SansalVamide A as a NoVel Antitumor Template
dipeptide was taken on to the next reaction without further
purification or characterization (355 mg, 100% yield).
Tripeptide 1e-2a-3a-NH2. Tripeptide 1e-2a-3a-NH2 was syn-
thesized following the General Amine Deprotection procedure. This
dipeptide was taken on to the next reaction without further
purification or characterization (399 mg, 100% yield).
Dipeptide 4a-5a. Dipeptide 4a-5a was synthesized following
the General Peptide Synthesis procedure, utilizing 400 mg (2.2
mmol, 1.1 equiv) of amine 4a, 500 mg (2.0 mmol, 1.0 equiv) of
acid, 1.4 mL (4 equiv) of DIPEA, and 770.6 mg (2.4 mmol, 1.1
equiv) of TBTU. The crude reaction was purified by column
chromatography (silica gel, EtOAc/Hex) to yield the dipeptide (660
Dipeptide 4a-5a. Dipeptide 4a-5a was synthesized following
the General Peptide Synthesis procedure, utilizing 799 mg (4.4
mmol, 1.1 equiv) of amine 4a, 1 g (4.0 mmol, 1.0 equiv) of acid,
2.8 mL (4 equiv) of DIPEA, and 1.5 g (1.4 mmol, 1.2 equiv) of
TBTU. The crude reaction was purified by column chromatography
(silica gel, EtOAc/Hex) to yield the dipeptide (660 mg, 98%
1
mg, 97% yield); Rf 0.5 (EtOAc/Hex 1:1); H NMR (200 MHz,
CDCl3) δ 0.8-1.0 (dd, 12H), 1.4 (s, 9H), 1.5-1.8 (m, 6H), 3.7 (s,
3H), 4.0 (m, RH), 4.6 (m, RH), 4.8 (br, 1H), 6.4 (br, 1H).
1
yield): Rf 0.5 (EtOAc/Hex 1:1); H NMR (200 MHz, CDCl3) δ
0.9-1.0 (d, 12H), 1.4 (s, 9H), 1.5-1.8 (br, 6H), 3.7 (s, 3H), 4.1
Dipeptide HO-4a-5a. Dipeptide HO-4a-5a was synthesized
following the General Acid Deprotection procedure. This dipeptide
was taken on to the next reaction without further purification or
characterization (564 mg, 87.8% yield): 1H NMR (200 MHz,
CDCl3) δ 0.7-0.9 (dd, 12H), 1.2-1.6 (m, 2H), 1.4 (s, 9H), 2.0-
2.2 (m, 2H), 3.2-3.3 (m, 2H), 3.6 (s, 3H), 3.8 (dd, RH), 4.2 (m,
RH), 4.8 (quint, RH), 4.9 (br, 1H), 6.3 (br, 1H), 6.6 (br, 1H), 7.0-
7.6 (m, 5H), 8.2 (br, 1H).
(dd, RH), 4.6 (dd, RH), 4.9 (d, 1H), 6.4 (d, 1H).
Dipeptide HO-4a-5a. Dipeptide HO-4a-5a was synthesized
following the General Acid Deprotection procedure. This dipeptide
was taken on to the next reaction without further purification or
characterization (564 mg, 89% yield).
Pentapeptide 1e-2a-3a-4a-5a. Pentapeptide 1e-2a-3a-4a-5a was
synthesized following the General Peptide Synthesis procedure,
utilizing 399 mg (0.92 mmol, 1.1 equiv) of amine 1e-2a-3a, 371
mg (0.84 mmol, 1.0 equiv) of acid, 600 µL (4 equiv) of DIPEA,
and 301 mg (1.01 mmol, 1.2 equiv) of DEPBT. The crude reaction
was purified by column chromatography (silica gel, EtOAc/Hex)
to yield the pentapeptide (194 mg, 30% yield): Rf 0.5 (EtOAc/
Pentapeptide 1f-2a-3a-4a-5a. Pentapeptide 1f-2a-3a-4a-5a was
synthesized following the General peptide Synthesis procedure,
utilizing 355 mg (0.00087 mmol, 1.1 equiv) of amine 1f, 416 mg
(0.00079 mmol, 1.0 equiv) of acid, 0.55 mL (4 equiv) of DIPEA,
and 283.4 mg (0.95 mmol, 1.2 equiv) of Depbt. The crude reaction
was purified by column chromatography (silica gel, EtOAc/Hex)
to yield the pentapeptide (252 mg, 43.4% yield): Rf 0.6 (EtOAc/
1
Hex 3:1); H NMR (500 MHz, CD3OD) δ 0.8-1.0 (m, 24H), 1.4
(m, 9H), 1.5-1.7 (m, 2H), 1.9-2.1 (d, 4H), 3.1 (m, 2H), 3.7 (s,
3H), 4.1 (d, 2RH), 4.3-4.4 (m, 2RH), 4.7 (m, RH), 7.0-7.1 (m,
4H), 7.2 (m, 1H), 7.3 (d, 1H), 7.5 (d, 1H), 7.8 (d, 1H), 8.0 (d, 1H).
1
Hex 3:1); H NMR (500 MHz, CD3OD) δ 0.8 (dd, 6H), 0.9-2.0
(m, 18H), 1.2-1.6 (m, 6H), 1.4 (s, 9H), 1.7 (m, 3H), 2.1 (m, 2H),
2.8-3.1 (m, 2H), 3.7 (s, 3H), 4.1 (m, 2RH), 4.4 (m, 2RH), 4.6 (m,
RH), 6.7-7.0 (dd, 4H).
Macrocycle 1e-2a-3a-4a-5a (Compound 3). Macrocycle 1e-
2a-3a-4a-5a (compound 3) was synthesized following the Macro-
cyclization procedure, utilizing 167 mg (0.26 mmol, 1.0 equiv) of
linear pentapeptide, 360 µL (8 equiv) of DIPEA, 42 mg (0.13 mmol,
0.5 equiv) of TBTU, 49.4 mg (0.13 mmol, 0.5 equiv) HATU, and
39 mg (0.13 mmol, 0.5 equiv) of DEPBT. The crude reaction was
purified by reverse phase HPLC to yield the macrocycle (5.5 mg,
Macrocycle 1f-2a-3a-4a-5a (Compound 2). Macrocycle 1f-2a-
3a-4a-5a (compound 2) was synthesized following the Macrocy-
clization procedure, utilizing 210.8 mg (0.34 mmol, 1.0 equiv) of
linear pentapeptide, 0.48 mL (4 equiv) of DIPEA, 55.4 mg (0.17
mmol, 0.5 equiv) of TBTU, 68.2 mg (0.179 mmol, 0.5 equiv)
HATU, and 51.4 mg (0.171 mmol, 0.5 equiv) of DEPBT. The crude
reaction was purified by reverse phase-HPLC to yield the macro-
cycle (8.0 mg, 5% yield): Rf 0.6 (EtOAc/Hex 1:0); 1H NMR (500
MHz, CD3OD) δ 0.6-0.8 (dd, 6H), 0.9-1.0 (m, 18H), 1.2-1.7
(m, 10H), 2.6-2.9 (m, 2H), 3.2 (m, RH), 4.1 (m, RH), 4.3 (m,
RH), 4.4 (m, RH), 4.5 (m, RH), 6.7-7.0 (dd, 4H), 7.2 (d, 1H), 8.1
(d, 1H), 8.2 (d, 1H), 8.4 (d, 1H), 8.7 (d, 1H); LCMS m/z calcd for
C32H51N5O6 (M + 1) 601.77, found 602.4.
Synthesis of Compound 3. Dipeptide 1e-2a. Dipeptide 1e-2a
was synthesized following the General Peptide Synthesis procedure,
utilizing 560.56 mg (2.2 mmol, 1.1 equiv) of amine 1e, 500 mg
(2.0 mmol, 1.0 equiv) of acid, 1.4 mL (4 equiv) of DIPEA, and
717.6 mg (2.39 mmol, 1.2 equiv) of DEPBT. The crude reaction
was purified by column chromatography (silica gel, EtOAc/Hex)
to yield the dipeptide (650 mg, 82% yield): Rf 0.65 (EtOAc/Hex
1:1); 1H NMR (200 MHz, CDCl3) δ 0.8 (d, 6H), 1.4 (s, 9H), 1.5-
1.7 (m, 3H), 3.3 (d, 2H), 3.6 (s, 3H), 4.0 (m, RH), 4.9 (m, RH), 4.8
(br, 1H), 6.6 (br, 1H), 7.0-7.5 (m, 5H), 8.1 (br, 1H).
1
33% yield): Rf 0.65 (EtOAc/MeOH 98:2); H NMR (500 MHz,
CD3OD) δ 0.8-1.0 (m, 24H), 1.2-1.4 (m, 6H), 1.5-1.7 (m, 4H),
3.1-3.2 (m, 2H), 3.6-3.8 (m, 2RH), 4.0 (d, RH), 4.5 (m, RH), 4.6
(m, RH), 6.6 (d, 1H), 7.1-7.2 (m, 4H), 7.3 (d, 4H), 7.4 (m, 1H),
7.5 (d, 1H), 8.0 (d, 1H), 8.1 (d, 1H); LCMS m/z calcd for
C34H52N6O5 (M + 1) 625.4, found 625.5.
Synthesis of Compound 4. Dipeptide 1b-2a. Dipeptide 1b-2a
was synthesized following the General Peptide Synthesis procedure,
utilizing 475 mg (2.2 mmol, 1.1 equiv) of amine 1b, 500 mg (2.0
mmol, 1.0 equiv) of acid, 1.39 mL (4 equiv) of DIPEA, and 708
mg (2.2 mmol, 1.1 equiv) of TBTU. The crude reaction was purified
by column chromatography (silica gel, EtOAc/Hex) to yield the
1
dipeptide (721 mg, 92% yield): Rf 0.5 (EtOAc/Hex 35:65); H
NMR (200 MHz, CDCl3) δ 1.0 (d, 6H), 1.5 (s, 9H), 1.7 (m, 3H),
3.1-3.3 (sept, 2H), 3.8 (s, 3H), 4.2 (m, RH), 4.8 (br, 1H), 5.0 (q,
RH), 6.6 (br, 1H), 7.2-7.4 (m, 5H).
Dipeptide 1b-2a-NH2. Dipeptide 1b-2a-NH2 was synthesized
following the General Amine Deprotection procedure. This dipep-
tide was taken on to the next reaction without further purification
or characterization (537 mg, assume quantitative yield).
Tripeptide 1b-2a-3a. Tripeptide 1b-2a-3a was synthesized
following the General Peptide Synthesis procedure, utilizing 537
mg (1.83 mmol, 1.1 equiv) of amine 1b-2a, 363 mg (1.67 mmol,
1.0 equiv) of acid 3a, 1.17 mL (4 equiv) of DIPEA, and 590.4 mg
(1.83 mmol, 1.1 equiv) of TBTU. The crude reaction was purified
by column chromatography (silica gel, EtOAc/Hex) to yield the
tripeptide (798 mg, 97% yield): Rf 0.6 (EtOAc/Hex 1:1); 1H NMR
(200 MHz, CDCl3) δ 0.9-1.0 (m, 12H), 1.57 (s, 9H), 1.6-1.7 (m,
3H), 2.1-2.3 (sept, 1H), 3.1-3.4 (m, 2H), 3.8 (s, 3H), 3.9-4.0
(dd, RH), 4.5 (m, RH), 4.8-5.0 (q, RH), 5.0 (br, 1H), 6.4 (d, 1H),
6.6 (br, 1H), 7.2-7.4 (m, 5H).
Dipeptide 1e-2a-NH2. Dipeptide 1e-2a-NH2 was synthesized
following the General Amine Deprotection procedure. This dipep-
tide was taken on to the next reaction without further purification
or characterization (498 mg, 100% yield).
Tripeptide 1e-2a-3a. Tripeptide 1e-2a-3a was synthesized
following the General Peptide Synthesis procedure, utilizing 498
mg (1.5 mmol, 1.1 equiv) of amine 1e-2a, 295.5 mg (1.36 mmol,
1.0 equiv) of acid, 0.95 mL (4 equiv) of DIPEA, and 488 mg (1.63
mmol, 1.2 equiv) of DEPBT. The crude reaction was purified by
column chromatography (silica gel, EtOAc/Hex) to yield the
tripeptide (488 mg, 67% yield): Rf 0.55 (EtOAc/Hex 1:1); 1H NMR
(200 MHz, CDCl3) δ 0.7-0.9 (dd, 12H), 1.2-1.6 (m, 2H), 1.4 (s,
9H), 2.0-2.2 (m, 2H), 3.2-3.3 (m, 2H), 3.6 (s, 3H), 3.8 (dd, RH),
4.2 (m, RH), 4.8 (quint, RH), 4.9 (br, 1H), 6.3 (br, 1H), 6.6 (br,
1H), 7.0-7.6 (m, 5H), 8.2 (br, 1H).
Tripeptide 1b-2a-3a-NH2. Tripeptide 1b-2a-3a-NH2 was syn-
thesized following the General Amine Deprotection procedure. This
J. Org. Chem, Vol. 72, No. 6, 2007 1991