-(ꢀ)-2-hydroxy-1-phenyl-1-pentan-1-one 1c
20
½aꢁD ¼ ꢀ19:9 (c 2.4, CHCl3) (88% ee) (0.042 g, 0.24 mmol),
ester 4c was obtained as a light yellow oil (0.079 g, 93%).
20
½aꢁD ¼ ꢀ11:7 (c 0.17, CHCl3), Rf = 0.4 (hexane/
EtOAc = 1.2:1); IR (film) mmax (cmꢀ1) 3063, 2997, 2882,
1
3
1771, 1643, 1501, 1440, 1270, 1079, 954, 777; H NMR
CH3), 16.1 (major isomer, d, JCP = 6.2 Hz, OCH2CH3),
3
(CDCl3): d 0.94 (t, J = 7.3 Hz, 3H, CH3), 1.33 (t,
J = 7.0 Hz, 6H, OCH2CH3), 1.42–1.49 (m, 2H, CH2),
1.85 (q, J = 6.5 Hz, 2H, CH2), 3.08 (dd(AB),
2JHP = 21.5 Hz, JAB = 14.5 Hz, 2H, CH2P), 4.17 (quint,
16.2 (minor isomer, d, JCP = 6.1 Hz, OCH2CH3), 38.7
1
(major isomer, d, JCP = 133.9 Hz, CHP), 39.3 (minor iso-
1
mer, d, JCP = 134.4 Hz, CHP), 62.6 (major isomer,
OCH2CH3), 62.7 (minor isomer, OCH2CH3), 78.1 (major
isomer, CHO), 78.2 (minor isomer, CHO), 128.5 (C6H5),
128.6 (C6H5), 128.62 (C6H5), 128.7 (C6H5), 128.98
(C6H5), 129.0 (C6H5), 129.2 (C6H5), 129.3 (C6H5), 133.1
(C-ipso), 133.5 (C-ipso), 133.8 (C-ipso), 134.4 (C-ipso),
168.8 (major isomer, OC(O)), 169.3 (minor isomer, d,
2JCP = 6.0 Hz, OC(O)), 192.9 (minor isomer, C6H5C@O),
193.3 (major isomer, C6H5CO); 31P NMR (CDCl3): d
23.1 ( 58%), 22.9 (42%); MS (CI): m/z % 405 [M+H]
(100), 211 (64), 197 (42), 195 (26); HRMS m/z calcd for
C21H25O6P 404.1388; found 404.1385. HPLC analysis:
Chiracel OD, 7% (i-PrOH/EtOH = 4:1) in hexane,
0.5 mL/min; major isomer tR[min] 14.4, tR[min] 18.2,
ee = 75%; minor isomer tR[min] 17.5, tR[min] 28.2,
ee = 85%.
3
3JHP = 7.5 Hz, JHH = 7.5 Hz, 4H, OCH2CH3), 5.92 (t,
J = 6.3 Hz, 1H, OCH), 7.43–7.59 (m, 3H, C6H5), 7.92 (d,
J = 7.1 Hz, 2H, C6H5); 13C NMR (CDCl3): d 10.9 (CH3),
16.3 (OCH2CH3), 18.2 (CH2), 28.1 (CH2), 35.0 (d,
1JCP = 133.7 Hz, CH2P), 62.7 (OCH2CH3), 73.5 (CHO),
128.4 (C6H5), 128.9 (C6H5), 129.6 (C6H5), 133.6, (C-ipso),
2
163.3 (d, JCP = 6.0 Hz, OC(O)), 199.0 (C6H5C@O); 31P
NMR (CDCl3): d 19.3; MS (CI): m/z % 357 [M+H]
(100); HRMS m/z calcd for C17H25O6P 356.1388; found
356.1385. HPLC analysis: Chiracel OD, 7% (i-PrOH/EtOH
4:1) in hexane, 0.5 mL/min; tR[min] 17.2 (R), tR[min] 23.4
(S), ee = 85%.
4.1.4. (R)-(+)-1-Benzoylbutyl(diethoxyphosphoryl)acetate
4c. From (R)-(+)-2-hydroxy-1-phenyl-1-pentan-1-one 1c
20
½aꢁD ¼ þ17:3 (c 1.3, CHCl3) (68% ee) (0.027 g, 0.15 mmol),
4.1.7. (S)-(ꢀ)-5-Oxo-6,7,8,9-tetrahydro-5H-benzo[7]annu-
len-6-yl 2-(diethoxyphosphoryl)acetate 8a. From (S)-(+)-
ester 4c was obtained as a light yellow oil (0.046 g, 87%).
20
½aꢁD ¼ þ5:0 (c 1.0, CHCl3).
6,7,8,9-tetrahydro-6-hydroxy-5H-benzocyclohepten-5-one
20
7a ½aꢁD ¼ þ44:2 (c 4.4, CHCl3) (94% ee) (0.096 g,
4.1.5.
(S)-(+)-2-Oxo-1,2-diphenylethyl(diethoxyphos-
0.54 mmol), ester 8a was obtained as a dark yellow oil,
20
phoryl)acetate 4d. From (S)-(+)-2-hydroxy-1,2-diphenyl-
(0.174 g, 91%). ½aꢁD ¼ ꢀ2:05 (c 1.4, CHCl3); Rf = 0.3 (hex-
20
ethanone 1d ½aꢁD ¼ þ138:4 (c 0.25, CHCl3) (83% ee)
ane/EtOAc = 1.3:1); IR (film) mmax (cmꢀ1) 2923, 2871,
1
(0.048 g, 0.23 mmol), ester 4d was obtained as a yellow
1742, 1650, 1504, 1452, 1255, 1129, 1027, 729; H NMR
20
oil (0.077 g, 86%). ½aꢁD ¼ þ73:5 (c 0.21, CHCl3),
(CDCl3): d 1.33 (t, J = 7.0 Hz, 6H, OCH2CH3), 1.78–2.35
(m, 4H, CH2), 2.96–3.0 (m, 2H, CH2) 3.06 (dd(AB),
2JHP = 21.5 Hz, JAB = 14.5 Hz, 2H, CH2P), 4.17 (quint,
Rf = 0.35 (hexane/EtOAc = 1.3:1); IR (film) mmax (cmꢀ1
)
2958, 2916, 2849, 1702, 1650, 1500, 1261, 1088, 1029,
3
801; 1H NMR (CDCl3): d 1.25, 1.27 (2 · t, J = 7.0 Hz,
3JHP = 7.3 Hz, JHH = 7.3 Hz, 4H, OCH2CH3), 5.45 (dd,
6H,
OCH2CH3),
3.12
(dd(AB),
2JHP = 20.2 Hz,
J = 10.4, 5.6 Hz, 1H, OCH), 7.18–7.43 (m, 3H, Ar), 7.71
(d, J = 7.4 Hz, 1H, Ar); 13C NMR (CDCl3): d 16.2
(OCH2CH3), 21.5, 23.4, 29.0 (CH2), 36.0 (d,
1JCP = 130.8 Hz, CH2P), 62.8 (OCH2CH3), 89.9 (CHO),
JAB = 14.6 Hz, 2H, CH2P), 4.12, 4.13 (2 · quint,
3
3JHP = 7.1 Hz, JHH = 7.1 Hz, 4H, OCH2CH3), 6.89 (s,
1H, OCH), 7.32–7.62 (m, 8H, C6H5), 7.91 (d, J = 7.8 Hz,
2H, C6H5); 13C NMR (CDCl3): d 16.3 (OCH2CH3), 33.9
126.8, 127.3, 129.9, 134.2 (C6H4), 154.3 (d, JCP = 5.9 Hz,
2
1
(d, JCP = 134.6 Hz, CH2P), 62.8 (OCH2CH3), 78.5
OC(O)), 192.98 (C@O); 31P NMR (CDCl3): d 19.2; MS
(CI): m/z % 355 [M+H] (100), 197 (48); HRMS m/z calcd
for C17H23O6P 354.1232; found 354.1228.
(CHO), 128.7 (C6H5), 128.8 (C6H5), 129.1 (C6H5), 129.4
(C6H5), 133.2 (C-ipso), 134.5 (C-ipso), 165.3 (d,
2JCP = 5.9 Hz, OC(O)), 192.98 (C6H5C@O); 31P NMR
(CDCl3): d 18.8; MS (CI): m/z % 391 [M+H] (100); HRMS
m/z calcd for C20H23O6P 390.1232; found 390.1237. HPLC
analysis: Chiracel OD, 7% (i-PrOH/EtOH 4:1) in hexane,
0.5 mL/min; tR[min] 30.3 (R), tR[min] 38.2 (S), ee = 82%.
4.1.8. (R)-(ꢀ)-2-Methyl-1-oxo-2,3-dihydro-1H-inden-2-yl 2-
(diethoxyphosphoryl)acetate 8b. From (R)-(+)-2-hydroxy-
20
2-methyl 1-indanone 7b ½aꢁD ¼ þ19:8 (c 3.1, CHCl3) (69%
ee) (0.04 g, 0.25 mmol), ester 8b was obtained as a yellow
20
oil, (0.049 g, 56%). ½aꢁD ¼ ꢀ15:0 (c 0.5, CHCl3),
1
4.1.6. (+)-2-Oxo-1,2-diphenylethyl-2-(diethoxyphosphoryl)
propanate 4e. From (S)-(+)-2-hydroxy-1,2-diphenyl-etha-
Rf = 0.36 (hexane/EtOAc = 1.1:1); H NMR (CDCl3): d
1.34, 1.35 (2 · t, J = 7.0 Hz, 6H, OCH2CH3), 1.50 (s, 3H,
20
2
none 1d ½aꢁD ¼ þ138:4 (c 0.25, CHCl3) (83% ee) (0.032 g,
CH3), 3.01 (d(AB), JHP = 24.6 Hz, JAB = 14.3 Hz, 2H,
0.15 mmol), ester 4e (two diastereoisomers in a ratio of
CH2P), 3.36 (d(AB), JAB = 16.9 Hz, 2H, CH2), 4.16, 4.18

E. Krawczyk et al. / Tetrahedron: Asymmetry 18 (2007) 1780–1787
1785
3
3
3
(2 · quint, JHP = 7.2 Hz, JHH = 7.2 Hz, 4H, OCH2CH3),
7.38–7.43 (m, 2H, Ar), 7.58–7.65 (m, 1H, Ar), 7.77–7.81
(m, 1H, Ar); 13C NMR (CDCl3): d 16.3(OCH2CH3), 26.7
CH2), 1.82–2.05 (m, 1H, CH2) 5.50 (dd, JHH = 4.4 Hz,
4JHH = 1.1 Hz, 1H, OCH), 6.27 (d, JHH = 1.2 Hz, 1H,
4
C@CH), 7.47 (s, 5H, C6H5); 13C NMR (CDCl3): d 13.7
(CH3), 17.9 (CH2), 35.6 (CH2), 82.1 (CHO), 114.3
(CH@C(C6H5)), 127.1 (C6H5), 127.4 (C6H5), 129.2
(C6H5), 130.2 (CH@C(C6H5)), 131.2 (C-ipso), 168, 172.8
(C@O); MS (CI): m/z % 203 [M+H] (100); HRMS m/z
calcd for C13H14O2 202.0994; found 202.0993. HPLC anal-
ysis: Chirobiotic T, 25% i-PrOH in hexane, 0.5 mL/min;
tR[min] 20.9 (R), tR[min] 23.7 (S), ee = 83.7%.
1
(CH3), 33.0 (d, JCP = 135.8 Hz, CH2P), 42.1 (CH2), 63.0
(OCH2CH3), 88.8 (C(Me)O), 126.2, 128.5, 129.2, 133.5,
2
147.4 (C6H4), 160.2 (d, JCP = 6.1 Hz, OC(O)), 198.98
(C@O); 31P NMR (CDCl3): d 19.1; MS (CI): m/z % 341
[M+H] (100), 183 (40); HRMS m/z calcd for C16H21O6P
340.1075; found 340.1077. HPLC analysis: Chiracel OD,
2% (i-PrOH/EtOH 4:1) in hexane, 0.5 mL/min; tR[min]
23.6 (S), tR[min] 25.8 (R), ee = 69.4%.
4.2.4. (R)-(ꢀ)-5-Propyl-4-phenylfuran-2-(5H)-one 2c.18
4.2. Intramolecular HWE reaction of 4a–e and 8a,b.
Synthesis of 2a as a general procedure
From (R)-(+)-4c (0.037 g, 0.1 mmol), 2c was obtained as
20
a semisolid (0.012 g, 61%). ½aꢁD ¼ ꢀ100 (c 0.36, CHCl3).
HPLC analysis: Chirobiotic T, 25% i-PrOH in hexane,
0.5 mL/min; tR[min] 19.4 (R), tR[min] 26.0 (S), ee =
67.3%.
4.2.1. (S)-(+)-5-Methyl-4-phenylfuran-2-(5H)-one 2a.17 To
a cooled (0 ꢁC) solution of crude (S)-(ꢀ)-4a (0.08 g,
0.24 mmol) in toluene (2 mL) were added 18-crown-6
(0.111 g, 0.308 mmol) and potassium carbonate (0.021 g,
0.15 mmol). The reaction mixture was stirred for 12 h at
5 ꢁC under an argon atmosphere, then 18-crown-6
(0,0277 g, 0.077 mmol) was added. The mixture was stirred
for 1.5 h and then K2CO3 (0.0053 g, 0.038 mmol) was
added. The mixture was stirred for an additional 7 h, diluted
with saturated brine, and extracted with ethyl acetate. The
organic layers were dried. The solvent was evaporated and
the crude product was purified by column chromatography
4.2.5. (S)-(+)-4,5-Diphenylfuran-2-(5H)-one 2d.3b From
the reaction with (S)-(+)-4d (0.05 g, 0.13 mmol), performed
at ꢀ20 ꢁC, 2d was obtained as a white solid, mp 150 ꢁC,
20
(0.147 g, 50%). ½aꢁD ¼ þ101 (c 0.1, CHCl3); Rf = 0.55 (hex-
ane/EtOAc = 1.3:1). HPLC analysis: Chiralpak AS, 20%
(i-PrOH/EtOH = 4:1) in hexane, 0.5 mL/min; tR[min]
37.2 (R), tR[min] 56.8 (S), ee = 74% (lit. mp 151–153,3b
13
149,19 148;20 1H, C NMR;3b IR, MS20).
(petroleum ether/EtOAc = 6:1). Product 2a was obtained as
4.2.6. (S)-(+)-3-Methyl-4,5-diphenylfuran-2-(5H)-one 2e.7e
20
white crystals mp 59–60.5 ꢁC, (0.0317 g, 76%). ½aꢁD ¼ þ200 . From (+)-4e (mixture of diastereomers) (0.065 g, 0.16 mmol),
(c 0.35, CHCl3); Rf = 0.51 (hexane/EtOAc = 1.5:1); 1H
NMR (CDCl3): d 1.54 (d, J = 6.7 Hz, 3H, CH3), 5.57 (dq,
2e was obtained as a white solid, mp 91–92 ꢁC, (0.015 g,
20
40%). ½aꢁD ¼ þ102:5 (c 0.16, CHCl3); Rf = 0.68
3JHH = 6.7 Hz, JHH = 1.3 Hz, 1H, OCH), 6.27 (d,
(hexane/EtOAc = 1.1:1); 1H NMR (CDCl3): d 2.18 (d,
4
4JHH = 1.2 Hz, 1H, C@CH), 7.48 (s, 5H, C6H5). HPLC
analysis: Chiracel OD, 5% i-PrOH in hexane, 0.5 mL/min;
tR[min] 35.5 (S), ee >99% (lit. mp 50–53,17a 55–56,17b 57–
5JHH = 1.6 Hz, 3H, CH3), 6.20 (d, JHH = 1.6 Hz, 1H,
5
C@CH), 7.28–7.31 (m, 10 H, 2 · C6H5); MS (CI): m/z %
281 [M+H] (100). HPLC analysis: Chiralpak AS, 50% (i-
PrOH/EtOH = 4:1) in hexane (50%), 0.5 mL/min; tR[min]
11.6 (S), tR[min] 17.4 (R), ee = 59%. (lit. mp 90 ꢁC;22 1H,
13C NMR, IR7e).
1
13
58,17c 61–63,6f 62.5–63.5;17d H NMR;17a,b C NMR;17d
IR17a–c).
4.2.2. (S)-(+)-5-Ethyl-4-phenylfuran-2-(5H)-one 2b. From
(S)-(ꢀ)-4b (0.04 g, 0.128 mmol), 2b was obtained as a col-
4.2.7.
hepta[1,2-b]furan-2-one 9a.13b,21 From (S)-(ꢀ)-8a (0.05 g,
(S)-(ꢀ)-3a,4,5,6-Tetrahydro-2H-benzo[3,4]cyclo-
20
orless oil (0.018 g, 75%). ½aꢁD ¼ þ160 (c 0.45, CHCl3);
Rf = 0.68 (hexane/EtOAc = 1.2:1); IR (film) mmax (cmꢀ1
)
0.138 mmol), 9a was obtained as a white solid, mp
20
1
2932, 2850, 1750, 1621,1049; H NMR (CDCl3): d 0.92
76 ꢁC, (0.011 g, 40%). ½aꢁD ¼ ꢀ186:5 (c 0.17, CHCl3);
3
3
(t, JHH = 7.3 Hz, 3H, CH3), 1.66 (septet, JHH = 7.2 Hz,
Rf = 0.58 (hexane/EtOAc = 1.3:1); 1H NMR (CDCl3): d
1.77 (q, 3JHH = 11.1 Hz, 2H, CH2), 2.73 (ddd,
3JHH = 15.6, 13.2, 10.7 Hz, 2.5 H, CH2), 2.94 (dd,
3
1H, CH2), 2.11 (ddq, JHH = 7.5, 4.0, 3.4 Hz, 1H, CH2),
5.50 (ddd, JHH = 4.6, JHH = 3.4 Hz, JHH = 1.2 Hz, 1H,
OCH), 6.29 (d, JHH = 1.0 Hz, 1H, C@CH), 7.47 (s, 5H,
3
3
4
4
3
3JHH = 15, 7.0 Hz, 1.5 H, CH2), 4.99 (dd, JHH = 9.7,
C6H5); 13C NMR (CDCl3): d 8.2 (CH3), 26.3 (CH2), 82.9
(CHO), 114.7 (CH@C(C6H5)), 127.1 (C6H5), 128.5
(C6H5), 129.2 (C6H5), 130.2 (CH@C(C6H5)), 131.2 (C-
ipso), 167.3, 172.9 (C@O); MS (CI): m/z % 189 [M+H]
(100); HRMS m/z calcd for C12H12O2 188.0837; found
188.0835. HPLC analysis: Chirobiotic T, 25% i-PrOH in
hexane, 0.5 mL/min; tR[min] 26.4 (R), tR[min] 28.8 (S),
ee = 94%.
5.6 Hz, 1H, CHO) 6.12 (d, JHH = 1 Hz, 1H, C@CH),
4
7.18–7.40 (m, 4H, Ar); 13C NMR (CDCl3): d 22.8, 23.4,
29.2 (CH2), 84.5 (HCO), 110.3 (C@CH), 127.0, 128.3,
130.8, 133.1 (Ar), 139.0 (C@CH), 169.4 (C@O); MS (CI):
m/z % 201 [M+H] (100). HPLC analysis: Chiralpack AS,
70% (i-PrOH/EtOH = 4:1) in hexane, 0.5 mL/min; tR[min]
18.8 (S), tR[min] 39.8 (R), ee = 83% (lit. mp 74 ꢁC;21 1H
NMR, IR, elemental analysis21).
4.2.3. (S)-(+)-5-Propyl-4-phenylfuran-2-(5H)-one 2c.18
4.2.8.
(R)-(+)-8a-Methyl-8,8a-dihydro-2H-inden[2,1-b]-
From (S)-(ꢀ)-4c (0.016 g, 0.045 mmol), 2c was obtained
furan-2-one 9b. From (R)-(ꢀ)-8b (0.01 g, 0.027 mmol),
20
as a semisolid (0.006 g, 67%). ½aꢁD ¼ þ148 (c 0.15, CHCl3);
9b was obtained as white crystals, mp 49 ꢁC, (0.005 g,
20
Rf = 0.72 (hexane/EtOAc = 1.2:1); IR (film) mmax (cmꢀ1
)
32%). ½aꢁD ¼ þ14:0 (c 0.2, CHCl3); Rf = 0.64 (hexane/
1
2952, 2905, 2823, 1755, 1618, 1071; H NMR (CDCl3): d
EtOAc = 1.1:1); IR (film) mmax (cmꢀ1) 2810, 1705, 1632,
3
1
0.91 (t, JHH = 7.1 Hz, 3H, CH3), 1.40–1.60 (m, 3H,
1491, 1202, 1080; H NMR (CDCl3): d 1.53 (s, 3H, CH3),

1786
E. Krawczyk et al. / Tetrahedron: Asymmetry 18 (2007) 1780–1787
3.09 (d(AB), JAB = 15.1 Hz, 2H, CH2), 5.96 (s, 1H,
C@CH), 7.40–7.71 (m, 4H, Ar); 13C NMR (CDCl3): d
26.3 (CH3), 42.9 (CH2), 84.6 (C(Me)O), 111.8 (C@CH),
127.0, 128.3, 129.9, 132.8 (C6H4), 135.8 (C@CH), 170.5
(C@O); MS (CI): m/z % 187 [M+H] (100); HRMS m/z
calcd for C12H10O2 186.0680; found 186.0681. HPLC anal-
ysis: Chiralpack AS, 70% (i-PrOH/EtOH = 4:1) in hexane
(30%), 0.5 mL/min; tR[min] 34.6 (R), tR[min] 57.5 (S),
ee = 94%.
at room temperature. Then, solid LiOHÆH2O (0.016 g,
0.38 mmol) was added slowly (0.5 h). The mixture was stir-
red for 24 h, and then filtered through a plug of Florisilꢂ,
washing with ether. After evaporation of solvent, the resi-
due was separated by column chromatography using petro-
leum ether/ethyl acetate (20:1 to 1:1, gradient elution) to
give 0.022 g (35%) of 2c together with 0.0517 g (60%) of
20
recovered ester 5. (S)-(+)-2c: ½aꢁD ¼ þ127:0 (c 0.8, CHCl3).
HPLC analysis: Chirobiotic T, EtOH–i-PrOH/hexane
(10:10:80), 0.5 mL/min; tR[min] 13.6 (R), tR[min] 15.2 (S);
ee = 76.5%.
4.3. Synthesis of 2d using LiN(Cy)2
To a stirred solution of LiN(Cy)2 (0.117 mmol) freshly pre-
pared from Cy2NH and BuLi (2.0 M in hexane) in THF
(1.5 mL), (S)-(+)-ester 4d (0.0217 g, 0.056 mmol) in THF
(1 mL) was added by syringe at ꢀ100 ꢁC. The mixture
was stirred at this temperature for 1 h and then allowed
to warm to room temperature. Then 0.1 M HCl was added
(5 mL), and the mixture was extracted with diethyl ether
(3 · 5 mL), after which the organic layer was washed with
brine, dried over MgSO4. Evaporation followed by column
chromatography (petroleum ether/EtOAc = 5:1) afforded
According to the modified procedure (5 ꢁC, 48 h) from (S)-
20
(ꢀ)-1b ½aꢁD ¼ ꢀ29:3 (c 1.1, CHCl3) (93% ee) (0.051 g,
0.31 mmol) and 5 (0.084 g, 0.37 mmol), (S)-(+)-2b was ob-
20
tained as a colorless oil, (0.035 g, 60%). ½aꢁD ¼ þ156:0 (c
0.63, CHCl3). HPLC analysis: Chirobiotic T, 25–100% i-
PrOH in hexane, 0.5 mL/min; tR[min] 15.4 (R), tR[min]
16.9 (S), ee = 88.8%.
4.5.1. 4-Oxo-3,4-diphenylbut-2-enoic acid ethyl ester 6.23
To a suspension of LiCl (0.006 g, 0.14 mmol) in THF
(1 mL), a solution of 5 (0.027 g, 0.12 mmol) was added at
0 ꢁC and the mixture was stirred for 15 min at this temper-
ature. DBU (0.02 g, 0.13 mmol) was added and the mixture
.
pure (S)-(+)-2d as a white solid, mp 151 ꢁC, (0.0117 g,
20
89%). ½aꢁD ¼ þ72:0 (c 0.2, CHCl3). HPLC analysis: Chir-
alpak AS, 20% (i-PrOH/EtOH = 4:1) in hexane, 0.5 mL/
min; tR[min] 45.5 (R), tR[min] 66.7 (S), ee = 63.3%.
was stirred for an additional 15 min. Then, (S)-(+)-1d
20
(0.025 g, 0.12 mmol), ½aꢁD ¼ þ138:4 (c 0.25, CHCl3)
The reaction of (S)-(+)-ester 4d in the presence of LiN(Cy)2
was carried out at ꢀ100 ꢁC for 2 h, after which it was
quenched with 10% HCl (2 mL) and then allowed to warm
(83% ee), was added dropwise at ꢀ20 ꢁC and the reaction
mixture was stirred for 2 h at ꢀ20 ꢁC and then 7 h at
5 ꢁC. After quenching with 0.1 M HCl (5 mL), the mixture
was diluted with diethyl ether (6 mL), aqueous layer was
extracted with diethyl ether (2 · 4 mL), organic extract
was dried with MgSO4 and concentrated in vacuo. The res-
idue was subjected to column chromatography using petro-
leum ether/ethyl acetate (25:1 to 1:2, gradient solution) to
to ambient temperature. An identical separation procedure
20
yielded (S)-(+)-2d (25%), ½aꢁD ¼ þ141:0 (c 0.2, CHCl3),
20
and remaining ester (S)-(+)-4d (60%), ½aꢁD ¼ þ70:4 (c
1.2, CHCl3). HPLC analysis for 2d: Chiralpak AS, 90%
(i-PrOH/EtOH = 4:1) in hexane (10%), 0.6 mL/min;
tR[min] 34.5 (R), tR[min] 49.9 (S), ee = 76%. HPLC analy-
sis for 4d: Chiracel OD, 7% (i-PrOH/EtOH 4:1) in hexane,
0.5 mL/min; tR[min] 30.7 (R), tR[min] 38.9 (S), ee = 75.4%.
give ester 6 (0.01 g, 30%) together with recovered 1d
20
(0.01 g, 40%), ½aꢁD ¼ þ88:6 (c 0.5, CHCl3), and
5
(0.013 g, 50%). Compound 6: (E/Z = 1.2/1), white solid,
mp 88–89 ꢁC; Rf = 0.6 (hexane/EtOAc = 1:1); 1H NMR
(CDCl3): d 1.13, 1.15 (2 · t, J = 7.1 Hz, 3H, OCH2CH3),
4.4. Synthesis of 2e using Et3N/LiCl
3
4.11, 4.12 (2 · quint, JHH = 7.1 Hz, 2H, OCH2CH3),
To lithium chloride (0.012 g, 0.28 mmol) was added a solu-
tion of (+)-4e (mixture of diastereomers) (0.0573 g,
0.14 mmol) in THF (2 mL) at ꢀ10 ꢁC. The mixture was
stirred for 15 min at this temperature. Then, triethyl amine
was added by syringe at ꢀ30 ꢁC. Stirring was continued for
36 h at that temperature and the solution was filtered
through a plug of SiO2, washing with ethyl acetate. The fil-
trate was concentrated and the residue chromatographed
6.28 (s, 1H, C@CH, E), 6.52 (s, 1H, C@CH, Z), 7.37–
7.60 (m, 8H, C6H5), 7.93–8.00 (m, 2H, C6H5); MS (CI):
m/z % 281 [M+H] (100), 235 (10). HPLC analysis: Chiral-
pack AS, 5% (i-PrOH/EtOH: 4:1) in hexane, 0.5 mL/min;
tR[min] 12.1 (Z), tR[min] 19.1 (E) (E/Z = 1.3:1) (lit.
1
13
91 ꢁC;23a H NMR, IR, UV;23a 1H, C NMR, IR23b).
using petroleum ether/EtOAc (5:1) to give (S)-(+)-2e as a
Acknowledgments
20
solid, mp 91 ꢁC, (0.012 g, 36%). ½aꢁD ¼ þ131:7 (c 0.2,
CHCl3). HPLC analysis: Chiralpack AS, 50% (i-PrOH/
EtOH = 4:1) in hexane, 0.5 mL/min; tR[min] 12.1 (S),
tR[min] 19.1 (R), ee = 77.6%.
Financial support by the Ministry of Science and Higher
Education of Poland (Grant No. 3 T09A 083 29; 2005-
2008) is gratefully acknowledged. The authors thank Pro-
´
fessor A. Skowronska for helpful discussion.
4.5. Sequential HWE-lactonization reaction of a-hydroxy
ketones 1b, 1c, and 1d
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To a suspension of activated 4 A molecular sieves (0.5 g) in
20
THF (3 mL), a solution of (S)-(ꢀ)-1c ½aꢁD ¼ ꢀ19:9 (c 2.4,
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