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mode) calcd for C22H34NO5Si: 420.2206, found m/z 420.2211 [M purication. C22H33NO7Si; brown oil; TLC (EtOAc–hexane ¼
ꢀ H]ꢀ; anal. calcd for C22H35NO5Si: C, 62.67; H, 8.37; N, 3.32%. 7 : 3) Rf ¼ 0.26; 1H NMR (400 MHz, CDCl3, a mixture of
Found: C, 62.47; H, 8.06; N 3.14%.
Benzyl
rotamers) d 7.36–7.25 (5H, m), 5.27–5.05 (3H, m), 5.54/4.51 (1H,
(2R,3S,5S)-3-acetoxy-2-(tert-butyldimethylsilyloxy)- d, J ¼ 10.0 Hz), 4.07–3.74 (3H, m), 2.74–2.59 (1H, m), 2.30/2.22
methyl-5-(hydroxymethyl)pyrrolidine-1-carboxylate (12). To a (1H, d, J ¼ 14.0 Hz), 1.97/1.94 (3H, s), 0.84/0.82 (9H, s), 0.00/
solution of 11 (2.24 g, 5.31 mmol) in anhydrous CH3CN (50 mL) ꢀ0.03/ꢀ0.07/ꢀ0.10 (6H, s); ESI-HRMS (negative mode) calcd for
was added mercuric(II) acetate (3.38 g, 10.60 mmol) at 0 ꢁC. The
mixture was slowly warmed to room temperature over 1.5 h, and
C
22H32NO7Si: 450.1954, found m/z 450.1948 [M ꢀ H]ꢀ.
Benzyl (2S,4S,5R)-4-hydroxy-5-hydroxymethyl-2-(2-phospho-
added a mixture of EtOAc–brine (v/v ¼ 1 : 1, 44 mL). The nylethylamino)carbonyl-pyrrolidine-1-carboxylate (14). To
a
resulting biphasic mixture was stirred at room temperature for solution of acid 13 (467 mg, 1.03 mmol) in anhydrous THF
30 min, and diluted with EtOAc. The aqueous phase was (5.0 mL) was added N-hydroxysuccinimide (146 mg, 1.26 mmol)
extracted twice with EtOAc. The combined organic extract was and N,N0-dicyclohexylcarbodiimide (DCC, 258 mg, 1.25 mmol)
dried over MgSO4, ltered, and concentrated under reduced at 0 ꢁC. The mixture was warmed to room temperature over 16 h,
pressure to afford a crude organomercuric compound (3.87 g) as and ltered. The ltrate was concentrated under reduced
colorless oil, which was used in the next step without further pressure, and puried by chromatography on a silica gel
purication.
column (EtOAc–hexane, 4 : 6 to 5 : 5) to yield 13-OSu, the suc-
A solution mixture of NaBH4 (333 mg, 8.80 mmol) in anhy- cinimide ester of 13 (480 mg, 85%). C26H36N2O9Si; colorless
drous DMF (100 mL) was bubbled with oxygen at room foam; TLC (EtOAc–hexane ¼ 5 : 5) Rf ¼ 0.45; [a]2D3 ꢀ53.3 (c 2.80,
1
temperature for 30 min. To this mixture was added dropwise a CHCl3); IR vmax (neat) 1824, 1788, 1741, 1714, 1215 cmꢀ1; H
DMF (50 mL) solution of the above-prepared organomercuric NMR (400 MHz, CDCl3, a mixture of rotamers) d 7.34–7.26 (5H,
compound via an addition funnel over 3 h with continuous m), 5.29–5.19 (2H, m), 5.07/5.06 (1H, d, J ¼ 12.0 Hz), 4.83/4.78
bubbling of oxygen. The resulting gray mixture was ltered (1H, dd, J ¼ 10.0, 0.8 Hz), 4.10–4.00 (2H, m), 3.79–3.73 (1H, m),
through a pad of Celite, and the ltrate was concentrated under 2.85–2.74 (5H, m), 2.46/2.44 (1H, s), 2.02/2.01 (3H, s), 0.83/0.82
reduced pressure. The residue was diluted with EtOAc, and (9H, s), 0.00/ꢀ0.04/ꢀ0.07/ꢀ0.10 (6H, s); 13C NMR (100 MHz,
washed with H2O and brine. The organic phase was dried over CDCl3, a mixture of rotamers) d 170.49, 170.45, 168.3, 167.2,
MgSO4, ltered, concentrated, and puried by chromatography 166.6, 153.8, 153.5, 135.8, 128.4, 128.3, 128.24, 128.19, 128.1,
on a silica gel column (EtOAc–hexane, 2 : 8 to 4 : 6) to yield 127.9, 76.8, 75.7, 67.7, 67.5, 66.2, 65.4, 62.2, 61.2, 57.5, 57.2,
pyrrolidine 12 (2.52 g, 78%). C22H35NO6Si; white solid; mp 94.9– 36.1, 34.8, 34.0, 25.88, 25.86, 25.7, 25.0, 21.1, 21.0, 18.2, ꢀ5.5,
96.8 ꢁC; TLC (EtOAc–hexane, 4 : 6) Rf ¼ 0.37; HPLC (Agilent HC- ꢀ5.6; ESI-HRMS calcd for C26H37N2O9Si: 549.2268, found m/z
C18 column, 4.6 ꢂ 250 mm, 5 mm porosity) tR 43.6 min 549.2271 [M + H]+.
(CH3CN–H2O (3 : 2) elution at a ow rate of 0.5 mL minꢀ1);
A solution of the above-prepared 13-OSu (87.0 mg, 0.17
mmol) in DMF (0.4 mL) was added slowly to a stirring solution
[a]D25 ꢀ29.2 (c 1.16, EtOAc); IR vmax (neat) 3459, 1739, 1701 cmꢀ1
;
1H NMR (400 MHz, CDCl3, a mixture of rotamers) d 7.34–7.31 of (2-aminoethyl)phosphonic acid (26.0 mg, 0.21 mmol) in
(5H, m), 5.22–5.05 (3H, m), 4.39–3.60 (7H, m), 2.61–2.52 (1H, H2O–Et3N (0.2 mL, v/v ¼ 1 : 1) at room temperature. The
m), 2.04/1.99 (3H, s), 1.86–1.71 (1H, m), 0.84/0.82 (9H, s), 0.00/ mixture was stirred at room temperature for 5 h, and then
ꢀ0.07 (3H, s), ꢀ0.03/ꢀ0.08 (3H, s); 1H NMR (400 MHz, with concentrated under reduced pressure. The crude product was
additive ZnCl2 in CDCl3) d 7.35 (5H, br), 7.18 (1H, br, OH), 5.29 dissolved in THF (5.0 mL), and treated with tributylammonium
(1H, d, J ¼ 12.0 Hz), 5.18–5.12 (2H, m), 4.56 (1H, m), 4.23 (1H, t, uoride (TBAF, 0.3 mL of 1 M solution in THF). The mixture
J ¼ 10.4 Hz), 4.03–3.96 (2H, m), 3.76–3.68 (2H, m), 2.61 (1H, was stirred at room temperature for 1 h, and concentrated
ddd, J ¼ 14.4, 9.6, 5.2 Hz), 2.08 (3H, s), 1.72 (1H, d, J ¼ 14.4 Hz), under reduced pressure. The residue was stirred in NH3 (3 mL
0.81 (9H, s), ꢀ0.08 (3H, s), ꢀ0.10 (3H, s); 13C NMR (100 MHz, of 2 M methanolic solution) at room temperature for 15 h,
with additive ZnCl2 in CDCl3) d 170.9, 158.1, 134.2, 128.7 (2ꢂ), concentrated under reduced pressure, and separated by anion-
128.6 (2ꢂ), 76.6, 70.1, 70.0, 67.1, 61.2, 59.8, 33.7, 25.8, 21.6 (3ꢂ), exchange chromatography (diethylaminoethyl cellulose, DE52)
18.1, ꢀ5.70 (2ꢂ), ꢀ5.74; ESI-HRMS calcd for C22H36NO6Si: with elution of 0.5 M ammonium acetate in methanol. The
438.2312, found m/z 438.2295 [M + H]+; anal. calcd for product fraction was concentrated under reduced pressure,
C
22H35NO6Si: C, 60.38; H, 8.06; N, 3.20%. Found: C, 60.44; H, desalted and puried by chromatography on a reversed-phase
7.95; N 2.91%. RP-C18 column (1% NH4OH in H2O) to afford phosphonate 14
Benzyl (2S,4S,5R)-4-acetoxy-5-[(tert-butyldimethylsilyloxy)- (47.0 mg, 62%). C16H29N4O8P; colorless foam; TLC (i-PrOH–
methyl]pyrrolidine-2-carboxylate (13). To a solution of alcohol NH4OH–H2O ¼ 10 : 3: 2) Rf ¼ 0.28; [a]2D4 ꢀ19.4 (c 0.60, MeOH);
;
12 (207 mg, 0.47 mmol) in CH3CN–CCl4–H2O (3 mL, v/v/v ¼ IR vmax (KBr) 3212, 1686 cmꢀ1 1H NMR (400 MHz, D2O, a
2 : 2 : 3) was added sodium periodate (405 mg, 1.89 mmol) and mixture of rotamers) d 7.46–7.34 (5H, m), 5.22–5.02 (2H, m),
RuCl3$3H2O (6 mg, 0.022 mmol). The mixture was stirred at 0 ꢁC 4.38–3.97 (2H, m), 3.95–3.73 (1H, br), 3.73–3.36 (3H, m), 3.22
(ice bath) for 3 h, and then ltered through a pad of Celite. The (1H, dd, J ¼ 16.0, 8.8 Hz), 2.63–2.51 (1H, m), 1.99–1.57 (3H, m);
ltrate was diluted with EtOAc, and washed with 1 M HCl and 13C NMR (100 MHz, D2O, a mixture of rotamers) d 174.6, 174.2,
brine. The organic phase was dried over MgSO4, ltered, and 156.1, 155.6, 135.7, 128.9, 128.8, 128.74, 128.67, 128.6, 128.2,
concentrated under reduced pressure to afford acid 13 (196 mg, 128.1, 127.6, 73.3, 73.0, 72.5, 68.8, 68.4, 68.2, 68.2, 61.8, 60.9,
92%), which was used in the next step without further 60.6, 59.7, 36.9, 36.3, 35.5, 28.7, 27.4; 31P NMR (162 MHz, D2O,
Med. Chem. Commun.
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