Synthesis of the chlorofusin cyclic peptide

Article abstract of DOI:10.1016/j.tet.2008.09.029

An efficient and convergent solution-phase synthesis of the cyclic peptide of the natural product chlorofusin, a reported inhibitor of the MDM2-p53 interaction, is detailed.

Full text of DOI:10.1016/j.tet.2008.09.029

Tetrahedron 65 (2009) 3281–3284
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of the chlorofusin cyclic peptide
*
Sang Yeul Lee, Dale L. Boger
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 July 2008
Received in revised form
10 September 2008
An efficient and convergent solution-phase synthesis of the cyclic peptide of the natural product
chlorofusin, a reported inhibitor of the MDM2–p53 interaction, is detailed.
Ó 2008 Elsevier Ltd. All rights reserved.
Accepted 11 September 2008
Available online 20 September 2008
1. Introduction
incorporating either a D-Ada8 or L
-Ada8 residue,4 and recently
Nakata5 has also reported a synthesis of this cyclic peptide.
Similarly, spectroscopic studies conducted by Williams
provided the structure and a relative assignment of the stereo-
chemistry for the unusual azaphilone-derived chromophore, but
did not permit an assignment of its absolute stereochemistry.1
Based on gradient 1D NOE studies, the chromophore’s relative
Chlorofusin (1, Fig. 1) was isolated from the fungal strain
Microdochium caespitosum and found to disrupt the MDM2–p53
interaction by directly binding to the N-terminal domain of
MDM2 (IC50¼4.6
m
M, KD¼4.7
m
M).1 Thus, chlorofusin represents
an exciting lead for antineoplastic intervention that acts by a rare
disruption of a protein–protein interaction, although the struc-
tural details of the inhibitory MDM2 binding have yet to be
established.2 On the basis of extensive spectroscopic and deg-
radation studies, the chlorofusin structure was proposed to be
stereochemistry was suggested to be 4R
*
,8R
*
,9R in which all
*
three oxygen substituents on the chromophore reside on the
same face. Recently, we reported the total synthesis of chlorofusin,
which displayed spectroscopic properties indistinguishable from
those reported for the natural product,6a and its distinguishable
seven alternative chromophore diastereomers6b that required the
reassignment of the chromophore relative stereochemistry and
provided an unambiguous assignment of its absolute stereo-
chemistry (4R,8S,9R). This assignment, which differed from that
reported near simultaneously by Yao,7 also confirmed the accu-
composed of
a
densely functionalized, azaphilone-derived
chromophore linked through the terminal amine of ornithine to
a 27-membered cyclic peptide composed of nine amino acid
residues.1 Two of the cyclic peptide amino acids possess a non-
standard or modified side chain and four possess the
D-con-
figuration. Although the spectroscopic and degradation studies of
chlorofusin permitted the identification of the cyclic peptide
structure and connectivity, the stereochemistry of two asparagine
residues Asn3 and Asn4 was only established to have opposite
racy of our earlier
assignment.
L-Asn3/D-Asn4 cyclic peptide stereochemical
stereochemistries (
not possible. In 2003, we reported the synthesis of the two cyclic
peptide diastereomers bearing either the -Asn3/ -Asn4 or
L and D) and their respective assignments were
(CH2)6CH3
D-Ada 8
L
D
12
Cl
OH
O
8
O
O
D
-Asn3/L-Asn4 stereochemistry and were able to correlate the
O
O
7
11
HN
O
6
3
former with the spectroscopic properties (1H and 13C NMR) of the
9
5
D-Leu 7
N
H
10
4
N
natural product.3 Concurrent with this disclosure, Searcey
O
2
1
OH
HN
L-Orn 9
HN
L-Thr 1
O
L-Thr 6
13
O
reported the synthesis of the
L-Asn3/D-Asn4 diastereomer
HO
NH
D-Leu 5
O
Chlorofusin (1)
NH
O
O
O
L-Ala2
O
NH
HN
O
Abbreviations: Ada, 2-aminodecanoic acid; EDCI, 1-ethyl-3-(3-dimethylamino-
propyl)carbodiimide; HOAt, 1-hydroxy-7-azabenzotriazole; MDM2, murine double
minute 2 protein; p53, protein 53; SES, 2-(trimethylsilyl)ethylsulfonyl; Trt, trityl
(triphenylmethyl).
N
O
H
NH2
D-Asn 4
L-Asn 3
H2N
* Corresponding author. Tel.: þ1 858 784 7522; fax: þ1 858 784 7550.
E-mail address: boger@scripps.edu (D.L. Boger).
Figure 1. Structure of chlorofusin.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.029

3282
S.Y. Lee, D.L. Boger / Tetrahedron 65 (2009) 3281–3284
(CH2)6CH3
O
(CH2)6CH3
O
O
O
N
H
OH
N
H
OH
HN
HN
O
O
HN
HN
O
O
RHN
SESHN
HO
HO
HN
O
HN
O
NH
NH
O
O
O
O
NH
NH
NH
NH
O
O
O
O
2, R = H
3, R = SES
4
HN
HN
N
H
N
H
O
O
NH2
NHTrt
O
O
O
NH2
NHTrt
TrtHN
OH
O
O
O
O
O
O
H
H
H
N
H
N
BocHN
N
N
N
H
N
H
N
H
N
H
OH
OMe
(CH2)7CH3
O
O
O
O
O
5
TrtHN
SESHN
O
TrtHN
OH
OH
(CH2)7CH3
OMe
O
O
O
O
H
H
H
BocHN
N
BocHN
N
N
+
N
N
H
N
H
N
H
OBn
O
H
O
O
O
O
NHTrt
7
SESHN
6
Figure 2. Retrosynthetic analysis of the cyclic peptide.
2. Retrosynthetic analysis
convergency of the synthesis, while permitting a deliberate late
stage incorporation of the subunit bearing the two Asn residues
thereby providing convenient access to both diastereomers re-
quired to assign the absolute stereochemistry. As this work pro-
gressed and facilitating its present continuation, an even more
For the synthesis of the chlorofusin cyclic peptide, the coupling
and macrocyclization sites in our original work3 were chosen to
minimize the use of protecting groups and to maximize the
NHTrt
O
OH
O
O
H
O
BocHN
N
N
H
OR
10, R = Fmoc
11, R = H
RHN
O
OBn
piperidine
N
H
O
+
O
8, R = Bn
H2
9, R = H
SESHN
NHTrt
EDCI, HOAt 87%
TrtHN
OH
(CH2)6CH3
OMe
O
O
OH
O
H
O
O
O
H
H
N
RHN
N
N
H
N
H
BocHN
N
N
H
N
H
OR
O
O
O
O
O
O
O
7, R = Bn
12, R = H
6, R = Boc
13, R = H
H2
TrtHN
HCl
SESHN
EDCI, HOAt 73%
TrtHN
OH
H
O
O
H
O
O
H
N
H
BocHN
N
N
N
N
N
N
H
N
H
OMe
(CH2)7CH3
H
O
H
O
O
O
O
OH
5
TrtHN
SESHN
1) LiOH, THF−H2O
2) HCl, dioxane
3) EDCI, HOAt
76%
TFA
HF
2
4
3
Scheme 1. Synthesis of cyclic peptide 4.

S.Y. Lee, D.L. Boger / Tetrahedron 65 (2009) 3281–3284
3283
convergent synthesis of the cyclic peptide was desired that might
facilitate the examination of a wider range of analogs as well as
provide the basis for an alternative total synthesis of the natural
product itself. Complementary to the solid phase synthesis detailed
by Searcey4 and analogous to the Nakata synthesis of the chloro-
fusin cyclic peptide,5 the macrocyclization site chosen was the
d 174.0, 172.0, 169.6, 155.6, 78.3, 66.7, 57.7, 56.1, 47.7, 46.9, 42.1, 28.3
(3C), 26.4, 19.6, 18.6, 17.5, 10.1, ꢁ1.8 (3C); IR (film) nmax 3316, 2953,
1653, 1526, 1315, 1167, 1139, 842, 756 cmꢁ1; HRESI-TOF m/z
23
569.2672 (MþHþ, C22H45N4O9SSi requires: 569.2671); [
a]
ꢁ16 (c
D
1.0, CHCl3).
L
-Orn9/
D
-Ada8 amide, constituting ring closure at a favorable
L/D
5.2. Boc-L-Orn(SES)-L-Thr-L-Ala-L-Asn(Trt)-D-Asn(Trt)-OBn (7)
amino acid pair (Fig. 2).8 Moreover, and distinct from the approach
disclosed by Nakata, the approach utilized the same three di-, tri-,
and tetrapeptide intermediates (6, 8, and 10) utilized in our original
approach, but avoided our prior late stage coupling and in-
corporation of 11 that can lead to competitive, but minor, diketo-
piperazine formation.3,9
A solution of 103 (285 mg, 0.27 mmol) in anhydrous CH2Cl2
(3 mL) was treated with piperidine (81 L, 0.82 mmol) and stirred
m
at 23 ꢀC for 100 min. Flash chromatography (SiO2, 70% EtOAc–
hexanes) afforded the unstable free amine 11 as a gray solid, which
was employed directly in the next reaction. A flask containing 9
(108 mg, 0.19 mmol), 11 (155 mg, 0.19 mmol), HOAt (78 mg,
0.57 mmol), and EDCI (109 mg, 0.57 mmol) at 0 ꢀC under Ar was
slowly treated with anhydrous DMF (2 mL), stirred at 0 ꢀC for 1 h
and then stirred at 23 ꢀC for 24 h. The reaction mixture was diluted
with EtOAc (30 mL) and washed with aqueous 1 N HCl (2ꢂ5 mL),
saturated aqueous NaHCO3 (2ꢂ5 mL), water (10 mL), and saturated
aqueous NaCl (10 mL). The organic phase was dried (Na2SO4) and
concentrated under reduced pressure. Flash chromatography (SiO2,
60% EtOAc–hexanes) afforded 7 as a gray-white solid (87%,
3. Synthesis of cyclic peptide
The synthesis of the cyclic peptide began with debenzylation of
83 to form tripeptide 9 (H2, Pd/C, 93%), Scheme 1. Coupling of 9 and
dipeptide 113 provided the pentapeptide 7 (EDCI, HOAt, DMF,
0–23 ꢀC, 87%). Benzyl ester cleavage of 7 under hydrogenation
conditions provided the carboxylic acid 12, which was coupled with
tetrapeptide 133 to provide the linear peptide 5 (EDCI, HOAt, DMF,
0–23 ꢀC, 73%). The methyl ester in 5 was hydrolyzed with LiOH in
THF–H2O at 0 ꢀC to provide the corresponding carboxylic acid, and
subsequent Boc removal with 4 M HCl in dioxane provided the
deprotected amino acid, which was used in the next step without
purification. The macrocyclization was achieved under dilute re-
action conditions to provide the cyclic peptide 4 (EDCI, HOAt, DMF,
0–23 ꢀC, 0.01 M, 76%).
Final global deprotection of both the SES and Trt groups was
accomplished with anhydrous HF to provide the fully deprotected
cyclic peptide 2,10 or the two Trt groups could be selectively re-
moved upon treatment with a 20:1 TFA–H2O mixture, a procedure
used in our previous work,3 to yield 3. This second improved route
to 2–4 has been used to provide large quantities of the cyclic
peptide that may be used in the preparation of chlorofusin and its
analogs.
226 mg). 1H NMR (DMSO-d6, 600 MHz)
d 8.76 (s, 1H), 8.54 (s, 1H),
8.21 (d, J¼8.0 Hz, 1H), 8.13 (d, J¼7.7 Hz, 1H), 7.94 (d, J¼7.0 Hz, 1H),
7.65 (d, J¼8.2 Hz, 1H), 7.32–7.39 (br m, 5H), 7.12–7.29 (br m, 31H),
6.93 (t, J¼5.8 Hz, 1H), 5.09 (m, 2H), 5.00 (d, J¼4.7 Hz, 1H), 4.63 (m,
1H), 4.58 (dd, J¼13.8, 6.3 Hz,1H), 4.30–4.36 (br m,1H), 4.05 (m, 1H),
3.97 (m, 1H), 2.86–2.92 (br m, 4H), 2.80 (m, 2H), 2.58 (br m, 2H),
1.71 (m, 1H), 1.48–1.57 (br m, 3H), 1.41 (s, 10H), 1.23 (d, J¼7.0 Hz,
3H), 1.05 (d, J¼6.4 Hz, 3H), 0.88 (m, 2H), 0.04 (s, 9H); 13C NMR
(DMSO-d6, 150 MHz)
d 172.3, 171.9, 171.0, 170.9, 169.4, 168.8, 168.5,
155.6, 144.8 (3C), 144.7 (3C), 135.9, 128.6 (12C), 128.5 (2C), 128.0,
127.7 (2C), 127.5 (6C), 127.5 (6C), 126.4 (6C), 78.3, 69.5, 69.4, 66.6,
66.1, 60.5, 57.5, 54.3, 50.1, 49.2, 48.4, 46.9, 42.1, 37.5, 28.9, 28.3 (3C),
26.5,19.3,18.8,10.1, ꢁ1.86 (3C); IR (film) nmax 3310, 2954,1655,1514,
1494, 1448, 1125, 1168, 851, 753, 699 cmꢁ1
; HRESI-TOF m/z
23
1371.6167 (MþHþ, C75H91N8O13SSi requires: 1371.6190); [
(c 1.2, CHCl3).
a]
ꢁ22
D
4. Conclusion
5.3. Boc-
L-Orn(SES)-L-Thr-L-Ala-D-Asn(Trt)-L-Asn(Trt)-D-Leu-L-
This alternative synthetic route to 2–4 provided a higher overall
yield of the cyclic peptide than our original route and required less
chromatographic purification in the late stages of the synthesis.
Ring closure of the cyclic peptide was accomplished by amide bond
Thr- -Leu-D
D
-Ada-OMe (5)
A solution of 7 (52 mg, 0.038 mmol) in EtOH (1 mL) was treated
with 10% Pd/C (16 mg). The resulting black suspension was stirred
under H2 (1 atm) for 2 h. The catalyst was removed by filtration
through a pad of Celite and washed with EtOAc (5 mL). The filtrate
was concentrated under reduced pressure to provide 12 as a white
foam, which was directly employed in the next reaction without
further purification. A sample of 63 (24 mg, 0.038 mmol) was
treated with 4 M HCl in dioxane solution (0.1 mL), and the resulting
mixture was stirred at 23 ꢀC for 1 h. The volatiles were removed
with a stream of N2. The residue was treated with Et2O (2ꢂ2 mL)
and concentrated under reduced pressure to afford amine 13 as
a white foam, which was directly employed in the next reaction
formation between an L-amine and a D-carboxylic acid that not only
improved the yield, but it also provided material containing smaller
amounts of separable minor side products. The cyclic peptide
prepared using this improved route is being employed in the
preparation of chromophore analogs of chlorofusin and related
materials.
5. Experimental
5.1. Boc-L-Orn(SES)-L-Thr-L-Ala-OH (9)
without further purification.
A flask containing 12 (49 mg,
A solution of 83 (106 mg, 0.16 mmol) in EtOH (2 mL) was treated
with 10% Pd/C (21 mg). The resulting black suspension was stirred
under H2 (1 atm) for 1 h. The catalyst was removed by filtration
through a pad of Celite and washed with EtOAc (5 mL). The filtrate
was concentrated under reduced pressure. Flash chromatography
(SiO2, 5% MeOH–CH2Cl2) afforded 9 as a white foam (93%, 85 mg).
0.038 mmol), 13 (20 mg, 0.038 mmol), HOAt (15 mg, 0.11 mmol),
EDCI (21 mg, 0.11 mmol), and NaHCO3 (10 mg, 0.11 mmol) at 0 ꢀC
was slowly treated with anhydrous DMF (0.4 mL). The reaction
mixture was stirred at 0 ꢀC for 1 h and then stirred at 23 ꢀC for 24 h
under Ar. The reaction mixture was diluted with EtOAc (10 mL) and
washed with aqueous 1 N HCl (2ꢂ2 mL), saturated aqueous
NaHCO3 (2ꢂ2 mL), water (2 mL), and saturated aqueous NaCl
(4 mL). The organic phase was dried (Na2SO4) and concentrated
under reduced pressure. Flash chromatography (SiO2, 3% MeOH–
CH2Cl2) afforded 5 as a white solid (73%, 49 mg). 1H NMR (DMSO-d6,
1H NMR (DMSO-d6, 600 MHz)
d
7.97 (d, J¼7.0 Hz, 1H), 7.59 (d,
J¼8.4 Hz, 1H), 7.07 (d, J¼7.9 Hz, 1H), 6.93 (t, J¼5.7 Hz, 1H), 4.23 (m,
2H), 3.97 (m, 2H), 3.46 (q, J¼7.0 Hz, 1H), 2.90 (m, 4H), 1.69 (br m,
1H), 1.48–1.53 (br m, 3H), 1.40 (s, 9H), 1.29 (d, J¼7.3 Hz, 3H), 1.07 (m,
4H), 0.88 (m, 2H), 0.05 (s, 9H); 13C NMR (DMSO-d6, 150 MHz)
600 MHz)
d
8.61 (s, 1H), 8.58 (s, 1H), 8.23 (d, J¼7.0 Hz, 3H), 7.93 (d,

3284
S.Y. Lee, D.L. Boger / Tetrahedron 65 (2009) 3281–3284
J¼6.7 Hz, 1H), 7.81 (d, J¼8.4 Hz, 1H), 7.75 (d, J¼7.4 Hz, 1H), 7.67 (app
t, J¼8.59 Hz, 2H), 7.15–7.29 (br m, 30H), 7.11 (d, J¼8.0 Hz, 1H), 6.93
(t, J¼5.6 Hz, 1H), 4.98 (d, J¼4.5 Hz, 1H), 4.75 (d, J¼5.4 Hz, 1H), 4.58
(m, 1H), 4.52 (dd, J¼12.7, 8.1 Hz, 1H), 4.31–4.41 (br m, 3H), 4.27 (dd,
J¼14.6, 8.0 Hz, 1H), 4.14 (br m, 2H), 4.04 (m, 1H), 3.97 (m, 1H), 3.92
(dd, J¼10.3, 5.6 Hz, 1H), 3.58 (s, 3H), 2.84–2.94 (br m, 4H), 2.70 (m,
1H), 2.55–2.66 (br m, 3H), 1.57–1.73 (br m, 4H), 1.43–1.56 (br m,
8H), 1.40 (s, 9H), 1.24 (br m, 16H), 1.03 (d, J¼6.2 Hz, 3H), 0.98 (d,
J¼6.3 Hz, 3H), 0.87 (br m, 10H), 0.82 (m, 6H), 0.04 (s, 9H); 13C NMR
3H), 1.33 (d, J¼6.2 Hz, 3H), 1.26 (br m, 16H), 1.00 (d, J¼5.9 Hz, 3H),
0.87 (app t, J¼6.9 Hz, 6H), 0.82 (m, 3H), 0.77 (m, 6H), 0.30 (d,
J¼6.3 Hz, 3H), 0.00 (s, 9H); HRMALDI-FTMS (DHB) m/z 1681.8610
23
(MþNaþ, C89H122N12O15SSi requires: 1681.8534); [
a
]
þ14 (c 0.34,
D
CHCl3).
5.5. cyclo-L-Thr-L-Ala-L-Asn-D-Asn-D-Leu-L-Thr-D-Leu-D-Ada-L-
Orn (2)
(DMSO-d6, 150 MHz)
d 172.5, 172.28, 172.26, 172.2, 171.2, 170.9,
A sample of 4 (30 mg, 18.1 mmol) was treated with two drops of
169.7,169.4,169.0,168.6,162.4,155.6,144.77 (3C),144.75 (3C),128.6
(12C), 127.54 (6C), 127.50 (6C), 126.40 (3C), 126.36 (3C), 78.4, 69.5,
66.7, 59.8, 58.5, 57.5, 54.3, 52.2, 51.9, 51.8, 50.7, 50.6, 50.1, 48.2, 46.9,
42.1, 40.9, 40.6, 36.3, 35.9, 31.3, 30.7, 28.9, 28.70, 28.68, 28.3 (3C),
26.5, 25.4, 24.2, 24.0, 23.2, 23.0, 22.2, 21.7, 21.5, 20.8, 19.6, 19.4, 18.7,
14.2, 14.0, 10.1, ꢁ1.9 (3C); IR (film) nmax 3309, 2928, 1650, 1518, 1448,
anisole at 23 ꢀC and attached to an HF (anhydrous) apparatus. HF(g)
was condensed in the reaction apparatus at ꢁ78 ꢀC for 30 min and
then allowed to warm to 0 ꢀC and stirred for 1.5 h. The HF was
removed with a stream of N2 and under reduced pressure. The
resulting mixture was triturated with Et2O (3ꢂ2 mL), dissolved in
TFA (2 mL), and placed on the lyophilizer for 8 h to provide 2 as
a white solid (26.4 mg, 88%) identical in all respects to authentic
material.4
1251, 1168, 1141, 841, 754 cmꢁ1; HRESI-TOF m/z 1791.9542 (MþHþ,
23
C95H135N12O18SSi requires: 1791.9501); [
a
]
ꢁ20 (c 1.3, CHCl3).
D
5.4. cyclo-L-Thr-L-Ala-L-Asn(Trt)-D-Asn(Trt)-D-Leu-L-Thr-D-Leu-
D
-Ada- -Orn(SES) (4)
L
Acknowledgements
A solution of 5 (90 mg, 0.050 mmol) in THF–H2O (1:1, 2 mL) was
We gratefully acknowledge the financial support of the National
Institutes of Health (CA41101) and the Skaggs Institute for Chemical
Biology. S.Y.L. is a Skaggs fellow.
treated with LiOH (21 mg, 1.0 mmol) at 0 ꢀC. The mixture was
stirred at 0 ꢀC for 18 h before being quenched with the addition of
aqueous 2 N HCl (0.5 mL). The mixture was extracted with EtOAc
(5ꢂ1 mL), and the combined extracts were dried (Na2SO4) and
concentrated under reduced pressure to provide the hydrolyzed
product that was directly employed in the next reaction without
further purification. The carboxylic acid was treated with 4 M HCl
in dioxane (1 mL) and the resulting solution was stirred at 23 ꢀC for
1 h. The volatiles were removed under a stream of N2. The residue
was triturated with Et2O (2ꢂ2 mL) and concentrated under re-
duced pressure to afford a gray solid, to which HOAt (27 mg,
0.20 mmol), EDCI (38 mg, 0.20 mmol), and NaHCO3 (17 mg,
0.20 mmol) were added. The combined mixture was cooled to 0 ꢀC
and anhydrous DMF (5 mL) was added. The reaction mixture was
stirred at 0 ꢀC for 48 h before being diluted with EtOAc (50 mL),
washed with aqueous 1 N HCl (2ꢂ5 mL), saturated aqueous
NaHCO3 (2ꢂ5 mL), water (10 mL), and saturated aqueous NaCl
(10 mL). The organic phase was dried (Na2SO4) and concentrated
under reduced pressure. Flash chromatography (SiO2, 2–3% MeOH–
CH2Cl2) afforded 4 as a viscous oil (76%, 463 mg). 1H NMR (DMSO-
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d6, 600 MHz)
d 9.37 (br s, 2H), 8.88 (s, 1H), 8.64 (s, 1H), 8.21 (d,
J¼3.2 Hz, 1H), 7.91 (s, 1H), 7.87 (d, J¼6.0 Hz, 1H), 7.77 (m, 1H), 7.15–
7.31 (br m, 30H), 7.01 (s, 1H), 6.89 (m, 1H), 6.84 (t, J¼5.5 Hz, 1H),
6.33 (br s, 1H), 5.35 (d, J¼4.0 Hz, 1H), 5.26 (d, J¼4.5 Hz, 1H), 5.07 (m,
1H), 4.77 (t, J¼11.3 Hz, 1H), 4.54 (m, 1H), 4.17 (m, 3H), 3.93 (m, 1H),
3.87 (m, 1H), 3.80 (m, 1H), 3.73 (m, 1H), 2.79–2.98 (br m, 4H), 2.73
(m, 2H), 1.78–1.95 (br m, 2H), 1.42–1.66 (br m, 8H), 1.38 (d, J¼7.3 Hz,