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10281
was then added dropwise to the mixture over 30 min. After
complete addition, the mixture was stirred at K78 8C for
20 min. The mixture was then slowly warmed to room
temperature overnight. The reaction solution was concen-
trated. The residue was purified by silica gel column
chromatography (eluted with hexane/EtOAc 3:1–1:1) to
give 11 (2.06 g, 72%) as white crystals, which could be
recrystallized from EtOAc/hexane, mpZ139–140 8C. RfZ
(1.26 g, 3.32 mmol) were dissolved in DMF (15 mL). The
mixture was cooled to 0 8C and treated with Et3N
(0.925 mL, 6.64 mmol). Stirring was continued in the ice
bath for 1 h and then the reaction was warmed to room
temperature and stirred overnight. The reaction was diluted
with H2O (30 mL), extracted with ethyl acetate (4!10 mL),
The combined organic layers were washed with 1 N HCl
(2!10 mL), 5% NaHCO3 (2!10 mL), brine (10 mL),
anhydrous MgSO4 and concentrated. The residue was
purified by silica gel column chromatography (eluted with
5% MeOH/CH2Cl2) to give 12 (0.9 g, 60%) as an oil. The
oil was crystallized in cold EtOAc to a white solid, mpZ
1
0.43 (3:1 hexane/EtOAc). H NMR (CDCl3) d 7.40–7.23
(m, 5H), 4.99 (s, 1H), 4.66 (s, 1H), 4.31 (d, JZ5.0 Hz, 1H),
3.26 (d, JZ14.2 Hz, 1H), 3.26 (d, JZ14.2 Hz, 1H), 1.44 (s,
4H). 13C NMR (CDCl3) d 171.3, 154.4, 133.5, 130.1, 129.5,
129.4, 128.3, 81.7, 70.5, 70.2, 39.5, 28.2. IR (CDCl3) 3435,
1838, 1717 cmK1. Anal. Calcd for C15H19NO4: C, 64.97; H,
6.91; N, 5.05. Found C, 64.82; H, 7.11; N, 5.07.
1
174–178 8C. H NMR (CDCl3) d 7.25 (m, 10H), 6.90 (d,
rotamer, 1H), 6.15 (d, rotamer, 1H), 5.10 (q, JZ19.2,
12.0 Hz, 2H), 4.42 (q, JZ15, 7.2 Hz, 1H), 3.86 (br s, 1H),
3.61 (br s, 1H), 3.12 (br s, 2H), 3.01 (s, rotamer, 2H), 2.88 (s,
rotamer, 1H), 1.94 (s, 3H), 1.27 (d, JZ7.2 Hz, 3H). 13C
NMR (CDCl3) d 172.7, 170.7, 155.4, 136.0, 134.7, 129.0,
127.9, 68.8, 65.9, 54.2, 49.0, 39.2, 35.7, 23.4, 18.2. IR
(CDCl3) 3428, 3052, 2988, 1788, 1721, 1687, 1421,
4.1.5. Benzyl N-(tert-butoxycarbonyl)-a-benzyl-serine-
azaalanine (2). To a solution of hydrazine 49 (2.10 g,
11.7 mmol) in CH2Cl2 (4 mL), trimethyl aluminum (2.0 M
in toluene, 5.83 mL, 11.7 mmol) was added dropwise and
stirred at room temperature for 1 h. b-Lactone 11 (1.10 g,
4.66 mmol) in CH2Cl2 (4 mL) was added to the mixture and
stirred overnight. The mixture was quenched with pH 7
phosphate buffer and extracted with CH2Cl2. The organic
extracts were combined, dried over anhydrous MgSO4 and
concentrated. The residue was purified by silica gel column
chromatography (eluted with hexane/EtOAc 1:1–2:1) to
give 9 (1.4 g, 68%) as colorless crystal. 1H NMR (CDCl3) d
8.9 (m, br, 1H), 7.20 (m, 10H), 5.59 (s, 1H), 5.13 (q, JZ
12.0 Hz, 2H), 4.61 (s, br, 1H), 3.78 (s, br, 1H), 3.41 (s, br,
2H), 3.22 (s, 4H), 1.40 (s, 9H). 13C NMR (CDCl3) d 173,
157.7, 155.5, 136.0, 130.9, 128.6, 80.5, 68.7, 66.7, 63.7,
1264 cmK1
.
HRMS calcd for C24H28N4O5C
NaC475.1957, found 475.1971.
4.1.8. 1-[(N-Methyl)-amino]-3-benzyl-3-[(N-acetyl-L-ala-
nine)amino]-2-azetidinone. b-Lactam 12 (0.45 g,
0.99 mmol) was dissolved in methanol (10 mL) at room
temperature under nitrogen, and Pd/C (4.5 mg) was added to
the solution. The reaction atmosphere was purged with H2,
stirring for 30 min. The reaction material was filtered
through Celite and concentrated to a white solid (0.30 g,
95%), which was used immediately without further
1
purification. H NMR (CD3OD) d 7.26 (m, 5H), 4.31 (m,
38.4, 36.3, 28.6. IR (CDCl3) 3407, 2981, 1715, 1694 cmK1
.
1H), 3.60 (dd, JZ4.8, 2.4 Hz, 1H), 3.50 (dd, JZ13.2,
5.1 Hz, 1H), 3.13 (d, JZ7.2 Hz, 2H), 2.16 (d, JZ18.6 Hz,
3H), 1.95 (s, 3H), 1.30 (dd, JZ9.9, 7.2 Hz, 3H). 13C NMR
(CDCl3) d 175.5, 173.6, 169.3, 136.2, 132.1, 130.0, 128.8,
66.5, 53.8, 52.9, 36.0, 23.0, 18.5. IR (CDCl3) 3295, 3294,
4.1.6. 1-[(N-Methyl,N-benzyloxycarbonyl)-amino]-3-
benzyl-3-[(tert-butoxycarbonyl)-amino]-2-azetidinone
(1). Triphenylphosphine (1.25 g, 4.78 mmol) was added to a
solution of 2 (2.08 g, 4.55 mmol) in THF (40 mL) and
stirred for 3 min. Diethyl azodicarboxylate (DEAD)
(0.753 mL, 4.78 mmol) was added in three portions over
15 min. The mixture was stirred overnight and concentrated.
The residue was purified by silica gel column chromato-
graphy (eluted with hexane/EtOAc 3:1) to give 1 (1.7 g,
85%) as white crystals, mpZ115–116 8C. 1H NMR
(CDCl3) d 7.22 (m, 10H), 5.12 (s, 2H), 4.99 (s, 1H), 3.83
(s, 2H), 3.61 (s, 1H), 3.15 (s, 2H), 2.95 (s, 3H), 1.43 (s, 9H).
13C NMR (CDCl3) d 166.5, 154.8, 154.2, 135.5, 134.7,
130.0, 128.5, 128.3, 127.9, 127.2, 80.4, 68.3, 65.5, 54.4,
39.1, 35.5, 28.2. IR (CDCl3) cmK1: 3431, 2981, 1784, 1716.
Anal. Calcd for C24H29N3O5: C, 65.59; H, 6.65; N, 9.56.
Found C, 65.38; H, 6.74; N, 9.42.
1752, 1654, 1542 cmK1
.
4.1.9.
1-[[N-Methyl,N-carbonyl-L-(methylleucyl)]-
amino]-3-benzyl-3-[(N-acetyl-L-alanine)amino]-2-aze-
tidinone (13). 1-[(N-Methyl)-amino]-3-benzyl-3-[(N-
acetyl-L-alanine)amino]-2-azetidinone (0.30 g, 0.94 mmol)
was dissolved in a mixture of dry CH2Cl2 (8 mL) and DMF
(5 mL), and cooled to 0 8C under N2. Leucine isocyanate,
methyl ester19 (0.34 g, 2 mmol) was added as a CH2Cl2
solution (4 mL). N,N-diisopropylethylamine (0.44 mL,
2.5 mmol) was added 2 min later. The solution was stirred
and allowed to slowly warm to room temperature. After
20 h, the reaction was quenched with 10% citric acid
(15 mL) and extracted with EtOAc (2!15 mL). The
organic layer was washed with 10% citric acid (1!
10 mL), H2O (1!10 mL), brine (1!10 mL), dried over
anhydrous MgSO4 and concentrated to give crude white wet
crystals (0.48 g). The residue was purified by silica gel
column chromatography (5% MeOH/CH2Cl2) to give 13
(0.40 g, 87%) as an oil. The oil was crystallized in EtOAc/
hexanes, mpZ155–158 8C. 1H NMR (CDCl3) as rotamers d
7.84 (s, 0.5H), 7.74 (s, 0.5H), 7.32 (m, 5H), 4.57 (dt, JZ7.2,
2.7 Hz, 1H), 4.40 (m, 0.5H), 4.29 (m, 0.5H), 3.91 (d, JZ
5.1 Hz, 0.5H), 3.80 (d, JZ5.1 Hz, 0.5H), 3.66 (s, 3H), 3.55
(dd, JZ7.5, 5.1 Hz, 1H), 3.24 (t, JZ13.8 Hz, 1H), 3.04 (dd,
JZ13.5, 7.8 Hz, 1H), 2.38 (d, JZ12.9 Hz, 3H), 2.00 (d,
4.1.7. 1-[(N-Methyl,N-benzyloxycarbonyl)-amino]-3-
benzyl-3-[(N-acetyl-L-alanine)amino]-2-azetidinone
(12). To a cold (0 8C) solution of 3 N HCl/EtOAc (15 mL),
b-lactam 1 (1.46 g, 3.32 mmol) was added and the reaction
was stirred, while slowly warming to room temperature.
After 1.5 h, the reaction was stopped and concentrated in
vacuo. Reconcentration from CHCl3 gave 1.6 g crude 12 as
the hydrochloride salt. 1H NMR (CD3OD) d 9.40 (br s, 2H),
7.26 (m, 10H), 4.93 (q, JZ12, 16.8, 12.0 Hz, 2H), 4.17 (s,
1H), 3.67 (s, 1H), 3.48 (br s, 2H), 2.92 (s, 3H). Crude 12
(1.6 g), N-acetyl-L-alanine (0.48 g, 3.65 mmol) and HATU