Trifunctional Scaffold for Biological Applications
1
9.07 mmol, 2 equiv.) was added to a solution of diamide salt 4
3ϫiPr), 4.17 (d, 3JH,H = 5.6 Hz, 2 H, N–CH
2
–), 8.84 (br. t, 3JH,H
]DMSO; T =
100 °C): δ = 127.43 (1 C, C-4), 127.59 (2 C, C-2 and C-6), 134.61
1
3
(7.0 g, 9.54 mmol), amine 5 (2.81 g, 14.3 mmol, 1.5 equiv.), and = 5.6 Hz, 1 H, NH) ppm. C NMR (125.8 MHz, [D
6
PyBroP (6.67 g, 14.3 mmol, 1.5 equiv.) in DMF (200 mL), and the
solution was stirred for 12 h at room temp. The reaction mixture
was then diluted with water (500 mL), and the product was ex-
1
3
(1 C, C-3), 134.72 (1 C, C-5), 135.23 (1 C, C-1), R : 26.19 (t, JC,F
2
= 4.6 Hz, 1 C, CH
2
), 29.73 (t, JC,F = 24.4 Hz, 1 C, CH
2
), 38.45 (1
), 75.12 (1 C,
),
tracted with diethyl ether (250 mL, 2ϫ 100 mL). The combined C, N–CH
2
), 48.56 (br. t, 2JC,F ca. 26 Hz, 1 C, N–CH
ϵC-H), 78.09 (1 C, –Cϵ), 122.95 (t, JC,F = 243.2 Hz, 1 C, CF
2
1
organic phase was washed with brine (250 mL), dried with anhy-
drous sodium sulfate, filtered, and the solvents evaporated. The
crude product was purified by flash chromatography on silica (elu-
2
2
169.96 (1 C, N–CO–), 172.16 (1 C, COOH), R : 3.72 (3 C, 3ϫSi–
CH ), 6.70 (3 C, 3ϫCH ), 29.38 (1 C, N–CH –), 83.20 (1 C, Si–
Cϵ), 104.37 (1 C, –Cϵ), 164.49 (1 C, –CO–NH), R : 10.50 (3 C,
), 29.38 (1 C, N–CH –), 81.79 (1
2
3
2
3
tion with a linear gradient of EtOAc in toluene) to give triamide 6
1
(3.957 g, 53%; R
f
0.92 in H3) as a white foam. H NMR (500 MHz, 3ϫSi–CHϽ), 18.02 (6 C, 6ϫCH
3
2
4
6
[D ]DMSO; T = 100 °C): δ = 8.00 (t, JH,H = 1.6 Hz, 1 H, 2-H), C, Si–Cϵ), 105.14 (1 C, –Cϵ), 164.54 (1 C, –CO–NH) ppm. IR
4
4
8
.01 (t, JH,H = 1.6 Hz, 1 H, 6-H), 8.42 (t, JH,H = 1.6 Hz, 1 H, 4- (neat): ν˜ max = 2956 (s), 2944 (s), 2866 (s), 1463 (m), 1366 (m), 1084
1
H), R : 1.41 [s, 9 H, 3ϫCH
3
(tBu)], 2.20 (m, 2 H, –CH
2
–CF
–CO), 3.12 (t, JH,H = 2.2 Hz, 1
–CF
–), R : 0.59 (q, JH,H = 7.9 Hz,
), 4.17 (m,
2
), 2.37
(m), 884 (m), 998 (m sh), 679 (m), 637 (m; TIPS), 2956 (s), 2944
(s), 1463 (m), 1416 (m), 1322 (m sh), 1018 (m), 990 (m), 727 (m;
3
4
(br. t, JH,H ca. 7.5 Hz, 2 H, –CH
2
3
H, ϵC-H), 4.01 (br. t, JH,F = 14.5 Hz, 2 H, N–CH
2
2 2
), 4.24 TES), 1252 (m; CF ), 3309 (m), 2124 (w; HCϵ), 2179 (m; CϵC),
4
2
3
(br. d, JH,H = 2.2 Hz, 2 H, N–CH
2
3334 (m), 3309 (m), 1648 (vs), 1537 (s), 1283 (m; CONH), 1719 (m;
3
6
2
2
1
H, 3ϫSi–CH
H, N–CH
1 H, 3ϫiPr), 4.17 (m, 2 H, N–CH
H, NH) ppm. 13C NMR (125.8 MHz, [D
2
–), 0.98 (t, JH,H = 7.9 Hz, 9 H, 3ϫCH
3
dim.), 1441 (m), 1283 (m; COOH), 1597 (m), 1441 (m sh), 1416
3
3
–1
2
–), 8.84 (br. t, JH,H ca. 6 Hz, 1 H, NH), R : 1.06 (m,
(m), 1182 (m), 1018 (m; ring) cm . HRMS: m/z calcd. for
3
[M + H]+ 728.37211; found 728.37237.
2
–), 8.84 (br. t, JH,H ca. 6 Hz,
]DMSO; T = 100 °C):
C
38
H
56
O
5
N
3
F
2
Si
-(tert-Butyl) 1-Ethyl-2,2-difluoropentanedioate (8): A mixture of
tert-butyl acrylate (29.5 mL, 201.4 mmol), bromodifluoroacetate
46.5 mL, 362.5 mmol, 1.8 equiv.), and copper (ca. 230 mesh,
2
6
5
δ = 127.44 (1 C, C-4), 127.61 (2 C, C-2 and C-6), 134.60 (1 C, C-
3
1
), 134.71 (1 C, C-5), 135.22 (1 C, C-1), R : 27.40 (1 C, CH
2
), 27.44
), 38.67 (1
), 75.12 (1 C,
(
2
3 2
[3 C, 3ϫCH (tBu)], 29.71 (t, JC,F = 24.3 Hz, 1 C, CH
2
5
6.88 g, 422.9 mmol, 2.1 equiv.) in THF (260 mL) was heated to
5 °C under intense stirring; then, N,N,NЈ,NЈ-tetramethylenedi-
2
C, N–CH
2
), 48.82 (br. t, JC,F ca. 26 Hz, 1 C, N–CH
2
1
ϵC-H), 78.10 (1 C, –Cϵ), 79.84 [1 C, ϾCϽ (tBu)], 122.93 (t, JC,F
244.5 Hz, 1 C, CF ), 169.95 (1 C, N–CO–), 170.19 (1 C,
O–CO–), R : 3.72 (3 C, 3ϫSi–CH ), 6.71 (3 C, 3ϫCH ), 29.38 (1
C, N–CH –), 83.17 (1 C, Si–Cϵ), 104.38 (1 C, –Cϵ), 164.46 (1 C,
amine (TMEDA; 15.1 mL, 100.7 mmol, 0.5 equiv.), followed by
acetic acid (10.37 mL, 181.3 mmol, 0.9 equiv.) were added. The
dark blue-brown reaction mixture was stirred for 1 h, cooled to r.t,
and a 10% aqueous solution of ammonium chloride (260 mL) and
diethyl ether (200 mL) was added. The resulting mixture was stirred
for 0.5 h at r.t. and filtered through Celite to remove insoluble inor-
ganic residues. The filtrate was diluted with a further portion of
ammonium chloride solution (200 mL), and the crude product was
extracted two times with diethyl ether (300 and 200 mL). The com-
bined organic phase was washed with another portion of ammo-
nium chloride solution (300 mL) to remove remaining copper com-
plexes (blue color) and, finally, with brine (250 mL). The solution
was dried with anhydrous sodium sulfate, filtered, and evaporated
=
2
2
2
3
2
3
–
2
1
2
CO–NH), R : 10.50 (3 C, 3ϫSi–CHϽ), 18.03 (6 C, 6ϫCH
3
),
9.38 (1 C, N–CH –), 81.76 (1 C, Si–Cϵ), 105.15 (1 C, –Cϵ),
2
64.51 (1 C, –CO–NH) ppm. IR (neat): ν˜ max = 2956 (s), 2945 (s),
867 (s), 1462 (m), 1369 (m), 997 (m), 883 (m), 679 (m), 664 (m
sh), 637 (m; TIPS), 2956 (m), 1462 (m), 1415 (m), 1326 (m), 1018
m), 990 (m), 739 (m), 727 (m; TES), 1250 (m; CF ), 3310 (m),
121 (w), 637 (m; HCϵ), 2179 (m; CϵC), 3342 (m sh), 1652 (s),
533 (s), 1279 (m; CONH), 1250 (m), 1733 (m, COO), 1393 (m),
(
2
2
1
1
–
1
368 (m), 1156 (m; tBu), 1598 (m), 1415 (m), 1018 (m; ring) cm .
+
63 5 3 2 2
HRMS: m/z calcd. for C42H O N F NaSi [M + Na] 806.41665;
found 806.41708.
to give diester 8 (52.43 g, quantitative; R
f
0.24 in toluene) as a pale-
1
yellow oil that was of satisfactory purity by TLC. H NMR
3
(
3 3
600 MHz, CDCl ): δ = 1.36 (t, JH,H = 7.1 Hz, 3 H, CH ), 1.45 (s,
4
,4-Difluoro-5-(N-(prop-2-yn-1-yl)-3-{[3-(triethylsilyl)prop-2-yn-1-
9
4
H, tBu), 2.38 (m, 2 H, –CH
2
–CF
2
), 2.47 (m, 2 H, –CH
2
–CO–),
yl]carbamoyl}-5-{[3-(triisopropylsilyl)prop-2-yn-1-yl]carbamoyl}-
benzamido)pentanoic Acid (7): Triamide 6 (3.93 g, 5.01 mmol) was
added to a solution of trifluoroacetic acid (10 mL) in dichlorometh-
ane (20 mL), and the reaction mixture was stirred for 2 h at room
temp. The solution was then transferred to a separatory funnel and
diluted with water (500 mL), and the product was extracted with
diethyl ether (200 mL, 2ϫ 100 mL). The combined organic phase
was washed with brine (250 mL) and dried with anhydrous sodium
sulfate, and the solvent was removed in vacuo. The residue was
purified by flash chromatography on silica (elution with a linear
3
13
.33 (q,
J
H,H
=
7.1 Hz,
2
H, O–CH
2
-) ppm.
), 27.68 (t,
C NMR
3
(
150.9 MHz, CDCl
3
): δ = 13.91 (1 C, –CH
), 27.98 [3 C, 3ϫCH (tBu)], 29.87 (t,
), 62.95 (1 C, O–CH
15.44 (t, JC,F = 250.5 Hz, 1 C, ϾCF ), 163.86 (t, JC,F = 32.6 Hz,
C, CH ), 170.76 (1 C, O–CO) ppm. IR (CCl ): ν˜ max = 1763 (vs),
735 (vs), 1283 (s), 1156 (s; COO), 2982 (s), 1456 (m), 1393 (m),
3
J
J
C,F
C,F
=
=
2
4
2
1
1
1
1
.5 Hz, 1 C, CH
2
3
3.9 Hz, 1 C, CH
2
2
), 81.11 [1 C, ϾCϽ (tBu)],
1
2
2
2
4
–
1
369 (s, tBu), 1156 (s), 1096 (s; CF
2 2
), 1429 (m; CH ) cm . HRMS:
m/z calcd. for C11
75.10622.
18 4 2
H O F
Na [M + Na]+ 275.10654; found
2
gradient of EtOAc in toluene) to give acid 7 (2.439 g, 67%; R
in H3 on NH -pretreated TLC plate) as a pale-yellow foam, which
was then lyophilized from dioxane. The RP-HPLC analysis
f
0.32
3
tert-Butyl 4,4-Difluoro-5-hydroxypentanoate (9): A suspension of
sodium borohydride (9.431 g, 249.3 mmol, 1.2 equiv.) in ethanol
(96%, 250 mL) was placed in a three-necked, 2 L round-bottom
1
(
(
Method B) of compound 7 is shown in Figure S1. H NMR
500 MHz, [D ]DMSO; T = 100 °C): δ = 8.00 (t, JH,H = 1.6 Hz, 1 flask equipped with a magnetic stirrer, a thermometer, and a vented
6
4
4
4
H, 2-H), 8.01 (t, JH,H = 1.6 Hz, 1 H, 6-H), 8.41 (t, JH,H = 1.6 Hz, addition funnel. The flask was cooled to 0 °C in an ice bath, and
1
1
3
H, 4-H), R : 2.23 (m, 2 H, –CH
2
–CF
2
), 2.41 (t, JH,H = 7.5 Hz,
a solution of diester 8 (52.43 g, 207.8 mmol) in ethanol (250 mL)
4
2
H, –CH
2
–CO), 3.12 (t, JH,H = 2.5 Hz, 1 H, ϵC-H), 4.02 (br. t, was added dropwise from the addition funnel under vigorous stir-
3
4
J
H,F = 14.5 Hz, 2 H, N–CH
2
–CF
2
), 4.24 (d, JH,H = 2.5 Hz, 2 H,
ring. The rate of dropping was carefully controlled to keep the reac-
tion mixture temperature between 0–15 °C. After the addition had
2
3
N–CH
2
–), R : 0.59 (q, JH,H = 8.0 Hz, 6 H, 3ϫSi–CH
2
–), 0.98 (t,
3
3
J
3
H,H = 8.0 Hz, 9 H, 3ϫCH ), 4.17 (d, JH,H = 5.6 Hz, 2 H, N– been finished (ca. 80 min), the reaction was quenched by dropwise
–), 8.84 (br. t, JH,H = 5.6 Hz, 1 H, NH), R : 1.07 (m, 21 H, addition of 10% aqueous citric acid (250 mL) with cooling. Brine
3
3
CH
2
Eur. J. Org. Chem. 2015, 3689–3701 © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org 3697