Asymmetric Michael reaction: novel efficient access to chiral β-ketophosphonates

Article abstract of DOI:10.1016/j.tetasy.2007.02.023

The asymmetric Michael reaction between chiral β-enaminophosphonates derived from (S)-1-phenylethylamine and various electrophilic alkenes furnished β,β-disubstituted ketophosphonates in good yields and with excellent enantioselectivity.

Full text of DOI:10.1016/j.tetasy.2007.02.023

Tetrahedron: Asymmetry 18 (2007) 685–691
Asymmetric Michael reaction: novel efficient access to chiral
b-ketophosphonates
c
a,b
a,b
Sandrine Delarue-Cochin,a,b, Jian-Jung Pan, Aurelie Dauteloup, Frederic Hendra,
*
´
´ ´
Roger Gagali Angoh,a,b Delphine Joseph,a,b Philip J. Stephens and Christian Cave
c
a,b
´
a
` ˆ
Univ. Paris-Sud, Equipe de Sythese Organique et Pharmacochimie, UMR CNRS 8076 BioCIS, Chatenay-Malabry F-92296, France
b
ˆ
CNRS, Chatenay-Malabry F-92296, France
cDepartment of Chemistry, University of Southern California, Los Angeles, CA 90089-0482, USA
Received 15 February 2007; accepted 26 February 2007
Abstract—The asymmetric Michael reaction between chiral b-enaminophosphonates derived from (S)-1-phenylethylamine and various
electrophilic alkenes furnished b,b-disubstituted ketophosphonates in good yields and with excellent enantioselectivity.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
which is secured by intramolecular hydrogen bonding
in the enaminoester reactant.2,3,16 By considering the
phosphonate as an ester analogue, we can anticipate
the existence of intramolecular hydrogen bonding in the
enaminophosphonate similar to that of the enaminoester
derivative. Herein, we report an investigation we have
made into the reaction between chiral enaminophos-
phonates and various electrophilic alkenes.
The Michael reaction is known to be one of the simplest
and most efficient methods for the construction of quater-
nary carbon centres. The use of asymmetric variants of this
reaction is well documented in the literature, the stereocon-
trolled synthesis of a quaternary carbon in particular being
a challenge for organic chemists. Asymmetric Michael
addition onto cyclic or acyclic b-ketoesters has been con-
sidered in various ways in the literature and particularly
via enaminoester derivatives.1–7 Until now, there has been
no report of such a study on b-ketophosphonates which
present great interest not only as precursors of b-amino-
and b-hydroxy-phosphonates8–11 but also as molecules of
biological importance.12–15 Thus, by developing simple
and efficient asymmetric synthetic pathways to chiral b-
ketophosphonates we would be able to find interesting
applications in both organic and medicinal chemistry.
2. Results and discussion
First of all, we synthesized the non-commercial b-keto-
phosphonate precursors 3a–3d (Scheme 1). For dialkyl-
phosphonates 3a (R = Et) and 3b (R = Me), the synthesis
was performed in a three step procedure developed by Cor-
bel et al: (a) protection of the ketone group via hydrazone
1, (b) Arbuzov reaction (intermediates 2a and 2b) then (c)
deprotection.17 This led to compounds 3a and 3b in good
yields, around 60–70% over three steps. For dibenzyl-
phosphonate 3c, the Arbuzov reaction was realized
under vacuum in an attempt to eliminate benzyl chloride
formed in the reaction and causing side reactions.18 This
proved to be unsuccessful, causing degradation. An alter-
native strategy was used with a direct nucleophilic substitu-
tion of the chlorine atom of compound 1 by the action of
the anion of dibenzylphosphite. When the reaction was car-
ried out at room temperature using Cs2CO3 as base,19 only
the b-elimination product was obtained. However, the use
In our laboratory, it has already been proven that Michael-
type additions of chiral acyclic enaminoesters derived from
(S)-1-phenylethylamine to various Michael acceptors fur-
nished, after hydrolysis, Michael adducts in good yields
and excellent enantiomeric excesses (ee).2,3,7 This remark-
able remote transfer of chirality can be explained by a
six-membered ‘aza-ene-synthesis-like’ transition state
*
Corresponding author. Tel.: +33 1 46 83 54 95; fax: +33 1 46 83 56 89;
e-mail: sandrine.delarue-cochin@u-psud.fr
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.02.023

686
S. Delarue-Cochin et al. / Tetrahedron: Asymmetry 18 (2007) 685–691
H
H
N
N
MeOOC
N
MeOOC
O
O
P
O
N
O
P
For R=Et, Me: P(OR)3,
PhCH3, reflux, 3h
HCl 3M
H2N-NH-COOMe
OR
OR
OR
OR
Cl
Cl
acetone
rt, 3h.
Et2O, rt, 3h
For R=CH2Ph, Ph:
LiHMDS, HPO(OR)2,
THF, -78˚C, 2h
3a: R=Et
3b: R=Me
3c: R=CH2Ph
3d: R=Ph
2a: R=Et
1
2b: R=Me
2c: R=CH2Ph
2d: R=Ph
Scheme 1. Synthesis of the ketophosphonate precursors 3a–3d.
at low temperature, ꢀ78 ꢁC, of LiHMDS,20 led, after
hydrolysis, to compound 3c in good yield (63%) over three
steps. The same procedure was performed successfully for
diphenylphosphonate 3d, even though in modest 35% yield,
over three steps.
Table 1. Reaction conditions, yield and enantiomeric excess for com-
pounds 5a–9a, 5b–5d
Entry Compd Reaction time T (ꢁC) Yield (%)
ee (%)
1
2
3
4
5a
6a
7a
8a
1 d
3 d
3 d
10 d
1 d (ZnCl2)
1 d
1 d
1 d
66
66
66
60
67
55
65
40
94a
88a
88b
85b
84b
—
These compounds were then condensed with (S)-1-phenyl-
ethylamine in refluxing toluene or cyclohexane to give
the corresponding imino/enaminophosphonates 4a–4d
(Scheme 2). Compounds 4a–4c exist in an approximately
35/65 imino/enamino ratio, while compound 4d exists only
in the enamino form. Additions of these crude imino/
enaminophosphonates 4a–4d to Michael acceptors, such
as phenylvinylsulfone, benzyl and methyl acrylates, acrylo-
nitrile and methylvinylketone (MVK), were performed
under neutral conditions in THF. Reaction evolution was
followed by 31P NMR and reaction conditions are summa-
rized in Table 1.
62
5
6
7
8
9a
5b
5c
5d
20
66
66
66
Degradation
Degradation
39
—
70c
—
1 d
No reaction
a Determined by chiral HPLC.
b Determined by chiral HPLC via the derivative 6a.
c Determined by 31P NMR on the imino intermediate.
are in general comparable to those obtained for enamino-
ester analogues.7
In the case of dimethylphosphonate derivative 5b (entry 6),
In the case of the diethylphosphonate derivatives, Michael
adducts were obtained, after hydrolytic workup (10%
AcOH in water, rt, 4 h), in good yields (55–67% over three
steps, entries 1–4) except for MVK derivative 9a (entry 5).
Whatever the hydrolytic conditions, it always led to the
degradation of the imino precursor. Yields and reactivities
the Michael adduct was obtained after hydrolytic workup
1
as the major product, according to the H and 31P NMR
spectra of the crude product, but was degraded during
attempts at purification by column chromatography or
distillation.
Ph
Ph
Me
Me
O
O
P
NH
O
P
N
O
P
H
H
OR
OR
(S)-1-phenylethylamine,
OR
OR
OR
OR
APTS, PhCH3 or C6H12
,
H2C=CH-X, THF,
60˚C or reflux, 1 day
to 10 days then
reflux, overnight
3a: R=Et
3b: R=Me
3c: R=CH2Ph
3d: R=Ph
4a: R=Et
AcOH 10%, rt, 4h;
4b: R=Me
4c: R=CH2Ph
4d: R=Ph
O
O
OR
P
5a: R=Et, X=SO2Ph
6a: R=Et, X=COOBn
7a: R=Et, X=COOMe
8a: R=Et, X=CN
5b: R=Me, X=SO2Ph
OR
BnOH, APTS,
50˚C, 72h
HCl(g), BnOH, -20˚C, 70 h
then HCl 6M, 0˚C, 10 min.
5c: R=CH2Ph, X=SO2Ph
5d: R=Ph, X=SO2Ph
X
9a: R=Et, X=COCH3
Scheme 2. Synthesis of the Michael adducts.

S. Delarue-Cochin et al. / Tetrahedron: Asymmetry 18 (2007) 685–691
687
The dibenzyl- and diphenyl-phosphonate groups should be
more interesting than their diethylphosphonate homo-
logues in the determination of enantiomeric excess by
HPLC. In fact, they possessed the chromophore necessary
for HPLC characterization.
The last goal of our work was determination of the
absolute configurations of these adducts. Many attempts
have been made to synthesize a solid derivative in order
to obtain a single-crystal sample for X-ray analysis, but
all attempts have proven unsuccessful. We have therefore
used the vibrational circular dichroism (VCD) technique,
now widely used to determine the absolute configurations
of small-to-medium sized organic molecules.23–26
Unfortunately, the introduction of such groups caused an
important decrease in the reactivity of the imino/enam-
inophosphonates 4c and 4d, probably due to disfavoured
steric hindrance for the formation of the six-membered
transition state. For benzyl imino/enaminophosphonate
4c, it led to a lower yield of the ketophosphonate 5c, only
39% (entry 7). For phenyl enaminophosphonate 4d, we did
not observe any reaction under the classical conditions
(entry 8).
The experimental VCD of 7a in CDCl3 solution is shown in
Figure 1. Conformational analysis (Section 4.8), followed
by the density functional theory (DFT) calculation (using
GAUSSIAN 0327) of the VCD spectra of the ten significantly
populated conformations identified leads, for (S)-7a, to the
conformationally averaged VCD spectrum shown in Fig-
ure 1. The agreement of the calculated and experimental
VCD spectra is moderately good (allowing for the shift in
frequency due to the absence of anharmonicity in the calcu-
lations, and the less-than-perfect signal-to-noise ratio of
Enantiomeric excesses (ees) of the Michael adducts 5a–8a
were then determined by chiral HPLC using a Daicel
Chiralcel OD column. UV detection needed a chromo-
phore group, existing in compounds 5a and 6a but not in
compounds 7a and 8a. Ees of compounds 5a and 6a were
thus determined directly but for compounds 7a and 8a it
was necessary to introduce a chromophoric group. A
transesterification of the methyl ester derivative 7a or the
Pinner reaction21 applied to the cyano derivative 8a in ben-
zylic alcohol led to benzyl ester 6a. The ees of the com-
pounds 5a–8a were in all cases good to excellent, between
85% and 94% (Table 1, entries 1–4), similar to those
obtained for enaminoester derivatives (ee > 90%).7
Contrary to our expectations, the ee of the Michael adduct
5c could not be obtained by chiral HPLC with the Daicel
OD column. Whatever the conditions used (varying the
chiral column, flow and solvents ratio), the two enantio-
mers could not be separated. However, analysis of the
31P NMR of the imino intermediate of 5c before hydrolysis
showed the presence of two diastereomers at 42.14 ppm
(85%) and 42.48 ppm (15%). This allowed us to evaluate
the ee of 5c as 70%. This low ee could be explained either
by considering the steric hindrance caused by the two benz-
ylic groups, which modified the usual approach of the two
reactants or by an interfering retro-Michael process taking
place during workup, a phenomenon already observed in
the case of benzylic enaminoester.22
Figure 1. The experimental mid-IR VCD spectrum of (ꢀ)-7a (normalized
We can conclude that the introduction of dibenzyl- or di-
phenyl-phosphonate groups caused a dramatic decrease
in reactivity and/or in enantioselectivity in comparison
with the results obtained for the diethylphosphonate
group.
to 100% ee), measured in
a 0.09 M solution in CDCl3, and the
conformationally averaged B3LYP/6-31G* VCD spectrum of (S)-7a,
obtained using Lorentzian band shapes (c = 4.0 cmꢀ1). The numbers
indicate the assignment of the experimental VCD spectrum, based on the
calculated spectrum.
Me
Ph
Me
Ph
Me
N
Ph
H
H
H
H
N
H
N
O
P
O
P
O
P
MeOOC
OEt
OEt
OEt
OEt
OEt
OEt
H
H
COOMe
4a
Scheme 3. Transition state of the reaction involving compound 4a and methyl acrylate.

688
S. Delarue-Cochin et al. / Tetrahedron: Asymmetry 18 (2007) 685–691
the experimental VCD). Compound 7a has a negative spe-
cific rotation ([a]D = ꢀ10, normalized to 100% ee). Thus it
follows that the absolute configuration of 7a is (S)-(ꢀ).
4.2. General procedure for the synthesis of derivatives
2c and 2d
To a solution of dibenzyl- or diphenylphosphite (12 mmol,
1.2 equiv) in 30 mL of THF was added at ꢀ78 ꢁC and
under argon a solution of LiHMDS freshly prepared from
a solution of BuLi 1.6 M in cyclohexane (8.3 mL, 13 mmol,
1.3 equiv) and HMDS (2.6 mL, 12 mmol, 1.2 equiv) in
5 mL of THF at ꢀ78 ꢁC. After 30 min, HMPA (5 mL)
was added and the mixture stirred for further 30 min. A
solution of compound 1 (1.8 g, 10 mmol, 1 equiv) in
25 mL of THF was added dropwise and the mixture stirred
at ꢀ78 ꢁC for 2 h, then at ꢀ15 ꢁC for 2 h. The mixture was
then quenched by the addition of aqueous NH4Cl, diluted
with water then extracted with EtOAc. The organic layers
were then mixed up, washed with NH4Cl, water, then
brine, dried over Na2SO4, filtered and concentrated. The
residue was then purified by column chromatography
(DCM 100 to DCM/MeOH 95/5) to yield the desired
compound.
This result is in accordance with the related six-membered
‘aza-ene-synthesis-like’ transition state postulated consist-
ing of (i) an intramolecular hydrogen bond between the
oxygen of the phosphonate group and the NH moiety in
compound 4a and (ii) the syn-approach of the methyl acryl-
ate on the less hindered Si p-face of enaminophosphonate
4a, anti to the bulky phenyl group of the chiral amine moi-
ety (Scheme 3).
3. Conclusion
In conclusion, we have demonstrated that the asymmetric
Michael reaction on acyclic enaminophosphonate com-
pounds with non-substituted Michael acceptors is practica-
ble with good yields and high enantiomeric excesses, in the
same way as for the acyclic enaminoester derivatives. This
method gives us the opportunity to access new chiral b-
ketophosphonates, as analogues of b-ketoesters. Work is
currently in progress to extend this reaction to substituted
Michael acceptors.
4.2.1. Dibenzyl [3-(methoxycarbonyl-hydrazono)-but-2-yl]-
phosphonate 2c. Colourless oil (2.96 g, 73% yield); Rf:
1
0.65 (DCM/MeOH 95:5); H NMR (CDCl3): d 1.28 (dd,
3J = 7.2 Hz, 3JP = 18.4 Hz, 3H, CH3CH), 1.79 (d,
4JP = 2.6 Hz, 3H, CH3C@N), 3.07 (qd, 3J = 7.2 Hz,
2JP = 22.6 Hz, 1H, CH3CH), 3.63 (s, 3H, COOCH3),
4.80–5.00 (m, 4H, PO(OCH2Ph)2), 7.00–7.20 (m, 10H,
Har), 8.58 (br s, 1H, NH); 31P NMR (CDCl3): d 41.00;
13C NMR (CDCl3): d 11.9 (d, 2JP = 5.7 Hz, CH3CH),
4. Experimental
4.1. General
1
13.4 (CH3C@N), 41.2 (d, JP = 135.8 Hz, CH3CH), 52.1
2
Commercial reagents were used without purification unless
otherwise mentioned. Prior to use, THF was freshly dis-
tilled from sodium-benzophenone, toluene and benzyl alco-
hol from CaH2. Acrylonitrile and methyl acrylate were
distilled and dried over molecular sieves. All anhydrous
reactions were carried out under argon. Analytical thin
layer chromatography was performed on Merck 60F-254
precoated silica (0.2 mm) on glass and was developed by
UV-light or Ka¨gi-Misher reagent. All flash chromatogra-
phy separations were performed with Merck Kieselgel 60
(250–500 lm). Melting points were recorded on an electro-
thermal digital apparatus and are uncorrected. Infrared
(IR) spectra were obtained as neat films and were recorded
(COOCH3), 67.1 (d, JP = 6.4 Hz, PO(OCH2Ph)2), 127.3
(CHar), 127.4 (CHar), 128.0 (CHar), 135.7 (Cqar), 149.3
(d, 2JP = 6.0 Hz, C@N), 154.3 (CO); IR (cmꢀ1): 3239,
2944, 1728, 1591, 1527, 1488, 1456, 1361, 1264, 1209,
1184, 1161, 1070, 1025.
4.2.2. Diphenyl [3-(methoxycarbonyl-hydrazono)-but-2-yl]-
phosphonate 2d. Colourless oil (1.86 g, 49% yield); Rf:
1
0.30 (DCM/MeOH 95:5); H NMR (CDCl3): d 1.60 (dd,
3J = 7.4 Hz, 3JP = 19.4 Hz, 3H, CH3CH), 1.96 (d,
4JP = 3.0 Hz, 3H, CH3C@N), 3.49 (qd, 3J = 7.2 Hz,
2JP = 23.2 Hz, 1H, CH3CH), 3.85 (s, 3H, COOCH3),
7.00–7.20 (m, 10H, Har), 7.90 (br s, 1H, NH); 31P NMR
(CDCl3): d 32.90; 13C NMR (CDCl3): d 12.2 (d, 2JP =
5.9 Hz, CH3CH), 13.6 (CH3C@N), 41.8 (d, 1JP = 136.7 Hz,
CH3CH), 52.7 (COOCH3), 120.5 (CHar), 125.0 (CHar),
129.39 (CHar), 148.4 (d, 2JP = 6.4 Hz, Cqar), 150.0 (d,
2JP = 9.3 Hz, C@N), 154.5 (CO); IR (cmꢀ1): 3242,
2244, 1727, 1591, 1527, 1489, 1456, 1371, 1264, 1210,
1184, 1161, 1070, 1025.
on a Bruker Vector 22 spectrophotometer. 1H, 31P and 13
C
NMR spectra were recorded respectively at 200 MHz,
81 MHz and 50 MHz on a Brucker ARX200. CDCl3 was
20
used as internal reference. Specific rotations ½aꢁD were
measured on a Polartronic E Schmidt+Haensch 2095
polarimeter at the sodium D line (589 nm) and at 20 ꢁC
in a 1 dm-cell. Elemental analyses were performed by the
Service de Microanalyse, Centre d’Etudes Pharmaceu-
tiques, Chaˆtenay-Malabry, France, with a Perkin–Elmer
2400 analyser. Enantiomeric excesses were measured either
by chiral HPLC on a Spectrasystem P1000XR with a Spec-
traseries UV100 spectrophotometer and a chiral column
Chiralcel OD, the spectra being treated with the AZUR
program, or by analysis of the 31P NMR of the imino inter-
mediate (before hydrolysis). VCD spectra were measured
using a Bomem/BioTools ChiralIR instrument. Com-
pounds 1, 2a and 2b and 3a and 3b were synthesized
according to the procedure described by Corbel.9
4.3. General procedure for the hydrolysis into derivatives
3c–3d
A solution of compound 2c–2d 1 M in an acetone/HCl
3 M: 1/1 mixture was stirred at room temperature for
3 h, then diluted with water. Acetone was removed and
the aqueous layer then extracted with dichloromethane.
The organic layers were then mixed up, dried over Na2SO4,
filtered and concentrated. The residue was then purified by

S. Delarue-Cochin et al. / Tetrahedron: Asymmetry 18 (2007) 685–691
689
column chromatography (DCM 100 to DCM/MeOH 95:5)
to yield the desired compound.
4.4.3. Dibenzyl (S)-[3-(1-phenyl-ethylimino)-but-2-yl]-phos-
phonate 4c. Yellow oil (quantitative yield); 1H NMR
(CDCl3): d 1.40–1.80 (m, 12H, CH3CH and CH32 and
CH3C@N), 2.90–3.20 (m, 1H, CH3CH imine), 3.50–5.20
(m, 5H, P(OCH2Ph)2 and CH2), 7.00–7.50 (m, 10H, Har),
8.35 (d, J = 7.2 Hz, NH enamine); 31P NMR (CDCl3): d
41.77 + 41.86 (imine), 42.49 (enamine).
4.3.1. Dibenzyl (3-oxo-but-2-yl)-phosphonate 3c. Colour-
less oil (90% yield); Rf: 0.75 (DCM/MeOH 95:5); 1H
NMR (CDCl3): d 1.36 (dd, 3J = 7.2 Hz, 3JP = 18.4 Hz,
3H, CH3CH), 2.28 (s, 3H, COCH3), 3.21 (qd,
3J = 7.2 Hz, 2JP = 25.6 Hz, 1H, CH3CH), 4.95–5.10 (m,
4H, PO(OCH2Ph)2), 7.10–7.30 (m, 10H, Har); 31P NMR
(CDCl3): d 37.10; 13C NMR (CDCl3): d 10.4 (d,
2JP = 6.3 Hz, CH3CH), 29.9 (CH3CO), 47.0 (d,
1JP = 126.5 Hz, CH3CH), 67.4 (PO(OCH2Ph)2), 127.5
(CHar), 128.7 (CHar), 128.8 (CHar), 135.5 (Cqar), 203.0
4.4.4. Diphenyl (S)-[3-(1-phenyl-ethylimino)-but-2-yl]-phos-
phonate 4d. Yellow oil (quantitative yield); 1H NMR
(CDCl3): d 1.30–1.50 (m, 6H, CH3CH and CH3), 1.62 (s,
2
2
3H, CH3C@N), 4.44 (qd, J = 8.0 Hz and JNH = 7.2 Hz,
1H, CH2), 6.90–7.40 (m, 10H, Har), 8.13 (d, J = 7.8 Hz,
1H, NH enamine); 31P NMR (CDCl3): d 35.56.
2
(d, JP = 3.8 Hz, CO); IR (cmꢀ1): 2944, 2894, 1713, 1452,
1377, 1358, 1304, 1244, 1213, 1149, 1082, 989.
4.5. General procedure for the Michael reaction between
derivatives 4a–4d and electrophilic alkenes
4.3.2. Diphenyl (3-oxo-but-2-yl)-phosphonate 3d. Colour-
less oil (73% yield); Rf: 0.65 (DCM/MeOH 95:5); 1H
NMR (CDCl3): d 1.58 (dd, 3J = 7.0 Hz, 3JP = 19.0 Hz,
3H, CH3CH), 2.45 (s, 3H, COCH3), 3.54 (qd,
3J = 7.2 Hz, 2JP = 25.8 Hz, 1H, CH3CH), 7.00–7.20 (m,
10H, Har); 31P NMR (CDCl3): d 29.10; 13C NMR (CDCl3):
To a solution of compound 4a–4d (1 equiv) in freshly dis-
tilled tetrahydrofuran (1 M) were added under an inert
atmosphere, catalytic amounts of hydroquinone and the
electrophilic alkene (1.5–8 equiv) dropwise. After stirring
the mixture at reflux for 1–10 days (evolution reaction
was monitored by 31P NMR) and cooling, AcOH 10%
was added. After further stirring at room temperature for
4 h at room temperature, tetrahydrofuran was evaporated
and the aqueous layer was extracted with dichloromethane.
The organic layer was then washed with HCl 1 M and
brine, dried over Na2SO4, filtered and concentrated. The
residue was purified by column chromatography (cyclo-
hexane/EtOAc 3:7) to yield the desired compound.
2
d 10.6 (d, JP = 6.7 Hz, CH3CH), 30.2 (CH3CO), 47.0 (d,
1JP = 127.8 Hz, CH3CH), 120.1 (d, 3JP = 3.7 Hz, CHar),
2
125.1 (CHar), 129.4 (CHar), 149.7 (d, JP = 9.2 Hz, Cqar),
2
202.2 (d, JP = 3.9 Hz, CO); IR (cmꢀ1): 3239, 2944, 1728,
1591, 1527, 1488, 1456, 1361, 1264, 1209, 1184, 1161,
1070, 1025.
4.4. General procedure for the synthesis of derivatives 4a–4d
4.5.1. Diethyl (S)-[2-(2-benzenesulfonyl-ethyl)-3-oxo-but-2-
yl]-phosphonate 5a. Colourless oil (67% yield); ee = 94%;
To a solution of compound 3a–3d (1 equiv) in freshly
distilled toluene or cyclohexane (1 M) were added under
an inert atmosphere, catalytic amount of APTS and
(S)-1-phenylethylamine (1.1 equiv). After stirring at reflux
overnight using a Dean-Stark apparatus, the mixture was
concentrated to yield the desired compound which was
used without any purification.
1
Rf: 0.15 (cyclohexane/EtOAc 5:5); H NMR (CDCl3): d
3
1.25 + 1.26 (t, J = 6.9 Hz, 2 · 3H, PO(OCH2CH3)2), 1.37
(d, 3JP = 17.1 Hz, 3H, CH3), 2.10–2.30 (m, 4H, CH2),
2.24 (s, 3H, COCH3), 2.95–3.10 (m, 2H, CH2SO2),
4.07 + 4.09 (2 qd, 3J = 7.0 Hz, 3JP = 9.2 Hz, 2 · 2H,
PO(OCH2CH3)2), 7.50–7.70 (m, 3H, Har), 7.75–7.95 (m,
2H, Har); 31P NMR (CDCl3): d 37.34; 13C NMR (CDCl3):
3
4.4.1. Diethyl (S)-[3-(1-phenyl-ethylimino)-but-2-yl]-phos-
phonate 4a. Yellow oil (quantitative yield); 1H NMR
(CDCl3): d 1.25–1.75 (m, 12H, P(OCH2CH3)2CH3CH
and CH3), 1.80 (s, 3H, CH3C@N enamine), 2.05 (d,
4Jp = 2.0 Hz, 3H, CH3C@N imine), 2.90–3.20 (m, 1H,
CH3CH imine), 3.90–4.30 (m, 4H, P(OCH2CH3)2), 4.57
d 15.8 + 15.9 (2d, JP = 5.7 Hz, PO(OCH2CH3)2), 16.9 (d,
2JP = 5.3 Hz, CH3), 26.0 (d, 2JP = 3.2 Hz, CH2), 27.2
(CH3CO), 51.4 (d, 3JP = 9.4 Hz, CH2SO2), 52.7 (d,
1JP = 130 Hz, Cq), 62.8 + 62.9 (2d, 2JP = 7.4 Hz,
PO(OCH2CH3)2), 127.6 (CHar), 128.9 (CHar), 133.4
(CHar), 138.3 (Cqar), 204.4 (CO); IR (cmꢀ1): 2984, 1707,
2
2
20
(qd, J = 6.9 Hz and JNH = 8.0 Hz, 1H, CH2 enamine),
1447, 1244, 1146, 1015; ½aꢁD ¼ ꢀ26 (c 2.00, CH2Cl2). Anal.
2
4.47 (q, J = 6.6 Hz, 1H, CH imine), 7.35 (m, 10H, Har),
Calcd for C16H25O6PS: C, 51.05; H, 6.69. Found: C, 51.28;
H, 6.89; HPLC (hexane/iPrOH 94/6, 1.5 mL/min,
k = 217 nm): tR = 21.6 min (minor enantiomer) and
23.3 min (major enantiomer).
8.17 (d, J = 8.0 Hz, 1H, NH enamine); 31P NMR (CDCl3):
d 40.75 + 40.89 (imine), 41.67 (enamine).
4.4.2. Dimethyl (S)-[3-(1-phenyl-ethylimino)-but-2-yl]-phos-
phonate 4b. Yellow oil (quantitative yield); 1H NMR
(CDCl3): d 1.30–1.60 (m, 12H, CH3CH and CH3), 1.73
(s, 3H, CH3C@N enamine), 1.96 (d, 4Jp = 1.8 Hz, 3H,
CH3C@N imine), 2.90–3.20 (m, 1H, CH3CH imine),
4.5.2. Diethyl (S)-[2-(2-benzyloxycarbonyl-ethyl)-3-oxo-but-
2-yl]-phosphonate 6a. Colourless oil (55% yield);
ee = 88%; Rf: 0.30 (cyclohexane/EtOAc 3:7); 1H NMR
(CDCl3):
d
1.28 + 1.29 (t, 3J = 7.1 Hz, 2 · 3H,
2
3
3.55–3.80 (m, 6H, P(OCH3)2), 4.64 (qd, J = 6.8 Hz and
PO(OCH2CH3)2), 1.38 (d, JP = 16.8 Hz, 3H, CH3), 2.00–
2.50 (m, 4H, CH2CH2COO), 2.30 (s, 3H, COCH3),
4.10 + 4.11 (2 qd, 3J = 7.1 Hz, 3JP = 9.0 Hz, 2 · 2H,
PO(OCH2CH3)2), 5.09 (s, 2H, OCH2Ph), 7.32 (s, 5H,
Ph); 31P NMR (CDCl3): d 38.58; 13C NMR (CDCl3): d
2JNH = 7.2 Hz, 1H, CH enamine), 4.47 (q, 2J = 7.0 Hz,
1H, CH imine), 7.00–7.50 (m, 10H, Har), 8.17 (d,
J = 7.2 Hz, 1H, NH enamine); 31P NMR (CDCl3): d
43.31 + 43.48 (imine), 44.74 (enamine).

690
S. Delarue-Cochin et al. / Tetrahedron: Asymmetry 18 (2007) 685–691
15.9 (d, 3JP = 5.6 Hz, PO(OCH2CH3)2), 16.1 (d,
H20NO4P: C, 50.57; H, 7.72; N, 5.36. Found: C, 50.45;
H, 7.83; N, 5.29.
2
2JP = 5.1 Hz, CH3), 27.4 (COCH3), 27.8 (d, JP = 3.5 Hz,
CH2), 28.9 (d, 3JP = 11.5 Hz, CH2COO), 53.3 (d,
1JP = 139.2 Hz, Cq), 62.3 + 62.4 (2d, 2JP = 6.0 Hz,
PO(OCH2CH3)2), 65.9 (OCH2Ph), 127.7 (CHar), 128.0
(CHar), 135.4 (Cqar), 172.0 (COOBn), 205.0 (CO); IR
4.5.5. Dibenzyl (S)-[2-(2-Benzenesulfonyl-ethyl)-3-oxo-but-
2-yl]-phosphonate 5c. Colourless oil (39% yield); Rf: 0.20
1
(cyclohexane/EtOAc 5:5); ee = 70%; H NMR (CDCl3): d
(cmꢀ1): 2983, 2932, 1734, 1705, 1498, 1389, 1358, 1245,
1.55 (d, 3JP = 17.2 Hz, 3H, CH3), 2.20–2.60 (m, 2H,
CH2Cq), 2.39 (s, 3H, COCH3), 3.10–3.60 (m, 2H,
CH2SO2), 5.00–5.30 (m, 4H, PO(OCH2Ph)2), 7.40–8.10
(m, 15H, Har); 31P NMR (CDCl3): d 38.63; 13C NMR
(CDCl3): d 17.2 (d, 2JP = 5.0 Hz, CH3Cq), 26.3 (d,
20
1163, 1046, 1016; ½aꢁD ¼ þ11 (c 2.00, CH2Cl2). Anal. Calcd
for C18H28O6P: C, 58.37; H, 7.35. Found: C, 58.12; H, 7.62;
HPLC (hexane/iPrOH 96/4, 1 mL/min, k = 208 nm):
tR = 13.2 min (minor enantiomer) and 16.5 min (major
enantiomer).
3
2JP = 2.9 Hz, CH2), 27.4 (CH3CO), 51.5 (d, JP = 9.2 Hz,
CH2SO2), 53.0 (d, 1JP = 135.1 Hz, Cq), 68.2 (d,
2JP = 7.2 Hz, PO(OCH2Ph)2), 127.8 (CHar), 128.4 (CHar),
129.0 (CHar), 138.5 (Cqar), 204.9 (CO); IR (cmꢀ1): 2976,
4.5.3. Diethyl (S)-[2-(2-methoxycarbonyl-ethyl)-3-oxo-but-
2-yl]-phosphonate 7a. Colourless oil (65% yield); ee =
1
2362, 1745, 1591, 1486, 1364, 1298, 1273, 1247, 1184,
88%; Rf: 0.20 (hexane/EtOAc 3:7); H NMR (CDCl3): d
20
3
1156, 1127, 1070, 1017, 999; ½aꢁD ¼ þ8 (c 1.00, CH2Cl2).
1.25 + 1.26 (t, J = 7.1 Hz, 2 · 3H, PO(OCH2CH3)2), 1.33
3
Anal. Calcd for C26H29O6PS: C, 62.39; H, 5.84. Found:
C, 62.56; H, 5.99.
(d, JP = 16.8 Hz, 3H, CH3), 1.90–2.40 (m, 4H, CH2CH2-
COO), 2.26 (s, 3H, COCH3), 3.59 (s, 3H, COOCH3),
4.06 + 4.07 (2 qd, 3J = 7.1 Hz, 3JP = 9.0 Hz, 2 · 2H,
PO(OCH2CH3)2); 31P NMR (CDCl3): d 38.57; 13C NMR
4.6. Transesterification of compound 7a into compound 6a
3
(CDCl3): d 15.5 (d, JP = 5.6 Hz, PO(OCH2CH3)2), 15.7
(d, 2JP = 5.1 Hz, CH3), 26.9 (COCH3), 27.4 (d, 2JP =
3.9 Hz, CH2), 28.3 (d, 2JP = 11.6 Hz, CH2COO), 50.7
(COOCH3), 53.0 (d, 1JP = 129 Hz, Cq), 61.9 + 62.0 (2d,
2JP = 7.3 Hz, PO(OCH2CH3)2), 172.1 (COOCH3), 204.4
A solution of 7a (400 mg, 1.36 mmol, 1 equiv) and a cata-
lytic amount of APTS in 1 mL of freshly distilled benzyl
alcohol was stirred at 50 ꢁC for 72 h. The mixture was con-
centrated and the residue purified by column chromatogra-
phy (cyclohexane/EtOAc 5:5–3:7) to yield compound 6a
(340 mg, 68% yield).
(CO); IR (cmꢀ1): 2984, 1737, 1705, 1438, 1245, 1046,
20
1016; ½aꢁD ¼ ꢀ10 (c 1.88, CH2Cl2). Anal. Calcd for C12-
H23O6P: C, 48.98; H, 7.88. Found: C, 48.68; H, 8.04.
4.7. Pinner reaction of compound 8a into compound 6a
4.5.4. Diethyl (S)-[2-(2-cyano-ethyl)-3-oxo-but-2-yl]-phos-
phonate 8a. Yellow oil (66% yield); Rf: 0.25 (hexane/
EtOAc 3:7); ee = 85%; H NMR (CDCl3): d 1.34 + 1.35
Anhydrous HCl(g) was bubbled into benzyl alcohol main-
tained in an ice bath over a period of 10 min to saturation.
Compound 8a (180 mg, 0.69 mmol, 1 equiv) was diluted
into 1 mL of this solution under an inert atmosphere and
the flask was capped with a septum and kept at ꢀ20 ꢁC
for 70 h. The mixture was then diluted at 0 ꢁC with
0.5 mL of HCl 6 M. After stirring for 10 min at 0 ꢁC, the
mixture was diluted with 2 mL of water, extracted with
3 · 5 mL of DCM. The organic layers were combined,
washed with 10 mL of brine, dried over Na2SO4, filtered
then concentrated and the residue purified by column chro-
matography (cyclohexane/EtOAc 5:5–3:7) to yield com-
pound 6a (60 mg, 24% yield).
1
(t, 3J = 7.1 Hz, 2 · 3H, PO(OCH2CH3)2), 1.50 (d, 3JP =
17.2 Hz, 3H, CH3), 2.00–2.50 (m, 4H, CH2), 2.35 (s, 3H,
COCH3), 4.14 + 4.16 (2 qd, 3J = 7.1 Hz, 3JP = 11.6 Hz,
2 · 2H, PO(OCH2CH3)2); 31P NMR (CDCl3): d 37.33;
13C NMR (CDCl3): d 12.2 (d, 2JP = 10.9 Hz, CH3Cq),
15.8 (d, 3JP = 5.4 Hz, PO(OCH2CH3)2), 16.4 (d, 2JP =
5.4 Hz, CH2Cq), 27.2 (CH3CO), 28.6 (d, 3JP = 2.9 Hz,
CH2CN), 53.0 (d, 1JP = 129.1 Hz, Cq), 62.5 + 62.7 (2d,
2JP = 7.7 Hz, PO(OCH2CH3)2), 118.8 (CN), 204.3 (CO);
IR (cmꢀ1): 2984, 2247, 1706, 1445, 1245, 1163, 1043,
20
1015; ½aꢁD ¼ ꢀ45 (c 1.5, CH2Cl2). Anal. Calcd for C11-
Table 2. B3LYP/6-31G* relative energies,a free energies,a population percentages,b and key dihedral anglesc of the conformations of 7a
DE
DG
P (%)
D1
D2
D3
D4
ꢀ93.34
D5
D6
D7
D8
D9
a
b
c
d
e
f
0.92
2.00
1.35
1.97
1.23
0.00
0.43
1.87
1.71
1.95
0.00
0.01
0.83
1.17
1.27
1.32
1.41
1.59
1.75
1.82
35.09
34.43
8.65
4.82
4.08
3.80
3.27
2.40
1.84
1.62
30.00
55.61
ꢀ53.59
64.83
ꢀ179.97
178.04
179.94
ꢀ4.32
ꢀ149.12
ꢀ136.65
ꢀ153.17
ꢀ151.03
ꢀ151.86
ꢀ157.36
ꢀ149.90
ꢀ147.07
ꢀ153.10
172.24
ꢀ172.69
ꢀ173.20
ꢀ87.35
14.31
29.03
30.58
30.12
29.95
29.17
29.61
29.48
ꢀ54.39
50.92
57.69
54.89
53.59
54.14
53.33
53.93
56.65
ꢀ22.53
117.57
ꢀ93.05
ꢀ91.80
ꢀ95.40
ꢀ87.03
ꢀ87.85
ꢀ91.63
ꢀ93.96
ꢀ112.67
177.14
179.27
ꢀ179.71
83.62
ꢀ58.42
ꢀ58.56
74.37
ꢀ14.13
ꢀ3.59
121.83
34.97
ꢀ52.95
ꢀ54.04
ꢀ55.03
ꢀ51.05
ꢀ53.37
ꢀ55.76
ꢀ53.76
ꢀ68.24
ꢀ179.99
ꢀ178.23
ꢀ177.05
ꢀ169.22
ꢀ168.69
178.44
ꢀ174.04
ꢀ174.23
ꢀ171.51
ꢀ88.93
87.74
87.69
g
h
i
ꢀ126.39
ꢀ173.57
ꢀ87.70
ꢀ177.63
83.49
85.62
34.57
j
ꢀ169.14
20.41
ꢀ142.46
a In kcal/mol.
b Based on DG.
c D1: O1PO2C4; D2: O1PO3C5; D3: O1PC6C7; D4: PC6C7O8; D5: PC6C9C10; D6: C6C9C10C11; D7: C9C10C11O12; D8: PO2C4C14; D9: PO3C5C15.

S. Delarue-Cochin et al. / Tetrahedron: Asymmetry 18 (2007) 685–691
691
´
7. Hendra, F. Ph.D. Dissertation, Universite de Bourgogne,
4.8. Conformational analysis of 7a
Dijon, France, 2005.
The conformations of 7a with B3LYP/6-31G* DFT free
energies within a range of 2.0 kcal/mol are given in Table
2. Room-temperature equilibrium populations, obtained
from the relative free energies using Boltzmann statistics,
and key dihedral angles, which define the conformational
structures, are also given in Table 2. All DFT calculations
were carried out using GAUSSIAN 03.27
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8
O
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6
O 2
C
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H3C
O
CH2CH3
9
CH2
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10CH2
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Acknowledgements
The authors are grateful to Sophie Mairesse for performing
microanalysis, and to the US National Science Foundation
for financial support of P.J.S. (CHE-0209957 and CHE-
0614577).
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