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K. Bodenschatz, J. Stockl, M. Winterer et al.
Tetrahedron xxx (xxxx) xxx
1716, 1612, 1588, 1506, 1455, 1439, 1419, 1371, 1334, 1288, 1247,
1206, 1155, 1131, 1034, 934, 920, 832, 776, 736, 697, 635, 606, 583,
(1H, d, JHH 3.6 Hz, H-1); dC (125 MHz, CDCl3) 24.6/24.7/25.1/26.1/
27.0 (C-4/5/6/13/14), 30.3 (C-7), 30.3/30.5 (C-8), 33.3 (C-3), 36.9 (C-
2), 37.8 (C-12), 46.7 (C-18), 53.4 (C-17), 55.5/55.6 (C-25/26), 58.4 (C-
15), 98.4 (C-21), 105.0 (C-23), 109.8 (C-19), 123.7/123.8 (C-10), 133.4
(C-24), 142.9/143.0 (C-9), 159.2 (C-20), 162.7 (C-22), 167.3 (C-11),
573, 552 cmꢁ1
; dH (500 MHz, CDCl3) 1.42e1.71 (4H, m, H-2/3), 3.13
(2H, q, JHH 6.4 Hz, H-1), 3.22 (1H, t, JHH 6.4 Hz, H-4), 3.60 (3H, s, H-6),
3.62 (2H, d, JHH 13.0 Hz, H-7), 3.66 (2H, d, JHH 13.0 Hz, H-7), 3.74 (3H,
s, H-14/15), 3.74 (3H, s, H-14/15), 5.05 (2H, s, H-17), 5.57 (1H, s, NH),
6.35e6.42 (2H, m, H-10/12), 7.09 (1H, d, JHH 8.1 Hz, H-13), 7.25e7.35
(5H, m, H-19/20/21/22/23); dC (125 MHz, CDCl3) 26.1 (C-2), 30.4 (C-
3), 40.5 (C-1), 46.9 (C-6), 51.4 (C-6), 55.0 (C-14/15), 60.2 (C-4), 66.2
(C-17), 98.2 (C-10), 103.5 (C-12), 119.9 (C-8), 127.8 (C-19/23), 127.8
(C-20/22), 128.2 (C-21), 130.2 (C-13), 136.6 (C-18), 156.3 (C-16),
158.4 (C-9), 160.0 (C-11), 175.4 (C-5).
169.0 (C-16), 206.0 (C-1); HRMS: m/z calcd for [M
C
þ
H,
26H39N2Oþ6 ]: 475.28026; found: 475.27935.
4.2.18. Methyl (S)-2-((2,4-dimethoxybenzyl)amino)-5-((Z)-4-((2-
((E)-2-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)vinyl)cyclohexyl)
but-2-enamido)pentanoate (35)
Compound 35 was synthesized analogously to a literature pro-
tocol [15a]. A solution of diisopropylamine (0.02 mL, 0.14 mmol,
1.05 eq) in 1.00 mL THF was treated with nBuLi (2.5 M in hexane,
0.14 mmol, 1.05 eq) at 0 ꢀC. After 30 min a solution of 13 (36 mg,
0.13 mmol, 1.00 eq) in 1 mL THF was added at ꢁ78 ꢀC. The reaction
mixture was allowed to warm up to 0 ꢀC and was stirred for 15 min
at that temperature. HMPA (0.04 mL, 0.23 mmol, 1.77 eq) was
added at ꢁ78 ꢀC and the reaction mixture was stirred for 30 min.
Then a solution of 34 (60 mg, 0.13 mmol, 1.00 equiv) in 1 mL THF
was added dropwise. The temperature was raised to 0 ꢀC and the
reaction mixture was stirred for an additional hour. Saturated
4.2.16. Methyl (S)-5-((Z)-4-(2-(1,3-dioxolan-2-yl)cyclohexyl)but-2-
enamido)-2-((2,4-dimethoxybenzyl)amino)pentanoate (33)
A solution of 12 (1.93 g, 4.49 mmol, 1.00 equiv) in 20 mL EtOAc
was treated with 10 wt-% Pd/C and TFA (0.40 mL, 5.39 mmol, 1.20
eq) and stirred in an H2-atmosphere at ambient temperature for
2 h. The reaction mixture was filtered over celite and the volatiles
were removed in vacuo. The crude product salt 32 was immediately
used without further purification. A solution of ( )-11 (920 mg,
3.83 mmol, 1.00 equiv) in 35 mL DMF was treated with DIPEA
(1.30 mL, 7.66 mmol, 2.00 eq) and HBTU (1.63 g, 4.21 mmol, 1.10
equiv) at 0 ꢀC and was stirred for 20 min. Crude 32 (1.57 g,
3.83 mmol, 1.00 equiv) was added and the solution was stirred at
ambient temperature for 24 h. Saturated NH4Cl (aq) was added and
the aqueous layer was extracted with EtOAc. The combined organic
layers were washed with brine and dried over Na2SO4 and the
volatiles removed in vacuo. The remainder was purified by column
chromatography (CH2Cl2/MeOH 20:1) to afford the product
mixture of two diastereomers as an orange resin (700 mg, 40%);
nmax 3423, 2927, 2856, 1739, 1656, 1614, 1588, 1532, 1509, 1454,
1440, 1375, 1332, 1291, 1260, 1242,1208, 1158, 1136, 1121, 1071, 1031,
NH4Cl
was added and the aqueous layer extracted with EtOAc.
(aq)
The combined organic layers were washed with brine and dried
over Na2SO4. The volatiles were removed in vacuo and the
remainder purified by column chromatography (CH2Cl2/MeOH
20:1) to give a product mixture of two diastereoisomers as a yellow
oil (50 mg, 64%); nmax 3320, 2999, 2924, 2853, 1722, 1649, 1614,
1588, 1534, 1506, 1456, 1389, 1374, 1273, 1249, 1205, 1156, 1135,
1018, 974, 935, 903, 859, 833, 800, 731, 697, 674, 639, 608, 591,
568 cmꢁ1
; dH (500 MHz, CDCl3) 1.12e1.97 (14H, m, H-1/2/3/4/5/6/
12/13),1.69 (6H, s, H-32/33), 2.40e2.73 (2H, m, H-7), 3.19e3.28 (3H,
m, H-11/14), 3.60e3.70 (2H, m, H-17), 3.64 (3H, s, H-16), 3.78/3.79
(6H, s, H-24/25), 5.21 (1H, s, H-29), 5.58 (1H, d, JHH 11.6 Hz, H-9),
5.81e5.90 (1H, m, H-26), 5.87 (1H, d, JHH 15.6 Hz, H-27) 6.30e6.44
(3H, m, H-8/20/22), 7.09 (1H, d, JHH 8.1 Hz, H-23); dC (125 MHz,
978, 940, 837, 738, 698, 637, 585, 573, 557 cmꢁ1
; dH (500 MHz,
CDCl3) 0.94e2.00 (12H, m, H-5/6/7/8/15/16),1.37e1.50 (2H, m, H-4/
9), 2.62e2.80 (2H, m, H-10), 3.14e3.28 (2H, m, H-14), 3.54e3.61
(1H, m, H17), 3.70 (3H, s, H-19), 3.77/3.83 (6H, s, H-27/28),
3.77e3.93 (4H, m, H-1/2), 3.86e4.02 (2H, m, H-20), 4.92 (1H, t, JHH
2.71 Hz, H-3), 5.42 (1H, s, NH), 5.70 (1H, d, JHH 11.5 Hz, H-12),
5.91e6.00 (1H, m, H-11), 6.38e6.45 (2H, m, H-23/25), 6.52e6.58
(1H, m, NH), 7.12e7.20 (1H, m, H-26); dC (125 MHz, CDCl3) 24.7/
25.5/25.8/28.6/32.1/32.6 (C-5/6/7/8/15/16), 32.6 (10), 38.3 (C-14),
38.4 (C-9), 44.5 (C-4), 47.6 (C-20), 52.9 (C-19), 55.5/55.6 (C-27/28),
59.6 (C-17), 64.9/65.1 (C-1/2), 98.5 (C-23), 104.6 (C-3), 104.9 (C-25),
113.7/113.8 (C-21), 122.7/122.8 (C-12), 132.2 (C-26), 144.7/144.8 (C-
11), 159.0 (C-22), 161.8/161.9 (C-24), 167.6 (C-13), 171.8 (C-18);
HRMS: m/z calcd for [M þ H, C28H43N2Oþ7 ]: 519.30648; found:
519.30542.
CDCl3)
d 25.1/25.2 (C-32/33), 25.7/25.9/31.0/31.5/32.9/33.9 (C-2/3/
4/5/7/12/13), 39.0 (C-11), 42.2 (C-6), 47.4 (C-1), 47.5 (C-17), 51.9 (C-
16), 55.4/55.5 (C-24/25), 60.6 (C-14), 93.4 (C-29), 98.6 (C-20), 103.9
(C-22), 106.4 (C-18), 119.9 (C-31), 122.4 (C-27), 123.4 (C-9), 130.7 (C-
23), 144.0 (C-26), 146.8 (C-8), 158.8 (C-19), 160.5 (C-21), 162.3 (C-
30), 163.6 (C-10), 166.5 (C-28), 175.5 (C-15); HRMS: m/z calcd for
[M þ H, C33H47N2Oþ8 ]: 599.33269; found: 599.33141.
4.2.19. Protected PTM-model 36
Compound 36 was synthesized analogously to a literature pro-
tocol [5a]. A solution of 35 (24 mg, 0.04 mmol, 1.00 eq) in 50 mL
toluene was added dropwise to 100 mL of toluene stirred at reflux.
After being stirred for 2 h the volatiles were removed in vacuo to
4.2.17. Methyl (S)-2-((2,4-dimethoxybenzyl)amino)-5-((Z)-4-(2-
formylcyclohexyl)-but-2-enamido)pentanoate (34)
leave the intermediate b-ketoamide which was taken up in 2 mL
tBuOH and treated with KOtBu (8 mg, 0.07 mmol, 2.00 eq). After
stirring for 20 min at ambient temperature, 5% citric acid was added
and the aqueous layer was extracted with EtOAc. The combined
organic phases were dried over Na2SO4 and the volatiles removed
in vacuo to afford the product mixture of two diastereomers an
orange oil (11 mg, 53% 2 steps); nmax 3314, 2921, 2852, 1705, 1640,
1612, 1583, 1508, 1455, 1363, 1290, 1263, 1237, 1208, 1185, 1157,
1130, 1116, 1033, 988, 941, 919, 830, 817, 786, 731, 698, 677, 640, 619,
A solution of 33 (106 mg, 0.20 mmol, 1.00 equiv) in 10 mL
acetone was treated with I2 (43 mg, 0.17 mmol, 0.83 equiv) and
stirred at ambient temperature for 2 h. 5% Na2S2O3 was added and
the aqueous layer extracted with CH2Cl2. The combined organic
layers were washed with water and brine and then dried over
Na2SO4. The volatiles were removed in vacuo to give the product
diastereomers as a yellow oil (57 mg, 59%); nmax 3421, 2930, 2855,
1746,1717,1655,1615,1589,1533,1511,1440,1368,1329,1293,1268,
599, 582 cmꢁ1
; dH (500 MHz, CDCl3) 0.64e2.47 (18H, m, H-1/2/3/4/
1245,1209,1160,1136,1121,1029, 979, 937, 832, 736, 701, 556 cmꢁ1
;
5/6/7/11/12/13), 3.59e3.70 (1H, m, H-14), 3.79 (6H, s, H-23/24), 4.15
(1H, d, JHH 14.8 Hz, H-16), 4.90 (1H, t, JHH 14.8 Hz, H-16), 5.70e5.81
(2H, m, H-9/26), 6.04e6.12 (1H, m, H-25), 6.41e6.47 (2H, m, H-19/
21), 6.70 (1H, dd, JHH 15.5, 10.5 Hz, H-8), 7.20 (1H, d, JHH 8.2 Hz, H-
22); dC (125 MHz, CDCl3) 24.2/25.4/26.4/26.7/30.2/33.0/33.5 (C-2/3/
4/5/7/12/13), 37.8/37.9 (C-11), 38.8/38.9 (C-16), 38.95/39.1 (C-6),
dH (500 MHz, CDCl3) 0.86e2.08 (16H, m, H-2/3/4/5/6/7/13/14),
2.48e2.65 (2H, m, H-8), 3.01e3.27 (2H, m, H-12), 3.70 (3H, s, H-17),
3.73/3.80 (6H, s, H-25/26), 3.77e3.82 (1H, m, H-15), 4.14/4.24 (2H,
d, JHH 12.9 Hz, H-18), 5.80e5.93 (2H, m, H-9/10), 6.34e6.44 (2H, m,
H-21/23), 7.02e7.08 (1H, m, NH), 7.30 (1H, d, JHH 8.4 Hz, H-24), 9.48
7