90
E. Abraham et al. / Tetrahedron: Asymmetry 22 (2011) 69–100
(1H, m, C(1)H), 2.61–2.65 (2H, m, 2 ꢃ C(1)H), 3.51–3.61 (1H, m,
C(2)H), 3.71–3.81 (1H, m, C(2)H), 3.92–4.02 (1H, m, C(2)H), 4.94
(1H, d, J 7.8, NH), 5.11 (2H, s, OCH2Ph), 7.22 (1H, d, J 7.3, NH),
7.31–7.42 (5H, m, Ph), 7.86 (1H, d, J 8.3, NH); dC (125 MHz, CDCl3)
17.4, 17.6, 17.7 (3 ꢃ C(3)Me), 26.2, 26.3, 26.5, 31.4, 31.5, 31.9
(3 ꢃ C(4), 3 ꢃ C(5)), 28.0 (CMe3), 41.1, 41.4, 41.7 (3 ꢃ C(3)), 51.5,
52.6, 52.7 (3 ꢃ C(1)), 60.8, 61.5, 62.7 (3 ꢃ C(2)), 67.2 (OCH2Ph),
79.9 (CMe3), 128.1, 128.4, 128.6 (o,m,p-Ph), 135.9 (i-Ph), 157.0
Following General Procedure 2, 53 (1.08 g, 2.10 mmol) and TFA
(1.23 mL) in CH2Cl2 (4.91 mL) gave 59 as a white solid (952 mg,
99%, >99:1 dr); mp 169–171 °C; ½a D23
¼ ꢂ5:8 (c 0.4 in CHCl3); mmax
ꢄ
(KBr) 3317 (N–H, O–H), 1698, 1546 (C@O); dH (400 MHz, CDCl3)
0.86–0.98 (12H, m, 2 ꢃ CHMe2), 1.24–1.91 (10H, m, 2 ꢃ C(3)H,
2 ꢃ C(4)H2, 2 ꢃ C(5)HA, 2 ꢃ CHMe2), 2.11–2.22 (1H, m, C(5)HB),
2.32–2.41 (1H, m, C(5)HB), 2.67–2.77 (2H, m, 2 ꢃ C(1)H), 3.67–
3.79 (2H, m, 2 ꢃ C(2)H), 4.98 (1H, d, J 6.8, NH), 5.11 (1H, d, J 12.5,
OCHAHBPh), 5.15 (1H, d, J 12.5, OCHAHBPh), 7.26–7.49 (5H, m, Ph),
8.29 (1H, d, J 4.1, NH); dC (100 MHz, CDCl3) 19.5, 20.2, 21.4, 21.5
(2 ꢃ CHMe2), 26.0, 26.5, 26.9, 28.5 (2 ꢃ C(4), 2 ꢃ C(5)), 30.2, 31.0
(2 ꢃ CHMe2), 52.9, 53.2, 53.5 (2 ꢃ C(1), 2 ꢃ C(3)), 59.5, 60.2
(2 ꢃ C(2)), 67.0 (OCH2Ph), 127.9, 128.3, 128.6 (o,m,p-Ph), 136.1 (i-
Ph), 156.9 (NCO [carbamate]), 175.8, 176.6 (NCO [amide], CO2H);
t
(NCO [carbamate]), 173.4, 174.6, 174.6 (2 ꢃ NCO [amide], CO2 Bu);
m/z (ESI+) 606 ([M+Na]+, 76%), 584 ([M+H]+, 100%); HRMS (ESI+)
þ
C
33H49N3NaO6 ([M+Na]+) requires 606.3514; found 606.3515.
4.36. Cbz-[(S,S,S)-3-iPr-ACPC]3-OtBu 62
m/z (ESI+) 481 ([M+Na]+, 66%), 459 ([M+H]+, 100%); HRMS (ESI+)
+
O
C
26H38N2NaO5 ([M+Na]+) requires 481.2673; found 481.2672.
Cbz
NH
OtBu
4.34. Cbz-[(S,S,S)-3-Bn-ACPC]3-OtBu 60
i
Pr
3
Following General Procedure 3, 50 (425 mg, 1.39 mmol), 56 (530 mg,
1.39 mmol), HOBt (226 mg, 1.67 mmol), EDCꢁHCl (320 mg, 1.67
mmol) and Et3N (0.97 mL, 6.96 mmol) in CHCl3 (60 mL) gave, after
purification via flash column chromatography (gradient elution,
0?18% MeOH in CHCl3), 62 as a white solid (634 mg, 68%, >99:1
O
Cbz
NH
OtBu
Bn
3
dr); Rf 0.55 (CHCl3/MeOH, 10:1); mp 49–51 °C; ½a D21
¼ þ27:6 (c 0.2
ꢄ
Following General Procedure 3, 48 (215 mg, 0.61 mmol), 54 (290 mg,
0.61 mmol), HOBt (99 mg, 0.73 mmol), EDCꢁHCl (140 mg, 0.73 mmol)
and Et3N (0.42 mL, 3.04 mmol) in CHCl3 (40 mL) gave, after purifica-
tion via recrystallisation (CHCl3/heptane), 60 as a white solid
in CHCl3); mmax (CHCl3) 3463, 3288 (N–H); mmax (KBr) 3311 (N–H),
1711, 1659, 1547 (C@O); dH (400 MHz, CDCl3) 0.79–1.02 (18H, m,
3 ꢃ CHMe2), 1.24–1.98 (16H, m, 3 ꢃ C(3)H, 3 ꢃ C(4)H2, 2 ꢃ C(5)HA,
C(5)H2, 3 ꢃ CHMe2) overlapping 1.43 (9H, s, CMe3), 2.01–2.13 (1H,
m, C(5)HB), 2.14–2.24 (1H, m, C(5)HB), 2.45–2.54 (1H, m, C(1)H),
2.58–2.71 (2H, m, 2 ꢃ C(1)H), 3.68–3.78 (1H, m, C(2)H), 3.86–3.97
(1H, m, C(2)H), 4.15–4.27 (1H, m, C(2)H), 4.95 (1H, d, J 7.5, NH),
5.11 (2H, s, OCH2Ph), 7.29–7.48 (5H, m, Ph) overlapping 7.45 (1H, d,
J 6.8, NH), 8.08 (1H, d, J 7.9, NH); dC (100 MHz, CDCl3) 19.2, 19.5,
20.1, 21.4, 21.5 (3 ꢃ CHMe2), 26.2, 26.4, 26.5, 26.9, 27.5 (3 ꢃ C(4),
3ꢃ C(5)), 28.0 (CMe3), 29.9, 30.2, 30.9 (3 ꢃ CHMe2), 52.1, 52.4, 53.3,
53.4, 53.7 (3 ꢃ C(1), 3 ꢃ C(3)), 57.1, 59.0, 59.8 (3 ꢃ C(2)), 67.1
(OCH2Ph), 79.8 (CMe3), 128.1, 128.3, 128.6 (o,m,p-Ph), 136.1 (i-Ph),
(358 mg, 72%, >99:1 dr); mp 179–181 °C; ½a D21
¼ þ42:5 (c 0.3 in
ꢄ
CHCl3); mmax (CHCl3) 3432, 3281 (N–H); mmax (KBr) 3302 (br, N–H),
1720, 1689, 1650, 1533 (C@O); dH (400 MHz, CDCl3) 1.31–2.31
(15H, m, 3 ꢃ C(3)H, 3 ꢃ C(4)H2, 3 ꢃ C(5)H2) overlapping 1.47 (9H, s,
CMe3), 2.36–2.64 (5H, m, 2 ꢃ C(1)H, 3 ꢃ C(3)CHAHBPh), 2.66–2.83
(3H, m, C(1)H, 2 ꢃ C(3)CHAHBPh), 2.96 (1H, dd,
J 13.7, 4.1,
C(3)CHAHBPh), 3.69 (1H, app q, C(2)H), 3.85–3.95 (1H, m, C(2)H),
4.13–4.24 (1H, m, C(2)H), 4.75 (1H, d, J 7.9, NH), 5.05 (2H, br s,
OCH2Ph), 7.01–7.41 (20H, m, Ph) overlapping 7.07 (1H, d, J 7.2, NH),
8.08 (1H, d, J 8.2, NH); dC (125 MHz, CDCl3) 25.8, 26.1, 26.6, 29.2,
29.6, 30.4 (3 ꢃ C(4), 3 ꢃ C(5)), 28.1 (CMe3), 39.2, 39.2, 39.6
(3 ꢃ C(3)CH2Ph), 47.7, 48.5, 48.7 (3 ꢃ C(3)), 51.6, 52.5, 52.7
(3 ꢃ C(1)), 59.4, 60.7, 61.3 (3 ꢃ C(2)), 67.1 (OCH2Ph), 80.1 (CMe3),
125.6, 125.8, 126.1, 128.1, 128.3, 128.4, 128.4, 128.6, 128.6, 128.8,
128.9 (o,m,p-Ph), 135.9, 139.9, 140.8, 141.2 (i-Ph), 156.7 (NCO [carba-
t-
156.8 (NCO [carbamate]), 173.0, 174.4, 174.6 (2 ꢃ NCO [amide], CO2
Bu); m/z (ESI+) 690 ([M+Na]+, 46%), 668 ([M+H]+, 100%); HRMS (ESI+)
+
þ
C
39H61N3NaO6 ([M+Na] ) requires 690.4453; found 690.4447.
4.37. Cbz-[(S,S,S)-3-Bn-ACPC]4-OtBu 63
mate]), 173.5, 174.4, 174.5 (2 ꢃ NCO [amide], CO2 Bu); m/z (ESI+) 834
t
([M+Na]+, 58%), 813 ([M+H]+, 100%); HRMS (ESI+) C51H61N3NaO6
þ
([M+Na]+) requires 834.4453; found 834.4453.
O
Cbz
NH
OtBu
4.35. Cbz-[(1S,2S,3R)-3-Me-ACPC]3-OtBu 61
Bn
4
O
Following General Procedure 3, 57 (453 mg, 0.82 mmol), 54 (389 mg,
0.82 mmol), HOBt (389 mg, 0.82 mmol), EDCꢁHCl (188 mg,
0.99 mmol) and Et3N (0.57 mL, 4.08 mmol) in CHCl3 (120 mL) gave,
after purification via flash column chromatography (gradient elution,
1?18% MeOH in CHCl3), 63 as a white solid (472 mg, 57%, >99:1 dr);
OtBu
Cbz
NH
Me
3
Following General Procedure 3, 49 (450 mg, 1.62 mmol), 55 (527 mg,
1.62 mmol), HOBt (263 mg, 1.95 mmol), EDCꢁHCl (374 mg,
1.95 mmol) and Et3N (1.13 mL, 8.12 mmol) in CHCl3 (60 mL) gave,
after purification via recrystallisation (CHCl3/heptane), 61 as a
Rf 0.48 (CHCl3/MeOH, 20:1); mp 183–185 °C (dec.); ½a D20
¼ þ47:2 (c
ꢄ
0.5 in CHCl3); mmax (CHCl3) 3430, 3344, 3267 (N–H); mmax (KBr)
3307 (N–H), 1699, 1646, 1552 (C@O); dH (400 MHz, CDCl3) 1.33–
2.38 (31H, m, 2 ꢃ C(1)H, 4 ꢃ C(3)H, 4 ꢃ C(4)H2, 4 ꢃ C(5)H2, CMe3),
2.40–2.69 (6H, m, C(1)H, 4 ꢃ C(3)CHAHBPh, C(3)CHAHBPh), 2.70–
2.79 (1H, m, C(3)CHAHBPh), 2.82–2.91 (2H, m, C(1)H, C(3)CHAHBPh),
3.04–3.11 (1H, m, C(3)CHAHBPh), 3.64–3.73 (1H, m, C(2)H), 3.90–
4.06 (2H, m, 2 ꢃ C(2)H), 4.13–4.23 (1H, m, C(2)H), 4.79 (1H, d, J 7.9
NH), 5.01 (1H, d, J 12.3, OCHAHBPh), 5.08 (1H, d, J 12.3, OCHAHBPh),
6.15 (1H, d, J 8.2, NH), 6.97–7.42 (25H, m, Ph), 7.68 (1H, d, J 7.8, NH),
white solid (479 mg, 51%, >99:1 dr); mp 204–206 °C; ½a D23
¼
ꢄ
þ14:0 (c 0.6 in CHCl3); mmax (CHCl3) 3433, 3287 (N–H); mmax (KBr)
3303 (N–H), 1719, 1693, 1651, 1542 (C@O); dH (400 MHz, CDCl3)
0.94–1.04 (6H, m, 2 ꢃ C(3)Me), 1.06 (3H, d, J 6.7, C(3)Me), 1.25–
1.97 (13H, m, 3 ꢃ C(3)H, 3 ꢃ C(4)H2, 2 ꢃ C(5)HA, C(5)H2) overlap-
ping 1.44 (9H, s, CMe3), 2.02–2.25 (2H, m, 2 ꢃ C(5)HB), 2.52–2.60