Synthesis of phosphonic analog of (S)-homoproline

Full text of DOI:10.1134/S1070363214010289

ISSN 1070-3632, Russian Journal of General Chemistry, 2014, Vol. 84, No. 1, pp. 169–170. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © O.O. Kolodyazhnaya, A.O. Kolodyazhnaya, O.I. Kolodyazhnyi, 2014, published in Zhurnal Obshchei Khimii, 2014, Vol. 84, No. 1,
pp. 162–163.
LETTERS
TO THE EDITOR
Synthesis of Phosphonic Analog of (S)-Homoproline
O. O. Kolodyazhnaya, A. O. Kolodyazhnaya, and O. I. Kolodyazhnyi
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kyiv, 02660 Ukraine
e-mail: olegkol321@rambler.ru
Received August 26, 2013
DOI: 10.1134/S1070363214010289
The reaction scheme for the synthesis of phos-
phonic analogue of homoproline was developed with
application of Barton-McCombie reaction on the key
step [1] (see Scheme 1).
McCombie method. The treatment of compound II
with thiocarbonylbis (imidazole) III in dichloroethane
at reflux afforded the compound IV, which was
purified by column chromatography and its structure
was confirmed by 1H, 13C, and 31P NMR spectra.
N-Boc-Prolinal I was obtained by reduction of N-
Boc-Proline methyl ester with H-DIBAL [2] and used
as a starting compound. The phosphonylation of N-
Boc-Prolinal I with triethylphosphite in the presence of
pyridinium perchlorate as a catalyst [3] led to the
formation of hydroxyphosphonate II, which was
obtained as a mixture of (S,RP) and (S,SP) diastereo-
isomers in very high yield. After that the hydroxyphos-
phonate II was dehydroxylated according to Barton–
Compound IV was then treated with tributyl-
stannane in boiling toluene during several hours, in the
presence of azobisisobutyrylnitrile to initiate the radical
reaction (the reaction did not occur in the absence of
azobisisobutyrylnitrile). The reaction progress was
monitored by TLC and NMR spectroscopy. The
protected S-homoproline V was isolated and purified
by column chromatography on silica gel. Deprotection
Scheme 1.
H
H
P(O)(OEt)2
O
(EtO)3P
N
N
[PyH]ClO4
OH
O
O
(S,RP)+(S,SP)-II
O
O
(S)-I
N
N
N
N
S
III
H
H
H
P(O)(OH)2
P(O)(OEt)2
P(O)(OEt)2
HCl
N
N
N
Bu3SnH
H
O
S
O
O
O
O
N
N
(S,RP)+(S,SP)-IV
(S)-VII
(S)-V
169

170
KOLODYAZHNAYA et al.
of V was performed by hydrochloric acid treatment.
The obtained S-homoproline analog is of potential
interest as an organocatalyst [cf. 4, 5].
(2H, CH2), 3.8 m (1H, CH), 4.33 m (4H, OCH2). 31Р
NMR spectrum (CDCl3): δP 28.3 ppm.
Diethyl (2-pyrrolidinmethyl)phosphonate (S)-(VI).
Compound V (0.23 g, 0.5 mmol) was treated with
2 mol/L HCl under short-term heating. After cooling,
the mixture was washed with ethyl acetate and water,
and then evaporated to give phosphonate VI, [α]D20 +15
Diethyl 1-(N-Boc-2-pyrrolidine)-1-hydroxymethyl-
phosphonate [a mixture of (S,RP) and (S,SP) diastereo-
isomers] (II). Pyridinium perchlorate (0.9 g, 0.05 mol)
was added to solution of diethyl phosphite (3.1 g,
0.022 mol) and N-Boc-prolinal (4 g, 0.02 mol) in
methylene chloride. The mixture was stirred at room
temperature during 3 h, then filtered and evaporated.
The residue was distilled under high vacuum. Yield
4.4 g (65 %), colorless liquid, bp 145°С (0.01 mm Hg).
1Н NMR spectrum (СDCl3), δН, ppm: 1.36 t (3Н, СH3,
JHH 7 Hz), 1.38 t (3Н, СH3, JHH 7 Hz), 1.46 s (9H,
СH3C), 1.78–1.83 m (2H, CH2), 2.17–2.23 m (2H,
CH2), 3.25–3.30 m (1H, CHO), 3.7–3.8 m (2H, CH2),
4.05–4.12 m (1H, CHN), 4.25–4.33 m (4H, CH2O). 31Р
NMR spectrum, (CDCl3): δP 24.90 and 24.31 ppm.
1
(с 1, СН3ОН). Н NMR spectrum (СDCl3), δН, ppm:
1.30–1.33 m (6H, СH3), 1.5–1.6 m (1H, CH2), 1.88–
1.92 m (3H, CH2), 2.15–2.25 m (3H, CH2), 3.0–3.10 m
(2H, CH2), 3.45–3.53 m (1H, CHN), 4.16–4.23 m (4H,
CH2O). 13С NMR spectrum (D2О), δC, ppm: 18.4 d
(3JCP 6 Hz), 26.4, 31.7 d (1JCP 140 Hz), 66.4 d (2JCP
6 Hz), 34.5 d (3JCP 9.0 Hz), 48.0, 56.5. 31Р NMR spec-
trum (D2O): δP 28 ppm.
(2-Pyrrolidinemethyl)phosphonic acid (S)-(VII).
Mixture of solution of V (0.9 g, 0.002 mol) in dioxane
and 8 mol/L hydrochloric acid was refluxed during 25–
30 h. After the reaction was completed (TLC), the
mixture was cooled, washed with ethyl acetate and
water, and then evaporated. The residue was dissolved
in ethanol and treated with 0.5 g of propylene oxide.
Diethyl 1-(N-Boc-2-pyrrolidine)-1-(1H-imidazol-
thiocarboxy)methylphosphonate (S)-(IV). Solution
of hydroxyphosphonate II (4.4 g, 0.013 mol) and 1,1-
thiocarbonyldiimidazole (4.6 g, 0.026 mol) in 100 mL
of 1,2-dichloroethane was heated at 70°C during 3 h.
After the reaction was completed (TLC), the mixture
was subsequently washed with 1 mol/L HCl, NaHCO3,
and saturated NaCl solutions, dried, and evaporated.
The residue was purified by silica gel column
chromatography (ethyl acetate–ethanol, 4 : 1). Yield
1
Yield 0.14 g (40%), colorless solid, mp >200°C. Н
NMR spectrum (СDCl3), δН, ppm: 1.6–2.0 m (4H,
CH2), 2.17–2.22 m (2H, CH2), 3.17–3.23 m (2H,
CH2N), 4.1 d. d (1H, CHN, JHP 11 Hz, JHH 3.5 Hz). 13С
NMR spectrum (CDCl3), δC, ppm: 23.0 d and 24.0 d
(JPH 100.0 Hz), 34.0, 49, 56.0. 31Р NMR spectrum
(DMSO): δP 18.0 ppm. Found Р, %: 18.9. C5H12NO3P.
Calculated P, %: 18.76.
1
(5.6 g, 90 %), yellowish solid. Н NMR spectrum
(СDCl3), δН, ppm: 1.28 t (3H, СН3, JHH 7 Hz), 1.32 t
(3H, СН3, JHH 7 Hz), 1.55 s [9H, (СН3)С], 2.00–2.40
m (4H, CH2), 3.10–3.4 m (2H, СН), 4.12–4.18 m (4H,
OCH2), 4.39 br. s (1Н, PCH), 6.80 d (1H, JHH 12 Hz),
7.70 d (1H, JHH 7 Hz), 8.35 d (1H, imidazolyl, JHH
15 Hz). 31Р NMR spectrum (CDCl3): δP 15.86 ppm.
NMR spectra were registered with Varian-300
spectrometer relative to internal TMS (1H and 13C) and
to external 85% Н3РО4 in D2O (31Р).
ACKNOWLEDGMENTS
This work was financially supported by the State
Foundation for Basic Research of Ukraine and the
Russian Foundation for Basic Research (collaborative
project no. F53.3/016).
Diethyl N-Boc-2-pyrrolidinemethylphosphonate
(S)-(V). Tributylstannane (6.8 g, 0.024 mmol) and 0.3 g
of azobisisobutyronitrile were added to solution of
thiocarbamate IV (5.2 g, 0.012 mol) in 15 mL of
anhydrous toluene. The mixture was refluxed during
about 5 h, adding small portions of azobisisobutyro-
nitrile from time to time. The mixture was cooled
down and evaporated under reduced pressure. The
residue was purified by silica gel column
chromatography. Yield 1.6 g (40%), [α]D20 –35 (с 1,
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 1 2014