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J ¼ 8.3, 6.1 Hz, 1H), 3.79 (dd, J ¼ 8.8, 2.9 Hz, 1H), 3.70 (dd, J ¼ (126 MHz, CDCl3) d 173.50, 173.23, 170.19, 169.03, 155.36,
8.3, 6.6 Hz, 1H), 3.53 (dd, J ¼ 8.8, 3.0 Hz, 1H), 3.05 (dd, J ¼ 82.06, 80.28, 73.26, 70.45, 63.63, 62.09, 54.12, 53.64, 35.77,
13.9, 5.9 Hz, 1H), 2.94 (dd, J ¼ 13.9, 6.3 Hz, 1H), 2.82 (dd, J ¼ 34.43, 34.23, 33.28, 32.07, 29.85, 29.81, 29.66, 29.51, 29.46,
13.5, 6.2 Hz, 1H), 2.71 (dd, J ¼ 13.5, 6.1 Hz, 1H), 1.46 (d, J ¼ 29.45, 29.29, 29.28, 28.43, 27.48, 25.04, 25.02, 22.84, 14.27. MS
1.7 Hz, 18H), 1.44 (s, 3H), 1.36 (s, 3H), 1.15 (s, 9H). 13C NMR (ESI) calculated for [M + Na]+ C54H102N2NaO10S+, m/z 993.71,
(126 MHz, CDCl3) d 170.18, 168.91, 155.28, 109.67, 81.94, found 993.19.
80.17, 75.59, 73.13, 68.74, 61.99, 54.07, 53.49, 35.56, 35.32,
28.30, 28.01, 27.35, 26.87, 25.56. MS (ESI) calculated for [M + S-((R)-2,3-Bis(palmitoyloxy)propyl)-N-(tert-butoxycarbonyl)-
Na]+ C25H46N2NaO8S+ m/z 557.28, found 558.26.
L-cysteinyl-L-serine (22)
The compound 20 (500 mg, 0.53 mmol) was stirred with tri-
uoroacetic acid (TFA, 8 mL) for 30 minutes at 25 ꢀC, fol-
lowed by purging nitrogen gas. Aer that remaining TFA was
co-evaporated with CHCl3 (5 mL ꢁ 3) and DCM (5 mL ꢁ 2) in
order to get solid crude compound which was puried by
column chromatography (10% MeOH/DCM) to get
compound 21 (350 mg, 89%). MS (ESI) calculated for [M + H]+
C41H78N2O8S m/z 758.54, found 758.28. To a solution of
compound 21 (286 mg, 0.32 mmol) in DCM, di-tert-butyl
dicarbonate (246 mg, 1.31 mmol) Et3N (133 mL, 0.92 mmol)
were added and the reaction mixture was stirred for 4 h. The
reaction mixture was diluted with DCM (300 mL) and organic
layer was sequentially washed with water (250 mL ꢁ 2),
saturated sodium bicarbonate solution (250 mL ꢁ 2), brine
(200 mL ꢁ 1). The organic layer was dried over anhydrous
sodium sulfate, ltered and evaporated under reduced pres-
sure to obtain the crude product which was puried using
column chromatography (5% MeOH/DCM) to afford
compound 22 (188 mg, 67%). 1H NMR (500 MHz, CDCl3)
d 12.17–11.77 (m, 1H), 7.59–7.48 (m, 1H), 5.67–5.54 (m, 1H),
5.20–5.13 (m, 1H), 4.63–4.53 (m, 1H), 4.44–4.36 (m, 1H), 4.32
(s, 1H), 4.14 (s, 1H), 4.09–4.01 (m, 1H), 3.96–3.82 (m, 1H),
3.10 (s, 1H), 3.06–2.88 (m, 2H), 2.76 (s, 2H), 2.29 (d, J ¼
7.4 Hz, 4H), 1.65–1.55 (m, 4H), 1.43 (s, 9H), 1.21 (s, 48H), 0.86
(s, 6H). 13C NMR (126 MHz, CDCl3) d 173.89, 173.74, 171.04,
156.02, 80.96, 77.41, 77.16, 76.91, 70.53, 63.84, 62.82, 55.31,
54.04, 45.82, 35.16, 34.50, 34.25, 32.91, 32.08, 29.87, 29.83,
29.70, 29.68, 29.53, 29.48, 29.32, 29.29, 28.42, 25.06, 25.02,
tert-Butyl-N-(N-(tert-butoxycarbonyl)-S-((R)-2,3-
dihydroxypropyl)-L-cysteinyl)-O-(tert-butyl)-L-serinate (19)
The compound 18 (2.9 g) was dissolved in 70% acetic acid (30
mL, AcOH : water ¼ 7 : 3) and the reaction mixture was stirred
at room temperature for 16 h. Aer completion of the reaction,
the reaction mixture was diluted with EtOAc (350 mL) and
washed with 10% sodium bicarbonate (200 mL ꢁ 2), water
(200 mL ꢁ 2) and brine (200 mL) and organic layer was
concentrated under reduced pressure to yield crude product
which was puried using column chromatography (5% MeOH/
DCM) to obtain compound 19 (2.5 g, 96%). 1H NMR (500 MHz,
CDCl3) d 7.23 (d, J ¼ 7.7 Hz, 1H), 5.63 (d, J ¼ 8.1 Hz, 1H), 4.57 (dt,
J ¼ 8.1, 2.9 Hz, 1H), 4.42 (d, J ¼ 5.8 Hz, 1H), 3.89–3.83 (m, 1H),
3.81–3.78 (m, 1H), 3.70 (dd, J ¼ 11.3, 3.6 Hz, 2H), 3.60 (dd, J ¼
11.3, 6.2 Hz, 1H), 3.55 (dd, J ¼ 8.9, 3.0 Hz, 1H), 3.00 (dd, J ¼ 14.1,
5.6 Hz, 1H), 2.91 (dd, J ¼ 14.1, 6.7 Hz, 1H), 2.78 (m, 2H), 1.47 (s,
9H), 1.45 (s, 9H), 1.16 (s, 9H). 13C NMR (126 MHz, CDCl3)
d 170.23, 169.20, 155.56, 82.26, 80.36, 73.34, 71.10, 65.23, 62.02,
53.49, 35.93, 28.30, 28.02, 27.34. MS (ESI) calculated for [M +
Na]+ C22H37N2NaO8S+ m/z 517.25, found 517.23. For large scale,
compound 19 was used further without any column
purication.
((R)-3-((R)-2-(tert-Butoxycarbonylamino)-3-((S)-1,3-di-tert-
butoxy-1-oxopropan-2-ylamino)-3-oxopropylthio)propane-1,2-
diyldipalmitate) (20)
To a solution of compound 19 (650 mg, 1.31 mmol) in anhy-
drous DCM (15 mL) were added Et3N (733 mL, 5.26 mmol) and
a catalytic amount of DMAP (20 mol%). The reaction mixture
was stirred at 0 ꢀC for 30 minutes. Palmitoyl chloride (1.2 mL,
3.94 mmol) was then added at 0 ꢀC, followed by stirring at
room temperature for 12 h. Aer completion of the reaction,
the reaction mixture was thoroughly washed with water
(250 mL ꢁ 2), saturated sodium bicarbonate solution (250 mL
ꢁ 2), brine (200 mL ꢁ 1). The organic layer was dried over
anhydrous Na2SO4, ltered and, evaporated under reduced
pressure to obtain crude product which was puried using
column chromatography (20% EtOAc/hexane) to obtain
compound 20 (880 mg, 68%). 1H NMR (500 MHz, CDCl3) d 7.04
(d, J ¼ 8.0 Hz, 1H), 5.40 (d, J ¼ 6.1 Hz, 1H), 5.18 (dd, J ¼ 5.7,
3.7 Hz, 1H), 4.53 (dt, J ¼ 8.1, 2.9 Hz, 1H), 4.33 (dd, J ¼ 11.9,
3.5 Hz, 2H), 4.17 (dd, J ¼ 11.9, 5.9 Hz, 1H), 3.79 (dd, J ¼ 8.8,
22.85, 14.28, 8.69. MS (ESI) calculated for [M + Na]+ C46H86
-
N2NaO10S+ m/z 881.58, found 881.58.
tert-Butyl-N2-(((9H-uoren-9-yl)methoxy)carbonyl)-N6-(tert-
butoxycarbonyl)-L-lysinate (Fmoc-Lys(Boc)-OtBu) (24)
The compound 24 was synthesized using precursor Fmoc-
Lys(Boc)-OH 23 (5.0 g, 10.7 mmol) using reported
a
protocol.38 Yield (3.91 g, 70%). 1H NMR (400 MHz, CDCl3);
d 7.76 (d, J ¼ 7.5 Hz, 2H), 7.60 (d, J ¼ 7.3 Hz, 2H), 7.40 (t, J ¼
7.5 Hz, 2H), 7.31 (t, J ¼ 7.5 Hz, 2H), 5.36 (d, J ¼ 8 Hz, 1H), 4.37–
4.42 (m, 2H), 4.20–4.27 (m, 2H), 3.10 (t, J ¼ 6.6 Hz, 2H), 1.77–
1.86 (m, 4H), 1.47 (s, 9H), 1.43 (s, 11H).
tert-Butyl-N6-(tert-butoxycarbonyl)-L-lysinate (H-Lys(Boc)-
OtBu) (25)
2.9 Hz, 1H), 3.53 (dd, J ¼ 8.8, 3.0 Hz, 1H), 2.96 (d, J ¼ 6.3 Hz, The compound 25 (4.0 g, 7.62 mmol) was synthesized as re-
2H), 2.82 (d, J ¼ 6.0 Hz, 2H), 2.32 (ddd, J ¼ 12.3, 6.7, 3.0 Hz, ported in the literature38 and conrmed by mass spectrometric
4H), 1.67–1.56 (m, 5H), 1.46 (d, J ¼ 3.5 Hz, 18H), 1.27 (d, J ¼ analysis. Yield (1.75 g, 76%). MS (ESI) calculated for [M + H]+
15.1 Hz, 48H), 1.15 (s, 9H), 0.88 (t, J ¼ 7.0 Hz, 6H). 13C NMR C15H31N2O4 m/z 303.22, found 303.53.
+
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RSC Adv., 2018, 8, 9587–9596 | 9593