Di(1R,2S,5R)-menthyl 2-hydroxy-3-chloropropylphosphonate as a useful chiral synthon for the preparation of enantiomerically pure phosphonic acids

Article abstract of DOI:10.1055/s-2007-985589

Stereochemically pure di(1R,2S,5R)-menthyl (S)- and (R)-2-hydroxy-3- chloropropylphosphonates were synthesized by reaction of di(1R,2S,5R)-menthyl ketophosphonate with chiral complexes prepared from sodium borohydride and (R,R)-(+)-tartaric acid or with (

Full text of DOI:10.1055/s-2007-985589

2400
LETTER
Di(1R,2S,5R)-menthyl 2-Hydroxy-3-chloropropylphosphonate as a Useful
Chiral Synthon for the Preparation of Enantiomerically Pure Phosphonic
Acids
Preparationof
E
na
i
ntiome
t
rically
a
Pure Phosp
l
honic
A
y
cids V. Nesterov, Oleg I. Kolodiazhnyi*
Institute of Bioorganic Chemistry of the National Academy of Sciences, Murmanska Str. 1, 02094 Kyiv, Ukraine
Fax 38(44)5732554; E-mail: oikol123@rambler.ru
Received 24 April 2007
nic acid (1b) of high optical purity, which represent useful
Abstract: Stereochemically pure di(1R,2S,5R)-menthyl (S)- and
(R)-2-hydroxy-3-chloropropylphosphonates were synthesized by
reaction of di(1R,2S,5R)-menthyl ketophosphonate with chiral
complexes prepared from sodium borohydride and (R,R)-(+)-tartar-
chiral synthetic building blocks (chirons) for the synthesis
of enantiomerically pure b-hydroxyphosphonates. By
means of these chirons we have obtained biologically
ic acid or with (S,S)-(–)-tartaric acid. Dimenthyl 2-hydroxy-3-chlo- important b-hydroxyphosphonic acids 2–6, including 2,3-
ropropylphosphonate was utilized as a chiron for the preparation of
biologically active products.
epoxypropylphosphonate (2a), chiral compounds 3–5, g-
amino-b-hydroxypropylphosphonic acid (phosphono-
Key words: asymmetric synthesis, reductions, double stereoselec-
tivity, phosphono-GABOB, phosphono-carnitine
GABOB, 4c) and phosphono-carnitine (6, Scheme 1).
The hydroxyphosphonates 1a were prepared by diastereo-
selective reduction of the corresponding di(1R,2S,5R)-
menthyl 2-keto-3-chloropropylphosphonate (7a). Asym-
metric reduction of prochiral ketophosphonates is a
common method to obtain enantiomerically pure hydro-
xyphosphonic acids and their derivatives.2,5,6 For the re-
duction of the ketophosphonate 7a we have used a chiral
reactant prepared from sodium borohydride and natural
(R,R)-tartaric acid or synthetic (S,S)-tartaric acid (TA,
Scheme 2).4
Hydroxyphosphonic acids are an important class of com-
pounds occurring in nature.1 Many of these compounds
have attracted considerable attention in recent years for
their role in biologically relevant processes.1–3 They
possess antibacterial, antiviral, antibiotic, pesticidal, anti-
cancer, and enzyme inhibitor properties.1,2 In our previous
publications we have reported methods for the preparation
of optically active a- and b-hydroxyphosphonic acids, in-
cluding efficient methods for the enantioselective reduc-
tion of ketophosphonates.2–4 Herein, we describe an
extension of this approach to the synthesis of the R- and S-
stereoisomers of dimenthyl 2-hydroxy-3-chloropropyl-
phosphonate (1a) and 2-hydroxy-3-chloropropylphospho-
The reduction of chiral di(1R,2S,5R)-menthyl ketophos-
phonate (7a) with the chiral complex (R,R)-TA/NaBH4
proceeded under control of double stereoselectivity7 to
yield the (S)-b-hydroxyphosphonate 1a with 96% de that
was considerably higher than the single stereoselectivity
O
(RO)2P
c
b
O
O
OH
H
OH
H
(RO)2P
(RO)2P(O)
NR'2
N3
2a
H
a
5a
O
–-N
O
+
(4a,b)
OH
H
R' = Bn2N (3a,b),
(RO)2P
Cl
d,e
d,f
OH
OH
+
HO(O2–)P
HO(O2–)P
NMe3
NH3
H
H
4c
1a,b ~100% de,
R = (1R,2S,5R)-Mnt (a), H (b) everywhere
6
Scheme 1 Representative transformations of (S)-1a to optically pure b-hydroxyphosphonates 2–6. Reagents and conditions: (a) K2CO3/KI in
MeCN–DMF; (b) HNR¢2, 80 °C; (c) NaN3/NH4Cl; (d) HCl–dioxane, 80–85 °C; (e) H2, Pd/C; (f) Me3N, H2O.
SYNLETT 2007, No. 15, pp 2400–2404
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Advanced online publication: 14.08.2007
DOI: 10.1055/s-2007-985589; Art ID: D12707ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Preparation of Enantiomerically Pure Phosphonic Acids
2401
O
ClCH2C(O)Cl
1) BuLi
ROH
[(RO)2P(O)CH2Cu]
(RO)2P(O)
Cl2P(O)Me
(RO)2P(O)Me
Cl
2) Cu2Br2
7a,c
HO
OH
(S,S)-TA/NaBH4
(R,R)-TA/NaBH4
7a,c
(RO)2P(O)
Cl
(RO)2P(O)
Cl
H
H
(R)-1a,c
R = (1R,2S,5R)-Mnt (a), Et (c)
(S)-1a,c
Scheme 2 Synthesis of (R)- and (S)-2-hydroxy-3-chloropropylphosphonates 1a,c.
when the achiral diethyl 2-keto-3-chloropropylphospho-
OH
H
OH
+
+
HO(O–)(O)P
NMe3
Me3N
P(O)(O–)OH
nate (7c) was reduced with (R,R)-TA/NaBH4 (80% ee,
Table 1). The diastereomeric ratio of (R)-1a/(S)-1a was
determined by means of 1H NMR and 31P NMR spectros-
copy. The enantiomeric purity of diethyl b-hydroxy-g-
chloropropylphosphonates (1c) was analyzed using cin-
chonidine as a chiral solvated reagent,8a and dimenthyl-
chlorophosphite as a chiral derivatizing reagent.8b The
absolute configurations of the new stereogenic centers at
C(2) in the b-hydroxyphosphonates 1a,c were determined
by chemical correlation.2b The di(1R,2S,5R)-menthyl 2-
hydroxy-3-chloropropylphosphonates [(S)-1a and (R)-1a]
were crystallized in acetonitrile or hexane and obtained as
chemically and stereochemically pure crystalline com-
pounds (ca. 100% de).9
H
(R)-(+)-6
(S)-(–)-6
Figure 1
The treatment of (S)-1a with K2CO3 in acetonitrile–DMF
in the presence of potassium iodide led quantitatively to
the formation of epoxide (R)-2a with 99% de
(Scheme 1).13 The epoxyphosphonate (R)-2a added
dibenzylamine and morpholine on heating to 80 °C to af-
ford crystalline optically pure (R)-hydroxyaminophos-
phonates 3a and 4a in ca. 90% yield. Regiospecific
opening of the epoxide cycle in dimenthyl (R)-2,3-
epoxypropylphosphonate (2a) with secondary amines
proceeded at C(3) and, after crystallization, the diastereo-
merically pure phosphonates 3a and 4a were isolated as
colorless solids. The reaction of epoxide 2a with sodium
azide in the presence of ammonium chloride in methanol
afforded the (R)-2-hydroxy-3-azidopropylphosphonate
(5a) in very high yield (Figure 2).
The (S)- and (R)-1a were used for the synthesis of R- and
S-enantiomers of phosphono-carnitine (6), which are
phosphonate analogues of natural L-carnitine playing an
important role in the transport of fatty acids into the mito-
chondrial matrix.10 Previously, the synthesis of phos-
phono-carnitine has been performed by chemoenzymatic
methods on the milligram scale.11 We have developed the
synthesis of (R)- and (S)-phosphono-carnitines on the
multigram scale. As shown in the Scheme 1, the hydroly-
sis of (S)-1a or (R)-1a with hydrochloric acid in dioxane
at 85 °C afforded acids (S)-1b and (R)-1b, which were
treated with an aqueous solution of trimethylamine to give
the crystalline enantiomerically pure (R)- and (S)-
phosphono-carnitines 6 in good yields (Figure 1).12
OH
H
OH
NR2
(MntO)2P(O)
N3
(MntO)2P(O)
H
(R)-3a,4a ~100% de
(R)-5a
Figure 2
Table 1 Stereoselective Reduction of b-Ketophosphonates 7a,c
R
Reductant
ee or de (%)
Config of 1
Stereoselectivity
–
Et
NaBH4
0
81
–
Eta
(R,R)-TA/NaBH4
(S,S)-TA/NaBH4
NaBH4
S
Single
Eta
81
R
R
S
Single
(1R,2S,5R)-Mnt
(1R,2S,5R)-Mnt
(1R,2S,5R)-Mnt
<30
96
Single
(R,R)-TA/NaBH4
(S,S)-TA/NaBH4
Matched double
Mismatched double
80
R
a The reduction of diethyl 2-keto-3-chloropropylphosphonate 7c with NaBH4/TA was reported earlier, see ref. 4.
Synlett 2007, No. 15, 2400–2404 © Thieme Stuttgart · New York

2402
V. V. Nesterov, O. I. Kolodiazhnyi
LETTER
(2) (a) Kolodiazhnyi, O. I. Russ. Chem. Rev. 2006, 75, 227.
The epoxyphosphonate (R)-2a was used for the asymmet-
ric synthesis of the phosphonic analogue of g-amino-b-
hydroxybutyric acid (L-GABOB) 4c, which is used for
the treatment of schizophrenia, epilepsy, and other illness-
es.14–16 Phosphonate analogues of GABA and GABOB
have been synthesized in recent years.17 We report here an
efficient approach to enantiomerically pure g-amino-b-
hydroxypropylphosphonic acid (4c), which delivers this
compounds in high stereochemical purity starting from
the dimenthyl (R)- or (S)-2-hydroxy-3-chloropropylphos-
phonate (1a). In the first step the reaction of optically pure
epoxide (R)-2a with dibenzylamine proceeded at C(3) to
yield the hydroxyaminophosphonate (R)-3a, which was
dealkylated by heating with hydrochloric acid in dioxane
to afford the crystalline phosphonic acid (R)-3b in 74%
yield and with ca. 100% ee. Then (R)-3b was debenzylat-
ed by hydrogenolysis in methanol in the presence of Pd/C
to result in the phosphonic analogue of natural b-hydroxy-
g-aminobutyric acid (R)-(+)-4c, which was isolated as a
solid in good yield and with high optical purity.18 The
crystalline compound 3a bearing menthyl groups was pu-
rified by crystallization in acetonitrile (Scheme 3), and its
stereochemical purity was determined by means of NMR
spectroscopy. The R-configuration of 4c was determined
from the value of the optical rotation, which is coincident
with that of the previously described phosphono-
GABOB.17
(b) Kolodiazhnyi, O. I. Tetrahedron: Asymmetry 2005, 16,
3295.
(3) Kolodiazhnyi, O. I. Tetrahedron: Asymmetry 1998, 9, 1279.
(4) Nesterov, V. V.; Kolodiazhnyi, O. I. J. Russ. Gen. Chem.
2005, 75, 1161.
(5) (a) Seyden-Penne, J. Reductions by the Alumino- and
Borohydrides in Organic Synthesis, 2nd ed.; Wiley-VCH:
New York, 1997, 6. (b) Hudlicky, M. Reductions in Organic
Chemistry; Ellis Horwood Ltd.: Chichester, 1984, 309.
(c) Asymmetric Synthesis, Vol. 2; Morrison, J. D., Ed.;
Academic Press: New York, 1983, Chap. 2 and 3.
(6) (a) Meier, C.; Laux, W. H. G. Tetrahedron: Asymmetry
1995, 6, 1089. (b) Meier, C.; Laux, W. H. G. Tetrahedron
1996, 52, 589.
(7) Kolodiazhnyi, O. I. Tetrahedron 2003, 59, 5923.
(8) (a) Kolodyazhnyi, O. I.; Kolodyazhnaya, A. O.; Kukhar’, V.
P. J. Russ. Gen. Chem. 2006, 76, 1342. (b) Nesterov, V. V.;
Grishkun, E. V.; Kolodiazhnyi, O. I. J. Russ. Gen. Chem.
2004, 74, 1947.
(9) Synthesis of Dimenthyl 2-Hydroxy-3-chloropropylphos-
phonates (1a)
Compound (S)-1a
(R,R)-Tartaric acid (5.35 g, 19.56 mmol) was added to a
suspension of NaBH4 (1.35 g, 19.56 mmol) in abs. THF (195
mL) and then the reaction mixture was refluxed with stirring
for 4 h. The reaction mixture was cooled to –30 °C, a
solution of 4.0 g of 7a19 in THF (15 mL) was added and the
mixture was left overnight at –30 °C with stirring. Then
EtOAc (50 mL) and 1 N HCl (40 mL) were added
consecutively to the mixture, the organic and the aqueous
layers were separated, and the latter was extracted with
EtOAc (3 × 20 mL). The combined organic extracts were
washed with sat. aq Na2CO3 and dried (Na2SO4). The solvent
was removed under reduced pressure and the residue was
purified by crystallization in MeCN to give (S)-1a as a
colorless solid (2.4 g, 60%). Mp 86.2 °C; [a]D20 –97.2 (c 3,
CHCl3). IR (film): 1256 (P=O), 3200 (OH) cm–1. 1H NMR
(400 MHz, C6D6): d = 0.71 (d, J = 6.9 Hz, 3 H, CH3), 0.76
(d, J = 6.9 Hz, 3 H, CH3), 0.81–0.84 (m, 12 H, CH3), 0.88–
2.18 (m, 17 H, CH2 and CH), 1.53 [m, 1 H, CH(CH3)2], 1.73
(m, 1 H, CHaP), 1.97 (m, 1 H, CHbP), 1.96 [m, 1 H,
CH(CH3)2], 3.29 (dd, J = 10.8, 6.7 Hz, 1 H, CHaCl), 3.43
(ddd, J = 10.8, 4.7, 2.8 Hz, 1 H, CHbCl), 3.90–4.10 (m, 2 H,
OCH), 4.15 (m, 1 H, CHOH), 4.44 (br, 1 H, OH). 13C NMR
(100.6 MHz, CDCl3): d = 16.13, 16.37, 21.34, 21.41, 22.24,
22.25, 23.40, 23.43, 26.00, 26.12, 31.98, 32.01, 32.64 (d,
J = 141.2 Hz, CH2P), 34.49, 34.49, 43.62, 44.13, 49.07 (d,
J = 6.5 Hz, CH), 49.08 (d, J = 6.5 Hz, CH), 49.36 (d,
J = 18.2 Hz, CH2Cl), 67.29 (d, J = 3.6 Hz, CHOH), 78.33 (d,
J = 7.5 Hz, OCH), 78.36 (d, J = 7.5 Hz, OCH). 31P NMR
(161.96 MHz, CDCl3): d = 28.81. Anal. Calcd for
C23H44ClO4P: C, 61.25; H, 9.83; P, 6.87. Found: C, 61.28; H,
9.86; P, 6.88.
OH
O
H
HNBn2
NBn2
(MntO)2P(O)
(MntO)2P(O)
H
3a, ~100% de
2a
H3O+
OH
H
OH
H2, Pd/C
+
NH3
+
HO(O2–)P
HO(O2–)P
NHBn2
H
(R)-(+)-4c, >99% de
(R)-3b
Scheme 3 Synthesis of (R)-(+)-phosphono-GABOB (4c).
In summary, a series of optically active g-amino-b-hy-
droxyphosphonic acids can be synthesized starting from
the dimenthyl (S)- or (R)-2-hydroxy-3-chloropropylphos-
phonates. These compounds give access to (R)- or (S)-
phosphono-carnitines, phosphono-GABOB, and 2-hy-
droxy-3-aminophosphonates. Di(1R,2S,5R)-menthyl (S)-
2-hydroxy-3-cloropropylphosphonate via the formation
of the epoxide and reaction with sodium azide was con-
verted into the (S)-2-hydroxy-3-azidopropylphosphonate.
All these products represent important biologically active
structures.
Compound (R)-1a
Colorless solid, mp 76.5 °C(hexane); [a]D20 –64.3 (c 2,
CHCl3). IR (film): 1256 (P=O), 3200 (OH) cm–1. 1H NMR
(400 MHz, C6D6): d = 0.72 (d, J = 6.9 Hz, 3 H, CH3), 0.73
(d, J = 6.9 Hz, 3 H, CH3), 0.81–0.84 (m, 12 H, CH3), 0.88–
2.18 (m, 17 H, CH2 and CH), 1.53 [m, 1 H, CH(CH3)2], 1.71
(ddd, J = 15.7, 15.5, 9.1 Hz, 1 H, CHaP), 1.97 (m, 1 H,
CHbP), 1.96 [m, 1 H, CH(CH3)2], 3.29 (dd, J = 10.8, 7.4 Hz,
1 H, CHaCl), 3.43 (ddd, J = 10.8, 4.4, 3.4 Hz, 1 H, CHbCl),
3.90–4.05 (m, 2 H, OCH), 3.95 (m, 1 H, CHOH), 4.25 (br, 1
H, OH). 13C NMR (100.6 MHz, CDCl3): d = 16.13, 16.36,
21.34, 21.41, 22.24, 22.25, 23.40, 23.41, 26.00, 26.12,
31.98, 32.01, 32.61 (d, J = 141.2 Hz, CH2P), 34.49, 34.49,
References and Notes
(1) (a) Hildebrand, R. L.; Henderson, T. O. The Role of
Phosphonates in Living Systems; Hildebrand, R. L., Ed.;
Chemical Rubber Company: Boca Raton, 1983, 5–29.
(b) Fields, S. C. Tetrahedron 1999, 55, 12237.
Synlett 2007, No. 15, 2400–2404 © Thieme Stuttgart · New York

LETTER
43.62, 44.13, 49.07 (d, J = 6.5 Hz, CH), 49.08 (d, J = 6.5 Hz,
Preparation of Enantiomerically Pure Phosphonic Acids
2403
CHCl3). 1H NMR (300 MHz, C6D6): d = 0.73 (d, J = 7.0 Hz,
3 H, CH3), 0.80 d (3H, J = 7.0 Hz, CH3), 0.87 (d, J = 7.0 Hz,
3 H, CH3), 0.90 (d, J = 7.0 Hz, 3 H, CH3), 0.91 (d, J = 7.0
Hz, 3 H, CH3), 0.92 (d, J = 7.0 Hz, 3 H, CH3), 0.96–2.25 (m,
19 H, CH2C, CH, and CHaP), 1.82 (ddd, J = 18.3, 15.1, 3.4
Hz, 1 H, CHbP), 2.48 (m, 2 H, CH2N), 3.55 (s, 4 H, CH2Ph),
3.60 (m, 1 H, OH), 3.90–4.00 (m, 3 H, OCH and CHOH),
7.10–7.30 (m, 10 H, 2 C6H5). 31P NMR (121.4 MHz,
CDCl3): d = 30.0.
CH), 49.36 (d, J = 18.2 Hz, CH2Cl), 67.29 (d, J = 3.6 Hz,
CHOH), 78.34 (d, J = 7.5 Hz, OCH), 78.37 (d, J = 7.5 Hz,
OCH). 31P NMR (161.96 MHz, CDCl3): d = 28.7. Anal.
Calcd for C23H44ClO4P: C, 61.25; H, 9.83; P, 6.87. Found: C,
61.25; H, 9.88; P, 6.85.
Synthesis of Compound (S)-1b
To a solution of dimenthyl hydroxyphosphonate (S)-1a (4.5
g, 9.97 mmol) in dioxane (270 mL) was added concd HCl
(80 mL) and the reaction mixture was left for 3 d at 85 °C.
Then the solvent was removed under reduced pressure, to the
residue was added H2O (50 mL) and the mixture was washed
with toluene (3 × 15 mL). Afterwards H2O was removed in
vacuo, the residue was dissolved in EtOH, and treated with
activated charcoal. The solvent was evaporated to give (S)-
1b as a colorless oil (1.63 g, 93.5%). The spectroscopically
pure product was used without further purification. 1H NMR
(300 MHz, C6D6): d = 1.6–1.9 (m, 2 H, PCH2), 3.2–3.4 (m,
2 H, CH2Cl), 4.8 (m, 1 H, CHO), 4.9 (br, OH). 31P NMR
(121.4 MHz, CDCl3): d = 25.5.20
Compound (R)-3b
Colorless solid; yield 3.1 g (85%). 1H NMR (300 MHz,
CD3OD): d = 1.73 (ddd, JHP = 32.4 Hz, JHH = 17.4 Hz, JHH
=
8.1 Hz, CHaP), 1.93 (ddd, J = 34.5, 14.7, 4.5 Hz, 1 H, CHbP),
2.96 (dd, J = 13.2, 9.3 Hz, 1 H, CHaN), 3.20 (dd, J = 13.2,
9.3 Hz, CHbN), 4.08–4.21 (m, 1 H, CHOH), 7.52–7.54 (m,
10 H, C6H5). 31P NMR (121.4 MHz, H2O): d = 26.5.
Compound (R)-4a
Colorless solid; yield 70%; mp 93 °C; [a]D20 –63.9 (c 1.17,
CHCl3). 1H NMR (300 MHz, C6D6): d = 0.75–1.63 (m, 13 H,
8 CH2 and 5 CH) 0.80 (d, J = 7.0 Hz, 3 H, CH3), 0.81 (d,
J = 7.0 Hz, 3 H, CH3), 0.90 (d, J = 7.0 Hz, 3 H, CH3), 0.91
(d, J = 7.0 Hz, 3 H, CH3), 0.92 (d, J = 7.0 Hz, 3 H, CH3),
0.93 (d, J = 7.0 Hz, 3 H, CH3), 1.79 (m, 1 H, CaH2P), 1.85
(m, 1 H, CbH2P), 2.02–2.49 [m, 10 H, CH2N, O(CH2CH2)2N,
2 CH2, and CH], 3.54 [m, 4 H, O(CH2CH2)2N], 3.59 (br, 1 H,
Compound (R)-1b
Colorless oil; yield 90%. 1H NMR (300 MHz, C6D6):
d = 1.6–1.9 (m, 2 H, PCH2), 3.2–3.4 (m, 2 H, CH2Cl), 4.8
(m, 1 H, CHOH). 31P NMR (121.4 MHz, CDCl3): d = 25.5.
(10) (a) De Simone, C.; Famularo, G. Carnitine Today; Springer:
Heidelberg, 1997. (b) Ferrari, R.; Di Mauro, S.; Sherwood,
G. l-Carnitine and its Role in Medicine: From Function to
Therapy; Academic Press: San Diego, 1992. (c) Vary, T.
C.; Neely, J. R. Am. J. Physiol. 1982, 242, H585.
(11) (a) Kielbasinski, P.; Luczak, J.; Mikolajczyk, M. J. Org.
Chem. 2002, 67, 7872. (b) Yuan, C.; Wang, K.; Li, Z.
Heteroat. Chem. 2001, 12, 551. (c) Wroblewski, A. E.;
Halajewska-Wosik, A. Eur. J. Org. Chem. 2002, 2758.
(12) Phosphono-carnitine (R)-(+)-6
OH), 3.96 (m, 1 H, CHOH), 4.10 (m, 2 H, 2 CHOH). 31
NMR (121.4 MHz, CDCl3): d = 30.0.
Compound (R)-5a
P
Colorless oil; yield 96%; [a]D20 –74.2 (c 2.5, CHCl3). IR
(film): nmax = 2120 (N3), 1200 (P=O) cm–1. 1H NMR (300
MHz, C6D6): d = 0.79 (d, J = 7 Hz, 3 H, CH3), 0.81 (d, J = 7
Hz, 3 H, CH3), 0.91 (d, J = 7 Hz, 3 H, CH3), 0.92 (d, J = 7
Hz, 3 H, CH3), 0.93 (d, J = 7 Hz, 3 H, CH3), 0.94 (d, J = 7
Hz, 3 H, CH3), 1.00–2.00 (m, 16 H, CH2C), 1.80 (m, 2 H,
PCH), 3.15 (m, 2 H, CH2N), 4.05 (m, 2 H, CHO), 4.14 (m, 2
H, CHOH and OH). 31P NMR (121.4 MHz, CDCl3):
d = 27.4.
A solution of 30% trimethylamine (80 mL) was added to a
solution of (S)-1b (1.74 g, 10 mmol) in H2O. The mixture
was left for 48 h at 40 °C, the solvent was evaporated under
reduced pressure and the residue was chromatographed on
silica gel (MeOH–H2O, 1:1) to give (R)-6 (2g, 80%) as a
white solid; yield 80%; mp >250 °C (decomp.); [a]D20 +26 (c
1, H2O). 1H NMR (400 MHz, CD3OD): d = 1.80 (ddd,
J = 18, 14.7, 6.6 Hz, 1 H, PCaH), 1.89 (ddd, J = 17.7, 14.8,
6.9 Hz, 1 H, PCbH), 3.20 [s, 9 H, (CH3)3N], 3.40 (dd,
J = 13.8, 9.8 Hz, 1 H, CHaN), 3.60 (dd, J = 13.8, 1.2 Hz, 1
H, CHbN), 4.50 (m, 1 H, CHOH). 13C NMR (100.6 MHz,
D2O): d = 35.55 (d, J = 131.7 Hz, CH2P), 54.91, 54.94,
54.98, 63.65, 71.57. 31P NMR (161.96 MHz, D2O): d = 18.1.
Phosphono-carnitine (S)-(–)-6
(14) (a) Falch, E.; Hegegaard, A.; Nielsen, L.; Jensen, B. R.;
Hjeds, H.; Krogsgaard-Larsen, P. J. Neurochem. 1986, 47,
898. (b) Kristiansen, U.; Fjalland, B. Pharmacol. Toxicol.
1991, 68, 332.
(15) (a) Banfi, S.; Fonio, W.; Allievi, E.; Raimondo, S.
Pharmacol. Res. Commun. 1983, 15, 553. (b) Garcia-
Flores, E.; Farias, R. Stereotact. Funct. Neurosurg. 1997, 69,
243.
(16) Wang, K.; Zhang, Y.; Yuan, C. Org. Biomol. Chem. 2003, 1,
3564.
(17) (a) Wroblewsky, A. E.; Halajewska-Wosik, A. Tetrahedron:
Asymmetry 2003, 14, 3359. (b) Ordonez, M.; Gonzales-
Morales, A.; Ruiz, C.; De la Cruz-Cordero, R.; Fernandez-
Zertuche, M. Tetrahedron: Asymmetry 2003, 14, 1775.
(18) Phosphono-GABOB (R)-(+)-4c
White solid; yield 80%; mp >250 °C (decomp.); [a]D20 –26.0
(c 1, H2O). The NMR spectroscopy data are identical to (R)-
(+)-6.
(13) Compound (R)-2a
To a stirred solution of (S)-(–)-1a (4.5 g, 10 mmol) in a
10:3.5 mixture of MeCN–DMF (100 mL) were added
K2CO3 (3.0 g) and KI (0.3 g). The mixture was refluxed for
8 h, filtered off, and the filtrate was evaporated to give (R)-
2a (4.05 g, 98%) as a colorless oil; [a]D20 –62.4 (c 7.0,
CHCl3). 1H NMR (400 MHz, C6D6): d = 0.80 (d, J = 7 Hz, 3
H, CH3), 0.88 (d, J = 7 Hz, 3 H, CH3), 0.89 (d, J = 7 Hz, 3 H,
CH3), 0.90 (d, J = 7 Hz, 3 H, CH3), 0.91 (d, J = 7 Hz, 3 H,
CH3), 0.80–1.65 (m, 16 H CH2C), 2.15–2.05 (m, 5 H, PCH2,
CH2, and CH), 2.40 (dd, J = 5.1, 2.1 Hz, 1 H, CHaO), 3.0 (dd,
J = 5.1, 4.0 Hz, 1 H, CHbO), 3.00 (m 1 H, CHO), 4.24 (m, 2
H, CHOP). 31P NMR (121.4 MHz, CDCl3): d = 25.3.
Compound (R)-3a
A solution of (R)-3b (1.85 g, 5 mmol) in MeOH (210 mL)
was hydrogenated over 10% Pd/C (1.75 g) for 20 h at r.t. The
mixture was filtered off and concentrated under reduced
pressure, washed with acetone, and dried in vacuo. The
residue was purified by ion-exchange chromatography to
20
give a colorless hygroscopic solid (0.69 g, 90%); [a]D
+10.2 (c 1, H2O). 1H NMR (400 MHz, D2O): d = 1.78 (ddd,
J = 31.2, 15.0, 6.3 Hz, CHaP), 1.86 (ddd, J = 32.1, 14.7, 6.3
Hz, CHbP), 2.99 (dd, J = 13.5, 8.5 Hz, CHaN), 3.27 (dd,
J = 13.1, 3.4 Hz, CHbN), 4.14 (m, 1 H, CHOH). 13C NMR
(100.6 MHz, D2O): d = 37.01 (d, J = 128.3 Hz, CH2P), 48.13
(d, J = 9.0 Hz, CH2N), 67.41. 31P NMR (161.96 MHz, D2O):
d = 18.1.
Colorless solid; yield 70%; mp 73 °C; [a]D20 –45.92 (c 4.57,
Synlett 2007, No. 15, 2400–2404 © Thieme Stuttgart · New York

2404
V. V. Nesterov, O. I. Kolodiazhnyi
LETTER
(19) Di(1R,2S,5R)-menthyl 2-keto-3-chloropropylphos-
phonate (7a)
NMR (100.6 MHz, CDCl3): d = 15.64, 15.81, 20.93, 20.99,
21.85, 22.88, 22.95, 25.53, 25.65, 31.58, 31.66, 33.98, 41.58
(d, J = 128.6 Hz, CH2P), 42.90, 43.54, 48.49 (d, J = 9.3 Hz,
CH), 48.51 (d, J = 9.3 Hz, CH), 48.53 (d, J = 19.3 Hz,
CH2Cl), 78.62 (d, J = 7.5 Hz, OCH), 78.90 (d, J = 7.5 Hz,
OCH), 193.10 [d, J = 6.1 Hz, C(O)]. 31P NMR (121.4 MHz,
CDCl3): d = 16.7.
Yield 70%; mp 65.5–65.6 °C; [a]D20 –78.0 (c 1, CHCl3). IR
(film): 1256 (P=O), 1725 (C=O) cm–1. 1H NMR (300 MHz,
C6D6): d = 0.79 (d, J = 7 Hz, 3 H, CH3), 0.81 (d, J = 7 Hz, 3
H, CH3), 0.89 (d, J = 7 Hz, 3 H, CH3), 0.90 (d, J = 7 Hz, 3 H,
CH3) 0.91 (d, J = 7 Hz, 3 H, CH3), 0.93 (d, J = 7 Hz, 3 H,
CH3), 0.90–2.10 (m, 16 H, CH2 and CH), 1.52 [m, 1 H,
CH(CH3)2], 1.94 [m, 1 H, CH(CH3)2], 3.04 (d, J = 23.5 Hz,
(20) All new compounds gave satisfactory analytical data in C, H,
P (or N).
2 H, PCH2), 4.04 (s, 2 H, CH2Cl), 4.07 (m, 2 H, 2 OCH). 13
C
Synlett 2007, No. 15, 2400–2404 © Thieme Stuttgart · New York

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