Asymmetric synthesis of (R)- and (S)-α-amino-3-piperidinylphosphonic acids via phosphite addition to iminium ions

Article abstract of DOI:10.1055/s-2006-958952

α-Amino-3-piperidinylphosphonates were conveniently prepared from 3-piperidinone, by nucleophilic addition of phosphite to the iminium ion formed by in situ condensation of this ketone with chiral benzylic amines. Subsequent deprotection of N-Boc group, c

Full text of DOI:10.1055/s-2006-958952

PAPER
289
Asymmetric Synthesis of (R)- and (S)-a-Amino-3-piperidinylphosphonic Acids
via Phosphite Addition to Iminium Ions
A
symmetric Synth
i
esis of
c
(
R
)- and(
S
o
)-
a
-Amino-3
l
-piperi
a
s
honic
A
cids Louaisil, Nicolas Rabasso, Antoine Fadel*
Laboratoire de Synthèse Organique et Méthodologie, UMR 8182, Institut de Chimie Moléculaire et des Matériaux d’Orsay, Bât. 420,
Université de Paris-Sud, 91405 Orsay, France
Fax +33(1)69156278; E-mail: antfadel@icmo.u-psud.fr
Received 26 September 2006; revised 24 October 2006
panecarboxylic acid (ACC) analogues], in three steps,
Abstract: a-Amino-3-piperidinylphosphonates were conveniently
starting from cyclopropanone hemiacetals. Furthermore,
we have very recently reported, in racemic series, an effi-
prepared from 3-piperidinone, by nucleophilic addition of phos-
phite to the iminium ion formed by in situ condensation of this ke-
tone with chiral benzylic amines. Subsequent deprotection of N-Boc
cient three step synthesis of new heterocyclic a-amino-
group, cleavage of the benzyl groups and acidic hydrolysis of the re- phosphonic acids 1a–c and 2 from readily available
heterocyclic ketones in good yields.12
sulting a-amino-3-piperidinylphosphonates gave, in a four-step
sequence from piperidinone, the enantiopure a-amino-3-piperi-
We decided to study the selectivity in the addition of tri-
dinylphosphonic acids. The absolute configuration has been estab-
alkyl phosphite to the iminium ions A, readily available
from 3-piperidinone 3. This one-pot reaction should occur
in the presence of chiral benzylamine derivatives to give
the desired aminophosphonates 4, precursors of amino-
phosphonic acid 2 (Scheme 1).
lished by X-ray crystal structure analysis of the N-(4-nitro-
benzoyl)aminophosphonate derivative.
Key words: amino acids, heterocycles, piperidines, asymmetric
synthesis, addition reaction
In recent years, due to their potential biological activity1
and their use as building blocks for peptide mimetics,
a-aminophosphonic acids are of considerable current in-
terest.2 Cyclic or heterocyclic rings introduced into the
molecular skeleton increase its rigidity and modify elec-
tronic effects. Thus, many cyclic a-aminophosphonic ac-
ids have been prepared.3–7 However, very few examples
of heterocyclic acids 1 or the corresponding phosphonates
presented in the literature have been reported in racemic
series.8–12 In all the synthetic approaches to introduce the
aminophosphonate moiety, the Kabachnick–Fields
reaction10a was used starting from heterocyclohexanones,
to provide a-aminophosphonates with moderate to good
yields. In contrast, enantiopure 3-piperidine acid 2 is still
unknown (Figure 1).
O
O
OH
OH
OEt
OEt
P
P
*
*
NH2
NHR*
HN
N
Boc
2
4
P(OEt)3
R*
N
O
H
N
N
Boc
Boc
3
A
Scheme 1
The standard one-pot procedure4,12 for the reaction of ke-
tone 3 with chiral amine 5a (X = H) was carried out in
EtOH in the presence of 2 equivalents of AcOH, 0.8
equivalent of MgSO4 and 1.5 equivalents of triethyl phos-
phite at 50 °C for 17 hours. The aminophosphonates 6
were obtained in good yield (75%) as an inseparable mix-
ture of two diastereoisomers 6A/6B in a 40:60 ratio as
shown by their 31P NMR spectra (d6A/d6B = 27.44/27.74).
The use of chiral amine 5b (X = OMe) did not change the
diastereoisomeric ratio (31P NMR, d7A/d7B = 27.56/27.30)
of the resulting inseparable mixture of aminophospho-
nates 7A/7B (55% yield) (Scheme 2).
O
O
P(OH)2
P(OH)2
X
*
NH2
NH2
HN
1a X = NH, NMe
1b X = O
2
1c X = S
Figure 1 Heterocyclic a-aminopiperidinylphosphonic acids
X
X
O
O
OEt
OEt
5
In the course of our work on the asymmetric synthesis of
cyclic analogues of a-aminophosphonic acids,4 we have
previously reported a simple and convenient synthesis of
1-aminocyclopropanephosphonic acids [aminocyclopro-
HN
P
H2N
Ph
Ph
OEt
+
N
X
P(OEt)3, AcOH
EtOH, 50 °C
N
P
N
N
H
Boc
OEt
Ph
Boc
Boc
O
X = H (5a)
(40:60)
(40:60)
3
6A
7A
6B
7B
X = OMe (5b)
SYNTHESIS 2007, No. 2, pp 0289–0293
x
x
.
x
x
.2
0
0
7
Advanced online publication: 21.12.2006
DOI: 10.1055/s-2006-958952; Art ID: T13906SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Preparation of aminophosphonates 6 and 7 from ketone
3.

290
N. Louaisil et al.
PAPER
O
We have previously reported that a bulky phosphite react-
ed with iminium ion in DMSO to enhance the selectivity
of addition reaction.4d Thus we treated ketone 3 with
chiral amine 5a under the same conditions as above, by
using triisopropyl phosphite in DMSO instead of P(OEt)3
in EtOH to obtain aminophosphonates 8A or 8B. Howev-
er, neither was formed (Scheme 3).
O
OH
OEt
OEt
P
P
i. 6 M HCl, reflux, 17 h
OH
O
ii. then EtOH,
NH2
NH2
N
N
N
H
98%
H
(R)-(–)-10
(R)-(+)-2
NH2
OH
NH2
i. 6 M HCl, reflux, 17 h
O
ii. then EtOH,
OEt
P
P
N
O
OEt
OH
98%
Oi-Pr
H
H
O
O
O
5a
P
Oi-Pr
H2N
Ph
(S)-(+)-10
(S)-(–)-2
*
*
P(Oi-Pr)3, AcOH
DMSO, 50 °C
N
N
N
Scheme 6
H
Ph
Boc
Boc
3
8A/8B
chloride in the presence of Et3N to give 11B in good yield
(Scheme 7). Suitable crystals of 11B were analyzed by
X-ray crystallography,13 which showed a (3R,1¢S)-abso-
lute configuration (Figure 2). Moreover, in the X-ray
structure two conformers in which the phosphonate group
at C-3 occupies an equatorial position were observed. By
comparison, the absolute configuration for the major iso-
mer should be (3R,1¢S)-9B and must be (3S,1¢S)-9A for
the minor isomer.
Scheme 3
We found that the chromatographic separation of diaste-
reoisomers 6A/6B from each other was not possible. Con-
versely, the cleavage of the N-Boc protecting group with
trifluoroacetic acid (TFA) at room temperature allowed
each diastereoisomer 9A and 9B to be separated on silica
gel column (Scheme 4).
O
O
OEt
O
O
HN
P
OEt
OEt
P
OEt
TFA
CH2Cl2, r.t.
90%
N
Ph
OEt
+
P
O
6A/6B
p-NO2C6H4COCl
O
N
H
H N
NO2
P
N
N
inseparable
mixture
N
OEt
Et3N (5 equiv), 3.5 h
68%
Ph
H
H
N
O
H
Ph
H
Ph
11B
9A
9B
separable mixture
(3R,1'S)-9B
Scheme 4
Scheme 7
We then submitted the heterocyclic phosphonates 9B and
9A to a deprotection sequence. These phosphonates react-
ed under mild conditions [20% Pd(OH)2/C and 1 atm H2]
to cleave the benzyl groups affording free diaminophos-
phonates (R)-10 and (S)-10, in good yields (Scheme 5).
O
O
OEt
OEt
OEt
OEt
P
P
H2, Pd(OH)2/C
AcOH, 18 h, r.t.
69%
N
NH2
N
N
H
Ph
H
H
H
(3R,1'S)-9B
(R)-(–)-10
NH2
HN
H2, Pd(OH)2/C
Ph
OEt
OEt
AcOH, 18 h, r.t.
83%
P
N
P
N
OEt
H
OEt
O
O
(3S,1'S)-9A
(S)-(+)-10
Figure 2 ORTEP plot of X-ray crystal structure of (3R,1¢S)-11B
Scheme 5
Phosphonate hydrolysis of (R)-10 and (S)-10 was accom-
plished in aqueous 6 M HCl solution at reflux, followed
by treatment with propylene oxide to provide the enan-
tiopure diaminophosphonic acid (R)-(+)-2 and (S)-(–)-2,
in quantitative yield {[a]D +2.4 (c = 0.25, 1 M NaOH) for
(R)-2} (Scheme 6).
In summary, we have developed an easy and efficient four
step synthesis of enantiopure (R)- and (S)-a-amino-3-pip-
eridinylphosphonic acids 2. Thus, starting from commer-
cially available N-Boc 3-piperidinone 3, we have
demonstrated that this iminium ion A formed from the
ketone 3 and chiral amine 5 undergoes an asymmetric
nucleophilic addition of phosphite to give a major
a-aminopiperidinylphosphonate. Good separation of the
To determine the absolute configuration of these isomers,
we have protected the major isomer with 4-nitrobenzoyl
Synthesis 2007, No. 2, 289–293 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of (R)- and (S)-a-Amino-3-piperidinylphosphonic Acids
31P NMR (101.25 MHz, CDCl3): d = 27.44/27.74.
291
major diastereoisomer required deprotection of the N-Boc
group. Subsequent cleavage of the benzyl group and acid-
HRMS (ESI): m/z [M + Na]+ calcd for C22H37N2O5P + Na:
ic hydrolysis of the resulting a-aminophosphonate provid- 463.2332; found: 463.2348.
ed the optically active (R)- and (S)-a-aminophosphonic
Aminophosphonates 7A/7B
The aminophosphonates 7A/7B were prepared following the proce-
acids in good yields. Efforts to improve the diastereose-
lective phosphite approach are currently in progress in our
laboratory.
dure used for the preparation of 6A/6B. N-Boc-piperidin-3-one 3
(208 mg, 1.045 mmol) was reacted in EtOH (3 mL) with (S)-meth-
oxymethylbenzylamine (5b; 215 mg, 1.57 mmol), AcOH (115 mL,
2.09 mmol), MgSO4 (94 mg, 0.78 mmol) and P(OEt)3 (270 mL, 1.57
mmol) at 50 °C for 24 h. Standard work-up and flash chromatogra-
phy on silica gel (MeOH–CH2Cl2, 5:95) gave 270 mg (55%) of ami-
nophosphonates 7A/7B as an inseparable mixture of two
diastereoisomers in a 40:60 ratio as determined from its 31P NMR
spectrum. The spectral data given are for 7A/7B diastereoisomeric
mixture.
1H NMR (250 MHz, CDCl3): d = 1.17 (t, J = 6.9 Hz, 1.2 H, CH3, A),
0.85–1.75 (m, 8.2 H, CH3, 2 H-5, and 1 H-4 A/B, and CH3 B, 1 H-
4 A), 1.53 (s, 9 H, t-C4H9, A/B), 1.75–2.10 (m, 0.6 H, B), 2.10–2.52
(m, 1 HN), 2.66 (dd, J = 7.5, 7.5, 0.6 H, H-6, B), 3.27 (s, 1.2 H,
OCH3, A), 3.37 (s, 1.8 H, OCH3, B), 2.79–3.70 (m, 3.4 H, 1 H-6,
CH2OMe A/B, and 1 H-6 A), 3.70–4.70 (m, 7 H, 2 H-2, 2 CH2O and
CHN, A/B), 7.10–7.50 (m, 5 Harom, A/B).
13C NMR (CDCl3, 62.9 MHz): d = 16.5/16.7 (d, JP,C = 3.7 Hz, 2
CH3CH2O, A/B), 19.2 (C-5, A), 20.1 (d, JP,C = 5.6 Hz, C-5, B),
26.8 (C-4, B), 28.4 [C(CH3)3, A/B], 29.8 (C-4, A), 43.7/44.8 (C-6,
B/A), 49.0/50.7 (C-2, A/B), 55.5/57.0 (d, JP,C = 143.7 Hz, C-3,
A/B), 56.2/57.0 (CHN, B/A), 58.9/59.0 (OCH3, A/B), 61.8/61.9 (d,
J = 6.5 Hz, 2 CH2OP, B), 62.2/62.3 (s, 2 CH2OP, A), 76.8/78.0
(CH2OMe, A/B), 78.4/79.4 [C(CH3)3, A/B], [6 arom: 126.9/127.2
(CH), 127.8/127.4 (2 CH), 128.0/128.5 (2 CH), 143.8/143.2 (C)],
154.1/154.7 (COO, A/B).
All reactions were carried out under argon with magnetic stirring.
(S)-a-Methylbenzylamine (5a), (R)-a-(methoxymethyl)benzyl-
amine (5b), AcOH, N-Boc-piperidin-3-one (3), trifluoroacetic acid
(TFA), Pd(OH)2/C (20%), 4-nitrobenzoyl chloride, P(OEt)3, and
P(Oi-Pr)3 were purchased from Aldrich. P(OEt)3, and P(Oi-Pr)3
were distilled under reduced pressure and stored on molecular
sieves 4 Å under argon. Et3N, DMSO and CH2Cl2 were freshly dis-
tilled over CaH2 under argon before use. Rf values refer to values ob-
tained by TLC on 0.25 mm silica gel plates (Merck F254). Flash
chromatography (FC) was performed on silica gel 60 (0.040–0.063
mm). Yields are reported for chromatographically and spectroscop-
ically pure compounds, unless otherwise noted. IR spectra were re-
corded on a Perkin-Elmer (spectrum one) spectrophotometer.
Melting points were determined on a Büchi B-545 capillary melting
point apparatus and are uncorrected. 1H NMR spectra were recorded
on a Bruker DRX250 (250 MHz) or Bruker AC360 (360 MHz)
spectrometer. Chemical shifts were recorded in parts per million
from the solvent resonance (CDCl3 at 7.27 ppm and D2O at 4.8
ppm). 13C NMR spectra were recorded on a Bruker DRX250 (62.9
MHz), or Bruker AC360 (90.56 MHz) spectrometer. Chemical
shifts are reported in parts per million from the solvent resonance
(CDCl3 at 77.16 ppm). 31P NMR spectra were recorded on a Bruker
AM250 (101.25 MHz), and chemical shifts are quoted relative to in-
ternal 85% H3PO4 (d = 0). High-resolution mass spectra were re-
corded on a Finnigan MAT 95S spectrometer. All new compounds
were determined to be >95% pure by 1H NMR spectroscopy.
3
3
1
3 1P NMR (101.25 MHz, C6D6): d = 27.56/27.30.
Aminophosphonates 9
To a solution of the inseparable mixture of 6A/6B (1.430 g, 3.25
mmol) in CH2Cl2 (40 mL), was added TFA (7.2 mL) and the mix-
ture was stirred at r.t. for 3 h. An aq sat. solution of NaHCO3 (30
mL) was added and the mixture was extracted with EtOAc. The or-
ganic layers were combined, dried (MgSO4), filtered and concen-
trated in vacuo. Purification by flash chromatography (MeOH–
CH2Cl2–aq NH3, 5:95:0.5) gave 9A (430 mg, 39%) and 9B (560 mg,
51%) as light yellow oils.
Aminophosphonates 6A/6B; General Procedure
To a solution of N-Boc-piperidin-3-one 3 (862 mg, 4.33 mmol) in
EtOH (10 mL), was added (S)-a-methylbenzylamine (5a; 6.50
mmol), AcOH (500 mL, 8.67 mmol) and MgSO4 (390 mg, 3.25
mmol). After stirring and heating at 50 °C for 5 h, P(OEt)3 (1.08 g,
1.13 mL, 6.50 mmol) was added. The mixture was heated at 50 °C
for 17 h. It was then concentrated in vacuo and concd aq ammonia
(1 mL) was added to the residue. The resulting mixture was purified
by flash chromatography on silica gel (MeOH–CH2Cl2, 10:90) to
afford 1.43 g (75%) of pure aminophosphonates 6A/6B as an insep-
arable mixture of two diastereoisomers in a 40:60 ratio as deter-
mined from its 31P NMR spectrum. The spectral data given are for
the 6A/6B diastereoisomeric mixture.
(3S,1¢S)-Diethyl 3-(1¢-Methylbenzyl)aminopiperidin-3-ylphos-
phonate (9A)
[a]D –62.6 (c = 0.65, CHCl3); Rf = 0.46 (MeOH–CH2Cl2–aq NH3,
10:90:0.5).
IR (neat): 3665, 3324, 2980, 1266, 1230, 1056, 1024, 960 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.14 (t, J = 7.0 Hz, 1.2 H, CH3, A),
0.85–1.45 (m, 8.8 H, CH3CHN, CH3CH2, and 1 HN, A/B, and CH3,
B), 1.50 (s, 9 H, t-C4H9, A/B), 1.45–2.10 (m, 3.4 H, 2 H-5 and H-4
A/B, and H-4, A), 2.60 (ddd, J = 3.2, 12.7, 12.7 Hz, 0.6 H, H-4, B),
2.80–3.65 (m, 2 H-6, A/B), 3.65–3.97 (m, 2 H-2, A/B), 3.97–4.22
(m, 4 H, 2 CH2O, A/B), 4.22–4.42 (m, 1 H, CHN, A/B), 7.03–7.20
(m, 5 Harom, A/B).
1H NMR (250 MHz, CDCl3): d = 1.33–1.48 (m, 9 H, 3 CH3), 1.50–
1.80 (m, 4 H, 2 HN and 2 H-5), 1.81–2.03 (m, 2 H-4), 2.46 (ddd,
J = 3.0, 11.5, 14.0 Hz, 1 H-6), 2.77 (dd, J = 2.7, 14.0 Hz, 1 H-2),
2.72–2.88 (m, 1 H-6), 2.92 (ddd, J = 2.0, 5.0, 14.0 Hz, 1 H-2), 4.07–
4.28 (m, 4 H, 2 CH2O), 4.45 (qd, J = 6.5 Hz, 4JP,H = 2.7 Hz, 1 CHN),
7.15–7.50 (m, 5 H).
3
13C NMR (CDCl3, 62.9 MHz): d = 16.4/16.6 (d, JP,C = 5.5 Hz, 2
13C NMR (62.9 MHz, CDCl3): d = 16.8 (2 CH3CH2O), 20.8 (d,
2JP,C = 7.3 Hz, C-5), 26.9 (CH3CHN), 31.0 (C-4), 45.7 (C-6), 47.4
(d, 2JP,C = 9.1 Hz, C-2), 52.8 (CHN), 56.3 (d, 1JP,C = 136.7 Hz, C-3),
CH3CH2O, A/B), 19.4 (d, 3JP,C = 10.4 Hz, C-5, B), 20.0 (d, J = 8.2
Hz, C-5, A), 26.5 (C-4, A/B), 27.1 (CH3CHN, A/B), 28.3/28.5
[C(CH3)3, A/B], 43.5/44.6 (C-6, A/B), 49.0/50.2 (d, J = 9.2 Hz, C-
2, B/A), 52.3 (CHN, B), 52.6 (CHN, A), 56.5 (d, J = 145.4 Hz, C-
3, A), 57.5 (d, J = 141.5 Hz, C-3, B), 61.7 (2 CH2O, B), 62.1 (d,
J = 7.7 Hz, 2 CH2O, A), 79.3 [C(CH3)3, A/B], [6 arom: 126.3 (CH),
126.4 (2 CH), 128.1 (2 CH), 148.1/148.7 (C, A/B)], 155.1/155.6
(COO, A/B).
2
2
61.7 (d, JP,C = 7.7 Hz, CH2O), 62.1 (d, JP,C = 7.8 Hz, CH2O), [6
arom: 126.4 (2 CH), 126.9 (CH), 128.7 (2 CH), 148.3 (C)].
31P NMR (101.25 MHz, CDCl3): d = 29.47.
HRMS (ESI): m/z [M + Na]+ calcd for C17H29N2O3P + Na:
363.1808; found: 363.1811.
Synthesis 2007, No. 2, 289–293 © Thieme Stuttgart · New York

292
N. Louaisil et al.
PAPER
(3R,1¢S)-Diethyl 3-(1¢-Methylbenzyl)aminopiperidin-3-ylphos-
phonate (9B)
3.17/3.26 (d, J = 12.7 Hz, 1 H-2), 3.24–3.42 (m, 1 H-6), 3.63/3.66
(dd, J = 1.5, 12.7 Hz, 1 H-2).
[a]D –74.0 (c = 0.60, CHCl3); Rf = 0.40 (MeOH–CH2Cl2–aq NH3,
13C NMR (D2O + NaOD, 62.9 MHz): d = 20.6 (d, 3JP,C = 8.0 Hz, C-
5), 30.3 (C-4), 44.7 (C-6), 50.15 (d, 1JP,C = 140.1 Hz, C-3), 50.9 (d,
2JP,C = 5.3 Hz, C-2).
31P NMR (101.25 MHz, D2O): d = 11.80.
MS (ESI+): m/z = 203.1 [M + Na]+.
10:90:0.5).
IR (neat): 3665, 3450, 3347, 2980, 1232 (P=O), 1056, 1024, 961
cm–1.
1H NMR (250 MHz, CDCl3): d = 0.96–1.10 (m, 2 H-5), 1.27 (t,
J = 7.2 Hz, 3 H, CH3CH2O), 1.29 (d, J = 6.8 Hz, 3 H, CH3CHN),
1.30 (t, J = 7.2 Hz, 3 H, CH3CH2O), 1.65–1.84 (m, 2 H-4), 1.90–
2.40 (br s, 2 HN), 2.56 (ddd, J = 7.2, 7.2, 13.5 Hz, 1 H-6), 2.75–2.95
(m, 2 H, H-6 and H-2), 3.07 (dd, J = 3.2, 13.7 Hz, 1 H-2), 4.08–4.15
All spectral data were identical with those reported for the racemic
compound.12
4
(S)-(–)-3-Aminopiperidin-3-ylphosphonic Acid [(S)-2]
[a]D –2.4 (c = 0.25, aq 1 M NaOH).
(m, 4 H, 2 CH2O), 4.41 (dq, JP,H = 2.2 Hz, J = 6.8 Hz, 1 CHN),
7.15–7.47 (m, 5 H).
13C NMR (62.9 MHz, CDCl3): d = 16.5 (CH3CH2O), 16.6
(CH3CH2O), 20.0 (d, 3JP,C = 9.4 Hz, C-5), 26.3 (d, JP,C = 3.4 Hz, C-
4), 26.8 (CH3CHN), 45.4 (C-6), 52.0 (d, 2JP,C = 6.8 Hz, C-2), 52.6
(CHN), 57.3 (d, JP,C = 140.7 Hz, C-3), 61.6 (d, JP,C = 7.7 Hz,
CH2O), 62.0 (d, 2JP,C = 7.7 Hz, CH2O), [6 arom: 126.3 (CH), 126.4
(2 CH), 128.1 (2 CH), 148.1 (C)].
31P NMR (101.25 MHz, CDCl3): d = 29.04.
HRMS (ESI): m/z [M + Na]+ calcd for C17H29N2O3P + Na:
(+)-Diethyl 3-(1¢-Methylbenzyl)amino-1-(4-nitrobenzoyl)pipe-
ridin-3-ylphosphonate (11B)
To a solution of major phosphonate 9B (75 mg, 0.220 mmol) in
CH2Cl2 (2 mL), was added Et3N (155 mL, 5 equiv) and 4-nitroben-
zoyl chloride (43 mg, 0.232 mmol) at 0 °C. The mixture was stirred
at 0 °C for 3.5 h. After dilution with Et2O (10 mL), the mixture was
washed with H2O, then with brine. The organic layer was dried
(MgSO4) and concentrated under vacuo. The residue was purified
by flash chromatography on silica gel (eluent, EtOAc–pentane–aq
NH3, 50:50:0.5) to provide 73 mg (68%) of (+)-11B as a viscous oil.
Crystallization from MeOH–Et2O gave suitable crystals; mp 95 °C;
[a]D +12.7 (c = 1.00, CHCl3).
1
2
363.1808; found: 363.1812.
Diaminophosphonate 10
To a solution of aminophosphonate 9A or 9B (1 mmol) in AcOH
(5 mL), was added 20% Pd(OH)2/C (Pearlman’s catalyst, 150 mg).
The mixture was stirred at r.t. under H2 (1 atm) for 18 h, then de-
gassed under a stream of argon, filtered and the collected solid was
washed with EtOH. The combined filtrate and washings were con-
centrated and purified by chromatography (silica gel, eluent:
MeOH–CH2Cl2–aq NH3, 5:95:0.5) to give the free diaminophos-
phonate 10 as yellow oils.
IR (neat): 3467, 3360 (NH), 2980, 1645, 1634 (C=O), 1286, 1238
(P=O), 1055, 1024 (P–O), 963 cm–1.
1H NMR (250 MHz, CDCl3): d [two conformers (a/b = 75:25)] =
1.00–1.20 (m, 1 H-5, a/b), 1.40 (d, J = 6.9 Hz, 3 H, CH3CHN, a/b),
1.41 (t, J = 7.0 Hz, 3 H, CH3-CH2O, a/b), 1.44 (t, J = 7.0 Hz, 3 H,
CH3CH2O, a/b), 1.50–1.88 (m, 2 H, 1 H-5 and HN, a/b), 1.88–2.05
(m, 1 H-4, a/b), 2.80–3.00 (m, 1 H-4, a/b), 3.30 (dd, J = 2.2, 14.0
Hz, 2 H-6, a), 3.56 (dd, J = 2.7, 14.0 Hz, 2 H-6, b), 3.98–4.13 (m, 1
H-2), 4.13–4.30 (m, 4 H, 2 CH2O), 4.37 (qd, J = 6.9 Hz, 3JP,H = 2.2
Hz, 1 CHN), 4.45 (dd, J = 7.2, 13.5 Hz, 1 H-2), 7.12–7.36 (m, 5
Hphenyl), 7.53 (d, J = 8.6 Hz, 2 Harom), 8.23 (d, J = 8.3 Hz, 2 Harom).
(R)-(–)-Diethyl 3-Aminopiperidin-3-ylphosphonate [(R)-10]
[a]D –3.4 (c = 0.60, CHCl3).
IR (neat): 3370, 3297 (NH), 2933, 1228 (P=O), 1055, 1024 (P–O),
963 cm–1.
13C NMR (62.9 MHz, CDCl3): d [two conformers (a/b =
75:25)] = 16.6/16.7 (CH3CH2O, b/a), 16.75 (CH3CH2O, a/b), 19.1/
1H NMR (250 MHz, CDCl3): d = 1.34 (t, J = 7.2 Hz, 6 H, CH3),
1.40–1.55 (m, 1 H-5), 1.55–1.78 (m, 5 H, 3 HN, 1 H-4 and 1 H-5),
1.78–2.10 (m, 1 H-4), 2.62 (ddd, J = 3.2, 10.5, 13.0 Hz, 1 H-6), 2.79
(ddd, J = 1.5, 8.5, 13.1 Hz, 1 H-2), 2.94 (br d, J = 13.0 Hz, 1 H-6),
3.02 (dd, J = 3.2, 13.1 Hz, 1 H-2), 4.14 (dq, 3JP,H = 1.7 Hz, J = 7.2
Hz, 2 H, CH2OP), 4.17 (mq, J = 7.2 Hz, 2 H, CH2OP).
2
20.2 (d, JP,C = 11.0 Hz, C-5, b/a), 26.2/26.5 (C-4, b/a), 26.7/27.1
(CH3CHN, a/b), 42.9/47.7 (C-6, b/a), 47.9/53.8 (d, J = 9.8 Hz, C-2,
a/b), 52.5/53.0 (CHN, a/b), 57.1 (d, 1JP,C = 142.0 Hz, C-3, a/b), 62.4
2
(d, JP,C = 8.3 Hz, CH2OP, a/b), 62.5 (d, J = 8.3 Hz, CH2OP, a/b),
[12 arom: 123.8 (2 CH, a/b), 126.5 (2 CH, a/b), 126.6/126.8 (CH,
a/b), 127.8/128.4 (2 CH, a/b), 128.2/128.7 (2 CH, a/b), 142.5 (s,
a/b), 148.2 (s, a/b), 148.7 (s, a/b)], 168.9 (CON, a/b).
31P NMR (101.25 MHz, CDCl3): d = 26.98.
HRMS (ES): m/z [M + Na]+ calcd for C24H32N3O6P + Na: 512.1921;
found: 512.1921.
13C NMR (62.9 MHz, CDCl3): d = 16.5 (CH3), 16.6 (CH3), 20.8 (d,
1
2JP,C = 8.6 Hz, C-5), 30.4 (C-4), 46.2 (C-6), 50.6 (d, JP,C = 151.2
2
2
Hz, C-3), 51.5 (d, JP,C = 5.6 Hz, C-2), 62.2 (d, JP,C = 7.3 Hz,
CH2O), 62.3 (d, 2JP,C = 7.5 Hz, CH2O).
31P NMR (101.25 MHz, CDCl3): d = 29.41.
HRMS (ESI): m/z [M + Na]+ calcd for C9H21N2O3P + Na: 259.1182;
found: 259.1193.
X-ray Crystal Structure Analysis of (+)-(3R,1¢S)-Phosphonate
11B13
Colorless crystal of 0.10 × 0.08 × 0.07 mm. C24H32N3O6P,
M = 489.50: triclinic system, space group P1 (No 1), Z = 2, with
a = 8.4002 (6), b = 10.3126 (6), c = 14.5471 (10) Å, a = 83.474 (2),
b = 77.733 (2), g = 81.702 (2)°, V = 1214.02 (14) A3, d = 1.339 g
cm–3, F(000) = 520, l: = 0.71073 Å (Mo-Ka), m = 0.158 mm–1,
17403 reflections measured (–14 ≤ h ≤ 14, –10 ≤ k ≤ 18, –25 ≤ l ≤25)
on a Bruker X8 diffractometer. The structure was solved and refined
with SHELXL-97.14 Hydrogen atom riding, refinement converged
to R(gt) = 0.0453 for the 14768 reflections having I > 2s(I), and wR
(gt) = 0.1163, Goodness-of-Fit S = 1.044, residual electron density:
–0.510 and 0.816 eÅ–3.
(S)-(+)-Diethyl 3-Aminopiperidin-3-ylphosphonate [(S)-10]
[a]D +3.4 (c = 0.60, CHCl3).
(R)-(+)-3-Aminopiperidin-3-ylphosphonic Acid [(R)- 2]
Hydrolysis of phosphonate (R)-10 was carried out with aq 6 M HCl
according to our previously reported method;12 [a]D +2.4 (c = 0.25,
aq 1 M NaOH); mp >250 °C (dec.).
1H NMR (250 MHz, D2O): d (two conformers) = 1.60–2.17 (m, 3
H, 2 H-5 and 1 H-4), 2.17–2.37 (m, 1 H-4), 2.97–3.13 (m, 1 H-6),
Synthesis 2007, No. 2, 289–293 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of (R)- and (S)-a-Amino-3-piperidinylphosphonic Acids
293
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Bosyakov, Y. G.; Maishinova, G. T.; Logunov, A. P.;
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(a) Kabatschnik, M. Izv. Akad. Nauk SSSR, Ser. Khim. 1967,
1357; Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.),
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Khim. 1967, 1367; Bull. Acad. Sci. USSR, Div. Chem. Sci.
(Engl. Transl.), 1967, 1379. (c) For unsubstituted pyran
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Acknowledgment
We wish to thank Mr. Régis Guillot for performing the X-ray crystal
structure analysis.
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Copies of the data can be obtained, free of charge, on
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UK; Fax: +44(1233)336033; E-mail:
deposit@ccdc.cam.ac.uk.
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Synthesis 2007, No. 2, 289–293 © Thieme Stuttgart · New York