Lanthanide-Catalyzed Transamidation
SCHEME 6
General Procedure for the Fmoc Protection of Lac-
tams. To a solution of the lactam in THF at -78 °C was added
LHMDS (0.95 equiv, 1 M solution in THF) slowly. The
resultant pale yellow mixture was stirred at -78 °C for 15
min, and slowly transferred by cannula to a solution of Fmoc-
Cl (5 equiv) in THF at -78 °C. The reaction was allowed to
stir at -78 °C for 2 h, after which it was allowed to rise to
room temperature. After 14 h of stirring at room temperature,
the reaction was quenched by addition of sat. NH4Cl (2 mL)
and H2O (1 mL). The solution was extracted with EtOAc and
washed with brine. The organic phase was dried over Na2SO4
and concentrated under reduced pressure. The crude product
was purified by flash column chromatography.
pressure, the crude product was purified by flash column
chromatography with 50% EtOAc/hexane followed by 80%
EtOAc/hexane, yielding 15 as a colorless oil (88 mg, 77%): IR
(NaCl, cm-1) 3345 (br), 3203, 3066, 2975, 2936, 1716, 1662,
1516, 1452, 1427, 1369, 1345, 1156; 1H NMR (300 MHz, CDCl3)
δ 7.79-7.76 (m, 2H), 7.60 (d, 2H, 7 Hz), 7.45-7.27 (m, 4H),
6.83 (br, 1H), 5.64 (d, 1H, 8.8 Hz), 5.57 (br, 1H), 4.60-4.55
(m, 1H), 4.46-4.40 (m, 1H), 4.25-4.17 (m, 1H), 2.37 (dd, 1H,
6.5, 3.5 Hz), 1.82 (br, 1H), 1.49 (s, 9H), 1.16 (d, 3H, 7 Hz),
0.94 (d, 3H, 7 Hz) ppm; 13C NMR (75 MHz, CDCl3) δ 175.9,
170.7, 156.8, 143.7, 143.4, 141.4, 141.3, 127.8, 127.1, 125.0,
124.9, 120.0, 119.9, 82.9, 66.9, 57.6, 47.3, 41.6, 40.0, 27.9, 16.1,
12.4 ppm; HRMS (ESI) calcd for C26H32N2O5 (Na+) 475.2209,
found 475.2213.
tert-Butyl N-Fmoc-(2S,3S,4R)-3,4-dimethylpyrogluta-
mate (7). The general procedure for Fmoc protection of lactam
was followed with use of tert-butyl (2S,3S,4R)-3,4-dimethylpy-
roglutamate (14) (27 mg, 0.13 mmol) in THF (2 mL). Flash
column chromatography with 20% EtOAc/petroleum ether
yielded 7 as a colorless oil (48 mg, 87%): IR (NaCl, cm-1) 3066,
2977, 2935, 2978, 1798, 1761, 1722, 1478, 1451, 1387, 1369,
1303, 1156; 1H NMR (300 MHz, CDCl3) δ 7.75 (d, 4H, 7.6 Hz),
7.41-7.24 (m, 4H), 4.55-4.3 (m, 3H), 4.14 (s, 1H), 2.85 (p, 1H,
7 Hz), 2.50 (p, 1H, 7 Hz), 1.44 (s, 9H), 1.16 (d, 3H, 7 Hz), 1.10
(d, 3H, 7 Hz) ppm; 13C NMR (75 MHz, CDCl3) δ 174.9, 169.6,
151.9, 143.6 143.4, 141.3, 141.2, 127.8, 127.3, 125.5, 119.9,
82.6, 69, 64.9, 46.7, 40.7, 34.7, 27.9, 15.4, 9.9 ppm; HRMS (ESI)
calcd for C26H29NO5 (Na+) 458.1943, found 458.1945.
tert-Butyl NR-Fmoc-(2S,3S,4R)-3,4-dimethylglutamine
(15). To a solution of Me2AlCl (2.52 mL of a 1 M solution in
CH2Cl2, 2.52 mmol) in CH2Cl2 (4 mL) at -8 °C was bubbled
gaseous NH3 for 4 min. The reaction was allowed to stir at
-8°C for 15 min and allowed to warm to room temperature.
Over 30 min CH2Cl2 was removed by using a flow of nitrogen
gas to afford a colorless slurry. The residue was added to THF
(7 mL) and allowed to stir at 25 °C for a minute. Lactam 7
(110 mg, 0.252 mmol) and Eu(OTf)3 (60 mg, 0.10 mmol) in THF
(1.1 mL) was added to the reaction mixture. After 30 min the
reaction was quenched with 0.1 N HCl (25.2 mL, 2.52 mmol)
and EtOAc (10 mL). The aqueous layer was extracted with
EtOAc. Organic fractions were combined, washed with brine,
and dried over Na2SO4. After removal of solvent under reduced
N-Fmoc-(2S,3S,4R)-3,4-dimethylglutamine (6). A solu-
tion of tert-butyl N-Fmoc-(2S,3S,4R)-3,4-dimethylglutamine
(15) (88 mg, 0.20 mmol) in 30% TFA-CH2Cl2 (1.5 mL) was
allowed to stir at room temperature for 90 min. Removal of
solvent and TFA by evaporation under reduced pressure
yielded N-Fmoc-(2S,3S,4R)-3,4-dimethylglutamine (6) as a
fine, colorless powder (72 mg, 93%): mp >210 °C dec; IR (NaCl,
cm-1) 3323 (br), 3066, 2923, 2851, 1702, 1671, 1609, 1515,
1
1450, 1412, 1319, 1227, 1034; H NMR (300 MHz, C2D6SO) δ
7.89 (d, 2H, 7.6 Hz), 7.75 (d, 2H, 6.5), 7.44-7.33 (4H, m), 6.82
(s, 1H), 4.25 (br s, 3H), 4.15 (m, 1H), 2.34 (t, 1H, 7 Hz), 1.97
(br s, 1H), 1.42 (s, 1H), 1.09 (d, 3H, 6.4 Hz), 0.87 (d, 3H, 5.9
Hz) ppm; 13C NMR (75 MHz, C2D6SO) δ 181, 174.5, 158.7,
145.5, 145.3, 142.7, 128.3, 126.5, 126.3, 121.2, 121.1, 68.2, 57.4,
48.3, 44.0, 40.5, 16.9, 10.5 ppm; HRMS (ESI) calcd for
C22H24N2O5 (Na+) 419.1583, found 419.1583.
Acknowledgment. We thank the National Insti-
tutes of Health (AI-50888) for financial support of this
work.
Supporting Information Available: Complete experi-
mental descriptions of transformations not included in the
Experimental Section and characterization for all new com-
pounds. This material is available free of charge via the
JO050518R
J. Org. Chem, Vol. 70, No. 16, 2005 6221