Asymmetric synthesis of phosphathreoninic acid [2]

Full text of DOI:10.1007/s11176-005-0123-3

Russian Journal of General Chemistry, Vol. 74, No. 12, 2004, pp. 1945 1946. Translated from Zhurnal Obshchei Khimii, Vol. 74, No. 12, 2004,
pp. 2058 2059.
Original Russian Text Copyright
2004 by Kolodyazhnaya, Kukhar’, Kolodyazhnyi.
LETTERS
TO THE EDITOR
Asymmetric Synthesis of Phosphathreoninic Acid
A. O. Kolodyazhnaya, V. P. Kukhar’, and O. I. Kolodyazhnyi
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Kiev, Ukraine
Received November 14, 2003
Hydroxy- and aminophosphonic acids exhibit in-
teresting biological and pharmacological properties and
therefore have been intensively studied [1 3]. In the
present work we prepared phosphathreoninic esters V
and VI and free phosphathreoninic acid VII, phospho-
rus analogs of the natural treoninic acid (threonate)
which plays an important role in the metabolism of
ascorbic acid and in some other biological processes [4].
HO
P
OH
HO
O
HO
O
O
O
O
HCl
O
Catalyst
+
(RO)2POH +
O
O
OH
O
P
P
O
OR
OR
OR
RO
RO
RO
I
II
(S,R)-III, IV
(R,R)-III, IV
V VII
Catalyst = DBU and aluminum lithium (S)- and (R)-bis(binaphtholates) [(S)- and (R)-ALB]; R = (1R,2S,5R)-menthyl
(III, V), Et (IV, VI), H (VII).
The asymmetric synthesis of chiral compounds III
and IV was carried out by reaction of dialkyl hydro-
gen phosphites I with (R)-glyceraldehyde acetonide
(II). The ordinary stereoselectivity of the reaction of
the achiral diethyl hydrogen phosphite with the chiral
aldehyde II is very low (de 10%). Therefore, for a
more stereoselective reaction we made use of multiple
asymmetric induction [5, 6]. The chiral dimenthyl
hydrogen phosphite reacted with the chiral aldehyde
II in the presence of the achiral DBU with double
asymmetric induction. As a result, the stereoselecti-
vity of the reaction increased to de 60%. A still higher
stereoselectivity (80% de) was observed in the reac-
tion of the chiral di[(1R,2S,5R)-mentyl] hydrogen
phosphite with the chiral (R)-glyceraldehyde aceto-
nide in the presence of the chiral (S)-ALB [7, 8]. With
the (R)-ALB catalyst, no stereoselectivity increase was
observed.
glyceraldehyde/(1R,2S,5R)-menthyl/(S)-ALB,
act
concordantly in one direction. If the absolute con-
figurations of chiral inductors act discordantly, like in
the (R)-glyceraldehyde/(1R,2S,5R)-menthyl/(R)-ALB
system, no stereoselectivity increase was observed.
The diastereomers of compound IV were separated
and purified by crystallization from acetonitrile.
Hydrolysis with HCl in dioxane was used to succes-
sively remove the isopropylidene and ester groups of
compounds III and IV to obtain chiral phosphasugars
V and VII. The absolute configuration of compounds
III and IV (S) was established by NMR spec-
troscopy and X-ray diffraction analysis.
Di[(1R,2S,5R)-menthyl] (S)-[hydroxy[(4R)-2,2-
dimethyl-1,3-dioxolan-4-yl]methyl]phosphonate
(III). Catalyst [1-2 drops of DBU or 25 mol% of
ALB] was added to a cold (0 C) mixture of 0.01 mol
of dimenthyl hydrogen phosphite and 0.01 mol of
glyceraldehyde acetonide in 5 ml of THF. The result-
ing mixture was left to stand at this temperature for
12 h. The 31P NMR spectrum of the reaction mixture
Hence, introduction of two or three asymmetric
inductors in the reacting system additively increases
the stereoselectivity of the reaction of (R)-glyceral-
dehyde acetonide phosphorous diesters if the absolute
configurations of the chiral inductors, like in the (R)-
showed the presence of two diastereomers ( 19.98
and 20.9 ppm) in the above-mentioned ratio. An
P
1070-3632/04/7412-1945 2004 MAIK Nauka/Interperiodica

1946
KOLODYAZHNAYA et al.
optically pure S,R diastereomer was isolated by crys-
3.80 br (2H, OH), 4.18 d.q (CH2, 2H, JHH 8), 4.15
4.35 m (6H, CH2OP). 31P NMR spectrum (CDCl3) ,
ppm: 23.0, 24.5. Found, %: P 13.00. C7H17O6P. Cal-
culated, %: P 13.57.
tallization from acetonitrile. Yield 50%, mp 98 100 C
(prisms), [ ]2D0 65 (c 2, CHCl3). H NMR spectrum
1
(CDCl3), , ppm (J, Hz): 0.76 d (6H, CH3 Mnt, JHH
7.0), 0.87 d [12H, (CH3)2CH Mnt, JHH 6.6], 1,1
2.2 m CH2 + CH Mnt), 1.33 s, 1.40 s [6H, (CH3)2C)],
1.62 d (2H, mentyl CH, JHH 11.1), 2.1 2.27 m (2H,
menthyl CH), 2.65 br (1H, OH, JHH 12), 4.05 d.t
(OCHCH2, JHH 6.5, PCH, JHP 10.5), 4.23 d.t (CH2,
ABX system, JAX 7, JAB 6), 4.39 m (2H, CH2). 31P
(1,2,3-Trihydroxypropyl)phosphonic acid (VII).
A solution of 0.005 mol of compound I in a 1:1 mix-
ture of 40% hydrochloric acid and dioxane, left to
stand at 80 C for 48 h, and then thoroughly evapora-
ted in a vacuum. The residue was dissolved in 4 ml
of ethanol, and 0.01 mol of cyclohexylamine was
added. The cyclohexylammonium salt that precipi-
tated was filtered off, yield 65%, mp > 200 C
NMR spectrum (CDCl3):
20.9 ppm.
P
The R,R diastereomer containing a small admixture
of the S,R diastereomer was isolated as an oil by
column chromatography (eluent ethyl acetate hexane,
4:1). Yield 5 15% (depending on the nature of the
1
(decomp.) H NMR spectrum (CD3OD + CDCl3), ,
ppm : 0.9 1.2 m (2H, CH2), 1.6 m (4H, CH2), 1.75 m
(4H, CH2), 2.7 m (2H, CH2), 3.1 s (4H, OH), 3.4
3.6 m (2H, NH + CH). 31P NMR spectrum (CD3OD),
catalyst). 31P NMR spectrum (CDCl3):
20.0 ppm.
P
Found, %: 6.2. C26H49O6P. Calculated, %: P 6.34.
18.1 ppm. Found, %: P 11.03. C9H22NO6P. Cal-
culated, %: P 11.42.
P
Diethyl (R/S)-[hydroxy[(4R)-2,2-dimethyl-1,3-
dioxolan-4-yl]methyl]phosphonate (IV) was ob-
tained analogously to compound III. Yield 85%,
The NMR spectra were recorded on a Varian-300
spectrometer against internal TMS (1H in CD3OD +
CDCl3) and 85% phosphoric acid (31P in D2O). The
optical rotations were measured on a Polax-2L
polarymeter (Japan).
[ ]2D0 8.5 (c 2, CHCl3). H NMR spectrum (CDCl3)
1
, ppm (J, Hz): 1.30 t (6H, CH3, JHH 7), 1.35 s, 1,43 s
[6H, (CH3)2C], 2.8 br (1H, OH), 3.8 d.d (1H, H1, JHP
9.5, JHH 6.5), 3.95 m (1H, H3), 4.07 m (1H, H3, JHH
8.5), 4.18 m (4H, CH2O), 4.45 d.d.t (1H, CH2, JHH
REFERENCES
6.6, JHH 6.4, JHH 4.0). 31P NMR spectrum (CDCl3), ,
ppm: 23.0, 24.5
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Di[(1R,1S,5R)-menthyl] (S,R)-(1,2,3-trihydroxy-
propyl)phosphonate (V). To a solution of 0.005 mol
of compound I in 5 ml of dioxane, 2 3 ml of con-
centrated sulfuric acid was added. The resulting mix-
ture was left overnight and then thoroughly evapo-
rated in a vacuum. The residue was crystallized from
hexane. Yield 90%, mp 108 109 C (needles). [ ]D20
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1
60 (c 2, CHCl3). H NMR spectrum, , ppm (J, Hz):
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0.782 d [3H, (CH3)2C, JHH 6.9 Hz], 0.887 d (6H,
menthyl CH3, JHH 6.0), 0.895 d (6H, CH3 Mnt, JHH
6.6), 1.0 1.5 m (CH2 + menthyl CH), 1.626 m (2H,
menthyl H), 1.662 m (2H, menthyl H), 2.131 m (2H,
menthyl H), 2.234 m (2H, menthyl H), 2.74 br (3H,
OH), 3.831 m (POCH, 2H), 3.899 m (PCH, 1H),
4.234 m (2H, CH2). 31P NMR spectrum (CDCl2), ,
ppm: 22.51.
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Heteroatom. Chem., 2000, vol. 11, no. 2, p. 138.
Diethyl (1,2,3-trihydroxypropyl)phosphonate
(VI) was obtained analogously, [ ]2D0 3.6 (c 5, CHCl3).
1H NMR spectrum (CDCl3), , ppm (J, Hz): 1.30 t
(6H, CH3, JHH 7), 3.30 3.45 br (1H, OH), 3.65
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 74 No. 12 2004