T. Bach and C. Ammer
2
D
0
(
ꢀ
25 mg, 20.6 mmol, 93%) as a yellow oil. R
f
=0.32 (EtOAc; UV); [a]
=
A
H
N
T
E
N
N
3
3
3
)
)
)
2
2
2
), 18.6 (q; D: CH
), 26.4 (q; E: NHCH
), 42.1 (t; E: CH CONHCH
A
H
N
T
E
N
N
(CH
3
)
2
), 19.3 (q; D: CH ), 19.6 (q; C: CH-
), 33.2 (d; C: CH(CH ), 34.3 (d; D: CH-
2
), 43.6 (t; Gly: CH ), 47.2 (d; E: CH),
A
H
U
T
E
N
N
(CH
3
)
2
1
35.7 (c=0.45 in CH
Sn(CH ), 0.94–0.99 (m, 12H; D: CH
m, 2H; D: CH(CH , C: CH(CH
NHCH ), 2.73 (s, 3H; E: C5-CH ), 2.93 (dd, J=16.0, J=5.0 Hz, 1H; E:
2
Cl
2
); H NMR (CDCl
(CH
), 2.63 (d, J=4.5 Hz, 3H; E:
3
, 500 MHz): d=0.37 (s, 9H;
A
H
N
T
E
N
G
3
A
T
N
R
N
N
3 2
)
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
3
)
3
A
H
U
G
R
N
U
G
3
)
2
, C: CH(CH ), 2.29–2.39
A
H
U
T
N
U
G
3
)
2
A
H
U
T
E
N
G
2
3
3
(
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
3
)
2
A
H
U
G
R
N
U
G
3
)
2
56.1 (d; D: CH), 56.3 (d; C: CH), 119.0 (d; C: C-5), 119.9 (d; A: C-5),
120.4 (d; B: C-5), 122.8 (d; D: C-5), 126.1 (d; F: C-5), 129.4 (s; A: C-3),
139.8 (d; A: C-4), 140.0 (s; A: C-2)*, 141.8 (s; E: C-5) , 142.9 (s; E: C-
4) , 148.9 (s; C: C-4), 149.3 (s; F: C-4), 150.0 (s; D: C-4), 153.3 (s; B: C-
4), 153.9 (s; A: C-6)*, 160.1 (s; F: CO)’, 161.5 (s; Gly: CO) , 162.1 (s; C:
C-2), 162.3 (s; B: C-2), 163.1 (s; F: C-2)’, 163.8 (s; E: C-2) , 168.6 (s; D:
CO) , 169.4 (s; E: CONHCH
2); HRMS (ESI): m/z: calcd for C38
2
3
3
3
2
3
#
CHHCONHCH
CHHCONHCH
(
3
),
3.25
(dd,
J=16.0,
J=4.0 Hz,
1H;
E:
2
3
#
3
), 4.13 (dd, J=16.5, J=4.5 Hz, 1H; Gly: CH
2
), 4.51
2
3
3
~
dd, J=16.5, J=7.0 Hz, 1H; Gly: CH
2
), 5.17 (dd, J=8.2, 6.0 Hz, 1H;
D: CH), 5.33 (dd, J=9.0, 6.0 Hz, 1H; C: CH), 5.73–5.79 (m, 1H; E:
), 7.31 (d, J=8.2 Hz, 1H; D:
NH), 7.35 (s, 1H; C: H-5), 7.61 (d, J=8.2 Hz, 1H; A: H-5), 7.90 (s, 1H;
3
§
3
3
~
§
CH), 6.83 (q, J=4.5 Hz, 1H; E: NHCH
3
3
) , 170.0 (s; E: CO), 174.2 ppm (s; D: C-
3
+
H
38BrN11NaO
5
S
5
: 990.0742 [M+Na] ;
B: H-5), 8.08 (s, 1H; D: H-5), 8.15 (brs, 1H; C: NH), 8.22–8.24 (m, 1H;
Gly: NH), 8.34 (s, 1H; F: H-5), 8.52 (d, J=8.2 Hz, 1H; A: H-4),
found: 990.0747.
3
Ethyl-(S,S)-2-{1-[(2-{1-[(2-{2-bromo-6-(4-tert-butoxycarbonyl-thiazole-2-
yl)pyridine-3-yl}thiazole-4-carbonyl)amino]-2-methylcarbamoyl-ethyl}-5-
methylthiazole-4-carbonyl)amino]-2-methylpropyl}thiazole-4-carboxylate
(35)
3
13
9
.65 ppm (d, J=9.0 Hz, 1H; E: NH); C NMR (CDCl
8.83 (q; Sn(CH ), 12.6 (q; E: C5-CH ), 17.9 (q; C: CH
q; D: CH(CH ), 19.2 (q; D: CH(CH ), 19.2 (q; C: CH
q; E: NHCH ), 33.6 (d; C: CH(CH ), 34.5 (d; D: CH(CH
CONHCH ), 43.2 (t; Gly: CH ), 48.4 (d; E: CH), 55.6 (d; D:
3
, 90 MHz): d=
(CH ), 18.1
(CH ), 26.1
), 38.3 (t;
ꢀ
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
3
)
3
3
A
H
U
T
E
N
N
3 2
)
)
3 2
(
(
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
3
)
2
A
H
U
G
R
N
U
G
3
)
2
A
H
U
G
E
N
N
3
A
H
N
T
E
N
N
3
)
2
A
T
N
T
E
N
N
3 2
)
Zincation: DMA (0.61 mL) and 1,2-dibromoethane (6.1 mL, 15 mg,
E: CH
2
3
2
8
0.8 mmol) were added to a flame-dried flask charged with zinc dust
41 mg, 0.625 mmol). The zinc suspension was shortly heated with a heat
gun until evolution of ethylene occurred and was then allowed to reach
CH), 56.8 (d; C: CH), 115.3 (d; C: C-5), 123.6 (d; D: C-5), 126.1 (d; F:
C-5), 126.3 (d; B: C-5), 127.8 (d; A: C-5), 129.0 (s; E: C-5), 130.1 (s; A:
C-3), 138.8 (s; A: C-2), 141.2 (d; A: C-4), 141.2 (s; A: C-6), 142.1 (s; E:
C-4), 148.9 (s; D: C-4), 149.7 (s; F: C-4), 149.8 (s; C: C-4), 160.5 (s; F:
CO), 161.3 (s; B: C-2), 161.4 (s; D: CO)*, 161.9 (s; F: C-2), 162.1 (s; E:
CO), 163.0 (s; B: C-4), 166.8 (s; E: C-2), 169.1 (s; Gly: CO)*, 169.9 (s;
(
258C. This procedure was repeated three times. TMSCl (16.7 mL, 14 mg,
0.131 mmol) was added neat and the reaction mixture was stirred for
5 min. tert-Butyl 2-iodothiazole-4-carboxylate (62 mg, 0.200 mmol) was
added. Stirring was continued for 45 min at 258C, then the zinc dust was
allowed to settle (30 min).
C: C-2), 170.5 (s; D: C-2), 171.3 ppm (s; E: CONHCH
3
); IR (ATR): n˜ =
3
1
C
297 (w; NH), 2961 (w; NH), 1654 (s; CONH), 1537 (s), 1490 (m; CH),
Negishi cross-coupling: The supernatant liquid containing the zinc organ-
ꢀ
1
406 (w; CH), 1070 (w), 773 cm (w); HRMS (ESI): m/z: calcd for
yl 34 was transferred to
.50 mmol, 30 mol%). Pyridine
1.5 mL) were added to this mixture, which was then stirred at 458C for
.5 h. The reaction mixture was partitioned between saturated aq. NH Cl
6 mL) and EtOAc (3ꢄ6 mL). The combined extracts were dried
Na SO ) and concentrated in vacuo. Purification by flash chromatogra-
a
flask containing [PdCl
2 3 2
ACHTUNGTRNENG(U PPh ) ] (5.3 mg,
1
20
+
41
H
48Br
2
N
11
O
5
S
5
Sn: 1211.9832 [M+H] ; found: 1211.9817.
7
(
3
5
(19.7 mg, 25.0 mmol) and DMA
Regiosiomeric macrocycles 27 and 28 by an intramoleculaur Stille cross-
coupling reaction: Stannane 26 (18 mg, 16.5 mmol) and tetrakis(triphenyl-
phosphane)palladium(0) (4.2 mg, 3.63 mmol, 22 mol%) were dissolved in
degassed toluene (16.5 mL) and stirred until full conversion (45 h) was
achieved at 858C. The reaction mixture was concentrated in vacuo. Flash
4
(
(
2
4
phy (P/EtOAc 1:1!0:1) afforded a yellow solid containing the desired
pyridine 35 (11 mg, 12.2 mmol, 49%, yellow solid) together with triphe-
nylphosphane oxide. Separation of the oxidated ligand from compound
chromatography (10% KF in silica, EtOAc!CH
2
Cl
6:4!94:6!92:8!90:10) yielded regioisomers 27 (4.0 mg, 4.13 mmol,
8%) and 28 (4.0 mg, 4.13 mmol, 28%).
=0.20 (CH Cl /MeOH 95:5; UV); H NMR (CDCl
60 MHz): d=0.89 (d, J=7.2 Hz, 3H; D: CH
2
/MeOH 98:2!
9
2
3
2
5 was performed by reverse-phase HPLC (RP, ODS-A, MeCN/H O
1
ꢀ1
20
Regioisomer 27: R
f
2
2
3
,
10:90, 7 mLmin ). M.p. 1358C; R
f
=0.36 (EtOAc; UV); [a] =ꢀ25.5
D
3
3
1
3
3
6
1
A
H
U
G
R
N
U
G
3
)
2
), 0.95 (d, J=
(CH ), 1.01–
), 1.13 (d, J=6.8 Hz, 3H; C: CH-
), 2.07–2.13 (m, 1H; D: CH(CH ), 2.26–2.31 (m, 1H; C: CH-
), 2.63 (d, J=4.9 Hz, 3H; E: NHCH ), 2.67 (s, 3H; E: C5-CH ),
), 3.86 (dd, J=17.3, J=3.4 Hz,
(c=0.45 in CHCl
3H; D: CH(CH
7.2 Hz, 3H; D: OCH
D: CH(CH ), 2.64 (d, J=4.7 Hz, 3H; E: NHCH
CH ), 3.02 (dd, J=14.8, J=5.8 Hz, 1H; E: CHHCONHCH
3
3
); H NMR (CDCl
3
, 360 MHz): d=0.98 (d, J=6.8 Hz,
3
3
3
.8 Hz, 3H; C: CH
.11 (m, 1H; E: CHHCONHCH
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(CH
3
)
2
A
H
U
G
R
N
N
3
)
2
A
H
U
G
R
N
U
G
3
)
2
), 1.01 (d, J=6.8 Hz, 3H; D: CH
A
H
U
G
R
N
U
G
3 2
) ), 1.41 (t, J=
3
3
2
CH ), 1.63 (s, 9H; G: C(CH )
3
A
H
U
G
R
N
U
G
3 3
3
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(CH
3
)
)
2
2
A
H
U
G
R
N
U
G
3
)
2
A
H
U
G
R
N
U
G
3
)
2
3
3
2
3
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(CH
3
3
3
3
2
3
2
3
3
2
1
.68–2.74 (m, 1H; E: CHHCONHCH
H; Gly: CHH), 4.94–5.23 (m, 2H; C: CH, Gly: CHH), 5.24 (dd, J=8.1,
3
J=14.8, J=4.3 Hz, 1H; E: CHHCONHCH
3
3
3
D: OCH
E: CH), 6.82 (q, J=4.7 Hz, 1H; E: NHCH
(s, 1H; G: H-5), 8.38 (s, 1H; F: H-5), 8.39 (d, J=8.3 Hz, 1H; A: H-5),
2 3
CH
3
3
3
J=4.7 Hz, 1H; D: CH), 5.39–5.44 (m, 1H; E: CH), 6.20 (d, J=6.1 Hz,
3
), 8.13 (s, 1H; D: H-5), 8.20
3
3
3
1
1
7
H; C: NH), 6.73 (q, J=4.9 Hz, 1H; E: NHCH
3
), 7.17 (t, J=3.4 Hz,
3
3
3
H; Gly: NH), 7.20 (s, 1H; C: H-5), 7.56 (d, J=8.0 Hz, 1H; A: H-5),
8.64 (d, J=8.6 Hz, 1H; D: NH), 8.74 (d, J=8.3 Hz, 1H; A: H-4),
3
3
13
.82 (d, J=8.0 Hz, 1H; A: H-4), 8.11 (s, 1H; D: H-5), 8.16 (s, 1H; B: H-
9.39 ppm (d, J=9.0 Hz, 1H; E: NH); C NMR (CDCl
12.5 (q; E: C5-CH ), 14.3 (q; D: OCH CH ), 18.0 (q; D: CH
(q; D: CH(CH ), 26.2 (q; E: NHCH ), 28.2 (q; G: C(CH
D: CH(CH ), 38.7 (t; E: CH CONHCH ), 48.5 (d; E: CH), 56.3 (d; D:
CH), 61.6 (t; OCH CH ), 82.4 (s; G: C(CH ), 119.3 (d; A: C-5), 126.1
d; F: C-5), 127.3 (d; D: C-5), 129.7 (d; G: C-5), 131.6 (s; A: C-3), 139.5
3
, 90 MHz): d=
(CH ), 19.1
), 34.5 (d;
3
5
), 8.35 (s, 1H; F: H-5), 8.78 (d, J=8.1 Hz, 1H; D: NH), 8.93 ppm (d,
3
2
3
A
H
U
G
R
N
U
G
3 2
)
3
J=9.0 Hz, 1H; E: NH); HRMS (ESI): m/z: calcd for
A
H
U
G
R
N
N
3
)
2
3
A
H
U
G
R
N
U
G
3 3
)
+
C
38
H
38BrN11NaO
5
S
5
: 990.0742 [M+Na] ; found: 990.0747.
A
H
U
G
R
N
N
3
)
2
2
3
2
D
0
2
3
A
H
U
G
R
N
U
G
3 3
)
Regioisomer 28: R
0
1
f
=0.18 (CH
2
Cl
2
/MeOH 95:5; UV); [a] =ꢀ9.6 (c=
(
3
.44 in CHCl ); IR (ATR): n˜ =3675 (w; NH), 1652 (s; CONH), 1536 (s),
495 (s, CH), 1347 (w), 1252 (w), 1074 (m), 734 (s), 693 cm (w);
#
ꢀ
1
(s; A: C-2), 140.7 (d; A: C-4), 141.9 (s; A: C-6), 142.2 (s; E: C-5) , 146.4
(s; D: C-4), 149.8 (s; E: C-4) , 150.2 (s; F: C-4), 151.3 (s; G: C-4), 160.2
(s; G: COO), 160.5 (s; F: CO), 161.4 (s; D: COO), 162.1 (s; E: CO),
162.3 (s; F: C-2), 166.5 (s; G: C-2), 166.6 (s; E: C-2), 170.7 (s; D: C-2),
#
1
3
H NMR (CDCl
3
, 360 MHz): d=0.97 (d, J=7.9 Hz, 3H; CH
A
H
U
G
R
N
U
G
3
)
3
)
3
)
2
2
2
),
),
),
3
3
1
1
2
.05 (d, J=6.8 Hz, 3H; CH
A
H
U
G
R
N
G
3
)
2
), 1.09 (d, J=6.8 Hz, 3H; CH
), 2.28–2.34 (m, 1H; D: CHACHTGNUTRENNUNG
ACHTUNGTRENNUNG
3
A
H
N
T
E
N
N
3
)
2
1
71.0 ppm (s; E: CONHCH
3
); IR (ATR): n˜ =2355 (m), 1719 (m; CO),
A
H
U
G
R
N
U
G
3
)
2
3
, E: C5-
2
3
1668 (s; CONH), 1530 (s), 1476 (m; CH), 1338 (w), 1232 (m), 1159 (m),
1068 (w), 1020 (w), 749 cm
CH
3
3
ꢀ
1
2
3
2
3
(w); HRMS (ESI): m/z: calcd for
+
J=15.1, J=5.4 Hz, 1H; E: CHHCONHCH
3
), 3.97 (dd, J=17.1, J=
2
3
C
36
H
39BrN
8
NaO : 925.0906 [M+Na] ; found: 925.0914.
7 4
S
5
5
.0 Hz, 1H; Gly: CHH), 4.49 (dd, J=17.1, J=7.6 Hz, 1H; Gly: CHH),
.28 (dd, J=8.5, 7.2 Hz, 1H; D: CH), 5.40 (dd, J=9.2, 8.6 Hz, 1H; C:
CH), 5.91–5.95 (m, 1H; E: CH), 6.05 (q, J=4.7 Hz, 1H; E: NHCH
.49 (d, J=8.5 Hz, 1H; D: NH), 7.67 (s, 1H; C: H-5), 7.73–7.76 (m, 1H;
Gly: NH), 7.97 (s, 1H; D: H-5), 8.03 (d, J=8.3 Hz, 1H; A: H-5), 8.05
d, J=9.2 Hz, 1H; C: NH), 8.26 (s, 1H; B: H-5), 8.35 (s, 1H; F: H-5),
.32 (d, J=9.0 Hz, 1H; E: NH), 8.55 ppm (d, J=8.3 Hz, 1H; A: H-4);
3
3
tert-Butyl-2-{2-bromo-3-[4-({[(1S)-3-(methylamino)-1-(5-methyl-4-{[((1S)-
2-methyl-1-{4-[4-({(1S)-2-methyl-1-[4-(trimethylstannyl)-2,4’-bithiazole-2’-
yl]propyl}amino)-2-oxo-ethylamino]thiazole-2-yl}propyl)amino]carbo-
nyl}thiazole-2-yl)-3-oxopropyl]amino}carbonyl)thiazole-2-yl]pyridine-6-
yl}thiazole-4-carboxylate (37)
3
3
),
3
7
3
3
(
3
3
8
Saponification: Aqueous lithium hydroxide solution (1m, 99.6 mL,
99.6 mmol) was added to a solution of the ethyl ester 35 (9.0 mg,
1
3
C NMR (CDCl
3
3
, 90 MHz): d=12.7 (q; E: C5-CH ), 17.5 (q; C: CH-
14090
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 14083 – 14093