Sprout et al.
cm-1; HRMS-FAB (M + Na+) calcd for C16H33N3O3SNa
oxo-3-(tritylthio)propan-2-ylcarbamic Acid tert-Butyl
Ester, Ligand 16. Carbamate 76 (0.215 g, 0.441 mmol) was
treated with TFA (0.68 mL, 8.8 mmol) in CH2Cl2 (5 mL) at
room temperature for 2 h. The excess TFA was removed by
rotary evaporation and the residue was dissolved in EtOAc
(100 mL) and washed with half saturated aqueous NaHCO3
(10 mL) and brine (5 mL). The organic layer was dried over
Na2SO4, and the solvent was removed to yield the crude amine
(0.112 g, 0.289 mmol, 66%). To the crude amine (0.112 g, 0.289
mmol) was added N-Boc-Cys(Tr)-OH (0.268 g, 0.579 mmol),
HBTU (0.329 g, 0.868 mmol), and enough DMF to dissolve all
the solids. After the solution was stirred for 5 min, DIEA (0.25
mL, 1.5 mmol) was added. The reaction was stirred at room
temperature for 3 h, then diluted with 50 mL of H2O. The
aqueous phase was extracted with EtOAc (75 mL), and the
organic phase was washed with H2O (2 × 50 mL) and brine
(25 mL). The organic layer was dried over Na2SO4, the solvent
was removed, and the crude product was purified by column
chromatography (0.7:6.3:93 30% aqueous NH4OH/MeOH/CH2-
Cl2) to yield compound 16 as a yellow solid (0.161 g, 0.193
mmol, 67%): mp 79-81 °C; 1H NMR (300 MHz, CDCl3) δ 7.43
(m, 7 H), 7.30 (m, 9 H), 7.22 (m, 3 H), 6.84 (s, 1 H), 6.82 (d, J
) 8.0 Hz, 1 H), 6.40 (br s, 1 H), 5.34 (m, 2 H), 4.78 (d, J ) 6.5
Hz, 1 H), 4.65 (m, 1 H), 4.54 (m, 2 H), 3.81 (br d, J ) 4.9 Hz,
1 H), 3.61 (t, J ) 4.5 Hz, 4 H), 3.25 (m, 1 H), 3.16 (m, 2 H),
3.02 (dd, J ) 15.2, 8.1 Hz, 1 H), 2.74 (dd, J ) 12.6, 6.6 Hz, 1
H), 2.59 (dd, J ) 12.9, 5.2 Hz, 1 H), 2.29 (m, 6 H), 1.42 (s, 9
H); 13C NMR (75 MHz, CDCl3) δ 170.7, 169.9, 155.8, 144.6,
138.9, 136.5, 129.9, 129.7, 129.1, 128.8, 128.6, 127.43, 127.37,
81.0, 77.7, 73.5, 70.5, 67.7, 67.2, 57.1, 54.1, 53.6, 52.7, 36.2,
34.0, 28.6, 27.1; IR (film) 3292, 2974, 2931, 2860, 2814, 1706,
370.2140, found 370.2136; [R]25 +2.6 (c 2.5, CHCl3).
D
(S)-(-)-2-Amino-N-(2-diethylaminoethyl)-4-methylsul-
fanylbutyramide, Amine 62. Carbamate 61 (1.89 g, 5.43
mmol) was treated with TFA (8.4 mL, 110 mmol) in CH2Cl2
(25 mL) at room temperature for 2 h. The excess TFA and
solvent was removed by rotary evaporation and the residue
was dissolved with EtOAc (75 mL) and washed with half
saturated aqueous NaHCO3 (4 mL). The organic layer was
dried over Na2SO4, the solvent was removed, and the crude
product was purified by column chromatography (gradient of
1:9:90 to 2:18:80 30% aqueous NH4OH/MeOH/CH2Cl2) to yield
compound 62 as a colorless oil (1.18 g, 4.78 mmol, 88%): 1H
NMR (300 MHz, CDCl3) δ 7.49 (br s, 1 H), 3.49 (dd, J ) 8.2,
4.7 Hz, 1 H), 3.33 (m, 2 H), 2.60 (m, 8 H), 2.14 (m, 1 H), 2.11
(s, 3 H), 1.83 (br s, 2 H), 1.81 (m, 2 H), 1.05 (t, J ) 7.1 Hz, 6
H); 13C NMR (75 MHz, CDCl3) δ 175.3, 54.7, 52.2, 47.4, 37.1,
34.6, 31.1, 15.7, 12.0; IR (neat) 3302, 2967, 2915, 2812, 1650,
1518 cm-1; HRMS-FAB (M + H+) calcd for C11H26N3OS
248.1797, found 248.1794; [R]24 -12 (c 1.5, CHCl3).
D
(-)-{1-[1-(2-Diethylaminoethylcarbamoyl)-3-methyl-
sulfanyl-(S)-1-propylcarbamoyl]-2-tritylsulfanyl-(R)-1-
ethyl}carbamic Acid tert-Butyl Ester, Ligand 54. To
N-Boc-Cys(Tr)-OH (4.43 g, 9.55 mmol) was added HBTU (3.80
g, 10.0 mmol), amine 62 (1.18 g, 4.78 mmol), DMF (27 mL),
and DIEA (2.50 mL, 14.3 mmol). The reaction mixture was
stirred at room temperature for 2 h and then diluted with H2O
(50 mL). The aqueous phase was extracted with EtOAc (70
mL) and the organic phase was washed with H2O (2 × 50 mL)
and brine (1 × 25 mL). The organic layer was dried over Na2-
SO4, the solvent was removed, and the crude product was
purified by column chromatography (gradient of 0.4:3.6:96 to
1:9:90 30% aqueous NH4OH/MeOH/CH2Cl2) to yield compound
54 as a white solid (1.81 g, 2.62 mmol, 55%): mp 109-111 °C;
1H NMR (300 MHz, CDCl3) δ 7.44 (m, 6 H), 7.34-7.22 (m, 9
H), 7.02 (br s, 2 H), 4.79 (d, J ) 5.5 Hz, 1 H), 4.47 (dd, J )
12.9, 7.5 Hz, 1 H), 3.83 (dd, J ) 11.6, 6.1 Hz, 1 H), 3.36 (br s,
2 H), 2.75 (br s, 6 H), 2.53 (m, 2 H), 2.12 (m, 1 H), 2.07 (s, 3
H), 2.00 (m, 1 H), 1.44 (s, 9 H), 1.11 (t, J ) 7.1 Hz, 6 H); 13C
NMR (75 MHz, CDCl3) δ 171.5, 171.0, 155.9, 144.2, 129.5,
128.2, 127.0, 80.9, 67.3, 54.1, 53.0, 52.2, 47.1, 36.5, 33.2, 30.3,
30.1, 28.2, 15.1, 10.8; IR (film) 3290, 3057, 2973, 2929, 1713,
1676, 1640, 1515, 1492, 1444, 1367, 1246, 1167, 845, 744, 701
cm-1; HRMS-FAB (M + H+) calcd for C38H53N4O4S2 693.3508,
1658, 1494, 1445, 1366, 1248, 1166, 1116, 746, 700 cm-1
;
HRMS-FAB (M + Na+) calcd for C47H56N6O6SNa 855.3880,
found 855.3895; [R]24 -5.6 (c 2.0, CHCl3).
D
Optimized Conditions for Alkenylzinc Addition to
Aldehydes. A flame-dried vial was cooled to 0 °C and BH3-
DMS (0.31 mL, 3.3 mmol) in CH2Cl2 (3 mL) was added,
followed by cyclohexene (0.67 mL, 6.6 mmol). This solution was
stirred at 0 °C for 2 h and appeared as a white cloudy solution.
Next, the alkyne (1.2 equiv, 3.6 mmol) was added and the
reaction was warmed to room temperature for 30 min yielding
a clear stock solution of vinylborane. Ligand 54 (13 mg, 0.019
mmol) was combined with 2.0 M Me2Zn (0.16 mL, 0.32 mmol)
in toluene at room temperature for 5 min, then cooled to -78
°C, and the vinylborane stock solution was added (approxi-
mately 0.37 mL or 1/12 the stock solution volume depending
on the alkyne used). After the reaction was stirred for 18 h at
-78 °C, the appropriate aldehyde (0.25 mmol) was added and
the reaction was surrounded with dry ice and placed in a -20
°C freezer for 48 h. The reaction was quenched with saturated
aqueous NH4Cl and diluted with diethyl ether. The organic
layer was washed with aqueous 1 N HCl (1 × 5 mL) and
saturated aqueous NaHCO3 (1 × 5 mL). The solvent was
removed and the product was purified by column chromatog-
raphy (8:92 EtOAc:hexanes).
found 693.3495; [R]24 -4.5 (c 0.99, CHCl3).
D
(-)-[1-(2-Morpholin-4-ylethylcarbamoyl)-2-(3-benzy-
loxymethyl-3H-imidazol-4-yl)-(S)-1-ethyl]carbamic Acid
tert-Butyl Ester, Carbamate 76. To N-Boc-His(Bom)-OH
(0.309 g, 0.824 mmol) was added HBTU (0.938 g, 2.47 mmol),
DIEA (0.72 mL, 4.1 mmol), and DMF (5 mL). After the mixture
was stirred for 5 min, 2-morpholin-4-ylethylamine (0.22 mL,
1.7 mmol) was added. The reaction was stirred at room
temperature for 3 h, then diluted with 50 mL of H2O. The
aqueous phase was extracted with EtOAc (75 mL), and the
organic phase was washed with H2O (2 × 50 mL) and 25 mL
of brine. The organic layer was dried over Na2SO4, the solvent
was removed, and the crude product was purified by column
chromatography (gradient of 0.2:1.8:98 to 0.7:6.3:93 30%
aqueous NH4OH/MeOH/CH2Cl2) to yield compound 76 as a
colorless oil (0.215 g, 0.441 mmol, 54%): 1H NMR (300 MHz,
CDCl3) δ 7.51 (s, 1 H), 7.37 (m, 5 H), 6.90 (s, 1 H), 6.40 (br s,
1 H), 5.36 (m, 3 H), 4.56 (m, 2 H), 4.40 (dd, J ) 14.5, 7.1 Hz,
1 H), 3.64 (t, J ) 4.6 Hz, 4 H), 3.26 (m, 2 H), 3.09 (m, 2 H),
2.35 (m, 6 H), 1.45 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ 170.9,
155.7, 138.8, 136.4, 129.8, 129.2, 128.8, 128.6, 127.6, 80.6, 77.6,
73.5, 70.5, 67.3, 57.0, 54.3, 53.6, 36.0, 28.7, 27.7; IR (neat) 3302,
2969, 2929, 2860, 2808, 1708, 1669, 1519, 1498, 1453, 1366,
1250, 1168, 1117 cm-1; HRMS-FAB (M + H+) calcd for
(R,E)-(-)-1-(4-Chlorophenyl)-4,4-dimethylpent-2-en-1-
ol, Allylic Alcohol 67. 95% ee by HPLC analysis (Chiralcel
OD-H column eluted with hexanes at 1.0 mL/min and detection
at 219 nm), tR ) 61.4 min for (R) and tR ) 75.6 min for (S);
1
[R]25 -56 (c 0.99, CHCl3); H NMR (300 MHz, CDCl3) δ 7.30
D
(br s, 4 H), 5.78 (dd, J ) 15.6, 0.6 Hz, 1 H), 5.50 (dd, J ) 15.6,
7.0 Hz, 1 H), 5.12 (d, J ) 7.0 Hz, 1 H), 1.89 (br s, 1 H), 1.01 (s,
9 H); 13C NMR (75 MHz, CDCl3) δ 144.5, 142.3, 133.5, 128.9,
127.9, 127.3, 75.1, 33.3, 29.8; HRMS-EI (M+) calcd for C13H17-
ClO 224.0968, found 224.0979.
(R,E)-(-)-1-(4-Bromophenyl)-4,4-dimethylpent-2-en-1-
ol, Allylic Alcohol 68. 95% ee by HPLC analysis (Chiralcel
OD-H column eluted with hexanes at 1.0 mL/min and detection
C25H37N5O5Na 510.2692, found 510.2680; [R]24 -7.5 (c 1.1,
D
at 219 nm), tR ) 67.1 min for (R) and tR ) 98.5 min for (S);
1
[R]25 -57 (c 2.2, CHCl3); mp 45-46 °C; H NMR (300 MHz,
CHCl3).
D
(R)-(-)-1((S)-3-(1-(benzyloxymethyl)-1H-imidazol-5-yl)-
1-(2-morpholinoethylamino)-1-oxopropan-2-ylamino)-1-
CDCl3) δ 7.48 (d, J ) 8.4 Hz, 2 H), 7.25 (d, J ) 8.4 Hz, 2 H),
5.80 (dd, J ) 15.5, 0.8 Hz, 1 H), 5.52 (dd, J ) 15.6, 6.9 Hz, 1
7416 J. Org. Chem., Vol. 70, No. 18, 2005