Towards enantiomeric 2,3-epoxypropylphosphonates

Article abstract of DOI:10.1016/S0957-4166(00)00171-3

Hydrolysis of diethyl 2,3-epoxypropylphosphonate in the presence of (R,R)-salen-Co(III)-OAc after 19 h afforded a mixture of (S)-epoxide (82% ee) and diethyl (R)-2,3-dihydroxypropylphosphonate (98% ee). Improved enantiomeric excess (93%) of the (S)-epoxide was obtained in the 72 h hydrolytic kinetic resolution experiment. Acid-catalyzed hydrolysis of (S)-epoxide (91% ee) gave (S)-diol (72% ee) due to low C-3 regioselectivity of the reaction. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00171-3

Tetrahedron: Asymmetry 11 (2000) 2053±2055
Towards enantiomeric 2,3-epoxypropylphosphonatesy
Andrzej E. Wroblewski* and Anetta Ha•ajewska-Wosik
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Institute of Chemistry, Faculty of Pharmacy, Medical University of —odz, 90-151 —odz, Muszynskiego 1, Poland
Received 6 April 2000; accepted 4 May 2000
Abstract
Hydrolysis of diethyl 2,3-epoxypropylphosphonate in the presence of (R,R)-salen±Co(III)-OAc after 19 h
a€orded a mixture of (S)-epoxide (82% ee) and diethyl (R)-2,3-dihydroxypropylphosphonate (98% ee).
Improved enantiomeric excess (93%) of the (S)-epoxide was obtained in the 72 h hydrolytic kinetic resolution
experiment. Acid-catalyzed hydrolysis of (S)-epoxide (91% ee) gave (S)-diol (72% ee) due to low C-3
regioselectivity of the reaction. # 2000 Elsevier Science Ltd. All rights reserved.
Enantiomeric 2,3-epoxypropylphosphonates would be useful three-carbon phosphonate chirons
for the syntheses of various phosphonate analogs, such as phosphocarnitine,1 phosphonic acid
antibiotics FR-33289 and FR-33699,2 and isosters of glycerophosphoric acid.3 However, standard
protocols for the oxirane ring closure require the application of basic reagents, and it was shown
that in the presence of bases diethyl 2,3-epoxypropylphosphonate isomerizes to 3-hydroxy-1-
propenylphosphonate.4 6
Design of low-molecular weight catalysts capable of reaching enantioselectivities similar to
those obtained in enzymatic reactions has become an important goal of asymmetric synthesis.
Hydrolytic kinetic resolution (HKR) processes introduced by Jacobsen7 are recent examples of
achievements in this area. Enantioselective hydrolyses of terminal epoxides7 12 have been extended
to oxirane ring openings with azides13 and thiols.14 A recent report on the application of HKR to
oxiranephosphonate15 has prompted us to communicate our results on enantioselectivity of
hydrolysis of diethyl 2,3-epoxypropylphosphonate 1.16
In the presence of 0.2 mol% (R,R)-salen±Co(III)-OAc 2 and 0.55 equiv. of water racemic 1 was
transformed into (S)-(^)-1 and diethyl (R)-(^)-2,3-dihydroxypropylphosphonate 3 (Scheme 1).
Based on signs of the optical rotation of the obtained diol and that synthesized from 2,3-O-iso-
propylidene-d-glyceraldehyde by Baer and Basu,3 application of (R,R)-2 produced (S)-1 and (R)-3.
The stereochemical outcome of the reaction followed that observed by Jacobsen.7
* Corresponding author. Fax: 48-42-678-83-98; e-mail: aewplld@ich.pharm.am.lodz.pl
y
Dedicated to Professor Jan Michalski on the occasion of his 80th birthday.
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00171-3

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A. E. Wroblewski, A. Ha•ajewska-Wosik / Tetrahedron: Asymmetry 11 (2000) 2053±2055
Scheme 1. Reagents and conditions: (a) (R,R)-salen±Co(III)-OAc (0.2 mol%), H2O (0.55 equiv.)
Comparison of speci®c rotations of the prepared diol: [ꢀ]D=^17.8 (c 1.43, ethanol) and the
literature value: [ꢀ]D=^12.2 (c 4.1, ethanol)3 does not allow the enantiomeric purity to be estimated.
However, complete esteri®cation of the obtained diol with (S)-O-methylmandelic acid 417 (4=3.0
equiv., DCC=3.0 equiv., DMAP=0.2 equiv.)18 gave diester 5 which showed 96% ee by 31P
NMR spectroscopy [(R,S,S)-5, ꢁ 31P=25.02 ppm; (S,S,S)-5, ꢁ 31P=24.95 ppm]. After correction
for the enantiomeric purity of (S)-4 (97.6%),19 the ee of the prepared diol (R)-3 was estimated as
98%.20
The enantiomeric excess of the unreacted epoxide (S)-1 was established in the following way:
Despite claims of the C-3 regioselectivity of the oxirane ring opening in (þ)-1,6,16 we found that,
among various amines tried, dibenzylamine attacted C-3 exclusively.21 Thus, after 20 h at 60ꢀC in
the presence of 1.1 equiv. of Bn2NH the unreacted (S)-1 was quantitatively transformed into
diethyl (S)-3-(N,N-dibenzylamino)-2-hydroxypropylphosphonate 6 (Scheme 2). Again, complete
esteri®cation18 with (S)-4 led to monoesters 7 [(S,S)-7, ꢁ 31P=27.13 ppm; (R,S)-7, ꢁ 31P=27.59
ppm], and the enantiomeric excess of (S)-1 was estimated20 as 82%.
Scheme 2. Reagents and conditions: (a) Bn2NH, 1.1 equiv., 60ꢀC, 20 h; (b) 4=1.5 equiv., DCC=1.5 equiv.,
DMAP=0.1 equiv., CH2Cl2
These results were obtained in the HKR experiment lasting 19 h which produced a 52:48 mixture
of (S)-1 and (R)-3 (by 31P NMR). After chromatography of this mixture on silica gel, (S)-1 and
(R)-3 were obtained in 44 and 41% yield, respectively. However, the epoxide (S)-1 was con-
taminated with traces of the catalyst and for this reason reliable measurements of the optical
rotation were not obtained. The 45 h hydrolysis led to a 46:54 mixture of (S)-1 and (R)-3 having
ee's of 86 and 95%, respectively. When hydrolysis was carried out for 72 h, a mixture of (S)-1
(93% ee) and (R)-3 (74% ee) in a 38:62 ratio was obtained. Summing up, shorter reaction times
gave the diol in high enantiomeric purity, while extended hydrolyses signi®cantly improved the ee
of the epoxide.

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A. E. Wroblewski, A. Ha•ajewska-Wosik / Tetrahedron: Asymmetry 11 (2000) 2053±2055
2055
Attempts at preparing the (S)-3 diol from the (S)-1 epoxide via acid-catalyzed opening of the
oxirane ring with water (Scheme 3) were partially successful. Under conditions described by Grin
and Kundu16 the epoxide was quantitatively transformed into the diol, which was contaminated
with ca. 5% of unidenti®ed organophosphorus compounds (ꢁ 31P 29.98 and 29.22 ppm). However,
from (S)-1 (91% ee), the (S)-3 diol (72% ee) was obtained. This result clearly showed concomitant
attack of water at C-2 in 1.
Scheme 3. Reagents and conditions: (a) H2O, H2SO4, 100ꢀC, 2.5 h
In conclusion, two important three-carbon phosphonate chirons, diethyl (S)-2,3-epoxypropyl-
phosphonate (93% ee) and diethyl (R)-2,3-dihydroxypropylphosphonate (98% ee) were synthesized
by the application of the Jacobsen's HKR process.
Acknowledgements
We thank Mrs Ma•gorzata Pluskota for her skilled experimental contributions. Financial support
from the Medical University of —odz (502-13-597) is gratefully acknowledged.
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