Synthesis of novel (R)- and (S)-piperidazine-3-phosphonic acids and transformation into (R)- and (S)-pyrrolidine-2-phosphonic acids

Article abstract of DOI:10.1016/S0040-4039(01)00283-0

The first synthesis of a pair of (R)- and (S)-piperidazine-3-phosphonic acids was performed via a one-pot process of hetero Diels-Alder reaction and Lewis acid-catalyzed phosphonylation. The absolute configuration of the target compounds was established b

Full text of DOI:10.1016/S0040-4039(01)00283-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2713–2716
Synthesis of novel (R)- and (S)-piperidazine-3-phosphonic acids
and transformation into (R)- and (S)-pyrrolidine-2-phosphonic
acids
Mamoru Kaname, Yasushi Arakawa and Shigeyuki Yoshifuji*
Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa 920-1181, Japan
Received 21 December 2000; accepted 16 February 2001
Abstract—The first synthesis of a pair of (R)- and (S)-piperidazine-3-phosphonic acids was performed via a one-pot process of
hetero Diels–Alder reaction and Lewis acid-catalyzed phosphonylation. The absolute configuration of the target compounds was
established by a novel transformation into known (R)- and (S)-pyrrolidine-2-phosphonic acids. © 2001 Elsevier Science Ltd. All
rights reserved.
a-Aminophosphonic acids 1 and a-hydrazinophospho-
nic acids 2 (Fig. 1) are considered as analogues of
naturally occurring a-amino acids and have received
considerable attention over the past two decades in the
areas of medicinal and agricultural chemistry on
account of their potential biological activities.1,2 There-
fore, these compounds, especially a-aminophosphonic
acids and their derivatives, have been synthesized by
various methods.3,4 However, a simple and general
synthetic method for the cyclic amino-type of com-
pounds such as 3 and 4 is relatively unknown. Recently,
as the first example of cyclic a-hydrazinophosphonic
acid, we reported the synthesis of racemic piperidazine-
3-phosphonic acid 4 (n=2) employing the hetero Diels–
Alder (D–A) reaction and subsequent phosphonylation
of the D–A adduct in the presence of a Lewis acid.5
Herein, we report the successful application of this
methodology to an asymmetric synthesis of (R)- and
(S)-piperidazine-3-phosphonic acids and a novel trans-
formation of these piperidazine derivatives into the
corresponding pyrrolidine-2-phosphonic acids 3 (n=2).
In the initial stage of the synthesis, a two-step proce-
dure of the hetero D–A reaction and subsequent phos-
phonylation, previously adopted for the racemic
compounds,5 was improved to a one-pot reaction, as
illustrated in Scheme 1. Thus, di-(−)-menthyl
azodicarboxylate6 was reacted in CH2Cl2 at room tem-
perature with 1-trimethylsilyloxybutadiene (or 1-
methoxybutadiene) in the presence of trimethyl
phosphite and TMSOTf (trimethylsilyl triflate) as a
Lewis acid to afford an inseparable mixture of two
diastereoisomers 5 in 100% (or 78% from 1-methoxybu-
tadiene) yield.7 Catalytic hydrogenation of 5 using Pd
on charcoal in methanol at 4 atm of H2 gave a mixture
of the saturated derivatives 6a and 6b in a ratio of 66:34
and 99% yield, which could be easily separated by
column chromatography on silica gel using AcOEt and
hexane (1:1) to provide 6a (yield 65%, [h]2D7 −71.7°
(c=0.93, CHCl3)) and 6b (yield 34%, [h]2D4 −39.9° (c=
1.23, CHCl3)). The ratio of 6a:6b is a reflection of the
stereoselectivity in the phosphonylation to the acyli-
minium intermediate generated from the hetero D–A
Figure 1.
Keywords: hexahydropyridazine-3-phosphonic acid; hetero Diels–Alder reaction; ruthenium tetroxide oxidation.
* Corresponding author. E-mail: s-yoshifuji@hokuriku-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00283-0

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M. Kaname et al. / Tetrahedron Letters 42 (2001) 2713–2716
Scheme 1.
adduct by TMSOTf. Finally, each of the diastereoiso-
mers 6a and 6b was hydrolyzed in boiling 6N HCl–
AcOH (1:1) and subsequently treated with propylene
oxide5 in methanol to give optically active piperidazine-
3-phosphonic acids (−)-7, mp 163–165°C, [h]2D5 −16.0°
(c=0.70, 2N HCl) and (+)-7, mp 161–163°C, [h]D26
+13.7° (c=0.67, 2N HCl), in 64 and 67% yield, respec-
tively. The structures of (−)-7 and (+)-7 were separately
confirmed by comparison of spectral data with those of
racemic piperidazine-3-phosphonic acid,5 except with
regard to the optical rotation.
ates 6a and 6b by reducing one of the two nitrogen
atoms into chiral pyrrolidine-2-phosphonic acids having
known absolute stereochemistry. For this purpose, it
was needed to cleave the C6ꢀN1 bond in the piperi-
dazine ring. One possible approach might be by an
effective RuO4 oxidation of the C6 methylene con-
structing a carbonyl function, followed by hydrolysis of
the resultant amide bond. Such synthetic outline is
shown in Scheme 2. RuO4 oxidation of the piperidazine
derivative 6a was carried out using a catalytic amount
of RuO2 under a two-phase system of 10% aqueous
NaIO4 and AcOEt,8 and the corresponding piperidazin-
6-one 8a was obtained in 57% yield as a single product.
Hydrolysis of 8a in boiling 6N HCl–AcOH (1:1)
afforded not the expected ring-opened product but,
In order to determine the absolute configurations of the
target compounds (−)-7 and (+)-7, we attempted a
novel transformation of these piperidazine intermedi-
Scheme 2.

M. Kaname et al. / Tetrahedron Letters 42 (2001) 2713–2716
2715
4. (a) Yuan, C.; Li, C. Synthesis 1996, 507–510; (b) Lan-
glois, N.; Rousseau, A.-R.; Decavallas, O. Tetrahedron:
Asymmetry 1996, 7, 1095–1100.
5. Kaname, M.; Yoshinaga, K.; Arakawa, Y.; Yoshifuji, S.
Tetrahedron Lett. 1999, 40, 7993–7994.
fortunately, the ring-contracted five-membered lactam
9a in 77% yield. Lactam 9a was smoothly hydrogenated
in 2N HCl using PtO2 at 4 atm of H2 through a one-pot
operation combined with hydrogenolysis of the NꢀN
bond and reduction of the lactam C=O function, and
then treated by ion-exchange chromatography (Dowex
50W) to furnish the desired pyrrolidine-2-phosphonic
6. Brimble, M. A.; Heathcock, C. H.; Nobin, G. N. Tetra-
hedron: Asymmetry 1996, 7, 2007–2016.
acid (−)-10, mp 275–276°C (lit.9 mp 275–276°C) in 73%
7. One-pot reaction (preparation of compound 5):
Trimethyl phosphite (8.85 ml, 75.0 mmol) was added
slowly to a solution of di-(−)-menthyl azodicarboxylate
(11.84 g, 30.0 mmol) and trimethylsilyloxy-1,3-butadiene
(or 1-methoxy-1,3-butadiene) (60.0 mmol) in CH2Cl2 (40
ml) at room temperature. Then, TMSOTf (8.14 ml, 45.0
mmol) was dropped slowly in the reaction mixture at
0°C. The solution was allowed to warm to room temper-
ature and was held there for 12 h. Water (30 ml) was
added dropwise to the reaction solution at 0°C, and the
mixture was vigorously stirred for 30 min. The mixture
was diluted with saturated aq. NaHCO3 (300 ml) and
extracted with AcOEt (twice, total 800 ml). The AcOEt
solution was washed with saturated aq. NaCl, dried over
anhyd. Na2SO4, and concentrated in vacuo. The residue
was purified by silica gel column chromatography
(AcOEt–hexane, 1:1ꢀ2:1 v/v) to give an inseparable mix-
ture of (3R)- and (3S)-di-(−)-menthyl 3-dimethylphos-
phoryl-1,2,3,6-tetrahydropyridazine-1,2-dicarboxylate (5).
Yield 100% (or 73% from 1-methoxy-1,3-butadiene), col-
orless oil. MS m/z: 556 (M+). 1H NMR (CDCl3) l:
0.64–1.18 (24H, m), 1.18–1.57 (4H, m), 1.57–1.83 (4H,
m), 1.87–2.30 (4H, m), 3.73–3.92 (7H, m), 4.28–4.76 (3H,
m), 4.91–5.33 (1H, m), 5.90–6.05 (2H, br).
20
578
yield. The specific rotation of (−)-10 ([h]
−64.2°
(c=1.03, 1N NaOH) was in accord with the reported
value for (S)-pyrrolidine-2-phosphonic acid ([h] −60°
20
578
(c=1, 1N NaOH)).9
In a similar way, piperidazine derivative 6b, a precursor
of (+)-7, was transformed into the pyrrolidine-2-phos-
phonic acid (+)-10, mp 276–277°C (lit.9 mp 272–273°C),
22
578
[h] +66.3° (c=1.0, 1N NaOH), the optical rotation of
which was in good agreement with that of the known
578
(R)-form, [h] +64° (c=1, 1N NaOH).9
20
Thus, the chemical conversion was successfully accom-
plished. The absolute configuration of the levorotatory
piperidazine-3-phosphonic acid (−)-7 and its precursor
6a was assigned to be (S)-configuration, while that of
the dextrorotatory compound (+)-7 and its derivative
6b to be (R)-configuration.
In summary, the first synthesis of (R)- and (S)-piperi-
dazine-3-phosphonic acids and the related compounds10
provides ready access to a new type of optically active
cyclic a-hydrazinophosphonic acids. Furthermore, the
transformation of the piperidazine derivatives into the
pyrrolidine compounds, which was effectuated by RuO4
oxidation, provides a new synthetic route to useful
compounds having a pyrrolidine ring system.
8. Yoshifuji, S.; Tanaka, K.; Kawai, T.; Nitta, Y. Chem.
Pharm. Bull. 1985, 33, 5515–5521.
9. Lejczak, B.; Kafarski, P.; Mastalerz, P. J. Chromatogr.
1985, 324, 455–461.
10. Data for new compounds are as follows:
Compound 6a: Colorless oil. [h]2D7 −71.7° (c=0.93,
1
References
CHCl3). IR (film): 1732, 1712 cm−1. H NMR (CDCl3) l:
0.67–1.14 (24H, m), 1.20–1.58 (5H, m), 1.61–1.74 (4H,
m), 1.74–2.23 (7H, m), 2.94–3.17 (1H, br), 3.74–3.89 (6H,
m), 3.99–4.22 (1H, m), 4.45–4.84 (3H, m). HRMS m/z:
Calcd for C28H51N2O7P: 558.3434. Found: 558.3434.
Compound 6b: Colorless oil. [h]2D4 −39.9° (c=1.23,
1. (a) De Lombaert, S.; Blanchard, L.; Stamford, L. B.;
Tan, J.; Wallace, E. M.; Satoh, Y.; Fitt, J.; Hover, D.;
Simonsbergen, D.; Moliterni, J.; Marcopoulos, N.; Sav-
age, P. J. Med. Chem. 2000, 43, 488–504; (b) Bird, J.; De
Mello, C. R.; Harper, P. G.; Hunter, J. D.; Karran, H.
E.; Markwell, E. R.; Miles-Williams, J. A.; Rahman, S.
S.; Ward, W. R. J. Med. Chem. 1994, 37, 158–169; (c)
Osipov, S. N.; Artyushin, O. I.; Kolomiets, A. F.;
Bruneau, C.; Dixneuf, P. H. Synlett 2000, 1031–1033; (d)
Tada, S.; Hatano, M.; Nakayama, Y.; Volrath, S.;
Guyer, D.; Ward, E.; Ohta, D. Plant Physiol. 1995, 109,
153–159; (e) Kafarski, P.; Lejczak, B. Phosphorus Sulfur
Silicon Relat. Elem. 1991, 63, 193–215.
1
CHCl3). IR (film): 1732, 1705 cm−1. H NMR (CDCl3) l:
0.72–1.17 (24H, m), 1.22–1.60 (5H, m), 1.60–1.75 (4H,
m), 1.75–2.30 (7H, m), 2.81–3.08 (1H, m), 3.76–3.84 (6H,
m), 4.05–4.25 (1H, m), 4.48–4.90 (3H, m). HRMS m/z:
Calcd for C28H51N2O7P: 558.3434. Found 558.3430.
Compound (−)-7: White powder, mp 163–165°C. [h]D25
−16.0° (c=0.70, 2N HCl). IR (KBr): 3433, 3278, 1157,
1
1084 cm−1. H NMR (D2O) l: 1.56–1.85 (2H, m), 1.90–
2.05 (2H, m), 3.03–3.12 (1H, m), 3.16–3.26 (1H, m),
2. Diel, P.; Maier, L. Eur. Pat. Appl. EP 143078, 1985;
Chem. Abstr. 1985, 103, 15544m.
3.30–3.40 (1H, m). 13C NMR (100 Mz, D2O) l: 21.30 (t),
1
23.72 (t), 46.04 (t), 54.88 (ddP, JCP=146.5 Hz). HRMS
3. (a) Alonso, E.; Alonso, E.; Sol´ıs, A.; del Pozo, C. Synlett
2000, 698–700; (b) Kim, K. S.; Hurh, E. Y.; Youn, J. N.;
Park, J. I. J. Org. Chem. 1999, 64, 9272–9274; (c)
Katritzky, A. R.; Cui, X.-L.; Yang, B.; Steel, P. J. J. Org.
Chem. 1999, 64, 1979–1985; (d) Ranu, B. C.; Haja, A.;
Jana, U. Org. Lett. 1999, 1, 1141–1143; (e) Yager, K. M.;
Taylor, C. M.; Smith, III, A. B. J. Am. Chem. Soc. 1994,
116, 9377–9378.
m/z: Calcd for C4H12N2O3P: 167.0586. Found: 167.0586.
Compound (+)-7: White powder, mp 161–163°C. [h]D26
+13.7° (c=0.67, 2N HCl). Other spectral data, identical
with those of (−)-7.
Compound 8a: Colorless oil. [h]2D2 −38.0° (c=0.73,
CHCl3). IR (film): 1790, 1755, 1720 cm−1 1H NMR
.
(CDCl3) l: 0.67–1.28 (24H, m), 1.28–1.62 (4H, br), 1.62–
1.76 (4H, br), 1.84–2.27 (6H, m), 2.44–2.62 (2H, m),

2716
M. Kaname et al. / Tetrahedron Letters 42 (2001) 2713–2716
3.75–3.88 (6H, m), 4.53–4.76 (2H, m), 4.84–5.00 (1H, br).
Compound 9a: Colorless prisms (H2O), mp 225–226°C
(dec.). [h]1D8 −11.7° (c=0.90, 2N HCl). MS (FAB) m/z:
13C NMR (CDCl3) l: 150.90 (s), 155.56 (s), 169.70 (s).
HRMS m/z: Calcd for C28H50N2O8P: 573.3305. Found:
573.3310.
181. IR (KBr): 3440, 3041, 1718, 1128, 1011, 989 cm−1
.
1H NMR (2N DCl) l: 2.18–2.33 (1H, m), 2.41–2.66 (3H,
Compound 8b: Yield 60% from 6b. Colorless oil. [h]D22
−78.9° (c=1.18, CHCl3). IR (film): 1790, 1755, 1720
cm−1. 1H NMR (CDCl3) l: 0.68–1.22 (24H, m), 1.25–1.59
(4H, m), 1.61–1.78 (4H, m), 1.83–2.27 (6H, m), 2.42–2.64
(2H, m), 3.74–3.89 (6H, m), 4.51–4.64 (1H, m), 4.64–4.85
(1H, m), 4.85–4.99 (1H, m). 13C NMR (CDCl3) l: 150.65
(s), 155.43 (s), 169.72 (s). HRMS m/z: Calcd for
C28H50N2O8P: 573.3305. Found: 573.3310.
m), 4.08–4.20 (1H, m). 13C NMR (2N DCl) l: 19.48 (t),
27.47 (t), 55.26 (ddP, JCP=158.4 Hz), 175.95 (s). Anal.
1
calcd for C4H9N2O4P: C, 26.68; H, 5.04; N, 15.55.
Found: C, 26.62; H, 4.80; N, 15.43.
Compound 9b: Yield 68% from 8b. Colorless prisms
(H2O), mp 225–226°C (dec.). [h]2D1 +12.4° (c=0.73, 2N
HCl). Anal. calcd for C4H9N2O4P: C, 26.68; H, 5.04; N,
15.55. Found: C, 26.61; H, 4.80; N, 15.43.
.
.