Chemical conversion of cyclic α-amino acids to cyclic α-aminophosphonic acids

Article abstract of DOI:10.1248/cpb.49.531

The oxidative decarboxylation of cyclic α-amino acids having urethane-type N-protecting groups with lead tetraacetate [Pb(OAc)₄] gave 2-hydroxy derivatives, which were transformed into the corresponding α-aminophosphonic acid esters by treatment of trialkyl phosphites in the presence of Lewis acids. Deprotection and ester cleavage of the products in the usual manner afforded cyclic α-aminophosphonic acids. The convenient chemical conversion of five- and six-membered cyclic α-amino acids to the corresponding cyclic α-aminophosphonic acids has been accomplished.

Full text of DOI:10.1248/cpb.49.531

May 2001
Chem. Pharm. Bull. 49(5) 531—536 (2001)
531
a
Chemical Conversion of Cyclic -Amino Acids to Cyclic
a
-Aminophosphonic Acids
Mamoru KANAME, Hironori MASHIGE, and Shigeyuki YOSHIFUJI*
Faculty of Pharmaceutical Sciences of Hokuriku University, Ho-3, Kanagawa-machi, Kanazawa 920–1181, Japan.
Received October 19, 2000; accepted January 27, 2001
The oxidative decarboxylation of cyclic a-amino acids having urethane-type N-protecting groups with lead
tetraacetate [Pb(OAc)4] gave 2-hydroxy derivatives, which were transformed into the corresponding a-
aminophosphonic acid esters by treatment of trialkyl phosphites in the presence of Lewis acids. Deprotection and
ester cleavage of the products in the usual manner afforded cyclic a-aminophosphonic acids. The convenient
chemical conversion of five- and six-membered cyclic a-amino acids to the corresponding cyclic a-aminophos-
phonic acids has been accomplished.
Key words a-aminophosphonic acid; a-amino acid; phosphonylation; acyliminium ion; Lewis acid; decarboxylation
a-Aminophosphonic acids are believed to be phosphorus ment of the carboxylic acid moiety by hydroxy group or its
analogs of naturally occurring a-amino acids and have equivalents such as acetoxy group had been realized by using
found applications as potent active compounds with a wide two methods of oxidative decarboxylation: lead tetraacetate
range of biological activities as antibiotics,1) enzyme in- [Pb(OAc)4] oxidation13) of carboxylic acids and m-chloroper-
hibitors,2) pharmacological agents,2b,3) antiviral agents,4) and benzoic acid (m-CPBA) oxidation14) of active esters. We ap-
herbicides.5) Their negligible mammalian toxicity, and the plied these methods to N-protected amino acids (3a—e, 4a—
fact that they bear a very close chemical resemblance to their c) and their active esters (3f, g), as summarized in Table1.
amino carboxylic counterparts, make them remarkably im- L-Proline derivatives (3a—e) having various N-protecting
portant structural units of phosphonopeptides and pep- groups were oxidized with Pb(OAc)4 to the desired 2-hy-
tidomimetics.6) During the last two decades, considerable droxy compounds (5a—e) in good yields. N-Benzoyl (Bz)
efforts toward the synthesis of a-aminophosphonic acids product (5e) was contaminated with an inseparable equiva-
have been made.7) However, a simple and general synthetic lent of the ring-opened aldehyde (11e) (Chart 2). In the case
method for cyclic amino-type of compounds, such as phos- of the substrates having urethane-type N-protecting groups,
phonic acid analogs of 2-pyrrolidinecarboxylic acid (proline) production of such ring-opened aldehydes was not be de-
and 2-piperidinecarboxylic acid, is not relatively known, and tectable, but treatment of the product (5b) having N-benzyl-
most of the reported methods are about acyclic compounds. oxycarbonyl (Z) group, as an example, with hydroxylamine
The cyclic analogues can be viewed as useful tools for the afforded the corresponding ring-opened oxime (N-Z-4-
elucidation of conformational requirements of a receptor, aminobutanal oxime) in quantitative yield.
since the conformation is easily fixed. Many synthetic routes
Decarboxylation of the esters (3f, g) using m-CPBA gave
to a-aminophosphonic acids and their derivatives include a the corresponding hydroxy compounds (5b) in satisfactory
key step of nucleophilic phosphonylation to either performed yields. In comparison with the Pb(OAc)4 method, however,
or in situ generated imines (Schiff bases) or iminium ions.8) this method seems to be disadvantageous for our purpose,
Shono9) and co-workers reported the phosphonylation of N- because esterification of the starting amino acids is neces-
protected 2-methoxyamines using trialkyl phosphites in the sary. Therefore, oxidation of the 2-piperidinecarboxylic acid
presence of Lewis acids. Similar transformation of 2-benzo- derivatives (4a—c) was achieved with Pb(OAc)4. N-Z deriva-
triazolylpyrrolidine derivatives into pyrrolidine-2-phosphonic tive (4b) afforded only the hydroxy compound (6b) in high
acid esters was reported by Katritzky10) and co-workers. We yield, while in the case of two substrates (4a, c) N-protected
wish to report herein the convenient conversion of cyclic a- with trichloroethoxycarbonyl (Troc) or p-nitrobenzyloxycar-
amino acids to cyclic a-aminophosphonic acids through the bonyl (PNZ) group, the oxidation products, estimated as the
corresponding N-protected 2-hydroxyamines, with which hydroxy compounds, were very unstable and were com-
easy generation of acyliminium ions in the presence of Lewis pletely transformed into the enecarbamates (12a, c) by elimi-
acids would be expected. To our knowledge, only a few stud- nation of H2O during the purification. Therefore, these prod-
ies concerning the chemical conversion of naturally occur- ucts were immediately used for the next step without further
ring cyclic a-amino acid (proline or proline-containing purification.
dipeptide) into the corresponding phosphonic acid analogues
Next, conversion of the 2-hydroxy compounds (5, 6) into
have been published,11,12) and these are not systematic or de- the phosphonic acid derivatives (7, 8) was studied. Condi-
tailed studies. In this paper, we describe a systematic study tions for the generation of the acyliminium ions and subse-
on a simple route to a series of phosphonic acid analogues quent nucleophilic phosphonylation were examined with N-
from proline and 2-piperidinecarboxylic acid, as illustrated in Troc-2-hydroxypyrrolidine (5a) as a model substrate. Upon
Chart 1.
treatment with trialkyl phosphites in the presence of 1 or
Initially, we examined the transformation of commercially 1.5 mol equivalent of various Lewis acids in CH2Cl2 at room
available cyclic a-amino acids (1, 2) into the key intermedi- temperature, compound 5a was transformed into the corre-
ates of cyclic N-protected 2-hydroxyamines (5, 6). Displace- sponding 2-phosphonic acid esters (7aa—7ac) in variable
To whom correspondence should be addressed. e-mail: s-yoshifuji@hokuriku-u.ac.jp
© 2001 Pharmaceutical Society of Japan

532
Vol. 49, No. 5
Chart 1
Chart 3
Chart 2
Table 1. Oxidative Decarboxylation of Cyclic a-Amino Acid Derivatives (3, 4)
Substrate
Reactiona)
Entry
Product
Yield (%)
R1
R2
Methodb)
Time
1
2
3
4
5
6
7
8
9
3a (nϭ1)
3b
3c
3d
3e
3f
3g
4a (nϭ2)
Troc
Z
PNZ
Boc
Bz
Z
Z
Troc
Z
PNZ
H
H
H
H
H
A
A
A
A
A
B
B
A
A
A
48 h
48 h
48 h
20 h
48 h
24 h
24 h
48 h
3 d
5a
5b
5c
5d
5ee)
5b
5b
12a
6b
12c
97
93
Quant.
65
60
90
62
Quant.
87
PNPc)
DPd)
H
4b
4c
H
H
10
48 h
99
a) Reaction was carried out at room temperature. b) Method A: Pb(OAc)4 oxidation. Method B: m-CPBA oxidation. c) PNP: p-nitrophenyl. d) DP: 2,5-dioxo-1-pyrro-
lidinyl. e) A mixture of 5e and the ring-opened aldehyde (11e).
Table 2. Phosphonylation of Cyclic 2-Hydroxyamines (5, 6)
Substrate
Trialkyl phosphite
(R2)
Lewis acid
(mole eq)
Entry
Product
Yield (%)
R1
1
2
3
4
5
6
7
8
9
5a (nϭ1)
Troc
Me
TiCl4 (1.5)
7aa
68
62
57
87
71
55
67
65
46
66
52
60
BF3·OEt2 (1.5)
TMSOTf (1.0)
TMSOTf (1.5)
Et
Isopropyl
Me
7ab
7ac
7ba
7ca
8aa
8ab
8ac
8ba
5b
5c
6a (nϭ2)
Z
PNZ
Troc
TMSOTf (1.5)
TMSOTf (1.5)
Me
Et
Isopropyl
Me
10
11
12
6b
Z
yields. The results are summarized in Table 2. Production of
7aa by the reaction using a combination of trimethyl phos-
phite and trimethylsilyl trifluoromethanesulfonate (TMSOTf)
as a Lewis acid gave the best yield of 87%. As bulkiness of
the alkyl group in trialkyl phosphite increased, yield of the
product was reduced. Use of the other substrates having dif-
ferent N-protecting groups did not improve for yield of the
phosphonylation. Reaction of six-membered cyclic 2-hy-
droxy compounds (6a, b) with trialkyl phosphites proceeded
smoothly under the same conditions, but moderate yields
(46—66%) of the desired products (8) were obtained.
All the N-protected cyclic a-aminophosphonic acid esters
(7, 8) prepared above are new compounds, which were
characterized on the basis of their spectral data, especially by
observation of C–P spin couplings (1JCPϭ154.1—163.3 Hz)
of the C-2 carbon in 13C-NMR spectra. These N-protected
derivatives would be very important for the synthesis of
peptides and the related compounds containing these
aminophosphonic acids. N-tert-Butoxycarbonyl (Boc) group
is one of the most common amino protecting groups as well
as N-Z group in the field of amino acid chemistry.15) How-
ever, it is impossible to use the N-Boc group in our phospho-

May 2001
533
Table 3. Preparation of Cyclic a-Aminophosphonic Acids (9, 10)
Substrate
Method
a-Aminophosphonic acid
Yield (%)a)
R1
Deprotection
Ester cleavage
7aa (nϭ1)
7ba
7da
8aa (nϭ2)
8ba
8da
Troc
Z
Boc
Troc
Z
Zn/AcOH
H2/10% Pd–C
6 N HCl
6 N HCl
9
9
9
10
10
10
80
81
87
82
80
97
6 N HCl
6 N HCl
Zn/AcOH
H2/10% Pd–C
6 N HCl
6 N HCl
Boc
a) Yield of salt-free acid.
Experimental
All melting points were taken on a Yanagimoto micro melting point appa-
ratus and are uncorrected. MS and HRMS were obtained on a JEOL JMS-
DX300 or JMS-SX102A spectrometer. IR spectra were recorded on a Hi-
tachi 270-30 spectrophotometer. 1H-NMR spectra were obtained at 23 °C on
a JEOL PMX-60-SI, JNM-EX90A or JNM-GSX-400 spectrometer using
tetramethylsilane (TMS, d 0 ppm) or dioxane (d 3.70 ppm from TMS) as an
internal standard. 13C-NMR spectra were measured on a JEOL JNM-EX90A
or JNM-GSX-400 spectrometer using TMS or dioxane (d 67.4 ppm from
TMS) as an internal standard. The following abbreviations are used:
mϭmultiplet, qϭquartet, tϭtriplet, dϭdoublet, sϭsinglet, and brϭbroad,
dpϭdoublet (H–P or C–P multiplicity). Column chromatography was carried
out on silica gel (Kieselgel 60, 70—230 mesh, Merck) or alumina (alu-
minium oxide 90, 70—230 mesh, Merck).
N-Protection of Cyclic a-Amino Acids All the N-protected cyclic a-
amino acids were prepared from commercially available amino acids (1, 2)
by acylation with di-tert-butyl dicarbonate (Boc2O) or the corresponding
acid chlorides under the Shotten-Baumann reaction conditions (dioxane–
H2O, NaHCO3, 0 °C—room temperature).
Chart 4
nylation under a Lewis acid catalyst. Therefore, we tried a
conversion of the N-Z products into the N-Boc derivatives by
the method developed for that of a-amino acids.16) The five-
and six-membered cyclic N-Z compounds (7ba, 8ba) were
treated with Boc reagent (Boc2O) in methanol under hy-
drogenolytic conditions (Pd-C/H2) to furnish the expected N-
Boc derivatives 7da and 8da in 97% and 74% yield, respec-
tively (Chart 4).
Finally, the cyclic a-aminophosphonic acids were obtained
in a two-step sequence from N-protected a-aminophosphonic
acid methyl esters (7, 8) in good yields (Table 3). Deprotec-
tion of the N-protecting groups by the appropriate procedure
utilizing in amino acid chemistry15,17) and hydrochloric acid-
catalyzed hydrolysis of the methyl phosphonate moieties fol-
lowed by desalting to the salt-free aminophosphonic acids
were successfully achieved. The structure of target com-
pounds (9, 10) was supported by their analytical and spectral
data, which were in accordance with literature data of the
compounds (9, 10) synthesized from a different non-amino
acids source.18,19)
Thus, the novel chemical conversion of five- and six-mem-
bered cyclic a-amino acids to cyclic a-aminophosphonic
acids and their N-protected derivatives has been established.
The route described in this paper is potentially applicable to
the preparation of optical active analogs of these compounds.
N-Protected cyclic 2-hydroxyamines were used in our ap-
proach for the formation of acyliminium ions. More recently,
direct formation of the acyliminium ions from N-acylated
cyclic a-amino acids by the novel oxidation with a combina-
tion of (diacetoxyiodo)benzene (DIB) and iodine has been
reported by Boto20) and co-workers, who applied the acylim-
inium ions to C–C bond formation for alkaloid synthesis.
1-(2,2,2-Trichloroethoxycarbonyl)pyrrolidine-2-carboxylic Acid (3a)21)
Yield quant.
:
1-(Benzyloxycarbonyl)pyrrolidine-2-carboxylic Acid (3b)22): Yield 88%.
1-(4-Nitrobenzyloxycarbonyl)pyrrolidine-2-carboxylic Acid (3c)23): Yield
quant.
1-(tert-Butoxylcarbonyl)pyrrolidine-2-carboxylic Acid (3d)24): Yield 84%.
1-Benzoylpyrrolidine-2-carboxylic Acid (3e)25): Yield quant.
1-(2,2,2-Trichloroethoxycarbonyl)piperidine-2-carboxylic Acid (4a): Yield
66%, colorless prisms, mp 117—119 °C (benzene–hexane). MS m/z: 303
(Mϩ), 305 (Mϩϩ2), 307 (Mϩϩ4), 309 (Mϩϩ6). IR (KBr) cmϪ1: 3172 (OH),
1740, 1684 (CϭO). 1H-NMR (CDCl3) [60 MHz] d: [1.15—2.01 (5H, m),
2.01—2.58 (1H, m), C3-H2, C4-H2, C5-H2], 2.75—3.53 (1H, m, C6-Ha),
3.88—4.40 (1H, m, C6-Hb), 4.79 (2H, s, OCH2CCl3), 4.85—5.16 (1H, m,
C2-H), 10.55 (1H, br s, COOH).
1-(Benzyloxycarbonyl)piperidine-2-carboxylic Acid (4b)26): Yield 76%.
1-(4-Nitrobenzyloxycarbonyl)piperidine-2-carboxylic Acid (4c): Yield
97%, colorless prisms, mp 138—140 °C (65% MeOH–H2O). MS m/z: 308
(Mϩ). IR (KBr) cmϪ1: 3088 (OH), 1740, 1662 (CϭO). 1H-NMR (CDCl3)
[60 MHz] d: 1.80—2.67 (6H, m, C3-H2, C4-H2, C5-H2), 2.67—3.48 (1H, m,
C6-Ha), [3.93—4.17 (0.6H, br), 4.17—4.40 (0.4H, br), C6-Hb], 4.80—5.17
(1H, br, C2-H), 5.33 (2H, br s, OCH2Ar), [7.53 (2H, d, Jϭ9.0 Hz), 8.29 (2H,
d, Jϭ9.0 Hz), aromatic protons] 10.90 (1H, br s, COOH).
1-Benzyl 2-(4-Nitrobenzyl) Pyrrolidine-1,2-dicarboxylate (3f)27)
A
solution of N-Z proline (3b) (4.99 g, 20 mmol) in DMF (25 ml) was stirred
under cooling at 0 °C. 4-Nitrophenol (3.06 g, 22 mmol) and 1,3-dicyclo-
hexylcarbodiimide (DCC, 4.33 g, 21 mmol) were added to the solution. The
reaction mixture was allowed to warm to room temperature, and stirring was
continued for 3 h. The yellow suspension of DCU was filtered off and
washed with DMF (20 ml). The filtrate was diluted with benzene–MeOH
(800 ml—3 ml) and H2O (700 ml). The solution was transferred to a separa-
tory funnel and the organic layer was separated, washed with H2O
(100 mlϫ5), dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The residue was purified by recrystallization. Yield 62%, colorless
needles, mp 94—95 °C (EtOH) (lit.27) mp 94—96 °C). MS m/z: 370 (Mϩ).
1
IR (KBr) cmϪ1: 1770, 1702 (CϭO). H-NMR (CDCl3) [60 MHz] d: 1.78—
2.65 (4H, m, C3-H2, C4-H2), 3.48—3.87 (2H, m, C5-H2), 4.42—4.78 (1H, m,
C2-H), 4.89—5.53 (2H, m, OCH2Ar), [6.78—7.32 (2H, m), 7.40 (5H, s),
8.02—8.45 (2H, m), aromatic protons].

534
1-Benzyl 2-(2,5-Dioxo-1-pyrrolidinyl) Pyrrolidine-1,2-dicarboxylate
Vol. 49, No. 5
tert-Butyl 2-Hydroxypyrrolidine-1-carboxylate (5d): Colorless oil. MS
(3g)28) A solution of N-Z proline (3b) (9.63 g, 38.6 mmol) in DMF (50 ml) m/z: 187 (Mϩ). IR (neat) cmϪ1: 3448 (OH), 1706 (CϭO). 1H-NMR (CDCl3)
was stirred under cooling at 0 °C. N-Hydroxysuccinimide (4.44 g, 38.6 [400 MHz] d: 1.47—1.55 (10H, m, tert-butyl protons, OH), 1.72—2.17 (4H,
mmol) and DCC (8.77 g, 42.5 mmol) were added to the solution. The reac- m, C3-H2, C4-H2), 3.14—3.36 (1H, m, C5-Ha), 3.40—3.58 (1H, m, C5-Hb),
tion mixture was allowed to warm to room temperature, and stirring was 5.25—5.57 (1H, m, C2-H).
continued for 24 h. The white suspension of DCU was filtered off and
1-Benzoyl-2-hydroxypyrrolidine (5e) and 4-(benzoylamino)butanal (11e):
washed with DMF (50 mlϫ2). The filtrate was concentrated under reduced Pale yellow oil was a mixture of 5e and 11e (80 : 20). MS m/z: 192 (MHϩ).
pressure. The residue was diluted with isoPrOH, the precipitate (DCU) was IR (neat) cmϪ1: 3319 (OH, NH), 1722, 1639 (CϭO). 1H-NMR (CDCl3)
filtered off and washed with isoPrOH (10 ml). The filtrate was diluted with [60 MHz] d: 1.64—2.41 (4.4H, m, OH, 5e C3-H, 5e C4-H, 11e C3-H),
benzene (350 ml), and washed with H2O (100 mlϫ3), dried over anhydrous 2.41—2.78 (0.4H, m, 11e C2-H), 3.23—4.00 (2H, m, 5e C4-H, 11e C5-H),
Na2SO4, and concentrated under reduced pressure. The residue was purified
5.03—5.96 (0.8H, m, 5e C2-H), 7.23—7.69 (5.2H, m, aromatic protons,
by recrystallization. Yield 84%, colorless needles, mp 88—89.5 °C (ben- NH), 9.79 (0.2H, s, CHO).
zene–hexane) (lit.28) mp 90 °C). MS m/z: 346 (Mϩ). IR (KBr) cmϪ1: 1816,
2,2,2-Trichloroethyl 1,2,3,4-Tetrahydropyridine-1-carboxylate (12a): Pale
1
1786, 1746, 1708 (CϭO). H-NMR (CDCl3) [60 MHz] d: 1.72—2.55 (4H, yellow oil. MS m/z: 258 ([MH]ϩ), 260 ([MHϩ2]ϩ), 262 ([MHϩ4]ϩ, 264
m, C3-H2, C4-H2), 2.80 (4H, s, COCH2CH2CO), 3.35—3.75 (2H, m, C5-H2), ([MHϩ6]ϩ). IR (neat) cmϪ1 1726, 1658 (CϭO). 1H-NMR (CDCl3)
:
4.50—4.79 (1H, m, C2-H), 5.14 and 5.19 (2H (1 : 1), s, OCH2Ar), 7.36 (5H,
s, aromatic protons).
[60 MHz] d: 1.67—2.33 (4H, m, C4-H2, C5-H2), 3.17—3.88 (2H, br, C6-H2),
4.81 (2H, s, OCH2CCl3), 4.82—5.27 (1H, m, C3-H), 6.87 (1H, d, Jϭ8.4 Hz,
Oxidative Decarboxylation of N-Protected Cyclic a-Amino Acids (3, C2-H).
4) Method A) Modified Hunsdiecker Reaction using Pb(OAc)4: A solu-
Benzyl 2-Hydroxypiperidine-1-carboxylate (6b): Pale yellow oil. MS m/z:
tion of an N-protected cyclic a-amino acid (3a—e, 4a—c, 50 mmol) in dry 235 (Mϩ). IR (neat) cmϪ1: 3460 (OH), 1706 (CϭO). 1H-NMR (CDCl3)
benzene (250 ml) was added to Pb(OAc)4 (1.2 mol eq), and the mixture was [60 MHz] d: 1.10—2.23 (7H, m, C3-H2, C4-H2, C5-H2, OH), 2.70—3.47
vigorously stirred at room temperature. After the reaction was completed, (1H, m, C6-Ha), 3.77—4.34 (1H, m, C6-Hb), 4.72—5.28 (1H, br, C2-H),
saturated aqueous NaCl (200 ml) was added dropwise to the reaction mix-
ture under ice-cooling. The mixture was vigorously stirred for 30 min to de-
5.18 (2H, br s, OCH2-Ar), 7.37 (5H, brs, aromatic protons).
4-Nitrobenzyl 1,2,3,4-Tetrahydropyridine-1-carboxylate (12c): Colorless
compose the oxidant, and the precipitate was collected by filtration with oil. MS m/z: 262 (Mϩ). IR (neat) cmϪ1: 1709 (CϭO). 1H-NMR (CDCl3)
Hyflo Super-cel (Celite Co.) and washed with AcOEt (250 ml). The filtrate [60 MHz] d: 1.5—2.28 (4H, m, C4-H2, C5-H2), 3.50—3.78 (2H, m, C6-H2),
was transferred to a separatory funnel and the organic layer was separated. 4.72—5.16 (1H, m, C3-H), 5.28 (2H, s, OCH2Ar), 6.82 (1H, d, Jϭ8.5 Hz,
The aqueous layer was extracted with AcOEt (250 ml). The combined or- C2-H), [7.52 (2H, d, Jϭ9.0 Hz), 8.22 (2H, d, Jϭ9.0 Hz), aromatic protons].
ganic solution was washed successively with saturated aqueous NaHCO3,
and saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated lution of the N-protected cyclic 2-hyroxyamines (5, 6) (10 mmol) in CH2Cl2
in vacuo. (60 ml) was treated with trialkyl phosphite (25 mmol) and TMSOTf (or other
Method B) m-CPBA Oxidation of the Activated Esters (3f, g): To a solu- Lewis acid) (15 mmol) at 0 °C. After 15 min the solution was allowed to
tion of the activated ester (3f, g) (1 mmol) in dioxane (24 ml), 0.1 M aqueous warm to room temperature and was stirred for a further 12 h. Water (5 ml)
NaHCO3 (12 ml) and 0.1 M aqueous Na2CO3 (12 ml), m-CPBA (2.0 mmol) was added dropwise to the reaction mixture under ice-cooling. After the
was added. The solution was allowed to stand for 3 h at room temperature, mixture was vigorously stirred for 30 min, it was added to AcOEt (150 ml)
and was treated with Na2CO3 (370 mg). After the reaction mixture was and saturated aqueous NaHCO3 (100 ml), and the organic layer (upper layer)
stirred for 24 h, H2O (30 ml) was added. The aqueous solution was extracted was separated. The aqueous layer was extracted with AcOEt (100 ml). The
with CHCl3 (80 mlϫ3). The combined organic solution was washed with combined organic solution was washed with saturated aqueous NaCl, dried
H2O (50 ml), dried over anhydrous Na2SO4, and concentrated in vacuo. over anhydrous Na2SO4, and concentrated in vacuo. The residue was treated
Phosphonylation of N-Protected Cyclic 2-Hyroxyamines (5, 6) A so-
2,2,2-Trichloroethyl 2-Hydroxypyrrolidine-1-carboxylate (5a): Pale yel- on silica gel (AcOEt–hexane) [or alumina (CHCl3–hexane)] by column
low oil. MS m/z: 260 ([MϪ1]ϩ), 262 ([Mϩ1]ϩ), 264 ([Mϩ3]ϩ). IR (neat) chromatography to give the phosphonylated compounds (7, 8).
cmϪ1: 3480 (OH), 1724 (CϭO). 1H-NMR (CDCl3) [60 MHz] d: 1.75—2.31
2,2,2-Trichloroethyl 2-(Dimethoxyphosphoryl)pyrrolidine-1-carboxylate
(4H, m, C3-H2, C4-H2), 2.85—4.01 (3H, m, C5-H2, OH), 4.78 (2H, s, (7aa): Yield 87%, colorless oil. MS m/z: 353 (Mϩ), 355 (Mϩϩ2), 357
OCH2CCl3), 5.43—5.83 (1H, m, C2-H).
(Mϩϩ4), 359 (Mϩϩ6). IR (neat) cmϪ1: 1724 (CϭO). 1H-NMR (CDCl3)
Benzyl 2-Hydroxypyrrolidine-1-carboxylate (5b): Colorless oil. MS m/z: [90 MHz] d: 1.70—2.67 (4H, m, C3-H2, C4-H2), 3.34—4.18 (2H, m, C5-H2),
220 ([MϪ1]ϩ). IR (neat) cmϪ1: 3425 (OH), 1705 (CϭO). 1H-NMR (CDCl3) 3.78 (3H, dP, JHPϭ10.6 Hz, OCH3), 3.81 (3H, dP, JHPϭ10.6 Hz, OCH3),
[60 MHz] d: 1.48—2.28 (5H, m, C3-H2, C4-H2, OH), 3.02—3.82 (2H, m, 4.21—4.52 (1H, br, C2-H), 4.52—5.17 (2H, m, OCH2CCl3). 13C-NMR
C5-H2), 5.15 (2H, s, OCH2Ar), 5.33—5.72 (1H, m, C2-H), 7.34 (5H, s, aro- (CDCl3) [22.5 MHz] d: 23.30 and 24.29 (t, C3), 26.85 (t, C4), 46.93 (t, C5),
matic protons). This sample was converted into the corresponding ring- [52.96 and 53.11 (qdP, 2JCPϭ6.7 Hz), 54.28 (qdP, 2JCPϭ6.0 Hz), OCH3],
opened oxime (N-Z-4-aminobutanal oxime) as follows.
53.36 (ddP, 1JCPϭ161.8 Hz, C2), 75.07 (t, OCH2CCl3), 95.59 (s, CCl3),
4-(Benzyloxycarbonylamino)butanal Oxime: A mixture of 2-hydroxy 153.20 (s, CϭO). HRMS m/z Calcd for C9H15NO5Cl3P: 352.9754 (Mϩ).
compound (5b) (664 mg, 3 mmol), hydroxylamine hydrochloride (211 mg, Found: 352.9761. Calcd for C7H9NO2Cl3: 243.9699 (MϩϪPO(OCH3)2).
3 mmol) and sodium acetate (369 mg, 4.5 mmol) in 65% aqueous EtOH Found: 243.9707. Calcd for C7H13NO4P: 206.0582 (MϩϪOCH2CCl3).
(15 ml) was refluxed in an oil bath for 2 h. The reaction solution was concen- Found: 206.0569.
trated under reduced pressure and the residue was dissolved in H2O (20 ml).
Benzyl 2-(Dimethoxyphosphoryl)pyrrolidine-1-carboxylate (7ba): Yield
The aqueous solution was extracted with ether (40 mlϫ2). The ether extracts 67%, colorless oil. MS m/z: 313 (Mϩ). IR (neat) cmϪ1: 1710 (CϭO). 1H-
were combined, washed with H2O (20 ml), dried over anhydrous Na2SO4, NMR (CDCl3) [60 MHz] d: 1.59—2.56 (4H, m, C3-H2, C4-H2), 3.26—3.73
and concentrated in vacuo to leave a white solid (quantitative yield). Recrys- (2H, m, C5-H2), 3.71 (6H, dP, JHPϭ10.7 Hz, 2ϫOCH3), 4.14—4.49 (1H, m,
tallization of the solid from benzene gave pure oxime (519 mg, 73%). White C2-H), 5.17 (2H, s, OCH2Ar), 7.37 (5H, br s, aromatic protons).
powder, mp 92—93 °C (benzene). (lit.13b) mp 94—95 °C). MS m/z: 236
4-Nitrobenzyl 2-(Dimethoxyphosphoryl)pyrrolidine-1-carboxylate (7ca):
(Mϩ). IR (KBr) cmϪ1: 3316 (OH, NH), 1682 (CϭO). 1H-NMR (CDCl3) Yield 65%, colorless oil. MS m/z: 358 (Mϩ). IR (neat) cmϪ1: 1708 (CϭO).
[400 MHz] d: 1.55—1.73 (2H, m, C3-H2), 2.14—2.25 and 2.30—2.45 (2H
1H-NMR (CDCl3) [400 MHz] d: 1.80—2.39 (4H, m, C3-H2, C4-H2), 3.30—
(1 : 9), m, C2-H2), 3.06—3.27 (2H, m, C4-H2), 5.09 (2H, s, OCH2Ar), 5.16 3.70 (2H, m, C5-H2), 3.76 (3H, dP, JHPϭ10.6 Hz, OCH3), 3.80 (3H, dP,
and 5.49 (1H (9 : 1), br s, OH), 6.71 (1H, t, Jϭ5.5 Hz, C1-H), 7.25—7.40
JHPϭ10.6 Hz, OCH3), 4.30—4.34 (1H, m, C2-H), 5.26 (2H, s, OCH2Ar),
(5H, m, aromatic protons), 8.74—9.50 (1H, br, NH). 13C-NMR (CDCl3) [7.58 (2H, d, Jϭ9.0 Hz), 8.22 (2H, d, Jϭ9.0 Hz), aromatic protons]. 13C-
[100 MHz] d: 22.21 (t, C3), 26.23 and 26.69 (t, C2), 40.12 and 40.35 (t, C4), NMR (CDCl3) [100 MHz] d: 23.42 and 24.44 (t, C3), 26.82 and 27.75 (t,
66.73 (t, OCH2Ar), [128.13 (d), 128.52 (d), 136.51 (s), aromatic carbons], C4), 46.84 and 47.15 (t, C5), 53.36 (ddP, 1JCPϭ163.3 Hz, C2), 52.96 (qdP,
151.05 and 151.46 (d, C1), 156.57 (s, COO).
2
2JCPϭ9.2 Hz, OCH3), 53.05 (qdP, JCPϭ9.1 Hz, OCH3), 65.79 (t, OCH2Ar),
4-Nitrobenzyl 2-Hydroxypyrrolidine-1-carboxylate (5c): Colorless oil. [123.74 (d), 128.08 (d), 144.03 (s), 147.60 (s), aromatic carbons], 154.57 (s,
MS m/z: 266 (Mϩ). IR (neat) cmϪ1: 3452 (OH), 1707 (CϭO). 1H-NMR CϭO).
(CDCl3) [60 MHz] d: 1.61—2.32 (4H, m, C3-H2, C4-H2), 3.16—3.46 (2H,
2,2,2-Trichloroethyl 2-(Diethoxyphosphoryl)pyrrolidine-1-carboxylate
m, C5-H2), 4.07—4.66 (1H, br, OH), 5.27 (2H, s, OCH2Ar), 5.32—5.72 (1H,
(7ab): Yield 71%, colorless oil. MS m/z: 381 (Mϩ), 383 (Mϩϩ2), 385
m, C2-H), [7.54 (2H, d, Jϭ8.7 Hz), 8.26 (2H, d, Jϭ8.7 Hz), aromatic pro- (Mϩϩ4), 387 (Mϩϩ6). IR (neat) cmϪ1: 1724 (CϭO). 1H-NMR (CDCl3)
tons].
[400 MHz] d: 1.32 (3H, t, Jϭ7.3 Hz, OCH2CH3), 1.34 (3H, t, Jϭ7.0 Hz,

May 2001
535
OCH2CH3), 1.90—2.40 (4H, m, C3-H2, C4-H2), 3.45—3.71 (2H, m, C5-H2),
4.04—4.27 (4H, m, 2ϫOCH2CH3), 4.27—4.43 (1H, br, C2-H), [4.51 (0.3H,
d, Jϭ11.0 Hz), 4.70 (0.7H, d, Jϭ11.7 Hz), OCHaCCl3], [4.82 (0.7H, d,
Jϭ12.1 Hz), 5.07 (0.3H, d, Jϭ11.7 Hz), OCHbCCl3]. 13C-NMR (CDCl3)
[100 MHz] d: 16.47 (q, OCH2CH3), 23.30 and 24.29 (t, C3), 26.81 and 27.50
methyl N-Z-a-aminophosphonate (7ba, 8ba) (12 mmol), Boc2O (15 mmol),
and 10% Pd-C (300 mg), under a hydrogen atmosphere (1 atm) in MeOH
(100 ml) was stirred at room temperature for 20 h. The reaction mixture was
filtered off and concentrated under reduced pressure to leave a colorless oil,
which was separated by column chromatography (SiO2, 3% MeOH–CHCl3)
to give the N-Boc analog (7da, 8da).
tert-Butyl 2-(Dimethoxyphosphoryl)pyrrolidine-1-carboxylate (7da):
Yield 97%, colorless oil. MS m/z: 279 (Mϩ). IR (neat) cmϪ1: 1700 (CϭO).
1H-NMR (CDCl3) [60 MHz] d: 1.49 (9H, s, tert-butyl protons), 1.63—2.80
(4H, m, C3-H2, C4-H2), 3.30—3.60 (2H, m, C5-H2), 3.80 (6H, dP, JHPϭ
10.5 Hz, 2ϫOCH3), 4.11—4.43 (1H, m, C2-H).
1
(t, C4), 46.89 and 47.13 (t, C5), 53.91 (ddP, JCPϭ163.3 Hz, C2), [62.39 (tdP,
2JCPϭ6.1 Hz), 62.52 (tdP, 2JCPϭ7.6 Hz), OCH2CH3], 75.09 (t, OCH2CCl3),
95.61 (s, OCH2CCl3), 153.29 (s, CϭO). HRMS m/z Calcd for
C11H19NO5Cl3P: 381.0067 (Mϩ). Found: 381.0076. Calcd for C7H9NO2Cl3:
243.9699 (MϩϪPO(OC2H5)2). Found: 243.9705. Calcd for C9H17NO4P:
234.0895 (MϩϪOCH2CCl3). Found: 234.0897.
2,2,2-Trichloroethyl 2-(Diisopropoxyphosphoryl)pyrrolidine-1-carboxy-
tert-Butyl 2-(Dimethoxyphosphoryl)piperidine-1-carboxylate (8da): Yield
74%, colorless oil. MS m/z: 293 (Mϩ). IR (neat) cmϪ1: 1696 (CϭO). 1H-
NMR (CDCl3) [60 MHz] d: 1.49 (9H, s, tert-butyl protons), 1.50—2.23
(6H, m, C3-H2, C4-H2, C5-H2), 2.85—3.47 (1H, m, C6-Ha), 3.78 (6H, dP,
late (7ac): Yield 55%, colorless oil. MS m/z: 409 (Mϩ), 411 (Mϩϩ2), 413
1
(Mϩϩ4), 415 (Mϩϩ6). IR (neat) cmϪ1: 1728 (CϭO). H-NMR (CDCl3)
[400 MHz] d: 1.21—1.39 (12H, m, 2ϫOCH(CH3)2), [1.88—2.00 (1H, m),
2.00—2.20 (1H, m), 2.20—2.37 (2H, m), C3-H2, C4-H2], 3.47—3.77 (2H, m,
C5-H2), 4.23—4.35 (1H, m, C2-H), 4.63—4.80 (2H, m, OCH(CH3)2), [4.33
(0.3H, d, Jϭ11.4 Hz), 4.67 (0.7H, d, Jϭ11.7 Hz), OCHaCCl3], [4.84 (0.7H,
d, Jϭ11.7 Hz), 5.12 (0.3H, d, Jϭ11.4 Hz), OCHbCCl3]. 13C-NMR (CDCl3)
J
HPϭ10.7 Hz, 2ϫOCH3), 3.70—4.28 (1H, m, C6-Hb), 4.40—4.97 (1H, m,
C2-H).
Deprotection of N-Protected Derivatives (7, 8) Deprotection of N-pro-
tected derivatives (7, 8) was achieved as follows.
3
[100 MHz] d: 23.82 and 23.95 (t, C3), 24.14 and 24.17 (qdP, JCPϭ7.7 Hz,
Deprotection of N-Troc Derivatives (7aa, 8aa): Activated zinc powder
(1.0 g) was added to a solution of N-Troc compound (5aa, 6aa) (2 mmol) in
acetic acid (12 ml). The suspension was stirred at room temperature for 3 d
and then filtered. The zinc powder was washed with a little acetic acid. The
filtrate and the washings were combined and concentrated in vacuo. The
residue was used for the next step.
OCH(CH3)2), 26.82 and 27.41 (t, C4), 46.84 and 46.98 (t, C5), 54.80 (ddP,
1JCPϭ163.2 Hz, C2), 71.11 and 71.24 (ddP, 2JCPϭ7.6 Hz, OCH(CH3)2), 75.09
(t, OCH2CCl3), 95.63 (s, CCl3), 153.26 (s, CϭO). HRMS m/z Calcd for
C13H23NO5Cl3P: 409.0380 (Mϩ). Found: 409.0380. Calcd for C7H9NO2Cl3:
243.9699 (MϩϪPO(O-isopropyl)2). Found: 243.9704.
2,2,2-Trichloroethyl 2-(Dimethoxyphosphoryl)piperidine-1-carboxylate
(8aa): Yield 46%, colorless oil. MS m/z: 367 (Mϩ), 369 (Mϩϩ2), 371
(Mϩϩ4), 373 (Mϩϩ6). IR (neat) cmϪ1: 1720 (CϭO). 1H-NMR (CDCl3)
[60 MHz] d: 1.14—2.47 (6H, m, C3-H2, C4-H2, C5-H2), 3.00—3.60 (1H, m,
C6-Ha), 3.79 (6H, dP, JHPϭ10.8 Hz, 2ϫOCH3), 3.98—4.44 (1H, m, C6-Hb),
4.44—5.00 (1H, m, C2-H), 4.80 (2H, s, OCH2CCl3). 13C-NMR (CDCl3)
[22.5 MHz] d: 20.05 and 20.11 (t, C3), [24.55 (t), 25.06 (t), C4, C5], 41.98 (t,
C6), 48.07 (ddP, JCPϭ154.4 Hz, C2), [52.78 (qdP, JCPϭ6.7 Hz), 52.88 (qdP,
2JCPϭ7.4 Hz), OCH3], 75.33 (t, OCH2CCl3), 95.53 (s, CCl3), 150.68 (s,
CϭO). HRMS m/z Calcd for C10H17NO5Cl3P: 366.9910 (Mϩ). Found:
366.9898. Calcd for C8H11NO2Cl3: 257.9855 (MϩϪPO(OCH3)2). Found:
257.9865.
Benzyl 2-(Dimethoxyphosphoryl)piperidine-1-carboxylate (8ba): Yield
60%, colorless oil. MS m/z: 327 (Mϩ). IR (neat) cmϪ1: 1704 (CϭO). 1H-
NMR (CDCl3) [60 MHz] d: 1.10—2.27 (6H, m, C3-H2, C4-H2, C5-H2),
2.97—3.52 (1H, m, C6-Ha), 3.69 (3H, dP, JHPϭ10.8 Hz, OCH3), 3.71 (3H,
dP, JHPϭ10.8 Hz, OCH3), 3.93—4.38 (1H, m, C6-Hb), 4.43—5.00 (1H, m,
C2-H), 5.18 (2H, s, OCH2Ar), 7.39 (5H, s, aromatic protons).
Deprotection of N-Z Derivatives (7ba, 8ba): A solution of N-Z compound
(7ba, 8ba) (2 mmol) and 10% Pd-C (30 mg), under hydrogen atmosphere
(1 atm) in MeOH–2 N HCl (5 ml—5 ml) was stirred at room temperature for
20 h. The reaction mixture was filtered off and concentrated under reduced
pressure to leave a colorless oil of residue, which was used for the next step.
Deprotection of N-Boc Derivatives (7da, 8da): Deprotection of N-Boc
compound (5da, 6da) (2 mmol) was done simultaneously with ester cleav-
age by acid hydrolysis as described below.
1
2
Hydrolysis of Esters and Preparation of Salt-free Cyclic a-
Aminophosphonic Acids (9, 10) A solution of the above residue in 6 N
HCl (4 ml) was refluxed in an oil bath for 12 h. The reaction solution was
concentrated under reduced pressure. The residue from 5-membered cyclic
amine derivatives was dissolved in a small amount of H2O. The aqueous so-
lution was applied to a column of Dowex 50Wϫ4 (50—100 mesh, Hϩ
form), and eluted with H2O. Concentration of the eluate to dryness afforded
the crude salt-free product as a white solid. Recrystallization of the solid
form H2O gave the pure sample (9). The residue from 6-membered cyclic
compounds was dissolved in a small amount of EtOH, and treated with
propylene oxide (1 ml). Concentration of the treated solution to dryness af-
forded the crude salt-free amino phosphonic acid as a white solid. Recrystal-
lization of the solid form ether–MeOH gave the pure sample (10). Total
yields from N-protected derivatives (7, 8) are summarized in Table 3.
Pyrrolidine-2-phosphonic Acid (9)18): Colorless prisms, mp 264—265 °C
(H2O) (lit.18a) mp 266—267 °C). MS (FAB) m/z: 152 (MHϩ). IR (KBr)
cmϪ1: 3408 (OH), 2962 (NH), 1136 (PϭO), 1068 (P–O). 1H-NMR (D2O)
[400 MHz] d: [1.88—2.16 (3H, m), 2.16—2.32 (1H, m), C3-H2, C4-H2],
3.22—3.38 (2H, m, C5-H2), 3.52 (1H, ddP, Jϭ18.8 Hz, JHPϭ9.3 Hz, C2-H).
2,2,2-Trichloroethyl 2-(Diethoxyphosphoryl)piperidine-1-carboxylate
(8ab): Yield 66%, colorless oil. MS m/z: 395 (Mϩ), 397 (Mϩϩ2), 399
(Mϩϩ4), 401 (Mϩϩ6). IR (neat) cmϪ1: 1722 (CϭO). 1H-NMR (CDCl3)
[90 MHz] d: 0.92—2.40 (6H, m, C3-H2, C4-H2, C5-H2), 1.32 (3H, t,
Jϭ7.1 Hz, OCH2CH3), 1.33 (3H, t, Jϭ7.1 Hz, OCH2CH3), 3.07—3.73 (1H,
m, C6-Ha), 3.73—4.47 (5H, m, 2ϫOCH2CH3, C6-Hb), 4.47—4.65 (1H, br,
C2-H), 4.65—4.95 (2H, br, OCH2CCl33). 13C-NMR (CDCl3) [22.5 MHz] d:
3
[16.48 (qdP, JCPϭ6.0 Hz), 16.59 (qdP, JCPϭ5.4 Hz), OCH2CH3], 20.08 and
20.14 (t, C3), [24.61 (t), 25.18 (t), C4, C5], 42.04 (t, C6), 48.45 (ddP,
1JCPϭ154.4 Hz, C2), [62.16 (tdP, 2JCPϭ7.4 Hz), 62.37 (tdP, 2JCPϭ7.4 Hz),
OCH2CH3], 75.39 (t, OCH2CCl3), 95.56 (s, CCl3), 153.80 (s, CϭO). HRMS
m/z Calcd for C12H21NO5Cl3P: 395.0223 (Mϩ). Found: 395.0216. Calcd for
C8H11NO2Cl3: 257.9855 (MϩϪPO(OC2H5)2). Found: 257.9843.
2
13C-NMR (D2O) [100 MHz] d: [24.80 (tdP, JCPϭ8.8 Hz, C3), 27.23 (t), C4],
47.67 (tdP, 3JCPϭ5.9 Hz, C5), 56.64 (ddP, 1JCPϭ143.8 Hz, C2). Anal. Calcd
for C4H10NO3P: C, 31.80; H, 6.67; N, 9.27. Found: C, 31.99; H, 6.41; N,
9.20.
Piperidine-2-phosphonic Acid (10)19): Colorless needles, mp 268—270 °C
(ether–MeOH) (lit.19a) mp 269—271 °C). IR (KBr) cmϪ1: 3425 (OH), 2958
(NH), 1130 (PϭO), 1076 (P–O). 1H-NMR (D2O) [400 MHz] d: [1.48—1.56
(1H, m), 1.56—1.78 (2H, m), 1.78—1.99 (2H, m), 1.99—2.50 (1H, m), C3-
H2, C4-H2, C5-H2], [2.90—3.05, (1H, m), 3.05—3.20 (1H, m), C6-H2], 3.39
(1H, dHP, JHPϭ12.5 Hz, C2-H). 13C-NMR (D2O) [100 MHz] d: [22.47 (t),
22.62 (t), 22.81 (t), C3, C4, C5], 46.61 (tdP, 3JCPϭ7.6 Hz, C6), 55.28 (ddP,
1JCPϭ141.9 Hz, C2). Anal. Calcd for C5H12NO3P: C, 36.37; H, 7.32; N, 8.48.
Found: C, 36.38; H, 6.96; N, 8.50.
2,2,2-Trichloroethyl 2-(Diisopropoxyphosphoryl)piperidine-1-carboxylate
(8ac): Yield 52%, colorless oil. MS m/z: 423 (Mϩ), 425 (Mϩϩ2), 427
(Mϩϩ4), 429 (Mϩϩ6). IR (neat) cmϪ1: 1722 (CϭO). 1H-NMR (CDCl3)
[400 MHz] d: [1.29 (3H, d, Jϭ5.9 Hz), 1.33 (9H, d, Jϭ6.2 Hz),
OCH(CH3)2], [1.37—1.53 (1H, m), 1.60—1.89 (3H, m), 1.91—2.20 (2H,
m), C3-H2, C4-H2, C5-H2], [3.32 (0.4H, t, Jϭ13.2 Hz), 3.45 (0.6H, t,
Jϭ12.8 Hz), C6-Ha], 4.16 (1H, t, Jϭ13.2 Hz, C6-Hb), 4.47—5.03 (5H, m,
C2-H, 2ϫOCH(CH3)2, OCH2CCl3). 13C-NMR (CDCl3) [100 MHz] d: 20.08
(t, C3), [24.04 (qdP, JCPϭ12.2 Hz), 24.18 (qdP, JCPϭ15.3 Hz), 24.20 (qdP,
3JCPϭ18.3 Hz), 24.71 (qdP, 3JCPϭ24.4 Hz), OCH(CH3)2], [25.06 (t), 25.38
(t), C4, C5], 42.03 (t, C6), [49.19 (ddP, 1JCPϭ157.2 Hz), 49.45 (ddP,
1JCPϭ154.1 Hz), C2], [71.09 (ddP, 2JCPϭ7.1 Hz), 72.01 (ddP, 2JCPϭ6.1 Hz),
OCH(CH3)2], 75.44 (t, OCH2CCl3), 95.54 (s, CCl3), [153.55 (s), 153.79 (s),
CϭO]. HRMS m/z Calcd for C14H25NO5Cl3P: 423.0536 (Mϩ). Found:
423.0528. Calcd for C8H11NO2Cl3: 257.9855 (MϩϪPO(O-isopropyl)2).
Found: 257.9863.
3
3
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