A. Avenoza et al. / Tetrahedron 57 (2001) 2745±2755
2753
3H); 1.50±1.80 (m, 2H); 1.81±1.90 (m, 3H); 4.13 (dd, 1H,
0
water (2£15 mL) and the combined aqueous phases were
extracted with ethyl acetate (2£15 mL). The combined
organic phases were washed with brine (2£15 mL), dried
over anhydrous Na2SO4, ®ltered and the solvent was evapo-
rated. The mixture of diastereoisomeric peptides was
chromatographed on silica gel eluting with toluene±ethyl
acetate (1:1), to yield 525 mg of the peptide (1S,2S,S)-23
as a white solid (36%) and 514 mg of the peptide (1R,2R,S)-
24 as a white solid (35%). (1S,2S,S)-23: Mp: 192±1948C;
Anal. calcd for C30H39N3O4: C, 71.26; H, 7.77; N, 8.31;
J2a±3a10.8 Hz, J2a±3e 5.1 Hz, H2a); 13C NMR (D2O): d
20.9, 24.8, 30.6, 32.8 (C3, C4, C5, C6); 67.0 (C1); 71.8
(C2); 175.8 (COO). rac-cis-1: Anal. calcd for C7H13NO3:
C, 52.82; H, 8.23; N, 8.80; found: C, 52.72; H, 8.18; N,
1
8.92; H NMR (D2O): d 1.10±1.50 (m, 3H); 1.55±1.80
(m, 2H); 1.82±2.00 (m, 3H); 4.02±4.09 (m, 1H, H2); 13C
NMR (D2O): d 21.5, 25.2, 31.1, 33.3 (C3, C4, C5, C6); 68.1
(C1); 72.1 (C2); 178.3 (COO).
4.1.18. trans-2-Methoxycyclohexane-1-spiro-{40 [20-phenyl-
50(40H)oxazolone]} (rac-22). A suspension of compound
rac-8 (500 mg, 1.72 mmol) and LiOH´H2O (722 mg,
17.2 mmol) in methanol±water (3:2) (25 mL) was stirred
under re¯ux for 7 h. The solvent was removed, the residue
was then dissolved in water and washed with CH2Cl2
(2£20 mL). The aqueous phase was acidi®ed with 2N HCl
and then extracted with CH2Cl2 (4£25 mL). The combined
last organic phases were dried over anhydrous Na2SO4,
®ltered and evaporated, to yield 444 mg of the 1-benza-
mido-c-2-methoxycyclohexane-r-1-carboxylic acid as a
white solid (93%). Mp: 49±518C; Anal. calcd for
C15H19NO4: C, 64.97; H, 6.91; N, 5.05; found: C, 64.91;
H, 6.93; N, 4.99; IR (CH2Cl2, cm21): 3430 (NH), 3119
found: C, 71.64; H, 7.62; N, 8.23; [a]25 (c 2.08,
D
CHCl3)232.1; IR (CH2Cl2, cm21): 3426, 3351 (NH),
1
1702, 1657 (CON); H NMR (CDCl3): d 1.02±1.42 (m,
5H); 1.43±1.93 (m, 12H); 2.19±2.36 (m, 1H); 3.15 (s, 4H,
CH3O1Hb1); 3.27 (dd, 1H, Jb2±b114.1 Hz, Jb2±a6.9 Hz,
0
Hb2); 3.64±3.82 (m, 1H, H1 ); 3.89±4.01 (m, 1H, H2); 4.66±
4.79 (m, 1H, Ha); 6.51 (br s, 1H, NHCOPh); 6.90 (d, 1H,
0
JNHCy-1 8.7 Hz, NHCy); 7.10±7.18 (m, 5H, Arom.); 7.34±
7.55 (m, 4H, Arom.1NHPhe); 7.63±7.72 (m, 2H, Arom.);
13C NMR (CDCl3): d 20.0, 21.2, 22.9, 25.1, 25.2, 25.6, 30.7,
0
0
0
0
0
32.5, 32.8 (C3, C4, C5, C6, C2 , C3 , C4 , C5 , C6 ); 37.0 (Cb);
0
48.5 (C1 ); 53.9 (Ca); 55.8 (CH3O); 61.8 (C1); 78.2 (C2);
126.6, 127.0, 128.4, 128.6, 129.4, 132.0, 133.8, 137.2
(Arom.); 167.4, 169.8, 172.3 (CON). (1R,2R,S)-24: Mp:
111±1138C; Anal. calcd for C30H39N3O4: C, 71.26; H,
1
(COOH), 1760 (COO), 1672 (CON); H NMR (CDCl3): d
1.42±1.82 (m, 5H); 1.89±2.04 (m, 1H); 2.10±2.24 (m, 2H);
3.40 (s, 3H, CH3O); 4.18±4.26 (m, 1H, H2); 6.93 (br s, 1H,
NH); 7.36±7.55 (m, 3H, Arom.); 7.74±7.85 (m, 2H,
Arom.); 10.46 (br s, 1H, COOH); 13C NMR (CDCl3): d
19.9, 20.9, 24.4, 28.6 (C3, C4, C5, C6); 57.1 (CH3O); 62.5
(C1); 77.7 (C2); 127.1, 128.5, 131.9, 133.8 (Arom.); 167.9
(CON); 174.9 (COOH). This carboxylic acid (444 mg,
1.6 mmol) and dimethylaminopyridine (192 mg, 1.6
mmol) were dissolved in CH2Cl2 (13 mL) at 08C. Dicyclo-
hexylcarbodiimide (335 mg, 1.6 mmol) was then added and
the mixture was allowed to warm up to 258C. After stirring
for 3 h, the solvent was evaporated and the residue was
chromatographed on silica gel eluting with hexane±ethyl
acetate (1:1), to yield 337 mg of the oxazolone rac-22 as a
white solid (91%). Mp: 82±848C; Anal. calcd for
C15H17NO3: C, 69.48; H, 6.61; N, 5.40; found: C, 69.86;
H, 6.43; N, 5.62; IR (CH2Cl2, cm21): 1805 (COO), 1657
7.77; N, 8.31; found: C, 71.89; H, 7.64; N, 8.42; [a]25 (c
D
1.02, CHCl3)257.4; IR (CH2Cl2, cm21): 3427, 3348
1
(NH), 1805, 1658 (CON); H NMR (CDCl3): d 0.92±2.02
(m, 17H); 2.09±2.22 (m, 1H); 3.08 (dd, 1H, Jb1±b2
14.1 Hz; Jb1±a6.0 Hz, Hb1); 3.21 (s, 3H, CH3O); 3.26
(dd, 1H, Jb2±b114.1 Hz, Jb2±a6.6 Hz, Hb2); 3.64±3.79
0
(m, 1H, H1 ); 3.87±3.94 (m, 1H, H2); 4.64±4.73 (m, 1H,
0
Ha); 6.35 (br s, 1H, NHCOPh); 6.62 (d, 1H, JNHCy-1
7.8 Hz, NHCy); 7.00 (d, 1H, JNHPhe-a7.8 Hz, NHPhe);
7.14±7.24 (m, 5H, Arom.); 7.39±7.48 (m, 2H, Arom.);
7.48±7.56 (m, 1H, Arom.); 7.68±7.77 (m, 2H, Arom.);
13C NMR (CDCl3): d 19.9, 21.2, 24.2, 25.0, 25.5, 28.0,
0
32.7, 32.9, 33.9 (C3, C4, C5, C6, C2 , C3 , C4 , C5 , C6 );
0
0
0
0
0
37.3 (Cb); 48.3 (C1 ); 54.0 (Ca); 58.8 (CH3O); 62.1 (C1);
78.6 (C2); 126.7, 127.0, 128.4, 128.6, 129.4, 132.0, 133.9,
136.8 (Arom.); 167.2, 169.6, 172.0 (CON).
1
(CON); H NMR (CDCl3): d 1.29±1.45 (m, 1H); 1.58±
1.72 (m, 1H); 1.76±2.02 (m, 5H); 2.03±2.14 (m, 1H);
4.1.20. Methyl (1S,2S)-1-benzamido-2-methoxycyclohex-
ane-1-carboxylate ((1S,2S)-8). Tri¯ic acid (0.11 mL,
2.37 mmol) was added to a solution of (1S,2S,S)-23
(400 mg, 0.79 mmol) in dry methanol (12 mL) at 08C,
under an inert atmosphere. The reaction mixture was
warmed up to 808C and after stirring for 48 h, the solvent
was evaporated. The residue was chromatographed on silica
gel eluting with hexane±ethyl acetate (1:1), to yield 210 mg
of the compound (1S,2S)-8 as a white solid (91%). Mp:
132±1338C; Anal. calcd for C16H21NO4: C, 65.96; H,
3.31 (s, 3H, CH3O); 3.49 (dd, 1H, J2a±3a11.2 Hz, J2a±3e
4.9 Hz, H2); 7.41±7.60 (m, 3H, Arom.); 7.95±8.06 (m, 2H,
Arom.); 13C NMR (CDCl3): d 19.8 (C3), 23.6, 25.5, 33.0
(C4, C5, C6); 58.0 (CH3O); 73.0 (C1); 82.3 (C2); 126.0,
127.8, 128.7, 132.5 (Arom.); 160.8 (CON); 177.3 (COO).
4.1.19. (1S,2S)-[1-Benzamido-2-methoxycyclohexane-1-
carboxamido]-(S)-phenylalanine cyclohexylamide ((1S,
2S,S)-23) and (1R,2R)-[1-benzamido-2-methoxycyclo-
hexane-1-carboxamido]-(S)-phenylalanine cyclohexyl-
amide ((1R,2R,S)-24). A solution of (S)-phenylalanine
cyclohexylamide (1.6 g, 6.66 mmol) in N-methylpyrro-
lidin-2-one (NMP) (3 mL) was added to a solution of
compound rac-22 (750 mg, 2.9 mmol) in NMP (3 mL)
under an inert atmosphere. After stirring for 48 h at 908C,
the reaction mixture was allowed to cool down to room
temperature and was then poured onto a mixture of ice
(12 g), 1N HCl (12 mL) and ethyl acetate (15 mL). After
stirring for 30 min, the organic phase was washed with
7.27; N, 4.81; found: C, 65.84; H, 7.32; N, 4.75; [a]25 (c
D
1.09, CHCl3)152.5. Spectral data for the compound
(1S,2S)-8 were identical to those described for rac-8.
4.1.21. Methyl (1R,2R)-1-benzamido-2-methoxycyclo-
hexane-1-carboxylate ((1R,2R)-8). As described for
(1S,2S)-8, compound (1R,2R)-8 (196 mg, 85%) was
obtained starting from (1R,2R,S)-24 (400 mg, 0.79 mmol).
Anal. calcd for C16H21NO4: C, 65.96; H, 7.27; N, 4.81;
found: C, 65.80; H, 7.22; N, 4.79; [a]25 (c 1.00,
D
CHCl3)254.9. Analytical and spectral data for the