10.1002/ejoc.202000439
European Journal of Organic Chemistry
FULL PAPER
procedure. Carboxylic acid building block 15 was obtained as a yellowish
oily substance (0.16 g, 75%) through flash chromatography purification
(Elution: isopropanol/DCM, 1/19). Analytical data for 15, Rf = 0.5
(isopropanol/DCM, 1/9). 1H NMR (400 MHz, CDCl3) δ 7.40-7.34 (m, 10H),
6.75 (br, 1H, C(=O)NH), 4.86 (s, 2H, PhCH2), 4.83 (s, 2H, PhCH2), 3.73 (t,
6.10 (t, J = 5.2 Hz, 1H, CONH), 5.91 (ddt, J = 17.6, 10.4, 5.6 Hz , 1H,
OCH2CH=CH2), 5.32 (dq, J = 17.2, 1.6 Hz,1H, OCH2CH=CH2), 5.22 (dq, J
= 10.4, 1.2 Hz, 1H, OCH2CH=CH2), 4.85 (s, 4H, PhCH2 × 2), 4.59 (dt, J =
5.6, 1.2 Hz, 2H, C(=O)OCH2), 3.63 (d, J = 5.2 Hz, 4H, N(OBn)CH2 × 2) ,
3.23 (d, J = 6.8 Hz, 2H, NHCH2), 2.79-2.73 (m, 4H, succinyl CH2 × 2), 2.68-
2.64 (m, 4H, succinyl CH2, CH2NH2 ), 2.50-2.44 (m, 2H, succinyl CH2),
1.68-1.59 (m, 4H, CH2 × 2), 1.52-1.40 (m, 4H, CH2 × 2), 1.34-1.26 (m, 4H,
CH2 × 2). 13C NMR (100 MHz, CDCl3) δ 173.2, 172.7, 172.20, 172.15,
134.5, 132.2, 129.19, 129.15, 129.0, 128.9, 128.74, 128.71, 118.1, 76.4,
76.3, 65.3, 45.4, 45.3, 42.0, 39.3, 33.2, 30.8, 30.6, 29.0, 28.6, 28.2, 28.0,
27.4, 26.7, 26.5, 24.0, 23.9. As dimeric HSC amino building block 18 was
directly taken to the coupling reaction, no HRMS data was obtained.
J
= 5.2 Hz, 2H, C(=O)N(OBn)CH2), 3.62 (t, J = 6.4 Hz, 2H,
C(=O)N(OBn)CH2), 3.25-3.20 (m, 4H, C(=O)NHCH2, N3CH2), 2.83 (t, J =
6.4 Hz, 2H, succinyl CH2), 2.67 (s, 4H, succinyl CH2 × 2), 2.53 (t, J = 6.8
Hz, 2H, succinyl CH2), 1.67-1.55 (m, 6H, CH2 × 3), 1.49-1.45 (m, 2H, CH2),
1.37-1.30 (m, 4H, CH2 × 2). 13C NMR (100 MHz, CDCl3) δ 175.3, 174.3,
173.8, 172.5, 134.6, 134.3, 129.3, 129.1, 128.8, 76.6, 76.3, 51.3, 45.4,
44.6, 39.5, 30.7, 28.5, 28.5, 28.2, 27.0, 26.6, 26.4, 23.9, 23.7. Of note,
signals at 64.3 and 25.3 ppm are residual signals from a trace of
isopropanol. HRMS (ESI) calcd. for C32H44N6O7 [M + H]+, 625.3344; found:
625.3347.
Allyl protected HSC trimer 19: Coupling of HSC dimeric amino building
block 18 (0.47 g, 0.74 mmol) with HSC carboxylic acid building block 6
(0.22 g, 0.74 mmol) followed the general intermolecular Steglich coupling
procedure. After the workup, the crude mixture was then diluted with DCM
(20 mL), then washed with 1 N HCl (20 mL × 2), brine, dried over MgSO4,
filtered, and concentrated for purification with flash chromatography
(Elution: isoprapanol/DCM, 1/19) to give HSC trimer 19 (0.53 g, 75%).
Analytical data for 19, Rf = 0.3 (5% isopropanol in DCM); 1H NMR (600
MHz, CDCl3) δ 7.38 (br, 15H), 6.29 (br, 2H, C(=O)NH × 2), 6.31 (s, 1H,
C(=O)NH), 5.92 (ddt, J = 17.4, 10.8, 5.4 Hz, 1H, OCH2CH=CH2), 5.31 (dq,
J = 17.4, 1.2 Hz, 1H, OCH2CH=CH2), 5.22 (dq, J = 10.8, 1.2 Hz, 1H,
OCH2CH=CH2) , 4.853 (s, 2H, PhCH2), 4.848 (s, 2H, PhCH2 × 2), 4.59 (dt,
J = 6.0, 1.2 Hz, 2H, C(=O)OCH2), 3.63 (br, 6H, N(OBn)CH2 × 3 ), 3.23 (t, J
= 7.2 Hz, 2H, CH2N3), 3.20 (m, 4H, C(=O)NHCH2 × 2), 2.80 (br, 4H,
succinyl CH2 × 2), 2.74 (t, J = 6.6 Hz, 2H, succinyl CH2), 2.65 (t, J = 7.2 Hz,
2H, succinyl CH2), 2.50-2.46 (m, 4H, succinyl CH2 × 2), 1.66-1.60 (m, 6H,
CH2 × 3), 1.57 (quintet, J = 7.2 Hz, 2H, CH2), 1.52-1.46 (m, 4H, CH2 × 2),
1.34 (quintet, J = 7.2 Hz, 2H, CH2), 1.30 (quintet, J = 7.2 Hz, 4H, CH2 × 2).
13C NMR (150 MHz, CDCl3) δ 174.0, 172.7, 172.1, 134.4, 132.2, 129.2,
129.1, 128.94, 128.92, 128.7, 118.1, 76.5, 76.3, 65.3, 51.2, 45.3, 44.8,
39.4, 30.7, 30.6, 29.1, 28.62, 28.55, 28.5, 28.2, 28.1, 28.0, 27.4, 26.5, 26.4,
24.0, 23.9, 23.7. HRMS (ESI) calcd. for C51H70N8O10 [M + H]+, 955.5288;
found: 955.5289.
Dimeric HSC amino-carboxylic acid 16: Reduction of dimeric carboxylic
acid building 15 (0.9 g, 1.44 mmol) followed the general Staudinger
reduction procedure. After the workup procedure, the reaction mixture was
purified
with
flash
column
chromatography
(Elution:
28%
NH3(aq)/isopropanol, 1/9) to give dimeric aminocarboxylic acid 16 (0.8 g,
92%) as an orange oily liquid. Analytical data for 16, Rf = 0.3 (28%
NH3(aq)/isopropanol, 1/19). 1H NMR (400 MHz, CD3OD) δ 7.45-7.38 (m,
10H), 4.92 (s, 2H, PhCH2), 4.91 (s, 2H, PhCH2), 3.72-3.64 (m, 4H,
C(=O)N(OBn)CH2 × 2), 3.13 (t, J = 6.8 Hz 2H, C(=O)NHCH2), 2.89 (t, J =
7.2 Hz, 2H, NH2CH2), 2.73 (br, 4H, succinyl CH2 × 2), 2.51 (t, J = 6.8 Hz,
2H, succinyl CH2), 2.45 (t, J = 6.4 Hz, 2H, succinyl CH2), 1.70-1.59 (m, 6H,
CH2 × 3), 1.49 (quintet, J = 7.6 Hz, 2H, CH2), 1.33 (quintet, J = 7.2 Hz, 4H,
CH2 × 2). 13C NMR (100 MHz, CDCl3) δ 179.1, 175.2, 174.2, 172.5, 134.8,
134.4, 129.3, 129.1, 128.9, 128.8, 128.71, 128.66, 76.3, 76.2, 45.0, 44.7,
39.5, 39.2, 32.0, 30.6, 28.7, 28.1, 27.3, 26.4, 26.3, 23.6, 23.4. Of note,
signals at 64.0 and 25.4 ppm are residual signals of isopropanol. HRMS
(ESI) calcd. for C32H46N4O7 [M + H]+, 599.3439; found: 599.3451.
Cyclized HSC dimer 17: Cyclization of dimeric HSC amino-carboxylic acid
16 (170 mg, 0.28 mmol) followed the general cyclization procedure. After
the workup, the crude product was purified with flash column
chromatography (Elution: EtOH/DCM, 1/19) to give cyclized HSC dimer 17
(90 mg, 55%) as an orange oily liquid. Analytical data for 17, Rf = 0.3
(EtOH/DCM, 1/19). 1H NMR (400 MHz, CDCl3): δ 7.39 (br, 10H), 6.65 (br,
2H, C(=O)NH × 2), 4.86 (s, 4H, PhCH2 × 2), 3.72 (t, J = 5.2 Hz, 4H,
C(=O)N(OBn)CH2 × 2), 3.20 3.18 (m, 4H, C(=O)NHCH2 × 2), 2.88 (t, J =
7.2 Hz, 4H, succinyl CH2 × 2), 2.59 (t, J = 7.2 Hz, 4H, succinyl CH2 × 2),
1.63 (quintet, J = 4.8 Hz, 4H, CH2 × 2), 1.55 (m, 4H, CH2 × 2), 1.26 (m, 4H,
CH2 × 2). 13C NMR (100 MHz, CDCl3) δ 175.1, 172.5, 134.4, 129.4, 129.2,
129.0, 76.5, 43.1, 39.7, 30.9, 28.5, 26.7, 26.2, 22.6. HRMS (ESI) calcd. for
C32H44N4O6 [M + H]+, 581.3334; found: 581.3337.
Trimeric HSC carboxylic acid 20: Deprotection of the allyl ester at HSC
trimer 19 (6.97 g, 5.6 mmol) followed the general deallylation procedure
and trimeric amino building block 20 (3.84 g, 4.2 mmol) was obtained as a
glassy yellowish solid after flash chromatography purification (Elution:
isopropanol/DCM, 1/19). Analytical data for 20, Rf = 0.5 (isopropanol/DCM,
1/19). 1H NMR (600 MHz, CD3OD) δ 7.44 (m, 15H), 4.90 (s, 6H, PhCH2 ×
3), 3.65 (br, 6H, C(=O)N(OBn)CH2 × 3), 3.25 (t, J = 7.2 Hz, 2H, N3CH2),
3.14 (t, J = 7.2 Hz, 4H, C(=O)NHCH2 × 2), 2.74 (br, 6H, succinyl CH2 × 3),
2.54 (br, 2H, succinyl CH2), 2.43 (t, J = 6.6 Hz, 4H, succinyl CH2 × 2), 1.63
(quintet, J = 7.2 Hz, 6H, CH2 × 3), 1.56 (quintet, J = 7.2 Hz, 2H, CH2), 1.49
(quintet, J = 7.2 Hz, 4H, CH2 × 2), 1.37-1.31 (m, 6H, CH2 × 3). 13C NMR
(150 MHz, CD3OD) δ 176.9, 175.4, 174.7, 174.6, 136.2, 130.6, 129.9,
129.7, 77.2, 52.3, 46.1, 40.3, 40.2, 31.2, 29.9, 29.8, 29.5, 28.9, 28.6, 27.5,
27.3, 25.0, 24.9, 24.8. HRMS (ESI) calcd. for C48H66N8O10 [M + H]+,
915.4975; found: 915.4989.
Bisucaberin (1): To a solution of protected cyclized HSC dimer 17 (66 mg)
in 1:1 MeOH-EtOAc (14 mL), acetic acid (70 μL) and 10% Pd-C (33 mg)
were added. The reaction mixture was stirred at RT for 30 min, then Pd-C
was removed by filtration (over celite). The filtrate was concentrated for
column chromatography (Elution: EtOH/DCM, 1/9) to afford 1 as a white
glassy solid (24 mg, 52%). Analytical data for 1: Rf = 0.25 (EtOH/DCM,
DFO G1 (4): To a solution of trimeric HSC carboxylic acid 20 (95 mg, 0.1
mmol) in MeOH (5 mL) and acetic acid additive (0.05 mL) was added 10%
Pd-C (60 mg). The reaction mixture was stirred under a H2 balloon at RT
for 20 min. Upon complete azido reduction and hydrogenolysis, the Pd-C
was filtered off through celite and filtrate was concentrated for flash
chromatography purification (Elution: 28% NH3(aq)/isopropanol, 1/9) to
obtain (4) (27 mg, 0.05 mmol, 50%). Analytical data for (4), Rf = 0.1 (28%
NH3(aq)/isopropanol, 1/9). 1H NMR (400 MHz, D2O) δ 3.66 (quintet, J = 6.4
Hz, 6H, C(=O)N(OBn)CH2 × 3), 3.19 (t, J = 6.4 Hz, 4H, C(=O)NHCH2 × 2),
3.01 (t, J = 7.6 Hz, 2H, CH2NH2), 2.82 (t, J = 7.2 Hz, 2H, succinamic CH2
× 1), 2.76 (t, J = 7.2 Hz, 2H, succinamic CH2 × 1), 2.54-2.49 (m, 8H,
succinyl CH2 × 4), 1.72-1.63 (m, 8H, CH2 × 4), 1.54 (quintet, J = 7.2 Hz,
4H, CH2 × 2), 1.42-1.30 (m, 6H, CH2 × 3). 13C NMR (100 MHz, D2O internal
standard CDCl3) δ 175.1, 174.2, 170.0, 167.3, 107.8, 48.2, 48.1, 48.0, 47.7,
39.6, 39.5, 32.14, 32.05, 30.8, 30.7, 28.22, 28.20, 28.0, 27.9, 26.61, 26.55,
1/9); 1H NMR (400 MHz, CD3OD)
δ 3.63 (t, J = 6.8 Hz, 4H,
C(=O)N(OH)CH2 × 2), 3.17 (t, J = 5.6 Hz, 4H, C(=O)NHCH2 × 2), 2.78 (t,
J = 7.2 Hz, 4H, succinyl CH2 × 2), 2.48 (t, J = 6.8 Hz, 4 H, succinyl CH2 ×
2), 1.63 (m, 4H, CH2 × 2), 1.52 (m, 4H, CH2 × 2), 1.30 (m, 4H, CH2 × 2).
13C NMR (100 MHz, CD3OD) δ 175.1, 174.4, 48.1, 39.9, 32.1, 29.3, 29.2,
26.9, 23.9. HRMS (ESI) calcd. for C18H32N4O6 [M + H]+, 401.2395; found:
401.2390.
Dimeric HSC amino building block 18: Reduction of protected HSC
dimer 14 (0.28 g, 0.42 mmol) followed the general Staudinger reduction
procedure. The crude reduction product was purified by flash column
chromatography (Elution: 28% NH3(aq)/isoprapanol, 1/19) to give 18 (0.25
g, 93%) as a yellow oily liquid. Analytical data for 18, Rf = 0.2 (28%
NH3(aq)/isopropanol, 1/19); 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 10H),
7
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