Preparation of (R)- and (S)-γ-amino-β-hydroxypropylphosphonic acid from glycine

Article abstract of DOI:10.1016/S0957-4166(03)00371-9

An efficient synthesis of both enantiomers of γ-amino-β-hydroxypropylphosphonic acid, an analogue of GABOB, has been achieved for the first time starting from glycine, through the resolution of dimethyl (±)-3-(N,N-dibenzylamino)-2-hydroxypropylphosphonate

Full text of DOI:10.1016/S0957-4166(03)00371-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1775–1779
Preparation of (R)- and (S)-g-amino-b-hydroxypropylphosphonic
acid from glycine
Mario Ordo´n˜ez,* Angelina Gonza´lez-Morales, Ce´sar Ru´ız, Ricardo De la Cruz-Cordero and
Mario Ferna´ndez-Zertuche
Centro de Investigaciones Qu´ımicas, Universidad Auto´noma del Estado de Morelos,
Av. Universidad No. 1001. 62210 Cuernavaca, Mor., Mexico
Received 10 October 2002; accepted 4 April 2003
Abstract—An efficient synthesis of both enantiomers of g-amino-b-hydroxypropylphosphonic acid, an analogue of GABOB, has
been achieved for the first time starting from glycine, through the resolution of dimethyl ( )-3-(N,N-dibenzylamino)-2-hydroxy-
propylphosphonate 7 with (S)-O-methylmandelic acid. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
Because of the importance of L-carnitine and L-
GABOB in medical science, many synthetic routes have
been developed.4
(R)-3-Hydroxy-4-trimethylaminobutyric acid (L-car-
nitine)
1
and (R)-g-amino-b-hydroxybutyric acid
(GABOB) 2 are two compounds with a very high level
of medical significance due to their interesting biologi-
cal properties and usefulness as pharmaceuticals. L-
Carnitine 1 plays an important role in the oxidation of
fatty acids and is involved in other important metabolic
pathways, both as free carnitine and as acetylcarnitine;
the latter are metabolic products of reactions that uti-
lize acetyl CoA catalyzed by carnitine acetyltrans-
ferase.1 The (S)-enantiomer of 1 acts as a competitive
inhibitor of carnitine acetyltransferase2 causing deple-
tion of carnitine. (R)-g-Amino-b-hydroxybutyric acid 2
is a well known drug that functions as an agonist of
gamma-aminobutyric acid (GABA). It has been
demonstrated to be effective in managing a variety of
clinical conditions including schizophrenia, epilepsy
and others illnesses that result in severe convulsions.3
Various analogues of carnitine have been synthesized,
including phosphocarnitine 3, an analogue in which the
carboxylic group has been replaced with a phosphonic
function. The stereoselective synthesis of phosphocar-
nitine 3 has been achieved from (R)-(−)-epichlorhidrin,5
by hydrolysis of racemic diethyl 2,3-epoxipropylphos-
phonate in the presence of (R,R)-salen-Co(III)-OAc,6
and by enzymatic kinetic resolution.7 However, in the
best of our knowledge the synthesis of the enantiomeri-
cally pure g-amino-b-hydroxypropylphosphonic acid 4
has not been described.8,9
As part of our ongoing program directed towards the
design of homochiral g-amino-b-hydroxyphospho-
nates,10 we report here a simple procedure for the
synthesis of (R)- and (S)-g-amino-b-hydroxypropyl-
phosphonic acid 4, which is based on reduction of the
carbonyl group of the b-ketophosphonate 6, derived
from the readily available N,N-dibenzylglycinate 5, and
its resolution with (S)-O-methylmandelic acid.
2. Results and discussion
Initially, treatment of glycine with K2CO3 and excess of
benzyl bromide under reflux, afford the mixture of the
N,N-dibenzylglycinates 5, which were cleanly separated
on column chromatography affording the less polar
N,N-dibenzylglycine benzyl ester11 5a in 64% yield as a
* Corresponding authors. E-mail: palacios@buzon.uaem.mx
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00371-9

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M. Ordo´n˜ez et al. / Tetrahedron: Asymmetry 14 (2003) 1775–1779
the more polar diastereomer (R,S)-9 in 45% yield as a
liquid (Scheme 2). Their purity was ascertained from
1H, 13C, 31P NMR spectra.
solid and the more polar N,N-dibenzylglycine methyl
ester12 5b in 32% yield as a liquid. The reaction of the
protected glycine 5a or 5b with two equivalents of the
lithium salt of dimethyl methylphosphonate at −78°C in
THF give the corresponding dimethyl 3-(N,N-dibenzyl-
The absolute configuration of the C3-stereogenic cen-
ters of the diastereomers (S,S)-8 and (R,S)-9 were
amino)-2-ketopropylphosphonate
6
in 87% yield.
1
assigned, based on the analysis of H and 31P NMR
Reduction of 2-oxophosphonate 6 with NaBH4 in
methanol at room temperature afford the racemic mix-
ture of the dimethyl 3-(N,N-dibenzylamino)-2-hydroxy-
propylphosphonate 7 in 96% yield (Scheme 1).
spectral data of the mandelates. Thus, according to the
Trost model,13 both the methylene and methyl protons
of the CH2P(O)(OMe)2 group in the diastereomer
(S,S)-8 are expected to be shielded, as well as the
methylene protons on the CH2NBn2 group in the
diastereomer (R,S)-9, since they are eclipsed with the
phenyl ring of the mandelic functionality in the
extended Newman projection (Fig. 1).
The resolution of ( )-7 was achieved via O-methylman-
delate derivatives.13 Thus, the reaction of the racemic
mixture ( )-7 with (S)-O-methylmandelic acid in the
presence of DCC and DMAP in dichloromethane at
room temperature afford the respective mandelates in
good yield. The mixture of diastereomers was cleanly
separated on column chromatography affording the less
polar diastereomer (S,S)-8 in 43% yield as a liquid and
1
Both H and 31P NMR spectra revealed some signifi-
cant differences between the (S,S)-8 and (R,S)-9
diastereomers (Table 1).
Scheme 1.
Scheme 2.
Figure 1. Extended Newman projections for the diastereomers (S,S)-8 and (R,S)-9.
Table 1. 1H and 31P NMR chemical shifts of the mandelates (S,S)-8 and (R,S)-9
Entry
Less polar mandelate
Dl (ppm)
More polar mandelate
Dl (ppm)
1
2
3
4
5
CH2P(O)
CH2NBn2
CH2Ph
(CH3O)2P
(CH3O)2P
1.79 and 2.11
2.60 and 2.66
3.59
3.40 and 3.52
30.47
0.32
0.06
0
0.12
–
1.97 and 2.14
2.45 and 2.55
3.38 and 3.43
3.63 and 3.65
30.78
0.17
0.10
0.05
0.02
–

M. Ordo´n˜ez et al. / Tetrahedron: Asymmetry 14 (2003) 1775–1779
1777
The less polar diastereomer showed upfield shifts for
3. Experimental
the two methylene protons in CH2P(O) at 1.79 and 2.11
ppm, Dl=0.32 ppm entry 1, and for the two methyl
signals in (CH3O)2P at 3.40 and 3.52 ppm, Dl=0.12
ppm entry 4. On the other hand, the more polar
diastereomer showed upfield shifts for two methylene
protons in CH2NBn2 at 2.45 and 2.55 ppm, Dl=0.10
ppm entry 2, and for the two methylenes in CH2Ph at
3.38 and 3.43 ppm, Dl=0.05 ppm entry 3. Addition-
ally, the 31P NMR chemical shifts for the less polar
diastereomer appear at a higher field (30.47 ppm) than
the more polar methylmandelate (30.78 ppm) entry 5.
The same similarities in their 31P NMR chemical shifts
have been observed for the diethyl phosphonate
analogs.6a These NMR data show that the less polar
compound is the (S,S) diastereomer and the more polar
compound is the (R,S) diastereomer.14
Optical rotations were taken on a Perkin–Elmer 241
polarimeter in an 1 dm tube; concentrations are given
in g/100 mL. For the flash chromatography, silica gel
1
60 (230–400 mesh ASTM, Merck) was used. H NMR
spectra were registered on a Varian (400 MHz) and 13C
NMR on AMX-500 (100 MHz). The spectras were
recorded in D2O or CDCl3 solution, using TMS as
internal reference. Microanalyses were registered on a
Elemental VARIO EL III.
Flasks, stirrings bars, and hypodermic needles used for
the generation of organometallic compounds were dried
for ca. 12 h at 120°C and allowed to cool in a dessica-
tor over anhydrous calcium sulfate. Anhydrous solvents
(ethers) were obtained by distillation from benzophe-
none ketyl. The (S)-O-methylmandelic acid was pre-
pared according to literature procedure.16
Treatment of (S,S)-8 with LiOH in a mixture of
MeOH:H2O (8:2) at room temperature followed by
separation of (S)-O-methylmandelic acid by column
chromatography give (S)-7 in 85% yield. In a similar
manner, (R)-7 was obtained from (R,S)-9 in 83% yield
(Scheme 3). Finally, hydrolysis of b-hydroxypropyl-
phosphonates (S)-7 and (R)-7 with bromotri-
methylsilane15 at room temperature afforded the acid
g - (N,N - dibenzylamino) - b - hydroxy-propylphosphonic
acid in quantitative yield, which without further purifi-
cation were treated with palladium on carbon in
methanol under hydrogen at room temperature to
obtain (S)- and (R)-g-amino-b-hydroxypropylphospho-
nic acid in 78% and 76% yield, respectively.
3.1. Dimethyl 3-(N,N-dibenzylamino)-2-oxopropylphos-
phonate 6
A solution of benzylbromide (45.6 g, 0.27 mol) in
methanol (150 mL) was slowly added to a solution of
the glycine (5 g, 0.07 mol) and K2CO3 (36.8 g, 0.27 mol)
in a 5:1 mixture of methanol–water (350 mL). The
reaction mixture was refluxed for 3 h, the solvent was
removed under reduced pressure and water was added
to the residue and extracted with ethyl acetate (3×150
ml). The combined organic layers were dried over
Na2SO4 and evaporated under reduced pressure. The
crude products were purified by flash chromatography
(hexane-ethyl acetate 9:1) to afford N,N-dibenzyl-
glycine benzyl ester10 5a (14.7 g, 64%) as a solid, and
the more polar N,N-dibenzylglycine methyl ester11 5b
(6.5 g, 32%) as a liquid. Dimethylmethylphosphonate
(2.87 g, 23.15 mmol) was dissolved in dry THF (50
mL), cooled at −78°C, and treated with (23.2 mL, 25.5
mmol) of n-BuLi in hexanes (1.1 M) under nitrogen
In conclusion, we have found a new methodology for
the preparation of enantiomerically pure (R)- and (S)-
g-amino-b-hydroxypropylphosphonic acid from glycine,
which are analogues of GABOB. Additionally, these
compounds can be useful intermediates for the synthe-
sis of (S)- and (R)-phosphocarnitine and other
aminophosphonic acids derivatives.
Scheme 3.

1778
M. Ordo´n˜ez et al. / Tetrahedron: Asymmetry 14 (2003) 1775–1779
atmosphere. The resulting solution was stirred at
−50°C for 1 h, and after this period of time the solu-
tion was cooled at −78°C and was slowly added to a
solution of the N,N-dibenzylglycine benzyl ester 5a
(4.0 g, 11.6 mmol) in THF (50 mL). The reaction
mixture was stirred at −78°C for 3 h before the addi-
tion of a saturated solution of NH4Cl. The organic
layer was separated and the aqueous layer was
extracted with ethyl acetate (3×50 ml). The combined
organic extracts were dried over Na2SO4 and concen-
trated in vacuo. The crude product was purified by
column chromatography (ethyl acetate–hexane 4:1) to
afford 6 (3.65 g, 87%) as yellow oil. (Identical yield
was obtained using the ester 5b.) 1H NMR (400
MHz, CDCl3) l 3.10 (d, J=22.4 Hz, 2H, CH2P(O)),
3.35 (s, 2H, CH2NBn2), 3.66 (d, J=11.2 Hz, 6H,
(CH3O)2P), 3.68 (s, 4H, CH2Ph), 7.24–7.38 (m, 10H,
Harom). 13C NMR (100 MHz, CDCl3) l 38.1 (d, J=
129.1 Hz, CH2P(O)), 53.0 (d, J=6.1 Hz, (CH3O)2P),
58.9 CH2Ph, 63.8 CH2NBn2, 127.5, 128.6, 129.3,
138.6, 201.7 CꢀO. 31P NMR (400 MHz, CDCl3) l
23.90.
purified by column chromatography (ethyl acetate–
hexane 3:1) to afford (S,S)-8 (2.1 g, 43%) as colorless
oil (less polar) and (R,S)-9 (2.2 g, 45%) as colorless
oil (more polar).
3.4. Less polar diastereomer (S,S)-8
[h]2D0=+32 (c 2.2, CHCl3). 1H NMR (400 MHz,
CDCl3) l 1.79 (ddd, J=17.6, 15.6, 7.2 Hz, 1H,
CH2P(O)), 2.11 (ddd, J=18.8, 15.6, 4.8 Hz, 1H,
CH2P(O)), 2.60 (dd, J=13.2, 6.0 Hz, 1H, CH2NBn2),
2.66 (ddd, J=13.2, 6.8, 2.4 Hz, 1H, CH2NBn2), 3.40
(d, J=11.0 Hz, 3H, (CH3O)2P), 3.42 (s, 3H, CH3O),
3.52 (d, J=11.0 Hz, 3H, (CH3O)2P), 3.59 (s, 4H,
CH2Ph), 4.67 (s, 1H, CH(OCH3)), 5.28–5.37 (m, 1H,
CHCH2P(O)), 7.30–7.39 (m, 10H, Harom). 13C NMR
(100 MHz, CDCl3)
l
27.9 (d, J=141.9 Hz,
CH2P(O)), 52.3 (d, J=6.1 Hz, (CH3O)2P), 56.9 (d,
J=6.1 Hz, (CH3O)2P), 57.5 (CH3OCH), 58.9
CH2NBn2, 59.0 CH2Ph, 68.4 (CHCH2P(O)), 82.7
CH(OCH3), 127.2, 127.6, 128.4, 128.7, 128.8, 129.2,
136.1, 138.9, 169.9 CꢀO. 31P NMR (400 MHz,
CDCl3) l 30.47. Anal. calcd for C28H34NO6P: C,
65.74; H, 6.70; N, 2.74. Found C, 65.57; H, 6.78; N,
2.69.
3.2. Dimethyl (RS)-3-(N,N-dibenzylamino)-2-hydroxy-
propylphosphonate ( )-7
3.5. More polar diastereomer (R,S)-9
A mixture of the dimethyl 3-(N,N-dibenzylamino)-2-
oxopropylphosphonate 6 (3.7 g, 10 mmol), sodium
borohydride (2.3 g, 60.7 mmol) and methanol (40
mL) was stirred at rt for 10 h under a nitrogen atmo-
sphere. After the reaction mixture was carefully
treated with a saturated solution of NH4Cl. The sol-
vent was removed in vacuo, and the residue was dis-
solved in water and extracted with ethyl acetate. The
combined organic extracts were dried over Na2SO4
and concentrated in vacuo. The crude product was
purified by column chromatography (ethyl acetate–
hexane 4:1) to afford ( )-7 (3.5 g, 96%) as colorless
oil. 1H NMR (400 MHz, CDCl3) l 1.79 (ddd, J=
16.8, 15.2, 8.4 Hz, 1H, CH2P(O)), 1.90 (ddd, J=18.8,
15.2, 4.0 Hz, 1H, CH2P(O)), 2.49–2.58 (m, 2H,
CH2NBn2), 3.49 (d, J=13.6 Hz, 2H, CH2Ph), 3.70 (d,
J=11.2 Hz, 3H, (CH3O)2P), 3.72 (d, J=11.2 Hz, 3H,
(CH3O)2P), 3.76 (d, J=13.6 Hz, 2H, CH2Ph), 4.03–
4.12 (m, 1H, CH(OH)), 7.24–7.34 (m, 10H, Harom).
13C NMR (100 MHz, CDCl3) l 30.8 (d, J=139.7 Hz,
CH2P(O)), 52.4 (d, J=6.1 Hz, (CH3O)2P), 52.6 (d,
J=6.1 Hz, (CH3O)2P), 59.0 CH2Ph, 60.2 (d, J=15.2
Hz, CH(OH)), 63.6 CH2NBn2, 127.4, 128.6, 129.3,
138.8. 31P NMR (400 MHz, CDCl3) l 33.45.
[h]2D0=+23.9 (c 1.09, CHCl3). 1H NMR (400 MHz,
CDCl3) l 1.97 (ddd, J=16.8, 15.6, 8.0 Hz, 1H,
CH2P(O)), 2.14 (ddd, J=19.2, 16.0, 4.4 Hz, 1H,
CH2P(O)), 2.45 (dd, J=13.6, 6.0 Hz, 1H, CH2NBn2),
2.55 (ddd, J=13.6, 6.0, 2.0 Hz, 1H, CH2NBn2), 3.38
(d, J=13.8 Hz, 2H, CH2Ph), 3.41 (s, 3H, CH3O),
3.43 (d, J=13.8 Hz, 2H, CH2Ph), 3.63 (d, J=10.8
Hz, 3H, (CH3O)2P), 3.65 (d, J=10.8 Hz, 3H,
(CH3O)2P), 4.74 (s, 1H, CH(OCH3)), 5.30–5.38 (m,
1H, CHCH2P(O)), 7.17–7.45 (m, 10H, Harom). 13C
NMR (100 MHz, CDCl3) l 28.4 (d, J=141.9 Hz,
CH2P(O)), 52.5 (d, J=6.8 Hz, (CH3O)2P), 52.7 (d,
J=6.8 Hz, (CH3O)2P), 57.1 CH2NBn2), 57.6
(CH3OCH), 68.5 (CHCH2P(O)), 59.0 CH2Ph, 82.9
CH(OCH3), 127.3, 127.7, 128.5, 128.8, 129.0, 129.2,
136.4, 139.1, 170.1 CꢀO. 31P NMR (400 MHz,
CDCl3) l 30.78. Anal. calcd for C28H34NO6P: C,
65.74; H, 6.70; N, 2.74. Found C, 65.71; H, 6.67; N,
2.65.
3.6. Dimethyl (S)-3-(N,N-dibenzylamino)-2-hydroxy-
propylphosphonate 7
The diastereomer (S,S)-8 (314 mg, 0.61 mmol) was
dissolved in MeOH/H2O 8:2 (20 mL) and stirred at rt
with LiOH (29.4 mg, 1.22 mmol). After 8 h the
volatiles were removed in vacuo. The residue was dis-
solved in ethyl acetate and washed with water. The
layer organic was dried over Na2SO4 and concen-
trated in vacuo. The crude product was purified by
column chromatography (ethyl acetate–hexane 4:1) to
afford (S)-7 (189 mg, 85%) as colorless oil. [h]2D0=
−31.7 (c 1.42, CHCl3). The NMR shifts are identical
to ( )-7. Anal. calcd for C19H26NO4P: C, 62.80; H,
7.21; N, 3.85. Found C, 62.65; H, 7.15; N, 3.79. In a
3.3. Esterification of ( )-7 with (S)-O-methylmandelic
acid
To a solution of ( )-7 (3.5 g, 9.6 mmol) and (S)-O-
methylmandelic acid (2.6 g, 15.4 mmol) in
dichloromethane (60 mL) containing dimethyl-
aminopyridine (176 mg, 1.45 mmol) and 1,3-dicyclo-
hexylcarbodiimide (3.2 g, 15.4 mmol) was added. The
reaction mixture was stirred at rt for 7 h. After 1,3-
dicyclohexylurea was filtered off and the liquid layer
was evaporated in vacuo. The crude product was

M. Ordo´n˜ez et al. / Tetrahedron: Asymmetry 14 (2003) 1775–1779
1779
References
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afford (R)-7 (281 mg, 83%) as colorless oil. [h]2D0=
+ 29.4 (c 1.8, CHCl3). Anal. calcd for C19H26NO4P: C,
62.80; H, 7.21; N, 3.85. Found C, 62.73; H, 7.12; N,
3.82.
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3.7. (S)-3-Amino-2-hydroxypropylphosphonic acid 4
Dimethyl (S)-2-hydroxy-3-(N,N-dibenzylamino)propyl-
phosphonate 7 (144 mg, 0.4 mmol) was treated with
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was stirred at rt for 4 h, and after this period of time
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2.04, H2O). H NMR (400 MHz, D2O) l 1.86 (ddd,
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36.4, 14.8, 6.8 Hz, 1H, CH2P(O)), 2.93 (dd, J=13.2,
9.6 Hz, 1H, CH2NH2), 3.27 (dd, J=13.2, 2.8 Hz, 1H,
CH2NH2), 4.08–4.17 (m, 1H, CHOH). 13C NMR (100
MHz, D2O) l 37.3 (d, J=128.5 Hz), 48.3 (d, J=9.9
Hz), 67.6. 31P NMR (200 MHz, D2O) l 19.94.
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1.03 mmol), and the crude product was treated with
palladium on carbon 316 mg (5% wt) in methanol (20
mL) and stirred for 16 h under hydrogen gas at rt,
obtaining (56 mg, 76%) of (R)-g-amino-b-hydrox-
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176–178°C, [h]2D0=+10.8 (c 2.04, H2O).
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Acknowledgements
We wish to thank CONACyT (Project 28762-E and
41657-Q) and Victoria Labastida for financial and
technical support. A.G.M. and R.C.C. would like to
thank CONACyT for scholarship.
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