Analogues of bleomycin: Synthesis of conformationally rigid methylvalerates

Article abstract of DOI:10.1021/ol010139u

(equation presented) Several conformationally rigid analogues of the methylvalerate subunit contained within the linker domain of the antitumor antibiotic bleomycin have been prepared. These compounds have been protected in a fashion suitable for the solid-phase synthesis of bleomycin. Bleomycin congeners containing these analogues should facilitate a more detailed understanding of the nature of the conformational bend that the methylvalerate moiety is thought to impart to the natural product.

Full text of DOI:10.1021/ol010139u

ORGANIC
LETTERS
2
001
Vol. 3, No. 18
867-2869
Analogues of Bleomycin: Synthesis of
Conformationally Rigid Methylvalerates
2
Michael J. Rishel and Sidney M. Hecht*
Departments of Chemistry and Biology, UniVersity of Virginia,
CharlottesVille, Virginia 22901
sidhecht@Virginia.edu
Received June 20, 2001
ABSTRACT
Several conformationally rigid analogues of the methylvalerate subunit contained within the linker domain of the antitumor antibiotic bleomycin
have been prepared. These compounds have been protected in a fashion suitable for the solid-phase synthesis of bleomycin. Bleomycin
congeners containing these analogues should facilitate a more detailed understanding of the nature of the conformational bend that the
methylvalerate moiety is thought to impart to the natural product.
5
The study of peptides containing unnatural â and γ amino
acids has been the topic of several recent investigations.
action have been studied intensively for more than 30 years.
Until recently, the role of the linker domain of bleomycin
1
,2
6
It has been shown that short peptides composed of â or γ
amino acids have well-defined secondary structures, even
in relatively polar solvents. Secondary structural predisposi-
tions of molecules composed entirely or in part of â or γ
amino acid constituents are actually precedented in nature.
For example, â-hydroxy-γ-amino acids are a class of amino
acids that can be found as structural components of a number
of natural products having interesting biochemical and
was poorly understood. Recent studies have suggested that
(
3) (a) Narita, M.; Otsuka, M.; Kobayashi, S.; Ohno, M.; Umezawa, Y.;
Morishima, H.; Saito, S.; Takita, T.; Umezawa, H. Tetrahedron Lett. 1982,
2
3, 525-528. (b) Castej o´ n, P.; Moyano, A.; Peric a` s, M. A.; Riera, A.
Tetrahedron 1996, 52, 7063-7086. (c) Xiao, D.; Carroll, P. J.; Mayer, S.
C.; Pfizenmeyer, A. J.; Joulli e´ , M. M. Tetrahedron: Asymmetry 1997, 8,
3
043-3046. (d) Hutchinson, T. L.; Saeed, A. S.; Wolkowicz, P. E.;
McMillin, J. B.; Brouillette, W. J. Bioorg. Med. Chem. 1999, 7, 1505-
511.
4) (a) Takita, T.; Umezawa, Y.; Saito, S.; Morishima, H.; Naganawa,
H.; Umezawa, H.; Tsuchiya, T.; Miyake, T.; Kageyama, S.; Umezawa, S.;
Muraoka, Y.; Suzuki, M.; Otsuka, M.; Narita, M.; Kobayashi, S.; Ohno,
M. Tetrahedron Lett. 1982, 23, 521-524. (b) Aoyagi, Y.; Katano, K.;
Suguna, H.; Primeau, J.; Chang, L.-H.; Hecht, S. M. J. Am. Chem. Soc.
1982, 104, 5537-5538. (c) Boger, D. L.; Honda, T. J. Am. Chem. Soc.
1994, 116, 5647-5656. (d) Katano, K.; An, H.; Aoyagi, Y.; Overhand,
M.; Sucheck, S. J.; Stevens, W.; Hess, C. D.; Zhou, X.; Hecht, S. M. J.
Am. Chem. Soc. 1998, 120, 11285-11296.
(5) (a) Natrajan, A.; Hecht, S. M. In Molecular Aspects of Anticancer
Drug-DNA Interactions; Neidle, S., Waring, M. J., Eds.; MacMillan
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Ed. 1999, 38, 449-476.
1
(
3
biological properties. Among these are the bleomycin group
4
antibiotics (Figure 1) whose synthesis and mechanism of
(
1) (a) Jacobi, A.; Seebach, D. HelV. Chim. Acta 1999, 82, 1150-1172.
b) Abele, S.; V o¨ gtli, K.; Seebach, D. HelV. Chim. Acta 1999, 82, 1539-
558. (c) Seebach, D.; Schreiber, J. V.; Abele, S.; Daura, X.; van Gunsteren,
(
1
W. F. HelV. Chim. Acta 2000, 83, 34-57. (d) Abele, S.; Seebach, D. Eur.
J. Org. Chem. 2000, 1-15.
(
2) (a) Hanessian, S.; McNaughten-Smith, G.; Lombart, H.-G.; Lubell,
W. D. Tetrahedron 1997, 53, 12789-12854. (b) Hanessian, S.; Luo, X.
H.; Schaum, R.; Michnick, S. J. Am. Chem. Soc. 1998, 120, 8569-8570.
(
4
c) Hanessian, S.; Luo, X. H.; Schaum, R. Tetrahedron Lett. 1999, 40,
925-4929.
1
0.1021/ol010139u CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/10/2001

Figure 1. Structure and functional domains of the bleomycin group antibiotics.
the (2S,3S,4R)-4-amino-3-hydroxy-2-methylpentanoic acid
methylvalerate) and S-threonine moieties are important for
aldehydes,10 10 was not stored for longer than 2-3 days at
(
-20 °C. Condensation of 10 with the acyloxazolidinone 1111
at -78 °C in the presence of dibutylborontriflate and Hunig’s
the activity of bleomycin and that they impart a characteristic
secondary structure to bleomycin that has a marked effect
on the efficiency with which the agent is able to cleave DNA.
On the basis of these findings, a set of conformationally rigid
methylvalerate analogues has been designed that should
facilitate an understanding of the secondary structure imposed
by the linker region of bleomycin (Figure 2). These analogues
can also be used to construct resin-bound combinatorial
libraries of BLM analogues, based on our solid-phase
1
2
base permitted synthesis of the aldol product 12 in 48%
yield. Using Grubbs’ catalyst, bis(tricyclohexylphosphine)-
1
3
benzylidene ruthenium(IV) dichloride, ring closure gave
the conformationally constrained intermediate 13. From this
intermediate two routes were pursued. First, the chiral
6
c
auxiliary could be removed using LiOOH, followed by
conversion of the amine protective moiety from Boc to Fmoc
to permit utilization of this amino acid analogue (3) in solid-
phase bleomycin synthesis. Alternatively, hydrogenation of
endocyclic olefin 13 over 5% Pt/C effected conversion to
saturated analogue 14. Removal of the chiral auxiliary from
14, and conversion of the amine protecting group from Boc
to Fmoc, provided analogue 1 in 9% overall yield. It was
found that representative derivatives could be utilized readily
in the solid-phase synthesis of deglycoBLM analogues.
7
methodology for the synthesis of deglycobleomycins. Scheme
1
details the strategy used for the synthesis of methylvalerate
analogues 1-8, as exemplified by the syntheses of 1 and 3.
Boc-protected R-allylglycine was converted to the respective
8
Weinreb amide. Reduction of 9 was achieved readily by
9
treatment with lithium aluminum hydride. Due to the well-
R
documented configurational instability of N -Boc amino-
Figure 2. Conformationally rigid methylvalerate analogues synthesized for incorporation into bleomycin congeners.
868 Org. Lett., Vol. 3, No. 18, 2001
2

Scheme 1. Synthesis of Conformationally Constrained Methylvalerate Analogues
Analysis of the conformations of 1-8 in the context of
5
fact, the synthesis of a deglycobleomycin A analogue that
an analysis of the conformation of the methylvalerate moiety
incorporated 2 within the structure afforded a species capable
6
2+
in bleomycin suggested that 2 has a conformational bias
of relaxing supercoiled plasmid DNA in the presence of Fe
most closely approximating that of the natural product. In
2 5
+ O , albeit less effectively than deglycoBLM A (data not
shown).
(6) (a) Owa, T.; Haupt, A.; Otsuka, M.; Kobayashi, S.; Tomioka, N.;
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Acknowledgment. This work was supported by a Na-
tional Institutes of Health Research Grant (CA77284),
awarded by the National Cancer Institute.
Supporting Information Available: Experimental pro-
(7) Leitheiser, C. J.; Rishel, M. J.; Wu, X.; Hecht, S. M. Org. Lett. 2000,
cedures and full characterization for the compounds shown
2
, 3397-3399.
1
in Scheme 1 including H NMR, optical rotary, and low-
(
(
(
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OL010139U
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1
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