A simple thiophosphate-based method for α-alkylidenation of lactones

Article abstract of DOI:10.1055/s-2006-926285

A variety of α-alkylidene lactones has been synthesized using a one-pot procedure based on the reaction of readily available thiophosphates with aldehydes under basic, mild conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926285

7
16
PAPER
A Simple Thiophosphate-Based Method for a-Alkylidenation of Lactones
a
E
-Alkylidenatio
w
n
of Lactones a Krawczyk*
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łódž, Poland
Fax +48(42)6847126; E-mail: ewakrsoj@bilbo.cbmm.lodz.pl
Received 28 July 2005; revised 1 September 2005
We have elaborated a new strategy for the stereoselective
Abstract: A variety of a-alkylidene lactones has been synthesized
using a one-pot procedure based on the reaction of readily available
thiophosphates with aldehydes under basic, mild conditions.
conversion of carbonyl compounds into unsaturated de-
rivatives based on intermediates thio- and selenophos-
7
phates. As part of a continuing program of research,
Key words: a-alkylidene lactones, lactones, thiophosphates, aldol
reactions, stereoselectivity
based on our methodology, studies on the construction of
exocyclic and endocyclic carbon–carbon double bonds
8
were undertaken. Recently, we have reported a one-pot
procedure for a-methylenation of lactones including race-
mic frullanolide, and a-methylenation of cycloal-
kanones.8a
a-Alkylidene lactones can serve as useful intermediates in
1
organic synthesis, particularly for the synthesis of com-
pounds exhibiting biological activity, i.e. natural cyto-
1
f–1h
This paper describes an extension of our methodology to
the synthesis of a-alkylidene g- and d-lactones. For this
purpose a variety of the corresponding, new thiophos-
phates 3 have been synthesized. The compounds 3 were
easily prepared from the appropriate lactones 1 adopting
toxic obtusilactones.
Ethylidene lactones with six-
membered rings are key intermediates in the synthesis of
2
some pyrrolizidine alkaloids. Several potentially cyto-
toxic lactones containing a long alkyl chain in alkylidene
moiety have been isolated from plants belonging to the
9
3
our previously described method (Scheme 1). Treatment
Lauraceae family. Therefore a-alkylidene lactones have
of 1 with trimethylsilyl chloride gave O-silylated lactones
been a subject of intensive synthetic studies. Two general
synthetic methods of these compounds have been devised.
One method is based on the introduction of the alkylidene
10
2
. Addition of readily available O,O-diethyl chlorothio-
11
phosphonate (4), an excellent thiophosphorylating
agent, afforded thiophosphates 3 in high yield and purity.
4
group on the a position of the lactone ring, the second one
involves a ring closure reaction from acyclic olefinic or
Next, the addition of thiophosphate anions, generating by
the action of sodium hydride on lactones 3, to various al-
dehydes was examined. This reaction proceeded at low
temperature for 1 hour and then another hour at room tem-
perature and led to the formation of a-alkylidene com-
pounds 5 in good yields (Scheme 2, Table 1). It is
noteworthy that the conversion of 1 into 5 can be per-
formed using crude intermediate silyl enol ethers 2 and
thiophosphates 3.
5
acetylenic precursors. Direct introduction of an a-alky-
lidene group to g-butyrolactone which included base-cat-
4
a–
alyzed condensation of g-butyrolactone with aldehyde,
4
d
reactions of aldehyde with anions of a-phosphonolac-
4
e–4g
4h,i
tones,
a-triphenylphosphoranylidene lactones,
a-
or
have
4
j,k
4l,m
silyl carbanions , a-thiomethylene intermediates
4
n,o
S-(tetrahydro-2-oxo-3-furanyl)dithiocarbonate
been described in the literature. Although numerous meth-
6
ods have been reported for the preparation of a-alky-
A number of a-alkylidene lactones 5 were obtained as a
mixture of E- and Z-diastereomers. These isomers were
easily separated by flash chromatography (Table 1).
lidene lactones, the development of new, simple and
stereoselective protocols for obtaining these compounds
still presents a synthetic problem.
O
SP(OEt)2
(
)n
(EtO)2P(O)SCl (4)
LDA, THF
Me3SiCl
(
)n
( )n
R
O
O
R
O
OSiMe3
R
O
O
1
2
3
1
, 2, 3
n
1
1
1
2
R
% Yield of 3
a
b
c
d
H
92
96
78
75
CH3
C7H15
H
Scheme 1
SYNTHESIS 2006, No. 4, pp 0716–0722
x
x
.
x
x
.2
0
0
6
Advanced online publication: 11.01.2006
DOI: 10.1055/s-2006-926285; Art ID: Z15305SS
Georg Thieme Verlag Stuttgart · New York
©

PAPER
a-Alkylidenation of Lactones
717
Table 1 Synthesis of a-Alkylidene g- and d-Lactones 5 from 3 and Various Aldehydesa
Entry
5
a
a
b
c
d
e
f
n
1
1
1
1
1
1
1
1
1
2
2
2
R
R¢
E/Zb
9:1
Yield (%)c
69
1
2
3
4
5
6
7
8
9
H
CH3
CH3
H
1:1
55d
H
C H
10:1
2:1
82e
2
5
H
C H
92e
5
11
19
H
C H
1:1.6
8:1
79f
9
CH3
CH3
CH3
72
C H
1:2
68f
9
19
19
g
h
i
C H
CH3
2.5:1
1:2.2
1:1
67.7g
7
15
15
e
h
C H
C H
54 (3: 33)
7
9
1
1
1
0
1
2
H
H
H
CH3
55
j
C H
1.2:1
1:2
80
2
5
k
C H
48 (3: 42)h
9
19
a
b
c
d
e
f
Conditions: 3 (1 equiv), NaH (1.2 equiv), Et O, –10 °C, 30 min, R¢CHO (1 equiv), –70 °C, 1 h → r.t., 1 h.
2
1
Determined by H NMR spectra of crude reaction mixtures.
Overall yield of both isomers.
Conditions: –70 °C, 1 h → –20 °C, 1 h.
Conditions: –70 °C, 1 h → r.t., 12 h.
Conditions: –70 °C, 1 h → r.t., 48 h.
g
h
Conditions: –70 °C, 1 h → –20 °C, 20 h.
31
Determined by P NMR spectra of crude reaction mixtures.
O
ied. Unfortunately no improvement in stereoselectivity
was observed.
R'
SP(OEt)2
1
) NaH, –10 °C
( )n
(
)n
E + Z
The basic concept of the transformation of thiophosphate
3 into a-alkylidene lactone 5 is illustrated in Scheme 3.
2
) R'CHO, –70 °C to r.t.
R
O
O
R
O
O
5a–k
3
a–d
The addition of thiophosphate anion 3¢ to aldehydes pro-
vides the corresponding diastereomeric oxyanion 6. Fur-
ther conversion of this intermediate proceeds via a
n = 1, 2
R' = CH3, C2H5, C5H11, C9H19
Scheme 2
O
The addition of thiophosphate 3a to aldehydes containing
a short carbon chain occurs with high stereoselectivity
producing predominantly E-a-alkylidene g-butyrolac-
tones (entries 1, 3). Increasing amount of Z-isomer of a-
alkylidene g-butyrolactones is observed with the elonga-
tion of the alkyl chain of aldehyde (entries 4, 5). When the
derivative of g-valerolactone 3b is used, the same trend of
stereoselectivity is observed (entries 6, 7). Condensation
of thiophosphorylated g-undecanoic lactone 3c with acet-
aldehyde as well as decanal affords a mixture of both E-
and Z-diastereomers in a similar ratio (entries 8, 9). When
these studies were extended to thiophosphate 3d derived
from d-valerolactone, a drop in the stereoselectivity of re-
actions with acetaldehyde and propionaldehyde was noted
SP(OEt)2
(
)n
R
O
O
NaH
3
O
O
SP(OEt)2
SP(OEt)2
C(R')(H)O–
(
)n
(
)n
–
O
+
R'CHO
R
O
R
O
O
3'
6
S
S–
O
(
)n
C(H)R'
O
(
)n
C(R')(H)OP(OEt)2
(EtO)2P(O)O–
–
R
O
R
O
O
8
7
(
entries 10, 11).
R'
–
Sx
The other base systems (LDA,4o K CO /18-crown-6 )
4g
(
)n
5 E + Z
2
3
that might favor E- or Z-olefination of 3 have been ex-
R
O
O
plored and the effect of added metal salt (ZnCl ) on the
yields and E/Z ratios of a-alkylidene lactones 5 was stud-
2
Scheme 3
Synthesis 2006, No. 4, 716–722 © Thieme Stuttgart · New York

7
18
E. Krawczyk
PAPER
rearrangement involving migration of phosphoryl group
from sulfur to oxygen affording thiolate anion 7. Subse-
quent cyclization of 7 with elimination of phosphate
group leads to episulfide 8. Finally a spontaneous desulfu-
rization of 8 gives a-alkylidene lactone 5. Examined reac-
tions proceed with a good to moderate stereoselectivity.
The main factors controlling of stereochemistry of a-alky-
lidene lactones are the size of alkyl substituent of the al-
dehyde, and the size of the substituent in the lactone ring,
and the reaction time and temperature.
3' R'CHO
+
R
R
R
O
R'
S
O
H
H
R'
S
O
O
O
P(OEt)2
P(OEt)2
H
O
O–
O–
B
A
erythro
threo
R
O
R' O
P(OEt)2
R' O
P(OEt)2
t-6
It is known that in kinetically controlled aldol-type reac-
tion the stereoselection is attributed to the form of a tran-
O
O
S
S
O–
H
H
O
e-6
O
1
2
13
sition state. It is reported in the literature that the
reaction of lithium enolate of dioxalanones with alde-
hydes occurs through the conventional Zimmerman–
R
R
R'
1
4
Traxler transition state (TS) with the hydrogen of the al-
O
O
O
H
O
R'
dehyde rather than R¢ group the facing the dioxalanone
S
O–
e-6a
P(OEt)2
–S P(OEt)2
4
o
O
ring. According to the suggestion by Matsui the follow-
O
O
t-6a
ing transition state models A and B are considered
(
Scheme 4).
R
O
R
O
From TS A, an erythro oxyanion intermediate e-6 and
from TS B, a threo oxyanion intermediate t-6, both fa-
vored for the steric reasons, are formed respectively. In
this aldol type condensation under the kinetically con-
trolled reaction conditions (low temperature) both diaste-
reomers E and Z should be formed. Indeed treatment of
thiophosphate 3a with acetaldehyde and sodium hydride
in diethyl ether at low temperature afforded the E- and Z-
olefins 5a in a 1:1 ratio. After warming the reaction mix-
ture to 0 °C or to room temperature it proceeds with E-ste-
reoselectivity. On the other hand, reactions of
thiophosphates 3a–d with the aldehyde containing a long
alkyl chain, afford Z-a-alkylidene lactones 5 predomi-
nantly. That means the examined reactions proceed via
erythro or threo 6 and 7 to give 5 under thermodynamical-
ly controlled reaction conditions. The marginal effect of
the metal salt on the stereoselectivity of alkylidene com-
pounds was noticed. These results can be rationalized by
considering that a retro-aldolization of oxyanion interme-
diates 6 to substrates can compete with their rearrange-
ment to thiolates anions 7. The erythro e-7 – precursor of
E-olefin is more favored when the steric interaction be-
tween R¢ group and carbonyl moiety of lactone is mini-
mized in it. The threo intermediate t-7, which provides Z-
olefin seems to be favored if R¢ of aldehyde and R substit-
uent in lactone ring are long chain alkyl groups. Therefore
H
R'
(EtO)2PO
(
EtO)2PO
O
O
S–
S–
H
R'
e-7
O
t-7
O
–
(EtO)2P(O)O
– (EtO)2P(O)O
H
R
R
O
R'
(
E)
O
S
(Z)
S
R'
–
H
–
O
8
O
8
Sx
Sx
R
R
O
H
(
E)
O
R'
(Z)
5
O
R'
5
O
H
Scheme 4
valuable alternative to previous methods described for the
synthesis of these compounds.
Chemicals (aldehydes, lactones) and solvents were obtained from
commercial sources (Fluka, Aldrich) and distilled or dried accord-
ing to standard methods. Petroleum ether (PE) refers to the fraction
boiling at 60–90 °C. Enol silyl ethers 1a–d were prepared as de-
1
0
one can assume that the temperature and also steric factors scribed. All reactions were carried out in an atmosphere of dry ar-
influence the E/Z ratio of the final a-alkylidene lactones.
gon. Chromatographic purification was performed on silica gel
1
columns (Merck, Kieselgel 70–230 mesh) with indicated eluent. H,
In summary we have demonstrated that application of our
methodology with the use of corresponding thiophos-
13
31
C and P NMR spectra were recorded on a Bruker AC 200 Spec-
trometer. IR spectra were measured on an Ati Mattson Infinity FT
phates, provides a general, simple and convenient route to IR 60. MS spectra (EI, CI, and HRMS) were recorded on a Finnigan
a-alkylidene g- and d-lactones, via a single and double MAT 95 spectrometer. Microanalysis obtained on a Carbo Erba
CHNS-OEA 1108 Elemental Analyzer. The products were charac-
carbon–carbon bond forming reaction. The conversion of
terized by comparison of their data with those of known samples or
by their spectral data.
lactones into their a-alkylidene derivatives can be per-
formed in one-pot procedure. It is noteworthy that Z-ste-
reoselectivity is achieved for a-alkylidene lactones
containing a long alkyl chain. Therefore this method is a
a-Alkylidene Lactones 5 from Lactones 1; General Procedure
A solution of SO Cl (2 mmol) in CH Cl (5 mL) was added drop-
2
2
2
2
wise to the stirred solution of O,O,O-triethyl phosphorothioate (376
Synthesis 2006, No. 4, 716–722 © Thieme Stuttgart · New York

PAPER
a-Alkylidenation of Lactones
719
1
3
mg, 1.9 mmol) in CH Cl (20 mL) at –30 °C, and the stirring was
continued for 20 min at r.t. After removal of about 50% of solvent,
C NMR (CDCl ): d = 14.0 (CH ), 22.6, 25.0, 28.1, 29.2, 29.24,
2
2
3
3
29.3, 29.4, 30.2, 31.8 (CH ), 65.3 (CH O), 125.0 (C=CH), 141.0
2 2
the crude (EtO) P(O)SCl (4) formed was added with stirring to a so-
(C=CH), 170.3 (C=O).
2
lution of freshly prepared (from the corresponding lactone by the
action of LDA, TMSCl in THF at –70 °C) O-silyl enol ether 2 (2.2
mmol) in CH Cl (40 mL) at –70 °C. The mixture was stirred and
+
+
+
MS (EI): m/z (%) = 224 (M , 3.6), 125 (C H , 20.8), 99 ([M –
9
17
+
C H ], 100), 86 ([M – C H ], 98).
9
17
10 18
2
2
Anal. Calcd for C H O : C, 74.95; H, 10.78. Found: C, 74.89; H,
allowed to warm slowly to r.t. The solvent and trimethylsilyl chlo-
ride were removed in vacuo. Crude thiophosphate 3 formed was dis-
solved in THF (5 mL) and added by a syringe (30 min) to a stirred
suspension of NaH (50 mg, 2.1 mmol) in THF (20 mL) at –10 °C
under argon. After cooling to –70 °C, a solution of aldehyde (2
mmol) in THF (5 mL) was added by a syringe over a period of 10
min and the reaction mixture was stirred at this temperature for 1 h.
Then it was warmed gradually to r.t. and was stirred for 1 h before
14 24
2
1
0.81.
(
Z/E)-3-Ethylidene-5-methyldihydrofuran-2-one (5e)
Yield: 72%; colorless oil; R 0.51 (1:1 hexane–EtOAc).
1H NMR data were identical with that previously reported.6b
f
+
+
MS (EI): m/z (%) = 126 (M , 28), 82 (75), 81 (M – COOH, 63), 53
(
100), 41 (24).
quenching with NH Cl (5 mL). The mixture was poured into dilute
4
HCl and extracted with Et O (3 ×). The organic extracts were com-
2
(
Z)-3-Decylidene-5-methyldihydrofuran-2-one (5f)
bined and washed with brine, dried (MgSO ), and the solvent evap-
4
Yield: 45%; yellow oil; R 0.61 (1:1 hexane–EtOAc).
f
orated in vacuo to give a crude product, which was purified by flash
chromatography with petroleum ether–EtOAc (10:1 to 5:1, gradient
elution).
–
1
IR (film): 2938, 1748, 1655, 1480, 1170, 1090 cm .
1
H NMR (CDCl ): d = 0.87 (t, J = 6.5 Hz, 3 H, CH ), 1.25 (br s,
3
H,H
3
1
4 H, CH ), 1.38 (d, J = 6.2 Hz, 3 H, CH CHO), 2.41 (qd,
2 H,H 3
(
Z/E)-3-Ethylidenedihydrofuran-2-one (5a)
JH,H = 1.9, 7.4 Hz, 1 H, CH CHO), 2.68 (tq, J = 1.9, 7.3 Hz, 2 H,
CH ), 2.99 (ddq, J = 1.8, 7.4, 15.7 Hz, 1 H, CH CHO), 4.58 (tq,
J
2
H,H
Yield: 69%; colorless oil; R 0.5 (1:1 hexane–EtOAc).
f
2
H,H
2
1H NMR data are identical with that previously reported.4n
H,H = 6.3, 6.4 Hz, 1 H, CHO), 6.16 (tt, JH,H = 2.3, 7.7 Hz, 1 H,
+
+
C=CH).
13C NMR (CDCl
MS (EI): m/z (%) = 112 (M , 35), 67 (M – COOH, 100), 54 (40),
1 (39).
4
3
): d = 13.5 (CH ), 20.7 (CH ), 22.8, 24.7, 28.3,
3 3
2
9.0, 29.1, 29.2, 29.8, 31.2, 34.5 (CH ), 75.4 (CHO), 124.5
2
(
Z/E)-3-Propylidenedihydrofuran-2-one (5b)
(C=CH), 146.4 (C=CH), 168.1 (C=O).
Yield: 82%; colorless oil; R 0.52 (1:1 hexane–EtOAc).
+
+
+
f
MS (EI): m/z (%) = 238 (M , 16.7), 125 (C H , 100), 113 ([M –
9
17
1
H NMR and 13C NMR data are identical with that previously re-
C
9
H17], 40), 41 (25).
6
a
ported.
Anal. Calcd for C H O : C, 75.58; H, 10.99. Found: C, 75.21; H,
1
5
26
2
+
+
MS (EI): m/z (%) = 126 (M , 80), 67 (M – CH COOH, 100), 41
11.23.
2
(
54), 39 (50).
(
E)-3-Decylidene-5-methyldihydrofuran-2-one (5f)
(
Z/E)-3-Hexylidenedihydrofuran-2-one (5c)
Yield: 23%; yellow oil; R 0.57 (1:1 hexane–EtOAc).
f
Yield: 92%; colorless oil; R 0.55 (1:1 hexane–EtOAc).
1H NMR data were identical with that previously reported.4o
IR (film): 2950, 1750, 1680, 1215, 1150 cm–1.
f
1
H NMR (CDCl ): d = 0.86 (t, J = 6.2 Hz, 3 H, CH ), 1.24 (br s,
3
H,H
3
+
+
MS (EI): m/z (%) = 168 (M , 43), 125 (100), 99 ([M – C H ], 20),
14 H, CH
H,H = 1.6, 7.3 Hz, 2 H, CH
ddq, JH,H = 1.6, 7.7, 13.9 Hz, 1 H, CH CHO), 4.60 (tq, J = 6.4,
2
), 1.38 (d, JH,H = 6.2 Hz, 3 H, CH
3
CHO), 2.13 (tq,
5
9
6
7 (C H , 38).
J
2
), 2.31–2.40 (m, 1 H, CH CHO), 2.97
2
5
7
(
2
H,H
(
Z)-3-Decylidenedihydrofuran-2-one (5d)
6.5 Hz, 1 H, CHO), 6.69 (tt, JH,H = 2.9, 7.6 Hz, 1 H, C=CH).
Yield: 30%; yellow oil; R 0.58 (1.2:1 hexane–EtOAc).
13
f
C NMR (CDCl ): d = 14.0 (CH ), 21.2 (CH ), 20.5, 25.0, 28.2,
3
3
3
–
1
IR (film): 2954, 1757, 1671, 1466, 1129, 1029 cm .
29.1, 29.2, 29.4, 30.5, 32.4, 35.0 (CH
2
), 75.9 (CHO), 125.0
1
(C=CH), 144.0 (C=CH), 169.4 (C=O).
H NMR (CDCl ): d = 0.86 (t, JH,H = 6.5 Hz, 3 H, CH ), 1.20 (br s,
3
3
+
+
+
1
2
2 H, CH ), 1.57–1.60 (m, 2 H, CH ), 2.69 (dt, J = 1.8, 7.3 Hz,
MS (EI): m/z = 238 (M , 11.5), 125 (C
9
H
17 , 30), 113 ([M – C
9
H17],
2
2
H,H
H, CH ), 2.89 (dt, JH,H = 2.0, 7.3 Hz, 2 H, CH CH O), 4.29 (t,
100), 41 (25).
2
2
2
JH,H = 7.4 Hz, 2 H, CH O), 6.22 (tt, J = 2.3, 7.5 Hz, 1 H, C=CH).
+
2
H,H
HRMS: m/z calcd for C H O [M + H] : 239.2011; found:
239.2010.
1
5
27
2
1
3
C NMR (CDCl ): d = 14.0 (CH ), 22.6, 27.4, 28.1, 29.0, 29.2,
3
3
2
9.4, 29.5, 30.2, 31.8 (CH ), 65.2 (CH O), 123.2 (C=CH), 144.4
2 2
(
C=CH), 170.1 (C=O).
(Z)-3-Ethylidene-5-heptyldihydrofuran-2-one (5g)
Yield: 19%; yellow oil; R 0.62 (1:1 hexane–EtOAc).
+
+
+
f
MS (EI): m/z (%) = 224 (M , 16), 125 (C H , 100), 99 ([M –
C H ], 24.5), 86 ([M – C H ], 32).
9
17
+
IR (film): 2929, 1715, 1638, 1259, 1154, 1072 cm–1.
1H NMR (CDCl
): d = 0.88 (t, JH,H = 6.3 Hz, 3 H, CH
10 H, CH ), 1.49–1.72 (m, 2 H, CH ), 2.09 (td, JH,H = 1.6, 7.2 Hz, 3
H, =CHCH ), 2.51–2.56 (m, 2 H, CH CHO), 4.07–4.34 (m, 1 H,
9
17
10 18
Anal. Calcd for C H O : C, 74.95; H, 10.78. Found: C, 74.71; H,
1
3
), 1.25 (br s,
3
1
4
24
2
0.93.
2
2
3
2
(
E)-3-Decylidenedihydrofuran-2-one (5d)
CHO), 6.14 (tq, JH,H = 1.7, 7.2 Hz, 1 H, C=CH).
Yield: 49%; yellow oil; R 0.55 (1.2:1 hexane–EtOAc).
13
f
C NMR (CDCl ): d = 14.1 (2 CH ), 22.5, 22.6, 25.2, 28.3, 29.1,
3
3
–1
IR (film): 2954, 1760, 1680, 1209, 1031 cm .
31.5, 35.3 (CH
(C=O).
2
), 79.4 (CHO), 124.1 (C=CH), 142.3 (C=CH), 165.8
1
H NMR (CDCl ): d = 0.86 (t, JH,H = 6.0 Hz, 3 H, CH ), 1.25 (br s,
3
3
+
1
2
2 H, CH ), 1.46 (t, JH,H = 6.6 Hz, 2 H, CH ), 2.17 (q, J = 7.2 Hz,
MS (CI): m/z = 211 (M + H, 100).
2
2
H,H
H, CH ), 2.84 (dt, J = 2.4, 6.4 Hz, 2 H, CH CH O), 4.36 (t,
+
2
H,H
2
2
HRMS: m/z calcd for C H O [M + H] : 211.1698; found:
1
3
23
2
JH,H = 7.5 Hz, 2 H, CH O), 6.73 (tt, J = 2.9, 7.6 Hz, 1 H, C=CH).
2
H,H
2
11.1695.
Synthesis 2006, No. 4, 716–722 © Thieme Stuttgart · New York

7
20
E. Krawczyk
PAPER
(
E)-3-Ethylidene-5-heptyldihydrofuran-2-one (5g)
(Z/E)-3-Decylidenetetrahydropyran-2-one (5k)
Yield: 48% of a nonseparable mixture of Z/E (2:1) isomers; yellow
oil; R 0.61 (1:1 hexane–EtOAc).
Yield: 48%; yellow oil; R 0.57 (1:1 hexane–EtOAc).
f
–1
f
IR (film): 2930, 2858, 1730, 1645, 1260, 1199, 1093 cm .
–
1
1
IR (film): 2954, 1727, 1631, 1447, 1218, 1057 cm .
H NMR (CDCl ): d = 0.85 (t, JH,H = 6.5 Hz, 3 H, CH ), 1.25 (br s,
3
3
1
1
1
1 H, CH ), 1.75 (ddd, JH,H = 1.2, 2.2, 7.2 Hz, 3 H, =CHCH ), 1.91,
H NMR (CDCl ): d = 0.85 (t, J = 6.1 Hz, 3 H, CH ), 1.23 (br s,
2
3
3
H,H
3
.98 (2 quintet, JH,H = 2.8 Hz, 1 H, CH ), 2.32–2.41 (m, 1 H,
12 H, CH ), 1.60–2.09 (m, 4 H, CH ), 2.33–2.40 (m, 2 H, CH ), 2.42
2
2
2
2
CH CHO), 2.54, 2.62 (2 br s, 1 H, CH CHO), 4.17 (ddt, J = 2.3,
(t, JH,H = 7.2 Hz, 2 H, CH ), 4.21 (t, J = 7.4 Hz, 2 H, CH O, ma-
2 H,H 2
2
2
H,H
5
.1, 7.3 Hz, 1 H, CHO), 7.08 (ddq, JH,H = 2.2, 7.2 Hz, 1 H, C=CH).
jor), 4.28 (t, JH,H = 7.5 Hz, 2 H, CH O, minor), 6.13 (tt, J = 1.8,
2 H H
1
3
7.5 Hz, 1 H, C=CH, major), 7.12 (tt, JH,H = 2.5, 7.6 Hz, 1 H, C=CH,
minor).
C NMR (CDCl ): d = 14.0 (2 CH ), 22.5, 22.55, 24.8, 27.4, 29.0,
3
3
3
1.6, 35.3 (CH ), 79.2 (CHO), 126.2 (C=CH), 140.6 (C=CH), 166.9
2
1
3
(
C=O).
MS (CI): m/z = 211 (M + H, 100%).
HRMS: m/z calcd for C H O [M + H] : 211.1698; found:
C NMR (CDCl ): d = 13.3 (CH ), 21.8, 22.6, 25.4, 28.1, 29.1,
3
3
+
29.2, 29.3, 29.5, 30.6, 31.5 (CH
2
), 67.9 (CH O, major and minor),
2
1
23.0 (C=CH, major), 125.3 (C=CH, minor), 143.4 (C=CH, minor),
+
13
23
2
145.0 (C=CH, major), 165.8 (C=O, major) 167.1 (C=O, minor).
2
11.1696.
+
+
17
+
MS (EI): m/z (%) = 238 (M , 15), 125 (C H , 100), 99 ([M –
9
C H ], 80).
1
0
19
(
Z)-3-Decylidene-5-heptyldihydrofuran-2-one (5h)
+
Yield: 37%; yellow semisolid; R 0.68 (1.5:1 hexane–EtOAc).
HRMS: m/z calcd for C H O [M + H] : 239.2011; found:
f
15 27
2
–1
239.2005.
IR (film): 2953-2855, 1722, 1634, 1465, 1146, 1115 cm .
1
H NMR (CDCl ): d = 0.86 (t, JH,H = 6.2 Hz, 6 H, CH ), 1.25 (br s,
3
3
O,O-Diethyl S-(2-Oxotetrahydrofuran-3-yl) Thiophosphate
(3a); General Procedure
O,O-Diethyl chlorothiophosphonate (4; 204 mg, 1 mmol) in CH Cl
(15 mL) was added dropwise with stirring to silyl enol ether 2a (1.1
2
2 H, CH ), 1.62 (br s, 3 H, CH ), 1.89 (dt, J = 2.9, 4.7 Hz, 0.5
2 2 H,H
H, CH ), 1.95 (dt, J = 2.8, 5.3 Hz, 0.5 H, CH ), 2.40 (dt,
JH,H = 1.8, 7.2 Hz, 2 H, CH ), 2.55 (pseudo quintet, J = 7.0 Hz, 2
H, CH CHO), 4.11–4.24 (m 1 H, CHO), 6.00 (dt, J = 1.6, 7.1 Hz,
1
2
H,H
2
2
2
2
H,H
2
H,H
mmol) in CH Cl (30 mL) at –70 °C. The mixture was stirred and
2
2
H, C=CH).
allowed to warm slowly to r.t. Then the solvent and volatile prod-
ucts were removed in vacuo (0.1 mm Hg) to give crude, pure thio-
phosphate 3a as a yellow oil in 92% yield. Analytically pure
compound was obtained by flash chromatography (PE–EtOAc,
1
3
C NMR (CDCl ): d = 13.9 (2 CH ), 21.9, 22.4, 22.5, 23.4, 24.8,
3
3
2
(
8.5, 29.1, 29.2, 29.24, 29.4, 29.8, 31.5, 31.7, 34.3, 35.3 (CH ), 79.3
2
CHO), 124.5 (C=CH), 147.2 (C=CH), 165.9 (C=O).
1
:1).
+
MS (CI): m/z = 323 (M + H, 100).
–
1
IR (film): 2983–2943, 1756, 1239, 1016, 794, 575 cm .
+
HRMS: m/z calcd for C H O [M + H] : 323.2950; found:
3
21
39
2
1
H NMR (CDCl ): d = 1.38 (t, J = 7.1 Hz, 6 H, CH CH OP), 2.40
23.2940.
3
H,H
3
2
(
AB, JH,H = 8.6 Hz, 2 H, CH CH O), 2.81 (dddd, J = 3.7, 6.7,
2 2 H,H
3
1
1
5.5 Hz, J = 10.4 Hz, 1 H, CHSP), 4.07 (dt, J = 8.9, 15.3 Hz,
P,H H,H
(
E)-3-Decylidene-5-heptyldihydrofuran-2-one (5h)
3
H, CH O), 4.25 (dq, J = 7.1 Hz, JP,H = 8.1 Hz, 2 H,
Yield: 17%; yellow semisolid; R 0.56 (1.5:1 hexane–EtOAc).
2
H,H
f
CH CH OP), 4.26 (dq, J = 7.2 Hz, 3JP,H = 8.1 Hz, 2 H,
–1
3
2
H,H
IR (film): 2924, 1735, 1656, 1378, 1161 cm .
1
CH CH OP), 4.43 (dt, J = 3.7, 9.2 Hz, 1 H, CH O).
3
2
H,H
2
H NMR (CDCl ): d = 0.87 (t, JH,H = 6.5 Hz, 6 H, CH ), 1.25 (br s,
13
3
3
C NMR (CDCl ): d = 15.3 (CH CH OP), 15.4 (CH CH OP), 31.3
3
3
2
2
3
2
2
0 H, CH ), 1.37–1.73 (m, 3 H, CH ), 1.46 (t, J = 6.6 Hz, 2 H,
(3
2 2 H,H
JP,C = 3.5 Hz, CH CH O), 40.9 ( J = 3.5 Hz, CHSP), 66.1
2
2
P,C
CH ), 1.91, 1.98 (2 quintet, J = 2.7, Hz, 1 H, CH ), 2.12 (pseudo
q, JH,H = 7.3 Hz, 2 H, CH ), 2.27–2.43 (m, 1 H, CH CHO), 2.62 (br
s, 1 H, CH CHO), 4.14–4.32 (m, 1 H, CHO), 7.02 (tt, J = 2.1, 7.4
Hz, 1 H, C=CH).
2
2
2
H,H
2
(
CH O), 63.7 ( J = 3.7 Hz, CH OP), 63.8 ( J = 3.7 Hz,
2 P,C 2 P,C
2
2
3
CH OP), 173.7 (C=O, J = 7.8 Hz).
2
P,C
2
H,H
3
1
P NMR (CDCl ): d = 23.5.
3
+
1
3
HRMS: m/z calcd for C H O PS [M + H] : 255.0456; found:
8 16 5
C NMR (CDCl ): d = 13.9, 13.93 (CH ), 22.4, 22.5, 22.7, 24.7,
3
3
2
55.0455.
2
7
7.4, 28.0, 28.2, 28.5, 28.9, 29.1, 29.2, 29.3, 31.5, 31.7, 35.3 (CH ),
2
9.1 (CHO), 125.0 (C=CH), 146.0 (C=CH), 166.9 (C=O).
O,O-Diethyl S-(5-Methyl-2-oxotetrahydrofuran-3-yl) Thio-
phosphate (3b)
Ratio of diastereomers 1:1.8; yield: 96%; white semisolid; mixture
of isomers.
Anal. Calcd for C H O : C, 78.20; H, 11.87. Found: C, 77.89; H,
1
2
1
38
2
1.51.
(
Z/E)-3-Ethylidenetetrahydropyran-2-one (5i)
–
1
IR (film): 2982–2936, 1738, 1254, 1018, 974, 757, 559 cm .
Yield: 55%; colorless oil; R 0.51 (1:1 hexane–EtOAc).
1H NMR data were identical with that previously reported.15
f
1
H NMR (CDCl ): d = 1.36 (t, J = 7.0 Hz, 3 H, CH CH OP), 1.37
3 H,H 3 2
(
t, JH,H = 7.0 Hz, 3 H, CH CH OP), 1.40 (d, J = 6.4 Hz, 3 H,
+
+
3 2 H,H
MS: m/z (%) = 126 (M , 50), 81 ([M – COOH], 40), 83 (27.5), 53
(
CH ), 1.45 (d, J = 6.4 Hz, 3 H, CH ), 2.00 (ddd, J = 12, 12.7
3
H,H
3
H,H
100).
3
Hz, JP,H = 10 Hz, 1 H, CHSP, major), 2.33–2.60 (m, 2 H,
3
CH CH O), 2.90 (ddd, J = 5.4, 12.9 Hz, J = 8.7 Hz, 1 H,
2
2
H,H
P,H
(
Z/E)-3-Propylidenetetrahydropyran-2-one (5j)
3
CHSP, minor), 4.22 (q, JH,H = 7.1 Hz, JP,H = 7.1 Hz, 2 H,
CH CH OP), 4.24 (q, J = 7.2 Hz, 3J = 7.1 Hz, 2 H,
Yield: 80%; colorless oil; R 0.51 (1:1 hexane–EtOAc).
1
f
3
2
H,H
P,H
H NMR and 13C NMR data were identical with that previously re-
CH CH OP), 4.53 (ddd, J = 5.5, 6.1, 10.0 Hz, 1 H, CH CHO, mi-
3
2
H,H
3
6
a
ported.
MS: m/z (%) = 140 (M , 40), 97 (24), 95 ([M – COOH], 32), 81
40), 67 (100).
nor), 4.77 (sextet, JH,H = 6.4, Hz, 1 H, CH CHO, major).
3
+
+
13
C NMR (CDCl ): d = 15.4 (CH CH OP), 15.5 (CH CH OP), 21.3
3 3 P,C
3
3
2
3
3
2
(
(CH CH, major), 24.1 (CH CH, minor), 36.7 ( J = 3.5 Hz,
3
CH CHO, major), 39.2 ( J = 3.5 Hz, CH CHO, minor), 41.5
2
P,C
2
2
2
(
JP,C = 4.1 Hz, CHSP), 62.8 ( J = 6.9 Hz, CH OP), 63.1
P,C 2
Synthesis 2006, No. 4, 716–722 © Thieme Stuttgart · New York

PAPER
a-Alkylidenation of Lactones
721
(2
minor), 172.3 (C=O, J = 7.8 Hz).
JP,C = 3.7 Hz, CH OP), 74.3 (CH CHO, major), 75.2 (CH CHO,
Chem. Commun. 1988, 1245. (f) Niwa, M.; Iguchi, M.;
Yamamura, S. Tetrahedron Lett. 1975, 1539. (g) Niwa, M.;
Iguchi, M.; Yamamura, S. Tetrahedron Lett. 1975, 4395.
2
3
3
3
P,C
3
1
P NMR (CDCl ): d = 24.4 (35%), 23.8 (65%).
3
(
h) Niwa, M.; Iguchi, M.; Yamamura, S. Chem. Lett. 1975,
655. (i) Amos, R. A.; Katzenellenbogen, J. A. J. Org. Chem.
978, 43, 560. (j) Larson, G. L.; Betancourt de Perez, R. M.
+
HRMS: m/z calcd for C H O PS [M + H] : 269.0612; found:
9
18
5
2
69.0611.
1
J. Org. Chem. 1985, 50, 5257. (k) Cromwell, M. E. M.;
Gebhard, R.; Li, X.-Y.; Batenburg, E. S.; Hopman, J. C. P.;
Lugtenburg, J.; Mathies, R. A. J. Am. Chem. Soc. 1992, 114,
O,O-Diethyl S-(5-Heptyl-2-oxotetrahydrofuran-3-yl) Thiophos-
phate (3c)
Ratio of diastereomers 1:2; yield: 78%; yellow semisolid; mixture
of isomers.
10860. (l) Hanessian, S.; Cooke, N. G.; De Hoff, B.; Sakito,
Y. J. Am. Chem. Soc. 1990, 112, 5276. (m) Lorimer, S. D.;
Mawson, S. D.; Perry, N. B.; Weavers, R. T. Tetrahedron
–
1
IR (film): 2977–2863, 1737, 1247, 1009, 972, 793, 572 cm .
1
995, 51, 7287. (n) Hanessian, S.; Grillo, T.-A.; Smith, G.-
1
H NMR (CDCl ): d = 0.87 (t, JH,H = 6.5 Hz, 3 H, CH ) 1.26 (br s,
3
3 ,
M. Tetrahedron 1997, 53, 6281. (o) Farrant, E.; Mann, J. J.
Chem. Soc., Perkin Trans. 1 1997, 1083. (p) Sai, H.;
Ohmizu, H. Tetrahedron Lett. 1999, 40, 5019. (q) Gasperi,
T.; Loreto, M. A.; Tardella, P. A.; Veri, E. Tetrahedron Lett.
8
H, CH ), 1.37 (t, J = 7.1 Hz, 3 H, CH CH OP), 1.374 (t,
2 H,H 3 2
JH,H = 7.0 Hz, 3 H, CH CH OP), 1.42–1.92 (m, 4 H, CH ), 1.97–
3
2
2
2
2
.08 (10 lines, JH,H = 2.1, 8.5, 11.0 Hz, 1 H, CHSP, major), 2.26–
.42 (m, 2 H, CH CHO, minor), 2.45–2.56 (8 lines, J = 2.5, 7.9,
2
H,H
2003, 44, 4953.
Hz, 2 H, CH CHO, major), 2.87 (ddd, J = 5.5, 13.0 Hz,
2
H,H
(
2) (a) White, J. D.; Amedio, J. C. Jr.; Gut, S.; Jayasinghe, L. R.
J. Org. Chem. 1989, 54, 4268. (b) White, J. D.; Amedio, J.
C. Jr.; Gut, S.; Ohira, S.; Jayasinghe, L. R. J. Org. Chem.
3
3
JP,H = 8.8 Hz, 1 H, CHSP, minor), 4.08 (dd, JH,H = 7.1 Hz,
JP,H = 7.8 Hz, 2 H, CH CH OP), 4.23 (q, J = 7.2 Hz, J = 7.1
3
3
2
H,H
P,H
Hz 2 H, CH CH OP), 4.44 (quintet, J = 6.3, Hz, 1 H, CH CHO,
3
2
H,H
2
1
992, 57, 2270. (c) Narasaka, K.; Sakakura, T.; Uchimaru,
major), 4.60 (quintet, JH,H = 6.5, Hz, 1 H, CH CHO, minor).
2
T.; Guendin-Vuong, D. J. Am. Chem. Soc. 1984, 106, 2954.
1
3
C NMR (CDCl ): d = 13.8 (CH ), 15.7 (CH CH OP), 15.9
3 2
(3) (a) Takeda, K.; Sakurawi, K.; Ishii, H. Tetrahedron 1972,
21, 3757. (b) Wollenberg, R. H. Tetrahedron Lett. 1980, 21,
3139. (c) Chen, S.-Y.; Joullie, M. M. Tetrahedron Lett.
1983, 24, 5027.
(4) (a) Zimmer, H.; Rothe, J. J. Org. Chem. 1959, 24, 28.
(b) Taniguchi, M.; Koga, K.; Yamada, S. Tetrahedron 1974,
30, 3547. (c) Takano, S.; Goto, E.; Hirama, M.; Ogasawara,
K. Heterocycles 1981, 16, 381. (d) Takano, S.; Goto, E.;
Hirama, M.; Ogasawara, K. Heterocycles 1981, 16, 951.
3
3
3
2
(
CH CH OP), 22.3, 24.3, 24.5, 24.7, 25.1, 25.2, 28.3, 28.4, 28.8,
2
9.1, 29.2 (CH , major and minor), 31.4 (CH CHSP, major), 31.6
2 2
(
CH CHSP, minor), 35.6 (CH CHO, minor), 35.9 (CH CHO, ma-
2
2
2
2
2
jor), 47.4 ( J = 4.5 Hz, CHSP), 63.3 ( J = 5.9 Hz, CH OP),
P,C
P,C
2
6
1
3.9 (CH OP), 77.2 (CH CHO, major), 77.22 (CH CHO, minor)
2
2
2
3
70.1 (C=O, J = 9.2 Hz).
P,C
3
1
P NMR (CDCl ): d = 24.4 (32.3%), 23.9 (67.7%).
3
+
MS (CI): m/z = 353 ([M + H] , 100%).
(
e) Minami, T.; Niki, I.; Agawa, T. J. Org. Chem. 1974, 39,
+
HRMS: m/z calcd for C H O PS [M + H] : 353.1551; found:
3236. (f) Falsone, G.; Wingen, U. Tetrahedron Lett. 1989,
30, 675. (g) Lee, K.; Jackson, J. A.; Wiemer, D. F. J. Org.
Chem. 1993, 58, 5967. (h) Lankin, D. C.; Scalise, M. R.;
Schmidt, J. C.; Zimmer, H. J. Org. Chem. 1974, 2, 95.
(i) Grieco, P. A.; Pogonowski, C. S. J. Org. Chem. 1974, 39,
1958. (j) Grieco, P. A.; Wang, C.-L. J.; Burke, S. D. J. Chem.
Soc., Chem. Commun. 1975, 537. (k)Yamamoto, K.; Tomo,
Y. Chem. Lett. 1983, 531. (l) Paterson, I.; Fleming, I.
Tetrahedron Lett. 1979, 20, 2179. (m) Paterson, I.
Tetrahedron Lett. 1988, 44, 4207. (n) Tanaka, K.; Uneme,
H.; Yamagishi, N.; Tanikaga, R.; Kaji, A. Bull. Chem. Soc.
Jpn. 1980, 53, 2920. (o) Matsui, S. Bull. Chem. Soc. Jpn.
1987, 60, 1853.
15
30
5
3
53.1548.
O,O-Diethyl S-(2-Oxotetrahydropyran-3-yl) Thiophosphate
3d)
Yield: 75%; yellow oil.
(
–1
IR (film): 2961–2848, 1748, 1260, 1016, 794, 596 cm .
1
H NMR (CDCl ): d = 1.34 (t, JH,H = 7.0 Hz, 6 H, CH CH OP),
3
3
2
1
.60–1.68 (m, 2 H, CH ), 1.85–2.22, (m, 2 H, CH ), 2.42 (dt,
2
2
3
JH,H = 7.2 Hz, J = 7.4 Hz, 1 H, CHSP), 4.02–4.24 (m, 6 H,
P,H
CH CH OP and CH O).
3
2
2
1
3
C NMR (CDCl ): d = 15.3 (CH CH OP), 15.4 (CH CH OP), 31.3
3
3
2
3
2
(3
(
2
(5) (a) Tamaru, Y.; Hojo, M.; Yoshida, Z.-I. J. Org. Chem.
1991, 56, 1099. (b) Ma, S.; Lu, X. J. Org. Chem. 1991, 56,
5120. (c) Liu, T.-L.; Carlson, R. M. Synth. Commun. 1993,
JP,C = 3.5 Hz, CH CH O), 40.9 ( J = 3.5 Hz, CHSP), 66.1
2
2
P,C
2
2
CH O), 63.7 ( J = 3.7 Hz, CH OP), 63.8 ( J = 3.7 Hz,
2 P,C 2 P,C
3
CH OP), 173.7 (C=O, J = 7.8 Hz).
2
P,C
23, 1437. (d) Belline, F.; Carpita, A.; De Santis, M.; Rosi,
3
1
P NMR (CDCl ): d = 25.0.
3
R. Tetrahedron 1994, 50, 12029. (e) Zhu, G.; Lu, X.
Tetrahedron: Asymmetry 1995, 6, 345. (f) Zhu, G.; Lu, X.
Tetrahedron: Asymmetry 1995, 6, 1657. (g) Zhu, G.; Lu, X.
J. Organomet. Chem. 1996, 508, 83. (h) Mincheva, Z. P.;
Gao, Y.; Sato, F. Tetrahedron Lett. 1998, 39, 7947.
(6) (a) Murray, A. W.; Reid, R. G. Synthesis 1985, 35.
+
HRMS: m/z calcd for C H O PS [M + H] : 269.0612; found:
9
18
5
2
69.0610.
Acknowledgment
(
5
b) Datta, A.; Ila, H.; Junjappa, H. Tetrahedron 1987, 43,
367. (c) Haaima, G.; Mawson, S. D.; Routledge, A.;
I thank Prof. A. Skowronska for inspiring discussions.
Weavers, R. T. Tetrahedron 1994, 50, 3557. (d) Corey, E.
J.; Letavič, M. J. Am. Chem. Soc. 1995, 117, 9616. (e) Sai,
H.; Ohmizu, H. Tetrahedron Lett. 1999, 40, 5019.
References
(1) (a) Edwards, O. E.; Ho, P.-T. Can. J. Chem. 1977, 55, 371.
(f) Častulik, J.; Mazal, C. Tetrahedron Lett. 2000, 41, 2741.
(7) (a) Dybowski, P.; Skowrońska, A. Tetrahedron Lett. 1991,
32, 4380. (b) Maciągiewicz, I.; Dybowski, P.; Skowrońska,
A. Synthesis 2003, 723; and references cited therein.
(b) Back, T. G.; Edwards, O. E.; Mac Alpine, G. A.
Tetrahedron Lett. 1977, 2651. (c) Hoye, T. R.; Caruso, A. J.
Tetrahedron Lett. 1978, 4611. (d) Rao, Y. S. Can. J. Chem.
1976, 76, 625. (e) Piers, E.; Wai, J. S. M. J. Chem. Soc,
Synthesis 2006, No. 4, 716–722 © Thieme Stuttgart · New York

7
22
E. Krawczyk
PAPER
(12) Evans, D. A.; Nelson, J. V.; Taber, T. R. In Topics in
Stereochemistry, Vol. 13; Allinger, N. L.; Eliel, E. L.; Wilen,
S. H., Eds.; Wiley: New York, 1982, 1–115.
(13) Heathcock, C. H.; Pirrung, M. C.; Young, S. D.; Hagen, J. P.;
Jarvi, E. T.; Badertscher, U.; Marki, H.-P.; Montgomery, S.
H. J. Am. Chem. Soc. 1984, 106, 8161.
(14) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957,
79, 1920.
(15) Miyata, O.; Shinada, T.; Ninomiya, I.; Naito, T. Synthesis
1990, 1123.
(8) (a) Krawczyk, E.; Skowrońska, A. Heteroat. Chem. 2000,
1, 353. (b) Krawczyk, E.; Owsianik, K.; Skowrońska, A.;
1
Wieczorek, M.; Majzner, W. New J. Chem. 2002, 26, 1703;
and references cited therein.
(
9) Dybowski, P.; Skowrońska, A. Synthesis 1990, 609.
(
(
10) Rubottom, G. M.; Gruber, J. M.; Marrero, R.; Juve, H. D. Jr.;
Kim, W.-H. J. Org. Chem. 1983, 48, 4940.
11) Skowrońska, A.; Dembiński, R.; Gwara, J.; Michalski, J.
Phosphorus Sulfur Relat. Elem. 1988, 39, 119; and
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