Asymmetric synthesis of 1-hydroxy-2-alkylphosphonic acids

Full text of DOI:10.1007/s11176-005-0524-3

Russian Journal of General Chemistry, Vol. 75, No. 11, 2005, pp. 1848 1849. Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 11, 2005,
pp. 1933 1934.
Original Russian Text Copyright
2005 by Gulyaiko, Kolodyazhnyi.
LETTERS
TO THE EDITOR
Asymmetric Synthesis of 1-Hydroxy-2-alkylphosphonic Acids
I. V. Gulyaiko and O. I. Kolodyazhnyi
Institute of Bioorganic Chemistry, National Academy of Sciences of Ukraine, Kiev, Ukraine
Received March 21, 2005
-Hydroxy- -aminoalkylphosphonic acids and
esters are important biologically active compounds
among which interesting medicine preparations and
bioregulators have been found [1, 2]. We synthesized
chiral compounds of this structure. We found that re-
action of dialkyl hydrogen phosphites with (S)-N,N-
dibenzylphenylalaninal proceeds stereoselectively and
leads to formation of chiral -hydroxy- -(dibenzyl-
amino)- -phenylpropylphosphonates with (1S,2S)-
configuration. Diastereomeric ratio obtained was 5:1
(R = Et) and 9:1 (R = Mnt, Brn). Compounds IIa IIc
were crystallized from acetonitrile, and this allowed
us to prepare chemically and optically pure (1S,2S)-
diastereomers of compound II, which then were con-
verted to 1-hydroxy-2-aminophosphonic acids (III)
by hydrolysis with 20% hydrochloric acid in dioxane
at 70 80 C.
In contrast, reaction of tris(trimethylsilyl)phosphate
with c phenylalaninal resulted in a mixture of hyd-
roxyaminophosphonic acid III (1S,2S)- and (1R,2S)-
diastereomers in a 3:1 ratio from which by crystalli-
zation from water we isolated optically pure (1R,2S)-
diastereomer. Structure of compounds obtained was
confirmed by NMR spectroscopy and elemental
analysis.
N
P(OSiMe3)3
Ph
Ph
Ph
_
N
_
Ph
Ph
Ph
O
_
_
_
_
H2O
P(OH)2
.
.
OH
(1R,2S)-III
(S)-I
N
H3O+
N
_
Ph
Ph
Ph
Ph
Ph
P(O)(OH)2
_
(R*O)2P(O)H
_
_
_
_
Ph
P(OR)2
_
_
_
_
_
_
-
-
OH
(1R,2S)-IIa IIc
OH
(1S,2S)-III
II, R = Brn = endo-borneol (a), Mnt = (1R,2S,3R)-menthol (b), Et (c).
Stereoselectivity of reaction of chiral dibornyl- and
and diazabicycluoundecene (2 3 drops) was added.
The reaction mixture was left for 24 h at room tem-
perature. Solvent was then evaporated and residue was
passed through a column with silica gel, eluent ethyl
acetate hexane, 1:4. Rf 0.3. The product obtained was
crystallized from acetonitrile. Yield 77%, mp 171
171.5 C (from acetonitrile). [ ]D 16.6 (c 1, CHCl3).
1H NMR spectrum (CDCl3), , ppm (J, Hz): 0.94 s
(3H, CH3); 0.96 s (3H, CH3); 1.04 s (3H, CH3); 1.07 s
(3H, CH3); 1.08 s (6H, CH3); 2.5 m (2H, PhCH2C);
3.73 s (1H, PhCH2N); 3.78 m (1H, CCHN); 4.23 s
dimenthylphosphites with chiral aldehyde I is higher
than that of achiral diethyl phosphite with I. This fact
can probably be explained by dual asymmetric induc-
tion [3, 4].
Dibornyl 2-(dibenzylamino)-1-hydroxy-3-
phenylpropylphosphonate (IIa). To a solution of
0.72 g (2.3 mmol) of aldehyde I in 0.7 ml of absolute
toluene 0.55 ml (1.55 mmol) of di-endo-bornyl
phosphite was added. The solution was cooled to 0 C
1070-3632/05/7511-1848 2005 Pleiades Publishing, Inc.

ASYMMETRIC SYNTHESIS OF 1-HYDROXY-2-ALKYLPHOSPHONIC ACIDS
1849
(1H, PhCHN); 4.3 s (1H, PhCHN); 4.9 m (3H, CHO +
CHC); 4.3 m (1H, CHP); 5.9 br (1H, OH); 7.17
CHP); 5.9 br (1H, OH); 7.17 7.31 m (15H, ArH).
7.31 m (15H, C6H5). 31P {1H} NMR spectrum ( ,
P
31P {1H} NMR spectrum ( , ppm, CDCl3): 28.3.
Found, %: N 2.15; P 4.26. CP43H58NO4P. Calculated,
%: N 2.05; P 4.53.
ppm, CDCl3): 17.4. Found, %: P 7.85. C23H26NO4P.
Calculated, %: P 7.53.
(1R,2S)-2-(Dibenzylamino)-1-hydroxy-3-phenyl-
propylphosphonic acid (III). 0.54 g (1.16 mmol) of
hydroxyaminophosphonate was dissolved in 4 ml of
dioxin and 4 ml of hydrochloric acid was added. The
mixture was heated for 7 h at 70 80oC. Volatile
products were removed in a vacuum. Crystalline
residue after common treatment and crystallization
from water was obtained as colorless crystalline com-
Dimenthyl 2-(dibenzylamino)-1-hydroxy-3-
phenylpropylphosphonate (IIb). Prepared similarly
to compound IIa. Purified by column chromatography
on silica gel. [ ]D 27.57 (c 6, CCl4), Rf 0.15
(CHCl3). 1H NMR spectrum (CDCl3), , ppm (J, Hz):
3
3
0.72 d (3H, CH3, JHH 6.5); 0.74 d (3H, CH3, JHH
3
6.5); 0.76 d (3H, CH3, JHH 6.5); 0.77 d (3H, CH3,
1
3JHH 6.5); 0.86 d (3H, CH3, JHH 6.5); 0.89 d (3H,
3
pound. H NMR spectrum (CDCl3), , ppm (J, Hz):
CH3, 3JHH 6.5); 0.8 1.6 m [16H, (CH2 + CH)]; 2.1 m
[1H, CH(CH3)2]; 3.3 m (2H, CCH2Ph); 3.5 m (2H,
PhCH2N); 3.70 m (1H, CHN); 3.8 m (2H, PhCH2N);
4.3 m (1H, CHO); 4.4 m (1H, CHO); 3.62 d (1H,
2.9 m (2H, CCH2Ph); 3.8 m (4H, PhCH2N); 3.70 m
(1H, CHC); 4.3 m (1H, CHP); 5.9 br (1H, OH); 7.17
7.31 m (15H, C6H5). 31P {1H} NMR spectrum ( ,
P
ppm, CDCl3): 17.4.
3
CHP, JHH 15,); 4.7 br (1H, OH); 7.1 7.4 m (15H,
NMR spectroscopic investigations were performed
on a Varian-300 instrument with internal reference
TMS (1H) and external 85% H3PO4 in D2O (31P).
C6H5). 31P {1H} NMR spectrum ( , ppm, CDCl3):
30.29. Found, %: N 2.04; P 4.5P0. C43H62NO4P.
Calculated, %: N 2.04; P 4.50.
ACKNOWLEDGMENTS
Diethyl (2R,3S)-2-(dibenzylamino)-1-hydroxy-3-
phenylpropylphosphonate (IIa). Obtained similarly
to compound IIa. Purified by column chromatography
on silica gel. Yield 50%, mp 127oC (from acetonitrile).
This work was financially supported by the DFFD
Foundation (State Fondation for Basic Research) of
Education and Science Ministry of Ukraine (project
03.07/00047).
1
[ ]D 28 (c 1, CHCl3). H NMR spectrum (CDCl3),
, ppm (J, Hz): 1.25 t (3H, CH3, 3JHH3 7.1). 1.29 (3H,
3
CH3, JHH 7.1), 1.29 d (3H, CH3, JHH 7.1), 3.15
REFERENCES
3.02 m (2H, CH2), 3.3 m (1H, CHN), 3.5 s (1H,
CHN); 3.55, s (1H, CHN); 3.9 s (1H, CHN); 3.95 s
(1H, CHN); 4.2 m (5H, CH2O + CHP); 4.39 br (1H,
OH), 7.1 7.3 m (15H, C6H5). 31P {1H} NMR spec-
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Phosphonates in Living Systems, Boca Raton: CRC
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23.85. Found, %: P 6.62.
P
C27H34NO4P. Calculated, P%: P 6.62.
2. Shibuya, S., Yakugaku Zasshi (The Pharmaceutical
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propylphosphonic acid. mp 118 120 C (from water).
1H NMR spectrum (CDCl3), , ppm (J, Hz): 2.9 m
(2H, CCH2Ph); 3.8 m (4H, PhCH2N); 3.70 m (1H,
p. 5923.
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 11 2005