Journal of Medicinal Chemistry
Article
39d (56 mg, 71%, four steps) as a colorless solid. HPLC: tR = 31.1 min
(method M1). HRMS calcd for [C40H51ClN2O9 + Na]+ 761.3175;
found 761.3175. 1H NMR (500 MHz, CDCl3, TMS): δ (ppm) = 0.85
(d, 3H), 0.87 (d, 3H), 1.14 (d, 3H), 1.36 (ddd, 1H), 1.54 (ddd, 1H),
1.59−1.84 (m, 6H), 2.45 (ddd, 1H), 2.54 (ddm, 1H), 2.60 (m, 1H),
2.92 (dd, 1H), 3.05 (dd, 1H), 3.12 (dd, 1H), 3.34 (ddd, 1H), 3.42−
3.46 (m, 2H), 3.51 (ddd, 1H), 3.69 (d, 1H), 3.84 (s, 3H), 3.94−3.97
(m, 2H), 4.80−4.84 (m, 2H), 5.13 (ddd, 1H), 5.16 (dm, 1H), 5.27
(dm, 1H), 5.63 (m, 1H), 5.75 (dm, 1H), 5.90 (dddd, 1H), 6.62 (ddd,
1H), 6.83 (d, 1H), 6.85 (m, 1H), 7.06 (dd, 1H), 7.21 (d, 1H), 7.24−
7.26 (m, 2H), 7.32−7.39 (m, 3H).
uC[(S)-(CH2)3OAll]-cryptophycin-1 (39e). The acetonide 32e (103
mg, 0.129 mmol) was converted to the corresponding epoxide 39e
according to GP-1−GP-4. Purification by column chromatography
(eluent: EtOAc/hexane 3:1 v/v) afforded the cryptophycin-1 analogue
39e (75 mg, 79%, four steps) as a colorless solid. HPLC: tR = 30.9 min
(method M1). HRMS calcd for [C40H51ClN2O9 + Na]+ 761.3175;
found 761.3178. 1H NMR (500 MHz, CDCl3, TMS): δ (ppm) = 0.84
(d, 3H), 0.85 (d, 3H), 1.15 (d, 3H), 1.33 (m, 1H), 1.53−1.84 (m,
7H), 2.45 (ddd, 1H), 2.56 (ddm, 1H), 2.67 (m, 1H), 2.93 (dd, 1H),
3.06 (dd, 1H), 3.12 (dd, 1H), 3.37−3.40 (m, 2H), 3.42 (ddd, 1H),
3.49 (ddd, 1H), 3.69 (d, 1H), 3.86 (s, 3H), 3.92−3.95 (m, 2H), 4.76
(dd, 1H), 4.90 (ddm, 1H), 5.12−5.18 (m, 2H), 5.25 (dm, 1H), 5.65
(m, 1H), 5.75 (dm, 1H), 5.88 (dddd, 1H), 6.66 (ddd, 1H), 6.71 (m,
1H), 6.83 (d, 1H), 7.06 (dd, 1H), 7.20 (d, 1H), 7.23−7.26 (m, 2H),
7.32−7.38 (m, 3H).
according to GP-1−GP-4. Purification by column chromatography
(eluent: EtOAc/hexane 3:1 v/v) afforded the cryptophycin-1 analogue
39i (65 mg, 54%, four steps) as a colorless solid. HPLC: tR = 28.5 min
(method M1). HRMS calcd for [C37H46ClN5O8 + Na]+ 746.2927;
found 746.2937. 1H NMR (500 MHz, CDCl3, TMS): δ (ppm) = 0.85
(d, 3H), 0.86 (d, 3H), 1.15 (d, 3H), 1.35 (ddd, 1H), 1.52−1.70 (m,
5H), 1.72 (ddd, 1H), 1.81 (m, 1H), 2.45 (ddd, 1H), 2.56 (dm, 1H),
2.65 (m, 1H), 2.93 (dd, 1H), 3.08 (dd, 1H), 3.12 (dd, 1H), 3.25−3.28
(m, 2H), 3.40 (ddd, 1H), 3.53 (ddd, 1H), 3.69 (d, 1H), 3.87 (s, 3H),
4.77 (ddd, 1H), 4.91 (dd, 1H), 5.14 (ddd, 1H), 5.67 (m, 1H), 5.76
(dm, 1H), 6.65 (ddd, 1H), 6.68 (m, 1H), 6.84 (d, 1H), 7.06 (dd, 1H),
7.21 (d, 1H), 7.23−7.26 (m, 2H), 7.32−7.39 (m, 3H).
uC[(R)-(CH2)4N3]-cryptophycin-1 (39j). The acetonide 32j (30 mg,
0.038 mmol) was converted to the corresponding epoxide 39j
according to GP-1−GP-4. Purification by column chromatography
(eluent: EtOAc/petroleum ether 2:1 v/v) afforded the cryptophycin-1
analogue 39j (11.5 mg, 41%, four steps) as a colorless solid. HPLC: tR
= 5.3 min (method M2). HRMS calcd for [C38H48ClN5O8 + Na]+
1
760.3098; found 760.3083. H NMR (500 MHz, CDCl3, TMS): δ
(ppm) = 0.85 (d, 3H), 0.87 (d, 3H), 1.14 (d, 3H), 1.35 (m, 1H),
1.45−1.55 (m, 3H), 1.59−1.64 (m, 2H), 1.68−1.76 (m, 3H), 1.80 (m,
1H), 2.46 (ddd, 1H), 2.51−2.59 (m, 2H), 2.92 (dd, 1H), 3.04 (dd,
1H), 3.11 (dd, 1H), 3.24−3.35 (m, 2H), 3.39 (m, 1H), 3.46 (m, 1H),
3.69 (d, 1H), 3.86 (s, 3H), 4.78 (ddd, 1H), 4.82 (dd, 1H), 5.16 (ddd,
1H), 5.60 (m, 1H), 5.74 (dm, 1H), 6.66 (ddd, 1H), 6.83 (d, 1H), 7.00
(m, 1H), 7.05 (dd, 1H), 7.20 (d, 1H), 7.22−7.26 (m, 2H), 7.33−7.39
(m, 3H).
uC[(R)-(CH2)2N3]-cryptophycin-1 (39f). The acetonide 32f (112
mg, 0.146 mmol) was converted to the corresponding epoxide 39f
according to GP-1−GP-4. Purification by column chromatography
(eluent: EtOAc/petroleum ether 2:1 v/v) afforded the cryptophycin-1
analogue 39f (36.4 mg, 35%, four steps) as a colorless solid. HPLC: tR
= 5.3 min (method M2). HRMS calcd for [C36H44ClN5O8 + Na]+
ASSOCIATED CONTENT
■
S
* Supporting Information
All details of the syntheses, molecular modeling coordinates,
and details on the conformational analysis. This material is
1
732.2770; found 732.2788. H NMR (500 MHz, CDCl3, TMS): δ
(ppm) = 0.83 (d, 3H), 0.85 (d, 3H), 1.14 (d, 3H), 1.32 (ddd, 1H),
1.65−1.76 (m, 3H), 1.80 (m, 1H), 2.01 (m, 1H), 2.45 (ddd, 1H), 2.57
(ddd, 1H), 2.76 (m, 1H), 2.92 (dd, 1H), 2.97 (dd, 1H), 3.11 (dd, 1H),
3.26 (ddd, 1H), 3.48 (ddd, 1H), 3.55- 3.67 (m, 2H), 3.68 (d, 1H),
3.86 (s, 3H), 4.69 (ddd, 1H), 4.83 (dd, 1H), 5.19 (ddd, 1H), 5.68−
5.76 (m, 2H), 6.71 (ddd, 1H), 6.83 (d, 1H), 7.03 (dd, 1H), 7.12 (d,
1H), 7.19−7.25 (m, 3H), 7.31−7.40 (m, 3H).
AUTHOR INFORMATION
■
Corresponding Author
*Phone: 49-521-1062051. Fax: 49-521-1068094. E-mail
uC[(S)-(CH2)2N3]-cryptophycin-1 (39g). The acetonide 32g (27.5
mg, 0.036 mmol) was converted to the corresponding epoxide 39g
according to GP-1−GP-4. Purification by column chromatography
(eluent: EtOAc/hexane 3:1 v/v) afforded the cryptophycin-1 analogue
39g (9 mg, 35%, four steps) as a colorless solid. HPLC: tR = 28.4 min
(method M1). HRMS calcd for [C36H44ClN5O8 + Na]+ 732.2770;
found 732.2769. 1H NMR (500 MHz, CDCl3, TMS): δ (ppm) = 0.86
(d, 3H), 0.88 (d, 3H), 1.15 (d, 3H), 1.39 (m, 1H), 1.64−1.77 (m,
4H), 1.82 (m, 1H), 2.47 (ddd, 1H), 2.54 (dd, 1H), 2.73 (m, 1H), 2.93
(dd, 1H), 3.04 (dd, 1H), 3.21 (dd, 1H), 3.28−3.35 (m, 2H), 3.38 (m,
1H), 3.69 (d, 1H), 3.74 (ddd, 1H), 3.87 (s, 3H), 4.84 (ddd, 1H), 4.87
(dd, 1H), 5.08 (m, 1H), 5.61(d, 1H), 5.80 (dm, 1H), 6.43 (m, 1H),
6.58 (ddd, 1H), 6.84 (d, 1H), 7.05 (dd, 1H), 7.21 (d, 1H), 7.22−7.25
(m, 2H), 7.33−7.39 (m, 3H).
Author Contributions
§These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank A. Nieß, C. Michalek, and M. Wißbrock for technical
assistance, K.-P. Mester and G. Lipinski for running NMR
spectra, and Dr. M. Letzel and S. Heitkamp (all Bielefeld
University) for recording mass spectra. Financial support from
Deutsche Forschungsgemeinschaft (DFG) is gratefully ac-
knowledged.
uC[(R)-(CH2)3N3]-cryptophycin-1 (39h). The acetonide 32h (184
mg, 0.235 mmol) was converted to the corresponding epoxide 39h
according to GP-1−GP-4. Purification by column chromatography
(eluent: EtOAc/hexane 2:1 v/v) afforded the cryptophycin-1 analogue
39h (75 mg, 50%, four steps) as a colorless solid. HPLC: tR = 31.0 min
(method M1). HRMS calcd for [C37H46ClN5O8 + Na]+ 746.2927;
found 746.2937. 1H NMR (500 MHz, CDCl3, TMS): δ (ppm) = 0.85
(d, 3H), 0.87 (d, 3H), 1.15 (d, 3H), 1.36 (ddd, 1H), 1.54 (ddd, 1H),
1.62−1.84 (m, 6H), 2.46 (ddd, 1H), 2.54−2.59 (m, 2H), 2.92 (dd,
1H), 3.03 (dd, 1H), 3.11 (dd, 1H), 3.28 (ddd, 1H), 3.33 (ddd, 1H),
3.41 (ddd, 1H), 3.47 (ddd, 1H), 3.69 (d, 1H), 3.87 (s, 3H), 4.79 (ddd,
1H), 4.83 (dd, 1H), 5.16 (ddd, 1H), 5.66 (m, 1H), 5.74 (dm, 1H),
6.66 (ddd, 1H), 6.83 (d, 1H), 7.00 (m, 1H), 7.05 (dd, 1H), 7.20 (d,
1H), 7.24−7.26 (m, 2H), 7.32−7.39 (m, 3H).
ABBREVIATIONS USED
■
AcBr, acetyl bromide; ADC, antibody−drug conjugate;
CuAAC, copper-catalyzed azide−alkyne cycloaddition; DIC,
N,N′-diisopropylcarbodiimide; DIPEA, N,N-diisopropylethyl-
amine; FmocOSu, N-(9-fluorenylmethoxycarbonyloxy)-
succinimide; HATU, 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-
tetramethyluronium hexafluorophosphate; HFIP, hexafluoro-
isopropanol; HOAt, 1-hydroxy-7-azabenzotriazole; HOBt, 1-
hydroxybenzotriazole; MeOH, methanol; NaHMDS, sodium
hexamethyldisilazide; nd, not determined; R, residue; RP,
reversed phase; t-BuOH, tert-butanol; TIS, triisopropylsilane; u
(as in uB), unit; Vn, vitronectin
uC[(S)-(CH2)3N3]-cryptophycin-1 (39i). The acetonide 32i (129 mg,
0.165 mmol) was converted to the corresponding epoxide 39i
J
dx.doi.org/10.1021/jm301346z | J. Med. Chem. XXXX, XXX, XXX−XXX