Enzymatic resolution of diethyl (3-hydroxy-1-butenyl) phosphonate

Article abstract of DOI:10.1016/S0040-4039(02)02067-1

The enzymatic esterification of diethyl (3-hydroxy-1-butenyl) phosphonate 1 with different enzymes has been carried out, and allows the preparation of (S)-1 and (R)-diethyl (3-acetoxy-1-butenyl) phosphonate 2 with very high enantiomeric excess. The absolute conguration of 1 was determined by independent synthesis from (S)-ethyl lactate.

Full text of DOI:10.1016/S0040-4039(02)02067-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8547–8549
Enzymatic resolution of diethyl (3-hydroxy-1-butenyl)
phosphonate
Mireille Attolini,a Gilles Iacazio,b Gilbert Peiffera and Michel Maffeia,*
aLaboratoire des Organo-Phosphore´s (UMR 6009 du CNRS), BP 552, Faculte´ de Saint Je´roˆme,
Avenue Escadrille Normandie-Nie´men, 13397 Marseille Cedex 20, France
bLaboratoire de Bioinorganique Structurale (UMR 6517 du CNRS), BP 432, Faculte´ de Saint Je´roˆme,
Avenue Escadrille Normandie-Nie´men, 13397 Marseille Cedex 20, France
Received 11 July 2002; accepted 19 September 2002
Abstract—The enzymatic esterification of diethyl (3-hydroxy-1-butenyl) phosphonate 1 with different enzymes has been carried
out, and allows the preparation of (S)-1 and (R)-diethyl (3-acetoxy-1-butenyl) phosphonate 2 with very high enantiomeric excess.
The absolute conguration of 1 was determined by independent synthesis from (S)-ethyl lactate. © 2002 Elsevier Science Ltd. All
rights reserved.
Functionalised vinyl phosphonates are useful building
blocks,1 particularly for the synthesis of biologically
active compounds. We have shown2 that dialkyl 3-ace-
toxy-1-alkenyl phosphonates can be used to prepare
phosphono amino acids which are known to be active
against epilepsy and Parkinson’s disease.3 They can also
be used to prepare the corresponding allyl alcohols
which have in turn been used as starting materials for
the synthesis of antiviral nucleosides.4,5 Moreover, the
related chiral 3-hydroxy-1-alkenyl phosphine oxides are
used for the synthesis of optically active cyclopropyl
ketones.6 Since chirality is determinant for the biologi-
cal activity of these above cited compounds, an enan-
tioselective synthesis of dialkyl 3-acetoxy (or
3-hydroxy)-1-alkenyl phosphonates is of interest.
matic resolution8 of diethyl (3-hydroxy-1-butenyl) phos-
phonate 19 (Scheme 1).
For this purpose, several enzymes were assayed as
summarised in Table 1.
It appears that lipozyme (entry 1) gave the best results,
since diethyl (3-acetoxy-1-butenyl) phosphonate 2 was
obtained with an enantiomeric excess (ee) of 96% and
unreacted 1 was recovered almost enantiomerically pure
(ee=99%) when the reaction was stopped after 51%
conversion. Lipases Amano AK (entry 2) and Amano
PS (entry 3) also gave rather good results, with lower ee
for unreacted 1, but Amano PS led to the highest ee for
compound 2 (ee=98%). In these cases, the reaction
occurred after rather short periods, and the enantiose-
lectivity factors10 E where superior to 200. Asp. melleus
acylase (entry 4) also gave very good enantioselectivity
for 2 (ee=98% after 33% conversion), but unreacted 1
Recently, the enzymatic resolution of several hydroxy
phosphonates has been described.7 Prompted by these
reports, we wish to disclose our results on the enzy-
Scheme 1.
Keywords: enzymatic esterification; resolution of organophosphorus compounds; diethyl (3-hydroxy-1-butenyl) phosphonate.
* Corresponding author. Fax: (+) 33 4 91 28 27 38; e-mail: michel.maffei@univ.u-3mrs.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02067-1

8548
M. Attolini et al. / Tetrahedron Letters 43 (2002) 8547–8549
Table 1. Enzymatic esterification of 1
Entry
Enzyme
Time
Conv. (%)a
1
2
E
ee (%)b,c Abs. conf.
ee (%)b,c Abs. conf.
1
2
3
4
5
6
7
8
Lipozyme (Fluka)
Amano AK
Amano PS
Asp. melleus Acyl. (Amano)
Amano AP6
Amano AY
CAL-B (Novo)
PPL (Sigma)
CRL (Meito Sangyo)
Amano R-10
21 h
21 h
17 h
72 h
10 d
10 d
17 h
49 h
10 d
10 d
17 h
51
50
45
33
9
15
87
19
13
8
99
97
81
49
7
12
91
22
8
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
96
96
98
98
74
67
14
99
54
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
\200
\200
\200
160
7
6
3
130
4
6
9
10
11
6
95
69
\99
Lipozyme (Fluka)
49
\200
a Conversion, determined by GC.
b Determined by chiral GC.
c Determined after acetylation.
was recovered with only 49% ee. The use of other
enzymes (entries 5–10) proceeded with lower kinetics
and enantioselectivities.
The absolute configuration of (+)-1 was shown to be S,
by an independent synthesis from (S)-ethyl lactate 3, as
depicted in Scheme 2.
Finally, the reaction carried out with lipozyme on a
preparative scale (1 g of 1) proceeded with identical
results (entry 11), and the chemical yields were 46% for
1 and 48% for 2, respectively.
O-Silylation followed by reduction with Dibal-H
yielded the protected aldehyde 411 which was subjected
to a Wadsworth–Emmons reaction with tetraethyl
methylene bis phosphonate, thus providing phospho-
nate 5,12 which led, after acidic deprotection to enan-
tiomerically pure (S)-1 whose optical rotation was
[h]2D0=+19 (c 0.315, CH2Cl2).
The enzymatic solvolysis of 2 was also studied, the
reaction being performed in diisopropyl ether with iso-
propanol as an acyl acceptor. Although the enantiose-
lectivities were high, reaction times were much more
important and the enzymes tested were found to be less
efficient (Table 2). As expected, 1 was produced as the
(R) enantiomer, whereas (S)-2 was recovered.
In summary, we have shown that enzymatic resolution
of diethyl (3-hydroxy-1-butenyl) phosphonate 1 can be
efficiently carried out through esterification with
lipozyme, leading to diethyl (3-acetoxy-1-butenyl)
Table 2. Enzymatic solvolysis of 2
Entry
Enzymea
Time (days)
Conv. (%)b
1
2
E
ee (%)c,d
Abs. conf.
ee (%)c
Abs. conf.
1
2
3
Lipozyme (Fluka)
Amano AK
Amano PS
7
7
6
45
38
25
98
82
89
(R)
(R)
(R)
80
51
30
(S)
(S)
(S)
\200
18
24
a 2 (40 mg) and the enzyme (50 mg) in diisopropyl ether (10 ml) and isopropanol (100 ml) were stirred at 30°C.
b Conversion, determined by GC.
c Determined by chiral GC.
d Determined after acetylation.
Scheme 2.

M. Attolini et al. / Tetrahedron Letters 43 (2002) 8547–8549
8549
phosphonate 2 and unreacted 1 with very high ee.
Upscaling to up to one gram of substrate led essentially
to the same results (95 and 99%, respectively for 1 and
2).
9. Compound 1 was prepared by rearrangement of diethyl
(2,3-epoxy-1-butyl) phosphonate according to: Just, J.;
Potvin, P.; Hakimelahi, G. H. Can. J. Chem. 1980, 58,
2780. It can alternatively be obtained by palladium-
catalysed acetoxylation of diethyl (1-butenyl) phospho-
nate to provide 2, followed by saponification, see:
Principato, B.; Maffei, M.; Siv, C.; Buono, G.; Peiffer, G.
Tetrahedron 1996, 52, 2087.
Acknowledgements
10. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. Am.
We wish to thank Mrs. Yolande Charmasson for tech-
nical assistance.
Chem. Soc. 1982, 104, 7294.
11. Hirama, M.; Shigemoto, T.; Itoˆ, S. J. Org. Chem. 1987,
52, 3342.
12. (S)-Diethyl-(E)-(3-tertbutyldimethylsilyloxy-1-butenyl)
phosphonate 5: A solution of tetraethyl methylene bis
References
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2
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dimethoxyethane (10 ml) was added to a suspension of
sodium hydride (48 mg; 2 mmol) in dimethoxyethane (10
ml) at 0°C. The mixture was stirred at room temperature
until hydrogen evolution ceased (ca. 1 h). It was then
cooled to 0°C and a solution of 4 (376 mg; 2 mmol) in
dimethoxyethane (5 ml) was added dropwise. Stirring was
continued for 2 h at room temperature after which the
mixture was quenched with a sat. NH4Cl solution. Ether
extraction, standard workup and flash chromatography
(silica, ethyl acetate) afforded 330 mg (51%) of 5. 1H
NMR (300 MHz, CDCl3): 0.04 (s, 6H); 0.89 (s, 9H); 1.22
(d, 3H, 3JHH=6.7 Hz); 1.30 (td, 6H, 3JHH=6.9 Hz,
4JHP=2.0 Hz); 4.05 (m, 4H); 4.40 (m, 1H); 5.80–5.93
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8. General procedure: The enzyme (50 mg) was added to a
solution of 1 (48 mg; 0.23 mmol) and vinyl acetate (1 ml)
in diisopropyl ether (10 ml), and the suspension was
stirred at 30°C. The reaction was monitored by GC.
After ca. 50% conversion (see Table 1), the mixture was
filtered to remove the enzyme, the solvents were removed
in vacuo, and the crude was subjected to flash chro-
matography (silica, ethyl acetate/methanol, 95:5) to yield
2 followed by 1. Ee’s were measured by GC on a chiral
column (CP-chirasil-DEX CB, 25 m, 32 mm I.D.),
isothermal 160°C. Retention times: rac. 1: 12.9 min,
(S)-2: 10.93 min, (R)-2: 11.38 min. Ee’s for 1 were
measured after acetylation.
2
3
4
(ddd, 1H, JHP=21.1 Hz, JHH=16.9 Hz, JHH=1.5 Hz);
6.69–6.83 (ddd, 1H, 3JHP=22.1 Hz, 3JHH=16.9 Hz,
3
3JHH=3.5 Hz). 13C NMR: −4.95 (s); 16.30 (d, JPC=6.2
Hz); 18.17 (s); 23.27 (d, 4JPC=2.2 Hz); 25.74 (s); 61.61 (d,
2JPC=5.7 Hz); 68.40 (d, 3JPC=21.9 Hz); 114.12 (d,
1JPC=188.0 Hz); 156.30 (d, 2JPC=5.0 Hz). 31P NMR:
19.9. [h]2D0=+7.76 (c 1.16, CH2Cl2).
Deprotection was carried out by stirring a solution of 5 in
THF with 1 M H2SO4. Standard workup and flash
chromatography (ethyl acetate/methanol, 95:5) afforded
enantiomerically pure (S)-1 as checked by chiral GC
analysis after acetylation.
1H NMR (300 MHz, CDCl3): 1.28 (d, 3H, 3JHH=6.8
3
Hz); 1.30 (t, 6H, JHH=7.1 Hz); 3.95 (br. s, 1H); 4.05 (q,
3
2
4H, JHH=7.2 Hz); 4.42 (m, 1H); 5.90 (ddd, 1H, JHP
=
3
4
20.8 Hz, JHH=17.0 Hz, JHH=1.7 Hz); 6.79 (ddd, 1H,
3JHP=22.5 Hz, 3JHH=17.0 Hz, 3JHH=4.0 Hz). 13C
3
2
NMR: 16.26 (d, JPC=7.0 Hz); 22.39 (s); 61.90 (d, JPC
=
3
1
5.9 Hz); 67.62 (d, JPC=21.8 Hz); 114.3 (d, JPC=189.3
Hz); 156.2 (d, JPC=4.6 Hz). 31P NMR: 19.4. [h]D20=+19
2
(c 0.315, CH2Cl2).