Self-catalytic Michael reaction of enolizable carbonyl compounds. A facile route to α-methylene-δ-valerolactones

Article abstract of DOI:10.1016/j.tet.2003.09.039

Various dicyclohexylammonium 2-phosphono-5-oxoalkanoates 3 were prepared by the Michael reaction of enolizable carbonyl compounds with the acrylate 1. The corresponding 2-phosphono-5-oxoalkanoic acids 4 were converted into α-phosphono-δ-valerolactones 6. The products were shown to be useful substrates for the synthesis of α-methylene-δ-valerolactones 7 by the Horner-Wadsworth-Emmons reaction.

Full text of DOI:10.1016/j.tet.2003.09.039

Tetrahedron 59 (2003) 9199–9211
Self-catalytic Michael reaction of enolizable carbonyl compounds.
A facile route to a-methylene-d-valerolactones
´
Henryk Krawczyk and Marcin Sliwinski
*
´
˙
´ ´
Institute of Organic Chemistry, Technical University (Politechnika), 90-924 L⁄ odz, Zeromskiego 116, Poland
Received 19 June 2003; revised 18 August 2003; accepted 11 September 2003
Abstract—Various dicyclohexylammonium 2-phosphono-5-oxoalkanoates 3 were prepared by the Michael reaction of enolizable carbonyl
compounds with the acrylate 1. The corresponding 2-phosphono-5-oxoalkanoic acids 4 were converted into a-phosphono-d-valerolactones
6. The products were shown to be useful substrates for the synthesis of a-methylene-d-valerolactones 7 by the Horner–Wadsworth–Emmons
reaction.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
Several approaches for the preparation of various
a-methylene-d-valerolactones have been reported.15–23
Recent literature has indicated an interest in the synthesis
of a-alkylidenelactones by means of Horner–Wadsworth–
Emmons (HWE) reaction of the corresponding a-phos-
phonolactones.24–28 Despite the synthetic significance of
a-phosphono-d-valerolactones only a few successful
methods for their synthesis are known. They can be made
by hydrogenation of a, b-unsaturated-a-phosphono-d-
lactones,29 by C-phosphorylation of d-valerolactones
through either of two Wiemer metodologies for C–P bond
formation26,30 and finally by the Wolf rearangement of
1-trimethylsililoxy-b-oxo-a-diazophosphonates derived
from g-lactones.31
The development of methods for the synthesis of
a-methylene-d-valerolactones is an important goal since
these motifs are found in compounds of biological intrest.
The presence of a-methylene-d-valerolactone unit is a
characteristic structural feature of several naturally occuring
terpenes such as vernolepin,1 vernomenin,1 pentaleno-
lactone E,2 teucriumlactone,3 artemisitene,4–6 crassin7,8
and crassin acetate7,8 noted for their cytotoxicity. They were
shown to possess significant pharmacological activities
ranging from simple antibiotic activity to antitumor
properties.
a-Methylene-d-valerolactones are also atractive precursors
for a whole series of a-saturated d-valerolactones. Michael
additions of various C-, N- and S-nucleophiles to
a-methylene-d-valerolactone moiety of artimisitene have
been used successfully in the synthesis of a-substituted
d-valerolactones possessing antimalarial activity.4 – 6
Reduction of methylene group of teucriumlactone has
been employed as a key step in the total synthesis of iridoid
lactones.9 Sugar derived a-methylene-d-valerolactones
have proven useful in the synthesis of methylene bridged
disacharides.10 Moreover, the synthetic utility of a-methyl-
ene-d-valerolactones have been demonstrated in other C–C
bond forming transformations such as Diels–Alder
reaction,11 1,3-Michael–Claisen annulation12,13 and
Michael addition.14
Recently, we have found that the Michael additions of
various C and N-nucleophiles to dicyclohexylammonium
2-(diethoxyphosphoryl) acrylate 1 proceed without any
external catalyst.32–36 Our preliminary studies have also
revealed that this self-catalytic reaction performed with
enolizable carbonyl compounds 2a, 2b, 2e provides a direct
route to 2-diethoxyphosphoryl-5-oxoalkanoic acids 4a, 4b,
4e32 (Scheme 1). It became clear that acids of this type are
particularly well suited for further transformation into the
corresponding a-phosphono-d-valerolactones. In this con-
text it was felt that another carbonyl compounds that could
serve as pronucleophiles would increase the scope of the
already performed additions.
In this paper we report that a variety of enolizable carbonyl
compounds are easily converted into 2-diethoxyphosphoryl-
5-oxoalkanoic acids by the Michael reaction with the
acrylate 1. Importantly, we demonstrate that this strategi-
cally new approach provides a powerful tool for the
synthesis of a-phosphono-d-valerolactones. Transformation
Keywords: Michael reaction; 5-oxoalkanoic acids; a-phosphonolactones;
a-methylene-d-valerolactones.
*
Corresponding author. Fax: þ48-42-6365530;
e-mail: henkrawc@p.lodz.pl
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.039

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9200
Scheme 1. Conditions: (a) 2a-c, benzene, 508C. 30 h; (b) 2e-f, ketone, 508C, 70 h; (c) 2d, 2g–k, benzene, rt, 36–48 h; (d) Dowex 50W, H2O/acetone.
of a-phosphono-d-valerolactones into the corresponding
a-methylene-d-valerolactones is also reported.
markedly dependent on the nature of the a-substituent of
the Michael donor. 2-Phenylpropanal 2d reacted with the
acrylate 1 at room temperature yielding within 3 days the
adduct 3d as a 2:1 mixture of diastereoisomers in 70% yield.
2. Results and discussion
Both procedures were not applicable to the conversion of
ketones into the corresponding 5-oxoalkanoates. After
screening a variety of reaction conditions it was found
that considerable excess of ketone had to be used to perform
effectively the desired reaction. The reaction of cyclo-
hexanone 2f used as both the reagent and solvent with 1
performed at 508C for 70 h resulted in the formation of the
adduct 3f as a mixture of diastereoisomers in a 1:1 ratio in
68% yield. This result is consistent with that previously
described for acetone.
In the course of our earlier studies the Michael adducts 3a,
3b and 3e were prepared from a-substituted aldehydes 2a,
2b and acetone 2e, respectively.32 The procedure described
for the synthesis of the alkanoates 3a and 3b consisted in
heating a mixture of reagents used in equimolar amounts in
benzene at 508C for 30 h. By using the same method the
reaction of 2-methylpentanal 2c with the acrylate 1 gave a
1:1 mixture of the diastereoisomeric adducts 3c in 67%
yield. Surprisingly, we found that the rate of addition was
Scheme 2. Conditions: (a) EtOH, KOH (1 equiv.), KBH4 (1 equiv.), rt, 24 h; (b) p-TSA (cat.), benzene, reflux 4 h; (c) 36% formaldehyde (5 equiv.), K2CO3
(2 equiv.), 0–58C, 30 min.

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H. Krawczyk, M. Sliwinski / Tetrahedron 59 (2003) 9199–9211
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Table 1. Phosponolactones 6a–k and methylenelactones 7a–k prepared
To demonstrate further the usefulness of our approach we
decided to study preparation of dicyclohexylammonium
2-diethoxyphosphoryl-5-oxoalkanoates from a series of
a-unsubstituted aldehydes 2g–2j. It was found that
reactions of 1 with equimolar amount of propanal 2g,
butanal 2h, hexanal 2i and 3-phenylpropanal 2j proceeded
readily in benzene at room temperature and were completed
within 36 h yielding the corresponding adducts 3g–3j in
69–75% yield. The 1,4-additions leading to 3g–3j proved
to be not diastereoselective. In fact, the diastereoisomeric
ratio in all four examples was invariably 1:1.
hexanone 2k to the acrylate 1. The adduct 3k was obtained
as a 1:1 mixture of diastereoisomers in 85% yield.
The dicyclohexylammonium 5-oxoalkanoates 3a–3k were
then converted into the corresponding 5-oxoalkanoic acids
4a–4k by ion-exchange chromatography in nearly
quantitative yields.
With the suitable substrates in hand we turned our attention
to their effective conversion into a-methylene-d-valero-
lactones (Scheme 2). The chemoselective reduction of
carbonyl group of the oxoacids 4a–4k by potassium
borohydride afforded the expected 2-diethoxyphosphoryl-
5-hydroxyalkanoic acids 5a–5k accompanied by the
Finally, the methodology presented above could be applied
to the conjugate addition of 2-ethoxycarbonylcyclo-

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9202
corresponding a-phosphono-d-valerolactones 6a–6k (31P
NMR). The hydroxyalkanoic acids 5a–5k were completly
converted into the lactones 6a–6k by simple heating of the
obtained mixtures in benzene in the presence of a catalytic
amount of p-toluenesulfonic acid.
to the literature procedure.32 Analytical data of the salts 3a,
3b, 3e and the corresponding acids 4a, 4b, 4e have not been
previously reported.32
4.2. Synthesis of dicyclohexylammonium alkanoates
3a–k
The a-phosphono-d-valerolactones 6c, 6d and 6f–6k were
formed as mixtures of diastereoisomers. Their ratios were
determined by 31P NMR or 1H NMR (6j) and are shown in
Table 1. All attempts to separate the diastereoisomers by
column chromatography were unsuccessful. The spectro-
scopic data of diastereoisomeric mixtures did not allow us to
assign the relative configuration to particular stereoisomers.
In any case relative configuration of the diastereoisomeric
products was of no importance since they were to be
converted into a-methylene-d-valerolactones.
In a typical experimental procedure to a solution of
phosphonate 1 (3.89 g, 0.01 mol) in dry benzene (30 ml) 2
(0.01 mol) was added and the mixture was stirred at the
given temperature until completion of the reaction was
confirmed by 31P NMR. After the reaction was completed
the solvent was evaporated and the solid residue was
suspended in hexane and collected by filtration. The crude
solid was crystallized from acetone or acetone/methylene
chloride to give 3.
Then, our efforts were focused on the HWE reaction of the
phosphonolactones 6a–6k. The use of aqueous potassium
carbonate to promote the HWE olefination of various
a-phosphonoalkanoates with formaldehyde is well
documented.24,27,28 By employing this method phosphono-
lactones 6a–6k were converted into the corresponding
a-methylene-d-valerolactones 7a–7k in good yields. The
HWE reaction of 6f gave the methylene lactone 7f as a
mixture of trans and cis stereoisomers in a 3:1 ratio. They
4.2.1. Dicyclohexylammonium 2-(diethoxyphosphoryl)-
4,4-dimethyl-5-oxopentanoate (3a). (3.31 g, 72% yield);
white crystals, mp 151–1538C; IR (KBr) 2928, 1728, 1601,
1240 cm21
;
31P NMR (CDCl3) d¼28.76; 1H NMR (CDCl3)
d¼1.07 (s, 3H, CH3), 1.08 (s, 3H, CH3), 1.21–1.32 (m, 6H,
3
3£CH2), 1.30 (t, 3H, JHH¼7.0 Hz, CH3CH2OP), 1.31 (t,
3
3H, JHH¼7.0 Hz, CH3CH2OP), 1.47–1.55 (m, 4H,
2£CH2), 1.61–1.65 (m, 2H, CH2), 1.77–1.82 (m, 4H,
2£CH2), 1.95–2.02 (m, 5H, 2£CH2, CHCHP), 2.43 (ddd,
1
3
3
2
could be easily separated by column chromatography. H
1H, JHP¼4.5 Hz, JHH¼9.7 Hz, JHH¼14.5 Hz, CHCHP),
3
2
NMR spectra of the both stereoisomers were in agreement
with the data reported in the literature.17 The HWE reaction
of 6k provided chromatographically separable trans and cis
stereoisomeric 7k in a 2:1 ratio. The configurational
2.75 (ddd, 1H, JHH¼1.7, 9.7 Hz, JHP¼24.5 Hz, CHP),
3.00 (m, 2H, 2£CHN), 4.01–4.20 (m, 4H, 2£CH2OP), 9.42
(s, 1H, CHO); 13C NMR (CDCl3) d¼16.45 (d, 3JCP¼6.1 Hz,
2£CH3CH2OP), 20.46 (CH3), 22.12 (CH3), 24.91 (4£CH2),
1
2
assignments of these diastereoisomers were based on H
NMR chemical shifts and coupling constants of the protons
at the lactone ring junction.17,37
25.17 (2£CH2), 28.90 (4£CH2), 35.01 (d, JCP¼4.1 Hz,
1
CH2CHP), 44.60 (d, JCP¼124.6 Hz, CHP), 46.12 (d,
3JCP¼15.8 Hz, C), 52.38 (2£CHN), 61.83 (d, JCP
¼
2
2
6.5 Hz, 2£CH2OP), 171.70 (d, JCP¼5.1 Hz, COO),
204.91 (CHO); FAB/MS MHþ 462. Anal. calcd for
C23H44NO6P: C, 59.85; H, 9.61; N, 3.03. Found: C, 59.98;
H, 9.52; N, 3.14.
3. Conclusions
In summary, we have succeeded in developing the efficient
three-step synthesis of a-phosphono-d-valerolactones from
easily available dicyclohexylammonium 2-(diethoxy-
phosphoryl) acrylate. The HWE olefination of the a-phos-
phono-d-valerolactones with formaldehyde allowed the
facile preparation of a-methylene-d-valerolactones.
4.2.2. Dicyclohexylammonium 2-(diethoxyphosphoryl)-
3-(1-formyl-cyclohexyl)-propionate (3b). (3.75 g, 75%
yield); white crystals, mp 141–1438C; IR (KBr) 2936,
1728, 1636, 1240 cm21
1
;
31P NMR (CDCl3) d¼28.97, H
3
NMR (CDCl3) d¼1.28 (t, 3H, JHH¼7.0 Hz, CH3CH2OP),
3
1.30 (t, 3H, JHH¼7.0 Hz, CH3CH2OP), 1.25–1.53 (m,
20H, 10£CH2), 1.61–2.03 (m, 11H, 5£CH2, CHCHP), 2.38
3
3
2
(ddd, 1H, JHP¼3.7 Hz, JHH¼10.2 Hz, JHH¼14.5 Hz,
4. Experimental
4.1. General
3
2
CHCHP), 2.70 (ddd, 1H, JHH¼1.5, 10.2 Hz, JHP
¼
24.5 Hz, CHP), 2.97–3.06 (m, 2H, 2£CHN), 3.99–4.23
(m, 4H, 2£CH2OP), 9.44 (s, 1H, CHO); 13C NMR (CDCl3)
3
d¼16.45 (d, JCP¼6.3 Hz, 2£CH3CH2OP), 22.51 (CH2),
NMR spectra were recorded on a Bruker DPX 250
1
instrument at 250.13 MHz for H and 62.9 MHz for 13C
22.62 (CH2), 24.90 (4£CH2), 25.22 (2£CH2), 25.77 (CH2),
and 101.3 MHz for 31P NMR, respectively, using tetra-
methylsilane as internal and 85% H3PO4 as external
standard. The multiplicity of carbons were determined by
DEPT experiments. IR spectra were measured on a Specord
M80 (Zeiss) instrument. FAB/MS were recorded on a PO
Electron Modell MI 1202 E mass spectrometer equipped
with FAB ion source (thioglycerol matrix). Elemental
analyses were performed on a Perkin–Elmer PE 2400
analyzer. Melting points were determined in open
capillaries and are uncorrected. Dicyclohexylammonium
2-(diethoxyphosphoryl) acrylate 1 was prepared according
28.92 (4£CH2), 30.61 (CH2), 30.92 (CH2), 34.07 (d,
2JCP¼4.7 Hz, CH2CHP), 43.76 (d, JCP¼124.2 Hz, CHP),
1
3
49.86 (d, JCP¼14.6 Hz, C), 52.33 (2£CHN), 61.70 (d,
2JCP¼6.5 Hz, 2£CH2OP), 171.74 (d, JCP¼4.7 Hz, COO),
2
205.61 (CHO); FAB/MS MHþ 502. Anal. calcd for
C26H48NO6P: C, 62.25; H, 9.64; N, 2.79. Found: C, 62.37;
H, 9.78; N, 2.68.
4.2.3. Dicyclohexylammonium 2-(diethoxyphosphoryl)-
4-formyl-4-methyl-heptanoate (3c). (3.28 g, 67% yield);
diasteroisomer ratio 1:1; white solid, mp 84–868C; IR

´
H. Krawczyk, M. Sliwinski / Tetrahedron 59 (2003) 9199–9211
´
9203
(KBr) 2936, 1724, 1632, 1244 cm21
;
31P NMR (CDCl3)
CH3CH2OP), 1.22–1.31 (m, 6H, 3£CH2), 1.41–1.52 (m,
2H, 2£CH2), 1.55–1.66 (m, 4H, 2£CH2), 1.71–1.86 (m,
4H, 2£CH2), 2.11 (s, 3H, CH3), 1.99–2.21 (m, 6H, 3£CH2),
1
3
d¼28.80, 29.02; H NMR (CDCl3) d¼0.85 (t, 3H, JHH
¼
7.2 Hz, CH3), 1.02 (s, 3H, CH3, dia A), 1.04 (s, 3H, CH3, dia
B), 1.18–1.38 (m, 8H, 4£CH2), 1.30 (t, 3H, JHH¼7.0 Hz,
3
3
2.48–2.71 (m, 2H, CH2), 2.74 (ddd, JHH¼4.7, 10.0 Hz,
3
CH3CH2OP), 1.31 (t, 3H, JHH¼7.0 Hz, CH3CH2OP),
2JHP¼21.7 Hz, CHP), 2.91–3.03 (m, 2H, 2£CHN), 4.02–
1.40–1.62 (m, 6H, 3£CH2), 1.60–1.65 (m, 2H, CH2),
4.21 (m, 4H, 2£CH2OP); 13C NMR (CDCl3) d¼16.15 (d,
3
1.75–1.79 (m, 5H, 2£CH2, CHCHP), 1.85–1.92 (m, 4H,
3JCP¼6.2 Hz, CH3CH2OP), 16.21 (d, JCP¼6.2 Hz, CH3-
3
3
2
2£CH2), 2.33 (ddd, 1H, JHP¼3.7 Hz, JHH¼10.5 Hz,
CH2OP), 22.15 (d, JCP¼4.3 Hz, CH2), 24.61 (4£CH2),
2JHH¼13.7 Hz, CHCHP, dia A), 2.42 (ddd, 1H, JHP
¼
25.01 (2£CH2), 28.81 (4£CH2), 29.60 (CH3), 42.26 (d,
3JCP¼15.0 Hz, CH2CHP), 47.21 (d, 1JCP¼127.6 Hz, CHP),
52.23 (2£CHN), 61.51 (d, 2JCP¼6.7 Hz, CH2OP), 61.65 (d,
3
3
2
3.7 Hz, JHH¼10.5 Hz, JHH¼13.7 Hz, CHCHP, dia B),
2.65 (ddd, 1H, 3JHH¼1.5 Hz, 10.5 Hz, 2JHP¼25.2 Hz, CHP,
3
2
2
dia A), 2.78 (ddd, 1H, JHH¼1.5 Hz, 10.5 Hz, JHP
¼
2JCP¼6.7 Hz, CH2OP), 171.52 (d, JCP¼3.8 Hz, COO),
25.2 Hz, CHP, dia B), 2.91–3.07 (m, 2H, 2£CHN), 4.07–
4.17 (m, 4H, 2£CH2OP), 9.43 (s, 1H, CHO, dia A), 9.44 (s,
1H, CHO, dia B); 13C NMR (CDCl3) d¼14.99 (CH3), 16.71
(d, 3JCP¼6.2 Hz, 2£CH3CH2OP), 17.10 (CH3, dia A), 17.44
(CH2, dia A), 17.52 (CH2, dia B), 18.41 (CH3, dia B), 25.15
(4£CH2), 25.43 (2£CH2), 29.29 (4£CH2), 32.91 (d,
207.9 (CO); FAB/MS MHþ 448. Anal. calcd for
C22H42NO6P: C, 59.04; H, 9.46; N, 3.13. Found: C, 59.16;
H, 9.32; N, 3.23.
4.2.6. Dicyclohexylammonium 2-(diethoxyphosphoryl)-
3-(2-oxocyclohexyl)-propionate (3f). (3.26 g, 69% yield);
diasteroisomer ratio 1:1; white crystals, mp 130–1328C; IR
2JCP¼4.9 Hz, CH2CHP, dia A), 33.84 (d, JCP¼4.9 Hz,
2
CH2CHP, dia B), 37.31 (CH2, dia A), 39.20 (CH2, dia B),
44.42 (d, JCP¼125.0 Hz, CHP, dia A), 44.71 (d, JCP
(KBr) 2936, 1712, 1632, 1242 cm21 31P NMR (CDCl3)
;
1
1
¼
d¼28.30, 28.91; 1H NMR (CDCl3) d¼1.29 (t, 3H,
3
3
125.0 Hz, CHP, dia B), 49.72 (d, JCP¼14.8 Hz, C, dia A),
3JHH¼7.0 Hz, CH3CH2OP), 1.32 (t, 3H, JHH¼7.0 Hz,
3
49.91 (d, JCP¼14.8 Hz, C, dia B), 52.84 (2£CHN), 62.21
CH3CH2OP), 1.14–1.31 (m, 8H, 4£CH2), 1.40–1.51 (m,
4H, 2£CH2), 1.61–1.73 (m, 4H, 2£CH2), 1.75–1.81 (m,
5H, 2£CH2, CH), 1.96–2.13 (m, 6H, 3£CH2), 2.21–2.52
(m, 4H, 2£CH2), 2.81–3.10 (m, 3H, 2£CHN, CHP), 4.01–
4.25 (m, 4H, 2£CH2OP); 13C NMR (CDCl3) d¼16.41 (d,
3JCP¼6.1 Hz, 2£CH3CH2OP), 24.91 (4£CH2), 25.05 (CH2,
dia A), 25.29 (CH2, dia B), 25.32 (2£CH2), 27.41 (d,
2JCP¼3.8 Hz, CH2CHP, dia A), 27.91 (CH2, dia A), 28.33
2
2
(d, JCP¼6.5 Hz, 2£CH2OP), 172.10 (d, JCP¼4.4 Hz,
2
COO, dia A), 172.30 (d, JCP¼4.4 Hz, COO, dia B),
205.01 (CHO, dia A), 205.99 (CHO, dia B); FAB/MS MHþ
490. Anal. calcd for C25H48NO6P: C, 61.33; H, 9.88; N,
2.86. Found: C, 61.19; H, 9.98; N, 2.99.
4.2.4. Dicyclohexylammonium 2-(diethoxyphosphoryl)-
4-methyl-5-oxo-4-phenyl-pentanoate (3d). (3.66 g, 70%
yield); diasteroisomer ratio 2:1; white crystals, mp 122–
2
(d, JCP¼3.8 Hz, CH2CHP, dia B), 28.40 (CH2, dia B),
29.10 (4£CH2), 32.90 (CH2, dia A), 35.31 (CH2, dia B),
1268C; IR (KBr) 3018, 2936, 1727, 1632, 1244 cm21 31P
;
42.20 (CH2, dia A), 42.55 (CH2, dia B), 45.30 (d,
1
1
NMR (CDCl3) d¼28.50, 28.62; H NMR (CDCl3) d¼1.31
1JCP¼125.2 Hz, CHP, dia A), 46.14 (d, JCP¼125.2 Hz,
3
3
(t, 3H, JHH¼7.2 Hz, CH3CH2OP), 1.33 (t, 3H, JHH
¼
CHP, dia B), 49.02 (d, 3JCP¼15.0 Hz, CH, dia A), 49.61 (d,
7.2 Hz, CH3CH2OP), 1.18–1.37 (m, 6H, 3£CH2), 1.44 (s,
3H, CH3, minor), 1.49 (s, 3H, CH3, major), 1.41–1.56 (m,
4H, 2£CH2), 1.62–1.73 (m, 2H, CH2), 1.75–1.80 (m, 4H,
2£CH2), 1.90–2.04 (m, 4H, 2£CH2), 2.37–2.87 (m, 3H,
CH2, CHP), 2.92–3.05 (m, 2H, 2£CHN), 3.86–4.17 (m,
4H, 2£CH2OP), 7.20–7.42 (m, 5H, C6H5), 9.43 (s, 1H,
CHO, major), 9.51 (s, 1H, CHO, minor); 13C NMR (CDCl3)
3JCP¼15.5 Hz, CH, dia B), 52.51 (2£CHN), 61.72 (d,
2
2JCP¼6.1 Hz, CH2OP), 61.91 (d, JCP¼6.1 Hz, CH2OP),
2
171.93 (d, JCP¼4.4 Hz, COO, dia A), 172.20 (d,
2JCP¼4.4 Hz, COO, dia B) 212.41 (CO, dia A), 212.91
(CO, dia B); FAB/MS MHþ 488. Anal. calcd for
C25H46NO6P: C, 61.58; H, 9.51; N, 2.87. Found: C, 61.69;
H, 9.65; N, 2.73.
3
d¼16.21 (d, JCP¼5.9 Hz, 2£CH3CH2OP), 17.43 (CH3,
major), 20.90 (CH3, minor), 24.64 (4£CH2), 24.96
4.2.7. Dicyclohexylammonium 2-(diethoxyphosphoryl)-
4-methyl-5-oxopentanoate (3g). (3.09 g, 69% yield);
diasteroisomer ratio 1:1; white crystals, mp 100–1028C;
2
(2£CH2), 28.67 (4£CH2), 33.27 (d, JCP¼3.1 Hz,
2
CH2CHP, major), 33.40 (d, JCP¼3.1 Hz, CH2CHP,
1
minor), 43.80 (d, JCP¼124.5 Hz, CHP, major), 44.61 (d,
IR (KBr) 2936, 1728, 1604, 1240 cm21 31P NMR (CDCl3)
;
1JCP¼124.5 Hz, CHP, minor), 52.18 (2£CHN), 54.15 (d,
d¼28.15, 28.32; 1H NMR (CDCl3) d¼1.12 (d, 3H,
3JCP¼16.0 Hz, C, major), 54.40 (d, JCP¼14.4 Hz, C,
3JHH¼6.7 Hz, CH3, dia A), 1.14 (d, 3H, JHH¼6.7 Hz,
3
3
2
3
minor), 61.56 (d, JCP¼6.3 Hz, CH2OP), 61.70 (d,
CH3, dia B), 1.30 (t, 3H, JHH¼7.0 Hz, CH3CH2OP), 1.31
2JCP¼6.3 Hz, CH2OP), 127.01 (CH, major), 127.16 (CH,
(t, 3H, JHH¼7.0 Hz, CH3CH2OP), 1.18–1.21 (m, 6H,
3
minor), 127.4 (4£CH, minor), 128.70 (4£CH, major),
3£CH2), 1.34–1.55 (m, 4H, 2£CH2), 1.63–1.70 (m, 3H,
CH2, CH), 1.75–1.81 (m, 4H, 2£CH2), 1.98–2.06 (m, 4H,
4£CH2), 2.42–2.56 (m, 2H, CH2), 2.83–3.05 (m, 3H, CHP,
2£CHN), 4.07 (m, 4H, 2£CH2OP), 9.61 (s, 1H, CHO, dia
A), 9.65 (s, 1H, CHO, dia B); 13C NMR (CDCl3) d¼12.61
2
139.34 (C, major), 140.61 (C, minor), 171.71 (d, JCP
¼
2
6.3 Hz, COO, minor), 171.82 (d, JCP¼6.3 Hz, COO,
major), 200.81 (CHO, major), 202.05 (CHO, minor);
FAB/MS MHþ 524. Anal. calcd for C28H46NO6P: C,
64.22; H, 8.87; N, 2.67. Found: C, 64.36; H, 8.99; N, 2.54.
3
(CH3, dia A), 13.62 (CH3, dia B), 16.10 (d, JCP¼6.1 Hz,
2£CH3CH2OP), 24.55 (4£CH2), 24.92 (2£CH2), 28.42 (d,
4.2.5. Dicyclohexylammonium 2-(diethoxyphosphoryl)-
5-oxohexanoate (3e). (3.14 g, 70% yield); white powder,
2JCP¼4.8 Hz, CH2CHP, dia A), 28.61 (4£CH2), 28.81 (d,
3
2JCP¼4.8 Hz, CH2CHP, dia B), 45.15 (d, JCP¼12.2 Hz,
mp 126–1288C; IR (KBr) 2950, 1716, 1635 1240 cm21
;
31P
CH, dia A), 45.22 (d, JCP¼11.6 Hz, CH, dia B), 45.62 (d,
3
1
1
NMR (CDCl3) d¼28.21; H NMR (CDCl3) d¼1.27 (t, 6H,
1JCP¼126.5 Hz, CHP, dia A), 45.73 (d, JCP¼126.5 Hz,
3JHH¼7.0 Hz, CH3CH2OP), 1.28 (t, 6H, JHH¼7.0 Hz,
CHP, dia B), 52.13 (2£CHN), 61.53 (d, JCP¼6.1 Hz,
3
2

´
´
H. Krawczyk, M. Sliwinski / Tetrahedron 59 (2003) 9199–9211
9204
2
3
CH2OP), 62.41 (d, JCP¼6.1 Hz, CH2OP), 171.05 (d,
1H NMR (CDCl3) d¼1.27 (t, 3H, JHH¼7.0 Hz, CH3CH2-
2JCP¼3.8 Hz, COO, dia A), 171.30 (d, JCP¼3.8 Hz,
OP), 1.29 (t, 3H, 3JHH¼7.0 Hz, CH3CH2OP), 1.17–1.26 (m,
6H, 3£CH2), 1.41–1.60 (m, 6H, 3£CH2), 1.74–1.87 (m,
6H, 3£CH2), 1.98–2.52 (m, 4H, 2£CH2), 2.75–3.03 (m,
6H, CH, CHP, CH2C6H5, 2£CHN), 4.03–4.16 (m, 4H,
2£CH2OP), 7.05–7.41 (m, 5H, C6H5), 9.61 (s, 1H, CHO,
dia A), 9.64 (s, 1H, CHO, dia B); 13C NMR (CDCl3)
d¼16.31 (d, 3JCP¼6.1 Hz, 2£CH3CH2OP), 24.60 (4£CH2),
2
COO, dia B), 204.02 (CHO, dia A), 204.13 (CHO, dia B);
FAB/MS MHþ 448. Anal. calcd for C22H42NO6P: C, 59.04;
H, 9.46; N, 3.13. Found: C, 59.18; H, 9.61; N, 3.27.
4.2.8. Dicyclohexylammonium 2-(diethoxyphosphoryl)-
4-formyl-hexanoate (3h). (3.23 g, 70% yield); diastero-
isomer ratio 1:1; white crystals, mp 111–1138C; IR (KBr)
2
25.01 (2£CH2), 26.83 (d, JCP¼3.8 Hz, CH2CHP, dia A),
2936, 1728, 1636, 1246 cm21
;
31P NMR (CDCl3) d¼28.02,
27.41 (d, JCP¼3.8 Hz, CH2CHP, dia B), 28.98 (4£CH2),
2
28.32; 1H NMR (CDCl3) d¼0.91 (t, 3H, 3JHH¼7.2 Hz, CH3,
dia A), 0.94 (t, 3H, 3JHH¼7.5 Hz, CH3, dia B), 1.30 (t, 3H,
34.15 (CH2, dia A), 35.75 (CH2, dia B), 45.65 (d,
1JCP¼127.0 Hz, CHP, dia A), 46.12 (d, JCP¼127.0 Hz,
1
3JHH¼7.0 Hz, CH3CH2OP), 1.31 (t, 3H, JHH¼7.0 Hz,
CHP, dia B), 51.80 (d, 3JCP¼15.4 Hz, CH, dia A), 52.30 (d,
3JCP¼14.5 Hz, CH, dia B), 52.51 (2£CHN), 61.80 (d,
2JCP¼6.4 Hz, 2£CH2OP), 126.21 (CH), 128.32 (2£CH),
128.72 (CH), 129.01 (CH), 138.32 (C, dia A), 138.51 (C, dia
3
CH3CH2OP), 1.21–1.27 (m, 6H, 3£CH2), 1.41–1.54 (m,
6H, 3£CH2), 1.59–1.70 (m, 2H, CH2), 1.81–1.86 (m, 5H,
CH, 2£CH2), 1.99–2.03 (m, 4H, 2£CH2), 2.09–2.41 (m,
2H, CH2), 2.80–3.01 (m, 3H, CH2, CHP), 4.08–4.12 (m,
4H, 2£CH2OP), 9.62 (s, 1H, CHO, dia A), 9.67 (s, 1H,
CHO, dia B); 13C NMR (CDCl3) d¼10.99 (CH3, dia A),
11.26 (CH3, dia B), 16.26 (d, 3JCP¼6.1 Hz, 2£CH3CH2OP),
21.20 (CH2, dia A), 22.30 (CH2, dia B), 24.65 (4£CH2),
2
B), 171.42 (d, JCP¼3.1 Hz, COO, dia A), 171.53 (d,
2JCP¼3.1 Hz, COO, dia B), 203.63 (CHO, dia A), 204.05
(CHO, dia B); FAB/MS MHþ 524.
4.2.11. Dicyclohexylammonium 2-(diethoxyphosphoryl)-
3-(1-ethoxycarbonyl-2-oxocyclohexyl) propionate (3k).
(4.75 g, 85% yield); diasteroisomer ratio 2:1; white crystals,
2
25.03 (2£CH2), 26.45 (d, JCP¼3.0 Hz, CH2CHP, dia A),
2
26.80 (d, JCP¼3.0 Hz, CH2CHP, dia B), 28.75 (4£CH2),
1
45.87 (d, JCP¼126.7 Hz, CHP, dia A), 45.97 (d,
mp 117–1208C; IR (KBr) 2936, 1720, 1712, 1632,
1248 cm21
1JCP¼126.7 Hz, CHP, dia B), 51.90 (d, JCP¼13.7 Hz,
;
31P NMR d¼28.53, 28.61; H NMR d¼1.23
3
1
3
CH, dia A), 52.20 (2£CHN), 52.41 (d, JCP¼11.7 Hz, CH,
(t, 3H, 3JHH¼7.2 Hz, CH3CH2O), 1.33 (t, 3H, 3JHH¼7.0 Hz,
2
3
dia B), 61.65 (d, JCP¼6.7 Hz, CH2OP), 61.70 (d,
CH3CH2OP), 1.35 (t, 3H, JHH¼7.0 Hz, CH3CH2OP),
2JCP¼6.7 Hz, CH2OP), 171.31 (d, JCP¼3.8 Hz, COO, dia
1.19–1.31 (m, 6H, 3£CH2), 1.46–1.78 (m, 14H, 7£CH2),
2
A), 171.52 (d, 2JCP¼3.8 Hz, COO, dia B), 204.23 (CHO, dia
A), 204.51 (CHO, dia B); FAB/MS MHþ 462. Anal. calcd
for C23H44NO6P: C, 59.85; H, 9.61; N, 3.03. Found: C,
59.71; H, 9.74; N, 3.18.
1.97–2.02 (m, 6H, 3£CH2), 2.31–2.60 (m, 4H, 2£CH2),
3
2
2.82 (ddd, 1H, JHH¼1.5, 10.0 Hz, JHP¼25.2 Hz, CHP,
3
2
major), 2.87 (ddd, 1H, JHH¼1.5, 10.0 Hz, JHP¼25.2 Hz,
CHP, minor), 2.91–3.02 (m, 2H, 2£CHN), 4.05–4.20 (m,
6H, CH2O, 2£CH2OP); 13C NMR (CDCl3) d¼13.61 (CH3),
3
4.2.9. Dicyclohexylammonium 2-(diethoxyphosphoryl)-
4-formyl-octanoate (3i). (3.52 g); diasteroisomer ratio 1:1;
viscous oil, the crude product (pure by 31P NMR) was used
16.20 (d, JCP¼3.8 Hz, 2£CH3CH2OP), 22.31 (CH2,
minor), 22.35 (CH2, major), 24.72 (4£CH2), 25.00
(2£CH2), 26.71 (CH2, minor), 27.52 (CH2, major), 28.85
for the next step; IR (film) 2867, 1726, 1632, 1243 cm21
;
(4£CH2), 31.22 (d, JCP¼3.0 Hz, CH2, minor), 31.51 (d,
2
31P NMR (CDCl3) d¼27.71, 28.13; 1H NMR (CDCl3)
2JCP¼3.0 Hz, CH2, major), 33.82 (CH2, minor), 34.35 (CH2,
3
d¼0.89 (t, 3H, JHH¼6.7 Hz, CH3), 1.10–1.31 (m, 10H,
major), 40.72 (CH2, minor), 40.84 (CH2, major), 43.83 (d,
3
1
5£CH2), 1.30 (t, 3H, JHH¼7.0 Hz, CH3CH2OP), 1.32 (t,
1JCP¼124.1 Hz, CHP, major), 43.72 (d, JCP¼124.1 Hz,
3
3
3H, JHH¼7.0 Hz, CH3CH2OP), 1.40–1.61 (m, 8H,
CHP, minor), 52.22 (2£CHN), 60.51 (d, JCP¼14.7 Hz, C,
3
4£CH2), 1.71–1.80 (m, 8H, 4£CH2), 2.02–2.45 (m, 3H,
CH, CH2), 2.81–3.06 (m, 3H, 2£CHN, CHP), 4.04–4.32
(m, 4H, 2£CH2OP), 9.61 (s, 1H, CHO, dia A), 9.72 (s, 1H,
CHO, dia B); 13C NMR (CDCl3) d¼13.50 (CH3, dia A),
13.60 (CH3, dia B), 16.09 (d, 3JCP¼6.0 Hz, 2£CH3CH2OP),
22.41 (CH2, dia A), 22.52 (CH2, dia B), 24.50 (4£CH2),
minor), 61.02 (d, JCP¼14.7 Hz, C, major), 60.91 (CH2O),
2
2
61.51 (d, JCP¼6.3 Hz, CH2OP), 61.75 (d, JCP¼6.3 Hz,
2
CH2OP), 170.81 (COOCH2CH3), 171.80 (d, JCP¼3.8 Hz,
2
COO, major), 171.91 (d, JCP¼3.8 Hz, COO, minor),
206.80 (CO, minor), 207.01 (CO, major); FAB/MS MHþ
560. Anal. calcd for C28H50NO8P: C, 60.09; H, 9.00; N,
2.50. Found: C, 60.23; H, 9.15; N, 2.34.
2
24.92 (2£CH2), 26.70 (d, JCP¼4.2 Hz, CH2CHP, dia A),
2
27.11 (d, JCP¼4.2 Hz, CH2CHP, dia B), 27.91 (CH2, dia
A), 28.63 (4£CH2), 28.71 (CH2, dia B), 28.81 (CH2, dia A),
28.93 (CH2, dia B), 45.76 (d, 1JCP¼126.5 Hz, CHP, dia A),
4.3. General procedure for transformation of 3a–k to
corresponding carboxylic acids 4a–k
1
3
45.92 (d, JCP¼126.5 Hz, CHP, dia B), 50.51 (d, JCP
¼
3
15.1 Hz, CH, dia A), 50.82 (d, JCP¼15.9 Hz, CH, dia B),
Ion-exchange chromatography of the salts 3 (a–k)
(6.0 mmol) was performed on a glass column packed with
Dowex 50W using H2O/acetone, 1:1 as eluent. The eluent
was evaporated to give acids as colorless oils.
52.11 (2£CHN), 61.40 (d, 2JCP¼6.7 Hz, CH2OP), 61.50 (d,
2JCP¼6.7 Hz, CH2OP), 171.07 (d, JCP¼4.4 Hz, COO, dia
2
A), 171.13 (d, 2JCP¼4.4 Hz, COO, dia B), 204.02 (CHO, dia
A), 204.31 (CHO, dia B); FAB/MS MHþ 490.
4.3.1. 2-(Diethoxyphosphoryl)-4,4-dimethyl-5-oxopenta-
noic acid (4a). Colorless oil; IR (film) 1728, 1240 cm21
;
4.2.10. Dicyclohexylammonium 4-benzyl-2-(diethoxy-
phosphoryl)-5-oxopentanoate (3j). (3.92 g); diastero-
isomer ratio 1:1; viscous oil, the crude product (pure by
31P NMR) was used for the next step; IR (film) 3020, 2936,
1
31P NMR (CDCl3) d¼24.11; H NMR (CDCl3) d¼1.06 (s,
3
3H, CH3), 1.08 (s, 3H, CH3), 1.34 (t, 6H, JHH¼7.2 Hz,
3
2
2£CH3CH2OP), 1.95 (dt, 1H, JHH¼2.0 Hz, JHH
¼
3
1724, 1632, 1244 cm
;
21 31P NMR (CDCl3) d¼27.62, 27.75;
3JHP¼14.5 Hz, CHCHP), 2.31 (ddd, 1H, JHP¼4.4 Hz,

´
H. Krawczyk, M. Sliwinski / Tetrahedron 59 (2003) 9199–9211
´
9205
2
3JHH¼10.5 Hz, JHH¼14.5 Hz, CHCHP), 3.01 (ddd, 1H,
d¼24.07, 24.15; 1H NMR (CDCl3) d¼1.31 (t, 3H,
3JHH¼2.0, 10.5 Hz, JHP¼25.5 Hz, CHP), 4.17 (qui, 2H,
3JHH¼7.0 Hz, CH3CH2OP), 1.32 (t, 3H, JHH¼7.0 Hz,
2
3
3JHH¼3JHP¼7.2 Hz, CH2OP), 4.21 (qui, 2H, JHH
¼
CH3CH2OP), 1.45 (s, 3H, CH3, major), 1.46 (s, 3H, CH3,
minor), 2.37–2.65 (m, 2H, CH2), 2.72 (ddd, 1H, 3JHH¼1.5,
3
3JHP¼7.2 Hz, CH2OP), 9.4 (s, 1H, CHO); 13C NMR
3
2
(CDCl3) d¼16.45 (d, JCP¼5.4 Hz, 2£CH3CH2OP), 21.01
9.7 Hz, JHP¼25.2 Hz, CHP, major), 2.96 (ddd, 1H,
2
2
(CH3), 21.72 (CH3), 32.84 (d, JCP¼4.9 Hz, CH2CHP),
3JHH¼1.5, 9.7 Hz, JHP¼25.2 Hz, CHP, minor), 3.89–4.23
1
3
41.05 (d, JCP¼128.5 Hz, CHP), 45.31 (d, JCP¼15.1 Hz,
C), 63.21 (d, 2JCP¼6.8 Hz, CH2OP), 63.53 (d, 2JCP¼6.8 Hz,
(m, 4H, 2£CH2OP), 7.21–7.42 (m, 5H, C6H5), 9.40 (s, 1H,
CHO, major), 9.45 (s, 1H, CHO, minor); 13C NMR (CDCl3)
2
3
CH2OP), 170.81 (d, JCP¼4.9 Hz, COO), 204.81 (CHO).
d¼16.11 (d, JCP¼6.0 Hz, 2£CH3CH2OP), 17.50 (CH3,
2
Anal. calcd for C11H21O6P: C, 47.14; H, 7.55. Found: C,
47.34; H, 7.73.
major), 18.75 (CH3, minor), 32.60 (d, JCP¼3.2 Hz,
2
CH2CHP, minor), 32.78 (d, JCP¼3.2 Hz, CH2CHP,
1
major), 41.14 (d, JCP¼128.1 Hz, CHP, major), 41.74 (d,
3
4.3.2. 2-(Diethoxyphosphoryl)-3-(1-formyl-cyclohexyl)-
propionic acid (4b). Colorless oil; IR (film) 1724,
1JCP¼128.1 Hz, CHP, minor), 54.01 (d, JCP¼13.4 Hz, C,
3
major), 54.21 (d, JCP¼13.4 Hz, C, minor), 63.11 (d,
1241 cm21
;
31P NMR (CDCl3) d¼24.13; 1H NMR
2JCP¼6.5 Hz, CH2OP), 63.74 (d, JCP¼6.5 Hz, CH2OP),
2
3
(CDCl3) d¼1.33 (t, 6H, JHH¼7.0 Hz, 2£CH3CH2OP),
1.21–1.61 (m, 8H, 4£CH2), 1.82–1.94 (m, 2H, CH2), 1.88
(dt, 1H, 3JHH¼1.5 Hz, 2JHH¼3JHP¼14.0 Hz, CHCHP), 2.31
127.21 (2£CH, minor), 127.53 (2£CH, major), 127.71 (CH,
minor), 127.81 (CH, major), 128.93 (2£CH, minor), 129.00
(2£CH, major), 137.81 (C, major), 138.91 (C, minor),
3
3
2
2
(ddd, 1H, JHP¼3.7 Hz, JHH¼10.0 Hz, JHH¼14.0 Hz,
170.94 (d, JCP¼5.0 Hz, COO, minor), 171.21 (d,
3
2
CHCHP), 3.00 (ddd, 1H, JHH¼1.5, 10.0 Hz, JHP
¼
2JCP¼5.0 Hz, COO, major) 200.32 (CHO, major), 200.94
(CHO, minor). Anal. calcd for C16H23O6P: C, 56.14; H,
6.77. Found: C, 56.34; H, 6.89.
25.7 Hz, CHP), 4.16 (qui, 2H, JHH¼3JHP¼7.0 Hz,
3
CH2OP), 4.19 (qui, 2H, JHH¼3JHP¼7.2 Hz, CH2OP),
3
9.38 (s, 1H, CHO); 13C NMR (CDCl3) d¼16.31 (d,
3JCP¼5.2 Hz, 2£CH3CH2OP), 22.30 (2£CH2), 25.45
4.3.5. 2-(Diethoxyphosphoryl)-5-oxohexanoic acid (4e).
2
(CH2), 30.71 (2£ CH2), 32.62 (d, JCP¼4.8 Hz, CH2CHP),
Colorless oil; IR (film) 1716, 1242 cm21 31P NMR
;
1
3
40.41 (d, JCP¼127.0 Hz, CHP), 49.81 (d, JCP¼14.7 Hz,
(CDCl3) d¼23.98; 1H NMR (CDCl3) d¼1.28 (t, 6H,
3JHH¼7.0 Hz, 2£CH3CH2OP), 2.08 (s, 3H, CH3), 2.05–
2.21 (m, 2H, CH2), 2.40–2.65 (m, 2H, CH2), 2.97 (dt, 1H,
C), 63.2 (d, 2JCP¼6.1 Hz, CH2OP), 63.81 (d, JCP¼6.1 Hz,
2
2
CH2OP), 170.84 (d, JCP¼4.7 Hz, COO), 204.80 (CHO).
2
3
Anal. calcd for C14H25O6P: C, 52.49; H, 7.87. Found: C,
52.33; H, 8.02.
3JHH¼7.0 Hz, JHP¼23.0 Hz, CHP), 4.13 (qui, 2H, JHH
¼
3JHP¼7.0 Hz, CH2OP), 4.14 (qui, 2H, JHH¼3JHP¼7.0 Hz,
3
CH2OP); 13C NMR (CDCl3) d¼15.41 (d, JCP¼6.3 Hz,
3
2
4.3.3. 2-(Diethoxyphosphoryl)-4-formyl-4-methyl-hepta-
noic acid (4c). Diasteroisomer ratio 1:1; colorless oil; IR
(film) 1728, 1240 cm
2£CH3CH2OP), 20.22 (d, JCP¼4.2 Hz, CH2CHP), 29.01
3
(CH3), 40.23 (d, JCP¼13.8 Hz, CH2), 43.32 (d,
2
;
21 31P NMR (CDCl3) d¼23.99, 24.01;
1JCP¼131.8 Hz, CHP), 62.42 (d, JCP¼6.8 Hz, CH2OP),
1H NMR (CDCl3) d¼0.86 (t, 3H, 3JHH¼7.0 Hz, CH3), 0.98
(s, 3H, CH3, dia A), 1.00 (s, 3H, CH3, dia B), 1.18–1.27 (m,
2H, CH2), 1.33 (t, 6H, 3JHH¼7.0 Hz, 2£CH3CH2OP), 1.43–
62.50 (d, JCP¼6.0 Hz, CH2OP), 169.70 (d, JCP¼4.1 Hz,
COO), 207.01 (CO). Anal. calcd for C10H19O6P: C, 45.11;
H, 7.19. Found: C, 45.25; H, 7.31.
2
2
3
2
1.50 (m, 2H, CH2), 1.93 (dt, 1H, JHH¼1.8 Hz, JHH
¼
3JHP¼14.7 Hz, CHCHP, dia A), 2.00 (dt, 1H, 3JHH¼1.8 Hz,
2JHH¼3JHP¼14.7 Hz, CHCHP, dia B), 2.19 (ddd, 1H,
4.3.6. 2-(Diethoxyphosphoryl)-3-(2-oxocyclohexyl)-pro-
pionic acid (4f). Diasteroisomer ratio 1:1; colorless oil;
3JHP¼3.0 Hz, JHH¼9.5 Hz, JHH¼14.7 Hz, CHCHP, dia
IR (film) 1712, 1236 cm21
;
31P NMR (CDCl3) d¼24.90,
3
2
A), 2.30 (ddd, 1H, 3JHP¼3.0 Hz, 3JHH¼9.5 Hz,
25.31; 1H NMR (CDCl3) d¼1.32 (t, 3H, JHH¼7.0 Hz,
3
2JHH¼14.7 Hz, CHCHP, dia B), 2.91 (ddd, 1H, JHH¼1.8,
CH3CH2OP), 1.33 (t, 3H, JHH¼7.0 Hz, CH3CH2OP),
3
3
2
9.5 Hz, JHP¼25.0 Hz, CHP, dia A), 3.13 (ddd, 1H,
1.30–1.42 (m, 2H, CH2), 1.61–1.85 (m, 4H, 2£CH2),
3JHH¼1.8, 9.5 Hz, JHP¼25.0 Hz, CHP, dia B), 4.18 (qui,
2.01–2.13 (m, 2H, CH2), 2.35–2.51 (m, 3H, CH2, CH), 3.13
2
2H, JHH¼3JHP¼7.0 Hz, CH2OP), 4.21 (qui, 2H, JHH
¼
(ddd, 1H, JHH¼5.0, 10.5 Hz, JHP¼23.2 Hz, CHP, dia A),
3.27 (ddd, 1H, 3JHH¼2.7, 11.5 Hz, 2JHP¼23.7 Hz, CHP, dia
B), 4.14–4.31 (m, 4H, 2£CH2OP); 13C NMR (CDCl3)
d¼16.31 (d, 3JCP¼6.1 Hz, 2£CH3CH2OP), 25.01 (CH2, dia
3
3
3
2
3JHP¼7.0 Hz, CH2OP), 9.38 (s, 1H, CHO); 13C NMR
3
(CDCl3) d¼14.51 (CH3), 16.20 (d, JCP¼5.9 Hz, 2£CH3-
CH2OP), 17.11 (CH3, dia A), 17.32 (CH2, dia A), 17.50
(CH2, dia B), 18.20 (CH3, dia B), 31.13 (d, JCP¼4.5 Hz,
2
2
A), 25.21 (CH2, dia B), 26.63 (d, JCP¼5.8 Hz, CH2CHP,
CH2CHP, dia A), 31.81 (d, 2JCP¼4.5 Hz, CH2CHP, dia B),
dia A), 27.33 (d, JCP¼5.8 Hz, CH2CHP, dia B), 27.91
2
37.31 (CH2, dia A), 39.62 (CH2, dia B), 40.81 (d,
(CH2, dia A), 28.33 (CH2, dia B), 33.10 (CH2, dia A), 35.42
(CH2, dia B), 42.11 (CH2, dia A), 42.42 (CH2, dia B), 42.51
(d, 1JCP¼130.1 Hz, CHP, dia A), 43.32 (d, 1JCP¼130.1 Hz,
CHP, dia B), 48.22 (d, 3JCP¼12.0 Hz, CH, dia A), 48.71 (d,
3JCP¼14.6 Hz, CH, dia B), 63.51 (d, 2JCP¼6.7 Hz, CH2OP),
1JCP¼128.0 Hz, CHP, dia A), 41.22 (d, JCP¼128.0 Hz,
1
3
CHP, dia B), 49.00 (d, JCP¼14.1 Hz, C, dia A), 49.52 (d,
3JCP¼14.1 Hz, C, dia B), 63.10 (d, JCP¼6.5 Hz, CH2OP),
2
2
2
63.40 (d, JCP¼6.5 Hz, CH2OP), 170.06 (d, JCP¼4.4 Hz,
COO, dia A), 170.40 (d, 2JCP¼4.4 Hz, COO, dia B), 205.11
(CHO, dia A), 205.22 (CHO, dia B). Anal. calcd for
C13H25O6P: C, 50.64; H, 8.17. Found: C, 50.81; H, 8.29.
2
2
63.72 (d, JCP¼6.0 Hz, CH2OP), 170.61 (d, JCP¼3.8 Hz,
COO, dia A), 170.72 (d, 2JCP¼3.8 Hz, COO, dia B), 212.31
(CO, dia A), 212.81 (CO, dia B). Anal. calcd for
C13H23O6P: C, 50.98; H, 7.57. Found: C, 51.12; H, 7.69.
4.3.4. 2-(Diethoxyphosphoryl)-4-methyl-5-oxo-4-phenyl-
pentanoic acid (4d). Colorless oil; diasteroisomer ratio 2:1;
4.3.7. 2-(Diethoxyphosphoryl)-4-methyl-5-oxopentanoic
acid (4g). Diasteroisomer ratio 1:1; colorless oil; IR (film)
IR (film) 3018, 1724, 1242 cm21
;
31P NMR (CDCl3)

´
H. Krawczyk, M. Sliwinski / Tetrahedron 59 (2003) 9199–9211
´
9206
1
2
1729, 1240 cm21
;
31P NMR (CDCl3) d¼23.51, 23.70; H
CH2CHP, dia A), 25.32 (d, JCP¼3.2 Hz, CH2CHP, dia
B), 27.82 (CH2, dia A), 28.31 (CH2, dia B), 28.45 (CH2, dia
A), 28.70 (CH2, dia B), 42.51 (d, 1JCP¼132.0 Hz, CHP, dia
3
NMR (CDCl3) d¼1.13 (d, 3H, JHH¼7.5 Hz, CH3, dia A),
3
1.16 (d, 3H, JHH¼7.5 Hz, CH3, dia B), 1.34 (t, 3H,
3JHH¼7.2 Hz, CH3CH2OP), 1.35 (t, 3H, JHH¼7.2 Hz,
A), 42.52 (d, JCP¼132.0 Hz, CHP, dia B), 49.30 (d,
3
1
CH3CH2OP), 1.70–2.61 (m, 3H, CH2, CH), 3.08 (ddd,
3JCP¼15.1 Hz, CH, dia A), 49.91 (d, 3JCP¼15.8 Hz, CH, dia
B), 63.10 (d, 2JCP¼6.5 Hz, CH2OP), 63.20 (d, 2JCP¼6.5 Hz,
CH2OP), 178.14 (d, 2JCP¼3.8 Hz, COO, dia A), 178.62 (d,
2JCP¼3.8 Hz, COO, dia B), 203.31 (CHO, dia A), 204.14
(CHO, dia B). Anal. calcd for C13H25O6P: C, 50.64; H, 8.17.
Found: C, 50.76; H, 8.28.
3
2
1H, JHH¼3.7, 7.7 Hz, JHP¼24.7 Hz, CHP, dia A), 3.18
3
2
(ddd, 1H, JHH¼4.0, 7.5 Hz, JHP¼24.0 Hz, CHP, dia B),
4.19 (qui, 2H, 3JHH¼3JHP¼7.2 Hz, CH2OP), 4.22 (qui, 2H,
3JHH¼3JHP¼7.2 Hz, CH2OP), 9.61 (s, 1H, CHO, dia A),
9.65 (s, 1H, CHO, dia B); 13C NMR (CDCl3) d¼16.22 (d,
3JCP¼5.6 Hz, 2£CH3CH2OP), 16.70 (CH3, dia A), 17.63
2
(CH3, dia B), 30.40 (d, JCP¼5.0 Hz, CH2CHP, dia A),
4.3.10. 4-Benzyl-2-(diethoxyphosphoryl)-5-oxopentanoic
acid (4j). Colorless oil; diasteroisomer ratio 1:1; analyti-
cally pure product was obtained by silica gel chromato-
graphy using acetone/CHCl3 (2:1) as eluent; total yield of 2
2
30.46 (d, JCP¼5.0 Hz, CH2CHP, dia B), 37.81 (d,
3JCP¼15.3 Hz, CH, dia A), 38.23 (d, JCP¼13.3 Hz, CH,
3
1
dia B), 42.81 (d, JCP¼130.0 Hz, CHP, dia A), 43.15 (d,
1JCP¼130.0 Hz, CHP, dia B), 63.41 (d, JCP¼6.5 Hz,
steps 75%; IR (film) 3029, 1728, 1241 cm21 31P NMR
;
2
2
CH2OP), 63.66 (d, JCP¼6.5 Hz, CH2OP), 170.83 (d,
(CDCl3) d¼23.51, 23.62; 1H NMR (CDCl3) d¼1.27 (t, 3H,
2JCP¼5.0 Hz, COO, dia A), 171.02 (d, JCP¼5.0 Hz,
3JHH¼7.0 Hz, CH3CH2OP), 1.28 (t, 3H, JHH¼7.0 Hz,
2
3
COO, dia B), 203.50 (CHO, dia A), 203.62 (CHO, dia B).
Anal. calcd for C10H19O6P: C, 45.11; H, 7.19. Found: C,
45.23; H, 7.31.
CH3CH2OP), 1.82–2.41 (m, 2H, CH2), 2.75–3.30 (m, 4H,
CHP, CH, CH2), 3.90–4.30 (m, 4H, 2£CH2OP), 7.00–7.29
(m, 5H, C6H5), 9.60 (s, 1H, CHO, dia A), 9.65 (s, 1H, CHO,
dia B); 13C NMR (CDCl3) d¼16.20 (d, JCP¼5.9 Hz,
3
2
4.3.8. 2-(Diethoxyphosphoryl)-4-formyl-hexanoic acid
(4h). Diasteroisomer ratio 1:1; colorless oil; IR (film)
2£CH3CH2OP), 25.01 (d, JCP¼4.1 Hz, CH2CHP, dia A),
2
25.32 (d, JCP¼4.1 Hz, CH2CHP, dia B), 34.82 (CH2, dia
1
1728, 1241 cm21
;
31P NMR (CDCl3) d¼23.73, 23.94; H
A), 35.80 (CH2, dia B), 42.81 (d, 1JCP¼132.4 Hz, CHP, dia
3
1
NMR (CDCl3) d¼0.92 (t, 3H, JHH¼7.5 Hz, CH3, dia A),
A), 43.31 (d, JCP¼132.4 Hz, CHP, dia B), 51.00 (d,
3
0.96 (t, 3H, JHH¼7.5 Hz, CH3, dia B), 1.34 (t, 3H,
3JCP¼12.3 Hz, CH, dia A), 51.72 (d, 3JCP¼11.4 Hz, CH, dia
B), 63.40 (d, 2JCP¼6.8 Hz, CH2OP), 63.50 (d, 2JCP¼6.8 Hz,
CH2OP), 126.61 (CH), 128.62 (2£CH), 128.94 (CH),
129.11 (CH), 137.72 (CH, dia A), 137.81 (CH, dia B),
3JHH¼7.0 Hz, CH3CH2OP), 1.36 (t, 3H, JHH¼7.0 Hz,
3
CH3CH2OP), 1.51–1.95 (m, 3H, CH, CH2), 2.03–2.13
(m, 1H, CH), 2.31–2.43 (m, 1H, CH), 3.07 (ddd, 1H,
3JHH¼5.0, 9.7 Hz, JHP¼24.7 Hz, CHP, dia A), 3.10 (ddd,
169.9 (d, JCP¼3.71 Hz, COO, dia A), 170.11 (d,
2
2
1H, 3JHH¼4.2, 10.0 Hz, 2JHP¼23.7 Hz, CHP, dia B), 4.11–
4.22 (m, 4H, 2£CH2OP), 9.42 (s, 1H, CHO, dia A), 9.51 (s,
1H, CHO, dia B); 13C NMR (CDCl3) d¼10.70 (CH3, dia A),
11.02 (CH3, dia B), 16.19 (d, 3JCP¼5.8 Hz, 2£CH3CH2OP),
21.20 (CH2, dia A), 22.41 (CH2, dia B), 24.94 (d,
2JCP¼3.7 Hz, COO, dia B), 203.21 (CHO, dia A), 203.43
(CHO, dia B), Anal. calcd for C16H23O6P: C, 56.14; H, 6.77.
Found: C, 56.29; H, 6.89.
4.3.11. 1-[2-Carboxy-2-(diethoxyphosphoryl)-ethyl]-2-
cyclohexanecarboxylic acid ethyl ester (4k). Diastero-
2JCP¼3.1 Hz, CH2CHP, dia A), 25.12 (d, JCP¼3.1 Hz,
2
1
CH2CHP, dia B), 42.91 (d, JCP¼130.5 Hz, CHP, dia A),
isomer ratio 2:1; colorless oil; IR (film) 1735, 1712,
1220 cm21
1
1
43.21 (d, JCP¼130.5 Hz, CHP, dia B), 50.80 (d,
;
31P NMR d¼24.05, 24.21; H NMR d¼1.26
3JCP¼13.0 Hz, CH, dia A), 51.14 (d, JCP¼11.5 Hz, CH,
(t, 3H, JHH¼7.0, CH3), 1.33 (t, 3H, JHH¼7.0, CH3CH2-
3
3
3
2
3
dia B), 63.31 (d, JCP¼6.5 Hz, CH2OP), 63.46 (d,
OP), 1.35 (t, 3H, JHH¼7.0, CH3CH2OP), 1.41–1.70 (m,
2JCP¼6.5 Hz, CH2OP), 170.21 (d, JCP¼3.6 Hz, COO, dia
4H, 2£CH2), 1.91–2.44 (m, 6H, 3£CH2), 3.11 (ddd, 1H,
2
A), 170.31 (d, 2JCP¼3.6 Hz, COO, dia B), 204.21 (CHO, dia
A), 204.34 (CHO, dia B). Anal. calcd for C11H21O6P: C,
47.14; H, 7.55. Found: C, 47.26; H, 7.67.
3JHH¼1.7, 3JHH¼10.7, JHP¼26.5 CHP, minor), 3.32 (ddd,
2
3
3
2
1H, JHH¼2.5, JHH¼9.0, JHP¼26.0, CHP, major), 4.07–
4.25 (m, 6H, CH2O, 2£CH2OP); 13C NMR (CDCl3)
3
d¼13.61 (CH3), 15.95 (d, JCP¼4.8, 2£CH3CH2OP),
4.3.9. 2-(Diethoxyphosphoryl)-4-formyl-octanoic acid
(4i). Colorless oil; diasteroisomer ratio 1:1; analytically
pure product was obtained by silica gel chromatography
using acetone/CHCl3 (2:1) as eluent; total yield of 2 steps
22.00 (CH2, minor) 22.17 (CH2, major), 26.81 (CH2,
minor) 27.35 (CH2, major) 30.62 (d, JCP¼3.6, CH2,
2
2
minor), 31.15 (d, JCP¼3.6, CH2, major), 34.72 (CH2,
minor), 36.10 (CH2, major), 40.51 (CH2, minor), 40.71 (d,
1JCP¼126.5, CHP, minor), 40.74 (CH2, major), 40.91 (d,
72%; IR (film) 1728, 1240 cm21 31P NMR (CDCl3)
;
d¼23.31, 23.50; 1H NMR (CDCl3) d¼0.88 (t,
1JCP¼126.5, CHP, major), 59.52 (d, JCP¼13.0, C, minor),
3
3JHH¼7.0 Hz, 3H, CH3), 1.34 (t, 3H, JHH¼7.0 Hz, CH3-
59.62 (d, JCP¼12.5, C, major), 61.32 (CH2O), 62.14 (d,
3
3
3
2
CH2OP), 1.36 (t, 3H, JHH¼7.0 Hz, CH3CH2OP), 1.31–
2JCP¼6.3, CH2OP), 63.51 (d, JCP¼6.3, CH2OP), 170.21
2
1.33 (m, 4H, 2£CH2), 1.46–1.74 (m, 2H, CH2), 2.01–2.53
(COOCH2CH3), 170.40 (d, JCP¼3.8, COOH, major),
3
2
(m, 3H, CH, CH2), 3.10 (ddd, 1H, JHH¼2.5, 11.2 Hz,
170.91 (d, JCP¼3.8, COOH, minor), 206.80 (CO, minor),
2JHP¼25.2 Hz, CHP, dia A), 3.20 (ddd, 1H, JHH¼3.5,
207.21 (CO, major); Anal. Calcd for C16H27O8P: C, 50.79;
H, 7.19; Found: C, 50.95; H, 7.27.
3
10.0 Hz, 2JHP¼25.2 Hz, CHP, dia B), 4.15 (qui, 2H, 3JHH
¼
3JHP¼6.7 Hz, CH2OP), 4.20 (qui, 2H, JHH¼3JHP¼6.7 Hz,
CH2OP), 9.71 (s, 1H, CHO, dia A), 9.82 (s, 1H, CHO, dia
B); 13C NMR (CDCl3) d¼13.52 (CH3, dia A), 13.61 (CH3,
dia B), 15.80 (d, 3JCP¼6.2 Hz, 2£CH3CH2OP), 22.13 (CH2,
3
4.4. General procedure for synthesis of phosphono-
lactones 6a–k
2
dia A), 22.41 (CH2, dia B), 25.22 (d, JCP¼3.2 Hz,
To a stirred solution of 4 (a–k) (4.0 mmol), in ethanol

´
H. Krawczyk, M. Sliwinski / Tetrahedron 59 (2003) 9199–9211
´
9207
3
(15 ml) was added potassium hydroxide (0.23 g, 4.0 mmol)
in ethanol (5 ml) and then potassium borohydride (0.22 g,
4.0 mmol). Stirring was continued for 24 h at room
temperature. The resulting mixture was neutralized to
pH,2 with 5% HCl. Solvent was evaporated and the
residue was taken up in chloroform. The solution was
washed with water (1£5 ml) dried (MgSO4) and evaporated.
The solution of p-toluenesufonic acid monohydrate (0.02 g,
0.1 mmol) in benzene (25 ml) was added to the residue and
the mixture was refluxed for 4 h. It was then concentrated,
diluted with CHCl3 (20 ml), washed with 5% NaHCO3
(2£10 ml), water (1£10 ml) dried (MgSO4) and evaporated.
The oily residue was purified by column chromatography on
silica gel using AcOEt as eluent.
3JHH¼7.0 Hz, CH3CH2OP), 1.36 (t, 3H, JHH¼7.0 Hz,
CH3CH2OP), 1.86–2.12 (m, 2H, CH2), 3.11 (dt, 1H,
3JHH¼8.2 Hz, JHP¼27.0 Hz, CHP, dia A), 3.21 (dt, 1H,
2
3JHH¼8.2 Hz, JHP¼27.0 Hz, CHP, dia B), 3.93 (dd, 1H,
2
4JHH¼2.5 Hz, JHH¼11.0 Hz, CHO, dia A), 4.02 (dd,
2
4JHH¼2.5 Hz, JHH¼11.0 Hz, CHO, dia B), 4.11 (d, 1H,
2
2JHH¼11.0 Hz, CHO, dia A), 4.15 (d, 1H, JHH¼11.0 Hz,
2
CHO, dia B), 4.13–4.31 (m, 4H, 2£CH2OP); 13C NMR
(CDCl3) d¼14.37 (CH3, dia A), 14.44 (CH3, dia B), 16.10
2
2
(d, JCP¼6.0 Hz, CH3CH2OP), 16.20 (d, JCP¼6.0 Hz,
CH3CH2OP), 16.31 (CH3, dia A), 16.56 (CH3, dia B),
20.35 (CH2, dia A), 22.61 (CH2, dia B), 32.26 (d,
2
2JCP¼3.2 Hz, CH2CHP, dia A), 32.39 (d, JCP¼3.2 Hz,
3
CH2CHP, dia B), 33.05 (d, JCP¼6.1 Hz, C, dia A), 33.15
3
(d, JCP¼6.1 Hz, C, dia B), 37.45 (CH2, dia A), 37.52 (d,
1
4.4.1. (5,5-Dimethyl-2-oxo-tetrahydropyran-3-yl)-phos-
phonic acid diethyl ester (6a). (0.73 g, 69% yield);
1JCP¼139.7 Hz, CHP, dia A), 37.63 (d, JCP¼139.7 Hz,
2
CHP, dia B), 41.35 (CH2, dia B), 62.41 (d, JCP¼6.3 Hz,
colorless oil; IR (film) 1732, 1248, 1168 cm21
;
31P NMR
CH2OP, dia A), 62.45 (d, JCP¼6.3 Hz, CH2OP, dia A),
2
(CDCl3) d¼23.30 (5a d¼24.84); 1H NMR (CDCl3) d¼1.06
63.21 (d, JCP¼6.3 Hz, CH2OP, dia B), 63.32 (d,
2
3
(s, 3H, CH3), 1.08 (s, 3H, CH3), 1.35 (t, 3H, JHH¼7.2 Hz,
2JCP¼6.3 Hz, CH2OP, dia B), 76.41 (CH2O, dia A), 77.23
3
2
CH3CH2OP), 1.36 (t, 3H, JHH¼7.2 Hz, CH3CH2OP), 1.91
(CH2O, dia B), 166.51 (d, JCP¼4.4 Hz, COO, dia A),
4
3
3
2
(dddd, 1H, JHH¼2.7 Hz, JHP¼6.2 Hz, JHH¼9.0 Hz,
166.63 (d, JCP¼4.4 Hz, COO, dia B), Anal. calcd for
2JHH¼13.7 Hz, CHCHP), 2.05 (ddd, 1H, JHH¼10.0 Hz,
C13H25O5P: C, 53.42; H, 8.62. Found: C, 53.58; H, 8.50.
3
2JHH¼13.7 Hz, JHP¼15.5 Hz, CHCHP), 3.18 (ddd, 1H,
3
3JHH¼9.0, 10.0 Hz, JHP¼27.5 Hz, CHP), 3.92 (dd, 1H,
4.4.4. (5-Methyl-2-oxo-5-phenyl-tetrahydro-pyran-3-yl)-
phosphonic acid diethyl ester (6d). (0.78 g, 60% yield);
diasteroisomer ratio 3:1; colorless oil; IR (film) 3058, 1732,
2
4JHH¼2.7 Hz, JHH¼11.0 Hz, CHO), 4.16 (d, 1H,
2
2JHH¼11.0 Hz, CHO), 4.15–4.32 (m, 4H, 2£ CH2OP);
13C NMR (CDCl3) d¼15.92 (d, 3JCP¼5.3 Hz, CH3CH2OP),
1240, 1172 cm21
;
31P NMR (CDCl3) d¼22.90, 23.02 (5d
2
1
16.01 (d, JCP¼5.3 Hz, CH3CH2OP), 22.73 (CH3), 25.51
d¼24.44, 24.61); H NMR (CDCl3) d¼1.32 (s, 3H, CH3,
major), 1.33 (t, 3H, 3JHH¼7.0 Hz, CH3CH2OP), 1.34 (t, 3H,
3JHH¼7.0 Hz, CH3CH2OP), 1.45 (s, 3H, CH3, minor), 2.30
3
2
(CH3), 29.42 (d, JCP¼8.4 Hz, C), 34.44 (d, JCP¼4.2 Hz,
1
CH2), 37.61 (d, JCP¼140.0 Hz CHP), 62.33 (d,
2JCP¼6.8 Hz, CH2OP), 63.21 (d, JCP¼6.8 Hz, CH2OP),
(ddt, 1H, JHH¼3.2 Hz, JHH¼9.0 Hz, JHH¼3JHP¼14.0
2
4
3
2
77.82 (CH2O), 166.11 (d, 2JCP¼4.4 Hz, COO). Anal. calcd
Hz, CHCHP, minor), 2.32 (dt, 1H, JHH¼11.7 Hz, JHH
¼
¼
3
2
4
for C11H21O5P: C, 50.00; H, 8.01. Found: C, 50.17; H, 8.14.
3JHP¼14.0 Hz, CHCHP, major), 2.55–2.72 (m, 1H, JHH
3
2
3.7 Hz, JHH¼7.7 Hz, JHH¼14.0 Hz, CHCHP, major),
3
2
4.4.2. (3-Oxo-2-oxa-spiro [5.5] undec-4-yl)-phosphonic
acid diethyl ester (6b). (1.08 g, 89% yield); colorless oil;
2.55–2.71 (m, 1H, JHH¼9.0 Hz, JHH¼14.0 Hz, CHCHP,
3
2
minor), 2.79 (ddd, 1H, JHH¼7.7, 11.7 Hz, JHP¼26.5 Hz,
IR (film) 1736, 1252, 1164 cm21
;
31P NMR (CDCl3)
CHP, major), 3.33 (dt, 1H, JHH¼9.0 Hz, JHP¼27.7 Hz,
3
2
1
d¼23.40 (5b d¼24.77); H NMR (CDCl3) d¼1.35 (t, 3H,
CHP, minor), 4.11–4.32 (m, 4H, 2£CH2OP), 4.21 (dd, 1H,
3JHH¼7.0 Hz, CH3CH2OP), 1.36 (t, 3H, JHH¼7.0 Hz,
4JHH¼3.2 Hz, JHH¼11.0 Hz, CHO, minor), 4.35 (d, 1H,
3
2
2
CH3CH2OP), 1.35–1.55 (m, 10H, 5£CH2), 1.92 (ddd, 1H,
2JHH¼11.7 Hz, CHO, major), 4.59 (d, 1H, JHH¼11.0 Hz,
2
3
4
2
3JHH¼10.0 Hz, JHH¼14.2 Hz, JHP¼17.0 Hz, CHCHP),
CHO, minor), 4.76 (dd, 1H, JHH¼3.7 Hz, JHH¼11.7 Hz,
CHO, major); 13C NMR (CDCl3) d¼16.05 (d, 3JCP¼4.9 Hz,
2.12 (dddd, 1H, 4JHH¼2.2 Hz, 3JHP¼5.5 Hz, JHH¼8.7 Hz,
3
2JHH¼14.2 Hz, CHCHP), 3.15 (ddd, 1H, JHH¼8.7,
CH3CH2OP), 16.12 (d, JCP¼4.9 Hz, CH3CH2OP), 22.61
3
3
2
4
2
10.0 Hz, JHP¼27.0 Hz, CHP), 4.08 (dd, 1H, JHH
¼
(CH3, minor), 26.96 (CH3, major), 33.94 (d, JCP¼3.8 Hz,
2
2
2.2 Hz, JHH¼11.0 Hz, CHO), 4.14 (d, 1H, JHH¼11.0 Hz,
CHO), 4.16–4.32 (m, 4H, 2£ CH2OP); 13C NMR (CDCl3)
CH2, minor), 34.83 (d, 2JCP¼3.5 Hz, CH2, major), 36.32 (d,
3JCP¼7.8 Hz, C, minor), 37.25 (d, 3JCP¼6.2 Hz, C, major),
3
3
1
1
d¼15.85 (d, JCP¼5.9 Hz, CH3CH2OP), 15.95 (d, JCP
¼
38.30 (d, JCP¼138.0 Hz, CHP, minor), 38.67 (d, JCP
¼
2
5.9 Hz, CH3CH2OP), 20.89 (CH2), 20.96 (CH2), 25.45
(CH2), 31.10 (CH2), 31.49 (d, JCP¼3.8 Hz, CH2CHP),
138.0 Hz, CHP, major), 62.31 (d, JCP¼6.8 Hz, CH2OP,
2
2
major), 62.52 (d, JCP¼6.8 Hz, CH2OP, minor), 63.33 (d,
3
1
2
32.11 (d, JCP¼8.0 Hz, C), 34.50 (CH2), 37.25 (d, JCP
¼
2JCP¼6.8 Hz, CH2OP, major), 63.42 (d, JCP¼6.8 Hz,
140.0 Hz, CHP), 62.20 (d, 2JCP¼6.8 Hz, CH2OP), 63.01 (d,
CH2OP, minor), 75.81 (CH2O, major), 76.58 (CH2O,
minor), 125.10 (2£CH, minor), 125.70 (2£CH, major),
126.90 (CH, major), 127.02 (CH, minor), 128.61 (2£CH,
minor), 128.92 (2£CH, major), 141.12 (C, major), 143.5 (C,
2JCP¼6.8 Hz, CH2OP), 76.4 (CH2O), 166.61 (d, JCP
¼
2
3.8 Hz). Anal. calcd for C14H25O5P: C, 55.25; H, 8.28.
Found: C, 55.38; H, 8.15.
2
minor), 165.12, (d, JCP¼4.4 Hz, COO, major), 165.93 (d,
4.4.3. (5-Methyl-2-oxo-5-propyl-tetrahydro-pyran-3-yl)-
phosphonic acid diethyl ester (6c). (0.84 g, 72% yield);
diasteroisomer ratio 1:1; colorless oil; IR (film) 1736, 1252,
2JCP¼4.4 Hz, COO, minor). Anal. calcd for C16H23O5P: C,
58.89; H, 7.10. Found: C, 59.03; H, 7.24.
1160 cm21
;
31P NMR (CDCl3) d¼23.37, 23.41 (5c
4.4.5. (6-Methyl-2-oxo-tetrahydro-pyran-3-yl)-phospho-
nic acid diethyl ester (6e). (0.75 g, 75% yield); diastero-
isomer ratio 1:1; colorless oil; IR (film) 1735, 1252,
d¼24.76, 24.89); 1H NMR (CDCl3) d¼0.92 (t, 3H,
3JHH¼6.5 Hz, CH3), 0.99 (s, 3H, CH3, dia A), 1.03 (s, 3H,
CH3, dia B), 1.23–1.33 (m, 4H, 2£CH2), 1.35 (t, 3H,
1136 cm21
;
31P NMR (CDCl3) d¼22.75, 23.09 (5e

´
´
H. Krawczyk, M. Sliwinski / Tetrahedron 59 (2003) 9199–9211
9208
d¼23.29, 23.35); 1H NMR (CDCl3) d¼1.35 (t, 3H,
2JHH¼11.0 Hz, CHO, 1H, minor); 13C NMR (CDCl3)
3
3
3JHH¼7.0 Hz, CH3CH2OP), 1.36 (t, 3H, JHH¼7.0 Hz,
d¼16.10 (d, JCP¼4.2 Hz, 2£CH3CH2OP), 16.19 (CH3CH),
3
CH3CH2OP), 1.37 (d, 3H, JHH¼6.2 Hz, CH3CHO, dia
25.54 (d, 2JCP¼4.4 Hz, CH2, major), 28.22 (d, 3JCP¼9.2 Hz,
A), 1.41 (d, 3H, 3JHH¼6.2 Hz, CH3CHO, dia B), 1.51–2.42
CH, major), 28.85 (d, JCP¼4.4 Hz, CH2, minor), 29.54 (d,
2
3
1
(m, 4H, 2£CH2), 3.10 (ddd, 1H, JHH¼4.7, 7.2 Hz,
3JCP¼4.3 Hz, CH, minor), 38.72 (d, JCP¼138.5 Hz, CHP,
3
1
2JHP¼26.2 Hz, CHP, dia A), 3.12 (dt, 1H, JHH¼8.2 Hz,
minor), 39.92 (d, JCP¼138.5 Hz, CHP, major), 62.41 (d,
2JHP¼27.7 Hz, CHP, dia B), 4.11–4.32 (m, 4H, 2£CH2OP),
2JCP¼6.6 Hz, CH2OP, major), 62.52 (d, JCP¼6.6 Hz,
2
3
2
4.45 (dq, 1H, JHH¼6.2, 12.5 Hz, CHO, dia A), 4.63 (ddq,
CH2OP, minor), 63.34 (d, JCP¼6.6 Hz, CH2OP, major),
3
1H, JHH¼2.5, 6.2, 10.7 Hz, CHO, dia B), 13C NMR
63.42 (d, 2JCP¼6.6 Hz, CH2OP, minor), 74.52 (CH2O, major),
3
(CDCl3) d¼15.94 (d, JCP¼5.9 Hz, CH3CH2OP), 16.03 (d,
74.80 (CH2O, minor), 165.91 (d, 2JCP¼4.4 Hz, COO, major),
2
2
3JCP¼5.9 Hz, CH3CH2OP), 20.11 (d, JCP¼4.3 Hz, CH2,
166.11 (d, JCP¼4.4 Hz, COO, minor). Anal. calcd for
2
dia A), 20.62 (d, JCP¼4.3 Hz, CH2, dia B), 21.02
C10H19O5P: C, 48.00; H, 7.65. Found: C, 48.21; H, 7.55.
(CH3CHO, dia A), 21.23 (CH3CHO, dia B), 27.20 (d,
3JCP¼5.5 Hz, CH2, dia A), 29.05 (d, 3JCP¼8.0 Hz, CH2, dia
4.4.8. (5-Ethyl-2-oxo-tetrahydro-pyran-3-yl)-phosphonic
acid diethyl ester (6h). (0.61 g, 58% yield); diasteroisomer
1
B), 38.66 (d, JCP¼137.1 Hz, CHP, dia A), 39.26 (d,
2
1JCP¼137.1 Hz, CHP, dia B), 62.33 (d, JCP¼6.9 Hz,
ratio 1.5:1; colorless oil; IR (film) 1736, 1252, 1176 cm21
;
2
CH2OP, dia A), 62.41 (d, JCP¼6.9 Hz, CH2OP, dia B),
31P NMR (CDCl3) d¼22.93, 22.88 (5h d¼24.06, 24.15); 1H
2
63.05 (d, JCP¼6.9 Hz, CH2OP, dia A), 63.21 (d,
NMR (CDCl3) d¼0.91 (t, 3H, 3JHH¼7.2 Hz, CH3CH2), 1.28
2JCP¼6.9 Hz, CH2OP, dia B), 77.12 (CHO, dia A), 77.37
(CHO, dia B), 166.21 (d, 2JCP¼3.8 Hz, COO, dia A), 166.62
(d, 2JCP¼3.8 Hz, COO, dia B). Anal. calcd for C10H19O5P:
C, 48.00; H, 7.65. Found: C, 48.12; H, 7.49.
(t, 3H, JHH¼7.0 Hz, CH3CH2OP), 1.29 (t, 3H,
3
3JHH¼7.0 Hz, CH3CH2OP), 1.31–1.91 (m, 3H, CH2, CH),
2.01–2.53 (m, 2H, CH2), 3.10 (ddd, 1H, 3JHH¼8.1, 10.8 Hz,
3
2JHP¼27.4 Hz, CHP, major), 3.15 (ddd, 1H, JHH¼4.2,
2
8.7 Hz, JHP¼27.4 Hz, CHP, minor), 3.97 (dd, 1H,
2
4.4.6. (2-Oxo-octahydro-chromen-3-yl)-phosphonic acid
diethyl ester (6f). (0.87 g, 75% yield); diasteroisomer ratio
3JHH¼9.0 Hz, JHH¼11.0 Hz, CHO, major), 4.06 (t, 1H,
3JHH¼2JHH¼11.0 Hz, CHO, minor), 4.08–4.22 (m, 4H,
2:1; colorless oil; IR (film) 1731, 1248, 1184 cm21
;
31P
2£CH2OP), 4.28 (ddd, 1H, JHH¼2.0 Hz, JHH¼5.0 Hz,
2JHH¼11.0 Hz, CHO, major), 4.41 (ddd, 1H, 4JHH¼2.0 Hz,
4
3
1
NMR (CDCl3) d¼22.70, 22.90 (5f d¼23.30, 23.50); H
3
2
NMR (CDCl3) d¼1.35 (t, 3H, JHH¼7.0 Hz, CH3CH2OP),
3JHH¼4.0 Hz, JHH¼11.0 Hz, CHO, minor); 13C NMR
1.36 (t, 3H, 3JHH¼7.0 Hz, CH3CH2OP), 1.03–1.60 (m, 4H,
2£CH2), 1.65–1.95 (m, 4H, 2£CH2), 2.05–2.44 (m, 3H,
CH2, CH), 3.07 (dt, 1H, 3JHH¼9.0 Hz, 2JHP¼27.5 Hz, CHP,
(CDCl3) d¼9.34 (CH3CH2, major), 9.40 (CH3CH2,
3
minor), 14.50 (d, JCP¼3.8 Hz, CH3CH2OP), 14.61 (d,
3JCP¼3.8 Hz, CH3CH2OP), 22.24 (CH2, minor), 22.60
3
2
2
minor), 3.15 (dt, 1H, JHH¼8.5 Hz, JHP¼27.7 Hz, CHP,
major), 3.91–4.15 (m, 5H, 2£CH2OP, CHO); 13C NMR
(CH2, major), 25.00 (d, JCP¼4.6 Hz, CH2CHP, minor),
2
25.62 (d, JCP¼4.2 Hz, CH2CHP, major), 30.58 (d,
3
3
(CDCl3) d¼15.81 (d, JCP¼4.7 Hz, CH3CH2OP), 15.91 (d,
3JCP¼4.9 Hz, CH, minor), 33.02 (d, JCP¼8.7 Hz, CH,
3JCP¼4.7 Hz, CH3CH2OP), 23.22 (CH2, major), 23.35
(CH2, minor), 24.32 (CH2, major), 24.41 (CH2, minor),
27.53 (d, 2JCP¼4.0 Hz, CH2, minor), 27.91 (d, 2JCP¼4.0 Hz,
CH2, major), 30.11 (CH2, major), 30.22 (CH2, minor), 31.32
major), 37.01 (d, JCP¼137.7 Hz, CHP, minor), 37.61 (d,
1
2
1JCP¼137.7 Hz, CHP, major), 60.91 (d, JCP¼6.5 Hz,
2
CH2OP, major), 61.01 (d, JCP¼6.5 Hz, CH2OP, minor),
2
61.62 (d, JCP¼6.5 Hz, CH2OP, major), 61.82 (d,
3
(CH2, minor), 31.51 (CH2, major), 36.05 (d, JCP¼4.0 Hz,
2JCP¼6.5 Hz, CH2OP, minor), 71.51 (CH2O, minor),
3
2
CH, major), 37.61 (d, JCP¼8.0 Hz, CH, minor), 39.16 (d,
71.64 (CH2O, major), 164.71 (d, JCP¼4.4 Hz, COO,
1
2
1JCP¼137.8 Hz, CHP, minor), 39.82 (d, JCP¼137.8 Hz,
major), 164.91 (d, JCP¼4.4 Hz, COO, minor). Anal. calcd
CHP, major), 61.72 (d, 2JCP¼6.8 Hz, CH2OP, minor), 61.92
for C11H21O5P: C, 50.00; H, 8.01. Found: C, 50.12; H, 8.14.
2
2
(d, JCP¼6.8 Hz, CH2OP, major), 62.73 (d, JCP¼6.8 Hz,
2
CH2OP, minor), 62.93 (d, JCP¼6.8 Hz, CH2OP, major),
4.4.9. (5-Butyl-2-oxo-tetrahydro-pyran-3-yl)-phosphonic
acid diethyl ester (6i). (0.76 g, 65% yield); diasteroisomer
82.21 (CHO, major), 82.92 (CHO, minor), 165.51 (d,
2JCP¼4.4 Hz, COO, major), 166.18 (d, 2JCP¼4.4 Hz, COO,
minor). Anal. calcd for C13H23O5P: C, 53.79; H, 7.99.
Found: C, 53.91; H, 7.73.
ratio 1.3:1; colorless oil; IR (film) 1736, 1252, 1160 cm21
;
31P NMR (CDCl3) d¼22.56, 22.64 (5i d¼23.89, 23.96); 1H
3
NMR (CDCl3) d¼0.84 (t, 3H, JHH¼6.2 Hz, CH3CH2),
3
1.17–1.27 (m, 6H, 3£CH2), 1.28 (t, 3H, JHH¼7.0 Hz,
3
4.4.7. (5-Methyl-2-oxo-tetrahydro-pyran-3-yl)-phos-
phonic acid diethyl ester (6g). (0.60 g, 60% yield);
diasteroisomer ratio 1.5:1; colorless oil; IR (film) 1737,
CH3CH2OP), 1.29 (t, 3H, JHH¼7.0 Hz, CH3CH2OP),
3
1.61–2.40 (m, 3H, CH2, CH), 3.09 (ddd, 1H, JHH¼8.5,
9.2 Hz, 2JHP¼27.2 Hz, CHP, major), 3.11 (ddd, 1H, 3JHH
¼
1252, 1160 cm21
;
31P NMR (CDCl3) d¼22.50, 22.61 (5g
5.5, 8.2 Hz, JHP¼27.2 Hz, CHP, minor), 3.91 (dd, 1H,
2
d¼23.59, 23.70); 1H NMR (CDCl3) d¼1.02 (d, 3H,
3JHH¼8.7 Hz, JHH¼11.0 Hz, CHO, major), 4.11 (t, 1H,
2
3JHH¼6.5 Hz, CH3CH), 1.26 (t, 3H, JHH¼7.0 Hz, CH3-
3JHH¼2JHH¼11.0 Hz, CHO, minor), 4.01–4.20 (m, 4H,
3
CH2OP), 1.28 (t, 3H, 3JHH¼7.0 Hz, CH3CH2OP), 1.73–2.51
2£CH2O), 4.25 (ddd, 1H, JHH¼3.0 Hz, JHH¼5.0 Hz,
4
3
3
4
(m, 3H, CH2, CH), 3.18 (ddd, 1H, JHH¼8.2, 9.7 Hz,
2JHH¼11.0 Hz, CHO, 1H, minor), 4.40 (ddd, 1H, JHH
¼
2JHP¼27.5 Hz, CHP, major), 3.20 (ddd, 1H, JHH¼4.7,
1.7 Hz, JHH¼4.7 Hz, JHH¼11.0 Hz, CHO, major); 13C
3
3
2
2
3
8.0 Hz, JHP¼27.7 Hz, CHP, minor), 3.94 (dd, 1H, JHH
¼
NMR (CDCl3) d¼13.63 (CH3CH2, major), 13.65 (CH3CH2,
2
3
3
9.0 Hz, JHH¼11.0 Hz, CHO, major), 4.06 (t, 1H, JHH
¼
minor), 16.05 (d, JCP¼3.8 Hz, CH3CH2OP), 16.15 (d,
2JHH¼11.0 Hz, CHO, minor), 4.15–4.30 (m, 4H, 2£CH2OP),
3JCP¼3.8 Hz, CH3CH2OP), 22.35 (CH2, minor), 22.41
4
3
2
2
4.25 (ddd, 1H, JHH¼2.0 Hz, JHH¼5.0 Hz, JHH¼11.0 Hz,
(CH2, major), 26.92 (d, JCP¼4.4 Hz, CH2CHP, minor),
4
3
2
CHO, major), 4.41 (ddd, JHH¼2.0 Hz, JHH¼4.0 Hz,
27.63 (d, JCP¼4.4 Hz, CH2CHP, major), 28.51 (CH2,

´
H. Krawczyk, M. Sliwinski / Tetrahedron 59 (2003) 9199–9211
´
9209
3
major), 28.60 (CH2, minor), 30.50 (CH2, major), 30.71 (d,
3JCP¼4.9 Hz, CH, minor), 30.91 (CH2, minor), 33.01 (d,
CHP, major), 44.51 (d, JCP¼9.1 Hz, C, minor), 45.21 (d,
3JCP¼6.5 Hz, C, major), 60.91 (CH2O, major), 61.22
1
2
3JCP¼8.7 Hz, CH, major), 38.61 (d, JCP¼138.0 Hz, CHP,
(CH2O, minor), 63.03 (d, JCP¼6.5 Hz, CH2OP), 63.61 (d,
1
minor), 39.71 (d, JCP¼138.0 Hz, CHP, major), 62.41 (d,
2JCP¼6.5 Hz, CH2OP), 78.71 (CHO, minor), 81.62 (CHO,
2
2
2JCP¼6.7 Hz, CH2OP, major), 62.51 (d, JCP¼6.7 Hz,
major), 165.11 (d, JCP¼4.4 Hz, COO, major), 165.91 (d,
2
CH2OP, minor), 63.22 (d, JCP¼6.7 Hz, CH2OP, major),
2JCP¼4.4 Hz, COO, minor), 171.71 (COOCH2CH3, major),
173.57 (COOCH2CH3, minor). Anal. calcd for C16H27O7P:
C, 53.03; H, 7.51. Found: C, 53.18; H, 7.69.
63.34 (d, 2JCP¼6.7 Hz, CH2OP, minor), 73.4 (CH2O, major),
73.51 (CH2O, minor), 166.21 (d, 2JCP¼4.4 Hz, COO, major),
2
166.45 (d, JCP¼4.4 Hz, COO, minor). Anal. calcd for
C13H25O5P: C, 53.42; H, 8.62. Found: C, 53.58; H, 8.79.
4.5. General procedure for synthesis of
methylenelactones 7a–k
4.4.10. (5-Benzyl-2-oxo-tetrahydro-pyran-3-yl)-phos-
phonic acid diethyl ester (6j). (0.81 g, 62% yield);
diasteroisomer ratio 1:1; colorless oil; IR (film) 3035,
A mixture of a-phosphonolactone 6 (a–k) (2.5 mmol),
potassium carbonate (1.04 g, 7.5 mmol) and aqueous 36%
formaldehyde (0.35 ml), in THF (3 ml) was stirred at 08C
for 30 min. The mixture was then extracted with diethyl
ether (3£15 ml). The organic layer was washed with
saturated sodium chloride solution (10 ml) dried (MgSO4)
and evaporated. The oil residue was purified by column
chromatography on silica gel using AcOEt/hexane (1:2) as
eluent.
1732, 1252, 1160 cm21
;
31P NMR (CDCl3) d¼22.65, 22.70
(5j d¼23.95, 24.05); 1H NMR (CDCl3) d¼1.32 (t, 3H,
3
3JHH¼7.0 Hz, CH3CH2OP), 1.34 (t, 3H, JHH¼7.0 Hz,
CH3CH2OP), 1.85–2.05 (m, 1H, CH), 2.11–2.45 (m, 2H,
CH2), 2.55–2.75 (m, 2H, CH2), 3.16 (ddd, 1H, JHH¼8.5,
3
2
3
9.6 Hz, JHP¼27.3 Hz, CHP, dia A), 3.15 (ddd, JHH¼5.0,
2
8.0 Hz, JHP¼27.5 Hz, CHP, dia B), 4.05 (dd, 1H,
3JHH¼7.7 Hz, JHH¼11.0 Hz, CHO, dia A), 4.03–4.11 (m,
2
1H, CHO, dia B), 4.12–4.26 (m, 4H, 2£CH2OP), 4.27–4.32
4.5.1. 5,5-Dimethyl-3-methylene-tetrahydro-pyran-2-
one (7a). (0.23 g, 65% yield); colorless oil; IR (film)
4
(m, 1H, CHO, dia B), 4.40 (ddd, 1H, JHH¼1.0 Hz,
3JHH¼4.0 Hz, JHH¼11.0 Hz, CHO, dia A), 7.11–7.36 (m,
3080, 1724, 1632, 1204 cm21; H NMR (CDCl3): d¼0.97
2
1
5H, C6H5,); 13C NMR (CDCl3) d¼16.01 (d, JCP¼4.2 Hz,
(s, 6H, 2£CH3), 2.37–2.39 (m, 2H, CH2), 3.96 (s, 2H,
CH2O), 5.53 (q, 1H, 2JHH¼4JHH¼1.7 Hz, CH), 6.45 (q, 1H,
2JHH¼4JHH¼1.7 Hz, CH); 13C NMR (CDCl3): d¼23.66
(2£CH3), 30.06 (C), 41.44 (CH2), 78.30 (CH2O), 128.40
(CH2), 132.60 (C), 164.50 (COO). Anal. calcd for C8H12O2:
C, 68.54; H, 8.63. Found: C, 68.67; H, 8.51.
3
3
CH3CH2OP), 16.11 (d, JCP¼4.2 Hz, CH3CH2OP), 26.44
2
2
(d, JCP¼4.2 Hz, CH2CHP, dia A), 27.32 (d, JCP¼4.2 Hz,
CH2CHP, dia B), 32.11 (d, 3JCP¼4.6 Hz, CH, dia A), 34.73
3
(d, JCP¼8.8 Hz, CH, dia B), 36.93 (CH2, dia A), 37.55
(CH2, dia B), 38.61 (d, 1JCP¼138.9 Hz, CHP, dia A), 39.41
1
2
(d, JCP¼138.9 Hz, CHP, dia B), 62.34 (d, JCP¼5.8 Hz,
2
CH2OP, dia A), 62.44 (d, JCP¼5.8 Hz, CH2OP, dia B),
4.5.2. 4-Methylene-2-oxaspiro [5.5] undecan-3-one (7b).
(0.32 g, 70% yield), colorless oil; IR (film) 3082, 1720,
2
63.25 (d, JCP¼5.8 Hz, CH2OP, dia A), 63.28 (d,
2JCP¼5.8 Hz, CH2OP, dia B), 72.60 (CH2O, dia A), 72.74
(CH2O, dia B), 126.31 (CH, dia A), 126.40 (CH, dia B),
128.31 (4£CH, dia A), 128.51 (4£CH, dia B), 137.62 (C, dia
A), 137.76 (C, dia B), 164.05 (d, 2JCP¼4.4 Hz, COO, dia A),
1640, 1201 cm21
;
1H NMR (CDCl3): d¼1.38–1.50 (m,
10H, 5£CH2), 2.49–2.51 (m, 2H, CH2), 4.10 (s, 2H, CH2O),
2
2
5.55 (q, 1H, JHH¼4JHH¼1.7 Hz, CH), 6.41 (q, 1H, JHH
¼
4JHH¼1.7 Hz, CH); 13C NMR (CDCl3): d¼20.24 (2£CH2),
25.01 (CH2), 31.58 (2£CH2), 32.02 (C), 37.90 (CH2), 77.30
(CH2O), 127.80 (C), 131.80 (CH2), 164.60 (COO). Anal.
calcd for C11H16O2: C, 73.30; H, 8.95. Found: 73.41; H,
9.12.
2
164.16 (d, JCP¼4.4 Hz, COO, dia B). Anal. calcd for
C16H23O5P: C, 58.89; H, 7.10. Found: C, 59.02; H, 7.25.
4.4.11. 3-(Diethoxyphosphoryl)-2-oxo-hexahydro-chro-
mene-4a-carboxylic acid ethyl ester (6k). (1.13 g, 78%
yield); diasteroisomer ratio 2:1; colorless oil; IR (film)
4.5.3. 5-Methyl-3-methylene-5-propyl-tetrahydro-
pyran-2-one (7c). (0.28 g, 67% yield), colorless oil; IR
1730, 1248, 1144 cm21
;
31P NMR (CDCl3) d¼23.11, 22.45
1
1
(5k d¼24.12, 24.25); H NMR (CDCl3) d¼1.27 (t, 3H,
(film) 3080, 1728, 1628, 1248 cm21; H NMR (CDCl3):
3JHH¼7.0 Hz, CH3CH2O), 1.35 (t, 3H, 3JHH¼7.2 Hz, CH3-
d¼0.82 (t, 3H, JHH¼7.0 Hz, CH3), 0.91 (s, 3H, CH3),
3
3
4
CH2OP), 1.36 (t, 3H, JHH¼7.2 Hz, CH3CH2OP), 1.41–
1.14–1.32 (m, 4H, 2£CH2), 2.33 (ddt, 1H, JHH¼1.2,
2
4
1.72 (m, 4H, 2£CH2), 1.82–2.12 (m, 4H, 2£CH2), 2.21–
1.7 Hz, JHH¼15.7 Hz, CH), 2.42 (ddt, 1H, JHH¼1.2,
2
4
2.31 (m, 1H, CHCHP, major), 2.33–2.42 (m, 1H, CHCHP
minor), 2.45 (ddd, 1H, JHP¼5.7 Hz, JHH¼9.5 Hz,
1.7 Hz, JHH¼15.7 Hz, CH), 3.94 (dd, 1H, JHH¼1.2 Hz,
3
3
4
2JHH¼11.0 Hz, CHO), 4.01 (dd, 1H, JHH¼1.2 Hz,
2JHH¼14.0 Hz, CHCHP, major), 2.60 (ddd, 1H,
2JHH¼11.0 Hz, CHO), 5.46 (q, 1H, JHH¼4JHH¼1.7 Hz,
2
2
3
2
3JHH¼9.0 Hz, JHH¼14.2 Hz, JHP¼17.0 Hz, CHCHP,
CH), 6.37 (q, 1H, JHH¼4JHH¼1.7 Hz, CH); 13C NMR
3
2
minor), 3.20 (ddd, 1H, JHH¼9.0, 10.0 Hz, JHP¼27.5 Hz,
(CDCl3): d¼13.67 (CH3), 15.54 (CH3), 20.24 (CH2), 32.14
(C), 38.18 (CH2), 39.48 (CH2), 76.62 (CH2O), 128.0 (CH2),
131.9 (C), 164.41 (COO). Anal. calcd for C10H16O2: C,
71.39; H, 9.59. Found: C, 71.51; H, 9.72.
3
2
CHP, minor), 3.32 (dt, 1H, JHH¼9.5 Hz, JHP¼27.5 Hz,
CHP, major), 4.15–4.32 (m, 7H, 2£CH2OP, CH3CH2O,
CHO); 13C NMR (CDCl3) d¼13.86 (CH3), 16.10 (d,
2JCP¼4.7 Hz, 2£CH3CH2OP), 18.15 (d, JCP¼4.7 Hz,
2
2
CH2, minor), 20.51 (CH2, minor), 21.61 (d, JCP¼4.7 Hz,
4.5.4. 5-Methyl-3-methylene-5-phenyl-tetrahydro-
pyran-2-one (7d). (0.32 g, 63% yield), colorless oil; IR
CH2, major), 23.41 (CH2, major), 26.61 (CH2, minor), 27.61
(CH2, major), 31.63 (CH2, minor), 32.41 (CH2, minor),
33.50 (CH2, major), 34.61 (CH2, major), 36.91 (d,
(film) 3080, 3050, 1728, 1630, 1230 cm21 1H NMR
;
4
(CDCl3): d¼1.29 (s, 3H, CH3), 2.74 (dq, 1H, JHH
¼
1JCP¼138.2 Hz, CHP, minor), 39.33 (d, JCP¼138.2 Hz,
1.7 Hz, JHH¼15.5 Hz, CH), 3.07 (dq, 1H, JHH¼1.7 Hz,
1
2
4

´
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H. Krawczyk, M. Sliwinski / Tetrahedron 59 (2003) 9199–9211
9210
4
2
2JHH¼15.5 Hz, CH), 4.28 (dd, 1H, JHH¼1.7 Hz, JHH
¼
4.5.9. 5-Butyl-3-methylene-tetrahydro-pyran-2-one (7i).
(0.27 g, 65% yield), colorless oil; IR (film) 3082, 1724,
11.2 Hz, CHO), 4.52 (dd, 1H, 4JHH¼1.7 Hz, 2JHH¼11.2 Hz,
CHO), 5.51 (q, 1H, JHH¼4JHH¼1.7 Hz, CH), 6.36 (q, 1H,
1645, 1220 cm21
;
1H NMR (CDCl3): d¼0.91 (t, 3H,
2
2JHH¼4JHH¼1.7 Hz, CH), 7.15–7.28 (m, 5H, C6H5);
13CNMR (CDCl3): d¼25.11 (CH3), 37.70 (C), 41.07
(CH2), 77.01 (CH2O), 125.70 (2£CH), 127.10 (CH),
128.85 (2£CH), 129.57 (CH2), 132.58 (C), 142.73 (C),
164.74 (COO). Anal. calcd for C13H14O2: C, 77.20; H, 6.98.
Found: C, 77.42; H, 7.12.
3JHH¼6.7 Hz, CH3), 1.21–1.37 (m, 6H, 3£CH2), 1.93–
3
2.04 (m, 1H, JHH¼3.7, 4.5, 9.2, 10.0 Hz, CH), 2.31 (ddt,
4
3
2
1H, JHH¼2.2 Hz, JHH¼10.0 Hz, JHH¼15.7 Hz, CH),
4
3
2
2.82 (ddq, 1H, JHH¼2.2 Hz, JHH¼4.5 Hz, JHH
¼
3
2
15.7 Hz, CH), 4.02 (dd, 1H, JHH¼9.2 Hz, JHH¼11.0 Hz,
4
3
CHO), 4.35 (ddd, 1H, JHH¼2.2 Hz, JHH¼3.7 Hz,
2JHH¼11.0 Hz, CHO), 5.52 (q, 1H, JHH¼4JHH¼2.2 Hz,
2
2
4.5.5. 6-Methyl-3-methylene-tetrahydro-pyran-2-one
(7e). (0.31 g, 60% yield), colorless oil; IR (film) 3065,
1720, 1628, 1190 cm21; 1H NMR (CDCl3): d¼1.40 (d, 3H,
CH), 6.40 (q, 1H, JHH¼4JHH¼2.2 Hz, CH); 13C NMR
(CDCl3): d¼13.91 (CH3), 22.71 (CH2), 28.85 (CH2), 30.53
(CH2), 33.55 (CH), 34.41 (CH2), 73.46 (CH2O), 128.43
(CH2), 133.62 (C), 165.61 (COO). Anal. calcd for
C10H16O2: C, 71.39; H, 9.59. Found: C, 71.52; H, 9.77.
3JHH¼6.2 Hz, CH3), 1.67 (dddd, 1H, JHH¼5.5, 10.2,
3
2
3
12.0 Hz, JHH¼14.0 Hz, CH), 1.94–2.03 (m, 1H, JHH
¼
2
4
2.5, 5.0 Hz, JHH¼14.0 Hz, CH), 2.57 (dddt, 1H, JHH
¼
2.5 Hz, 3JHH¼5.0, 12.0 Hz, 2JHH¼16.2 Hz, CH), 2.60–2.78
4.5.10. 5-Benzyl-3-methylene-tetrahydro-pyran-2-one
(7j). (0.32 g, 65% yield), colorless oil; IR (film) 3090,
3016, 1724, 1627, 1228 cm21; 1H NMR (CDCl3): d¼2.23–
2.43 (m, 2H, CH2), 2.61–2.74 (m, 3H, CH2, CH), 4.05 (dd,
4
3
2
(m, 1H, JHH¼1.5 Hz, JHH¼5.5 Hz, JHH¼16.2 Hz, CH),
3
4.5 (ddq, 1H, JHH¼2.5, 6.2, 10.2 Hz, CHO), 5.50 (dt, 1H,
4JHH¼2JHH¼1.5 Hz, JHH¼2.5 Hz, CH), 6.40 (dt, 1H,
4
4JHH¼2JHH¼1.5 Hz, JHH¼2.5 Hz, CH); 13C NMR
1H, JHH¼9.2 Hz, JHH¼11.0 Hz, CHO), 4.32 (ddd, 1H,
4JHH¼2.0 Hz, 3JHH¼3.5 Hz, 2JHH¼11.0 Hz, CHO), 5.53 (q,
1H, 2JHH¼4JHH¼1.7 Hz, CH), 6.42 (q, 1H, 2JHH¼4JHH¼1.7
Hz, CH), 7.11–7.35 (m, 5H, C6H5); 13C NMR (CDCl3):
d¼33.91 (CH2), 35.25 (CH), 37.32 (CH2), 73.01 (CH2O),
126.72 (CH), 128.33 (2£CH), 128.71 (2£CH), 129.11
(CH2), 133.12 (C), 138.25 (C), 165.31 (COO). Anal. calcd
for C13H14O2: C, 77.20; H, 6.98. Found: C, 77.35; H, 7.15.
4
3
2
(CDCl3): d¼20.80 (CH3), 26.60 (CH2), 29.50 (CH2),
77.70 (CHO), 127.80 (CH2), 133.40 (C), 169.60 (COO).
Anal. calcd for C7H10O2: C, 66.65; H, 7.99. Found: C,
66.78; H, 8.15.
4.5.6.
3-Methylene-octahydro-chromen-2-one
(7f).
(0.29 g, 70% yield); diasteroisomer ratio 2:1; trans: white
solid, mp 33–358C (lit.17 34–368C); cis: white solid, mp
61–638C (lit.17 61–638C). Anal. calcd for C10H14O2: C,
72.26; H, 8.49. Found: C, 72.38; H, 8.62. All spectroscopic
data for trans and cis isomers are in according with the
literature.17
4.5.11. 3-Methylene-2-oxo-hexahydro-chromene-4a-car-
boxylic acid ethyl ester (7k). (0.41 g, 68% yield); ethyl
acetate/hexane (1:9) as eluent; diasteroisomer ratio 2:1; IR
(KBr) 3085, 1723, 1620, 1236 cm21; trans: white solid mp
45–478C; 1H NMR (CDCl3): d¼1.28 (t, 3H, 3JHH¼7.0 Hz,
CH3), 1.35–2.01 (m, 7H, 3£CH2, CH), 2.28 (dq, 1H,
4.5.7. 5-Methyl-3-methylene-tetrahydro-pyran-2-one
(7g). (0.20 g, 63% yield), colorless oil; IR (film) 3089,
1721, 1645, 1232 cm21; 1H NMR (CDCl3): d¼1.02 (d, 3H,
3JHH¼6.5 Hz, CH3), 2.08–2.22 (m, 1H, CH), 2.31 (ddt, 1H,
2
4
4JHH¼2.7 Hz, JHH¼13.5 Hz, CH), 2.51 (dt, 1H, JHH
¼
2
4
2.7 Hz, JHH¼16.0 Hz, CH), 2.95 (dt, 1H, JHH¼1.2 Hz,
2JHH¼16.0 Hz, CH), 4.20 (q, 2H, 3JHH¼7.0 Hz, CH2), 4.21
4JHH¼2.2 Hz, JHH¼10.5 Hz, JHH¼15.5 Hz, CH), 2.76
(d, 1H, JHH¼16.0 Hz, CHO), 5.63 (dt, 1H, JHH
¼
3
2
3
2
(dddt, 1H, 4JHH¼1.5, 2.2 Hz, 3JHH¼5.5 Hz, 2JHH¼15.5 Hz,
4JHH¼1.2 Hz, JHH¼2.7 Hz, CH), 6.52 (dt, 1H, JHH
¼
4
2
4
3
2
CH), 3.99 (dd, 1H, JHH¼9.5 Hz, JHH¼11.0 Hz, CHO),
JHH¼1.2, 4JHH¼2.7 Hz, CH), 13C NMR (CDCl3): d¼13.81
(CH3), 21.67 (CH2), 23.78 (CH2), 27.88 (CH2), 34.59
(CH2), 40.31 (CH2), 46.62 (C), 60.37 (CH2O), 82.64 (CHO),
128.44 (CH2), 132.58 (C), 164.77 (COO), 172.44
(COOCH2CH3); cis: colorless oil; 1H NMR (CDCl3):
4.32 (ddd, 1H, 4JHH¼2.2 Hz, 3JHH¼3.7 Hz, 2JHH¼11.0 Hz,
CHO), 5.52 (dt, 1H, JHH¼4JHH¼1.5 Hz, JHH¼2.2 Hz,
CH), 6.43 (dt, 1H, 2JHH¼4JHH¼1.5 Hz, 4JHH¼2.2 Hz, CH);
13C NMR (CDCl3): d¼15.71 (CH3), 28.24 (CH), 35.86
(CH2), 74.55 (CH2O), 127.91 (CH2), 133.24 (C), 164.93
(COO). Anal. calcd for C7H10O2: C, 66.65; H, 7.99. Found:
C, 66.79; H, 8.16.
2
4
3
d¼1.26 (t, 3H, JHH¼7.1 Hz, CH3), 1.35–2.01 (m, 8H,
4
2
4£CH2), 2.72 (dt, 1H, JHH¼1.5 Hz, JHH¼16.1 Hz, CH),
4
2
2.87 (dt, 1H, JHH¼ 2.4 Hz, JHH¼16.1 Hz, CH), 4.23 (q,
2H, 3JHH¼7.1 Hz, CH2O), 4.89 (t, 1H, 3JHH¼5.0 Hz, CHO),
5.62 (dt, 1H, 2JHH¼4JHH¼1.5, 4JHH¼2.4 Hz, CH), 6.51 (dt,
4.5.8. 5-Ethyl-3-methylene-tetrahydro-pyran-2-one (7h).
(0.21 g, 60% yield), colorless oil; IR (film) 3080, 1730,
1H, JHH¼4JHH¼1.5, JHH¼2.4 Hz, CH); 13C NMR
(CDCl3): d¼13.94 (CH3), 19.91 (CH2), 21.32 (CH2),
28.50 (2£CH2), 35.59 (CH2), 44.95 (C), 61.08 (CH2O),
78.90 (CHO), 129.11 (CH2), 130.96 (C), 164.43 (COO),
173.34 (COOCH2CH3). Anal. calcd for C13H18O4: C, 65.53;
H, 7.61. Found: C, 65.72; H, 7.85.
2
4
1628, 1225 cm21
;
1H NMR (CDCl3): d¼0.98 (t, 3H,
3JHH¼7.5 Hz, CH3), 1.25–1.47 (m, 2H, CH2), 1.84–2.02
4
3
(m, 1H, CH), 2.33 (ddt, 1H, JHH¼2.2 Hz, JHH¼10.2 Hz,
2JHH¼15.7 Hz, CH), 2.77 (ddq, 1H, JHH¼2.2 Hz,
4
3JHH¼4.5 Hz, JHH¼15.7 Hz, CH), 4.03 (dd, 1H, JHH
¼
2
3
9.0 Hz, 2JHH¼11.0 Hz, CHO), 4.37 (ddd, 1H, 4JHH¼2.2 Hz,
3JHH¼3.7 Hz, JHH¼11.0 Hz, CHO), 5.52 (q, 1H, JHH
¼
2
2
4JHH¼2.2 Hz, CH), 6.42 (q, 1H, JHH¼4JHH¼2.2 Hz, CH);
13C NMR (CDCl3): d¼11.21 (CH3), 23.85 (CH2), 34.02
(CH), 35.15 (CH2), 73.42 (CH2O), 128.41 (CH2), 133.53
(C), 165.61 (COO). Anal. calcd for C8H12O2: C, 68.54; H,
8.63. Found: C, 68.42; H, 8.80.
2
Acknowledgements
This work has been supported by the Polish State Commitee
for Scientific Research (KBN, Project No 4 T09B 054 24).

´
H. Krawczyk, M. Sliwinski / Tetrahedron 59 (2003) 9199–9211
´
9211
17. Ghera, E.; Yechezkel, T.; Hassner, A. J. Org. Chem. 1990, 55,
5977–5982.
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