Diazabicyclo[4.3.0]nonene-Based Peptidomimetics
dd, J ) 8.4, 17.1 Hz), 3.68 (3H, s), 3.74 (1H, dd, J ) 5.1, 14.1
Hz), 3.88 (1H, dd, J ) 7.0, 14.0 Hz), 4.02 (1H, dd, J ) 8.3, 14.1
Hz), 5.05 (1H, d, J ) 12.3 Hz), 5.08 (1H, d, J ) 12.3 Hz), 5.42
(1H, br s), 7.32 (5H, m), 7.72 (2H, m), 7.84 (2H, m); 13C NMR
(100 MHz, CDCl3) δ 22.2, 32.9, 37.2, 42.7 (2 C’s), 44.4, 52.4,
57.7, 66.5, 123.4, 127.9, 128.0, 128.4, 131.8, 134.1, 136.3, 154.9,
167.9, 172.0, 175.0; MS (FAB) m/z 494 (100, M + H+). Anal.
Calcd for C26H27N3O7‚0.5H2O: C, 62.1; H, 5.6; N, 8.4. Found: C,
62.4; H, 5.7; N, 8.1. The second eluting diastereomer was obtained
as a viscous oil: IR ν 3423, 3405, 1775,1718 (br), 1503, 1399,
1075 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.37 (3H, s), 2.31 (1H,
m), 2.43 (1H, m), 3.30 (2H, m), 3.45 (1H, m), 3.61 (2H, m), 3.67
(3H, s), 3.87 (1H, dd, J ) 5.1, 13.0 Hz), 4.00 (1H, dd, J ) 7.5,
13.0 Hz), 5.04 (1H, d, J ) 12.3 Hz), 5.05 (1H, d, J ) 12.3 Hz),
5.36 (1H, br s), 7.32 (5H, m), 7.71 (2H, m), 7.84 (2H, m); 13C
NMR (100 MHz, CDCl3) δ 22.1, 30.8, 37.3, 42.4, 42.8, 44.0, 52.3,
57.7, 66.5, 123.4, 127.9, 128.0, 128.4, 131.8, 134.1, 136.3, 154.9,
167.9, 171.9, 174.9; MS (FAB) m/z 494 (100, M + H+).
was concentrated under reduced pressure. The residue was purified
by chromatography on silica, eluting with a gradient of CH2Cl2/
MeOH/isopropylamine (90:10:1-80:20:1), to give the bicyclic
amidine 41 (567 mg, 62%) as a colorless oil. Further chromatog-
raphy enabled isolation of pure samples of each of the diastereomers
of amidine 41. The first eluting diastereomer was obtained as a
colorless oil: IR ν 3408, 3275, 1738, 1717, 1692, 1508, 1310, 1275,
1
1089 cm-1; H NMR (400 MHz, acetone-d6) δ 1.66 (3H, s), 2.16
(1H, ddd, J ) 2.9, 7.9, 12.7 Hz), 2.61 (1H, ddd, J ) 8.8, 9.2, 12.7
Hz), 3.22 (1H, m), 3.64 (2H, m), 3.70 (3H, s), 3.79 (4H, m), 5.06
(1H, d, J ) 12.7 Hz), 5.12 (1H, d, J ) 12.7 Hz), 7.28 (1H, m),
7.35 (2H, m), 7.44 (2H, m), 7.74 (1H, br s); 13C NMR (100 MHz,
acetone-d6) δ 23.2, 32.9, 34.2, 39.5, 44.5, 50.7, 52.0, 61.3, 66.0,
127.5, 127.6, 128.3, 137.0, 155.4, 166.2, 170.5; MS (FAB) m/z
346 (100, M + H+); HRMS (FAB) m/z 346.1773, C18H24N3O4
requires 346.1767. Anal. Calcd for C18H23N3O4‚HCl‚2H2O: C, 51.7;
H, 6.8; N, 10.1. Found: C, 51.7; H, 6.7; N, 10.4. The latter eluting
diastereomer was obtained as a colorless oil: IR ν 3412, 3278,
1
1739, 1717, 1691, 1508, 1311, 1279, 1091 cm-1. H NMR (400
(3R)-3-Benzyloxycarbonylamino-3-methyl-1-((2RS)-2-meth-
oxycarbonyl-3-phthalimido)propyl)pyrrolidin-2-thione 38. To a
solution of the lactam 37 (1:1 mixture of diastereomers) (11.6 g,
23.5 mmol) in toluene (250 mL) was added Lawesson’s reagent
(5.4 g, 13.4 mmol). The mixture was refluxed for 1.5 h and then
was allowed to cool and the solvent removed under reduced
pressure. Chromatography of the residue on silica, eluting with 3:2
ethyl acetate/hexanes, gave the dithio compound 39 (1.2 g, 10%),
the starting lactam 37 (2.8 g, 24%), and the thiolactam 38 (6.7 g,
56%, 74% based on recovered starting material) as a white foam
as a 1:1 mixture of diastereomers: IR ν 3433, 3360, 1774, 1720
(br), 1511, 1496, 1398, 1088 cm-1; 1H NMR (400 MHz, CDCl3) δ
1.40 (1.5H, s), 1.41 (1.5H, s), 2.38 (1H, m), 2.55 (1H, m), 3.48
(0.5H, m), 3.62 (2.5H, m), 3.69 (1.5H, s), 3.70 (1.5H, s), 3.84 (1H,
m), 3.91 (1H, m), 4.03 (1.5H, m), 4.40 (0.5H, m), 5.05 (2H, s),
5.95 (0.5H, br s), 6.00 (0.5H, br s), 7.30 (5H, m), 7.71 (2H, m),
7.83 (2H, m); 13C NMR (100 MHz, CDCl3) δ 20.8, 24.3, 24.5,
34.2, 34.3, 37.0, 37.2, 41.7, 47.5, 47.6, 52.3, 52.6, 66.1, 66.4, 123.2,
127.7, 127.8, 128.2, 131.6, 134.0, 136.2, 154.5, 167.8, 171.8, 204.7;
MS (FAB) m/z 510 (100, M + H+). Anal. Calcd for C26H27N3O6S:
C, 61.3; H, 5.3; N, 8.2. Found: C, 61.6; H, 5.7; N, 7.8.
MHz, acetone-d6) δ 1.76 (3H, s), 2.15 (1H, ddd, J ) 3.3, 8.3, 12.7
Hz), 2.57 (1H, ddd, J ) 7.8, 9.3, 12.7 Hz), 3.42 (1H, m), 3.59
(2H, m), 3.66 (3H, s), 3.75 (2H, m), 3.90 (2H, m), 5.08 (2H, m),
7.28 (1H, m), 7.36 (2H, m), 7.44 (2H, m), 7.72 (1H, br s); 13C
NMR (100 MHz, acetone-d6) δ 23.8, 32.9, 34.6, 39.1, 44.1, 50.7,
52.0, 61.3, 65.8, 127.3, 127.5, 128.3, 137.0, 155.3, 166.1, 170.0;
MS (FAB) m/z 346 (100, M + H+); HRMS (FAB) m/z 346.1764,
C18H24N3O4 requires 346.1767.
(3S,7S)-7-Benzyloxycarbonylamino-3-methoxycarbonyl-3,7-
dimethyl-1,5-diazabicyclo[4.3.0]non-5-ene 42. The amidine 41
(1:1 mixture of diastereomers) (1.0 g, 2.9 mmol) was dissolved in
dry THF, and the solution was cooled to -78 °C. Lithium
hexamethyldisilazide (1.0 M in THF, 10.2 mL) was added slowly,
and the solution was stirred for 2 h, at which time methyl iodide
(1.0 g, 7.0 mmol) was added. The solution was stirred for 3 h at
-78 °C and then was allowed to warm to ca. 0 °C and stirred for
1 h. The solution was cooled to -78 °C, a further 2 equiv of
LHMDS was added (5.8 mL), and stirring was continued for 30
min. Methyl iodide (1 equiv, 185 µL) was added, and the solution
was stirred at -78 °C for 3 h. The solution was then allowed to
warm to ambient temperature overnight. Methanol (ca. 50 mL) was
added to quench the reaction, and the solution was evaporated to
dryness under reduced pressure. The crude product was purified
by chromatography on silica, eluting with CH2Cl2/MeOH/isopro-
pylamine (80:20:1) to give the product 42 (487 mg, 47%) as a
colorless oil: IR ν 3395, 3293, 1738, 1717, 1690, 1538, 1375, 1261,
(3R)-3-Benzyloxycarbonylamino-3-methyl-1-((2RS)-3-amino-
2-methoxycarbonyl)propyl)pyrrolidin-2-thione 40. To a solution
of the thiolactam 38 (6.44 g, 12.7 mmol) in dry methanol (80 mL)
was added anhydrous hydrazine (445 mg, 13.9 mmol). The solution
was stirred under argon at room temperature for 24 h, after which
time a white precipitate had formed. The precipitate was removed
by filtration, and the filtrate was concentrated under reduced
pressure. The residue was partitioned between methylene chloride
and 2 N HCl. The aqueous layer was made basic (pH 10) by the
addition of 6 N NaOH and then was then extracted with methylene
chloride. The combined organic phases were dried, and the solvent
was removed under reduced pressure to give the amine 40 (3.27 g,
68%) (1:1 mixture of diastereomers) as a pale yellow oil: IR ν
1
1219, 1090 cm-1; H NMR (400 MHz, CDCl3) δ 1.27 (3H, s),
1.65 (3H, s), 2.08 (1H, m), 2.62 (1H, m), 3.11 (1H, d, J ) 13 Hz),
3.29 (1H, d, J ) 13 Hz), 3.58-3.87 (4H, m), 3.64 (3H, s), 5.05
(2H, m), 7.28 (5H, m), 7.35 (1H, br s); 13C NMR (100 MHz, CDCl3)
δ 20.7, 24.3, 30.8, 32.9, 38.9, 46.6, 50.3, 52.8, 60.4, 66.1, 127.1,
127.6, 128.3, 136.5, 156.0, 166.2, 172.9; MS (FAB) m/z 360 (100,
M + H+); HRMS (FAB) m/z 360.1915, C19H26N3O4 requires
360.1923.
1
3431, 3356, 1717 (br), 1515, 1497, 1443, 1088 cm-1; H NMR
(400 MHz, CDCl3) δ 1.40 (1.5H, s), 1.42 (1.5H, s), 1.47 (2H, br
s), 2.41 (1H, m), 2.52 (1H, m), 2.87 (0.5H, m), 2.95 (1H, m), 3.00
(1H, m), 3.09 (0.5H, m), 3.63 (2H, m), 3.70 (1.5H, s), 3.72 (1.5H,
s), 3.74 (0.5H, m), 3.95 (0.5H, dd, J ) 7.6, 13.4 Hz), 4.06 (0.5H,
m), 4.25 (0.5H, dd, J ) 6.6, 13.4 Hz), 5.07 (2H, s), 6.01 (0.5H, br
s), 6.05 (0.5H, br s), 7.33 (5H, m); 13C NMR (100 MHz, CDCl3)
δ 24.6, 34.0, 34.1, 41.1, 41.2, 45.0, 45.3, 47.3, 47.5, 52.0, 52.1,
52.7, 66.3, 66.5, 66.6, 127.8, 127.9, 128.3, 136.2, 154.6, 173.1,
173.3, 204.4, 204.7; MS (FAB) m/z 380 (100, M + H+); HRMS
(FAB) m/z 380.1650, C18H26N3O4S requires 380.1644.
(3RS,7S)-7-Benzyloxycarbonylamino-3-methoxycarbonyl-7-
methyl-1,5-diazabicyclo[4.3.0]non-5-ene 41. To a solution of the
amine 40 (1.0 g, 2.6 mmol) in dioxane (25 mL) was added mercuric
chloride (1.07 g, 3.9 mmol). The mixture was stirred at reflux for
24 h and then was allowed to cool to room temperature. The mixture
was filtered through Celite, washed with acetone, and the filtrate
(3S,7S)-7-Benzyloxycarbonylamino-3-carboxy-3,7-dimethyl-
1,5-diazabicyclo[4.3.0]non-5-ene 43. The amidine ester 42 (300
mg, 0.84 mmol) was dissolved in 1:1:1 THF/MeOH/1.0 M LiOHaq
(5 mL). The solution was stirred at room temperature for 18 h and
lyophilized to give a white foam. The residue was taken up in
methanol (5 mL), and 3 N HCl (ca. 0.3 mL) was added to lower
the pH to 6. The mixture was filtered, and the filtrate was evap-
orated under reduced pressure to give the acid 43 (288 mg, 100%)
as a white solid: 1H NMR (400 MHz, MeOH-d4) δ 1.20 (3H, s),
1.56 (3H, s), 2.17 (1H, m), 2.58 (1H, m), 3.24 (2H, m), 3.53
(1H, m), 3.75 (3H, s), 5.09 (2H, s), 7.36 (5H, m); 13C NMR
(100 MHz, MeOH-d4) δ 20.1, 22.5, 32.7, 39.1, 46.0, 50.1, 50.9,
60.7, 66.4, 127.5, 127.7, 128.1, 155.6, 165.4, 177.2; MS (FAB)
m/z 368 (8, M + Na+), 352 (38, M + Li+), 346 (44, M + H+),
313 (100); HRMS (FAB) m/z 346.1773, C18H24N3O4 requires
346.1767.
J. Org. Chem, Vol. 72, No. 18, 2007 6871