An efficient synthesis of enantiomerically pure diethyl 2,3-dihydroxypropylphosphonate

Article abstract of DOI:10.1016/j.tetasy.2004.05.039

A reliable method for the synthesis of the enantiomerically pure diethyl (R)-2,3-dihydroxypropylphosphonate from 1,2;5,6-di-O-cyclohexylidene-D-mannitol is elaborated.

Full text of DOI:10.1016/j.tetasy.2004.05.039

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2075–2077
An efficient synthesis of enantiomerically pure
diethyl 2,3-dihydroxypropylphosphonate
*
Andrzej E. Wr oꢀ blewski and Anetta Hałajewska-Wosik
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Ł ꢀo d ꢀz , 90-151 Ł ꢀo d ꢀz , Muszy ꢀn skiego 1, Poland
Received 18 May 2004; accepted 27 May 2004
Available online
Abstract—A reliable method for the synthesis of the enantiomerically pure diethyl (R)-2,3-dihydroxypropylphosphonate from
,2;5,6-di-O-cyclohexylidene- -mannitol is elaborated.
2004 Elsevier Ltd. All rights reserved.
1
D
ꢀ
1. Introduction
propylphosphonate 4 in the presence of the Jacobsen’s
catalyst (Scheme 1).
3;4
The search for lipid analogues having a nonhydrolyz-
able P–C bond have prompted Baer and Basu to
synthesise optically active diethyl (R)- and (S)-2,3-di-
Besides applications in the studies on modified lipids,
the phosphonate (R)-1 has also been used in configu-
rational studies and chemical synthesis of 5 (FR-33289)
and 6 (FR-33699), antibiotics from the fosmidomycin
1
hydroxypropylphosphonates 1. They applied 1,2;5,6-di-
O-isopropylidene-
D
- (or
materials and prepared 2,3-O-isopropylidene-
L
)-mannitols 2 as starting
- (or )-
5;6
D
L
family (Scheme 2).
glycerols 3 as key intermediates (Scheme 1). Further
transformations included the formation of a tosylate, an
iodide, Michaelis–Arbuzov reaction and the acetal
hydrolysis. The total yield of (R)-1 from
2
D
-3 was about
4%. A similar approach to (R)-1 (total yield 18% from
PO H
P(O)(OEt)2
3
2
CH2
CH2
OH
OH
D
-2) has recently been presented by Thomas et al. in
OH
N OH
R
2
their study on phosphonate lipid tubules II. In both
strategies all the intermediates had to be purified, and
the enantiomeric purity of (R)-1 was not established. On
the other hand, the phosphonate (R)-1 (ee up to 98%)
was obtained in a one-step procedure by a hydrolytic
kinetic resolution (HKR) of racemic diethyl 2,3-epoxy-
5
6
R=Ac
R=CHO
(R)-1
Scheme 2.
O
O
P(O)(OEt)
2
HO
CH
2
OH
CH2
OH
OH
O
OH
O
O
O
P(O)(OEt)2
O
D-2
D-3
(R)-1
4
Scheme 1.
*
0
Corresponding author. Fax: +48-42-678-83-98; e-mail: aewplld@ich.pharm.am.lodz.pl
957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.05.039

2076
A. E. Wr ꢀo blewski, A. Hałajewska-Wosik / Tetrahedron: Asymmetry 15 (2004) 2075–2077
Because the enantiomeric purity of (R)-1 obtained
7
4. Experimental
through the intermediacy of the racemisation prone
D-3
1
has never been measured and the ee of the phosphonate
prepared by HKR was found to be at best 98%, an
unambiguous method for the synthesis of the enantio-
merically pure (R)-1 is required.
H NMR spectra were recorded with a Varian Mercury-
300 spectrometer; chemical shifts d in ppm with respect
13
31
to TMS; coupling constants J in Hz. C and P NMR
spectra were recorded on a Varian Mercury-300 ma-
chine at 75.5 and 121.5 MHz, respectively. IR spectral
data were measured on an Infinity MI-60FT-IR spec-
trometer. Polarimetric measurements were conducted on
a Perkin Elmer 241 MC apparatus.
2
. Results and discussion
Our strategy for the synthesis of the enantiomerically
pure (R)-1 is based on the application of the configu-
1,2;5,6-Di-O-cyclohexylidene-
according to the literature procedure.
D-mannitol was prepared
13
rationally stable 2,3-O-cyclohexylidene-D-glyceralde-
8
hyde, formation of the P–C bond via the Abramov
reaction and deoxygenation at C(1) (Scheme 3).
4.1. Diethyl (R)-2,3-dihydroxypropylphosphonate, (R)-1
A mixture of the aldehyde -8 (2.625 g, 15.40mmol) and
Addition of diethyl phosphite to
D
-8 was carried out as
D
9
described earlier and gave a 35:65 mixture of (1R,2R)-
and (1S,2R)-9, quantitatively. The crude 1-hydroxy-
phosphonates 9 were reacted with thiocarbonyldiimi-
diethyl phosphite (1.98 mL, 15.4 mmol) containing tri-
ethylamine (0.202 mL, 1.46 mmol) was left at room
temperature for 16 h. After removal of the catalyst in
vacuo, a mixture of diastereoisomeric phosphonates 9
10
dazole to furnish a mixture of diastereoisomeric
thiocarbamates (1R,2R)- and (1S,2R)-10 in 93% yield,
31
(4.75 g, 100%) was obtained as a yellowish oil. P NMR
(CDCl
for (1S,2R)-9.
1
31
which was found to be pure by H and P NMR
spectroscopy. In the presence of tributyltin hydride (the
3
): d ¼ 21:60ppm for (1 R,2R)-9 and 22.14 ppm
11
Barton procedure ) the phosphonates 10 were cleanly
deoxygenated to afford (R)-11 in 91% yield, which was
pure enough to be used in the next step. Hydrolysis of
the cyclohexylidene protecting group in (R)-11 was
A solution of diastereoisomeric phosphonates 9 (4.67 g,
15.1 mmol) in dry 1,2-dichloroethane (250mL) con-
0
taining 1,1 -thiocarbonyldiimidazole (5.40g, 30.3 mmol)
9
accomplished with 0.1 N HCl in dioxane and the
phosphonate (R)-1 was finally purified on a silica gel
column. The total yield of (R)-1 from D-8 exceeds 67%.
was stirred at 70 ꢁC for 3 h. The cooled solution was
washed with 1 M HCl (2 · 200 mL), saturated aqueous
sodium bicarbonate (200 mL) and water (200 mL). The
4
organic phase was dried over MgSO and solvents were
The enantiomeric purity of (R)-1 (100%) was established
after derivatisation with (S)-O-methylmandelic acid as
described earlier.
evaporated in vacuo to leave a crude diastereoisomeric
mixture of the phosphonates 10 (5.872 g, 93%) as a
12
3;4
1
yellowish oil. H NMR (CDCl
): d ¼ 1:28–1:60(m,
and cyclohexylidene),
and H CO), 4.60–4.72
3
1
4
6H, CH
3
CH
2
OPOCH
.09–4.30 (m, 6H, CH OPOCH
2 3
CH
2
2
2
(
m, 1H, HCCP), 6.07 (dd, J ¼ 9:7, 6.8 Hz, 0.35H, HCP),
3. Conclusions
6.33 (dd, J ¼ 11:1, 2.7 Hz, 0.65H, HCP), 7.15 (br s, 1H),
13
7
.71 (br s, 1H), 8.52 (br s, 1H). C NMR (CDCl
major diastereoisomer: d ¼ 16:5 (d, J ¼ 5:7 Hz,
CH CH OP), 23.8, 23.9, 25.1, 34.3, 35.8, 63.5 and 63.6
OPOCH
3
):
A stereochemically unequivocal synthesis of enantio-
merically pure diethyl (R)-2,3-dihydroxypropylphosph-
3
2
onate from 2,3-O-cyclohexylidene-
D
-glyceraldehyde has
(2d, J ¼ 7:1 Hz, CH
2
2
), 64.8 (d, J ¼ 1:7 Hz,
been elaborated. The reaction sequence, which involves
only one chromatographic purification, can be easily
extended for the preparation of other esters, since the
addition of dialkyl(aryl)phosphites (the Abramov reac-
tion) is less sterically demanding than alternative ap-
proach through the Arbuzov reaction.
CCCP), 73.7 (d, J ¼ 9:4 Hz, CCP), 75.8 (d,
J ¼ 161:8 Hz, CP), 110.4, 118.1, 131.0, 137.2, 183.2 (d,
J ¼ 5:8 Hz, OC@S); minor diastereoisomer: d ¼ 16:5
and 16.6 (2d, J ¼ 5:7 Hz, CH
3 2 2 3
CH OPOCH CH ), 23.9,
24.0, 25.1, 34.8, 36.1, 63.4 and 63.6 (2d, J ¼ 6:5 Hz,
CH OPOCH
2
2
), 65.3 (d, J ¼ 5:4 Hz, CCCP), 73.4 (d,
O
O
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)
2
CHO
CH2
CH2
HO
a
b, c
OR
O
O
d
e
O
O
OH
OH
OH
O
O
O
O
D-7
D-8
9 R = H
(R)-11
(R)-1
10 R = C(S)Im
Scheme 3. Reagents and conditions: (a) NaIO , ether–water; (b) (EtO)
refluxing toluene, 2.5 h; (e) 0.1 N HCl in dioxane, reflux, 1 h.
4
2
P(O)H, cat. NEt
3
; (c) Im
2
3
C@S, 1,2-dichloroethane, 70 ꢁC, 3 h; (d) Bu SnH,

A. E. Wr ꢀo blewski, A. Hałajewska-Wosik / Tetrahedron: Asymmetry 15 (2004) 2075–2077
2077
1
13
31
J ¼ 5:2 Hz, CCP), 77.0(d, J ¼ 160:6 Hz, CP), 110.9,
ethanol). H, C and P NMR spectral data of this
material were identical to those described in the litera-
ture.
31
1
18.4, 131.0, 137.0, 183.5 (d, J ¼ 5:7 Hz, OC@S).
P
4
NMR (CDCl ): d ¼ 15:65.
3
A solution of a crude mixture of diastereoisomeric
phosphonates 10 (3.00 g, 7.17 mmol) in dry toluene
(
190mL) was treated under argon atmosphere with
Acknowledgements
tributyltin hydride (3.28 mL, 12.4 mmol). The reaction
mixture was refluxed for 2.5 h, cooled to room temper-
ature and all volatiles were evaporated, finally in vacuo
We thank Mrs Małgorzata Pluskota for her skilled
experimental contributions. Financial support from the
Medical University of Ł oꢀ d ꢀz (503-314-1) is gratefully
acknowledged.
(
(
(
0.05 mmHg). The residue was dissolved in acetonitrile
200 mL) and the solution was extracted with hexanes
200 mL and 2 · 100 mL). Concentration of the aceto-
nitrile solution left crude (R)-11 (1.905 g, 91%) as a
colourless oil. A part of this material was purified on a
silica gel column with chloroform/methanol (100:1, v/v).
References and notes
20
½
aŠ ¼ þ8:3 (c 1.05, CHCl
3
). IR (film): m ¼ 2981, 2936,
D
448, 1366, 1252, 1030, 964 cm . H NMR (CDCl
ꢀ
1
1
1
3
):
1. Baer, E.; Basu, H. Can. J. Biochem. 1969, 47, 955–960.
2. Thomas, B. N.; Lindemann, C. M.; Corcoran, R. C.;
Cotant, C. L.; Kirsch, J. E.; Persichini, P. J. J. Am. Chem.
Soc. 2002, 124, 1227–1233.
d ¼ 1:33 (t, J ¼ 7:0Hz, C H CH OP), 1.30–1.45 (m,
3
2
2
1
H), 1.5–1.7 (m, 8H), 1.98 (ddd, J ¼ 18:3, 15.0, 8.7 Hz,
H, H
CP), 2.26 (ddd, J ¼ 19:0, 15.0, 5.2 Hz, 1H,
a
H
b
3
. Wr oꢀ blewski, A. E.; Hałajewska-Wosik, A. Tetrahedron:
Asymmetry 2000, 11, 2053–2055.
4. Wr
oꢀ blewski, A. E.; Hałajewska-Wosik, A. Eur. J. Org.
H H CP), 3.67 (dd, J ¼ 8:1, 6.6 Hz, 1H, H H CO),
a
b
a
b
3
1
.99–4.20(m, 5H, CH
3
CH
H, HCO). C NMR (CDCl
CH OPOCH
1.3 (d, J ¼ 138:3 Hz, CP), 35.4, 36.8, 61.9 and 62.1 (2d,
J ¼ 6:6 Hz, CH OPOCH ), 69.7 (d, J ¼ 6:6 Hz, CCCP),
0.7, 109.7. P NMR (CDCl
): d ¼ 27:86. HRMS
FAB+) C H O P (m=z): calcd 293.1518. Found
2
OP, H
): d ¼ 16:6 and 16.7 (2d,
CH ), 24.1, 24.2, 25.3,
a b
H CO), 4.32–4.43 (m,
13
3
Chem. 2002, 2758–2763.
. Hashimoto, M.; Hemmi, K.; Takeno, H.; Kamiya, T.
Tetrahedron Lett. 1980, 21, 99–102.
. Hemmi, K.; Takeno, H.; Hashimoto, M.; Kamiya, T.
Chem. Pharm. Bull. 1981, 29, 646–650.
7. Jurczak, J.; Pikul, S.; Bauer, T. Tetrahedron 1986, 42, 447–
J ¼ 6:3 Hz, CH
3
2
2
3
5
6
3
2
2
31
7
(
3
13
26
5
2
93.1520.
488.
8
. Chattopadhyay, A.; Mamdapur, V. R. J. Org. Chem.
995, 60, 585–587.
. Wr oꢀ blewski, A. E.; Balcerzak, K. B. Tetrahedron 1998, 54,
833–6840.
0. Oshikawa, T.; Yamashita, M. Bull. Chem. Soc. Jpn. 1990,
3, 2728–2730.
1
A solution of the crude phosphonate (R)-11 (1.22 g,
.17 mmol) in dioxane (25 mL) containing 0.1 N HCl
46 mL) was maintained under reflux for 1 h. The cooled
9
4
(
6
1
1
solution was concentrated and co-evaporated with
anhydrous dioxane (5 ꢁ 20mL). The residue was dis-
6
1. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1574–1585.
4
solved in methylene chloride, dried over MgSO /
NaHCO
with chloroform/methanol (20:1, v/v) to give (R)-1
3
and chromatographed on a silica gel column
12. Bonner, W. A. J. Am. Chem. Soc. 1951, 73, 3126–3132.
13. Sugiyama, T.; Sugawara, H.; Watanabe, M.; Yamashita,
K. Agric. Biol. Chem. 1984, 48, 1841–1844.
20
(
0.705 g, 80%) as a colourless oil. ½aŠD ¼ ꢀ15:3 (c 1.94,