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PAPER
Dipeptides 15; General Procedure 4 (GP4)
N-tert-Butoxycarbonylglycinyl[(1-benzyloxymethyl-2-phenyl-
cyclopropylcarbamoyl)cycloxehyl](3-chlorobenzyl)amide (15c)
Crude 15c was prepared according to GP4 from cyclohexanone (49
mg, 0.5 mmol), 3-chlorobenzylamine (71 mg, 0.5 mmol), isonitrile
4c (132 mg, 0.50 mmol) and N-Boc-Gly-OH (88 mg, 0.5 mmol) in
MeOH (5 mL) and was purified by column chromatography on sil-
ica gel to give dipeptide 15c (285 mg, 86%) as a colorless solid; mp
57–59 °C; Rf = 0.13 (Et2O–hexane, 1:1).
A solution of the respective aldehyde (or ketone) 12, the amine 13,
the isonitrile 4a–c, 7, 11 and the acid 14 in MeOH was stirred for 2
h at 25 °C. The solvent was removed in vacuo, and the crude prod-
uct was purified by recrystallization or column chromatography on
silica gel.
Cyclopropanecarboxylic Acid Benzyl{[1-(4-chlorobenzyl)-2-
ethylcyclopropylcarbamoyl]cyclopropylmethyl}amide (15a)
Crude 15a was prepared according to GP4 from cyclopropanecarb-
aldehyde (210 mg, 3.00 mmol), benzylamine (107 mg, 1.00 mmol),
isonitrile 4b (220 mg, 1.00 mmol) and cyclopropanecarboxylic acid
(129 mg, 1.50 mmol) in MeOH (5 mL) and was purified by column
chromatography on silica gel to give 15a (322 mg, 69%) as a pale
yellow oil; Rf = 0.45 (Et2O–hexane, 1:1).
IR (KBr): 3428, 3358, 3067, 3028, 2979, 2933, 2865, 1684, 1497,
1165 cm–1.
1H NMR (300 MHz): d = 1.05–1.44 (m, 11 H, t-C4H9, Cpr-H),
1.48–1.64 (m, 8 H, cHex-H), 2.42 (m, 2 H, cHex-H), 2.48 (t, J = 7.2
Hz, 1 H, Cpr-H), 3.08 (d, J = 10.8 Hz, 1 H, CH2O), 3.51 (d, J = 10.8
Hz, 1 H, CH2O), 3.84 (br s, 2 H, NCOCH2NHCOO), 4.25 (d,
J = 12.0 Hz, 1 H, CH2Ph), 4.33 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.55
(s, 2 H, CH2Ar), 5.38 (br s, 1 H, NH), 6.70 (s, 1 H, NH), 7.08–7.42
(m, 14 H, Ph-H + Ar-H).
13C NMR (75.5 MHz, APT, add. HSQC, CDCl3): d = 16.4 (–, Cpr-
CH2), 22.8 (–, cHex-CH2), 25.3 (–, cHex-CH2), 28.3 [+, C(CH3)3],
29.7 (+, Cpr-CH), 32.8 (–, cHex-CH2), 38.2 (–, Cpr-Cquat), 43.7 (–,
NCOCH2NHCOO), 46.5 (–, CH2Ar), 66.5 (–, cHex-Cquat), 71.6 (–,
Cpr-CH2O), 72.9 (–, PhCH2O), 79.6 [–, C(CH3)3], 124.0, 126.0,
126.4, 127.4, 127.5, 127.8, 128.0, 128.2, 129.3, 130.4 (+, 14 C, Ph-
CH + Ar-CH), 135.0, 137.2, 138.3, 139.9 (–, Ph-Cquat + Ar-Cquat),
155.6, 170.1, 173.2 (–, CON).
IR (film): 3313, 3067, 3006, 2961, 2930, 2873, 1739, 1684, 1617,
1492, 1430, 1241 cm–1.
1H NMR (300 MHz, CDCl3): d (mixture of the 8 diastereomers) =
0.05–0.20 (m, 4 H, Cpr-CH), 0.30–1.80 (m, 32 H, Cpr-CH,
CH2CH3), 2.55–3.25 (m, 4 H, CH2Ar), 3.82 (t, J = 12.0 Hz, 2 H,
CH), 4.65–4.75 (m, 4 H, NCH2Ph), 6.40–6.75 (m, 2 H, NH), 7.05–
7.35 (m, 18 H, Ph-H + Ar-H).
13C NMR (50.3 MHz, CDCl3): d (mixture of the 8 diastereomers) =
4.78, 4.83, 4.91, 5.04, 5.14, 5.29, 8.09, 8.29, 8.36, 8.53, 8.78, 8.89,
8.94, 9.03, 10.06, 10.14, 10.18, 10.30, 11.90, 11.97, 12.01, 12.54,
12.94, 13.70, 13.80, 13.82, 18.72, 18.79, 19.21, 19.32, 21.85, 21.94,
23.06, 23.15, 25.92, 26.06, 28.03, 28.19, 35.84, 35.94, 37.07, 37.30,
38.01, 38.06, 41.27, 41.37, 48.63, 48.74, 48.85 (Cpr-C, CH2CH3,
CH2Ph, CH2Ar), 63.40, 63.56, 63.90, 64.04 (CH), 126.14, 126.20,
126.97, 127.03, 128.22, 128.25, 128.30, 128.33, 128.40, 128.43,
128.73, 130.46, 130.50, 130.55, 130.63, 130.73, 131.91, 132.01,
137.80, 137.92, 137.97, 138.01, 138.04 (Ph-CH/Cquat + Ar-CH/
MS (ESI): m/z (%) = 1345/1343/1341 (8/39/71, [2 M + Na+]), 684/
682 (5/19, [M + Na+]).
Anal. Calcd for C38H46ClN3O5: C, 69.13; H, 7.02; N, 6.36. Found:
C, 68.94; H, 6.89; N, 6.08.
Cyclopropanecarboxylic Acid (Benzyl)[(3-tert-butoxy-N-carbo-
nyl-3-azabicclo[3.1.0]hexylcarbamoyl)cyclopropylmethyl]-
amide (15d)
Cquat), 170.70, 170.82, 171.13, 171.63, 175.72, 175.80 (CNO); it
was not possible to single out all carbon signals.
Crude 15d was prepared according to GP4 from cyclopropanecarb-
aldehyde (107 mg, 1.53 mmol), benzylamine (54.6 mg, 0.51 mmol),
isonitrile 7 (161 mg, 0.77 mmol) and cyclopropanecarboxylic acid
(66.2 mg, 0.77 mmol) in MeOH (5 mL) and was purified by column
chromatography on silica gel (Et2O–Hexane, 1:1) to give dipeptide
15d (186 mg, 81%) as a colorless solid; mp 122–124 °C; Rf = 0.08
(Et2O–hexane, 1:1).
MS (EI): m/z (%) = 466/464 (<1/<1, [M+]), 291/289 (6/21), 256
(98), 228 (42), 160 (100), 91 (89).
Anal. Calcd for C28H33ClN2O2: C, 72.32; H, 7.15; N, 6.02. Found:
C, 72.10; H, 6.99; N, 5.88.
Cyclopropanecarboxylic Acid Benzyl-{[1-(4-chlorobenzyl)cy-
clopropylcarbamoyl]cyclopropylmethyl}amide (15b)
IR (KBr): 3440, 3281, 3067, 2973, 2932, 2859, 1705, 1612, 1420,
1394, 1114 cm–1.
Crude 15b was prepared according to GP4 from cyclopropanecarb-
aldehyde (350 mg, 5.00 mmol), benzylamine (107 mg, 1.00 mmol),
isonitrile 4a (287 mg, 1.50 mmol) and cyclopropanecarboxylic acid
(129 mg, 1.50 mmol) in MeOH (5 mL) and was purified by column
chromatography on silica gel to give dipeptide 15b (242 mg, 55%)
as a colorless solid; mp 112–114 °C; Rf = 0.23 (Et2O–hexane, 1:1).
1H NMR (250 MHz, CDCl3): d = 0.10–0.30 (m, 3 H, Cpr-H), 0.40–
1.30 (m, 5 H, Cpr-H), 1.39 (s, 9 H, tBu), 1.50–1.70 [m, 4 H, Cpr-H,
CH (bicycle)], 2.37 [m, 1 H, CHNH (bicycle)], 3.30–3.40 [m, 2 H,
CH2 (bicycle)], 3.55–3.70 [m, 2 H, CH2 (bicycle)], 3.93 (d, J = 10.3
Hz, 1 H, CH), 4.92 (s, 2 H, CH2Ph), 6.77 (s, 1 H, NH), 7.10–7.35
(m, 5 H, Ph-H).
13C NMR (62.9 MHz, CDCl3): d = 5.1, 8.3, 8.7, 9.0, 10.4, 12.2 (Cpr-
CH), 23.7, 24.2 [CH (bicycle)], 28.4 [C(CH3)3], 32.3 [CHNH (bicy-
cle)], 47.4, 47.6 [CH2 (bicycle)], 48.9 (CH2Ph), 63.5 (CH), 79.4
[C(CH3)3], 126.1, 127.0, 128.4, 137.9 (6 C, Ph-CH + Ph-Cquat),
154.4 (NCOO), 171.8, 175.9 (CON).
IR (KBr): 3429, 3307, 3083, 3022, 2953, 2929, 2853, 1640, 1533,
1431 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.10–0.20 (m, 2 H, Cpr-H), 0.50–
1.10 (m, 11 H, Cpr-H), 1.50–1.60 (m, 1 H, Cpr-H), 2.78 (d, J = 13.2
Hz, 1 H, CH2Ar), 2.98 (d, J = 13.2 Hz, 1 H, CH2Ar), 3.82 (d,
J = 10.8 Hz, 1 H, CH), 4.74 (s, 2 H, CH2Ph), 6.52 (s, 1 H, NH),
7.10–7.40 (m, 9 H, Ph-H + Ar-H).
13C NMR (50.3 MHz, APT, CDCl3): d = 4.8, 5.3, 8.3, 8.9 (–, Cpr-
CH2), 10.1, 11.9 (+, Cpr-CH), 13.3, 13.4 (–, Cpr-CH2), 33.7 (–, Cpr-
Cquat), 40.4 (–, CH2Ph), 48.8 (–, CH2Ar), 63.7 (+, CH), 126.2, 127.0,
128.6, 128.4, 130.6 (+, 9 C, Ph-CH + Ar-CH), 132.2, 137.6, 137.9
(–, Ph-C + Ar-C), 171.2, 175.8 (–, CON).
MS (ESI): m/z (%) = 498 (57, [M + HCOO–]), 452 (100, [M – H+]).
Anal. Calcd for C26H35N3O4: C, 68.85; H, 7.78; N, 9.26. Found: C,
68.64; H, 7.51; N, 9.04.
Cyclopropanecarboxylic Acid [(3-tert-Butoxycarbonyl-3-azabi-
cyclo[3.1.0]hexylcarbamoyl)cyclopropylmethyl](phenyl)amide
(15e)
Crude 15e was prepared according to GP4 from cyclopropanecarb-
aldehyde (105 mg, 1.50 mmol), aniline (47 mg, 0.5 mmol), isoni-
trile 7 (156 mg, 0.75 mmol) and cyclopropanecarboxylic acid (64.5
MS (EI): m/z (%) = 438/436 (<1/<1, [M+]), 256 (54), 228 (43), 160
(100), 91 (60).
Anal. Calcd for C26H29ClN2O2: C, 71.46; H, 6.69; N, 6.41. Found:
C, 71.65; H, 6.60; N, 6.53.
Synthesis 2007, No. 1, 131–139 © Thieme Stuttgart · New York