Synthesis of the bicyclic [7.3.0] enediyne system of the maduropeptin chromophore: Remarkable atropisomerism of ansamacrolactam and isomerization of the C4-C13 double bond

Article abstract of DOI:10.1055/s-2004-831314

A nine-membered diyne system of the maduropeptin chromophore was constructed for the first time using Nozaki-Hiyama-Kishi reaction. Unexpected atropisomerism of deoxyansamacrolactam and cis/trans isomerization of the exo-double bond of the chromophore wer

Full text of DOI:10.1055/s-2004-831314

LETTER
2107
Synthesis of the Bicyclic [7.3.0] Enediyne System of the Maduropeptin
Chromophore: Remarkable Atropisomerism of Ansamacrolactam and
Isomerization of the C4-C13 Double Bond
Synthesis of the
B
i
o
cyclic
[
7.3.0
b
]
E
nediyne uki Kato, Satoshi Shimamura, Yoko Kikai, Masahiro Hirama*
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Fax +81(22)2176566; E-mail: hirama@ykbsc.chem.tohoku.ac.jp
Received 8 June 2004
12
1
13
Abstract: A nine-membered diyne system of the maduropeptin
4
14
10
chromophore was constructed for the first time using Nozaki–Hiya-
8
OMe
5
HO
O
ma–Kishi reaction. Unexpected atropisomerism of deoxyansamac-
rolactam and cis/trans isomerization of the exo-double bond of the
chromophore were observed.
NH
O
OH
OMe
3'
HO
O
4'
O
5'
Me
HO
HN
Me
1'
Key words: maduropeptin, chromophore, atropisomerism, ene-
diyne, macrolactam
Cl
Me
8'
7'
O
HO
Maduropeptin consists of a 1:1 complex of a carrier apo-
protein and a nine-membered enediyne chromophore, and
shows extremely potent anti-tumor activity.1 Maduropep-
tin chromophore 1, which was isolated from methanol ex-
tract of the broth filtrate of Actinomadura madurae,
possesses the labile enediyne core and a fifteen-mem-
bered macrolactam ansa-bridge.1,2 Our synthetic studies
have targeted ent-1,2f,g an enantiomer of the compound,
arbitrarily described in the literature,1b as well as 7¢-deoxy
ent-1, due to the structural similarity of 1 to the related
chromophores of C-10273 and kedarcidin.4 The complex
architecture of ent-1 featuring the highly functionalized
bicyclic [7.3.0] enediyne core, the ansamacrolactam
bridge with a single atropisomerism, and the glycoside of
a tertiary alcohol renders the total synthesis a formidable
challenge (Figure 1).2 In this communication, we describe
for the first time successful construction of the bicyclic
[7.3.0] enediyne system of the maduropeptin chro-
mophore, and furthermore report an unexpected atrop-
isomerism of the ansamacrolactam, and cis/trans
isomerization of the C-4-exo-double bond.
Maduropeptin Chromophore (ent-1)
Figure 1
triphenylphosphine8 in THF–H2O (27:1) under reflux
over a period of eight hours in high dilution conditions
yielded in one-pot9 the sixteen-membered macrolactam
610 as a single atropisomer. The structure of 6 was con-
firmed by X-ray crystallographic analysis after conver-
sion to the corresponding p-bromobenzoate 7 (Figure 2).11
Interestingly, the chloroanisole ring of the ansabridge
takes the desired conformation in which the methoxy
group is projecting over the cyclopentene ring.
Construction of the nine-membered diyne core possessing
the macrolactam was then examined (Scheme 2). At first
we attempted CeCl3/LiN(TMS)2-mediated cyclization of
Since the nine-membered diyne core is labile,1b we
planned to construct the macrolactam first and then to
form the nine-membered ring by linking C5 and C6.5 The
atropselective construction of the ansa-bridge of 7¢-
deoxy-ent-1 is summarized in Scheme 1. Coupling of the
epoxydienediyne fragment 22g with phenol 36 via CsF-me-
diated etherification7 followed by protection of the result-
ing 1,2-diol as an acetonide and removal of the pivaloyl
group yielded allyllic alcohol 4. Formation of the azide,
saponification of the methyl ester, and condensation with
pentafluorophenol afforded active ester 5. Slow addition
of the azido-pentafluorophenyl ester 5 to excess
SYNLETT 2004, No. 12, pp 2107–2110
0
1
.1
0
.2
0
0
4
Advanced online publication: 31.08.2004
DOI: 10.1055/s-2004-831314; Art ID: U16504ST
© Georg Thieme Verlag Stuttgart · New York
Figure 2 X-Ray structure of p-bromobenzoate 7.

2108
N. Kato et al.
LETTER
alkyne-aldehyde 9a, but this resulted in a nine-membered
ring product in 11% yield at best under various
conditions5,12 irrespective of the protection of the lactam
as an N-Boc carbamate. Thus, Nozaki–Hiyama–Kishi
reaction13 was then attempted.14 The terminal alkyne of
OH
OMPM
OPiv
OMPM
iv, v, vi
O
O
i, ii, iii
Cl
CO2Me
O
macrolactam
6
was iodinated with iodine and
OMe
7'
O
morpholine15 followed by removal of the MPM group
with B-bromocatechol borane16 to yield allylic alcohol 8,
which was subsequently subjected to Dess–Martin
oxidation17 to afford more stable E-a,b-unsaturated alde-
hyde 9b instead of the desired Z-isomer. Monitoring the
oxidation by NMR revealed isomerization of the double
bond occurred quickly, which could not be avoided irre-
spective of the basic additives (NaHCO3, pyridine, and
2,6-di-t-butylpyridine), or in the absence of the basic ad-
ditives, or by using other oxidation reactions (IBX, MnO2,
Swern, PCC). The broadened 1H NMR signals of the aro-
matic protons in particular of 9b indicated that atropi-
somerization took place at room temperature with the
geometry of the C4,C13-double bond changing to the E-
form. Nozaki–Hiyama–Kishi reaction using CrCl2 (3
equiv) and NiCl2 (0.1 equiv)13 in the presence of 4-t-bu-
tylpyridine (9 equiv) gave rise to the nine-membered ring
product 1018 in 67% yield, whereas in the absence of 4-t-
butylpyridine, 10 was obtained in only 5% yield.13d 1H
NMR and NOESY experiments confirmed that macrolac-
tam 10 existed as a single, but undesired, atropisomer
(Figure 3). The stereochemistry of the C5 alcohol of 10
was suggested to be b by NOESY. Furthermore, we found
that Dess–Martin oxidation of N-Boc protected derivative
of 8 in the absence of base prevented isomerization of the
C4,C13-double bond. However, the subsequent Nozaki–
Hiyama–Kishi reaction caused double bond isomerization
to occur before cyclization.
HO
OH
MeO
2
4
Cl
CO2Me
7'
3
N3
vii
O
OMPM
OMPM
NH
O
O
OMe
O
O
O
Cl
CO2C6F5
O
Cl
MeO
6
5
13
1
4
10
5
O
viii, ix
O
O
O
OMe
NH
O
C6H4Br
O
Cl
7
Scheme 1 Reagents and conditions: (i) 3 (3 equiv), CsF (3 equiv),
DMF, 60 °C, 10 h, 55%; (ii) p-TsOH (0.1 equiv), Me2C(OMe)2, r.t.,
1 h, 90%; (iii) NaOMe (2 equiv), MeOH, r.t., 6 h, 89%; (iv) PPh3 (1.5
equiv), CBr4 (1.5 equiv), NaN3 (1.5 equiv), DMF, 0 °C, 1 h, 92%; (v)
LiOH (2 equiv), THF–H2O (5:1), r.t., 10 h; (vi) C6F5OH (1.5 equiv),
EDC (1.5 equiv), DMAP (1.5 equiv), CH2Cl2, r.t., 75% (2 steps); (vii)
PPh3 (40 equiv), THF–H2O (27:1, 1 mM), reflux, 9 h, 89%; (viii) B-
bromocatechol borane (1.8 equiv), CH2Cl2, –90 °C, 98%; (ix) p-
BrC6H4COCl (5 equiv), DMAP (10 equiv), pyridine, r.t., 17 h, 85%.
In conclusion, the highly strained bicyclo[7.3.0]enediyne
10, which possesses a macrolactam ring, was synthesized
for the first time via Nozaki–Hiyama–Kishi reaction. Al-
though the isomerization of the C4,13-double bond as
I
NH
OH
O
i, ii
NH
O
iii
OMPM
OMe
OMe
O
O
O
O
O
O
Cl
Cl
8
6
NH
4
13
4
13
NH
6
CHO
5
R
6
O
O
OH
iv
5
O
O
O
O
OMe
Cl
O
4'
5'
O
Cl
MeO
9a, R = H
9b, R = I
10
Scheme 2 Reagents and conditions: (i) I2 (3 equiv), morpholine (10 equiv), toluene, 50 °C, 2 h, 81%; (ii) B-bromocatechol borane (1.8 equiv),
CH2Cl2, –90 °C, 10 min, 88%; (iii) Dess–Martin periodinane (1.4 equiv), NaHCO3 (20 equiv), CH2Cl2, r.t., 40 min, 69%; (iv) NiCl2 (0.1 equiv),
CrCl2 (3 equiv), 4-t-butylpyridine (9 equiv), THF, 30 °C, 24 h, 67%.
Synlett 2004, No. 12, 2107–2110 © Thieme Stuttgart · New York

LETTER
Synthesis of the Bicyclic [7.3.0] Enediyne
2109
H
H
H
H
H
H
H
H
OH
H
O
N
Cl
O
O
4
H
Me
H
H
H
13
H
N
O
H
Cl
H
4
O
H
O
5
8
O
13
H
OH
H
5
8
O
H
H
H
Me
H
HO
O
H
OMe
Sugar
Me
Me
10
1
Figure 3 NOE Correlations observed in 11b and 10.
E.; Doyle, T. W.; Matson, J. A. J. Am. Chem. Soc. 1992, 114,
7946.
well as the atropisomerization is yet to be resolved, the
syntheses described herein will facilitate the total synthe-
sis of maduropeptin chromophore 1. Further studies based
on the above findings are currently underway.
(5) (a) Kobayashi, S.; Ashizawa, S.; Takahashi, Y.; Sugiura, Y.;
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Hirama, M. Synlett 1998, 1308. (c) Inoue, M.; Kikuchi, T.;
Hirama, M. Tetrahedron Lett. 2004, 45, 6439.
(6) Phenol 3 was prepared from TBS ether2g of chloroisovanilin
through standard procedure in 87% overall yield:
Ph3PCHCO2Me, toluene, reflux, 2 h; H2, Pd/C, EtOAc, 10 h;
TBAF, THF, 30 min.
Acknowledgment
This work was supported by CREST, Japan Science and Technolo-
gy Agency (JST). We thank Dr. Chizuko Kabuto for her assistance
in X-ray crystallographic analysis, and Mr. Kazuo Sasaki for NMR
spectroscopic analysis. A fellowship to N. K. from the Japan Socie-
ty for the Promotion of Science (JSPS) for Young Japanese Scien-
tists is gratefully acknowledged.
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(10) NMR data for 6: 1H NMR (500 MHz, CDCl3): d = 1.44 (s, 3
H), 1.52 (s, 3 H), 2.28 (br s, 1 H), 2.41 (d, 1 H, J = 2.4 Hz),
2.58 (br s, 1 H), 2.63 (dd, 1 H, J = 19.6, 3.0 Hz), 2.76 (ddd,
1 H, J = 19.6, 5.3, 2.4 Hz), 2.91 (br s, 1 H), 3.29 (br s, 1 H),
3.67–3.85 (m, 8 H), 3.94 (d, 1 H, J = 12.4 Hz), 3.96 (d, 1 H,
J = 12.4 Hz), 4.39 (d, 1 H, J = 11.1 Hz), 4.42 (d, 1 H,
J = 11.1 Hz), 4.77 (d, 1 H, J = 5.3 Hz), 5.19 (br s, 1 H), 5.48
(br t, 1 H, J = 6.0 Hz), 5.55 (br s, 1 H), 6.04 (br s, 1 H), 6.77
(d, 1 H, J = 8.0 Hz), 6.84 (d, 2 H, J = 8.4 Hz), 6.93 (d, 1 H,
J = 8.0 Hz), 7.23 (d, 2 H, J = 8.4 Hz). 13C NMR (125 MHz,
CDCl3): d = 27.33, 27.95, 28.88, 36.48, 38.06, 38.62, 55.10,
56.01, 65.85, 71.36, 73.59, 75.15, 79.22, 80.62, 85.65,
93.40, 97.18, 111.29, 112.61, 113.56, 121.67, 124.97,
128.15, 128.37, 129.36, 129.85, 131.34, 134.55, 139.74,
142.18, 151.80, 159.04, 171.19.
(11) Crystal data for 7: C34H31O7NClBr·C4H8O2, M = 769.08,
monoclinic, space group P21/c(#14), Dc = 1.481 g/cm3,
Z = 4, a = 19.180 (7) Å, b = 7.690 (2) Å, c = 23.430 (3) Å,
b = 93.330 (8)°, V = 3450 (4) Å3, F(000) = 1592.00,
m(MoKa) = 13.31 cm–1, R = 0.050, Rw = 0.056.
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2110
N. Kato et al.
LETTER
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5.25 (s, 1 H, H-8), 6.16 (t, 1 H, J = 2.6 Hz, H-12), 6.25 (td, 1
H, J = 7.2, 2.1 Hz, H-13), 6.40 (br t, 1 H, J = 7.2 Hz, NH),
6.66 (d, 1 H, J = 8.3 Hz, H-4¢), 6.91 (d, 1 H, J = 8.3 Hz, H-
5¢). 13C NMR (125 MHz, CDCl3): d = 27.64 (acetonide Me),
27.90 (acetonide Me), 29.00 (C7¢), 34.61 (C8¢), 37.18 (C14),
39.43 (C11), 55.61 (OMe), 66.07 (C5), 76.84 (C8), 81.71
(C10), 89.23 (C6), 93.96 (C7), 94.90 (C3), 95.87 (C2),
101.35 (C9), 109.21 (C4¢), 112.06 (acetonide C), 125.90
(C5¢), 125.96 (C1), 127.01 (C1¢), 128.93 (C-13), 129.24
(C6¢), 131.42 (C-4), 138.75 (C12), 141.22 (C2¢), 152.13
(C3¢), 171.27 (C9¢). ESI-TOFMS (positive-ion): calcd for
C27H26ClNO6H [M + H]+: 496.1527; found: 496.15; calcd
for C27H26ClNO6NH4 [M + NH4]+: 513.1792; found 513.17.
(18) NMR and MS data for 10: 1H NMR (500 MHz, CDCl3): d =
1.45 (s, 3 H), 1.49 (s, 3 H), 2.56 (m, 1 H, H-8¢), 2.71 (ddd, 1
H, J = 19.3, 2.6, 1.3 Hz, H-11), 2.91–3.07 (m, 4 H, 2 × H-7¢,
H-8¢, H-11), 3.42 (dtd, 1 H, J = 14.6, 7.2, 1.6 Hz, H-14), 3.82
(s, 3 H, C3¢-OMe), 4.00 (dt, 1 H, J = 14.6, 7.2 Hz, H-14),
5.01 (br s, 1 H, H-5), 5.11 (br dd, 1 H, J = 6.6, 1.3 Hz, H-10),
Synlett 2004, No. 12, 2107–2110 © Thieme Stuttgart · New York