C. Cativiela et al. / Tetrahedron 60 (2004) 11923–11932
11931
calcd (%) for C31H39N3O3: C, 74.22; H, 7.84; N, 8.38;
found: C, 74.16; H, 7.79; N, 8.45.
4.4.5. N2-[(Ra)-N1-Benzoyl-(4-tert-butylcyclohexylidene)-
glycyl]-(S)-phenylalanine cyclohexylamide [(Ra,S)-4c].
The above general procedure, starting from 5(4H)-oxa-
zolone 2c (445 mg, 1.5 mmol), gave compound 4c (688 mg,
82%) as an equimolecular mixture of diastereoisomers.
Compound (Ra,S)-4c was eluted first upon additional
column chromatography and isolated as a white solid.
MpZ158 8C (dec); [a]2D5ZK72.4 (c 0.5, MeOH); IR
4.4.2. N2-[(Sa)-N1-Benzoyl-(4-methylcyclohexylidene)-
glycyl]-(S)-phenylalanine cyclohexylamide [(Sa,S)-4a].
Compound (Sa,S)-4a was eluted second upon additional
column chromatography and isolated as a white solid. MpZ
245 8C (dec); [a]2D5ZK84.2 (c 0.5, MeOH); IR absorption
absorption (nujol) 3319, 1661, 1640 cmK1 1H NMR
;
(nujol) 3303, 1656, 1631 cmK1 1H NMR (300 MHz,
;
(300 MHz, CDCl3) d 0.82 (s, 9H), 0.98–1.98 (m, 17H),
2.37 (bd, JZ13.3 Hz, 1H), 2.62 (bd, JZ14.0 Hz, 1H), 3.24
(d, JZ6.7 Hz, 2H), 3.66–3.84 (m, 1H), 4.80 (ddd, JZ8.7,
6.7, 6.7 Hz, 1H), 6.03 (d, JZ8.7 Hz, 1H), 7.15–7.27 (m,
6H), 7.31–7.39 (m, 2H), 7.42–7.50 (m, 1H), 7.67–7.73 (m,
2H), 8.00 (bs, 1H); 13C NMR (75 MHz, CDCl3) d 25.1, 25.2,
25.7, 27.4, 27.5, 28.6, 29.7, 30.1, 32.4, 32.6, 32.7, 37.3,
47.4, 48.7, 54.3, 122.7, 127.0, 127.2, 128.4, 128.8, 129.4,
131.8, 132.4, 136.7, 140.5, 166.6, 166.8, 169.4. Elemental
analysis calcd (%) for C34H45N3O3: C, 75.10; H, 8.34; N,
7.73; found: C, 75.22; H, 8.25; N, 7.83.
CDCl3) d 0.88 (d, JZ6.5 Hz, 3H), 1.00–1.97 (m, 17H),
2.09 (bd, JZ14.0 Hz, 1H), 2.49 (bd, JZ13.6 Hz, 1H), 3.12
(dd, JZ14.7, 8.9 Hz, 1H), 3.41 (dd, JZ14.7, 4.6 Hz, 1H),
3.70–3.85 (m, 1H), 4.89 (ddd, JZ8.9, 8.9, 4.6 Hz, 1H), 6.04
(d, JZ8.9 Hz, 1H), 7.17–7.28 (m, 7H), 7.33–7.41 (m, 1H),
7.58 (d, JZ8.1 Hz, 1H), 7.64–7.72 (m, 2H), 8.91 (bs, 1H);
13C NMR (75 MHz, CDCl3) d 21.7, 25.3, 25.4, 25.7, 29.1,
29.3, 32.4, 32.6, 32.9, 35.0, 36.0, 37.3, 48.7, 54.6, 123.1,
127.0, 127.4, 128.1, 128.7, 129.0, 131.7, 132.1, 137.2,
138.3, 166.7, 167.8, 169.3. Elemental analysis calcd (%) for
C31H39N3O3: C, 74.22; H, 7.84; N, 8.38; found: C,
74.21; H, 7.92; N, 8.42.
4.4.6. N2-[(Sa)-N1-Benzoyl-(4-tert-butylcyclohexylidene)-
glycyl]-(S)-phenylalanine cyclohexylamide [(Sa,S)-4c].
Compound (Sa,S)-4c was eluted second upon additional
column chromatography and isolated as a white solid. MpZ
129 8C (dec); [a]2D5ZK87.2 (c 0.5, MeOH); IR absorption
4.4.3. N2-[(Ra)-N1-Benzoyl-(4-phenylcyclohexylidene)-
glycyl]-(S)-phenylalanine cyclohexylamide [(Ra,S)-4b].
The above general procedure, starting from 5(4H)-oxa-
zolone 2b (475 mg, 1.5 mmol), gave compound 4b
(709 mg, 84%) as an equimolecular mixture of diastereo-
isomers. Compound (Ra,S)-4b was eluted first upon
additional column chromatography and isolated as a white
solid. MpZ201 8C (dec); [a]2D5ZK103.0 (c 0.5, MeOH);
1
(nujol) 3298, 1634 cmK1; H NMR (300 MHz, CDCl3) d
0.89 (s, 9H), 0.94–1.98 (m, 17H), 2.24 (bd, JZ13.9 Hz,
1H), 2.56 (bd, JZ13.3 Hz, 1H), 3.23 (dd, JZ14.3, 8.4 Hz,
1H), 3.34 (dd, JZ14.3, 4.9 Hz, 1H), 3.77–3.85 (m, 1H),
4.89 (ddd, JZ8.7, 8.4, 4.9 Hz, 1H), 6.02 (d, JZ8.7 Hz, 1H),
7.11–7.37 (m, 7H), 7.31–7.42 (m, 1H), 7.60 (d, JZ8.5 Hz,
1H), 7.63–7.73 (m, 2H), 8.89 (bs, 1H); 13C NMR (75 MHz,
CDCl3) d 25.3, 25.4, 25.7, 27.5, 27.7, 28.7, 29.6, 29.9, 32.4,
32.7, 32.8, 37.2, 47.8, 48.7, 54.5, 122.7, 127.1, 127.4, 128.2,
128.8, 129.2, 131.7, 132.1, 137.0, 138.5, 166.8, 167.7,
169.3. Elemental analysis calcd (%) for C34H45N3O3: C,
75.10; H, 8.34; N, 7.73; found: C, 74.98; H, 8.28; N, 7.79].
IR absorption (nujol) 3297, 1637 cmK1
;
1H NMR
(300 MHz, CDCl3) d 1.00–2.04 (m, 17H), 2.32 (bd, JZ
14.4 Hz, 1H), 2.60 (bd, JZ12.2 Hz, 1H), 3.11 (dd, JZ14.3,
8.6 Hz, 1H), 3.36 (dd, JZ14.3, 5.3 Hz, 1H), 3.72–3.84 (m,
1H), 4.82 (ddd, JZ8.7, 8.6, 5.3 Hz, 1H), 6.13 (d, JZ8.7 Hz,
1H), 7.09–7.32 (m, 11H), 7.36–7.44 (m, 2H), 7.46–7.54 (m,
1H), 7.73–7.76 (m, 2H), 7.91 (bs, 1H); 13C NMR (75 MHz,
CDCl3) d 25.2, 25.3, 25.7, 29.5, 29.7, 32.7, 32.8, 33.9, 34.5,
37.4, 43.5, 48.7, 54.4, 123.5, 126.3, 126.6, 127.0, 127.4,
128.4, 128.5, 128.7, 129.2, 131.9, 132.3, 136.9, 138.9,
145.6, 166.9, 167.0, 169.4. Elemental analysis calcd (%) for
C36H41N3O3: C, 76.70; H, 7.33; N, 7.45; found: C, 76.83; H,
7.25; N, 7.38.
Acknowledgements
This work was supported by the Spanish MCYT and
FEDER (Project PPQ2001-1834). G. S. was supported by an
AECI fellowship.
4.4.4. N2-[(Sa)-N1-Benzoyl-(4-phenylcyclohexylidene)-
glycyl]-(S)-phenylalanine cyclohexylamide [(Sa,S)-4b].
Compound (Sa,S)-4b was eluted second upon additional
column chromatography and isolated as a white solid. MpZ
130 8C (dec); [a]2D5ZK98.8 (c 0.5, MeOH); IR absorption
References and notes
1
(nujol) 3315, 1637 cmK1; H NMR (300 MHz, CDCl3) d
1.20–2.00 (m, 16H), 2.27 (bd, JZ14.3 Hz, 1H), 2.57 (dt,
JZ11.8, 2.9 Hz, 1H), 2.67 (bd, JZ14.4 Hz, 1H), 3.15 (dd,
JZ14.7, 8.7 Hz, 1H), 3.43 (dd, JZ14.7, 4.9 Hz, 1H), 3.75–
3.90 (m, 1H), 4.95 (ddd, JZ8.9, 8.7, 4.9 Hz, 1H), 6.11 (d,
JZ8.9 Hz, 1H), 7.12–7.28 (m, 12H), 7.28–7.39 (m, 1H),
7.65 (d, JZ8.5 Hz, 1H), 7.68–7.72 (m, 2H), 9.20 (bs, 1H);
13C NMR (75 MHz, CDCl3) d 25.3, 25.4, 25.7, 29.5, 29.7,
32.7, 32.9, 34.3, 35.0, 37.3, 44.3, 48.7, 54.7, 123.7, 126.5,
126.7, 127.0, 127.5, 128.1, 128.6, 128.8, 129.1, 131.7,
131.9, 137.1, 137.3, 166.8, 167.9, 169.2. Elemental analysis
calcd (%) for C36H41N3O3: C, 76.70; H, 7.33; N, 7.45;
found: C, 76.81; H, 7.39; N, 7.51.
1. (a) Balaram, P. Curr. Opin. Struct. Biol. 1992, 2, 845–851. (b)
Rizo, J.; Gierasch, L. M. Annu. Rev. Biochem. 1992, 61,
387–418. (c) Liskamp, R. M. J. Recl. Trav. Pays-Bas 1994,
113, 1–19. (d) McDowell, R. S.; Artis, R. D. Annu. Rep. Med.
Chem. 1995, 30, 265–274. (e) Hanessian, S.; McNaughton
Smith, G.; Lombart, H. G.; Lubell, W. D. Tetrahedron 1997,
53, 12789–12854. (f) Hruby, V. J.; Li, G.; Haskell-Luevano,
C.; Shenderovich, M. Biopolymers 1997, 43, 219–266.
2. (a) Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1988,
159–172. (b) Smith, M. J.; Kim, D.; Horenstein, B.; Nakanishi,
K.; Kustin, K. Acc. Chem. Res. 1991, 24, 117–124.
3. (a) Gross, L. M.; Morell, P. M.; Craig, G. T. Proc. Natl. Acad.