Enantio- and diastereoselective synthesis of β,γ,γδ, -tetrasubstituted -methylene -δ-lactones

Article abstract of DOI:10.1055/s-0031-1289629

The synthesis of two -(diethoxyphosphoryl)-,-unsaturated -lactones with 98% ee has been developed using (S)-3-aryl-3-hydroxy-2,2-dimethylpropanals, easily accessible via direct, asymmetric organocatalytic aldol reaction, as the starting materials. The lac

Full text of DOI:10.1055/s-0031-1289629

PAPER
247
Enantio- and Diastereoselective Synthesis of b,g,g,d-Tetrasubstituted
a-Methylene-d-lactones
Łukasz Albrecht,a Dariusz Deredas,a Jakub Wojciechowski,b Wojciech M. Wolf,b Henryk Krawczyk*a
a
Institute of Organic Chemistry, Technical University (Politechnika), Żeromskiego 116, 90-924 Łódź, Poland
Fax +48(42)63655 30; E-mail: henkrawc@p.lodz.pl
b
Institute of General and Ecological Chemistry, Technical University (Politechnika), Żeromskiego 116, 90-924 Łódź, Poland
Received 5 September 2011; revised 10 November 2011
In recent years asymmetric synthesis of differently substi-
tuted a-(diethoxyphosphoryl)-d-lactones has emerged as
very attractive method for the construction of enantiomer-
ically pure or highly enantiomerically enriched a-methyl-
Abstract: The synthesis of two a-(diethoxyphosphoryl)-a,b-unsat-
urated d-lactones with 98% ee has been developed using (S)-3-aryl-
3-hydroxy-2,2-dimethylpropanals, easily accessible via direct,
asymmetric organocatalytic aldol reaction, as the starting materials.
The lactones were transformed into the corresponding a-methylene- ene-d-lactones. We have shown that homochiral enamines
d-lactones in a two-step process involving Michael addition fol-
lowed by Horner–Wadsworth–Emmons olefination without loss of
enantiomeric purity. Furthermore, it was shown that diastereoselec-
tivity of the Michael addition can be fully controlled by the C6 ste-
reogenic center in the intermediate lactones. A transition-state
model rationalizing the stereochemical outcome of the reaction was
proposed.
derived from 2-substituted cycloalkanones and enantio-
merically pure a-phenylethylamine add to dicyclohexyl-
ammonium 2-(diethoxyphosphoryl)acrylate with high
diastereoselectivity to provide access to bicyclic a-meth-
ylene-d-lactones containing adjacent quarternary and ter-
tiary stereogenic centers.3 More recently, based on the
highly efficient organocatalytic direct addition of enoliz-
able aldehydes to ethyl 2-(diethoxyphosphoryl)acrylate,
Jørgensen et al. prepared series of g-substituted a-methyl-
ene-d-lactones in good yields and high enantioselectivi-
ties.4 In spite of these advances, it is evident that methods
to access enantiomerically enriched a-(diethoxyphospho-
ryl)-d-lactones, particularly via conceptually different ap-
proaches, are still of significant interest.
Key words: Knoevenagel condensation, Michael addition, HWE
olefination, b-hydroxyaldehydes, a-methylene-d-lactones
The a-methylene-d-lactone framework can be found in
several naturally occurring compounds such as vernol-
epin,1a vernomenin,1a pentalenolactone E,1b teucriumlac-
tone,1c artemisitene,1d–f and crassin (Figure 1).1g,h
Moreover, a-methylene-d-lactones are very attractive pre-
cursors in the preparation of a wide variety of compounds,
since they readily undergo conjugate addition,1d–f,2a reduc-
tion of a double bond,2b Diels–Alder reaction,2c 1,3-
Michael–Claisen annulation,2d,e or cross methathesis.2f
In the course of our studies aimed at finding new synthetic
routes to diversely substituted a-methylene-d-lactones
based on the use of enantiomerically enriched a-(diethoxy-
phosphoryl)-d-lactones, we envisioned that an alternative
approach to these key intermediates could rely on the di-
astereoselective Michael addition of carbon nucleophiles
to homochiral a-(diethoxyphosphoryl)-a,b-unsaturated d-
lactones containing a stereochemically defined stereogen-
ic center in the ring (Scheme 1). It was anticipated that the
stereochemical outcome of the Michael addition should
be fully governed by stereoelectronic effects, offering a
diastereoselective route to optically active a-(diethoxy-
phosphoryl)-d-lactones.
OH
O
O
O
CO2H
O
O
O
H
O
H
O
O
OH
vernomenin
O
vernolepin
pentalenolactone E
CH3
H
Furthermore, a-(diethoxyphosphoryl)-a,b-unsaturated d-
lactones can be efficiently accessed from b-hydroxyalde-
hydes and (diethoxyphosphoryl)acetic acid. Knoevenagel
reaction of achiral b-hydroxyaldehydes with ethyl (di-
ethoxyphosphoryl)acetate has been used to a limited ex-
tend for the construction of achiral g,g-disubstituted a-
(diethoxyphosphoryl)-a,b-unsaturated d-lactones.5 Sur-
prisingly, the scope of this reaction has not been exam-
ined.
OH
O
H
O
H
O
O
O
O
H
H
O
O
H
OH
O
teucriumlactone
artemisitene
crassin
Figure 1 Naturally occurring a-methylene-d-lactones
We decided to expand this reaction into a synthetic meth-
od for the preparation of enantiomerically enriched a-(di-
ethoxyphosphoryl)-a,b-unsaturated d-lactones bearing a
homochiral C6 stereogenic center. It was important to
show that this kind of compound could be prepared start-
SYNTHESIS 2012, 44, 247–252
Advanced online publication: 01.12.2011
DOI: 10.1055/s-0031-1289629; Art ID: Z86011SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
1

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Ł. Albrecht et al.
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O
O
O
O
O
O
(EtO)2P
CO2H
(EtO)2P
(EtO)2P
O
O
O
+
O
OH
R2
R2
R2
Nu
R1
R2
Nu
R1
R1
R1
R1
R1
R1
R1
easily available via
asymmetric organocatalysis
Scheme 1 Diastereoselective synthesis of optically active a-methylene-d-lactones
ing from optically active b-hydroxyaldehydes. However, port of Barbas and co-workers is due to the enhancement
at the outset of our studies, we were aware of the earlier by a single crystallization from diethyl ether.
report from Wiemer6 showing that 3-oxopropyl (diethoxy-
phosphoryl)acetates bearing a non-quaternary carbon
atom in the a-position to the carbonyl group are very
We reasoned that lactones 6a,b could be prepared by a
two-step reaction involving acylation of b-hydroxyalde-
hydes 3a,b with (diethoxyphosphoryl)acetic acid 4 fol-
prone to retro-Michael reaction with the acetate moiety
lowed by intramolecular Knoevenagel reaction of the
acting as a leaving group. For this reason, their cyclization
resulting oxoalkyl phosphorylacetates 5a,b. Thus, esteri-
fication of phosphorylacetic acid 4 with b-hydroxyalde-
hydes 3a,b was carried out by a standard procedure using
via Knoevenagel condensation cannot be realized. There-
fore, homochiral b-hydroxyaldehydes containing a qua-
ternary carbon in the a-position to the carbonyl group
N,N¢-dicyclohexylcarbodiimide as the condensing agent
were chosen as the optimal starting material. In particular,
in the presence of catalytic 4-(dimethylamino)pyridine to
the use of (S)-3-aryl-3-hydroxy-2,2-dimethylpropanals as
give the oxoalkyl phosphorylacetates 5a,b in high yields
chiral building blocks seemed promising due to the devel-
after column chromatography. The Knoevenagel reaction
opment of asymmetric aldol reaction between isobutyral-
of 5a,b could be efficiently performed in boiling benzene
in the presence of catalytic amounts of piperidine and ace-
tic acid with azeotropic removal of water. The crude prod-
dehyde and benzaldehydes bearing an electron-
withdrawing substituent at C4 by Barbas et al. in 2004.7
The authors have shown that the use of (S)-1-(pyrrolidin-
2-ylmethyl)pyrrolidine as the catalyst in this reaction pro-
ucts were purified by column chromatography and their
structures were unambiguously confirmed by 1H and 13C
vides the corresponding products 3 with excellent yields
NMR spectral data. The enantiomeric purity of the a-(di-
and enantioselectivities.
ethoxyphosphoryl)-d-lactones 6a,b was shown to be 98%
Herein we report an effective protocol for the preparation ee. Thus, we have reason to believe that the enantioselec-
of a-(diethoxyphosphoryl)-a,b-unsaturated d-lactones tivities of the lactones represent the minimal enantiomeric
starting from (diethoxyphosphoryl)acetic acid 4 and (S)- excess actually induced in the aldol reaction.
3-aryl-3-hydroxy-2,2-dimethylpropanals 3a,b and the
first examples of their use as Michael acceptors. Transfor-
O
O
OH
O
a
mation of the resulting enantiomerically enriched b,g,g,d-
tetrasubstituted a-(diethoxyphosphoryl)-d-lactones into
the corresponding a-methylene-d-lactones by means of
Horner–Wadsworth–Emmons reaction with formalde-
hyde is also reported.
+
Ar
Ar
1
3a: 88%
3b: 81%
2a: Ar = 4-O2NC6H4
2b: Ar = 4-NCC6H4
O
OH
O
b
In our studies (S)-3-hydroxy-2,2-dimethyl-3-(4-nitrophe-
nyl)propanal (3a) and (S)-3-(4-cyanophenyl)-3-hydroxy-
2,2-dimethylpropanal (3b) obtained by the organocatalyt-
ic direct aldol reaction between isobutyraldehyde and
electron-poor aromatic aldehydes7 2a,b were evaluated
for the preparation of the corresponding a-(diethoxyphos-
phoryl)-a,b-unsaturated d-lactones 6a,b (Scheme 2). A
simple procedure was developed for the isolation of the
products 3a,b. The reaction mixture was diluted with di-
ethyl ether and dimethyl sulfoxide was removed by ex-
traction with water. Hydroxyaldehydes 3a,b were isolated
as crystalline solids. The enantiomeric purity of the thus
obtained hydroxyaldehydes 3a,b was determined as 98%
ee after their transformation into the corresponding lac-
tones 6a,b. We believe that the higher enantiomeric purity
of the aldehydes 3a,b when compared to the original re-
(EtO)2P
CO2H
+
Ar
4
3a: Ar = 4-O2NC6H4
3b: Ar = 4-NCC6H4
O
O
O
O
O
(EtO)2P
c
(EtO)2P
O
Ar
Ar
O
5a: 95%
5b: 74%
6a: 85%, 98% ee
6b: 83%, 98% ee
Scheme 2 Reagents and conditions: (a) 1 (2.0 equiv), 2 (1.0 equiv),
(S)-1-(pyrrolidin-2-ylmethyl)pyrrolidine (10 mol%), TFA (10
mol%), DMSO, r.t., 12 h; (b) 4 (1.1 equiv), DCC (1.1 equiv), DMAP
(0.1 equiv), CH2Cl2, r.t., 24 h; (c) benzene, AcOH (1.0 equiv), piperi-
dine (0.5 equiv), 5a: reflux, 6 h; 5b: reflux, 14 h. Enantiomeric excess
(ee) was determined by chiral stationary phase HPLC.
Synthesis 2012, 44, 247–252
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b,g,g,d-Tetrasubstituted a-Methylene-d-lactones
249
In the course of the further studies, the application of the
lactones 6a,b as acceptors in the Michael addition was in-
vestigated (Scheme 3). Acetone was chosen as a model
nucleophile in order to determine the influence of the C6
stereogenic center in 6a,b on the stereochemical outcome
of this reaction. Furthermore, it was anticipated that this
reaction can be realized via enamine organocatalysis em-
ploying an achiral secondary amine as a catalyst. The use
of acetone as the reagent and solvent and pyrrolidine as a
catalyst ensured good results in terms of yield and purity
of the products. Under these conditions, the additions pro-
ceeded efficiently at room temperature and were terminat-
ed within 48 and 120 hours, respectively (31P NMR). The
phosphonates 7a,b were formed as inseparable mixtures
of diastereomers which differ in their configuration at the
C3 stereogenic center. This was confirmed after their
transformation into the corresponding a-methylene-d-lac-
tones 8a,b. The Horner–Wadsworth–Emmons reaction of
a-(diethoxyphosphoryl)-d-lactones 7a,b with excess
paraformaldehyde performed in diethyl ether in the pres-
ence of potassium tert-butoxide afforded a-methylene-d-
lactones 8a,b in high yields as single diastereomers.
Figure 2 The crystal structure of a-methylene-d-lactone 8b; dis-
placement ellipsoids are drawn at the 50% probability level
••
N
O
O
9
H
(EtO)2P
O
Ar
H3C
O
Ar
P(O)(OEt)2
CH3
O
X-ray crystallographic analysis conducted on 8b
(Figure 2) revealed that the oxopropyl and aryl groups are
in a mutual trans relationship and allowed us to assign the
(4S,6R) absolute configuration to the products 8a,b. In the
crystal the d-lactone ring adopts a conformation close to
the 3E envelope,8 with endocyclic atoms O1, C1, C2, C3,
and C5 almost coplanar (the average r.m.s. deviation from
the mean plane is 0.05 Å). The Cremer and Pople pucker-
ing parameters9 for the ring sequence O1/C1/C2/C3/C5
are Q = 0.525(1) Å, q = 132.9(2)°, and j = 46.6(2)°. The
d-aryl substituent occupies a pseudoequatorial position,
while the b-oxopropyl is placed pseudoaxially with re-
spect to the ring system. The bond lengths are close to
those observed in similar compounds.10 In particular, both
exocyclic double bonds O2=C1 [1.205(2) Å] and C2=C6
[1.326(2) Å] are shorter than similar bonds observed in
O=C–C=C systems (1.222 and 1.340 Å, respectively).11
These bonds are separated by a relatively long C1–C2
bond [1.483(2) Å] and are not strictly coplanar, as shown
by a non-zero value for the O2=C1–C2=C6 torsion angle
[–16.4(2)°].
O
6
7
••
N
Scheme 4 Proposed stereochemical outcome for reaction of lac-
tones 6 and acetone enamine 9
The formation of two epimeric products 7a,b with differ-
ent absolute configuration at the C3 stereogenic center can
be rationalized by the high acidity of the hydrogen at this
stereogenic center.
In conclusion, enantiomerically enriched b-hydroxyalde-
hydes 3a,b were efficiently transformed into the corre-
sponding a-(diethoxyphosphoryl)-a,b-unsaturated d-
lactones 6a,b without loss of enantiomeric purity. Further
elaboration of these lactones provided the first diastereo-
selective entry to highly enantiomerically enriched
b,g,g,d-tetrasubstituted a-methylene-d-lactones. It was
shown that the diastereoselectivity in the Michael addition
is fully controlled by the C6 stereogenic center derived
from b-hydroxyaldehydes, which are easily accessible via
asymmetric organocatalytic aldol reaction.
The observed stereoselectivity in the Michael addition
step can be accounted for in these findings by assuming an
axial attack of the acetone enamine 9 on a half-chair con-
formation of the unsaturated lactone 6 with a pseudoequa-
torial aryl group (Scheme 4).
NMR spectra were recorded on a Bruker DPX 250 instrument at
250.13 MHz for 1H and 62.9 MHz for 13C and 101.3 MHz for 31P
NMR, respectively, using TMS as the internal and 85% H3PO4 as
O
O
O
O
O
(EtO)2P
O
O
a
b
(EtO)2P
O
Ar
Ar
Ar
O
O
6a: Ar = 4-O2NC6H4, 98% ee
6b: Ar = 4-NCC6H4, 98% ee
7a: 87%, 22:78 dr
7b: 77%, 20:80 dr
8a: 79%, >20:1 dr
8b: 66%, >20:1 dr
Scheme 3 Reagents and conditions: (a) acetone, pyrrolidine (0.2 equiv), r.t., 6a: 48 h; 6b: 120 h; (b) t-BuOK (1.2 equiv), Et2O, r.t., 0.5 h then
(HCHO)n (5 equiv), r.t., 1 h.
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250
Ł. Albrecht et al.
PAPER
the external standard. The multiplicities of carbons were determined
by DEPT experiments. IR spectra were measured on Specord M80
(Zeiss) instrument. Elemental analyses were performed on Perkin-
Elmer PE 2400 analyser. Melting points were determined in open
capillaries on Büchi SMP 30 aparatus and were uncorrected. Enan-
tiomeric excess were established on Waters (Vienna, Austria) Mod-
el 590 HPLC pump using chiralpak ADH column and a UV-Vis
detector Model 490. Optical rotations were measured at 20 °C using
Perkin-Elmer 241 polarimeter. Flash chromatography was carried
out using silica gel 60 (230–400 mesh). TLC was carried out on
commercially available pre-coated plates (Fluka Silica gel on TLC
plates).
31P NMR (CDCl3): d = 19.12.
Anal. Calcd for C18H24NO6P: C, 56.69; H, 6.34. Found: C, 56.89; H,
6.43.
Diethyl [(6R)-6-Aryl-5,5-dimethyl-2-oxo-5,6-dihydro-2H-pyr-
an-3-yl]phosphonates 6a,b; General Procedure
To a soln of acetate 5a,b (3 mmol) in benzene (30 mL), AcOH (180
mg, 3 mmol) and piperidine (128 mg, 1.5 mmol) was added and the
resulting mixture was heated under reflux using Dean–Stark appa-
ratus. The reaction progress was occasionally monitored by 31P
NMR. After reaction was complete, the solvent was removed under
reduced pressure and crude residue was dissolved in CH2Cl2 (20
mL). The soln was washed successively with 1 M HCl (10 mL), sat.
NaHCO3 (10 mL), and H2O (5 mL), dried (MgSO4), and evaporat-
ed. Crude products 6a,b were purified by flash chromatography
(CHCl3–acetone, 9:1) to give pure products.
(S)-1-Aryl-2,2-dimethyl-3-oxopropyl (Diethoxyphosphoryl)ace-
tates 5a,b; General Procedure
To a stirred soln of (diethoxyphosphoryl)acetic acid (4, 892 mg, 4.4
mmol) and (S)-3-aryl-3-hydroxy-2,2-dimethylpropanal 3 (4 mmol)
in CH2Cl2 (20 mL), DMAP (49 mg, 0.4 mmol) was added at 0 °C.
To this soln DCC (906 mg, 4.4 mmol) in CH2Cl2 (10 mL) was added
dropwise and the resulting mixture was stirred for 24 h at r.t. The
precipitated solid of dicyclohexylurea was then collected by filtra-
tion and mother liquor was washed successively with 1 M HCl (15
mL), sat, NaHCO3 (15 mL), and H2O (10 mL), dried (MgSO4), and
evaporated. Crude products 5a,b were purified by flash chromatog-
raphy (CHCl3–acetone, 9:1) to give pure products.
Diethyl [(6R)-5,5-Dimethyl-6-(4-nitrophenyl)-2-oxo-5,6-dihy-
dro-2H-pyran-3-yl]phosphonate (6a)
Pale-yellow oil; yield: 85%; 98% ee [HPLC (Chiralpak ADH col-
umn, hexane–i-PrOH, 70:30, flow rate 1.0 mL/min): tR = 9.2 (ma-
jor), 11.8 min (minor)].
[a]D20 +11.4 (c 1.05, CH2Cl2).
IR (film): 1712, 1520, 1348, 1252, 1176, 1056, 1028 cm–1.
1H NMR (CDCl3): d = 8.29–8.25 (m, 2 H, CHAr), 7.74–7.53 (m, 2
(S)-2,2-Dimethyl-1-(4-nitrophenyl)-3-oxopropyl (Diethoxy-
phosphoryl)acetate (5a)
Colorless oil; yield: 95%.
[a]D20 +7.4 (c 1.1, CH2Cl2).
IR (film): 1744, 1524, 1348, 1268, 1112, 1020 cm–1.
H, CHAr), 7.36 (s, 1 H, CH=C), 5.32 (s, 1 H, OCHAr), 4.33–4.19 [m,
3
4 H, (CH3CH2O)2P], 1.42 [t, JHH = 7.0 Hz, 3 H, (CH3CH2O)2P],
1.38 [t, 3JHH = 7.0 Hz, 3 H, (CH3CH2O)2P], 1.18 (s, 3 H, CH3), 0.98
(s, 3 H, CH3).
2
13C NMR (CDCl3): d = 168.17 (d, JCP = 3.8 Hz, CH), 160.45 (d,
2JCP = 13.8 Hz, COO), 147.81 (CAr), 141.03 (CAr), 128.47 (2 CHAr),
1H NMR (CDCl3): d = 9.62 (s, 1 H, CHO), 8.21 (d, 3JHH = 12.5 Hz,
1
3
123.01 (2 CHAr), 121.94 (d, JCP = 194.7 Hz, CP), 84.80 (CHAr),
2 H, CHAr), 7.52 (d, JHH = 12.5 Hz, 2 H, CHAr), 6.01 (s, 1 H,
2
2
OCHAr), 4.21–4.06 [m, 4 H, (CH3CH2O)2P], 3.00 (dd, 2JHP = 22.5
Hz, 4JHH = 2.5 Hz, 2 H, CHP), 1.38–1.26 [m, 6 H, (CH3CH2O)2P],
1.06 (s, 3 H, CH3), 1.04 (s, 3 H, CH3).
63.02 (d, JCP = 6.9 Hz, CH3CH2OP), 62.90 (d, JCP = 7.5 Hz,
3
CH3CH2OP), 37.19 [d, JCP = 12.6 Hz, (CH3)2C], 23.60 (CH3),
3
19.19 (CH3), 16.10 (d, JCP = 6.9 Hz, CH3CH2OP), 16.04 (d,
3JCP = 6.9 Hz, CH3CH2OP).
31P NMR (CDCl3): d = 10.33.
2
13C NMR (CDCl3): d = 202.25 [C(O)H], 164.08 (d, JCP = 6.7 Hz,
COO), 147.55 (CAr), 142.95 (CAr), 128.33 (2 CHAr), 123.01 (2
2
CHAr), 78.14 (CHAr), 62.59 (d, JCP = 6.1 Hz, CH3CH2OP), 62.53
Anal. Calcd for C17H22NO7P: C, 53.26; H, 5.78. Found: C, 53.42; H,
6.00.
2
(d, JCP = 6.0 Hz, CH3CH2OP), 49.63 [(CH3)2C], 33.92 (d,
1JCP = 133.5 Hz, CH2P), 19.24 (CH3), 16.79 (CH3), 16.00 (d,
3JCP = 6.1 Hz, CH3CH2OP).
Diethyl [(6R)-6-(4-Cyanophenyl)-5,5-dimethyl-2-oxo-5,6-dihy-
dro-2H-pyran-3-yl]phosphonate (6b)
Colorless oil; yield: 83%; 98% ee [HPLC (Chiralpak ADH column,
hexane–i-PrOH, 70:30, flow rate 1.0 mL/min): tR = 9.0 (major),
12.0 min (minor)].
31P NMR (CDCl3): d = 19.04.
Anal. Calcd for C17H24NO8P: C, 50.87; H, 6.03. Found: C, 50.63; H,
6.17.
[a]D20 +8.4 (c 1.00, CH2Cl2).
IR (film): 1724, 1520, 1348, 1252, 1168, 1056, 1020 cm–1.
1H NMR (CDCl3): d = 7.72–7.65 (m, 2 H, CHAr), 7.50–7.46 (m, 2
H, CHAr), 7.36 (s, 1 H, CH=C), 5.26 (s, 1 H, OCHAr), 4.32–4.15 [m,
(S)-1-(4-Cyanophenyl)-2,2-dimethyl-3-oxopropyl (Diethoxy-
phosphoryl)acetate (5b)
Colorless oil; yield: 74%.
[a]D20 +6.7 (c 1.24, CH2Cl2).
IR (film): 1748, 1520, 1348, 1268, 1112, 1024 cm–1.
3
4 H, (CH3CH2O)2P], 1.38 [t, JHH = 7.3 Hz, 3 H, (CH3CH2O)2P],
1.37 [t, 3JHH = 6.6 Hz, 3 H, (CH3CH2O)2P], 1.16 (s, 3 H, CH3), 0.97
1H NMR (CDCl3): d = 9.61 (s, 1 H, CHO), 7.66 (d, 3JHH = 8.2 Hz, 2
(s, 3 H, CH3).
H, CHAr), 7.45 (d, 3JHH = 8.2 Hz, 2 H, CHAr), 5.95 (s, 1 H, OCHAr),
13C NMR (CDCl3): d = 168.12 (d, JCP = 3.5 Hz, CH), 160.45 (d,
2
2
4.17–4.08 [m, 4 H, (CH3CH2O)2P], 2.99 (dd, JHP = 21.6 Hz,
2JCP = 14.4 Hz, COO), 139.08 (CAr), 131.58 (CAr), 128.18 (2 CHAr),
4JHH = 2.9 Hz, 2 H, CHP), 1.34–1.28 [m, 6 H, (CH3CH2O)2P], 1.15
1
123.39 (2 CHAr), 121.83 (d, JCP = 194.8 Hz, CP), 112.41 (CN),
(s, 3 H, CH3), 1.02 (s, 3 H, CH3).
2
84.93 (CHAr), 62.93 (d, JCP = 6.8 Hz, CH3CH2OP), 62.82 (d,
2
13C NMR (CDCl3): d = 202.37 [C(O)H], 164.16 (d, JCP = 6.7 Hz,
2JCP = 7.0 Hz, CH3CH2OP), 37.12 [d, JCP = 12.4 Hz, (CH3)2C],
3
COO), 141.04 (CAr), 131.73 (2 CHAr), 128.21 (2 CHAr), 118.5 (CAr),
3
23.53 (CH3), 19.12 (CH3), 16.03 (d, JCP = 5.9 Hz, CH3CH2OP),
112.15 (CN), 78.44 (CHAr), 62.65 (d, 2JCP = 4.5 Hz, CH3CH2OP),
15.97 (d, 3JCP = 5.8 Hz, CH3CH2OP).
31P NMR (CDCl3): d = 10.39.
2
62.57 (d, JCP = 5.9 Hz, CH3CH2OP), 49.73 [(CH3)2C], 34.05 (d,
1JCP = 133.5 Hz, CH2P), 19.34 (CH3), 16.87 (CH3), 16.08 (d,
3JCP = 6.1 Hz, CH3CH2OP).
Anal. Calcd for C18H22NO5P: C, 59.50; H, 6.10. Found: C, 59.42; H,
6.17.
Synthesis 2012, 44, 247–252
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b,g,g,d-Tetrasubstituted a-Methylene-d-lactones
251
Diethyl [(4S,6R)-6-Aryl-5,5-dimethyl-2-oxo-4-(2-oxopropyl)tet-
rahydro-2H-pyran-3-yl]phosphonates 7a,b; General Procedure
To a soln of the d-lactone 6a,b (0.5 mmol) in acetone (2 mL), pyr-
rolidine (7.1 mg, 0.1 mmol) was added and the resulting mixture
was stirred at r.t. until 31P NMR indicated that 6a,b had disappeared.
After evaporation of the solvent, the crude residue was treated with
1 M HCl and extracted with CH2Cl2 (3 × 10 mL). The combined or-
ganic layers were washed with H2O (5 mL) and dried (MgSO4). Af-
ter evaporation, crude products were purified by flash
chromatography (EtOAc–hexanes, 2:1) to give pure products.
CH3CH2OP, minor), 45.04 (CH2, major and minor), 44.19 (d,
1JCP = 140.6 Hz, CHP, major), 42.77 (d, 1JCP = 141.5 Hz, CHP, mi-
nor), 40.70 (CH, major), 38.12 (d, 2JCP = 3.0 Hz, CH, minor), 36.57
3
3
[d, JCP = 8.7 Hz, (CH3)2C, major], 35.64 [d, JCP = 7.6 Hz,
(CH3)2C, minor], 34.52 (CH3, minor), 29.71 (CH3, minor), 29.41
(CH3, major), 22.14 (CH3, minor), 22.03 (CH3, major), 21.54 (CH3,
3
major), 15.88 (d, JCP = 6.5 Hz, CH3CH2OP, major and minor),
15.78 (d, 3JCP = 6.2 Hz, CH3CH2OP, major and minor).
31P NMR (CDCl3): d = 20.57 (20%), 21.96 (80%).
Anal. Calcd for C21H28NO6P: C, 59.85; H, 6.70. Found: C, 59.75; H,
6.56.
Diethyl [(4S,6R)-5,5-Dimethyl-6-(4-nitrophenyl)-2-oxo-4-(2-
oxopropyl)tetrahydro-2H-pyran-3-yl]phosphonate (7a)
Pale-yellow oil; yield: 87%.
IR (film): 1728, 1524, 1348, 1248, 1164, 1056 cm–1.
1H NMR (CDCl3): d = 8.27–8.19 (m, 2 H, CHAr, major and minor),
7.68–7.47 (m, 2 H, CHAr, major and minor), 5.64 (s, 1 H, OCHAr,
minor), 5.39 (s, 1 H, OCHAr, major), 4.42–4.20 [m, 4 H,
(CH3CH2O)2P, major], 4.19–4.08 [m, 4 H, (CH3CH2O)2P, minor],
3.40–3.13 (m, 2 H, CHP, major and minor), 3.02–2.63 (m, 3 H, CH,
CH2, major and minor), 2.26 (s, 3 H, CH3, minor), 2.17 (s, 3 H, CH3,
major), 1.48–1.32 [m, 6 H, (CH3CH2O)2P, major and minor], 1.01
(s, 3 H, CH3, minor), 0.94 (s, 3 H, CH3, major), 0.86 (s, 3 H, CH3,
major), 0.85 (s, 3 H, CH3, minor).
(4S,6R)-6-Aryl-5,5-dimethyl-3-methylene-4-(2-oxopropyl)tet-
rahydro-2H-pyran-2-ones 8a,b; General Procedure
To a soln of d-lactone 7a,b (0.25 mmol) in Et2O (2.5 mL), t-BuOK
(33.5 mg, 0.3 mmol) was added and the resulting mixture was
stirred at r.t. for 0.5 h. Paraformaldehyde (37.5 mg, 1.25 mmol) was
then added and stirring was continued for 1 h. The reaction was
quenched with brine (3 mL) and Et2O was evaporated. The residue
was extracted with CH2Cl2 (2 × 5 mL) and combined organic layers
were dried (MgSO4). After filtration and evaporation of the solvent,
crude products were purified by flash chromatography (EtOAc–
hexanes, 1:4) to give the products.
(4S,6R)-5,5-Dimethyl-3-methylene-6-(4-nitrophenyl)-4-(2-oxo-
propyl)tetrahydro-2H-pyran-2-one (8a)
White solid; yield: 79%; mp 187–188 °C.
[a]D20 +45.6 (c 1.25, CH2Cl2).
IR (film): 1720, 1520, 1352, 1300, 1176, 1032 cm–1.
1H NMR (CDCl3): d = 8.24 (d, 3JHH = 10.0 Hz, 2 H, CHAr), 7.46 (d,
3JHH = 10.0 Hz, 2 H, CHAr), 6.53 (s, 1 H, CH2=C), 5.73 (s, 1 H,
CH2=C), 5.37 (s, 1 H, OCHAr), 3.19–3.15 (m, 1 H, CH), 2.89–2.65
(m, 2 H, CH2), 2.17 (s, 3 H, CH3), 0.94 (s, 3 H, CH3), 0.86 (s, 3 H,
CH3).
13C NMR (CDCl3): d = 205.28 [C(O)], 164.03 (COO), 147.58 (CAr),
143.12 (CAr), 136.21 (CH2=C), 130.78 (CH2=C), 128.28 (2 CHAr),
122.84 (2 CHAr), 84.44 (CHAr), 44.15 (CH), 43.61 (CH2), 35.89
[(CH3)2C], 30.95 (CH3), 23.17 (CH3), 21.33 (CH3).
13C NMR (CDCl3): d = 205.82 (CO, major), 205.43 (CO, minor),
166.17 (d, 2JCP = 3.1 Hz, COO, major and minor), 147.49 (CAr, ma-
jor and minor), 142.62 (CAr, major), 142.53 (CAr, minor), 128.68 (2
CHAr, major), 128.28 (2 CHAr, minor), 122.73 (2 CHAr, major and
minor), 85.64 (CHAr, major), 84.46 (CHAr, minor), 63.66 (d,
2
2JCP = 6.9 Hz, CH3CH2OP, minor), 63.45 (d, JCP = 6.9 Hz,
2
CH3CH2OP, major), 62.70 (d, JCP = 6.9 Hz, CH3CH2OP, major),
61.99 (d, 2JCP = 6.6 Hz, CH3CH2OP, minor), 45.12 (CH2, major and
1
minor), 44.32 (d, JCP = 140.6 Hz, CHP, major), 42.97 (d,
1JCP = 141.3 Hz, CHP, minor), 40.93 (CH, major), 38.32 (CH, mi-
nor), 36.83 [d, 3JCP = 8.8 Hz, (CH3)2C, major], 35.89 [d, 3JCP = 7.5
Hz, (CH3)2C, minor], 34.79 (CH3, minor), 29.90 (CH3, minor),
29.62 (CH3, major), 22.65 (CH3, minor), 22.35 (CH3, major), 21.76
3
(CH3, major), 16.09 (d, JCP = 6.2 Hz, CH3CH2OP, major and mi-
nor), 15.99 (d, 3JCP = 6.9 Hz, CH3CH2OP, major and minor).
31P NMR (CDCl3): d = 20.57 (22%), 21.96 (78%).
Anal. Calcd for C17H19NO5: C, 64.34; H, 6.03. Found: C, 64.52; H,
6.18.
Anal. Calcd for C20H28NO8P: C, 54.42; H, 6.39. Found: C, 54.84; H,
6.03.
4-[(2R,4S)-3,3-Dimethyl-5-methylene-6-oxo-4-(2-oxopro-
pyl)tetrahydro-2H-pyran-2-yl]benzonitrile (8b)
White solid; yield: 66%; mp 162–165 °C.
[a]D20 +69.7 (c 1.20, CH2Cl2).
Diethyl [(4S,6R)-6-(4-Cyanophenyl)-5,5-dimethyl-2-oxo-4-(2-
oxopropyl)tetrahydro-2H-pyran-3-yl]phosphonate (7b)
Pale-yellow oil; yield: 77%.
IR (film): 1720, 1524, 1356, 1248, 1164, 1048 cm–1.
IR (film): 1724, 1520, 1352, 1300, 1168 cm–1.
1H NMR (CDCl3): d = 7.69–7.65 (m, 2 H, CHAr, major and minor),
7.54–7.39 (m, 2 H, CHAr, major and minor), 5.57 (s, 1 H, OCHAr,
minor), 5.32 (s, 1 H, OCHAr, major), 4.37–4.17 [m, 4 H,
(CH3CH2O)2P, major], 4.16–4.06 [m, 4 H, (CH3CH2O)2P, minor],
3.49–3.11 (m, 2 H, CHP, major and minor), 3.00–2.61 (m, 3 H, CH,
CH2, major and minor), 2.26 (s, 3 H, CH3, minor), 2.17 (s, 3 H, CH3,
major), 1.41–1.32 [m, 6 H, (CH3CH2O)2P, major and minor], 0.99
(s, 3 H, CH3, minor), 0.93 (s, 3 H, CH3, major), 0.85 (s, 3 H, CH3,
major), 0.84 (s, 3 H, CH3, minor).
1H NMR (CDCl3): d = 7.67 (d, 3JHH = 8.5 Hz, 2 H, CHAr), 7.39 (d,
3JHH = 8.5 Hz, 2 H, CHAr), 6.51 (dd, 2JHH = 0.9 Hz, 4JHH = 1.4 Hz, 1
2
H, CH2=C), 5.71 (dd, JHH = 0.9 Hz, 4JHH = 1.4 Hz, 1 H, CH2=C),
5.32 (s, 1 H, OCHAr), 3.18–3.13 (m, 1 H, CH), 2.88–2.56 (m, 2 H,
CH2), 2.21 (s, 3 H, CH3), 0.92 (s, 3 H, CH3), 0.84 (s, 3 H, CH3).
13C NMR (CDCl3): d = 205.24 [C(O)], 164.11 (COO), 141.17 (CAr),
136.24 (CH2=C), 131.52 (CH2=C), 130.77 (CAr), 128.10 (2 CHAr),
118.22 (2 CHAr), 112.09 (CN), 84.66 (CHAr), 44.13 (CH), 43.62
(CH2), 35.89 [CH3)2C], 31.03 (CH3), 23.20 (CH3), 21.36 (CH3).
13C NMR (CDCl3): d = 205.56 (CO, major), 205.19 (CO, minor),
166.04 (d, 2JCP = 4.1 Hz, COO, major and minor), 140.52 (CAr, ma-
jor and minor), 140.40 (2 CHAr, minor), 131.15 (2 CHAr, major),
128.27 (2 CHAr, major), 127.90 (2 CHAr, minor), 117.92 (CAr, major
and minor), 111.65 (CN, major), 111.55 (CN, minor), 85.47 (CHAr,
major), 84.43 (CHAr, minor), 63.31 (d, 2JCP = 6.7 Hz, CH3CH2OP,
Anal. Calcd for C18H19NO3: C, 72.71; H, 6.44. Found: C, 72.72; H,
6.15.
Single Crystal X-ray Structure Analysis for 8b12
Formula:
0.30 × 0.15 × 0.10 mm,
c = 10.8998(2) Å, b = 98.596(1)°, V = 811.62(2), rcalcd = 1.217
C18H19NO3,
Mw = 297.34,
a = 9.2505(1),
colorless
crystal
b = 8.1410(1),
2
minor), 63.11 (d, JCP = 6.9 Hz, CH3CH2OP, major), 62.36 (d,
2
2JCP = 6.7 Hz, CH3CH2OP, major), 61.71 (d, JCP = 6.9 Hz,
g cm–3, m = 0.669 mm–1, semiempirical absorption correction based
© Thieme Stuttgart · New York
Synthesis 2012, 44, 247–252

252
Ł. Albrecht et al.
PAPER
on multiple scanned equivalent reflections (0.666 < T < 0.753),
Z = 2, crystal system: monoclinic, space group: P21, CuKa radia-
tion, l = 1.54178 Å, T = 293 K, w scans, 11,674 reflections collect-
Tetrahedron 1996, 52, 2065. (f) Raju, R.; Allen, L. J.; Le,
T.; Taylor, C. D.; Howell, A. R. Org. Lett. 2007, 9, 1699.
(3) (a) Krawczyk, H.; Śliwiński, M.; Wolf, W. M.; Bodalski, R.
Synlett 2004, 1995. (b) Krawczyk, H.; Śliwiński, M.;
Kędzia, J.; Wojciechowski, J.; Wolf, W. M. Tetrahedron:
Asymmetry 2006, 17, 908. (c) Krawczyk, H.; Śliwiński, M.;
Kędzia, J.; Wojciechowski, J.; Wolf, W. M. Tetrahedron:
Asymmetry 2007, 18, 2712.
ed ( h,
k,
l), 2qmax = 136°, 2,926 unique reflections
(Rint = 0.0173) and 2,916 observed reflections [I ≥ 2s (I)], 254 re-
fined parameters, refinement on F2, Rall = 0.0326, wR (F2) = 0.0865,
max (min) residual electron density Drmax = 0.101 (Drmin = –0.150)
e Å–3, Flack parameter13 calculated with 668 Friedel pairs
h = 0.03(17). X-ray data were collected with Bruker Smart Apex II
CCD area detector diffractometer. Computer programs used: data
collection APEX2,14 data reduction SAINT-Plus,15 absorption cor-
rection SADABS,16 structure solution, refinement, and molecular
graphics SHELXTL.17
(4) Albrecht, Ł.; Richter, B.; Krawczyk, H.; Jørgensen, K. A.
J. Org. Chem. 2008, 73, 8337.
(5) (a) Falsone, G.; Spur, B. Liebigs Ann. Chem. 1981, 565.
(b) Falsone, G.; Wingen, U.; Wendisch, D. Tetrahedron Lett.
1989, 30, 675.
(6) Chen, X.; Wiemer, D. F. J. Org. Chem. 2003, 68, 6597.
(7) Mase, N.; Tanaka, F.; Barbas, C. F. III Angew. Chem. Int.
Ed. 2004, 43, 2420.
Acknowledgment
(8) Boeyens, J. C. A. J. Cryst. Mol. Struct. 1978, 8, 317.
(9) Cremer, D.; Pople, J. A. J. Am. Chem. Soc. 1975, 97, 1354.
(10) Wojciechowski, J.; Krawczyk, H.; Śliwiński, M.; Kafarska,
K.; Wolf, W. M. Acta Crystallogr., Sect. C 2007, 63, o280.
(11) Allen, F. H.; Watson, D. G.; Brammer, L.; Orpen, A. G.;
Taylor, R. In International Tables for Crystallography, Vol.
C; Prince, E., Ed.; Kluwer: Dordrecht, 2004, 790–811.
(12) Crystallographic data (excluding structure factors) for the
structure reported herein have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication CCDC 822405. Copies of the data can be
obtained free of charge on application to The Director,
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. Any
request should be accompanied by a full literature citation.
(13) Flack, H. D. Acta Crystallogr., Sect. A 1983, 39, 876.
(14) Bruker APEX2, Version 2010/3; Bruker AXS: Madison (WI,
USA), 2010.
(15) Bruker SAINT-Plus, Version 7.68A; Bruker AXS: Madison
(WI, USA), 2009.
(16) Bruker SADABS - Bruker Nonius area detector scaling and
absorption correction, Version 2008/1; Bruker AXS:
Madison (WI, USA), 2008.
(17) Sheldrick, G. M. SHELXTL Version 2008/4; Bruker AXS:
Madison (WI, USA), 2008.
This work was financed by the Ministry of Science and Higher Edu-
cation (Project No. N N204 005736).
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Synthesis 2012, 44, 247–252
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