Facile synthesis of both enantiomers of (pyrrolidin-2-yl)phosphonate from L-proline

Article abstract of DOI:10.1016/j.tet.2011.09.080

Diastereoselective introduction of phosphono groups into l-proline derivatives at the 5-position was achieved with suitable selection of N-protecting group. N-Benzoyl-l-prolinate preferentially gave trans-phosphorylated products, which could be easily tra

Full text of DOI:10.1016/j.tet.2011.09.080

Tetrahedron 67 (2011) 9411e9416
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Facile synthesis of both enantiomers of (pyrrolidin-2-yl)phosphonate from
L
-proline
*
Shigeo Hirata, Masami Kuriyama, Osamu Onomura
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 August 2011
Received in revised form 18 September 2011
Accepted 20 September 2011
Available online 25 September 2011
Diastereoselective introduction of phosphono groups into
achieved with suitable selection of N-protecting group. N-Benzoyl-
L
-proline derivatives at the 5-position was
-prolinate preferentially gave trans-
phosphorylated products, which could be easily transformed into (S)-(pyrrolidin-2-yl)phosphonates. On
the other hand, N-benzyloxycarbonyl- -prolinate reacted with phosphite to give cis-substituted products,
which could be easily transformed into (R)-(pyrrolidin-2-yl)phosphonates.
Ó 2011 Elsevier Ltd. All rights reserved.
L
L
Keywords:
Diastereoselective phosphorylation
Arbusov reaction
(Pyrrolidin-2-yl)phosphonate
L-Proline
1. Introduction
pinenone,3b (þ)-camphor,3c (R)- or (S)-phenylglycinol,3d,e
L-men-
thol,3f (S)-(þ)-p-toluenesulfinamide3g as chiral auxiliaries, while
Optically active
a
-amino phosphonates and their derivatives
easily available
the synthesis.
L-proline on manufacturing scale has not used for
are biologically important compounds structurally analogous to
-amino acids.1 A lot of useful methods have been developed for
the diastereo- or enantio-selective synthesis of acyclic -amino
phosphonates.2 On the other hand, there are fewer methods for the
diastereoselective synthesis of optically active cyclic -amino
a
Recently, we have reported Lewis acid-catalyzed arylation of
N-acylated 5-methoxy- -proline 2, which are electrochemically pre-
pared from -proline derivatives 1 proceeded diastereoselectively.
Namely, N-benzoylated prolinate 2a afforded trans-5-arylated
a
L
L
a
phosphonates, which have found promising applications as surro-
L
-proline trans-3a, while N-benzyloxycarbonylated prolinate 2b
gates of proline.3 These methods use (þ)- or (ꢀ)-2-hydroxy-3-
afforded cis-5-arylated
L
-proline cis-3b (Eq. 1).4
-2e
ArH
MeO2C
or
(1)
MeO2C
MeO2C
N
PG
Ar
Ar
N
PG
N
PG
N
PG
OMe
MeO2C
MeOH
Lewis acid
1a: PG=Bz
1b: PG=Cbz
trans-3a
(PG=Bz)
cis-3b
(PG=Cbz)
2a: PG=Bz
2b: PG=Cbz
* Corresponding author. Tel.: þ81 95 819 2429; fax: þ81 95 819 2476; e-mail
address: onomura@nagasaki-u.ac.jp (O. Onomura).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.080

9412
S. Hirata et al. / Tetrahedron 67 (2011) 9411e9416
We wish herein to report the effect of N-acyl groups on the
diastereoselective introduction of phosphonate groups into -pro-
line derivatives 2 at the 5-position and its application to synthesis
of both enantiomers of (pyrrolidin-2-yl)phosphonate 6 (Scheme 1).
N-tert-butoxycarbonylated proline 2d8 (entries 1 and 2 in Table 2)
L
lowered compared with that of N-benzyloxycarbonylated proline
5bp (entry 9 in Table 1). Similarly, diastereoselectivities of phos-
phorylated products 5ep and 5fp, which were obtained from
N-acetylated proline 2e and N-p-toluenesulfonylated proline 2f
(entries 3 and 4 in Table 2) did not exceed that of N-benzoylated
proline 5ap (entry 2 in Table 1).
O
P(OR)3
4
O
P
OR
N
Bz
2a
MeO2C
N
Bz
(R)-6a
OMe
N
Bz
trans-5a
MeO2C
MeO2C
P
OR
BF3-OEt2
OR
OR
O
P(OEt)3(4p) (2.0 equiv)
BF3-OEt2 (2.0 equiv)
P(OR)3
4
O
P
OR
N
Cbz
2b
MeO2C
N
Cbz
OMe
N
Cbz
cis-5b
O
P
OR
N
PG
OMe
BF3-OEt2
OR
MeO2C
P
N
PG
MeO2C
(3)
OR
OEt
CH2Cl2, rt, 12h
OEt
(S)-6b
2c: PG=CO2Me
2d: PG=Boc
2e: PG=Ac
5cp: PG=CO2Me
5dp: PG=Boc
5ep: PG=Ac
Scheme 1.
2f: PG=Ts
5fp: PG=Ts
2. Results and discussion
2.1. Effect of Lewis acid on the Arbusov reaction
First, we investigated effect of Lewis acid on introduction of tri-
Table 2
ethyl phosphite 4p5 into N-benzoylated or N-benzyloxycarbonylated
Effect of N-protective group on the Arbusov reaction
-prolinate6 2a or 2b (Eq. 2). The results are shown
Entry
Substrate
PG
Product
Yielda (%)
deb (%)
Major
5-methoxylated
L
in Table 1. In the case of 2a, TiCl4 mediated
a-phosphorylation in
isomer
good yield but with low diastereoselectivity (entry 1). BF3$OEt2
promoted the phosphorylation in moderate diastereoselectivity
(entry 2), while SnCl4 did not work as an effective Lewis acid (entry
3).7 Using Cu(OTf)2, AlCl3, Hf(OTf)4, or In(OTf)3 as Lewis acid afforded
phosphorylated product 5ap in low yields (entries 4e7).7 In the case
of 2b, similar tendency for tested Lewis acids was observed (entries
8e14), and BF3$OEt2 afforded the best result (entry 9).
1
2
3
4
2c
2d
2e
2f
CO2Me
Boc
Ac
5cp
5dp
5ep
5fp
68
20
60
98
50
41
15
29
nd
nd
nd
nd
Ts
a
Yield of isolated product as a mixture of diastereomers after purification by
column chromatography.
b
The diastereomer excess was determined by 1H NMR spectroscopy after
purification.
P(OEt)3 (4p) (2.0 equiv)
Lewis acid (2.0 equiv)
O
P
N
PG
MeO2C
N
PG
2.3. Effect of ester group in phosphite
OMe
MeO2C
(2)
OEt
OEt
CH2Cl2, rt, 12h
2a: PG=Bz
5ap: PG=Bz
Next, we investigated effect of ester group of phosphites on the
diastereoselectivity for the Arbusov reaction of 2a or 2b in the
presence of BF3$OEt2 (Eq. 4). The results are shown in Table 3.
N-Benzoylated proline 2a reacted with trimethyl phosphite 4q gave
trans-phosphorylated product 5aq in similar yield and diaster-
eoselectivity (entry 1 in Table 3) to those of 5ap (entry 2 in Table 1).
Although triphenyl phosphite 4r, tribenzyl phosphite 4s, and tri-n-
butyl phosphite 4u were ineffective (entries 2, 3, and 5 in Table 3),7
triisopropyl phosphite 4t was effective to afford trans-phosphory-
lated product 5at in good yield with high diastereoselectivity (entry
4 in Table 3). In the case of N-benzyloxycarbonylated proline 2b,
similar tendencies were observed with respect to effect of phos-
phites (entries 6e10 in Table 3).7 The reaction of 2b with 4t gave the
best result to afford cis-5bt in 50% yield with 85% de (entry 9 in
Table 3).
2b: PG=Cbz
5bp: PG=Cbz
Table 1
Effect of Lewis acid on the Arbusov reaction
Entry Substrate PG Lewis acid Product Yielda (%) deb (%) Major isomer
1c
2
3
4
5
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
Bz TiCl4
Bz BF3$OEt2
Bz SnCl4
Bz Cu(OTf)2
Bz AlCl3
Bz Hf(OTf)4
Bz In(OTf)3
Cbz TiCl4
Cbz BF3$OEt2
Cbz SnCl4
Cbz Cu(OTf)2
Cbz AlCl3
Cbz Hf(OTf)4
Cbz In(OTf)3
5ap
5ap
5ap
5ap
5ap
5ap
5ap
5bp
5bp
5bp
5bp
5bp
5bp
5bp
66
59
0
27
37
32
14
49
45
0
26
43
d
trans
trans
d
30
53
15
32
51
78
d
trans
trans
trans
trans
cis
6
7
8c
9
cis
d
10
11
12
13
14
35
44
33
26
55
29
61
70
cis
cis
cis
cis
2.4. Determination of stereoconfiguration
Transformation of 5bp into diethyl (S)-(pyrrolidin-2-yl)phos-
phonate (S)-9p shown in Eq. 5 revealed that the relative stereo-
configuration of 5bp was cis-form. Namely, removal of
2-methoxycarbonyl group of 5bp was accomplished by alkaline
hydrolysis of 5bp to afford carboxylic acid 7bp, and decarboxylative
methoxylation9 of 7bp, followed by reduction of N,O-acetal 8bp10
to give N-benzyloxycarbonyl-2-pyrrolidinylphosphonate 6bp. Suc-
cessive debenzyloxycarbonylation of 6bp afforded (S)-9p.3c,11
Opposite diastereoselectivity for the reaction of 2b with 4p was
confirmed by transformation of cis-5bp into cis-5ap shown in Eq. 6.
The major diastereomer of cis-5ap in Eq. 6 was consistent with the
minor diastereomer obtained in entry 1 of Table 1. Accordingly, 5ap
shown in entry 1 in Table 1 was trans-configuration.
a
Yield of isolated product as a mixture of diastereomers after purification by
column chromatography.
b
The diastereomer excess was determined by 1H NMR spectroscopy after
purification.
c
Reaction temperature: ꢀ78 ꢁC to rt.
2.2. Effect of N-protective group
Next, we investigated effect of N-protecting group on the dia-
stereoselectivity for the Arbusov reaction of 2cef with 4p in the
presence of BF3$OEt2 (Eq. 3). The results are shown in Table 2.
Diastereoselectivities of phosphorylated products 5cp and 5dp,
which were obtained from N-methoxycarbonylated proline 2c and

S. Hirata et al. / Tetrahedron 67 (2011) 9411e9416
9413
P(OR)3 (4q-u) (2.0 equiv)
BF3-OEt2 (2.0 equiv)
O
MeO2C
N
PG
N
PG
OMe
P
MeO2C
(4)
OR
CH2Cl2, rt, 12h
OR
2a: PG=Bz
2b: PG=Cbz
5aq: PG=Bz, R=Me
5ar: PG=Bz, R=Ph
5as: PG=Bz, R=Bn
5at: PG=Bz, R=iPr
5au: PG=Bz, R=nBu
5bq: PG=Cbz, R=Me
5br: PG=Cbz, R=Ph
5bs: PG=Cbz, R=Bn
5bt: PG=Cbz, R=iPr
5bu: PG=Cbz, R=nBu
Table 3
Effect of alcohol residue of phosphites on the Arbusov reaction
Entry
Substrate
PG
P(OR)3
R
Product
Yielda (%)
deb (%)
Major
isomer
1
2
3
4
5
6
7
8
9
10
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
Bz
Bz
Bz
Bz
Me
Ph
Bn
i-Pr
n-Bu
Me
Ph
Bn
i-Pr
n-Bu
4q
4r
4s
4t
4u
4q
4r
4s
4t
5aq
5ar
5as
5at
5au
5bq
5br
5bs
5bt
5bu
52
17
0
61
28
72
34
0
40
57
d
trans
trans
d
84
10
59
84
d
trans
trans
cis
cis
d
Bz
Cbz
Cbz
Cbz
Cbz
Cbz
50
45
85
75
cis
cis
4u
a
Yield of isolated product as a mixture of diastereomers after purification by column chromatography.
The diastereomer excess was determined by 1H NMR spectroscopy after purification.
b
O
P
OEt
O
−2e (3 F/mol)
2,6-lutidine
MeOH
O
NaOH
MeO
P
MeO2C
P
HO2C
N
Cbz
OEt
N
Cbz
5bp
OEt
N
OEt
H2O : THF = 1 : 1
OEt
OEt
Cbz
7bp
8bp
78% de
O
P
OEt
O
H2, Pd/C
MeOH
Et3SiH, MeSO3H
CH2Cl2
(5)
P
N
Cbz
6bp
OEt
N
H
OEt
OEt
66% yield
(S)-9p
50% yield from 5bp
78% ee
BzCl
O
H2
O
O
(6)
P
MeO2C
P
MeO2C
P
MeO2C
N
Bz
cis-5ap
78% de
OEt
N
Cbz
OEt
N
H
OEt
H2O : THF
OEt
OEt
OEt
cis-5bp
78% de
cis-10bp
71% yield from cis-5bp
Similarly, demethoxylation of 8at10 obtained from 5at by hy-
drolysis and successively decarboxylative methoxylation smoothly
proceeded to give diisopropyl N-benzoylated (R)-(pyrrolidin-2-yl)
phosphonate 6at (Eq. 7).
2.5. C2-Symmetrical pyrrolidine-2,5-diphosphate
C2-Symmetrical pyrrolidine derivative 11ap was prepared from
trans-phosphorylated N-benzoylproline 5ap as follows (Eq. 8);
O
O
O
Et3SiH, MeSO3H
CH2Cl2
(7)
P
P
P
MeO2C
MeO
N
Bz
O-i-Pr
N
Bz
O-i-Pr
N
Bz
O-i-Pr
O-i-Pr
O-i-Pr
O-i-Pr
5at (84% de)
8at
(R)-6at (32% yield from 5at, 83% ee)

9414
S. Hirata et al. / Tetrahedron 67 (2011) 9411e9416
O
O
O
NaOH
−2e (3 F/mol)
2,6-lutidine
MeOH
P
P
P
MeO2C
HO2C
MeO
N
Bz
5ap
OEt
N
Bz
OEt
N
Bz
8ap
OEt
H2O : THF = 1 : 1
OEt
OEt
OEt
7ap
43% de
O
P
OEt
O
P
EtO
P(OEt)3 (4p)
BF3-OEt2
CH2Cl2
N
Bz
OEt
EtO
35% yield from 5ap
88% de, 43% ee
(R,R):(S,S):meso=68:26:6
(8)
(R,R)-11ap
Alkaline hydrolysis of 5ap afforded carboxylic acid 7ap. Electro-
chemical decarboxylative methoxylation7 of 7ap in methanol
afforded methoxylated compound 8ap,10 which reacted with tri-
ethyl phosphite in the presence of BF3$OEt2 to majorly afford trans-
2,5-diphosphorylated pyrrolidine 11ap in 35% yield from 5ap.12
795 cmꢀ1; MS [EI (þ)]: m/z calcd for C17H24NO6P [M]þ: 369.1341,
found: 369.1351; HPLC chiralpak AD column (4.6 mmf, 250 mm),
n-hexane/isopropanol¼10:1, wavelength: 254 nm, flow rate:
1.0 mL/min, retention time: 33.7 min (trans), 38.1min (cis).
4.3.2. Dimethyl (5R)-[N-benzoyl-(2S)-methoxycarbonylpyrrolidin-5-
3. Conclusion
yl]phosphonate (5aq). Colorless oil; ½a D20
ꢀ102.9 (c 1.9, EtOH, 40%
ꢃ
de); 1H NMR (400 MHz, CDCl3)
d 7.60e7.31 (m, 5H), 5.05e4.96 and
We have accomplished diastereoselective introduction of
4.78e4.72 (2m, 1H), 4.61 (d, J¼9.3 Hz, 1H), 3.90e3.50 (m, 6H),
phosphono groups into
N-Benzoylated -proline derivative 2a mainly gave trans-phos-
phorylated products, while N-benzyloxycarbonylated -proline 2b
L-proline derivatives at the 5-position.
3.42e3.25 (m, 3H), 2.78e2.04 (m, 4H); 13C NMR (100 MHz, CDCl3)
L
d 176.0, 172.3, 136.0, 130.4, 128.3, 127.3, 62.1, 53.8, 53.2, 53.0, 52.2,
L
30.8, 24.6; IR (neat) 1743, 1655, 1375, 1246, 1061, 833 cmꢀ1; HRMS
was majorly transformed into cis-phosphorylated products.
[EI (þ)]: m/z calcd for C15H20NO6P [M]þ: 341.1028, found: 341.1020;
HPLC chiralpak AD column (4.6 mmf, 250 mm), n-hexane/iso-
4. Experimental section
propanol¼10:1, wavelength: 254 nm, flow rate: 1.0 mL/min, re-
tention time: 43.3 min (trans), 56.3 min (cis).
4.1. General
4.3.3. Diphenyl (5R)-[N-benzoyl-(2S)-methoxycarbonylpyrrolidin-5-
1H-NMR spectra were measured on a JEOL JNM-AL 400 spec-
trometer with TMS as an internal standard. 13C NMR spectra were
measured on a JEOL JNM-AL 400 spectrometer with TMS as an in-
ternal standard. IR spectra were obtained on a Shimadzu FTIR-
8100A. Mass spectra were obtained on a JEOL JMS-700N instrument.
All reagents and solvents were used as supplied without further
purification.
yl]phosphonate (5ar). Colorless oil; ½a D20
ꢀ148.2 (c 0.8, EtOH, 57%
ꢃ
de); 1H NMR (400 MHz, CDCl3)
d 7.93e6.75 (m, 15H), 5.88e5.29 (m,
1H), 4.93e4.59 (m, 1H), 3.82e3.70 and 3.38 (m and s, 3H),
2.93e2.03 (m, 4H); 13C NMR (100 MHz, CDCl3)
d
172.2, 171.7, 150.2,
135.8, 129.8, 129.6, 128.2, 127.4, 125.3, 120.2, 62.2, 55.3, 52.3, 31.0,
24.9; IR (neat) 1746, 1661, 1360, 1273, 1210, 1188, 933 cmꢀ1; MS [EI
(þ)]: m/z calcd for C25H25NO6P [M]þ: 465.1341, found: 465.1339;
HPLC chiralpak AD column (4.6 mmf, 250 mm), n-hexane/iso-
4.2. Methyl N-protected 5-methoxy-
L
-prolinates 2aef
propanol¼10:1, wavelength: 254 nm, flow rate: 1.0 mL/min, re-
tention time:49.2 min (trans), 58.2 min (cis).
N-Protected 5-methoxy-
L
-prolinates 2a,6b 2b,6e 2c,6a 2d,6c 2e,6d
and 2f5b were known compounds.
4.3.4. Diisopropyl (5R)-[N-benzoyl-(2S)-methoxycarbonylpyrrolidin-
5-yl]phosphonate (5at). Colorless oil; ½a D20
ꢀ74.6 (c 4.6, EtOH, 84%
ꢃ
4.3. General procedure for phosphorylation of methyl
de); 1H NMR (400 MHz, CDCl3)
d 7.70e7.32 (m, 5H), 5.30 and
N-protected-5-methoxy-
L
-prolinates 2aef
5.10e4.20 (s and m, 4H), 3.90e3.55 and 3.37 (m and s, 3H),
2.87e1.97 (m, 4H), 1.60e1.01 (m, 12H); 13C NMR (100 MHz, CDCl3)
Under an argon atmosphere, BF3$OEt2 (0.246 mL, 2 mmol) was
added dropwise to the solution of 2a (291 mg, 1 mmol) and triethyl
phosphite 4p (332 mg, 2 mmol) in CH2Cl2 (10 mL) at room tem-
perature. After stirring for 12 h, the solution was poured in brine
(10 mL) and extracted with CH2Cl2 (3ꢂ10 mL). The combined or-
ganic layer was dried over MgSO4 and the solvent removed under
reduced pressure. The residue was purified by silica gel column
chromatography (n-hexane/AcOEt¼1:1) to afford a mixture of cis-
and trans-5ap as a colorless oil (218 mg, 59%).
d 172.3, 136.3, 135.9, 129.9, 128.2, 127.3, 62.0, 55.1, 53.4, 52.4, 30.8,
24.7, 23.9; IR (neat) 1747, 1655, 1387, 1242, 1018, 729 cmꢀ1; MS [EI
(þ)]: m/z calcd for C19H28NO6P [M]þ: 397.1654, found: 397.1657;
HPLC chiralpak AD column (4.6 mmf, 250 mm), n-hexane/iso-
propanol¼10:1, wavelength: 254 nm, flow rate: 1.0 mL/min, re-
tention time: 16.1 min (cis), 22.6 min (trans).
4.3.5. Di-n-butyl (5R)-[N-benzoyl-(2S)-methoxycarbonylpyrrolidin-
5-yl]phosphonate (5au). Colorless oil; ½a D20
ꢀ73.4 (c 4.7, EtOH, 10%
ꢃ
de); 1H NMR (400 MHz, CDCl3)
d 7.59e7.31 (m, 5H), 5.04e4.58 (m,
4.3.1. Diethyl (5R)-[N-benzoyl-(2S)-methoxycarbonylpyrrolidin-5-yl]
2H), 4.22e3.80 (m, 4H), 3.80e3.37 (m, 3H), 2.87e1.98 (m, 4H),
phosphonate (5ap). Colorless oil; ½a D20
ꢀ74.3 (c 1.1, EtOH, 43% de);
ꢃ
1.72e1.51 (m, 4H), 1.51e1.13 (m, 4H), 1.01e0.82 (m, 6H); 13C NMR
1H NMR (400 MHz, CDCl3)
d
7.60e7.30 (m, 5H), 5.30 and 5.02e3.30
(100 MHz, CDCl3) d 172.3, 171.2, 136.2, 130.2, 128.2, 127.3, 66.1, 62.1,
(s and m, 9H), 2.90e1.95 (m, 4H), 1.45e1.05 (m, 6H); 13C NMR
(100 MHz, CDCl3) 172.3, 171.4, 136.1, 130.0, 128.2, 127.2, 62.0, 54.2,
52.6, 52.1, 30.8, 24.6, 16.3; IR (neat) 1743, 1655, 1394, 1242, 1016,
54.2, 52.1, 32.5, 30.8, 24.7,18.6,13.5; IR (neat) 1744,1655,1308,1240,
d
1028, 731, 702 cmꢀ1; MS [EI (þ)]: m/z calcd for C21H32NO6P [M]þ:
425.1967, found: 425.1960; HPLC chiralpak AD column (4.6 mmf,

S. Hirata et al. / Tetrahedron 67 (2011) 9411e9416
9415
250 mm), n-hexane/isopropanol¼10:1, wavelength: 254 nm, flow
rate: 1.0 mL/min, retention time: 21.8 min (trans), 25.3 min (cis).
4.3.11. Diethyl [N,(2S)-di(methoxycarbonyl)pyrrolidin-5-yl]phospho-
nate (5cp). Colorless oil; ½a D20
ꢃ
ꢀ6.2 (c 0.9, EtOH, 50% de); 1H NMR
(400 MHz, CDCl3) d 4.11e3.78 (m, 6H), 3.51e3.24 (m, 3H), 2.51e1.42
4.3.6. Diethyl (5S)-[N-benzyloxycarbonyl-(2S)-methoxycarbonylpy-
(m, 4H),1.22e0.98 (m, 6H); 13C NMR (100 MHz, CDCl3)
d 171.2,154.9,
rrolidin-5-yl]phosphonate (5bp). Colorless oil; ½a D20
ꢃ
þ4.78 (c 1.55,
61.7, 59.7, 52.2, 51.5, 47.8, 20.4, 15.8, 13.6; IR (neat) 1750, 1717, 1448,
EtOH, 78% de); 1H NMR (400 MHz, CDCl3)
d
7.45e7.25 (m, 5H),
1375, 1049, 776 cmꢀ1; MS [EI (þ)]: m/z calcd for C12H22NO7P [M]þ:
5.30e4.95 (m, 2H), 4.47e3.90 (m, 6H), 3.90e3.46 (m, 3H),
323.1134, found: 323.1121; HPLC chiracel OD-H column (4.6 mmf,
2.81e1.95 (m, 4H), 1.39e1.24 (m, 6H); 13C NMR (100 MHz, CDCl3)
250 mm), n-hexane/isopropanol¼500:1, wavelength: 254 nm, flow
d
172.2, 153.6, 136.1, 128.4, 127.8, 67.7, 60.0, 55.8, 54.1, 52.0, 29.6,
rate: 1.0 mL/min, retention time: 7.31 min (cis), 8.78 min (trans).
16.3; IR (neat) 1759, 1710, 1354, 1248, 1053, 772 cmꢀ1; MS [EI (þ)]:
m/z calcd for C18H26NO7P [M]þ: 399.1447, found: 399.1450; HPLC
4.3.12. Diethyl [N-tert-buthoxycarbonyl-(2S)-methoxycarbonylpy-
chiralpak AD column (4.6 mm
f
,
250 mm), n-hexane/iso-
rrolidin-5-yl]phosphonate (5dp). Colorless oil; ½a D20
ꢀ2.0 (c 1.0,
ꢃ
propanol¼10:1, wavelength: 254 nm, flow rate: 1.0 mL/min, re-
EtOH, 41% de); 1H NMR (400 MHz, CDCl3)
d 4.42e4.01 (m, 6H),
tention time: 18.8 min (cis), 25.9 min (trans).
3.82e3.62 (m, 3H), 2.49e1.70 (m, 4H), 1.66e1.01 (m, 15H); 13C NMR
(100 MHz, CDCl3) d 172.3, 153.8, 61.8, 51.8, 48.4, 29.5, 28.0, 16.3, 6.4;
4.3.7. Dimethyl (5S)-[N-benzyloxycarbonyl-(2S)-methoxycarbonyl-
IR (neat) 1698, 1445, 1395, 1063, 793 cmꢀ1; MS [EI (þ)]: m/z calcd
pyrrolidin-5-yl]phosphonate (5bq). Colorless oil; ½a D20
ꢃ
ꢀ1.01 (c 4.10,
for C15H28NO7P [M]þ: 365, 1607, found: 365.1613; HPLC chiracel
EtOH, 59% de); 1H NMR (400 MHz, CDCl3)
d
7.55e7.21 (m, 5H),
OD-H column (4.6 mm
wavelength: 254 nm, flow rate: 1.0 mL/min, retention time:
f
, 250 mm), n-hexane/isopropanol¼500:1,
5.29e4.95 and 4.51e4.25 (2m, 4H), 3.87e3.47 (m, 9H), 2.80e1.85
(m, 4H); 13C NMR (100 MHz, CDCl3)
d
171.9, 154.5, 136.0, 128.3,
7.37 min (cis), 8.62 min (trans).
128.1, 127.7, 67.6, 59.9, 53.6, 52.8, 52.0, 29.5, 26.5; IR (neat) 1757,
1701, 1354, 1252, 1055, 833 cmꢀ1; MS [EI (þ)]: m/z calcd for
C16H22NO7P [M]þ: 371.1134, found: 371.1150; HPLC chiralpak AD
4.3.13. Diethyl [N-acetyl-(2S)-methoxycarbonylpyrrolidin-5-yl]phos-
phonate (5ep). Colorless oil; ½a D20
ꢃ
ꢀ21.1 (c 1.1, EtOH,15% de); 1H NMR
column (4.6 mmf, 250 mm), n-hexane/isopropanol¼10:1, wave-
(400 MHz, CDCl3) d 4.76e4.08 (m, 6H), 3.81e3.68 (m, 3H), 2.84e1.90
length: 254 nm, flow rate: 1.0 mL/min, retention time: 26.9 min
(m, 7H), 1.39e1.24 (m, 6H); 13C NMR (100 MHz, CDCl3)
d 171.4, 170.6,
(cis), 37.1 min (trans).
59.4, 56.6, 55.0, 52.0, 27.7, 22.2, 16.3; IR (neat) 1755,1665, 1406,1244,
1063, 799 cmꢀ1; MS [EI (þ)]: m/z calcd for C12H22NO6P [M]þ:
4.3.8. Diphenyl
(5S)-[N-benzyloxycarbonyl-(2S)-methoxycarbon-
307.1185, found: 307.1191; HPLC chiracel OD-H column (4.6 mmf,
ylpyrrolidin-5-yl]phosphonate (5br). Colorless oil; ½a D20
ꢃ
ꢀ43.9 (c
250 mm), n-hexane/isopropanol¼500:1, wavelength: 254 nm, flow
3.85, EtOH, 84% de); 1H NMR (400 MHz, CDCl3)
d
7.40e6.98 (m,
rate: 1.0 mL/min, retention time: 6.9 min (cis), 8.0 min (trans).
15H), 5.18 and 4.99 (2d, J¼11.7 Hz, 1.2H and 0.8H), 4.88 and 4.80
(2d, J¼9.3 and 9.2 Hz, 0.6H and 0.4H), 4.52 and 4.45 (2d, J¼9.3 and
9.2 Hz, 0.4H and 0.6H), 3.75 and 3.49 (2s, 1.2H and 1.8H),
4.3.14. Diethyl [(2S)-methoxycarbonyl-N-p-toluenesulfonylpyrroli-
din-5-yl]phosphonate (5fp). Colorless oil; ½a D20
ꢀ21.1 (c 1.1, EtOH,
ꢃ
2.76e1.81 (m, 4H); 13C NMR (100 MHz, CDCl3)
d
172.7, 154.3, 150.1,
29% de); 1H NMR (400 MHz, CDCl3)
d
7.80 (q, J¼12.0 and 8.6 Hz, 2H),
135.8, 128.2, 125.2, 124.9, 120.5, 120.2, 67.6, 59.8, 52.1, 29.4, 25.4; IR
(neat) 1748, 1707, 1348, 1192, 938 cmꢀ1; MS [EI (þ)]: m/z calcd for
C26H26NO7P [M]þ: 495.1447, found: 495.1465; HPLC chiralpak AD
7.35 and 7.29 (2d, J¼8.1 and 7.6 Hz, 2H), 4.42e3.76 (m, 6H), 3.75 (d,
J¼3.2 Hz, 3H) 2.65e1.93 (m, 7H) 1.37e1.15 (m, 6H); 13C NMR
(100 MHz, CDCl3)
d 171.4, 170.6, 59.4, 56.6, 55.0, 52.0, 27.7, 22.2,
column (4.6 mm
length: 254 nm, flow rate: 1.0 mL/min, retention time: 40.0 min
f
, 250 mm), n-hexane/isopropanol¼10:1, wave-
16.3; IR (neat) 1755, 1665, 1406, 1244, 1063, 799 cmꢀ1; MS [EI (þ)]:
m/z calcd for C12H22NO6P [M]þ: 307.1185, found: 307.1191; HPLC
(trans), 48.7 min (cis).
chiracel AD column (4.6 mm
f
,
250 mm), n-hexane/iso-
propanol¼10:1, wavelength: 254 nm, flow rate: 1.0 mL/min, re-
4.3.9. Diisopropyl (5S)-[N-benzyloxycarbonyl-(2S)-methoxycarbon-
tention time:31.0 min (trans), 35.2 min (cis).
ylpyrrolidin-5-yl]phosphonate (5bt). Colorless oil; ½a D20
ꢀ10.1 (c
ꢃ
3.6, EtOH, 85% de); 1H NMR (400 MHz, CDCl3)
d
7.50e7.08 (m,
4.4. Decarboxylation of 5bp
5H), 5.30e4.60 (m, 4H), 4.48e3.85 (m, 2H), 3.85e3.37 (m, 3H),
2.72e1.85 (m, 4H), 1.50e1.11 (m, 12H); 13C NMR (100 MHz,
To a solution of 5bp (1.945g, 5.27 mmol, 78% de) in a mixture of
THF and water (1:1, 50 mL) was added NaOH (0.422 g, 10.54 mmol).
After stirred for 12 h at room temperature, to the resulting mixture
was acidified by conc. HCl. Organic portion was extracted with ethyl
acetate (3ꢂ30 mL). Combined organic layer was dried over MgSO4
and then the solvent was removed under reduced pressure to give
the corresponding acid 7bp.
CDCl3)
d 172.3, 154.7, 136.1, 128.3, 127.9, 127.8, 71.7, 67.4, 60.1,
55.3, 51.9, 24.4, 23.9, 14.1; IR (neat) 1752, 1717, 1350, 1244, 1013,
772 cmꢀ1
;
MS [EI (þ)]: m/z calcd for C20H30NO7P [M]þ:
427.1760, found: 427.1758; HPLC chiralpak AD column
(4.6 mm
f
, 250 mm), n-hexane/isopropanol¼10:1, wavelength:
254 nm, flow rate: 1.0 mL/min, retention time: 12.8 min (cis),
17.8 min (trans).
The 7bp and 2,6-lutidine (0.798 mL, 6.85 mmol) were placed in
a beaker type cell containing a stirring bar. Methanol (50 mL) was
added and the mixture was stirred at 0 ꢁC. Graphite anode
(10 cmꢂ5 cm) and platinum cathode (10 cmꢂ5 cm) were fitted and
a 3 F/mol of electricity was passed through. The solvent was
evaporated and to the residue was added saturated aqueous NaCl
(50 mL). The mixture was extracted with ethyl acetate (3ꢂ50 mL)
and the combined organic layer was dried over anhydrous MgSO4
and filtered. The solvent was removed under vacuo to give the
corresponding methoxylated compound 8bp.
4.3.10. Di-n-butyl (5S)-[N-benzyloxycarbonyl-(2S)-methoxycarbon-
ylpyrrolidin-5-yl]phosphonate (5bu). Colorless oil; ½a D20
þ2.4 (c 5.6,
ꢃ
EtOH, 75% de); 1H NMR (400 MHz, CDCl3)
d 7.42e7.22 (m, 5H),
5.29e4.95 and 4.48e4.25(m, 4H), 4.25e3.90 (m, 4H), 3.77e3.45 (m,
3H), 2.81e1.85 (m, 4H), 1.70e1.56 (m, 2H), 1.56e1.28 (m, 2H),
0.93e0.89 (m, 6H); 13C NMR (100 MHz, CDCl3)
d 171.7, 154.4, 136.0,
128.2, 127.9, 127.5, 66.9, 65.6, 59.9, 54.8, 51.8, 32.4, 29.4, 26.5, 18.5,
13.4; IR (neat) 1759, 1717, 1352, 1248, 1030, 752 cmꢀ1; MS [EI (þ)]:
m/z calcd for C22H34NO7P [M]þ: 455.2073, found: 455.2055.
To a stirred solution of 8bp (0.731 g, 2.14 mmol) in CH2Cl2
(15 mL) was added Et3SiH (0.410 mL, 2.57 mmol) and MeSO3H
(0.208 mL, 3.21 mmol) under nitrogen. After stirring for 4 h at room
temperature, to the resulting mixture was added saturated aqueous
HPLC chiralpak AD column (4.6 mmf, 250 mm), n-hexane/iso-
propanol¼10:1, wavelength: 254 nm, flow rate: 1.0 mL/min, re-
tention time: 11.9 min (cis), 18.4 min (trans).

9416
S. Hirata et al. / Tetrahedron 67 (2011) 9411e9416
NaHCO3 (20 mL). The mixture was extracted with ethyl acetate
(3ꢂ50 mL) and the combined organic layer was dried over anhy-
drous MgSO4 and filtered. The solvent was removed under vacuo
and the residue was purified using a silica gel column chromatog-
raphy to give diethyl N-benzoylpyrrolidine-(2R)-phosphonate
(6bp) in 50% yield from 5bp.
extracted with CH2Cl2 (3ꢂ20 mL). The combined organic layer was
dried over MgSO4 and the solvent removed under reduced pres-
sure. The residue was purified by silica gel column chromatography
(AcOEt/methanol¼10:1) to afford 11ap as a colorless oil (259 mg,
35% yield from 5ap).
4.7.1. Tetraethyl (2R,5R)-[N-benzoylpyrrolidin-2,5-diyl]phosphonate
4.4.1. Diethyl
(2S)-(N-benzyloxycarbonylpyrrolidin-2-yl)phospho-
[(R,R)-11ap]. Yellow oil;
½
a 2D0
ꢃ
ꢀ25.5 (c 1.4, EtOH, (S,S):(R,R):
nate (6bp). Colorless oil; ½a D20
ꢃ
þ25.3 (c 2.3, EtOH, 79% ee); 1H NMR
meso¼26:68:6); 1H NMR (400 MHz, CDCl3)
d 7.75e7.33 (m, 5H),
(400 MHz, CDCl3)
d
7.46e7.10 (m, 5H), 5.23e5.01 (m, 2H),
4.78e3.52 (m, 10H), 2.81e2.00 (m, 4H), 1.45e0.88 (m, 12H); 13C
4.38e3.83 (m, 5H), 3.65e3.33 (m, 2H), 2.31e1.62 (m, 4H), 1.38e1.11
NMR (100 MHz, CDCl3) d 171.3, 136.7, 130.4, 128.1, 128.1, 62.2, 52.2,
(m, 6H); 13C NMR (100 MHz, CDCl3)
d
154.7, 136.4, 128.1, 127.7, 127.6,
26.9, 16.4; IR (neat) 1651, 1362, 1240, 1019, 963 cmꢀ1; MS [EI (þ)]:
66.8, 61.9, 53.3, 46.4, 25.2, 16.1, 6.2; IR (neat) 1717, 1699, 1362, 1244,
m/z calcd for C19H31NO7P2 [M]þ: 447.1576, found: 447.1573; HPLC
1058, 768 cmꢀ1; MS [EI (þ)]: m/z calcd for C16H24NO5P [M]þ:
AS coating type column (4.6 mm
wavelength: 254 nm, flow rate: 1.0 mL/min, retention time:
30.5 min (S,S), 33.4 min (R,R), 50.9 min (meso).
f
, 500 mm), n-hexane/EtOH¼10:1,
341.1392, found: 341.1390; HPLC Chiralcel OJ-H column (4.6 mm
f,
250 mm), n-hexane/isopropanol¼10:1, wavelength: 254 nm, flow
rate: 1.0 mL/min, retention time: 14.2 min (S), 19.7 min (R).
Acknowledgements
4.5. Deprotection of 6bp
This work was supported by a Grant-in-Aid for Scientific Re-
search on Innovative Areas ‘Molecular Activation Directed toward
Straightforward Synthesis’, and a Grant-in-Aid for Young Scientists
(B) from the Ministry of Education, Science, Sports and Culture,
Japan.
Under a hydrogen atmosphere, to a solution of 6bp (2.148 g,
6.29 mmol) and triethylamine (0.877 mL, 6.29 mmol) in methanol
(20 mL) was added 10% palladium-carbon (0.107 g). After stirring at
room temperature for 12 h, the resulting mixture was filtered by
Celite. The filtrate was concentrated under reduced pressure to give
diethyl (2S)-(pyrrolidin-2-yl)phosphonate (9p)3c in 66% yield.
References and notes
4.5.1. Diethyl (2S)-(pyrrolidin-2-yl)phosphonate (9p). Colorless oil;
a 2D0
ꢃ
þ6.82 (c 1.45, EtOH, 78% ee); 1H NMR (400 MHz, CDCl3)
1. (a) Allen, J. G.; Atherton, F. R.; Hall, M. J.; Hassal, C. H.; Holmes, S. W.; Lambert,
R. W.; Nisbet, L. J.; Ringrose, P. S. Nature 1978, 272, 56e58; (b) Atherton, F. R.;
Hassall, C. H.; Lambert, R. W. J. Med. Chem. 1986, 29, 29e40; (c) Hirschmann, R.;
Smith, A. B., III; Taylor, C. M.; Benkovic, P. A.; Taylor, S. D.; Yager, K. M.;
Sprengeler, P. A.; Benkovic, S. J. Science 1994, 265, 234e237; (d) Smith, A. B.;
Yager, K. M.; Taylor, C. M. J. Am. Chem. Soc. 1995, 117, 10879e10888; (e) Alonso,
E.; Alonso, E.; Solís, A.; del Pozo, C. Synlett 2000, 698e700.
½
d
4.25e4.08 (m, 4H), 3.40e3.27 (m, 1H), 3.11e3.00 (m, 1H),
3.00e2.89 (m, 1H), 2.50e2.30 (s, 1H), 2.12e1.70 (m, 4H), 1.34 (t,
J¼6.8 Hz, 6H); MS [EI (þ)]: m/z calcd for C8H18NO3P [M]þ: 207.1025,
found: 207.1012; HPLC Chiralcel AY-H column (4.6 mmf, 250 mm),
n-hexane/EtOH¼10:1, wavelength: 254 nm, flow rate: 1.0 mL/min,
2. Representative reviews, see: (a) Yokomatsu, T.; Yamaguchi, T.; Shibuya, S. Yuki
Gosei Kagaku Kyokaishi 1995, 53, 881e892; (b) Shibuya, S. Yakugaku Zasshi
2004, 124, 725e749; (c) Ordonez, M.; Rojas-Cabrera, H.; Cativiela, C. Tetrahedron
retention time: 27.1 min (R), 46.9 min (S).
ꢀ~
2009, 65, 17e49.
4.6. Preparation of diisopropyl (2R)-(N-benzoylpyrrolidin-2-
yl)phosphonate [(R)-6at]
3. A representative recent review, see: (a) Moonen, K.; Laureyn, I.; Stevens, C. V.
Chem. Rev. 2004, 104, 6177e6215; (b) Representative literatures, see: Jacquier,
R.; Ouazzani, F.; Roumestant, M.-J.; Viallefont, P. Phosphorus Sulfur 1988, 36,
€
73e77; (c) Groth, U.; Richter, L.; Schollkopf, U. Tetrahedron 1992, 48, 117e122;
In a similar manner to preparation of 6bp from 5bp, diisopropyl
(5R)-[N-benzoyl-(2S)-methoxycarbonylpyrrolidin-2-yl]phospho-
nate (5at) was transformed into diisopropyl (2R)-(N-benzyolpyr-
rolidin-2-yl)phosphonate [(R)-6at] in 32% yield.
(d) Katritzky, A. R.; Cui, X.-L.; Yang, B.; Steel, P. J. J. Org. Chem. 1999, 64,
1979e1985; (e) Amedjkouh, M.; Westerlund, K. Tetrahedron Lett. 2004, 45,
5175e5177; (f) Kaname, M.; Arakawa, Y.; Yoshifuji, S. Tetrahedron Lett. 2001, 42,
2713e2716; (g) Davis, F. A.; lee, S. H.; Xu, H. J. Org. Chem. 2004, 69, 3774e3781;
(h) Wuggenig, F.; Schweifer, A.; Mereiter, K.; Hammerschmidt, F. Eur. J. Org.
Chem. 2011, 1870e1879.
4. Onomura, O.; Kirira, P. G.; Tanaka, T.; Tsukada, S. Tetrahedron 2008, 64,
7498e7503.
4.6.1. Diisopropyl (2R)-(N-benzoylpyrrolidin-2-yl)phosphonate [(R)-
6at]. Colorless oil; ½a D20
ꢃ
ꢀ49.4 (c 1.2, EtOH, 83% ee); 1H NMR
5. Arbusov reaction of electrochemically prepared N,O-acetal with phosphites: (a)
Shono, T.; Matsumura, Y.; Tsubata, K. Tetrahedron Lett. 1981, 22, 3249e3252; (b)
Shono, T.; Matsumura, Y.; Tsubata, K.; Uchida, K.; Kanazawa, T.; Tsuda, K. J. Org.
Chem. 1984, 49, 3711e3716; (c) Renaud, P.; Seebach, D. Helv. Chim. Acta 1986, 69,
1704e1710.
(400 MHz, CDCl3) d 7.82e7.31 (m, 5H), 4.91 and 4.29e4.05 (s and m,
4H), 3.83e3.31 (m, 3H), 2.38e1.65 (m, 4H), 1.45e1.12 (m, 6H); 13C
NMR (100 MHz, CDCl3) 170.3, 130.3, 128.5, 128.2, 127.5, 62.2, 52.5,
d
50.3, 25.6, 25.1, 16.3; IR (neat) 1640, 1397, 1246, 1028, 968,
6. (a) Shono, T.; Matsumura, Y.; Tsubata, K.; Sugihara, Y.; Yamane, S.-I.; Kanazawa,
T.; Aoki, T. J. Am. Chem. Soc. 1982, 104, 6697e6703; (b) Shono, T.; Matsumura, Y.;
Kanazawa, T.; Habuka, M.; Uchida, K.; Toyoda, K. J. Chem. Res., Synop. 1984,
320e321; J. Chem. Res., Miniprint 1984, 2873e2889; (c) Asada, S.; Kato, M.; Asai,
K.; Ineyama, T.; Nishi, S.; Izawa, K.; Shono, T. J. Chem. Soc., Chem. Commun. 1989,
486e488; (d) Wong, P. L.; Moeller, K. D. J. Am. Chem. Soc. 1993, 115,
791 cmꢀ1; MS [EI (þ)]: m/z calcd for C15H22NO4P [M]þ: 311.1287,
found: 311.1312; HPLC Chiralcel OJ-H column (4.6 mmf, 250 mm),
n-hexane/isopropanol¼10:1, wavelength: 254 nm, flow rate:
1.0 mL/min, retention time: 17.0 min (R), 28.9 min (S).
ꢀ
ꢁ
11434e11435; (e) Celimene, C.; Dhimane, H.; Lhommet, G. Tetrahedron 1998, 54,
10457e10468.
4.7. Preparation of C2-symmetrical (N-benzoylpyrrolidin-2,5-
diyl)phosphonate
7. Recoveries of starting methoxylated compounds caused low yields.
8. In case of N-tert-butoxycarbonylated proline 2d, deprotection of the tert-bu-
toxycarbonyl group occurred.
9. (a) Iwasaki, T.; Horikawa, H.; Matsumoto, K.; Miyoshi, M. J. Org. Chem. 1979, 44,
1552e1554; (b) Shono, T.; Matsumura, Y.; Onomura, O.; Sato, M. J. Org. Chem.
1988, 53, 4118e4121; (c) Matsumura, Y.; Wanyoike, G. N.; Onomura, O.; Maki, T.
Electrochim. Acta 2003, 48, 2957e2966; (d) Minato, D.; Mizuta, S.; Kuriyama,
M.; Matsumura, Y.; Onomura, O. Tetrahedron 2009, 65, 9742e9748.
10. Diastereoselectivity in these decarboxylative methoxylation was not clear.
11. Hydrolysis of enantiomerically enriched (S)-9p and successive recrystallization
of the obtained acid might afford enantiomerically pure (S)-(pyrrolidine-2-yl)
phosphonic acid.3f,h
In a similar manner to preparation of 8bp from 5bp, diethyl
(5R)-[N-benzoyl-(2S)-methoxycarbonylpyrrolidin-5-yl]phosphonate
(5ap) was transformed into diethyl (2R)-[N-benzoyl-5-methox-
ypyrrolidin-2-yl]phosphonate (8ap). Under an argon atmosphere,
BF3$OEt2 (0.246 mL, 2 mmol) was added dropwise to the solution of
8ap (341 mg, 1 mmol) and triethyl phosphite 4p (332 mg, 2 mmol)
in CH2Cl2 (5 mL) at room temperature. After stirred for 12 h, the
solution was poured in saturated aqueous NaCl (10 mL) and
12. Although similarly 8at was transformed into the corresponding tetraisopropyl
ester, its stereochemistry could not be determined.