9806
M. C. Evans, R. L. Johnson / Tetrahedron 56 (2000) 9801±9808
15a (100 mg, 0.48 mmol) and HOBt´H2O (75 mg,
0.55 mmol) were dissolved in CH2Cl2 (10 mL) under N2.
The mixture was cooled to 2788C after which was added
NEt3 (0.13 mL, 0.97 mmol), followed by EDC´HCl
(106 mg, 0.55 mmol). The mixture was stirred at a low
temperature for 30 min and then warmed to room tempera-
ture where it was kept for two days. The organic layer was
extracted with 1 M NaHCO3, 10% citric acid, water and
brine. The organic layer was dried over MgSO4, ®ltered
and concentrated under aspirator pressure. The crude
product was puri®ed by silica gel ¯ash chromatography
(EtOAc/hexanes, 2:1) to give 52 mg (29%) of product:
for C22H30N2O5: C, 65.65; H, 7.51; N, 6.96. Found: C,
65.64; H, 7.47; N, 7.03.
N-tert-Butoxycarbonyl-l-prolyl-trans-3-phenyl-l-proline
methyl ester (18b). Boc-l-Pro-OH (102 mg, 0.47 mmol)
and 16b (100 mg, 0.41 mmol) were coupled together by
the same method as that described above for 17a to
give 44 mg (26%) of product after silica gel ¯ash
chromatography (EtOAc/hexanes, 2:1). Analytical HPLC
analysis on a Waters Spherisorbw 4.6£150 mm column
(CHCl3/MeOH, 5:1) gave a single peak (tR1.25 min):
1
[a]D110.9 (c 0.54, CH2Cl2); H NMR (CDCl3, rotomers
1
[a]D250.4 (c 0.91, CH2Cl2); H NMR (CDCl3, rotomers
observed) d 7.22±7.36 (m, 5H), 4.57±4.62 (m, 1.5H), 4.46
(dd, J8.1 and 3.6 Hz, 0.5H), 4.05±4.13, 3.80±3.90
(m, 1H), 3.67, 3.70 (2s, 3H), 3.35±3.75 (m, 4H), 1.83±
2.50 (m, 6H), 1.40, 1.46 (2s, 9H); 13C NMR (CDCl3, roto-
mers observed) d 24.1, 24.8, 29.1, 29.2, 29.8, 30.8, 33.9,
34.7, 46.6, 47.1, 47.4, 47.4, 47.9, 48.8, 52.8, 53.0, 58.1,
58.4, 65.8, 65.9, 80.1, 80.2, 127.5, 127.8, 127.9, 128.0,
129.4, 129.5, 140.8, 141.0, 154.4, 155.2, 172.0, 172.2,
173.0, 173.2; FAB HRMS (MNBA matrix) m/z403.2241
(C22H30N2O5 1 H1 requires 403.2233).
observed in a ratio of 4:3) d 4.49 (dd, J8.4, 2.7 Hz,
0.57H), 4.37 (dd, J8.1, 3.6 Hz, 0.43H), 4.25 (dd, J6.0,
2.7 Hz, 1H), 3.82±3.86 (m, 1H), 3.67, 3.68 (2s, 3H), 3.33±
3.58 (m, 3H), 1.66±2.16 (m, 8H), 1.36, 1.41 (s, 9H), 0.97
(dd, J6.6 Hz), 0.91 (dd, J6.9 Hz, 3H); 13C NMR (CDCl3,
rotomers observed) d 20.2, 21.6, 21.8, 24.1, 24.7, 29.0, 29.1,
29.3, 29.4, 30.5, 30.8, 30.9, 46.8, 47.0, 47.3, 47.4, 49.7,
50.1, 52.7, 52.8, 58.1, 58.3, 63.0, 63.2, 80.0, 154.4, 155.1,
171.7, 172.1, 174.0, 174.3; FAB MS (MNBA matrix)
m/z369 (40%) [M1H]1. Anal. Calcd for C19H32N2O5: C,
61.93; H, 8.75; N, 7.60. Found: C, 61.87; H, 8.50; N, 7.39.
N-tert-Butoxycarbonyl-l-prolyl-cis-3-isopropyl-l-prolyl-
l-prolinamide (19a). Dipeptide 17a (41 mg, 0.11 mmol)
was reacted with 3N NaOH (0.06 mL, 0.17 mmol)/MeOH/
THF (1:1:5) for 2 d at room temperature. The MeOH and
THF were removed under aspirator pressure and the remain-
ing aqueous residue was diluted with distilled water. The
solution was washed with EtOAc (3£) and acidi®ed to
pH3 with solid citric acid. The aqueous solution was
extracted with EtOAc (3£) and the combined organic layers
were washed with brine, dried over MgSO4 and ®ltered. The
®ltrate was concentrated under aspirator pressure to afford
the dipeptide free acid (20 mg, 0.13 mmol). This material
was dissolved in CH2Cl2 (10 mL) along with l-prolin-
amide´HCl (40 mg, 0.11 mmol) and HOBt´H2O (18 mg,
0.13 mmol). The solution under nitrogen was cooled to
2788C and then NEt3 (0.03 mL, 0.23 mmol) and EDC´HCl
(25 mg, 0.13 mmol) were added. The mixture was stirred at
a low temperature for 30 min and then warmed to room
temperature where the reaction was allowed to proceed
for two days. The organic layer was extracted with 1 M
NaHCO3, 10% citric acid, water and brine. The organic
layer was dried over MgSO4, ®ltered and concentrated
under aspirator pressure and the crude product
obtained was puri®ed by silica gel ¯ash chromatography
(CH2Cl2/MeOH, 30:1!20:1) to give 29 mg (57%) of
material, which yielded a single peak (tR1.3 min) by
HPLC analysis on a Waters Spherisorbw 4.6£150 mm
column (CHCl3/MeOH, 20:1): [a]D284.3 (c 0.19,
CH2Cl2); FAB HRMS (MNBA matrix) m/z451.2926
(C22H30N2O5 1 H1 requires 451.2922).
N-tert-Butoxycarbonyl-l-prolyl-trans-3-isopropyl-l-proline
methyl ester (17b). Boc-l-Pro-OH (72 mg, 0.33 mmol) and
15b (60 mg, 0.29 mmol) were coupled together by the same
method as that described above for 17a to give 36 mg (34%)
of product after silica gel ¯ash chromatography (EtOAc/
1
hexanes, 2:1): [a]D223.2 (c 1.08, CH2Cl2); H NMR
(CDCl3, rotomers observed in a ratio of 3:2) d 4.69
(d, J7.5 Hz, 0.6H), 4.64 (d, J7.2 Hz, 0.4H), 4.43 (dd,
J8.1, 3.3 Hz, 0.6H), 4.32 (dd, J9, 4.2 Hz, 0.4H), 3.69,
3.67 (2s, 3H), 3.35±3.65 (m, 4H), 1.78±2.17 (m, 7H), 1.41,
1.43 (2s, 9H), 1.06 (apparent dd, J6.0, 10.8 Hz, 3H), 0.92
(apparent t, J6.6 Hz, 3H); 13C NMR (CDCl3, rotomers
observed) d 22.2, 22.8, 22.9, 24.2, 24.7, 29.0, 29.1, 29.5,
29.6, 29.7, 30.4, 46.7, 46.8, 47.3, 47.6, 49.9, 50.2, 52.2,
52.4, 57.9, 58.1, 62.0, 80.0, 80.1, 155.2, 171.8, 172.3,
172.7, 173.0; LCQ MS (Direct Infusion Electrospray)
m/z391.1 (100%) [M1Na]1. Anal. Calcd for
C19H32N2O5: C, 61.93; H, 8.75; N, 7.60. Found: C, 62.15;
H, 8.60; N, 7.39.
N-tert-Butoxycarbonyl-l-prolyl-cis-3-phenyl-l-proline
methyl ester (18a). Boc-l-Pro-OH (102 mg, 0.47 mmol)
and 16a (100 mg, 0.41 mmol) were coupled together by
the same method as that described above for 17a to give
85.5 mg (52%) of product after silica gel ¯ash chroma-
tography (EtOAc/hexanes, 2:1): mp 149±1518C; [a]D2
1
8.0 (c 0.57, CH2Cl2); H NMR (CDCl3, rotomers observed
in a 9:5 ratio) d 7.19±7.34 (m, 5H), 4.82 (d, J8.7 Hz,
0.65H), 4.77 (d, J9.0 Hz, 0.35H), 4.51 (dd, J8.4,
3.0 Hz, 0.65H), 4.41 (dd, J8.4, 3.7 Hz, 0.35H), 3.83±
3.93 (m, 1H), 3.30±3.71 (m, 4H), 3.22, 3.20 (2s, 3H),
2.62±2.70 (m, 1H), 1.81±2.27 (m, 5H), 1.45, 1.43 (2s,
9H); 13C NMR (CDCl3, rotomers observed) d 24.7, 24.8,
29.1, 29.2, 29.4, 29.5, 29.7, 30.5, 46.5, 46.7, 46.8, 46.8,
47.3, 47.6, 52.0, 52.1, 58.0, 58.2, 64.3, 80.1, 80.2, 128.2,
128.3, 128.4, 128.5, 129.0, 129.1, 136.7, 137.1, 154.4,
155.2, 171.7, 171.9, 172.0, 172.4; LCQ MS (Direct Infusion
Electrospray) m/z425.1 (100%) [M1Na]1. Anal. Calcd
N-tert-Butoxycarbonyl-l-prolyl-trans-3-isopropyl-l-prolyl-
l-prolinamide (19b). Dipeptide 17b (224 mg, 0.61 mmol)
was converted to 19b by the same procedures as those
described above for the synthesis of 19a. A yield of
35 mg (15%) of material was obtained, which yielded a
single peak (tR1.2 min) by HPLC analysis on a Waters
Spherisorbw 4.6£150 mm column (CHCl3/MeOH, 5:1):
[a]D250 (c 0.15, CH2Cl2); FAB HRMS (MNBA matrix)
m/z451.2943 (C23H38N4O5 1 H1 requires 451.2922).