10.1002/cplu.202000322
ChemPlusChem
FULL PAPER
To a suspension of 9-BBN protected amino acids (L-glutamic acid/L-
aspartic acid) (18.6 mmol) in dry THF (75 mL), BH3-DMS (18.6 mmol)
was added dropwise through an addition funnel over 20 min at 0 ºC
under argon atmosphere. After stirring 1 h at 0 ºC, the reaction mixture
was stirred overnight at room temperature. After completion of the
reaction, the solvent was evaporated by applying a vacuum. The
residue obtained was purified by silica gel column chromatography
using ethyl acetate as eluent to get 9-BBN protected 2-amino-5-
hydroxypentanoic acid/9-BBN protected 2-amino-4-hydroxybutanoic
acid as white solid (yield: 4.2 gm, 89.7 % for 2a and 83 % for 2ax).
during which the volatiles was removed under vacuum, yielding clear
and colorless oil (yield: 15.5 gm, 90 %).
Compound 2b: 1H NMR (200.13 MHz, CDCl3): δ(ppm) 1.24-1.27 (d,
12H), 3.69-3.85(m, 2H), 4.69-4.94(m, 4H), 7.29-7.43(m, 10H); 31P NMR
(202.46 MHz, CDCl3): δ(ppm) 146.68
General
procedure
for
the
synthesis
of
2-amino-5-
((bis(benzyloxy)phosphoryl)oxy)pentanoic acid (NH2-(OBn)2P(O)-pent-
COOH)/2-amino-4-((bis(benzyloxy)phosphoryl)oxy)butanoic
((NH2-(OBn)2P(O)-but-COOH)
acid
Compound 2a: 1H NMR (200.13 MHz, DMSO-D6): δ(ppm) 0.47-0.57(d,
2H, J=0.04), 1.57-1.84(m, 14H), 3.39-3.53(m, 3H), 4.63(br, 1H), 5.82-
5.92(m, 1H), 6.36-6.46 (m, 1H); 13C NMR (50.32 MHz, DMSO-D6):
δ(ppm) 22.40, 23.99, 24.33, 25.21, 27.41, 28.84, 30.79, 30.84, 31.30,
54.50, 60.40, 67.11, 173.89.
9-BBN protected 2-amino-5-hydroxypentanoic acid/2-amino-4-
hydroxybutanoic acid (16.6 mmol), and dibenzyl diisopropyl
phosphoramidite (29.8 mmol) were evaporated twice with dry MeCN
(30 mL) and then dissolved in dry MeCN (75 mL). In another RB, 29.8
mmol of 1H-tetrazole (dried by twofold evaporation with MeCN) was
dissolved in 20 mL of MeCN. The 1H-tetrazole solution was then added
dropwise to the reaction mixture on an ice bath with continuous stirring.
After addition, the ice bath was removed, and the reaction mixture was
stirred at room temperature for 30 mins upon which precipitation of
white solid was observed. Precipitated white crystalline side product
was filtered, discarded, and the filtrate was concentrated on a rotary
evaporator. The crude product obtained after removal of solvent was
used further without any purification.
Synthesis of 1,1-dichloro-N,N-diisopropylphosphinamine
Phosphorous trichloride (5 mL, 57.3 mmol) was dissolved in 50 ml of
dry hexane under N2, and the mixture was cooled to -78 ºC. A solution
of freshly distilled di-isopropylamine (16 mL, 114.6 mmol) in 50 mL of
dry hexane added to the reaction mixture over 1h using an addition
funnel. Following the addition, the reaction was stirred at -70 oC for an
additional hour 25. The cooling bath was then removed, and the reaction
was stirred at room temperature for another 4 h. The reaction was then
filtered through a glass frit under positive N2 pressure, and the solvent
with excess phosphorus trichloride was removed by short-path
distillation at 40 oC with a high vacuum. The product was obtained as a
clear, colorless liquid and was stored at -22 oC (yield: 10 gm, 88%),
which transformed into crystalline solid at low temperature.
t
The crude product was dissolved in MeCN and (6M) Bu-OOH (16.6
mmol) was added dropwise at 0 oC. Then the reaction mixture was
stirred till reaction completed, monitored by TLC. The solvent was
evaporated to dryness, and the crude product was purified by silica gel
column chromatography using 2 % MeOH in ethyl acetate as eluent.
The fractions containing the product were combined and concentrated
under reduced pressure, and the volatiles was removed under vacuum,
Compound 1b: 1H NMR (200.13 MHz, CDCl3): δ(ppm) 1.27-1.30(d,
12H), 3.84-4.07(m, 2H); 31P NMR (202.46 MHz, CDCl3): δ(ppm) 169.57
yielding
a clear and colorless oil 9-BBN protected 2-amino-5-
((bis(benzyloxy)phosphoryl)oxy)pentanoic acid (yield: 8 gm, 94 % for 3
and 90 % for 3x).
Synthesis of dibenzyl N, N-diisopropyl phosphoramidite
9-BBN protected 2-amino-5-((bis(benzyloxy)phosphoryl)oxy)pentanoic
acid/9-BBN
protected
2-amino-4-
1,1-dichloro-N, N-diisopropylphosphinamine (10 gm, 50.1 mmol) was
dissolved in 100 mL of dry diethyl ether under N2, and the mixture was
cooled to -10 oC. A solution of benzyl alcohol (11.45 mL, 110.2 mmol),
triethylamine (15.35 mL, 110.2 mmol), and 100 mL of dry diethyl ether
was added to the reaction vessel through an addition funnel over the
course of 1.5 h. After completion of the addition, the cooling bath was
then removed, and the reaction was stirred at room temperature for 6
h. The reaction was filtered through a glass frit, and the solvent was
removed under reduced pressure yielding yellowish oil. The crude oil
was then purified by column chromatography. The column was packed
with silica gel (100-200 mesh) using 2.5 % triethylamine in hexane until
the smell of triethylamine persisted. After loading the crude reaction
mixture, the desired product was eluted using 2 % ethyl acetate-2.5 %
triethylamine in hexane as the eluent. The fractions containing the
product were combined and concentrated under reduced pressure
((bis(benzyloxy)phosphoryl)oxy)butanoic acid was dissolved in
MeOH:CHCl3 (1:10) mixture and stirred it for 24 h at room temperature.
After complete cleavage of 9-BBN complex, the reaction mixture was
concentrated and treated with hot petroleum ether to remove excess 9-
BBN. The crude product was directly subjected to the next reaction
without any further purification.
Compound 3: 1H NMR (200.13 MHz, CDCl3): δ(ppm) 1.62-2.03(m, 6H),
3.92(s, 3H), 4.89(s, 2H), 4.93(s,2H), 7.29(10H), 8.31(2H); 13C NMR
(50.32 MHz, CDCl3): δ(ppm) 25.35, 25.41, 28.01, 56.88, 66.82, 66.88,
69.71-69.81(1C), 127.95-128.11(4C), 128.60-128.84(4C), 135.38-
135.43(1C), 151.87, 169.95; 31P NMR (202.46 MHz, CDCl3): δ(ppm) -
2.42.
10
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