Cyclic Amidoalkylation of Hydrophosphorylic Compounds. Synthesis of Proline Analogs

Article abstract of DOI:10.1134/S107036321712026X

A method for the synthesis of N-Cbz-protected phosphorylic analogs of proline by cyclic amidoalkylation of various hydrophosphorylic compounds was developed. Combination of amide and carbonyl fragments in the 4-N-Cbz-aminobutyraldehyde molecule allows to

Full text of DOI:10.1134/S107036321712026X

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 12, pp. 2898–2901. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © A.V. Vinyukov, M.E. Dmitriev, A.N. Yarkevich, V.V. Ragulin, 2017, published in Zhurnal Obshchei Khimii, 2017, Vol. 87, No. 12,
pp. 2087–2090.
LETTERS
TO THE EDITOR
Cyclic Amidoalkylation of Hydrophosphorylic Compounds.
Synthesis of Proline Analogs
A. V. Vinyukov, M. E. Dmitriev, A. N. Yarkevich, and V. V. Ragulin*
Institute of Physiologically Active Substances, Russian Academy of Sciences,
Severnyi proezd 1, Chernogolovka, Moscow oblast, 142432 Russia
*e-mail: rvalery@dio.ru
Received August 3, 2017
Abstract―A method for the synthesis of N-Cbz-protected phosphorylic analogs of proline by cyclic
amidoalkylation of various hydrophosphorylic compounds was developed. Combination of amide and carbonyl
fragments in the 4-N-Cbz-aminobutyraldehyde molecule allows to realize the three-center two-component
amide version of the Kabachnik–Fields reaction.
Keywords: phosphorylic analogs of proline, cyclic amidoalkylation, 4-aminobutyraldehyde
DOI: 10.1134/S107036321712026X
Amidoalkylation of hydrophosphorylic compounds
is a promising general method for constructing the
α-aminophosphoryl function, which allows preserving
the protection at the nitrogen atom of the target
molecule. By earlier studies of the amide version of the
Kabachnik–Fields reaction we developed an effective
convenient procedure for carrying out the reactions of
hydrophosphorylic compounds with aldehydes and alkyl
carbamates in acetic anhydride under acid catalysis at
room temperature [1–4].
reported in [5]. 4-N-Cbz-Aminobutyraldehyde 1 was
taken as the starting compound, in whose molecule the
length of the hydrocarbon chain between two reaction
sites makes it possible to obtain a five-membered
pyrrolidine ring, present in the best known cyclic
amino acid proline.
The reaction of 4-N-Cbz-aminobutyraldehyde 1
with hydrophosphorylic compounds 2 in acetic anhyd-
ride under acid catalysis at room temperature led to the
formation of phosphorylic proline analogs 3 (Scheme 1).
This work deals with the development of a two-
component three-center amide (carbamate) version of
this reaction combining the carbamate and carbonyl
reaction sites in one molecule. We proposed a
modification of the approach based on the known
ability of α,ω-aminoaldehydes to cyclization [5, 6]
In accordance with the mechanism of amido-
alkylation of the hydrophosphorylic compounds we
have suggested earlier the formation of the phosphorus-
carbon bond proceeds through the Arbuzov reaction
including the nucleophilic attack of the P(III) atom of
the acetyloxy derivative on the carbon atom of the
Scheme 1.
O
O
O
H
X
Y
Ac2O (H+)
H2O
+
P X
P
N
Y
Cbz
NH-Cbz
1
2
3a−3e
X = Y = OH (a); X = Y = OEt (b); X = Me, Y = OH (c); X = CH2OH, Y = OH (d); X = Y = Ph (e).
2898

CYCLIC AMIDOALKYLATION OF HYDROPHOSPHORYL COMPOUNDS
2899
Scheme 2.
O
Ac2O
OH
OAc
N
N
Cbz
Cbz
NH-Cbz
1
7
6
OAc
O
:
P
X'
Y'
O
H+
−Ac2O
+
N
P+ X'
Y'
4
3
Ac2O
N
Cbz
Cbz OAc−
XYP(O)H
5
2
8
X', Y' = X, Y or OАс.
Scheme 3.
O
Cbz
N
O
OH
H
O
+
+
H O
H2O
AAcc22O((HH ))
P
2
P
+
N
H
HO
Cbz
NH-Cbz
9
1
positively charged Schiff base form [1–4]. Probably,
the PIIIOAc derivative 4 generated in situ in the acetic
anhydride medium from the startig hydrophosphorylic
compound 2 (Scheme 2) also acts as a nucleophilic
agent in the studied reaction.
its phosphorylation in acetic anhydride medium under
acid catalysis at room temperature. The known methods
for the synthesis of phosphorylic proline analogs are
based on the use of various starting compounds already
containing the pyrrolidine ring [8–11]. Phosphorous
acid, diethyl phosphite, methylphosphonous, hydroxy-
methylphosphonous and diphenylphosphinic acids
were studied as a hydrophosphorylic component. In
general, acid catalysis is carried out by the addition of
p-toluenesulfonic acid, as well as in the presence of
acetyl chloride. The latter is especially necessary when
using phosphorous acid, since in this case acylation of
three acid groups occurs to form triacetyl phosphite as
a nucleophilic three-coordinated component [4]. The
use of hypophosphorous acid (0.5 equiv.) in this
reaction resulted in symmetric phosphinic acid 9 as a
double cyclization product (Scheme 3).
We assumed the formation of a highly reactive
positively charged form of the cyclic Schiff base 5 as
an electrophilic component. Probably, it was generated
in situ from 2-acetyloxy-N-Cbz-pyrrolidine 6 under the
acid catalysis. The compound 6 was formed by
acylating 2-hydroxy-N-Cbz-pyrrolidine 7 in acetic an-
hydride (Scheme 2). Perhaps the process of cyclization
of 4-N-Cbz-aminobutyraldehyde 1 into 2-hydroxy-N-
Cbz-pyr-rolidine 7 begins immediately after the
removal of the acetal protection under acidic conditions.
The proposed procedure is a convenient method for
the synthesis of phosphorylic proline analogs 3, which
includes one-pot formation of the pyrrolidine ring and
The obtained phosphorylic analogs of proline are a
mixture of diastereomers and conformers, which is due
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 12 2017

2900
VINYUKOV et al.
to the presence of several chiral centers and the
relative conformational rigidity of the pyrrolidine ring,
which was registered by the NMR spectra [8–11].
marked with an asterisk refer to minor isomers):
27.13*, 27.38*, 28.06, 28.62*, 29.07*. Mass spectrum
(LCМS), m/z: 286.3711 [M + H] (calculated for
C12H16NO5P: 285.2329).
In summary, an approach to the synthesis of
phosphorylic proline analogs by cyclic amidoalkylation
of hydrophosphorylic compounds using 4-N-Cbz-amino-
butyraldehyde in acetic anhydride medium under acid
catalysis at room temperature was developed.
Diethyl 1-N-(benzyloxycarbonyl)pyrrolidin-2-yl-
phosphonate (3b). Yield 68%, Rf ~0.6 (CHCl3 :
i-PrOH = 10 : 1), ~0.5 [CHCl3 : (CH3)2CO = 3 : 1]. 1H
NMR spectrum (CDCl3), δ, ppm: 1.19 t (6Н, СН3, 3JHH
=
6.9 Hz), 1.70–2.30 m (4H, СCH2CH2С, ring), 3.35–
3.55 m (2Н, СH2N), 3.85–4.30 m (5H, 2CH2O +
NCH), 5.08 br.m (2Н, PhСН2О), 7.28 br.s (5H, Ph).
13С NMR spectrum (CDCl3), δС, ppm: 16.09* d and
Dimethyl acetal 4-aminobutyraldehyde, acetic
anhydride, acetyl chloride, and hypophosphorous acid
were purchased from the Reakor company (Alfa
Aesar). 4-[N-(Benzyloxycarbonyl)]aminobutyric aldehyde
1 was prepared by acylation of 4-aminobutyraldehyde
dimethyl acetal using benzyloxycarbonyl chloride [12]
in aqueous dioxane followed by gentle removal of
acetal protection with hydrochloric acid and thorough
drying of the compound in a vacuum [13].
3
16.16 d (2CH3, JPC = 5.8 Hz), 23.10, 24.08* (CH2,
СH2CH, ring), 26.42 and 27.22* (CH2, СH2СH2, ring),
1
46.44 (CH22N), 53.35 d (РCH, JPC = 162.6 Hz), 61.85
2
d (CH2O, JPC = 6.9 Hz), 62.09* d (CH2O, JPC
=
7.3 Hz), 66.84 (PhCH2O), 127.70* and 128.12 (Ph),
154.7 [NC(O)]. 31Р NMR spectrum (CDCl3), δР, ppm:
14.82, 12.31*. Found, %: С 55.94, 56.03; Н 7.34, 7.23.
N 3.93, 3.96. C16H24O5P. Calculated, %: C 56.30; H
7.09; N 4.10.
General procedure of cyclic amidoalkylation of
hydrophosphoryl compounds using 4-N-Cbz-amino-
butyraldehyde. p-Toluenesulfonic acid (0.15–0.50 mmol)
was added to a mixture of the hydrophosphorylic
component (5 mmol) and 4-N-Cbz-aminobutyral-
dehyde (5 mmol) in 5 mL of acetic anhydride. When
using phosphorous acid as the hydrophosphorylic
component, acetyl chloride (~5 mL) was used as the
catalyst. After 24 h, the reaction mixture was treated
with water and evaporated. The residue was partitioned
between 10 mL of chloroform and 25–35 mL of a
saturated NaHCO3 solution. The aqueous layer was
separated, washed with 5–7 mL of diethyl ether,
acidified to pH ~ 1–3 and extracted with ethyl acetate
or chloroform (3 × 15 mL). If necessary, the
purification procedure was repeated until the signal of
the starting hydrophosphorylic compound in the 31P
NMR spectrum (20–30 ppm) disappeared. The organic
layer was dried with sodium or magnesium sulfate and
evaporated. The residue was chromatographed on
silica gel eluting with chloroform, chloroform–
isopropanol (3–7% or up to 12% in the case of
compound 3a). The obtained compounds were oily
substances, that is typical for compounds containing
N-protected pyrrolidine fragment [8–10].
1-N-(Benzyloxycarbonyl)pyrrolidin-2-ylmethyl-
posphinic acid (3c). Yield 65%, Rf ~0.3–0.4 (CHCl3:i-
PrOH = 10 : 1), ~0.1–0.3 [CHCl3 : (CH3)2CO = 3 : 1].
1H NMR spectrum (CDCl3), δ, ppm: 1.32*d and 1.52 d
3
(3Н, СН3, JHH = 14.0 Hz), 1.70–2.50 m (4H,
СCH2CH2С, ring), 3.40–3.55 m (2Н, СH2N), 4.10 br.s
(1H, NCH), 5.11 br.s (2Н, СН2О), 7.33 br.m (5H, Ph),
8.08 br.s (OH). 13С NMR spectrum (CDCl3), δС, ppm:
1
1
14.4 d (CH3, JPC = 90.9 Hz), 13.8* d (CH3, JPC
=
93.8 Hz), 23.52* and 24.52 (СH2, СH2CH2, ring),
25.24 and 25.85 (СH2, СH2CH, ring), 47.06 and
1
51.21* (CH2N), 56.62 d (РCH, JPC = 110.4 Hz),
1
56.25* (РCH, JPC = 113.9 Hz), 64.84* and 67.27
(PhCH2O), 127.74*, 128.01* and 128.42 (Ph), 155.79
3
and 154.82* d [NC(O), JPC = 14.6 Hz]. 31Р NMR
spectrum (CDCl3), δP, ppm: 55.18*, 55.72, 56.05*,
56.96*. Found, %: С 54.94, 55.02; Н 6.63, 6.46. N
4.77; 4.83. C13H18O4P. Calculated, %: C 55.12; H 6.41;
N 4.94.
1-N-(Benzyloxycarbonyl)pyrrolidin-2-yloxyme-
1
thylphosphinic acid (3d). Yield 56%. H NMR spec-
1-N-(Benzyloxycarbonyl)pyrrolidin-2-yl-phosphonic
acid (3a). Yield 57% (mixture of diastereomers and
conformers). 1H NMR spectrum (CDCl3), δ, ppm: 1.49–
2.48 m (4H, CH2CH2, ring), 3.36–4.12 m (3Н, СH2N +
CHN), 4.12 m (2H, CH2O), 5.15 d (2Н, PhСН2О,
2JHH = 6.4 Hz), 7.35 br.m (5H, Ph), 11.04 br.s (OH).
31Р NMR spectrum (CDCl3), δС, ppm (the signals
trum (CDCl3), δ, ppm: 1.70–2.50 m (4H, СCH2CH2С,
ring), 3.40–3.54 m (2Н, СH2N), 3.55–4.10 m (2H,
CH2OH), 4.35 br.s (1H, NCH), 5.23 br.s (2Н, СН2О),
7.42 br.m (5H, Ph), 8.50 br.s (2H, OH). 31Р NMR
spectrum (CDCl3), δР, ppm: 45.03*, 47.02, 49.53*,
52.03*. Mass spectrum (LCМS), m/z: 300.3787 [M +
H] (calculated for C12H16NO5P: 299.2595).
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CYCLIC AMIDOALKYLATION OF HYDROPHOSPHORYL COMPOUNDS
2901
1-N-(Benzyloxycarbonyl)pyrrolidin-2-yldiphenyl-
phosphine oxide (3e). Yield 67%. H NMR spectrum
by column chromatography on Silpearl and L100/160
(Chemapol) silica gel.
1
(CDCl3), δ, ppm: 1.75–2.56 m (4H, СCH2CH2С, ring),
3.38–3.70 m (2Н, СH2N), 3.80–4.15 m (1H, CHN),
4.88 br.s (2Н, СН2О), 7.14–8.01 m (15H, Ph). 31Р
NMR spectrum (CDCl3), δР, ppm: 32.21*, 34.24. Mass
spectrum (LCМS), m/z: 406.4298 [M + H] (calculated
for C24H24NO3P: 405.4261).
ACKNOWLEDGMENTS
This work was financially supported by the Russian
Foundation for Basic Research (grant no. 15-03-
06062).
Bis{N-(benzyloxycarbonyl)pyrrolidin-2-yl}phos-
phinic acid (9). A solution of 10 mmol of 4-N-Cbz-
aminobutyraldehyde in 5 mL of glacial acetic an-
hydride was added to a solution of 5 mmol of hypo-
phosphorous acid in 5 mL of glacial acetic anhydride
at 0–10°C. Next, 0.5 mmol of p-toluenesulfonic acid
was added to the resulting mixture. After 24 h, the
reaction mixture was treated with water and eva-
porated. The oily residue was partitioned between 20–
25 mL of chloroform or ethyl acetate and 10 mL of
water. The organic layer was separated, washed with a
NaHCO3 solution until the hypophos-phorous acid
signal in the 31P NMR spectrum dis-appeared, dried
with sodium or magnesium sulfate, and evaporated.
The residue was chromatographed on silica gel eluting
with chloroform, chloroform–iso-propanol (5%). Yield
41% (mixture of diastereomers and conformers),
viscous oil, Rf ~ 0.5 (CHCl3 : i-PrOH = 10 : 1), ~ 0.2–0.3
[CHCl3 : (CH3)2CO = 3 : 1]. 1H NMR spectrum
(CDCl3), δ, ppm: 1.35–2.50 m (8H, CH2CH2, ring),
3.05–3.85 m (6Н, СH2N + CHN), 5.12 br.s (4Н,
PhСН2О), 7.33 m (10H, Ph). 31Р NMR spectrum
(CDCl3), δР, ppm: 48.26*, 48.84*, 50.02*, 50.37,
50.59*, 51.89*, 52.35*. Mass spectrum (LCМS), m/z:
473.4913 [M + H] (calculated for C24H29N2O6P:
472.4707).
The 1H, 31P and 13C NMR spectra were recorded on
a Bruker DPX-200 Fourier spectrometer, internal
reference TMS (1H, 13C) and external reference 85%
H3PO4 (31P). Chromatographic analysis was performed
on an Agilent 1100 LC/MSD system with DAD, ELSD
and a one-quadrupole mass-selective detector at
electrospray ionization. TLC analysis was carried out
on Silufol plates, Merck glass plates coated with
0.2 mm UV-254 silica gel, and Alufol (Kavalier) plates
(neutral alumina on aluminum foil), developing with
iodine vapor or UV light. N-Benzyloxycarbonyl-
protected phosphorylic proline analogs were isolated
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