A novel and simple method for the preparation of (R)- and (S)-pyrrolidine-2-phosphonic acids: Phosphonic acid analogues of proline

Article abstract of DOI:10.1016/j.tetasy.2013.10.013

A simple and convenient method has been developed for the preparation of (R)- and (S)-pyrrolidine-2-phosphonic acids. The thermal reaction of proline with diethyl phosphite in the presence of benzaldehyde gave an N-benzyl derivative of diethyl pyrrolidine-2-phosphonate, which was transformed into two diastereomeric amides by sequential debenzylation and acylation with (+)-dibenzoyl-l-tartaric anhydride. The two diastereomeric amides were separated by column chromatography and the structure of one of them was determined by X-ray crystallographic analysis. Hydrolysis of the amides in the usual manner afforded (R)- and (S)-pyrrolidine-2-phosphonic acids. The advantages of the present method are that it is easy, rapid, and prepares both enantiomers of pyrrolidine-2-phosphonic acids.

Full text of DOI:10.1016/j.tetasy.2013.10.013

Tetrahedron: Asymmetry 24 (2013) 1562–1566
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A novel and simple method for the preparation of (R)- and
(S)-pyrrolidine-2-phosphonic acids: phosphonic acid analogues
of proline
b
b
b,
Babak Kaboudin a,b, , Jun-ya Kato , Hiroshi Aoyama , Tsutomu Yokomatsu
⇑
⇑
a Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Gava Zang, Zanjan 45137-66731, Iran
b School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 July 2013
Accepted 17 October 2013
A simple and convenient method has been developed for the preparation of (R)- and (S)-pyrrolidine-2-
phosphonic acids. The thermal reaction of proline with diethyl phosphite in the presence of benzaldehyde
gave an N-benzyl derivative of diethyl pyrrolidine-2-phosphonate, which was transformed into two dia-
stereomeric amides by sequential debenzylation and acylation with (+)-dibenzoyl-L-tartaric anhydride.
The two diastereomeric amides were separated by column chromatography and the structure of one of
them was determined by X-ray crystallographic analysis. Hydrolysis of the amides in the usual manner
afforded (R)- and (S)-pyrrolidine-2-phosphonic acids. The advantages of the present method are that it is
easy, rapid, and prepares both enantiomers of pyrrolidine-2-phosphonic acids.
Ó 2013 Elsevier Ltd. All rights reserved.
O
O
1. Introduction
CO2H
P(OH)2
P(OH)2
N
H
N
H
N
H
a
-Aminoalkylphosphonic acids are considered to be structural
(R)-1
(S)-1
analogues of -amino acids and possess potential biological activ-
a
L-Proline
ities applicable to antibiotics, enzyme inhibitors, pharmacological
agents, antiviral agents, and herbicides.1,2 Since the structure of
the phosphonic functional group mimics the unstable tetrahedral
intermediates formed in enzyme-mediated peptide bond cleavage,
Figure 1. Structures of L-proline and the phosphonic acid analogues of proline.
some peptides derived from a-aminophosphonic acids are known
Chiral non-racemic pyrrolidine-2-phosphonic acid (R)-1 has
previously been prepared through the chemoenzymatic kinetic
to act as inhibitors of proteolytic enzymes, such as metallo- and
serine-proteases.3
resolution of racemic
x-halo-a-(chloracetoxy)phosphonates using
Despite a number of reports on the synthesis of acyclic
a protease (ChirazymeÒ P-2), followed by amination and cycliza-
tion.8 For another method, the diastereoselective phosphorylation
of 2-benzotriazolylpyrrolidine fused to a chiral oxazoldine has
been applied to the synthesis of (S)-1.9 In order to synthesize both
(S)-1 and (R)-1 efficiently and with high enantiomeric excess, the
resolution of the racemate should constitute a straightforward
method. As part of our efforts to develop facile and practical meth-
a
-aminophosphonic acids in racemic and optically active forms,4
few methods are available for the preparation of cyclic
phosphonic acids in either racemic or optically active forms.5 Cyc-
lic -aminophosphonic acids have been found to be promising
a-amino-
a
candidates as surrogates of proline in medicinal chemistry.6 In
addition, chiral pyrrolidine-2-phosphonic acid (S)-1 and its esters,
surrogates of proline, have recently been found to be efficient
organocatalysts in asymmetric aldol and/or Michael reactions
(Fig. 1).7 Therefore, the preparation of pyrrolidine-2-phosphonic
acids in enantiomerically pure forms is an attractive research area
in terms of medicinal chemistry and catalyst development.
ods for the synthesis of a
-aminophosphonates,10 we have recently
developed a catalyst-free three-component coupling method for
the synthesis of N-benzylpyrrolidine-2-phosphonate 2 from pro-
line (Scheme 1).10 Herein we report on the preparation of (R)-
and (S)-pyrrolidine-2-phosphonic acids via the resolution of ( )-
diethyl pyrrolidine-2-phosphonate 3, readily derived from proline
through our method.11 The method involves the formation of dia-
stereomeric amides from 3 and (+)-dibenzoyl-L-tartaric anhydride,
and subsequent separation of the resulting diastereomeric amides
by column chromatography.
⇑
Corresponding authors. Tel.: +98 241 4153220; fax: +98 241 4214949 (B.K.);
tel./fax: +81 42 676 3239 (T.Y.).
E-mail addresses: kaboudin@iasbs.ac.ir (B. Kaboudin), yokomatu@ps.toyaku.ac.jp
(T. Yokomatsu).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.10.013

B. Kaboudin et al. / Tetrahedron: Asymmetry 24 (2013) 1562–1566
1563
O
O
O
O
Pd(OH)2/C
H2, AcOH
toluene
reflux, 2h
P(OEt)2
CO2H
+
+
H
P(OEt)2
P(OEt)2
N
H
N
H
N
Ph
H
Ph
3
2
Scheme 1. Preparation of racemic pyrrolidine-2-phosphonate 3 via a decarboxylative three-component coupling reaction from proline.
The individual diastereoisomers 4 and 5 were obtained as foa-
my solids and attempts to obtain their single-crystals for X-ray
analysis were unsuccessful. However we found that a potassium
salt of diastereoisomer 4 gave good crystals for X-ray analysis.14
The crystalline structure of the potassium salt of compound 4,
determined by X-ray analysis, is illustrated in Figures 2 and 3. In
the crystalline structure of the asymmetric unit, four molecules
of 4 surround two potassium atoms via their interactions through
the individual phosphonate and carboxylate functional groups of 4
as shown in Figure 3. This analysis also showed us the absolute
configuration at the 2-position of the pyrrolidine moiety for diaste-
reoisomer 4 to be (S) (Fig. 2).
2. Results and discussion
Proline was converted into N-benzyl a-aminophosphonate 2 via
a one-pot decarboxylation–phosphonylation reaction in refluxing
toluene in the presence of benzaldehyde and diethyl phosphite
as previously described (Scheme 1).11 Debenzylation of 2 was
examined under various catalytic hydrogenation conditions. When
10% palladium on activated carbon was used as the catalyst under
an atmosphere of hydrogen in EtOH at room temperature, com-
pound 2 was not converted into the debenzylated product 3; only
the starting material was recovered. Less than 10% of desired com-
pound 3 was obtained when the reaction was carried out at 60 °C
under a hydrogen atmosphere in EtOH for 48 h using 20% Pd(OH)2/
C as the catalyst. We found that the debenzylation gave 3 in quan-
titative yield under Silverman conditions12 using 20% Pd(OH)2/C in
the presence of acetic acid (1.5 equiv) in EtOH (Scheme 1).
With racemic pyrrolidine-2-phosphonate 3 in hand, the diaste-
reomeric salt formation of 3 was first examined using a variety of
chiral acid resolving agents, expecting one of the diastereomeric
salts to be preferably crystallized. However, all our efforts to pre-
pare crystalline salts failed even when fine-tuning combinations
of chiral acid resolving agents [(R)-camphorsulfonic acid,
acid, -maleic, and -mandelic acid] and reaction media (EtOH,
MeOH, i-PrOH, and these solvents containing water).
In an effort to discover readily separable diastereomeric mix-
tures, we next focused on the use of (+)-dibenzoyl- -tartaric anhy-
L-tartaric
L
L
L
dride as an easily accessible resolving agent (Scheme 2). This
resolving agent has been used for the resolution of racemic chi-
ral-amines and acyclic diphenyl 1-aminoalkylphosphonates via
the formation of diastereomeric amides.13 We have found that
rac-3 reacts very quickly with (+)-dibenzoyl-L-tartaric anhydride
in dioxane to give a 1:1 mixture of diastereomeric amides 4 and
5 in high yield. The 31P NMR spectrum for the mixture of foamy
solids
4 and 5 exhibited two singlet peaks at 24.00 and
24.49 ppm, respectively. These amides were separated by column
chromatography on silica-gel using a mixture of EtOAc/MeOH
(100:0 to 95:5 v/v) as eluents. The total yield of the separated dia-
stereomers was 80%. It should be noted that the first eluted com-
pound (using only EtOAc as an eluent) corresponds to the more
polar diastereomer 5 on TLC (EtOAc/MeOH = 95:5).
Figure 2. ORTEP drawing of carboxylate salt 4.
O
P(OEt)2
N
O
O
BzO
HCl
P(OH)2
OBz
N
H
HO2C
4
OBz
BzO
(S)-1
4
5
O
+
P(OEt)2
N
H
O
O
O
O
P(OEt)2
N
3
O
HCl
TLC
O
P(OH)2
BzO
N
4
5
OBz
H
(R)-1
HO2C
5
Scheme 2. Preparation of (R)- and (S)-pyrrolidine-2-phosphonic acids.

1564
B. Kaboudin et al. / Tetrahedron: Asymmetry 24 (2013) 1562–1566
a = 14.6124(4) Å,
b = 14.6124(4) Å,
c = 60.6198(19) Å,
V =
) =
12943.7(6) Å3, T = 90 K, Z = 4, Dx = 1.341 mg/m3, (Mo-K
a
0.71073 Å, R = 0.0914 over independent reflections. Crystallo-
graphic data (excluding structure factors) for the X-ray crystal
structure analysis reported in this paper have been deposited with
the Cambridge Crystallographic Data Center (CCDC) as Supplemen-
tary publication No. CCDC 915670, copies of these data can be
obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44 (0) 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk].
4.2. Diethyl 1-benzylpyrrolidin-2-ylphosphonate 2
This compound was obtained according to the literature.11
Diethyl phosphite (20 mmol) was added to a stirred mixture of
proline (30 mmol) in toluene (15 mL) at reflux. Benzaldehyde
(30 mmol) was then added to the reaction mixture in small por-
tions over 3 h. The resultant solution was portioned to H2O
(100 mL), and extracted with EtOAc (2 ꢂ 100 mL). The organic
layer was washed with brine and dried over Na2SO4. The filtrate
was evaporated in vacuo and the residue was purified by column
chromatography using n-hexane/EtOAc (9:1 to 6:4) to give 2
(4.5 g, 75%).
Figure 3. The structure for an asymmetric unit of potassium salt of 4.15
Finally, hydrolysis of 4 and 5 in an acidic medium (6 mol/L of
HCl) at reflux for 8 h yielded (S)- and (R)-pyrrolidine-2-phosphonic
acids (S)-1 and (R)-1 in high yields, respectively. The specific rota-
tions of (S)-1 and (R)-1, prepared by our present method, were
4.2.1. Diethyl 1-benzylpyrrolidin-2-ylphosphonate 2
determined to be ½a D20
ꢀ
¼ ꢁ58:9 (c 1, 1 M NaOH) and ½a D20
¼ þ62:6
ꢀ
Yellow oil, 1H NMR (400 MHz, CDCl3) d: 1.33–1.38 (m, 6H),
1.76–1.85 (m, 2H), 2.04–2.17 (m, 2H), 2.12–2.28 (m, 1H), 2.92–
2.96 (m, 1H), 3.01 (dd, J1 = 10.0, J2 = 4.0 Hz, 1H), 3.43 (d,
J = 13.0 Hz, 1H), 4.16–4.29 (m, 4H), 4.46 (d, J = 13.0 Hz, 1H), 7.23–
7.38 (m, 5H); 13C NMR (CDCl3, 100.6 MHz) d: 16.6 (d, JP–C = 5.0 Hz),
16.7 (d, JP–C = 6.0 Hz), 24.4 (d, JP–C = 6.0 Hz), 27.0 (d, JP–C = 2.0 Hz),
54.3 (d, JP–C = 15.1 Hz), 59.4 (d, JP–C = 174.0 Hz), 60.2 (d, JPC = 3.0 -
Hz), 61.8 (d, JP–C = 7.0 Hz), 62.7 (d, JP–C = 7.0 Hz), 126.9, 128.2,
128.9, 139.3; 31P NMR (CDCl3/H3PO4, 162.0 MHz) d: 27.17. HRMS
Calcd for C15H25NO3P (MH+): 298.1572. Found: 298.1563.
(c 1, 1 M NaOH), respectively. These data are in good agreement
with those reported independently by Yoshifuji5a and Lejczak.5d
3. Conclusion
We have shown that both enantiomers of pyrrolidine-2-phos-
phonic acids can be accessed by the resolution of racemic diethyl
pyrrolidine-2-phosphonate which is readily available from proline.
In this resolution, the chromatographic separation of diastereo-
meric amides formed from diethyl pyrrolidine-2-phosphonate
and (+)-dibenzoyl-L-tartaric anhydride has been applied. The struc-
4.3. Diethyl pyrrolidin-2-ylphosphonate 3
ture of one of the diastereoisomers was determined by X-ray crys-
tallographic analysis. Hydrolysis of the individual diastereomeric
amides in the usual manner afforded (R)- and (S)-pyrrolidine-2-
phosphonic acids. The advantages of our reported method are an
easy, rapid, and good yielding preparation of both enantiomers of
pyrrolidine-2-phosphonic acids.
To a solution of 2 (2.97 g, 10 mmol) in EtOH (100 mL) was
added HOAc (15 mmol) at room temperature. The solution was
then treated with 20 wt % Pd(OH)2 on carbon (1.5 g). The reaction
mixture was stirred at room temperature under an atmosphere
of hydrogen for 48 h. The catalyst was filtered through Celite.
The Celite pad was washed with EtOH (2 ꢂ 30 mL). The combined
filtrate was concentrated in vacuo. The residue was purified by sil-
ica gel column chromatography using EtOAc/MeOH (95:5, v/v) as
an eluent to afford 3 (1.93 g, 93% yield).
4. Experimental
4.1. Materials and methods
All chemicals were commercial products and distilled or recrys-
tallized before use. All melting points were obtained by a Yanagim-
oto micro-melting point apparatus and are uncorrected. Optical
rotations were recorded on a JASCO Polarimeter with a path length
4.3.1. Diethyl pyrrolidin-2-ylphosphonate 3
Yellow oil, 1H NMR (400 MHz, CDCl3) d: 1.10–1.20 (m, 6H),
1.56–1.95 (m, 3H), 2.77–2.87 (m, 1H), 2.89–2.95 (m, 1H),
3.20–3.25 (m, 1H), 3.65–3.75 (m, 1H), 3.95–4.10 (m, 4H),
4.40–4.80 (br, 1H, NH); 13C NMR (CDCl3, 100.6 MHz) d: 16.2
(d, JP–C = 5.0 Hz), 16.3 (d, JP–C = 5.0 Hz), 25.4 (d, JP–C = 8.0 Hz),
26.6, 47.2 (d JP–C = 10.0 Hz), 53.5 (d, JP–C = 162.0 Hz), 62.1 (d,
JP–C = 6.0 Hz), 62.2 (d, JP–C = 7.0 Hz); 31P NMR (CDCl3/H3PO4,
162.0 MHz) d: 27.09. HRMS Calcd for C8H19NO3P (MH+):
208.1103. Found: 208.1103.
1 dm using the 589.3 nm D-line of sodium. Solutions were prepared
using spectroscopic grade solvents and concentrations (c) are
quoted in g/100 mL. The NMR spectra were taken with a 400 Bruc-
ker Avance instrument with the chemical shifts being reported as d
ppm and couplings expressed in Hertz. Silica gel column chroma-
tography was carried out with Silica gel 100 (Merck No. 10184).
TLC was carried out with Merck plates precoated with silica gel
60 F254 (0.25 mm thick).
The X-ray crystal data of potassium salt of 4 were collected by a
Bruker SMART APEX II diffractometer. The structure was solved by
a direct method using SHLEXS-97 (Scheldrik, 1997) and refined with
a full matrix laser-squares method. Molecular formula = C120H145-
K2N4O48P4 (including: four molecules of compound 4 + two
K + four EtOAc), MW = 2613.49, tetragonal, space group = P43,
4.4. (2R,3R)-Bis(benzoyloxy)-4-[(2S)-(diethoxyphosphoryl)
pyrrolidin-1-yl]-4-oxabutanoic acid and (2R,3R)-
bis(benzoyloxy)-4-[(2R)-(diethoxyphosphoryl)pyrrolidin-1-yl]-
4-oxabutanoic acid 4 and 5
A mixture of 3 (1.87 g, 9 mmol) and (+)-dibenzoyl-
anhydride (3.45 g, 10 mmol) in dioxane (60 ml) was stirred at
L-tartaric

B. Kaboudin et al. / Tetrahedron: Asymmetry 24 (2013) 1562–1566
1565
room temperature for 3 h and then left for one day at room tem-
perature. The solvent was removed in vacuo and the residue was
passed through a short (2 ꢂ 10 cm) column (silica-gel) using
EtOAc/MeOH (100:0 to 95:5 v/v) as an eluent to give a crude mix-
ture of 4 and 5 (4.5 g) as a white foamy solid. The individual diaste-
162.0 MHz) d: 13.50. HRMS Calcd for C4H11NO3P (MH+):
152.0477. Found: 152.0470.
4.6. (R)-Pyrrolidin-2-ylphosphonic acid (R)-1
reomers
4 and 5 were subsequently separated by silica-gel
Compound (R)-1 was obtained from amide 5 as a white solid in
chromatography on a longer column (2 ꢂ 40 cm) using a mixture
of EtOAc/MeOH (100:0 to 95:5 v/v) as the eluent. Well-separated
fractions were collected and evaporated. The first eluted fraction
gave 5 (2.35 g, 48%) and the second fraction gave 4 (1.58 g, 32%).
Total yield: 3.93 g (80%).
a quantitative yield in an analogous manner for the preparation of
(S)-1. ½a 2D0
ꢀ
¼ þ46:3 (c 0.1, H2O), ½a D20
¼ þ62:6 (c 1, 1 M NaOH),
ꢀ
20
578
(lit.5d
½
a
ꢀ
¼ þ64:0 (c 1, 1 M NaOH)). Other spectroscopic data
were identical to those of (S)-1.
Acknowledgments
4.4.1. (2R,3R)-Bis(benzoyloxy)-4-[2(S)-(diethoxyphosphoryl)-
pyrrolidin-1-yl]-4-oxabutanoic acid 4
The Japan Society for the Promotion of Science is thanked for
supporting this work. This work was also supported by Grant-in-
Aid for Scientific Research (C) Grant No: 25460155 from the Japan
Society for the Promotion of Science. The authors also wish to
thank Mr. Haruhiko Fukaya, Tokyo University of Pharmacy and Life
Sciences, for his help in carrying out the X-ray crystallographic
analysis.
White foamy solid: mp 114–116 °C (EtOAc); Rf = 0.36 (EtOAc/
MeOH = 95:5); Rf = 0.06 (EtOAc); ½a D20
ꢀ
¼ ꢁ12:6 (c 0.1, MeOH); 1H
NMR (400 MHz, CDCl3) d: 0.95–1.20 (m, 6H), 1.70–1.95 (m, 2H),
2.0–2.20 (m, 2H), 3.70–3.85 (m, 1H), 3.85–4.15 (m, 5H), 4.40–
4.50 (m, 1H), 5.86 (d, 1H, J = 7.2 Hz), 5.99 (d, 1H, J = 7.2 Hz),
7.10–7.25 (m, 4H), 7.25–7.35 (m, 2H), 7.80–7.95 (m, 4H),
9.50–10.0 (br, 1H); 13C NMR (CDCl3, 100.6 MHz) d: 16.1 (d,
JP–C = 6.0 Hz), 16.2 (d, JP–C = 5.7 Hz), 24.4, 25.9, 46.7, 53.4 (d,
JP–C = 158.9 Hz), 62.8 (d, JP–C = 6.4 Hz), 63.2 (d, JP–C = 7.3 Hz),
70.3, 70.7, 128.4, 128.5, 128.7, 129.0, 129.9, 130.0, 133.4,
133.6, 164.7, 165.2, 165.4, 168.3 (N-CO); 31P NMR (CDCl3/
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162.0 MHz) d: 24.49; HRMS Calcd for
C26H31NO10P
(MH+):
548.1686. Found: 548.1682.
4.5. (S)-Pyrrolidin-2-ylphosphonic acid (S)-1
A solution of (2R,3R)-bis(benzoyloxy)-4-[2(S)-(diethoxyphos-
phoryl)pyrrolidin-1-yl]-4-oxabutanoic acid 4 (550 mg, 1 mmol)
in 6 M HCl (20 mL) was heated at reflux for 24 h. Water was
then removed in vacuo. The residue was dissolved in water
and the resulting precipitate (benzoic acid) was filtered out.
The filtrates were clarified with charcoal. The clear solution
was applied to a column of Dowex 50W X8 (50–100 mesh, H+
form), and eluted with water. Ninhydrin-positive fractions were
then collected. Concentration of the collected solution to dryness
afforded the crude salt-free (S)-pyrrolidin-2-ylphosphonic acid as
a white solid in 90% yield. Recrystallization of the solid from
ether–MeOH gave pure (S)-1 (112 mg, 74%). White solid: mp
7. (a) Diner, P.; Amedjkouh, M. Org. Biomol. Chem. 2006, 4, 2091–2096; (b) Tao, Q.;
Tang, G.; Lin, K.; Zhao, Y. F. Chirality 2008, 20, 833; (c) Malmgren, M.; Granader,
J.; Amedjkouh, M. Tetrahedron: Asymmetry 2008, 19, 1934; (d) Gang, C.; Zheng,
W.; Kuiling, D. Chin. J. Chem. 2009, 27, 163–168.
8. Wuggenig, F.; Schweifer, A.; Mereiter, K.; Hammerschmidt, F. Eur. J. Org. Chem.
2011, 1870–1879.
9. Kartritzky, A. R.; Cui, X.-L.; Yang, B.; Steel, P. J. J. Org. Chem. 1999, 64, 1979–
1985.
10. (a) Kaboudin, B.; Haruki, T.; Yamaghishi, T.; Yokomatsu, T. Tetrahedron 2007,
63, 8199–8205; (b) Kaboudin, B.; Haruki, T.; Yamagishi, T.; Yokomatsu, T.
Synthesis 2007, 3226–3232; (c) Kaboudin, B.; Saadati, F. Tetrahedron Lett. 2009,
50, 1450–1452; (d) Kaboudin, B.; Saadati, F.; Yokomatsu, T. Synlett 2010, 1837–
1840; (e) Kaboudin, B.; Saadati, F.; Yokomatsu, T. Phosphorus, Sulfur, and Silicon
2011, 186, 804–805; (f) Kaboudin, B.; Haghighat, H.; Yokomatsu, T. Synthesis
2011, 3185–3189; (g) Kaboudin, B.; Haghighat, H.; Yokomatsu, T. J. Org. Chem.
2006, 71, 6604–6606; (h) Kaboudin, B.; Haghighat, H.; Yokomatsu, T.
Tetrahedron: Asymmetry 2008, 19, 862–866; (i) Kaboudin, B.; Alaie, S.;
265–267 °C (decomposed) (lit.7d mp 264–265 °C); ½a 2D0
ꢀ
¼ ꢁ42:5
20
578
(c 0.1, H2O), ½a 2D0
ꢀ
¼ ꢁ58:9 (c 1, 1 M NaOH), (lit.5d
½aꢀ
¼ ꢁ60:0
(c 1, 1 M NaOH)); 1H NMR (400 MHz, D2O) d: 1.80–2.0 (m,
3H), 2.10–2.20 (m, 1H), 3.20–3.30 (m, 2H), 3.32–3.38 (m, 1H);
13C NMR (D2O, 100.6 MHz) d: 23.9 (d, JP–C = 5.8 Hz), 26.4, 46.8
(d, JP–C = 5.8 Hz), 55.8 (d, JP–C = 143.3 Hz); 31P NMR (D2O/H3PO4,

1566
B. Kaboudin et al. / Tetrahedron: Asymmetry 24 (2013) 1562–1566
Yokomatsu, T. Tetrahedron: Asymmetry 2011, 22, 1813–1816; (j) Kaboudin, B.;
14. Compound 4 was transformed into the potassium salt upon passing through a
column (2 ꢂ 40 cm) packed with a mixture of SiO2/KOH (9:1 w/w, ground by a
mortar and pestle) in a thin layer (2 cm) using EtOAc/MeOH (95:5 to 50:50) as
an eluent. Crystals suitable for X-ray analysis were obtained by re-
crystallization of the crude from EtOAc/n-hexane.
Haghighat, H.; Alaie, S.; Yokomatsu, T. Synlett 2012, 1965–1969.
11. Kaboudin, B.; Karami, L.; Kato, J.; Aoyama, H.; Yokomatsu, T. Tetrahedron Lett.
2013, 54, 4872–4875.
12. Ji, H.; Jing, Q.; Huang, J.; Silverman, R. B. Tetrahedron 2012, 68, 1359–1366.
13. (a) Bell, K. H. Aus. J. Chem. 1987, 40, 399–404; (b) Kafarsi, P.; Lejczak, B. Can. J.
Chem. 1983, 61, 2425–2430.
15. This picture was created by Chem-3D Pro (Ver 12) using the cif-data obtained
by X-ray analysis.