Internal amide-triggered cycloaromatization of maduropeptin-like nine-membered enediyne

Article abstract of DOI:10.1039/b811355f

In the Masamune-Bergman cyclization of a nine-membered non-conjugated enediyne with an internal, maduropeptin-like nucleophile, the exocyclic alkene migrated to form the nine-membered conjugated enediyne, triggered by the intramolecular addition of the amide group; final aromatized products showed up to 85% yield. The Royal Society of Chemistry.

Full text of DOI:10.1039/b811355f

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Internal amide-triggered cycloaromatization of maduropeptin-like
nine-membered enediyne
Yutaro Norizuki,a Kazuo Komano,a Itaru Sato*b and Masahiro Hirama*a
Received (in Cambridge, UK) 3rd July 2008, Accepted 29th July 2008
First published as an Advance Article on the web 15th September 2008
DOI: 10.1039/b811355f
In the Masamune–Bergman cyclization of a nine-membered non-
conjugated enediyne with an internal, maduropeptin-like nucleo-
phile, the exocyclic alkene migrated to form the nine-membered
conjugated enediyne, triggered by the intramolecular addition
of the amide group; final aromatized products showed up to
85% yield.
Maduropeptin was isolated from the broth filtrate of
actinomadura madurae in 1991 by the scientists of Bristol-
Myers Squibb.1,2 Maduropeptin is a novel member of the
family of chromoprotein antitumor antibiotics, consisting of a
1 : 1 complex of a nine-membered enediyne chromophore and
a carrier apoprotein. The chromophore was isolated as solvent
artifacts 1a–d at the C-5 position along with an aromatized
dihydroindene 2 (Fig. 1).1b,3,4 The activity of methanol adduct
1a was similar to that of the maduropeptin holoprotein, but
100 times smaller.1c It was proposed that the addition of
methanol is reversible1b,c and that 1a undergoes intramole-
cular addition of the lactam nitrogen to the exo-olefin, causing
a vinylogous elimination of methanol. This results in forma-
tion of the conjugated enediyne and an aziridine functionality
(3). The strained nine-membered enediyne equilibrates with its
p-benzyne biradical form, which can abstract hydrogen from
double stranded DNA in tumor cells.2,4 Other than these
synthetic studies toward 1a,5,6 only model studies on the above
allylic rearrangement for acyclic7 and ten-membered cyclic8
compounds have been reported.
Fig. 1 Proposed structure and reaction mechanism of maduropeptin
chromophore.
Staudinger reaction and subsequent condensation with penta-
fluorophenyl ester 11 gave an amide.5b Acid hydrolysis of the
p-methoxybenzylidene acetal gave diol 12. The bis-p-trifluoro-
methylbenzoate of 12 was converted into the olefin (E/Z =
6 : 1) 13 via SmI2-mediated reductive elimination.12 The
geometry of the C4,13-exo double bond was unambiguously
determined by comparison of NOE experiments on the
isomers of 13. Separation of the E/Z-isomers and oxidative
cleavage of the NAP ether afforded the non-conjugated
enediynes C4,13-E-14 and C4,13-Z-14, respectively, which
correspond to the maduropeptin chromophore artifact 1c.
With the successfully synthesized non-conjugated enediynes
in hand, allylic rearrangement and cycloaromatization reactions
were examined. When C4,13-E-14 was treated with methane-
sulfonyl chloride in the presence of triethylamine in CH2Cl2 at
0 1C, the conjugated enediyne (13S)-15 was produced within
5 min (Scheme 2). The characteristic olefin proton H-5 appeared
as a singlet at d 5.80. The spectral data indicated formation of
the 1,3-oxazoline via O-attack of the amide13,14 instead of the
formation of a strained N-acyl aziridine,13a,15 which could be
produced by N-attack of the amide.16 The preferred mode of the
cyclization is common in nucleophilic substitution of amides,14
and was contrary to the degradation product (2) of maduro-
peptin chromophore. The peculiar fashion shown in 2 was
Here we describe the first internal amide-triggered cyclo-
aromatization of a nine-membered cyclic enediyne 14. The
enantiomerically pure 14 was synthesized as shown in
Scheme 1.6 Hagihara–Sonogashira coupling between vinyl
triflate 5 and terminal alkyne 6 gave 7 in 89% yield after
removal of a carbon-bound trimethylsilyl group. Oxidation of
the primary hydroxyl group provided aldehyde 8. An intra-
molecular acetylide–aldehyde condensation reaction utilizing
CeCl3/lithium disilazide proceeded smoothly and 9 was iso-
lated as a single isomer.6,9,10 After the newly formed hydroxyl
group was protected as a 2-naphthylmethyl (NAP) ether, the
TBS ether was cleaved to give the primary alcohol 10.
The hydroxyl group was converted to an azide by the
Bose–Mitsunobu procedure using the Shioiri reagent.11
A
a Department of Chemistry, Graduate School of Science, Tohoku
University, Sendai, 980-8578, Japan.
E-mail: hirama@mail.tains.tohoku.ac.jp; Fax: +81-22-795-6566
b Research and Analytical Center for Giant Molecules, Graduate
School of Science, Tohoku University, Japan.
E-mail: isato@mail.tains.tohoku.ac.jp
ꢀc
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Scheme 1 Reagents and conditions: (a) Pd(PPh)4 (5 mol%), CuI, i-Pr2NEt, 2,6-lutidine, DMF, 0 1C; (b) K2CO3, MeOH, 89% (2 steps); (c)
Dess–Martin periodinane, NaHCO3, CH2Cl2; (d) CeCl3, LiN(SiMe2Ph)2, THF (35 mM), ꢁ40 1C; (e) 2-naphthylmethyl bromide, NaH, THF; (f)
Bu4NF, THF, 51% (4 steps); (g) (PhO)2P(O)N3, DEAD, PPh3, THF, 94%; (h) 11, PPh3, Et3N, THF, H2O, rt to 40 1C, 76%; (i) PPTS, TsOH,
MeOH, 81%; (j) p-CF3C6H4COCl, DMAP, CH2Cl2, 0 1C, 79%; (k) SmI2, THF, 10 min then separation, 60% for C4,13-E-13, 10% for C4,13-Z-
13; (l) DDQ, CH2Cl2, pH 7 buffer, 80% for C4,13-E-14, 76% for C4,13-Z-14.
Scheme 2 Cycloaromatization of enediyne 14 triggered by an internal nucleophile.
possibly due to the presence of an ansa-macrolide. The forma-
tion of 1,3-oxazoline from 1a reduces the ring size of the highly
strained ansa-macrolide and would increase unfavorable trans-
annular interaction. The diastereoface selectivity of the addition
to C13 was 8 : 1. It is noteworthy that enediyne (13S)-15 was
isolable by rapid silica gel chromatography.17 Treatment of the
nine-membered enediyne (13S)-15 with excess 1,4-cyclohexa-
diene in CH2Cl2 at room temperature afforded the cycloaroma-
tized product (13S)-18 in 85% yield from C4,13-E-14, via ready
hydrolysis of (13S)-17. The absolute configuration of C13
(S)-MTPA ester derivatives.18 Treatment of (13S)-15 with
methanol only gave a trace amount of 17 and 18. Under these
conditions, methanol adducts such as the one corresponding to
1a were not detected. The reaction with excess 1,4-cyclohexa-
diene in methanol or ethanol also did not give any alcohol
adducts and instead afforded the cycloaromatized products
(13S)-17 and (13S)-18 in a 19–27% combined yield. When
C4,13-Z-14 was mesylated in the presence of triethylamine in
CH2Cl2 at 0 1C, conjugated enediyne (13R)-15 was obtained.
Cycloaromatization of (13R)-15 in 1,4-cyclohexadiene–CH2Cl2
(1 : 1) at room temperature gave only (13R)-18. Thus, it is most
1
was determined to be S by H NMR analysis of its (R)- and
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likely that both E- and Z-14 underwent a concerted allylic
substitution reaction triggered by the internal amide nucleophile
in a stereospecific manner, i.e., anti-SN20 fashion. In experimen-
tal19 and theoretical20 studies on SN20 reactions without transi-
tion metals, syn/anti selectivity is often controlled by the
attractive and/or repulsive interaction between a nucleophile
and a leaving group. The anti-selective outcome in our model
system is attributed to the steric repulsion between the leaving
mesylate and the amide anion and/or the electrostatic repulsion
between these two groups in non-polar solvents.
Iida, I. Sato, F. Yoshimura, T. Usuki and S. Tero-Kubota,
Heterocycles, 2006, 69, 83, and references therein.
5 (a) K. Iso, M. Inoue, N. Kato and M. Hirama, Chem.–Asian J.,
2008, 3, 447; (b) N. Kato, S. Shimamura, Y. Kikai and M. Hirama,
Synlett, 2004, 2107; (c) N. Kato, S. Shimamura, S. Khan, F.
Takeda, Y. Kikai and M. Hirama, Tetrahedron, 2004, 60, 3161;
(d) S. Khan, N. Kato and M. Hirama, Synlett, 2000, 1494; (e) C.
Roger and D. S. Grierson, Tetrahedron Lett., 1998, 39, 27; (f) J.
Suffert and D. Toussaint, Tetrahedron Lett., 1997, 38, 5507; (g) K.
C. Nicolaou, K. Koide, J. Xu and M. H. Izraelewicz, Tetrahedron
Lett., 1997, 38, 3671; (h) K. C. Nicolaou, K. Koide and H.
Khatuya, Tetrahedron Lett., 1997, 38, 3667; (i) P. Magnus, R.
Carter, M. Davies, J. Elliott and T. Pitterna, Tetrahedron, 1996, 52,
6283.
In conclusion, we successfully synthesized a non-conjugated
nine-membered enediyne possessing an amide as an internal
nucleophile, which corresponds to the maduropeptin chromo-
phore artifacts. For the first time, we demonstrated that an
intramolecular nucleophilic substitution reaction provided a nine-
membered conjugated enediyne and subsequent Masamune–
Bergman cyclization gave cycloaromatized products with up to
85% yield. The results would also be expedient for designing a
prodrug system of labile enediynes.
6 K. Komano, S. Shimamura, M. Inoue and M. Hirama, J. Am.
Chem. Soc., 2007, 129, 14184.
7 (a) W.-M. Dai, K. C. Fong, H. Danjo and S. Nishimoto, Angew.
Chem., Int. Ed. Engl., 1996, 35, 779; (b) W.-M. Dai, J. Wu, K. C.
Fong, M. Y. H. Lee and C. W. Lau, J. Org. Chem., 1999, 64, 5062.
8 (a) Y. Tachi, W.-M. Dai, K. Tanabe and S. Nishimoto, Bioorg.
Med. Chem., 2006, 14, 3199; (b) A. Poloukhtine and V. V. Popik,
J. Org. Chem., 2005, 70, 1297; (c) W.-M. Dai, K. C. Fong, C. W.
Lau, L. Zhou, W. Hamaguchi and S. Nishimoto, J. Org. Chem.,
1999, 64, 682.
9 (a) I. Sato, K. Toyama, T. Kikuchi and M. Hirama, Synlett, 1998,
1308; (b) K. Iida and M. Hirama, J. Am. Chem. Soc., 1994, 116,
10310; (c) A. G. Myers, P. M. Harrington and E. Y. Kuo, J. Am.
Chem. Soc., 1991, 113, 694; (d) T. Nishikawa, M. Isobe and T.
Goto, Synlett, 1991, 393.
This work was supported financially by a Grant-in-Aid for
Specially Promoted Research from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT) and by a
Grant-in-Aid from SORST, Japan Science and Technology
Agency (JST).
10 S. Masamune, J. W. Ellingboe and W. Choy, J. Am. Chem. Soc.,
1982, 104, 5526.
11 (a) B. Lal, B. N. Pramanik, M. S. Manhas and A. K. Bose,
Tetrahedron Lett., 1977, 18, 1977; (b) T. Shioiri, K. Ninomiya
and S. Yamada, J. Am. Chem. Soc., 1972, 94, 6203.
Notes and references
1 (a) M. Hanada, H. Ohkuma, T. Yonemoto, K. Tomita, M.
Ohbayashi, H. Kamei, T. Miyaki, M. Konishi, H. Kawaguchi
and S. Forenza, J. Antibiot., 1991, 44, 403; (b) D. R. Schroeder, K.
L. Colson, S. E. Klohr, N. Zein, D. R. Langley, M. S. Lee, J. A.
Matson and T. W. Doyle, J. Am. Chem. Soc., 1994, 116, 9351; (c)
N. Zein, W. Solomon, K. L. Colson and D. R. Schroeder,
Biochemistry, 1995, 34, 11591.
12 M. Inoue, I. Ohashi, T. Kawaguchi and M. Hirama, Angew.
Chem., Int. Ed., 2008, 47, 1777, and references therein.
13 (a) E. P. Pretsch, W. Simon, J. Seibl and T. Clerc, Tables of
Spectral Data for Structure Determination of Organic Compounds,
Springer-Verlag, New York, 2nd edn, 1989; (b) A. Padwa, J. R.
Gasdaska, M. Tomas, N. J. Turro, Y. Cha and I. R. Gould, J. Am.
Chem. Soc., 1986, 108, 6739.
2 (a) A. L. Smith and K. C. Nicolaou, J. Med. Chem., 1996, 39, 2103;
(b) Z. Xi and I. H. Goldberg, in Comprehensive Natural Product
Chemistry, ed. D. H. R. Barton and K. Nakanishi, Pergamon,
Oxford, 1999, vol. 7, p. 553; (c) M. Kar and A. Basak, Chem. Rev.,
2007, 107, 2861.
14 For examples, see: (a) J. Barluenga, J. M. Gonzalez, P. J. Campos
´
and G. Asensio, Tetrahedron Lett., 1988, 29, 6497; (b) M. C. Elliot
and E. Druiswijk, Chem. Commun., 1997, 2311; (c) J. Legters, L.
Thijs and B. Zwanenburg, Recl. Trav. Chim. Pays-Bas, 1992, 111,
16.
3 For related chromoprotein antibiotics, C-1027, see: (a) K.
Yoshida, Y. Minami, R. Azuma, M. Saeki and T. Otani, Tetra-
hedron Lett., 1993, 34, 2637; (b) K. Iida, T. Ishii, M. Hirama, T.
Otani, Y. Minami and K. Yoshida, Tetrahedron Lett., 1993, 34,
4079; (c) K. Iida, S. Fukuda, T. Tanaka, M. Hirama, S. Imajo, M.
Ishiguro, K. Yoshida and T. Otani, Tetrahedron Lett., 1996, 37,
4997; Kedarcidin: (d) J. E. Leet, D. R. Schroeder, S. J. Hofstead, J.
Golik, K. L. Colson, S. Huang, S. E. Klohr, T. W. Doyle and J. A.
Matson, J. Am. Chem. Soc., 1992, 114, 7946; (e) S. Kawata, S.
Ashizawa and M. Hirama, J. Am. Chem. Soc., 1997, 119, 12012; (f)
F. Ren, P. C. Hogan, A. J. Anderson and A. G. Myers, J. Am.
Chem. Soc., 2007, 129, 5381.
4 For the structure and reactivity of nine-membered enediynes, see:
(a) K. Iida and M. Hirama, J. Am. Chem. Soc., 1995, 117, 8875; (b)
M. Hirama, Pure Appl. Chem., 1997, 69, 525; (c) T. Usuki, T. Mita,
M. J. Lear, P. Das, F. Yoshimura, M. Inoue, M. Hirama, K.
Akiyama and S. Tero-Kubota, Angew. Chem., Int. Ed., 2004, 43,
5249; (d) M. Hirama, K. Akiyama, P. Das, T. Mita, M. J. Lear, K.
15 H. Stamm, A. Sommer, A. Woderer, W. Weisert, T. Mall and
P. Assithianakis, J. Org.Chem., 1985, 50, 4946.
16 P. Wipf and C. P. Miller, Tetrahedron Lett., 1992, 33, 907.
17 The observed stability of the bicyclo[7.3.0]dodecadienediyne
system was comparable to our recent model (ref. 4a). The
facile formation of enediyne 15 allowed its isolation and characteri-
zation.
18 I. Ohtani, T. Kusumi, Y. Kashman and H. Kakisawa, J. Am.
Chem. Soc., 1991, 113, 4092.
19 For selected examples, see: (a) A. Claesson and L. I. Olsson, J. Am.
Chem. Soc., 1979, 101, 7302; (b) G. Stork and A. F. Kreft, J. Am.
Chem. Soc., 1977, 99, 3851; (c) G. Cardillo, S. Fabbroni, L.
Gentilicci, R. Perciaccante, F. Piccinelli and A. Tolomelli, Org.
Lett., 2005, 7, 533Review: (d) R. M. Magid, Tetrahedron, 1980, 36,
1901.
20 (a) B. L. Kormos and C. J. Cramer, J. Org. Chem., 2003, 68, 6375,
and references therein; (b) R. D. Bach and G. J. Wolber, J. Am.
Chem. Soc., 1985, 107, 1352.
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5374 | Chem. Commun., 2008, 5372–5374