Convergent synthesis of a complex oxime library using chemical domain shuffling

Article abstract of DOI:10.1021/ol051023r

(Chemical Equation Presented) The synthesis of a complex hybrid oxime library is reported utilizing convergent ligation of alkoxyamine and carbonyl monomers via "chemical domain shuffling". Initial biological screening of the library against human small cell lung carcinoma (A549) cells led to the identification of a novel hybrid dimer in contrast to the corresponding monomeric compounds which were found to be inactive.

Full text of DOI:10.1021/ol051023r

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2751-2754
Convergent Synthesis of a Complex
Oxime Library Using Chemical Domain
Shuffling
Shun Su, Dayle E. Acquilano, Jeevanandam Arumugasamy, Aaron B. Beeler,
Erin L. Eastwood, Joshua R. Giguere, Ping Lan, Xiaoguang Lei, Geanna K. Min,
Adam R. Yeager, Ya Zhou, James S. Panek, John K. Snyder,
Scott E. Schaus,* and John A. Porco, Jr.*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment, Boston UniVersity, 590 Commonwealth AVenue,
Boston, Massachusetts 02215
porco@bu.edu; seschaus@bu.edu
Received May 4, 2005
ABSTRACT
The synthesis of a complex hybrid oxime library is reported utilizing convergent ligation of alkoxyamine and carbonyl monomers via “chemical
domain shuffling”. Initial biological screening of the library against human small cell lung carcinoma (A549) cells led to the identification of
a novel hybrid dimer in contrast to the corresponding monomeric compounds which were found to be inactive.
The synthesis of chemical libraries rich in structural diversity
is an emerging field with immediate applications in biomedi-
cal research.1 Strategies for library synthesis have mainly
focused on combinatorial synthesis of molecules that vary
substituents on a core structural type.2 Diversity-oriented
synthesis is a new strategy for constructing libraries with
both skeletal and functional group diversity.3 In an effort to
formulate novel approaches to complex library synthesis, we
have taken a number of lessons from biologically active,
hybrid molecules4 (Figure 1). For example, thiomarinol (1),5
a natural product hybrid of pseudomonic acid and the
pyrrothine antibiotic holothin, displays more potent antimi-
(1) Recent reviews: (a) Ortholand, J. Y.; Ganesan, A. Curr. Opin. Chem.
Biol. 2004, 8, 271-280. (b) Boldi, A. M. Curr. Opin. Chem. Biol. 2004, 8,
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7, 631-643.
(2) (a) Dolle, R. E. J. Comb. Chem. 2003, 5, 693-753. (b) Dolle, R. E.
J. Comb. Chem. 2004, 6, 623-679.
(3) (a) Schreiber, S. L. Science 2000, 287, 1964-1969. (b) Liao, Y.;
Hu, Y.; Wu, J.; Zhu, Q.; Donovan, M.; Fathi, R.; Yang, Z. Curr. Med.
Chem. 2003, 10, 2285-2316. (c) Burke, M. D.; Schreiber, S. L. Angew.
Chem., Int. Ed. 2004, 43, 46-58. (d) Arya, P.; Joseph, R.; Gan, Z.; Rakic,
B. Chem. Biol. 2005, 12, 163-180.
Figure 1. Hybrid molecules with variable chemical domains.
10.1021/ol051023r CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/21/2005

crobial activity than either of the parent fragments. The
potential for hybrid molecules to possess enhanced biological
activity is also supported by the recent preparation of
synthetic hybrid molecules.6 For example, a quinacrine-
netropsin hybrid molecule 2 was found to enhance C1027-
induced DNA cleavage by combining the DNA sequence
selectivity of netropsin and the cell permeability and DNA
binding affinity of quinacrine to sensitize DNA toward
C1027 cleavage.7 Further examination of hybrid molecular
structures illustrates the interchange of discrete chemical
domains. For example, the natural product fissistigmatin A
(3)8 is a eudesmane-flavone hybrid, whereas the fungal toxin
(4)9 is a eudesmane-peptide hybrid natural product. In
addition, the CDK inhibitor flavopyridol (5)10 has identifiable
flavone and piperidyl domains. Inspired by these and related
hybrid molecules, we have considered a convergent11 ap-
proach to library synthesis involving “chemical domain
shuffling”. In this approach, discrete fragments or “chemical
domains” may be “shuffled”12 to prepare complex hybrid
structures (Scheme 1). Herein, we report the successful
implementation of this approach in the construction of a
library of hybrid oximes13,14 from complex alkoxyamine and
carbonyl domains.
Scheme 1. Convergent Library Synthesis Using Chemical
Domain Shuffling
monomers included â-hydroxy alkoxyamines (6), pyrans (7-
10), carbohydrate-derived alkoxyamines (11 and 12), and
heterocyclic alkoxyamines13 (13-17). Carbonyl-containing
monomers included naphthyridines and pyridoazepines16
(18-21), complex pyrans (22-24), polyketide-like fragments
(25-27), angular scaffolds (28 and 29), benzopyrans (30),
and pipecolate esters17 (31).
Representative monomer syntheses are illustrated in
Scheme 2 (a-d). Starting from the readily available furan-
containing epoxide 32,18 phthalimide-protected alkoxyamine
33 was prepared in high yield and excellent optical purity
(95% ee) under the mediation of a Co-oligosalen catalyst.19
Subsequent phthalimide deprotection using PS-ethylenedi-
amine20 afforded alkoxyamine 13 without further purification.
For the synthesis of naphthyridine-containing ketone 18,
CpCo(CO)2-catalyzed21 intermolecular [2 + 2 + 2] cyclo-
condensation of alkynyl nitrile 3422 and diphenylacetylene
35 was conducted to afford naphthyridine 36. Yb(OTf)3-
mediated23 Michael addition of 36 to methyl vinyl ketone
provided the desired â-amino ketone 18. To prepare
polyketide-like alkoxyamine 6 and aldehyde 27, a three-
component asymmetric crotylation24 of aldehyde 37, silyl
ether 38, and chiral silane 39 was employed to prepare
To demonstrate convergent synthesis of a complex hybrid
oxime library using chemical domain shuffling, we prepared
26 monomer fragments emphasizing both structural and
stereochemical complexity. Approximately 10 chemotypes
were represented per monomer set (Figure 2).15 Alkoxyamine
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1842.
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Wulff, C.; Schubert, I.; Rubeling, A. Angew. Chem., Int. Ed. 1998, 37,
2469-2470. (c) Tietze, L. F.; Schneider, G.; Wolfling, J.; Fecher, A.; Nobel,
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3760. (d) Hoppen, S.; Emde, U.; Friedrich, T.; Grubert, L.; Koert, U. Angew.
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Org. Lett., Vol. 7, No. 13, 2005

Figure 2. Alkoxyamine and carbonyl fragments utilized in chemical domain shuffling.
homoallylic ether 40. Ozonolysis of 40, followed by reduc-
tion using NaBH4, afforded alcohol 41. This central inter-
mediate was subjected to N-alkoxyphthalimide formation
using Mitsunobu conditions, followed by phthalimide depro-
tection,20 to afford alkoxyamine 6. Alternatively, TPAP-
mediated25 oxidation of 41 afforded aldehyde 27, illustrating
the use of a common building block for alternate preparation
of carbonyl and alkoxyamine domain monomers. For prepa-
ration of alkoxyamine 7 and ketone 22, allylic carbonate 43
was generated employing palladium-catalyzed addition of
phenyl boronic acid to glycal 42.26 Diastereoselective phenol
addition (Pd2(dba)3‚CHCl3, (1S,2S)-(-)-1,2-diaminocyclo-
hexane-N,N′-bis-(2′-diphenylphosphinobenzoyl)),27 followed
by desilylation, provided alcohol 44. The stereochemical
assignment of 44 was based on X-ray crystallographic
analysis of a related derivative.15 Primary alcohol 44 was
transformed to the corresponding alkoxyamine 7 and keto
ester 22, the latter via acylation with levulinic acid.
Scheme 2. Representative Monomer Syntheses
Upon completion of the monomeric fragment syntheses,
we next evaluated the reactivity of carbonyl domain frag-
ments in oxime formation. All aldehydes and ketones 28 and
29 were found to smoothly condense with O-benzylhydroxy-
lamine at rt using 20 mol % of AcOH in EtOAc. For
monomer 29, the amount of alkoxyamine was limited to 1.0
equivalent in order to prevent epoxide ring-opening. Con-
densation of most ketone monomers with O-benzylhydroxy-
lamine was effected within 20 min using microwave
irradiation28 (EtOAc, 20 mol % AcOH, 100 °C). However,
for benzopyran 30, PPTS (20 mol %) was required for oxime
formation (microwave, 130 °C, EtOAc). The unreactive
benzopyran 30 was selected to test the reactivity of complex
alkoxyamine monomers. After reaction optimization, most
oximes were found to cleanly condense with 30 in THF at
110 °C using PPTS as catalyst. Acetic acid was used in
(24) Panek, J. S.; Yang, M.; Xu, F. J. Org. Chem. 1992, 57, 5790-
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Org. Lett., Vol. 7, No. 13, 2005
2753

Scheme 3. Representative Complex Oxime Syntheses
reactions with alkoxyamine 12 to avoid decomposition. An
analytical scale rehearsal employing one alkoxyamine and
five ketones (3.0 µmol of ketone) was performed to further
evaluate optimized conditions for complex oxime forma-
tion.15 Polymer-supported methylisatoic anhydride (PL-
MIA)29 was utilized to scavenge excess alkoxyamines.
Following the optimized oxime formation conditions, greater
than 95% purity was obtained for all 5 hybrid oximes
synthesized in the analytical rehearsal after resin scavenging.
Preparative-scale (0.019 mmol) library synthesis was next
conducted using chemical domain shuffling of a 14 × 12
array of monomers to produce a library of 168 complex
hybrid oximes. Representative conditions for oxime forma-
tion reactions are shown in Scheme 3. After scavenging with
PL-MIA resin, 161 products (96%) were found to have
purities greater than 95% as indicated by HPLC-ELSD
analysis (isolated yields 49%-99%, 160 reactions >85%).
Representative library members are shown in Figure 3 and
illustrate ligation between pyran-polyketide (45), bis-pyran
(46 and 48), 1,5-naphthyridine-triazole (53), and benzo-
pyran-triazole (56) domains. 1H NMR analysis of randomly
selected library members (Figure 3) indicates that a signifi-
cant number of hybrid oximes exist as inseparable mixtures
of E/Z isomers.15 The corresponding acetone oximes of
alkoxyamine monomers and the O-methylhydroxylamine
oximes of the ketone/aldehyde monomers were also prepared
for comparison to hybrid dimers in subsequent biological
screening.
The 168-member library and 26 monomer derivatives were
assayed for human small cell lung carcinoma (A549) growth
inhibition. Previous studies have reported the rapid isomer-
ization of aldehyde-derived oximes in polar media, which
should permit selection of the most active oxime isomer by
biological targets of interest.14g Compound 47 (Figure 3) was
found to inhibit growth of A549 cells with an IC50 value of
6.2 µM. Interestingly, the corresponding monomeric acetone
oxime of 16 and O-methylhydroxylamine oxime of 29 ex-
hibited no antiproliferative activity. This preliminary result
indicates that ligation of two discrete chemical domains may
be used to generate complex structures with novel biological
activities.4,6
Figure 3. Representative library members.
developed approach for library synthesis involving inter-
change of chemical motifs through convergent ligation.
Further biological evaluation of the complex oxime library
and additional applications of chemical domain shuffling to
generate complex chemical libraries which address novel
chemical space30 are currently in progress
Acknowledgment. Financial support from the NIGMS
CMLD initiative (P50 GM067041) is gratefully acknowl-
edged. We thank Synthematix, Inc., for assistance with
chemical reaction planning software, AutoChem (Millers-
ville, MD), Waters Corp. (Milford, MA), and CEM Corp.
(Matthews, NC) for assistance with instrumentation, and Dr.
Michael Creech (Boston University) for high-resolution mass
spectroscopy.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds
including X-ray crystal structure coordinates. X-ray crystal-
lographic files (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
OL051023R
In summary, we have successfully synthesized a complex
oxime library via “chemical domain shuffling”, an under-
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