Highly enantioselective synthesis of α-methylene-δ-valerolactones by an asymmetric Michael reaction

Article abstract of DOI:10.1016/j.tetasy.2006.03.007

The synthesis of α-methylene-δ-valerolactones 7, 13, and 19 with enantiomeric excesses of 90-97% was achieved by the asymmetric Michael reaction of chiral imines 3, 9, and 15 with the acrylate 1. Reduction of the carbonyl group of the resulting adducts fo

Full text of DOI:10.1016/j.tetasy.2006.03.007

Tetrahedron: Asymmetry 17 (2006) 908–915
Highly enantioselective synthesis of a-methylene-d-valerolactones
by an asymmetric Michael reaction
a
a
b
Henryk Krawczyk,a, Marcin Sliwinski, Jacek Ke˛dzia, Jakub Wojciechowski
´
*
´
and Wojciech M. Wolfb
a
_
Institute of Organic Chemistry, Technical University (Politechnika), 90-924 Ło´dz´, Zeromskiego 116, Poland
b
_
Institute of General and Ecological Chemistry, Technical University (Politechnika), 90-924 Ło´dz´, Zeromskiego 116, Poland
Received 9 January 2006; revised 7 March 2006; accepted 9 March 2006
Available online 4 April 2006
Abstract—The synthesis of a-methylene-d-valerolactones 7, 13, and 19 with enantiomeric excesses of 90–97% was achieved by the asym-
metric Michael reaction of chiral imines 3, 9, and 15 with the acrylate 1. Reduction of the carbonyl group of the resulting adducts fol-
lowed by lactonization and HWE reaction with formaldehyde yielded the lactones as mixtures of diastereoisomers.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
with the transition-state model proposed for similar
Michael reactions.3
In recent years the asymmetric Michael addition of imines
derived from enantiomerically pure amines to electron-defi-
cient olefins has been extensively exploited for enantioselec-
tive construction of quaternary stereocenters adjacent to a
carbonyl group.1
Since optically active a-methylene-d-valerolactones may
serve as attractive building blocks for the construction of
different natural products and their accessibility is limited,4
we decided to clarify the generality of our synthetic method
for the imines of both cyclic and acyclic ketones.
Recently, we reported that dicyclohexylammonium 2-
(diethoxyphosphoryl)acrylate 1 can be used as particularly
attractive acceptor in this type of reaction. We have dem-
onstrated that the sequence involving the addition of
imines derived from 2-methylcyclohexanone, 2-ethoxy-
carbonylcyclohexanone, and enantiomerically pure 1-phenyl-
ethylamine to acrylate 1, followed by the diastereoselec-
tive reduction of the carbonyl group in the resultant
2-diethoxyphosphoryl-5-oxoalkanoic acids, lactonization
of the reduction products, and finally Horner–Wads-
worth–Emmons olefination of the a-phosphono-d-valero-
lactones provides the corresponding a-methylene-d-
valerolactones with 97% enantiomeric excess.2 It was also
established that the 2-diethoxyphosphoryl-5-oxoalkanoic
acids were mixtures of epimers that differ in configuration
at the tertiary stereogenic center and their absolute config-
uration at the quaternary stereogenic center is in agreement
Herein we report on the effective and general protocol for
the highly enantioselective preparation of a-methylene-d-
valerolactones derived from 2-methoxycyclohexanone 2
(Scheme 1), 2-ethoxycarbonylcyclopentanone 8 (Scheme
2), and 2-acetylbutyrolactone 14 (Scheme 3). We believed
that using acyclic ketolactone 14 as a starting material
would make it possible to obtain optically active spirocyclic
bislactones.
2. Results and discussion
The starting (R)-a-imine 3,5 (S)-b-enaminoester 9,6 and
(R)-b-enaminolactone 156 were prepared by reported meth-
ods. Addition reactions of the imine 3 and enamines 9 and
15 to the salt 1 proceeded smoothly in benzene at room
temperature. Complete consumption of salt 1 was observed
after 2 days (31P NMR). Ion-exchange chromatography of
the crude Michael adducts gave 2-diethoxyphosphoryl-5-
oxoalkanoic acids 4, 10, and 16, respectively, each as a mix-
ture of two diastereoisomers in a 1:1 ratio. Acids 4, 10, and
*
Corresponding author. Tel.: +48 (42) 631 3104; fax: +48 (42) 636
5530; e-mail: henkrawc@p.lodz.pl
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.03.007

H. Krawczyk et al. / Tetrahedron: Asymmetry 17 (2006) 908–915
909
O
(EtO)2P
CO2 NH2(c-Hex)2
Ph Me
1
O
O
O
OMe
H
N
OMe
P(OEt)2
a
b,c
OMe
CO2H
2
3
4
H
H
OH
O
O
O
O
O
d or e
OMe
f
P(OEt)2
(EtO)2P
O
(EtO)2P
O
CO2H
OMe
OMe
6b
6a
5
g
MClX
7a
7b
H
CaCl2. 2H2O
BaCl2. 2H2O
CeCl3. 7H2O
H
3
2
3
2
3
1
O
O
O
O
trans-7a : cis-7b = 3:2
ee=96%
OMe
cis-7b
OMe
trans-7a
˚
Scheme 1. Reagents and conditions: (a) (R)-phenylethylamine, SiO2, Al2O3, molecular sieves 5 A, rt, 6 days, 85%; (b) benzene, rt, 48 h; (c) Dowex 50W,
acetone/water, 80%; (d) MeOH, KBH4 (2 equiv), rt, 24 h; (e) MeOH, MClX (1 equiv), KBH4 (2 equiv), ꢀ70 ꢁC, 1 h, rt, 24 h; (f) TFAA (1 equiv), toluene,
rt, 24 h, 70%; (g) t-BuOK (1 equiv), t-BuOH, (HCHO)n (5 equiv), Et2O, rt, 1 h, 80%.
O
(EtO)2P
CO2 NH2(c-Hex)2
Me Ph
1
O
O
O
H
CO2Et
H
N
P(OEt)2
CO2Et
a
b,c
CO2Et
CO2H
8
9
10
H
H
d or e
OH
O
O
O
O
O
f
CO2Et
P(OEt)2
(EtO)2P
O
(EtO)2P
O
CO2H
CO2Et
CO2Et
12b
12a
11
g
MClX
13b
13a
H
H
O
O
O
O
CaCl2. 2H2O
BaCl2. 2H2O
CeCl3. 7H2O
13
1
87
2
trans-13a : cis-13b = 1:2
ee=97%
17
83
CO2Et
CO2Et
cis-13b
trans-13a
Scheme 2. Reagents and conditions: (a) (R)-phenylethylamine, BF3ÆOEt2 (cat), benzene, reflux, 18 h, 90%; (b) benzene, rt, 48 h; (c) Dowex 50W, acetone/
water, 86%; (d) MeOH, KBH4 (2 equiv), rt, 24 h; (e) MeOH, MClX (1 equiv), KBH4 (2 equiv), ꢀ70 ꢁC, 1 h, rt, 24 h; (f) TFAA (1 equiv), toluene, rt, 24 h,
70%; (g) t-BuOK (1 equiv), t-BuOH, (HCHO)n (5 equiv), Et2O, rt, 1 h, 75%.
16 were converted to a-methylene-d-valerolactones 7, 13,
and 19 by a standard procedure. Reduction of the carbonyl
group was easily accomplished under mild conditions with
KBH4 in methanol. Lactonization of the hydroxyacids ob-
tained 5, 11, and 17 was performed in toluene at room tem-
perature in the presence of trifluoroacetic anhydride as the
dehydrating agent,7 and provided the phosphonolactones
6, 12, and 18, each as a mixture of two diastereoisomers. 31P
NMR spectra of these compounds revealed the presence
of two signals in ratios of 1:1, 2:1, and 2:1, respectively.

910
H. Krawczyk et al. / Tetrahedron: Asymmetry 17 (2006) 908–915
O
(EtO)2P
CO2 NH2(c-Hex)2
O
O
Ph Me
1
O
O
H
O
Me
O
N
H
a
b,c
O
Me
O
Me
(EtO)2P
O
CO2H
14
15
16
O
OH
Me
O
O
H
O
d or e
Me
O
O
Me
f
O
O
O
O
P(OEt)2
O
H
P(OEt)2
(EtO)2P
O
CO2H
O
17
18a-ul:18b-lk = 1:2
18a-ul
18b-lk
ee=90%
g, h
g, h
18a-ul
18b-lk
MClX
CaCl2. 2H2O
BaCl2. 2H2O
CeCl3. 7H2O
1
2
1
1
1
1
O
H
O
O
O
Me
Me
O
O
O
O
H
19a-ul
19b-lk
Scheme 3. Reagents and conditions: (a) (R)-phenylethylamine, BF3ÆOEt2 (cat), benzene, reflux, 18 h, 90%; (b) benzene, rt, 48 h; (c) Dowex, acetone/water,
80%; (d) MeOH, KBH4 (2 equiv), rt, 24 h; (e) MeOH, MClX (1 equiv), KBH4 (2 equiv), ꢀ70 ꢁC, 1 h, rt, 24 h; (f) TFAA (1 equiv), toluene, rt, 24 h, 85%; (g)
column chromatography; (h) t-BuOK (1 equiv), t-BuOH, (HCHO)n (5 equiv), benzene, rt, 1 h, 85%.
The mixtures of diastereoisomeric lactones 6 and 12
could not be separated by column chromatography. On
the contrary, 18a-ul and 18b-lk diastereoisomers of lactone
18 were easily isolated by this method. Finally, the HWE
reaction of the phosphonolactones 6, 12, 18a-ul, and
18b-lk afforded the corresponding a-methylene-d-valero-
lactones 7, 13, 19a-ul, and 19b-lk. Lactones 7 and 13 were
formed as mixtures of trans- and cis-diastereoisomers in
ratios of 3:2 and 1:2, respectively. These ratios reflect the
degree of diastereoselection, which is attained in the reduc-
tion of oxoacids 4 and 10. On the other hand, the diastereo-
selectivity of the reduction of oxoacid 16 is expressed by the
ratio of diastereoisomeric a-phosphonolactones 18a-ul:18b-
lk = 1:2.
The mixtures of diastereoisomeric lactones 7 and 13 were
separated by column chromatography. Pure diastereoiso-
mers trans-7a and 19b-lk were isolated as crystalline solids.
The enantiomeric purities of the lactones 7, 13, and 19 were
established unambiguously by chiral GC analysis and in
comparison with the authentic racemic samples. The high-
est level of enantiomeric excesses of 97% and 96% were ob-
tained for the lactones 13 and 7, respectively, while the
enantiomeric excess of spirolactone 19 did not exceed
90%. In addition, the enantiomeric excess of acid 4 was fur-
ther enhanced by a single recrystallization of its dicyclo-
hexylammonium salt 20 (Scheme 4) from ethyl acetate.
Salt 20 was converted by standard means into lactone 7
with 99% ee. The enantiomeric purity of lactone 19b-lk
was enhanced to 97% by a single recrystallization from
diethyl ether.
In order to find an effective, alternative procedure for the
highly diastereoselective synthesis of lactones 7, 13, and
19 we examined the stereoselectivity of reduction of the
corresponding oxoacids 4, 10, and 16 with KBH4 in
the presence of metal chlorides such as CaCl2Æ2H2O,
BaCl2Æ2H2O, and CeCl3Æ7H2O.8 Under these conditions,
the reductions of acid 4 in the presence of CeCl3 (trans-
7a:cis-7b = 3:1) and acid 10 in the presence of CaCl2
(trans-13a:cis-13b = 13:87) or CeCl3 (trans-13a:cis-13b =
17:83) were more diastereoselective then those with
KBH4. On the other hand, reduction of 4 and 16 in the
presence of BaCl2 gave the expected products, but with
reverse diastereoselectivity. No change of selectivity was
observed in the reduction of 4 with CaCl2/KBH4 and 10
with BaCl2/KBH4 systems.
The assignment of absolute configuration to the acids 4, 10,
and 16 and lactones 7, 13, and 19 was based on X-ray crys-
tallographic analysis of lactones trans-7a and 19-lk. The
absolute stereochemistry of lactone trans-7a was deter-
mined to be (4aR,8aR).9 This result indicates that the
quaternary stereogenic center of acid 4 has an (R)-configu-
ration meaning that lactone cis-7b is undoubtedly the
(4aR,8aS)-isomer. The absolute configuration of lactone
19b-lk was determined to be (5R,6R) as shown in Figure
1. As a consequence, the stereochemistry at the quaternary
stereogenic center in the acid 16 was assigned to be R and
therefore the lactone 19a-ul must be (5R,6S)-isomer.

H. Krawczyk et al. / Tetrahedron: Asymmetry 17 (2006) 908–915
911
O
O
H
H
O
O
OMe
O
O
O
O
OMe
a
b, c, d, e
P(OEt)2
P(OEt)2
CO2 NH2(c-Hex)2
CO2H
OMe
OMe
4
20
trans-7a
cis-7b
trans -7a : cis-7b= 3:1
ee >99%
Scheme 4. Reagents and conditions: (a) (C6H11)2NH, crystallization from EtOAc; (b) Dowex, 50W, acetone/water, 80%; (c) MeOH, KBH4 (2 equiv), rt,
24 h; (d) TFAA (1 equiv), toluene, rt, 24 h; 70%; (e) t-BuOK (1 equiv), t-BuOH, (HCHO)n (5 equiv), Et2O, rt, 1 h, 80%.
overlapping of the occupied np lone pair orbital of the
O4 atom with the vacant p* unoccupied of the C2@O2
and C3@C4 double bonds (Table 1 and Fig. 2). The mole-
cular conformation is also affected by the mutual anti r–r*
stereoelectronic interactions16 of the endocyclic C2–O1 and
exocyclic vinyl C3@C4 bond (9.17 and 5.03 kJ molꢀ1).
Table 1. Energy of the selected non-bonding stereoelectronic interactions
calculated with the natural bond orbital theory at the RHF/6-311+G(d,p)
level of theory (Gaussian 03) for the X-ray determined coordinates
Interaction
Stabilization energy (kJ/mol)
np(O4)–p*(C2@O2)
np(O4)–p*(C3@C4)
r(C3@C4)–r*(C2–O1)
r(C2–O1)–r*(C3@C4)
1.31
1.80
9.17
5.03
Figure 1. View of the 19b-lk with atom numbering. Displacement
ellipsoids were drawn at the 50% probability level.
The structure of 19b-lk was determined by the single crystal
X-ray diffraction analysis. The molecule investigated
adopts an unusual spiro conformation with the c-lactone
and d-lactone rings sharing the pivotal C6 atom and
strongly twisted in respect to one another. While the single
c-lactone and d-lactone fragments exist in a number of
investigated crystal structures their combined arrangement
is unique among crystal structures reported to date.10 The
former ring adopts an envelope conformation with the C9
atom shifted out of the O3, C8, C6, and C10 plane, while
the d-lactone ring exists in the distorted half-chair arrange-
ment with the C1, O1, C2, C3, and C5 atoms approxi-
mately coplanar and the C6 atom situated at the flap.
Within the d-lactone fragment both exocyclic double bonds
Figure 2. Natural bond orbitals involved in the stabilizing through space
interactions: (a) np(O4)–p*(C2@O2); (b) np(O4)–p*(C3@C4).
The absolute configuration at the quaternary stereogenic
center in adducts 4 and 16 is fully consistent with the tran-
sition-state model proposed for asymmetric Michael addi-
tion of chiral imines to electron-deficient alkenes17 and
with the results of our earlier studies.2 The alkylation
occurs preferentially on the less hindered p-face at the more
substituted secondary enamine, in tautomeric equilibrium
with the starting imine, anti- to the phenyl group. By anal-
ogy with the above results, the absolute configuration at
the quaternary stereogenic center in adduct 10 was assigned
to be S. Therefore, the absolute configuration of lactone
trans-13a must be (4aS,7aS) while that of cis-13b which
differs in configuration at around C-7a is 4a(S), 7a(R).
˚
˚
O2@C2 [1.212(2) A] and C3@C4 [1.320(2) A] are shorter
than similar bonds observed in the O@C–Ca@Cb moiety11
˚
(1.222 and 1.340 A). These bonds are separated by a rela-
tively long C2–C3 bond [1.484(2), standard value
˚
1.465 A] and are not strictly coplanar, as shown by a
non-zero value of the O2@C2–C3@C4 torsion angle
[ꢀ7.9(2)ꢁ]. These results suggest that the highly polar char-
acter of the C2@O2 carbonyl group hinders p electron den-
sity delocalization within the O@C–Ca@Cb fragment of the
molecule. The exocyclic O4 atom is involved in two intra-
molecular interactions, namely with atoms C2 and C3 of
the O@C–Ca@Cb moiety, the respective interatomic dis-
˚
tances: 3.060(2) and 3.064(2) A are shorter than the sum
12
˚
of oxygen and carbon van der Waals radii: 3.22 A. As
indicated by the natural bond orbital analysis13 calculated
at the RHF/6-311 + G(d,p) level (Gaussian 0314) those
unusual, through space,15 interactions follow from the
3. Conclusions
In summary, we have demonstrated that the asymmetric
Michael reactions of chiral imines to acrylate 1 can be

912
H. Krawczyk et al. / Tetrahedron: Asymmetry 17 (2006) 908–915
3
exploited for highly enantioselective and diastereoselective
synthesis of multifunctional a-methylene-d-valerolactones
containing adjacent quaternary and tertiary stereogenic
centers.
(3H, CH3CH2OC), 1.33 (t, JHH = 7.0) and 1.35 (t,
3JHH = 7.0), (3H, 2 · CH3CH2OP), 1.90–2.10 (m, 4H,
2 · CH2), 2.21–2.58 (m, 4H, 2 · CH2), 3.21 (ddd,
3JHH = 1.5, JHH = 10.2, JHP = 25.9) and 3.32 (ddd,
3
2
3JHH = 1.5, JHH = 10.2, JHP = 24.9), (1H, CHP), 4.05–
3
2
4.21 (m, 6H, 2 · CH2OP, CH2OC); 13C NMR (CDCl3)
3
4. Experimental
4.1. General
d = 13.64 and 13.68 (CH3CH2CO), 15.92 (d, JCP = 6.3)
3
and 15.96 (d, JCP = 6.1), (2 · CH3CH2OP), 19.22 and
2
19.43 (CH2), 29.60 (d, JCP = 3.3) and 29.80 (d,
2JCP = 4.4), (CH2), 32.00 and 33.93 (CH2), 37.00 and 37.58
1
1
NMR spectra were recorded on a Bruker DPX 250 instru-
(CH2), 41.62 (d, JCP = 126.6) and 41.84 (d, JCP = 126.9),
(CHP), 59.11 (d, JCP = 13.1) and 59.69 (d, JCP = 13.9),
(C), 61.24 and 61.30 (CH2OC), 62.82 (d, JCP = 6.6) and
63.00 (d, JCP = 6.6), (CH2OP), 63.13 (d, JCP = 6.6) and
1
3
3
ment at 250.13 MHz for H and 62.9 MHz for 13C and
101.3 MHz for 31P NMR, respectively, using tetramethyl-
silane as internal and 85% H3PO4 as external standard.
The multiplicities of carbons were determined by DEPT
experiments. IR spectra were measured on Specord M80
(Zeiss) instrument. Gas chromatographic analyses were
obtained on Hewlett–Packard 5890 II instrument equipped
with c-Dex 225 column. Elemental analyses were per-
formed on Perkin–Elmer PE 2400 analyzer. Melting points
were determined in open capillaries and are uncorrected.
Dicyclohexylammonium 2-(diethoxyphosphoryl)acrylate 1
was prepared according to the literature procedure.18
2
2
2
2
63.31 (d, JCP = 6.6), (CH2OP), 169.70 and 170.9
2
(COOCH2CH3), 170.6 (d, JCP = 5.1) and 171.0 (d,
2JCP = 5.1), (COOH), 213.7 and 214.4 (CO). Anal. Calcd
for C15H25O8P: C, 49.45; H, 6.92. Found: C, 49.53; H, 6.86.
4.2.3. 3-(3-Acetyl-2-oxo-tetrahydrofuran-3-yl)-2-(diethoxy-
phosphoryl)propanoic acid 16. (2.69 g, 80% yield); diaste-
reoisomer ratio 1:1; colorless oil; IR (film); 1759, 1696,
1245, 1150 cmꢀ1
;
31P NMR (CDCl3) d = 23.10, 23.00; H
1
3
NMR (CDCl3) d = 1.30 (t, 3H, JHH = 7.0, CH3CH2OP),
1.34 (t, 3H, JHH = 7.0, CH3CH2OP), 2.02–2.21 (m, 2H,
3
4.2. General procedure for the preparation of phospho-
alkanoic acids 4, 10, and 16
CH2), 2.32 (s, 3H, CH3), 2.40–3.00 (m, 3H, CH2, CHP),
4.08–4.38 (m, 6H, CH2O, 2 · CH2OP); 13C NMR (CDCl3)
d = 16.00 (d, 3JCP = 5.9, 2 · CH3CH2OP), 25.40 and 25.60
A mixture of acrylate 1 (3.89 g, 0.01 mol) and imine
(0.011 mol) in benzene (50 ml) was stirred at room temper-
ature for 48 h. After the reaction was completed (31P
NMR), the solvent was evaporated and the residue was
subjected to ion-exchange chromatography performed on
a glass column packed with Dowex 50W using H2O/ace-
tone, 1:1 as eluent. The eluent was evaporated to give the
acid as colorless oil.
2
(CH3), 28.51 and 29.72 (CH2), 29.91 (d, JCP = 3.0) and
2
1
30.93 (d, JCP = 3.2), (CH2CHP), 42.11 (d, JCP = 128.0)
and 42.64 (d, JCP = 129.0), (CHP), 60.52 (d, JCP = 14.7)
and 60.71 (d, JCP = 15.2), (C), 63.23 (d, JCP = 7.0) and
63.41 (d, JCP = 7.0), (CH2OP), 63.62 (d, JCP = 6.8) and
63.71 (d, 2JCP = 6.8), (CH2OP), 66.22 and 66.52 (CH2OC),
170.21 (d, 2JCP = 4.4) and 170.53 (d, 2JCP = 4.4), (COOH),
174.73 and 175.25 (COO), 201.62 and 202.13 (CO). Anal.
Calcd for C13H21O8P: C, 46.43; H, 6.29. Found: C, 46.38;
H, 6.37.
1
3
3
2
2
2
4.2.1.
2-(Diethoxyphosphoryl)-3-(1-methoxy-2-oxocyclo-
hexyl)propanoic acid 4. (2.69 g, 80% yield); diastereoiso-
mer ratio 1:1; colorless oil; IR (film) 1759, 1685, 1453,
1256 cmꢀ1
;
31P NMR (CDCl3): d = 24.48, 24.86; 1H
4.3. General procedure for the preparation of phosphono-
lactones 6, 12, and 18
3
NMR (CDCl3): d = 1.34 (t, 6H, JHH = 7.0, 2 ·
CH3CH2OP), 1.44–1.76 (m, 2H, CH2), 1.90–2.15 (m, 4H,
2 · CH2), 2.18–2.37 (m, 2H, CH2), 2.48–2.71 (m, 2H,
CH2), 3.02–3.20 (m, 1H, CHP), 3.11 (s) and 3.13 (s), (3H,
CH3), 4.21 (m, 2H, 2 · CH2OP); 13C NMR (CDCl3):
d = 15.75 (d, JCP = 6.1, 2 · CH3CH2OP), 20.14 and
20.50 (CH2), 26.94 and 27.30 (CH2), 28.22 (d, JCP = 4.1)
and 28.34 (d, JCP = 4.1), (CH2), 36.01 and 36.44 (CH2),
To a stirred solution of 4 (2.69 g, 0.008 mol) in methanol
(50 ml) was added KBH4 (0.86 g, 0.016 mol). Stirring was
continued for 24 h at room temperature. The resulting mix-
ture was neutralized to pH ꢁ3 with 5% HCl. The solvent
was evaporated and the residue diluted with water
(20 ml) and extracted with chloroform (3 · 20 ml). The
organic layer was dried over MgSO4 and evaporated. The
oily residue was dissolved in toluene (20 ml) and trifluoro-
acetic anhydride (1.68 g, 0.008 mol) added. The resulting
solution was stirred for 24 h at room temperature. The
solvent was evaporated and the residue was dissolved in
chloroform (50 ml), washed with saturated aq NaHCO3
solution (1 · 15 ml) and H2O (2 · 15 ml), dried over
MgSO4, and evaporated. The oily residue was purified by
column chromatography on silica gel using ethyl acetate/
hexane (3:1) as eluent to give pure lactone 6.
3
2
2
1
38.88 and 39.16 (CH2), 38.89 (d, JCP = 129.7) and
1
38.96 (d, JCP = 129.7), (CHP), 50.39 and 50.44 (CH3O),
2
2
62.76 (d, JCP = 5.8) and 62.85 (d, JCP = 5.8), (CH2OP),
2
2
63.12 (d, JCP = 5.9) and 63.20 (d, JCP = 5.9), (CH2OP),
3
3
81.44 (d, JCP = 13.1) and 81.55 (d, JCP = 13.5), (C),
170.20 (d, 2JCP = 5.0) and 170.68 (d, 2JCP = 5.0), (COOH),
211.04 and 211.57 (CO); Anal. Calcd for C14H25O7P: C,
50.00; H, 7.49. Found: C, 50.53; H, 7.38.
4.2.2. 2-(Diethoxyphosphoryl)-3-(1-(ethoxycarbonyl)-2-oxo-
cyclopentyl)propanoic acid 10. (3.13 g, 86% yield); diaste-
reoisomer ratio 1:1; colorless oil; IR (film) 1735, 1713,
4.3.1. Diethyl 4a-methoxy-2-oxo-octahydro-2H-chromen-3-
ylphosphonate 6. (1.79 g, 70% yield); diastereoisomer
ratio 1:1; colorless oil; IR (film); 1790, 1455, 1267,
1
1222 cmꢀ1
;
31P NMR (CDCl3) d = 23.63, 23.58; H NMR
3
3
(CDCl3) d = 1.23 (t, JHH = 7.1) and 1.24 (t, JHH = 6.9),

H. Krawczyk et al. / Tetrahedron: Asymmetry 17 (2006) 908–915
913
1194 cmꢀ1
;
31P NMR (CDCl3): d = 23.79, 23.66; 1H NMR
4.3.3.1. Diastereoisomer 18a-ul. 31P NMR (CDCl3): d
3
(CDCl3): d = 1.36 (t, 3H, 3JHH = 7.0, CH3CH2OP), 1.39 (t,
3H, 3JHH = 7.0, CH3CH2OP), 1.30–1.63 (m, 4H, 2 · CH2),
1.70–1.95 (m, 2H, CH2), 2.00–2.40 (m, 4H, 2 · CH2), 3.19
(s) and 3.25 (s), (3H, CH3O), 3.10–3.40 (m, 1H, CHP),
4.19–4.36 (m, 5H, 2 · CH2OP, CHO); 13C NMR (CDCl3):
21.00; 1H NMR (CDCl3): d = 1.34 (d, 3H, JHH = 6.5,
3
CH3), 1.37 (t, 6H, JHH = 7.2, 2 · CH3CH2OP), 2.00–2.33
(m, 2H, CH2), 2.47–2.65 (m, 2H, CH2), 3.32 (dt, 1H,
2
3JHP = 7.5, JHP = 28.2, CHP), 4.16–4.48 (m, 6H,
3
2 · CH2OP, CH2O), 4.76 (q, 1H, JHH = 6.5, CHO); 13C
3
3
3
d 15.99 (d, JCP = 5.0, CH3CH2OP), 16.09 (d, JCP = 5.0,
CH3CH2OP), 19.86 and 21.71 (CH2), 22.88 and 23.31
(CH2), 25.51 (d, JCP = 3.5) and 28.45 (d, JCP = 3.5),
(CH2CHP), 26.49 and 29.69 (CH2), 30.17 and 31.44
(CH2), 36,64 (d, JCP = 146.5) and 37.80 (d, JCP
145.0), (CHP), 48.09 and 48.33 (CH3O), 63.41 (d, JCP
NMR (CDCl3): d 15.72 (CH3), 15.82 (d, JCP = 3.5,
3
CH3CH2OP), 16.03 (d, JCP = 3.5, CH3CH2OP), 25.43
2
2
2
1
(CH2), 30.93 (d, JCP = 3.0, CH2), 37.15 (d, JCP = 137.4,
3
2
CHP), 45.62 (d, JCP = 8.2, C), 63.01 (d, JCP = 6.9,
CH2OP), 63.54 (d, JCP = 6.9, CH2OP), 65.42 (CH2O),
78.25 (CHO), 164.61 (d, JCP = 5.1, COO), 176.73 (COO).
1
1
2
=
=
2
2
2
5.5) and 63.52 (d, JC2P = 5.5), (CH2OP), 64.48 (d,
2JCP = 6.9) and 64.61 (d, JCP = 6.9), (CH2OP), 70.34 (d,
4.3.3.2. Diastereoisomer 18b-lk. 31P NMR (CDCl3): d
3JCP = 9.1) and 72.13 (d, JCP = 10.0), (C), 81.85 and
22.01; 1H NMR (CDCl3): d 1.36 (t, 6H, JHH = 7.0,
3
3
2
3
83.86 (CHO), 165.40 (d, JCP = 3.3) and 165.67 (d,
2 · CH3CH2OP); 1.44 (d, 3H, JHH = 6.5, CH3), 2.27–
2JCP = 3.3), (COO). Anal. Calcd for C14H25O6P: C,
2.45 (m, 4H, 2 · CH2), 3.60 (dt, 1H, JHP = 9.0,
3
52.49; H, 7.87. Found: C, 52.60; H, 7.79.
2JHP = 27.0, CHP), 4.10–4.46 (m, 6H, 2 · CH2OP,
3
CH2O), 4.67 (q, 1H, JHH = 6.5, CHO); 13C NMR
3
4.3.2. Ethyl 3-(diethoxyphosphoryl)-2-oxo-octahydrocyclo-
penta[b]pyran-4a-carboxylate 12. (1.95 g, 70% yield); dia-
(CDCl3): d 15.51 (d, JCP = 3.3, CH3CH2OP), 15.63
(d, 3JCP = 3.3, CH3CH2OP), 16.19 (CH3), 30.10
2
1
stereoisomer ratio 2:1; colorless oil; IR (film); 1731, 1247,
(d, JCP = 3.2, CH2), 31,03 (CH2), 37.12 (d, JCP = 137.0,
1142 cmꢀ1
;
31P NMR (CDCl3): d 20.91, 21.31; H NMR
CHP), 42.52 (d, JCP = 6.3, C), 62.11 (d, JCP = 6.8,
CH2OP), 63.14 (d, JCP = 6.8, CH2OP), 64.91 (CH2O),
78.85 (CHO), 164.21 (d, JCP = 6.3, COO), 176.01 (COO).
1
3
2
3
2
(CDCl3): d 1.29 (t, 3H, JHH = 7.2, CH3CH2OC), 1.32 (t,
3
2
3H, JHH = 6.8, 2 · CH3CH2OP, major), 1.36 (t, 3H,
3JHH = 7.1, 2 · CH3CH2OP, minor), 1.70–1.80 (m, 2H,
CH2), 1.85–2.00 (m, 2H, CH2), 2.03–2.10 (m, 3H, CHCH2P,
4.4. General procedure for the preparation of methylene-
lactones 7, 13, and 19
CH2), 2.75 (dt, 1H, JHP = 3JHH = 4.3, JHH = 14.0,
3
2
3
3
CHCH2P, major), 2.81 (ddd, 1H, JHP = 2.8, JHH = 7.5,
2JHH = 14.0, CHCHP, minor), 2.98 (ddd, 1H, JHH = 4.3,
To a stirred solution of a-phosphonolactone 6 (1.92 g,
0.0060 mol) in diethyl ether (50 ml), potassium tert-butox-
ide (0.74 g, 0.0066 mol) was added and the resulting mix-
ture stirred for 15 min at room temperature. Then satd
NaCl solution (20 ml) was added and the mixture extracted
with diethyl ether (3 · 10 ml). The organic layer was dried
over MgSO4 and evaporated. The oily residue was purified
by column chromatography on silica gel using ethyl ace-
tate/hexane (1:5) as eluent to give lactone 7.
3
3JHH = 13.6, JHP = 23.3, CHP, major), 3.09 (ddd, 1H,
2
3JHH = 5.8, JHH = 7.5, JHP = 25.5, CHP, minor), 4.10–
3
2
4.25 (m, 6H, 2 · CH2OP, CH2OC), 4.26–4.30 (m, 1H,
CHO, minor), 4.96 (t, 1H, JHH = 4.9, CHO, major); 13C
3
NMR (CDCl3): d 13.55 (CH3CH2OC, major), 13.62
3
(CH3CH2OC, minor), 16.03 (d, JCP = 4.7, 2 · CH3CH2-
3
OP, major), 16.12 (d, JCP = 4.7, 2 · CH3CH2OP, minor),
19.61 (CH2, minor), 22.51 (CH2, minor), 28.72 (d,
2JCP = 4.0, CH2CHP, major), 30.15 (d, JCP = 2.5,
2
CH2CHP, minor), 33,25 (CH2, major), 34.41 (CH2, minor),
36.42 (CH2, major), 36.74 (CH2, minor), 38.55 (d,
4.4.1. (4aR,8aR)- and (4aR,8aS)-4a-Methoxy-3-methylene-
octahydrochromen-2-one 7a and 7b. (0.88 g, 80% yield);
trans:cis ratio 3:2; IR (film); 3089, 1774, 1633, 1456,
1242 cmꢀ1. Anal. Calcd for C11H16O3: C, 67.32; H, 8.22.
Found: C, 67.24; H, 8.29.
1
1JCP = 151.2, CHP, major), 39.73 (d, JCP = 129.2, CHP,
3
minor), 50.05 (d, JCP = 7.8, C, minor), 51.81 (d,
3JCP = 13.2, C, major), 60.91 (CH2OC, minor), 61.32
2
(CH2OC, major), 62.51 (d, JCP = 7.0, CH2OP, major),
2
2
62.93 (d, JCP = 6.9, CH2OP, minor), 63.21 (d, JCP = 7.0,
4.4.1.1. Compound trans-7a. White crystals mp 118–
25
2
1
CH2OP, major), 63.83 (d, JCP = 6.9, CH2OP, minor),
120 ꢁC; ½aꢂD ¼ þ80:0 (c 0.65, MeOH); H NMR (CDCl3):
83.82 (CHO, minor), 85.02 (CHO, major), 166.93 (d,
2JCP = 3.8, COO, major), 165.91 (d, 2JCP = 3.8, COO, min-
or), 172.61 (COOCH2CH3, minor), 174.13 (COOCH2CH3,
major). Anal. Calcd for C15H25O7P: C, 51.72; H, 7.23.
Found: C, 51.59; H, 7.35.
d 1.07–1.57 (m, 4H, 2 · CH2), 1.80–2.06 (m, 4H,
4 2
2 · CH2), 2.37 (dt, JHH = 2.5, JHH = 16.5, CH–C@),
2
2.88 (d, JHH = 16.5, CH–C@), 3.13 (s, 3H, CH3O), 4.20
3
3
(dd, 1H, JHH = 5.0, JHH = 12.5, CHO), 5.56 (t, 1H,
2JHH = 4JHH = 2.5, @CH), 6.47 (t, 1H, 2JHH = 4JHH = 2.5,
@CH); 13C NMR (CDCl3): d 19.96 (CH2), 23.69 (CH2),
26.68 (CH2), 29.84 (CH2), 36.30 (CH2), 47.76 (CH3O),
71.31 (C), 83.71 (CHO), 128.79 (@CH2), 132.49 (C@),
165.11 (COO).
4.3.3. 6-Methyl-1,8-dioxo-2,7-dioxa-spiro[4.5]dec-9-yl-phos-
phonic acid diethyl ester 18a-ul and 18b-lk. (2.05 g, 80%
yield); diastereoisomer ratio 2:1; colorless oil; IR (film)
1795, 1776, 1267, 1190 cmꢀ1. Anal. Calcd for C13H21O7P:
C, 48.75; H, 6.61. Found: C, 48.65; H, 6.73.
25
4.4.1.2. Compound cis-7b. Colorless oil; ½aꢂD ¼ þ4:2 (c
1.12, MeOH); 1H NMR (CDCl3): d 1.02–1.35 (m, 2H,
CH2), 1.50–1.71 (m, 4H, CH2), 2.07–2.17 (m, 2H, CH2),
Lactones 18a-ul and 18b-lk were separated by column chro-
matography on silica gel using ethyl acetate/acetone (2:1)
as eluent.
4
2
2.60 (dt, 1H, JHH = 1.5, JHH = 15.0, CH–C@), 2.90 (dt,
4
2
1H, JHH = 2.5, JHH = 15.0, CH–C@), 3.23 (s, 3H,

914
H. Krawczyk et al. / Tetrahedron: Asymmetry 17 (2006) 908–915
3
3
3
2
CH3), 4.34 (dd, 1H, JHH = 2.5, JHH = 7.5, CHO), 6.45
CH–CH2O), 2.51 (dt, 1H, JHH = 7.8, JHH = 14.0, CH–
(dt, 1H, JHH = 4JHH = 2.5, JHH = 1.5, @CH), 6.58 (dt,
CH2O), 2.72 (dt, 1H, JHH = 1.0, JHH = 16.0, CH–C@),
2
4
4
2
1H, JHH = 4JHH = 2.5, JHH = 1.5, @CH); 13C NMR
(CDCl3): d 21.15 (CH2), 23.28 (CH2), 26.65 (CH2), 28.78
(CH2), 33.68 (CH2), 47.30 (CH3O), 70.89 (C), 80.86
(CHO), 128.15 (@CH2), 131.66 (C@), 164.40 (COO).
3.06 (dt, 1H, JHH = 2.6, JHH = 16.0, CH–C@), 4.40
3 3
2
4
4 2
(dd, 2H, JHH = 7.0, JHH = 7.8, CHO), 4.72 (q, 1H,
3JHH = 6.4, CHO), 5.74 (dt, 1H, JHH = 1.0, JHH
=
=
4
4
2JHH = 2.6, @CH), 6.61 (dt, 1H, JHH = 1.0, JHH
4
4
2JHH = 2.6, @CH); 13C NMR (CDCl3): d 16.29 (CH3),
25.98 (CH2), 37.54 (CH2), 46.19 (C), 65.51 (CH2O), 78.19
(CHO), 129.94 (C), 131.35 (@CH2), 163.73 (COO),
176.83 (COO). Anal. Calcd for C10H12O4: C, 61.22; H,
6.16. Found: C, 61.31; H, 6.13.
4.4.2. (4aS,7aS)- and (4aS,7aR)-Ethyl 3-methylene-2-oxo-
octahydrocyclopenta[b]pyran-4a-carboxylate 13a and 13b.
(0.84 g, 75% yield); trans:cis ratio 1:2; IR (film); 3080, 1722,
1623, 1232 cmꢀ1. Anal. Calcd for C13H18O4: C, 64.27; H,
7.19. Found: C, 64.03; H, 7.28.
4.5. X-ray single crystal structure analysis for 19b-lk
25
4.4.3. Compound trans-13a. Colorless oil; ½aꢂD ¼ ꢀ40:0 (c
0.28, MeOH); 1H NMR (CDCl3); d 1.23 (t, 3H, 3JHH = 7.2,
CH3CH2OC), 1.76–1.90 (m, 4H, 2 · CH2), 1.95–2.16 (m,
Formula: C10H12O4, Mw = 196.20, colorless crystal
0.40 · 0.10 · 0.05 mm, a = 6.3499(1), b = 6.6755(1), c =
4
2
3
q ,
calcd = 1.389 g cmꢀ3
˚
˚
2H, CH2), 2.51 (dt, 1H, JHH = 2.7, JHH = 16.5, CH),
22.1270(3) A, V = 937.94(2) A ,
4
2
3.17 (dt, 1H, JHH = 1.5, JHH = 16.5, CH), 4.16 (q, 2H,
l = 9.10 cmꢀ1, semi-empirical absorption correction based
on multiple scanned equivalent reflections19 (0.837 <
T < 0.973), Z = 4, crystal system: orthorhombic, space
3JHH = 7.2, CH2OC), 4.28 (dd, 1H, JHH = 7.2, JHH
=
3
3
2
4
11.0, CHO), 5.61 (dt, 1H, JHH = 4JHH = 1.5, JHH = 2.7,
CH), 6.52 (dt, 1H, JHH = 4JHH = 1.5, JHH = 2.7, CH);
13C NMR (CDCl3): d 13.68 (CH3CH2OC), 19.51 (CH2),
26.23 (CH2), 31.22 (CH2), 37.05 (CH2), 49.61 (C), 61.21
(CH2O), 83.41 (CHO), 128.36 (CH2), 133.25 (C), 166.29
(COO), 172.59 (COOCH2CH3).
group: P212121, k = 1.54178 A, T = 293 K, x scans,
2
4
˚
10,795 reflections collected ( h, k, l), 2hmax = 142ꢁ,
1794 unique reflections (Rint = 0.021) and 1763 observed
reflections [I P 2r(I)], 176 refined parameters, refinement
in F2, Rall = 0.029, wR(F2) = 0.072, max (min) residual
electron density Dqmax = 0.10Dqmin = ꢀ0.18 e Aꢀ3, Flack
˚
25
4.4.3.1. Compound cis-13b. Colorless oil; ½aꢂD ¼ ꢀ46:3
parameter20 with 712 Friedel pairs g = 0.01(17), all hydro-
gen atoms refined with individual isotropic temperature
factors. X-ray data were collected with Bruker SMART
APEX CCD area detector diffractometer. Computer pro-
grams used: data collection SMART APEX,21 data reduction
SAINT-PLUS,22 absorption correction SADABS,23 structure
solution, refinement, and molecular graphics SHELXTL.24
(c 0.82, MeOH); 1H NMR (CDCl3): d 1.27 (t, 3H,
3JHH = 7.0, CH3CH2OC), 1.63–1.80 (m, 3H, CH2, CH),
1.82–2.01 (m, 1H, CH), 2.10–2.24 (m, 2H, CH2), 2.65 (d,
2
2
1H, JHH = 14.7, CH), 3.02 (d, 1H, JHH = 14.7, CH),
3
4.19 (q, 2H, JHH = 7.1, CH2OC), 5.12 (dd, 1H,
3JHH = 4.5, JHH = 6.0, CHO), 5.57 (d, 1H, JHH = 1.5,
3
2
CH), 6.30 (d, 1H, JHH = 1.5, CH); 13C NMR (CDCl3): d
2
13.81 (CH3CH2OC), 21.61 (CH2), 33.55 (CH2), 34.95
(CH2), 51.36 (C), 61.21 (CH2OC), 85.07 (CHO), 127.64
(CH2), 131.96 (C), 165.56 (COO), 173.91 (COOCH2CH3).
Crystallographic data (excluding structure factors) for the
structure reported herein, have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication CCDC 294427. Copies of the data
can be obtained free of charge on application to The Direc-
tor, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK.
Any request should be accompanied by a full literature
citation.
4.4.4. (5R,6R)-6-Methyl-9-methylene-2,7-dioxa-spiro[4.5]-
decane-1,8-dione 19b-lk. (1.00 g, 85% yield); white crys-
25
tals mp 118–120 ꢁC; ½aꢂD ¼ 40:4 (c 0.48, MeOH); IR
(KBr); 3084, 1787, 1760, 1640, 1232 cmꢀ1
;
1H NMR
3
(CDCl3); d 1.53 (d, 3H, JHH = 7.0, CH3), 2.22 (dt, 1H,
2
3JHH = 8.4, JHH = 13.4, CH–CH2), 2.46 (ddd, 1H,
3
2
3JHH = 4.8, JHH = 7.4, JHH = 13.4, CH–CH2), 2.63 (dq,
References
4
2
1H, JHH = 1.0, JHH = 16.6, CH–C@), 3.17 (dt, 1H,
4JHH = 2.7, JHH = 16.6, CH–C@), 4.36 (ddd, 1H,
2
1. (a) Ross, G. Compendium of Chiral Auxiliary Applications;
Academic Press, 2002; pp 542–559; (b) d’Angelo, J.;
Desmae¨le, D.; Dumas, F.; Guingant, A. Tetrahedron: Asym-
metry 1992, 3, 459–505; (c) Christoffers, J. Chem. Eur. J. 2003,
9, 4862–4867.
3
2
3JHH = 7.4, JHH = 8.3, JHH = 15.5, CHO), 4.48 (ddd,
3
3
2
1H, JHH = 4.8, JHH = 8.4, JHH = 15.5, CHO), 4.56
4
3
(dq, 1H, JHH = 1.0, JHH = 7.0, CHO), 5.69 (dt, 1H,
4JHH = 1.0, JHH = 2JHH = 2.1, @CH), 6.57 (dt, 1H,
4
4JHH = 1.0, JHH = 2JHH = 2.1, @CH); 13C NMR
4
´
´
2. (a) Krawczyk, H.; Sliwinski, M.; Wolf, W. M.; Bodalski, R.
´
´
Synlett 2004, 1995–1999; (b) Krawczyk, H.; Sliwinski, M.;
Wolf, W. M. Acta Crystallogr. C 2004, 60, o897–o899.
3. (a) Lucero, M. J.; Houk, K. N. J. Am. Chem. Soc. 1997, 119,
826–827; (b) Tran Huu Dau, M. E.; Riche, C.; Dumas, F.;
d’Angelo, J. Tetrahedron: Asymmetry 1998, 9, 1059–
1064.
(CDCl3): d 17.16 (CH3), 32.51 (CH2), 34.43 (CH2),
44.60 (C), 64.75 (CH2O), 77.81 (CHO), 131.96 (@CH2,
C), 163.62 (COO), 175.63 (COO). Anal. Calcd for
C10H12O4: C, 61.22; H, 6.16. Found: C, 61.03; H, 6.33.
4.4.5. (5R,6S)-6-Methyl-9-methylene-2,7-dioxa-spiro[4.5]-
decane-1,8-dione 19a-ul. (1.01 g, 85% yield); colourless
4. (a) Giese, B.; Hoch, M.; Lamberth, C.; Schmidt, R. R.
Tetrahedron Lett. 1988, 29, 1375–1378; (b) Kast, J.;
Hoch, M.; Schmidt, R. R. Liebigs Ann. Chem. 1991, 481–
485; (c) Ramana, C. V.; Nagarajan, M. Synlett 1997, 763–
764; (d) Hamann, H. J.; Ho¨ft, E.; Mostowicz, D.; Mishnev,
25
oil; ½aꢂD ¼ ꢀ62:7 (c 0.69, MeOH); IR (KBr); 3084, 1787,
1
1760, 1640, 1232 cmꢀ1; H NMR (CDCl3); d 1.36 (d, 3H,
3
2
3JHH = 6.4, CH3), 2.02 (dt, 1H, JHH = 7.0, JHH = 14.0,

H. Krawczyk et al. / Tetrahedron: Asymmetry 17 (2006) 908–915
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