Peptidomimetics
2730±2739
1H), 3.41 (s, 3H), 2.64 (d, J 5.4 Hz, 1H), 2.07 (d, J 5.4 Hz, 1H);
13C NMR (CDCl3, 75 MHz): d 171.1, 142.1, 140.7, 137.2, 130.8, 129.9, 128.7,
128.3, 128.3, 128.2, 127.1, 126.8, 126.7, 126.6, 126.07, 51.8, 47.1, 38.8, 22.5; IR
(51 mg, 0.26 mmol), TFFH (90 mg, 0.34 mmol), CH2Cl2 (1.0 mL), and then
NEtiPr2 (110 mg, 0.85 mmol, 148 mL). This was stirred at 258C for 34 min.
This acid fluoride was added to a solution of the free amine, CH2Cl2
(2.0 mL) and NEtiPr2 (300 mL) at 258C. The reaction mixture was
concentrated after 30 min yielding a thick oil. The crude product was
purified by flash chromatography with a gradient of 25 ± 30% EtOAc/
hexanes as the eluting solvent and 4 was yielded (60.2 mg, 74% yield) as a
white powder. Rf 0.40 (40% EtOAc/hexanes); m.p. 231 ± 2328C; 1H NMR
(CDCl3, 300 MHz): d 7.60 ± 7.43 (m, 6H), 7.35 ± 7.16 (m, 8H), 6.91 (br,
1H), 3.85 (d, J 6.9 Hz, 1H), 2.66 (d, J 6.0 Hz, 1H), 2.04 (d, J 6.3 Hz,
1H), 1.11 (d, J 6.3 Hz, 3H), 0.96 (d, J 6.6 Hz, 1H); 13C NMR (CDCl3,
75 MHz): d 168.6, 167.6, 140.1, 139.4, 132.5, 131.7, 129.5, 128.9, 128.5,
128.4, 128.4, 127.2, 127.2, 126.5, 46.3, 45.4, 41.8, 23.8, 22.4, 22.4; IR (neat):
(neat): u 3065, 3034, 2951, 2368, 1739, 1494 cm 1; [a]D25
137 (c 8.85 in
CHCl3); HRFAB: calcd [MH] 354.1620, found 354.1632; C25H22O2
(354.45): C 84.7, H 6.26; found: C 84.6, H 6.33.
(1S)-Methyl-1-{N-[(1,1-dimethylethyl)oxycarbonyl]amino}-2,2-diphenyl-
cyclopropane-1-carboxylate (7): RuCl3 ´ H2O (7 mg, 0.0036 mmol, 2 mol%)
was added to a rapidly stirred solution of 6 (591 mg, 1.7 mmol, 1 equiv),
sodium periodate (2.9 g, 13.6 mmol, 8 equiv), MeCN, CCl4 (3.4 mL,
2 mLmol 1), and H2O (5.1 mL, 3 mLmol 1). This solution was stirred at
258C for 2 h. The crude reaction mixture was filtered through a plug of
silica gel on Celite, washed with EtOAc (500 mL), concentrated to a dark
viscous oil, and azeotroped with benzene (3 Â 4 mL) to remove water. The
crude acids were dissolved in freshly distilled tBuOH (30 mL), diphenyl-
phosphoryl azide (1.0 g, 0.4 mmol, 2.2 equiv), and triethylamine (413 mg,
4.1 mmol, 2.4 equiv), and then heated to reflux for 33 h. The reaction
mixture was then concentrated to a thick oil. The crude product was
purified by flash chromatography using 1:1 CH2Cl2/10% (EtOAc/hexanes)
as the eluent yielding 7 (624 mg, 90% yield) as a yellow oil. Rf 0.38 (10%
EtOAc/hexanes); 1H NMR (CDCl3, 300 MHz): d 7.38 ± 7.10 (m, 10H),
4.91 (brs, 1H), 3.46 ± 3.32 (m, 3H), 2.62 ± 2.54 (m, 1H), 2.06 ± 2.01 (m, 1H),
1.35 (s, 9H); 13C NMR (CDCl3, 75 MHz): d 170.9, 155.8, 141.2, 129.0,
128.8, 128.6, 128.5, 127.3, 127.0, 80.3, 52.0. 28.2, 25.9; HRFAB: calcd
1
u 2933, 2409, 1665 cm
;
HRFAB: calcd [MH] 499.0997, found
499.1006; [a]D25 79.3 (c 0.56 in CHCl3); C26H25N2O2Br (477.40): C
65.41, H 5.28, N 5.87; found: C 65.77, H 5.72, N 5.69.
(S)-N-(4-Bromobenzoyl)phenylalanine-N'-(methylethyl)carboxamide (1):
Compund Boc-Phe-NHiPr was prepared by means of a procedure similar
to 9 except that Boc-Phe-OH (Advanced ChemTech) (150 mg, 0.565 mmol,
1 equiv) was used as substrate and the reaction time was reduced to 30 min
to give 125 mg (75%) of the intermediate Boc-Phe-NHiPr as a white solid.
Rf 0.29 (20% EtOAc/hexanes); m.p. 102 ± 1048C; 1H NMR (CDCl3,
300 MHz): d 7.31 ± 7.23 (m, 5H), 5.60 (d, J 6.6 Hz, 1H), 5.25 (s, 1H),
4.25 (q, J 8.4 Hz, 1H), 3.95 (m, 1H), 3.12 ± 2.95 (m, 2H), 1.43 (s, 9H), 1.05
(d, J 6.6 Hz, 4H), 0.95 (d, J 6.3 Hz, 2H); 13C NMR (CDCl3, 75 MHz):
d 170.0, 153.8, 136.9, 129.3, 128.5, 126.8, 95.0, 41.3, 39.0, 28.3, 22.5, 22.4;
[MH] 368.1862, found 368.1891.
(1S)-1-{N-[(1,1-Dimethylethyl)oxycarbonyl]amino}-2,2-diphenylcyclopro-
pane-1-carboxylic acid (8): Compound 7 (428 mg, 1.16 mmol, 1 equiv),
MeOH (10 mL), H2O (5 mL), and LiOH (487 mg, 11.6 mmol) were heated
to reflux for 4 h. The reaction mixture was concentrated and taken up in
EtOAc. The organic layer was extracted with NaOH (1m, 3 Â 5 mL). The
aqueous layer was then acidified with Hcl (1m), extracted with EtOAc (3 Â
50 mL), dried (Na2SO4), filtered, and concentrated yielding a yellow solid
(356 mg, 86% yield). Recrystallization from EtOAc/CHCl3 and hexanes
produced long white needles. Rf 0.13 (6% MeOH/CH2Cl2), 0.41 (11%
MeOH/CH2Cl2); m.p. 189 ± 1908C; 1H NMR (CDCl3, 300 MHz): d
10.65 ± 10.01 (brs, 1H), 7.43 ± 7.14 (m, 10H), 5.63 (brs, 1H), 2.56 (d, J
4.8 Hz, 1H), 1.96 (d, J 5.1 Hz, 1H), 1.36 (s, 9H); 13C NMR (CDCl3,
75 MHz): d 174.6, 156.5, 140.6, 139.2, 128.8, 128.6, 128.5, 127.3, 127.2, 80.2,
46.6, 44.5, 28.1, 26.0; IR (neat): u 3021, 2979, 1723, 1537 cm 1; HRFAB:
IR (KBr): n 3303, 2979, 1679, 1646, 1165 cm 1; HRFAB: [MNa] calcd
329.1841, found 329.1852; [a]2D5 9.7 (c 0.75 in CHCl3).
Product 1 was prepared by means of the procedure outlined above for the
synthesis of 4, but with compound Boc-Phe-NHiPr as prepared above
(166 mg, 0.57 mmol, 1 equiv) as substrate to give 200 mg (91%) of 1 as a
white solid. Rf 0.68 (40% EtOAc/hexanes); m.p. 217 ± 2188C; 1H NMR
(500 MHz, CDCl3): d 7.55 (q, J 33.5, 8.5 Hz, 4H), 7.33 ± 7.26 (brm, 5H),
7.21 (d, J 8.0 Hz, 1H), 5.54 (d, J 7.5 Hz, 1H), 4.74 (m, 1H), 3.95 (m, 1H),
3.26 (dd, J 7.5, 6.0 Hz, 1H), 3.03 (m, 1H), 0.96 (dd, J 36.0, 6.5 Hz, 6H);
13C NMR (125 MHz, CDCl3): d 169.6, 165.9, 136.7, 132.7, 131.9, 129.4,
128.7, 128.65, 127.1, 126.5, 55.3, 41.6, 39.2, 22.5, 22.3; IR (KBr): n 3421,
1717, 1656, 1287, 1073 cm 1; HRFAB: calcd [MNa] 411.0684, found
411.0694; [a]2D5 5.04 (c 0.67 in CHCl3).
calcd [MH] 368.1862, found 368.1891; [a]2D5 121 (c 8.15 in CHCl3);
(2S)-N-(4-Bromobenzoyl)-N-(methyl)phenylalanine-N'-(methylethyl)car-
boxamide (2): Boc-N-MePhe-NHiPr was prepared by means of the method
outlined above for Boc-Phe-NHiPr, but with Boc-N-MePhe-OH (Ad-
vanced ChemTech; 250 mg, 0.895 mmol) as substrate to give 211 mg (74%)
of Boc-N-MePhe-NHiPr as a colorless oil: Rf 0.36 (20% ethyl acetate/
hexanes); 1H NMR (CDCl3, 300 MHz): d 7.29 ± 7.20 (brm, 5H), 5.82 (s,
1H), 4.72 (d, J 5.7 Hz, 1H), 4.03 ± 4.08 (m, 1H), 3.30 (brm, 1H), 2.90 ±
2.98 (m, 1H), 2.76 (s, 3H), 1.38 (s, 6H), 1.29 (s, 3H), 1.10 ± 1.18 (m, 6H);
13C NMR (CDCl3, 75 MHz): d 169.4, 156.5, 138.1, 137.6, 128.9, 128.2,
126.3, 80.2, 62.0, 59.47, 41.4, 41.1, 34.0, 30.9, 30.5, 28.1, 22.6, 22.5; IR (NaCl):
C12H23NO4 (245.32): C 71.4, H 6.56, N 3.96; found: C 71.3, H 6.58, N 3.87.
(1S)-1-{N-[(1,1-Dimethylethyl)oxycarbonyl]amino}-2,2-diphenylcyclopro-
pane-1-N'-(methylethyl)carboxamide (9): Compound 8 (150 mg, 0.42 mmol),
tetramethylfluoroformamidium hexafluorophosphate (TFFH; 168.1 mg,
0.64 mmol, 1.5 equiv), CH2Cl2 (2.1 mL), and diisopropylethylamine (NE-
tiPr2; 82.3 mg, 0.64 mmol, 1.5 equiv, 111 mL) were stirred at 258C for
40 min. This solution was transferred through a cannula to a 08C solution of
isopropylamine (501 mg, 8.48 mmol, 722 mL) in CH2Cl2 (1.0 mL). The
reaction mixture was allowed to warm to 258C for 30 min after the
addition, and stirred for an additional 4 h. The reaction mixture was then
concentrated, taken up in EtOAc, and extracted with Hcl (0.5m, 3 Â
40 mL). The organic layer was dried, filtered, and concentrated yielding
an off-white viscous liquid. The crude product was purified by flash
1
n 3418, 1689, 1219 cm
;
HRFAB: calcd [MH] 321.2178, found
321.2181; [a]2D5
84.5 (c 1.01 in CHCl3).
Compound 2 was prepared by means of the procedure described for 1
above with Boc-N-MePhe-NHiPr (120 mg, 0.375 mmol) as substrate to give
111 mg (74%) of 2 as a white foam: Rf 0.33 (40% EtOAc/hexanes);
1H NMR (CDCl3, 300 MHz): d 7.43 (d, J 8.4 Hz, 2H), 7.29 ± 7.26 (brm,
5H), 6.93 (d, J 8.1 Hz, 2H), 6.32 (d, J 6.9 Hz), 5.28 (q, J 6.8, 3 Hz,
1H), 4.00 (m, 1H), 3.26 ± 3.31 (m, 1H), 3.09 ± 3.14 (m, 1H), 2.81 (s, 3H),
1.10 (d, J 6.3 Hz, 6H); 13C NMR (75 MHz, CDCl3): d 172.0, 168.7, 137.0,
134.22, 131.6, 128.8, 128.6, 126.7, 124.5, 57.6, 41.34, 33.7, 33.5, 22.7, 22.5; IR
chromatography with 30 ± 40% EtOAc/hexanes as eluent yielding
9
(144 mg, 92% yield) as an off-white viscous liquid. Rf 0.44 (EtOAc/
hexanes); m.p. 206 ± 2078C; 1H NMR (CDCl3, 300 MHz): d 7.50 ± 7.10 (m,
10H), 5.30 (brs, 1H), 3.87 (d, J 6.3 Hz, 1H), 2.59 (d, J 5.7 Hz, 1H), 1.78
(d, J 5.7 Hz 1H,), 1.28 (s, 9H), 1.09 ± 1.02 (m, 6H); 13C NMR (CDCl3,
75 MHz): d 168.0, 156.7, 140.7, 139.5, 129.4, 128.9, 128. 1, 126.9, 80.3, 46.1,
45.2, 41.4, 27.9, 23.6, 22.4; IR (neat): u 3439, 3316, 2976, 1694, 1652,
(CH2Cl2): n 3418, 1676, 1622, 1281, 1074 cm 1; HRFAB: calcd [MNa]
1175 cm 1; HRFAB: calcd [MH] 395.2335, found 395.2346; [a]2D5 171
425.0841, found 425.0859; [a]D25
105 (c 0.53 in CHCl3).
(c 0.52 in CHCl3); C24H30N2O3 (394.51): C 73.1, H 7.66, N 7.10; found: C
73.0, H 7.57, N 7.13.
(2S,3S)-1-[N-(4-Bromobenzoyl)amino]-2-phenylcyclopropyl-1-N'-(meth-
ylethyl)carboxamide (3): Boc-cyclo-Phe-NHiPr was prepared as described
above for Boc-Phe-NHiPr, but with (2S,3S)-Boc-cyclo-Phe-OH[29] (300 mg,
1.08 mmol) as the substrate and increasing the reaction time to 8 h to give
263 mg (64%) of Boc-cyclo-Phe-NHiPr as a white powder. Rf 0.48 (40%
ethyl acetate/hexanes); 1H NMR (CDCl3, 300 MHz): d 7.36 ± 7.16 (m,
5H), 6.28 (d, J 7.8 Hz, 1H), 4.11 ± 4.18 (m, 1H), 3.06 (brm, 1H), 2.10
(brm, 1H), 1.33 (brs, 9H), 1.17 (dd, J 5.1, 1.2 Hz, 6H); 13C NMR
(75 MHz, CDCl3): d 170.25, 155.53, 128.34, 126.95, 80.65, 41.71, 31.84,
(1S)-1-[N-(4-Bromobenzoyl)amino]-2,2-diphenylcyclopropane-1-N'-
(methylethyl)carboxamide (4): Compound
9 (62 mg, 0.17 mmol) and
CH2Cl2 (2.0 mL, 0.09m) were cooled to 08C. A solution of 50% TFA/
CH2Cl2 (2.0 mL) was added to this mixture, and it was stirred for 10 min.
The reaction mixture was allowed to warm to 258C and stirring was
continued for an additional 1.5 h. The reaction mixture was concentrated
and co-evaporated with CH2Cl2 (2 Â 2 mL) then placed in a high vacuum
for 0.5 h. Aside, a flame-dried flask was charged with 4-bromobenzoic acid
Chem. Eur. J. 1999, 5, No. 9
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2737