A straightforward approach to protected (S)-dolaphenine (Doe), the unusual amino acid component of dolastatin 10

Article abstract of DOI:10.1055/s-0031-1289594

A short, four-step synthesis of Boc-protected (S)-dolaphenine is described, starting from protected phenylalanyl glycine. The key step is the cyclization of an endothiodipeptide to give a thiazolyl triflate, which can be subjected to a palladium-catalyzed

Full text of DOI:10.1055/s-0031-1289594

PAPER
4033
A Straightforward Approach to Protected (S)-Dolaphenine (Doe), the Unusual
Amino Acid Component of Dolastatin 10
Synthesis
e
of
(
S
)-Dola
n
phenine s L. Burkhart, Uli Kazmaier*
Institut für Organische Chemie, Universitaet des Saarlandes, 66123 Saarbruecken, Germany
Fax +49(681)3022409; E-mail: u.kazmaier@mx.uni-saarland.de
Received 16 September 2011; revised 6 October 2011
Dil
Dap
Doe
Abstract: A short, four-step synthesis of Boc-protected (S)-dola-
phenine is described, starting from protected phenylalanyl glycine.
The key step is the cyclization of an endothiodipeptide to give a
thiazolyl triflate, which can be subjected to a palladium-catalyzed
reduction with formic acid.
O
H
N
N
O
N
N
N
O
OMe
O
N
MeO
Key words: dolaphenine, dolastatin, endothiopeptides, peptides,
H
S
thiazoles, triflates
dolastatin 10
Dolastatin 10, a linear pentapeptide, was isolated from the
Indian ocean sea hare Dolabella auricularia by Pettit et al.
in 1987.1 This organism was found to be an excellent
source of a wide range of biologically highly active natu-
ral products.2–5 Dolastatin 10 shows antitumor activity in
sub-nanomolar concentrations against a wide range of tu-
mor cell lines,6–8 and has entered clinical trials.9,10 At the
time of its discovery, it was the most powerful antimitotic
natural product known. The antiproliferative agent inter-
acts with the tubulin skeleton11,12 by binding to the so-
called vinca domain.7,13 The same mode of action is also
found for other peptidic natural products, such as the tu-
bulysins.14–16
N
H2N
S
(S)-dolaphenine
(Doe)
Figure 1 Dolastatin 10 and dolaphenine
oped a new procedure for the synthesis of thiazoles based
on a thio-Ugi reaction (Scheme 1).45,46 With isocyanoace-
tates and thioacids (as acid component), endothiopeptides
1 are formed in good yield. Saponification gives rise to the
free carboxylic acid, which can be cyclized to the 5-sub-
stituted thiazole derivatives in the presence of acyl halides
or anhydrides.47 When triflic anhydride is used, the corre-
From a structural point of view, dolastatin 10 contains
three rather unusual amino acids, dolaisoleuine (Dil)17,18
and dolaproine (Dap),19–23 two ‘prolonged’ g-amino
acids,24,25 and dolaphenine (Doe),26–30 the C-terminal thia- sponding triflates 2 are formed directly in acceptable
yield. These triflates are excellent substrates for a wide
range of cross-coupling reactions, giving access to 5-sub-
stituted thiazoles 3. Herein, we report an application of
this protocol for the synthesis of (S)-Doe.
zole building block (Figure 1). This fragment is also
found in the closely related natural product symplostatin
131–33 and in N-methylated form in barbamide and dichlo-
robarbamide.34,35
During the synthesis of dolastatin 10 and analogues, sev-
eral synthetic approaches towards these unusual amino
acids have been developed.17–30 Although dolaphenine
looks rather simple, its synthesis is not a trivial issue, es-
pecially because of the configurative lability of the stereo-
genic center. The approaches reported so far are either
multistep syntheses using expensive reagents,26–28 contain
low-yield synthetic steps,30 or face the problem of racem-
ization.29
O
Ph
O
R1
H
SH
N
COOMe
Ph
N
Bn NH2
R1 CHO
75–89%
Bn
S
1
CN
COOMe
1) NaOH
2) Tf2O
50%
Our group is involved in the synthesis of unusual amino
acids36–40 and tubulin binding agents.41–44 As a result, we
were interested in developing a straightforward approach
to the synthesis of dolaphenine (Doe). Recently, we devel-
O
R1
O
N
R1
R2X, Pd0
51–95%
N
N
Ph
N
Ph
S
S
Bn
Bn
R2
OTf
3
2
SYNTHESIS 2011, No. 24, pp 4033–4036
Advanced online publication: 07.11.2011
x
x.
x
x
.
2
0
1
1
Scheme 1 Synthesis of 5-substituted thiazoles
DOI: 10.1055/s-0031-1289594; Art ID: T89611SS
© Georg Thieme Verlag Stuttgart · New York

4034
J. L. Burkhart, U. Kazmaier
PAPER
Starting from the dipeptide 4, the corresponding endo- dolaphenine, the unusual amino acid component of dola-
thiopeptide 5 was obtained by sulfurylation with P4S10 statin 10.
(Scheme 2). Unfortunately, the yield could not be in-
creased to more than 46%, even when the reaction time
All reactions were carried out in oven-dried glassware (100 °C) un-
der nitrogen. All solvents were dried before use; THF was distilled
was prolonged to five days. Nevertheless, this was not a from LiAlH4. The products were purified by flash chromatography
on silica gel (0.063–0.2 mm); mixtures of EtOAc and hexanes were
serious problem because the unreacted starting material
generally used as eluents. Analysis by TLC was carried out on com-
could be easily recovered and recycled. Subsequent sa-
mercially precoated Polygram SIL-G/UV 254 plates (Macherey–
Nagel, Dueren). Visualization was accomplished with UV light,
KMnO4 solution or iodine. Optical rotation measurements were per-
ponification of 5 gave rise to carboxylic acid 6 in almost
quantitative yield. Because, in our previous investiga-
tions, formation of the thiazole triflate directly from the
carboxylic acid occurred in only moderate yield
(Scheme 1), we converted 6 into the corresponding thia-
zolone 7 using N,N-dicyclohexylcarbodiimide (DCC). In-
terestingly, all attempts to convert 7 into the required
triflate 8 failed, and only complete decomposition of 7
was observed. Therefore, we tried the direct conversion of
6 into 8 by using two equivalents of triflic anhydride. We
were pleased to find that at 0 °C the required thiazole 8
was obtained in excellent yield in a very clean reaction. In
principle, this intermediate compound 8 should allow the
convenient synthesis of a wide range of dolaphenine de-
rivatives. Here, 8 was subjected to a Pd-catalyzed reduc-
tion using formic acid to give the desired Boc-protected
dolaphenine in high yield and excellent ee (93% ee) as de-
termined by HPLC.
formed with a Perkin-Elmer 341 polarimeter, with concentrations
given in g/100 mL. Melting points were determined with a MEL-
TEMP II apparatus and are uncorrected. 1H and 13C NMR spectro-
scopic analyses were performed with a Bruker Avance II 400 MHz
spectrometer. Chemical shifts are reported in d units (ppm), and
coupling constants (J) are given in Hz. HRMS were measured with
a Finnigan MAT 95S mass spectrometer. Elemental analyses were
carried out at the Department of Chemistry at Saarland University.
(S)-2-[2-(tert-Butoxycarbonylamino)-3-phenylpropanethio-
amido]acetic Acid (6)
To a solution of thiopeptide 548 (879 mg, 2.49 mmol) in MeOH (15
mL) at 0 °C, aq NaOH (1 M, 2.7 mL, 2.7 mmol) was added drop-
wise and the reaction mixture was allowed to warm to r.t. overnight.
The solvent was evaporated, and the residue was dissolved in H2O
(20 mL), acidified to pH 1 with aq 1 M KHSO4, and extracted with
EtOAc (3 × 20 mL). The combined organic layers were washed
with brine (10 mL), dried over Na2SO4 and the solvent was evapo-
rated in vacuo to give acid 6.
In conclusion, we have developed a very fast and easy,
high-yielding, almost racemization-free synthesis of (S)-
21
Yield: 810 mg (2.39 mmol, 96%); white foam; mp 49–52 °C. [a]D
+28.2 (c 1.1, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.36 (s, 9 H, 1-H), 3.07 (m, 2 H,
2
2
5-H), 4.05 (d, J11a–11b = 19.5 Hz, 1 H, 11-Ha), 4.34 (d, J11b–11a
=
19.2 Hz, 1 H, 11-Hb), 5.33 (m, 1 H, 4-H), 5.75 (d, 3JNH–4 = 9.2 Hz,
1 H, NH), 7.24–7.31 (m, 5 H, 7-H, 8-H, 9-H), 8.64 (s, 1 H, NH),
10.11 (br s, 1 H, OH).
Na2CO3 (0.5 equiv)
P4S10 (0.5 equiv)
H
H
N
COOMe
N
COOMe
HN
Boc
13C NMR (100 MHz, CDCl3): d = 28.2 (q, C-1), 43.5 (t, C-5), 46.9
(t, C-11), 60.3 (d, C-4), 81.3 (s, C-2), 126.8 (d, C-9), 128.4 (d, C-7),
129.3 (d, C-8), 136.5 (s, C-6), 155.7 (s, C-3), 170.9 (s, C-12), 203.3
(s, C-10).
HN
Boc
THF, r.t., 16 h
46%
S
O
5
4
NaOH (1.1 equiv)
MeOH–H2O
0 °C to r.t., 16 h
96%
HRMS (CI): m/z [M + H]+ calcd for C16H23N2O4S: 339.1378; found:
339.1372.
Anal. Calcd for C16H22N2O4S: C, 56.78; H, 6.55; N, 8.28. Found: C,
56.57; H, 6.41; N, 7.80.
O
DCC (1.0 equiv)
H
N
N
(S)-tert-Butyl 1-(5-Oxo-4,5-dihydrothiazol-2-yl)-2-phenylethyl-
carbamate (7)
To a solution of carboxylic acid 6 (89 mg, 0.26 mmol) in anhydrous
THF (2 mL), DCC (54 mg, 0.26 mmol) was added. After stirring for
30 min at r.t., the urea was filtered off and the solvent was removed
in vacuo. The crude product was purified by flash chromatography
(SiO2; hexanes–EtOAc, 8:2) to yield thiazolone 5.
BocHN
BocHN
OH
THF, r.t., 30 min
80%
S
S
O
7
6
Tf2O (2.0 equiv)
NMM (5.0 equiv)
Tf2O (1.1 equiv)
Py (5.0 equiv)
CH2Cl2, 0 °C
95%
CH2Cl2, 0 °C, 30 min
Yield: 67 mg (0.21 mmol, 80%); white solid; mp 128–130 °C;
[a]D21 –30.2 (c 1.1, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.42 (s, 9 H, 1-H), 3.10 (dd,
3
2
2J5a–5b = 13.9 Hz, J5a–4 = 7.2 Hz, 1 H, 5-Ha), 3.28 (dd, J5b–5a
=
=
Pd(OAc)2 (5 mol%)
Ph3P (20 mol%)
HCOOH (2.0 equiv)
Et3N (2.0 equiv)
3
2
2
14.0 Hz, J5b–4 = 5.7 Hz, 1 H, 5-Hb), 4.64 (d, J11a–11b = J11b–11a
2
2.0 Hz, 2 H, 11-H), 4.91 (m, 1 H, 4-H), 5.15 (d, JNH–4 = 6.9 Hz,
N
N
1 H, NH), 7.21 (m, 2 H, 8-H), 7.26–7.35 (m, 3 H, 7-H, 9-H).
BocHN
BocHN
THF, 60 °C, 4 h
88%
13C NMR (100 MHz, CDCl3): d = 28.2 (q, C-1), 38.6 (t, C-5), 55.8
(d, C-4), 72.3 (t, C-11), 80.3 (s, C-2), 127.1 (d, C-9), 128.6 (d, C-7),
129.3 (d, C-8), 135.9 (s, C-6), 154.9 (s, C-3), 172.6 (s, C-10), 206.0
(s, C-12).
S
S
OTf
9
8
Scheme 2 Synthesis of Boc-(S)-dolaphenine
Synthesis 2011, No. 24, 4033–4036 © Thieme Stuttgart · New York

PAPER
Synthesis of (S)-Dolaphenine
4035
HRMS (CI): m/z [M + H]+ calcd for C16H21N2O3S: 321.1273; found:
321.1241.
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Anal. Calcd for C16H20N2O3S: C, 59.98; H, 6.29; N, 8.74. Found: C,
59.79; H, 6.34; N, 8.70.
(S)-2-[1-(tert-Butoxycarbonylamino)-2-phenylethyl]thiazol-5-
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1H NMR (400 MHz, CDCl3): d = 1.42 (s, 9 H, 1-H), 3.26 (m, 1 H,
5-Ha), 3.32 (dd, 2J5b–5a = 13.8 Hz, 3J5b–4 = 5.8 Hz, 1 H, 5-Hb), 4.94–
5.28 (m, 2 H, 4-H, NH), 7.11 (m, 2 H, 8-H), 7.25–7.33 (m, 3 H, 7-
H, 9-H), 7.60 (s, 2 H, 11-H).
13C NMR (100 MHz, CDCl3): d = 28.2 (q, C-1), 40.8 (t, C-5), 54.2
(d, C-4), 80.6 (s, C-2), 118.6 (q, 2J13,F = 320 Hz, C-13), 127.2 (d, C-
9), 128.7 (d, C-7), 129.3 (d, C-8), 133.5 (s, C-11), 135.7 (s, C-6),
146.0 (s, C-12), 154.8 (s, C-3), 169.2 (s, C-10).
19F NMR (400 MHz, CDCl3): d = –71.2.
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453.0740.
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C, 45.43; H, 4.13; N, 5.90.
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A solution of triflate 8 (916 mg, 2.03 mmol), Pd(OAc)2 (35 mg, 0.16
mmol) and Ph3P (168 mg, 0.64 mmol) in anhydrous THF (10 mL)
was heated to 60 °C under N2, before a mixture of Et3N (0.57 mL,
4.1 mmol) and formic acid (0.16 mL, 4.1 mmol) was added drop-
wise. The solution was stirred for 4 h at this temperature. After cool-
ing to r.t., the reaction mixture was diluted with EtOAc (40 mL) and
washed with aq 1 M KHSO4 (20 mL), sat. NaHCO3 (20 mL), H2O
(20 mL), and brine (10 mL), dried over Na2SO4 and concentrated in
vacuo. The crude product was purified by flash chromatography
(SiO2; hexanes–EtOAc, 8:2) to yield Boc-dolaphenine 9.
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21
[a]D –25.5 (c 1.1, CHCl3); HPLC (chiralcel OD-H; hexanes–
i-PrOH, 98:2; 1 mL/min): tR = 14.16 [(S)-9], 17.40 [(R)-9] min.
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5-H), 5.33 (br s, 2 H, 4-H, NH), 7.11 (m, 2 H, 8-H), 7.22–7.28 (m,
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(d, C-4), 79.9 (s, C-2), 118.7 (d, C-12), 126.8 (d, C-9), 128.4 (d, C-
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305.1311.
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63.47; H, 7.27; N, 9.12.
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J. L. Burkhart, U. Kazmaier
PAPER
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Synthesis 2011, No. 24, 4033–4036 © Thieme Stuttgart · New York