Generation of libraries of pharmacophoric structures with increased complexity and diversity by employing polymorphic scaffolds

Article abstract of DOI:10.1002/1521-3773(20021004)41:19<3677::AID-ANIE3677>3.0.CO;2-Y

Antimicrobials, antifungals, anticoccidials, pesticides, and herbicides - druglike scaffolds with potential applications such as these are provided by a combinatorial library containing oxazolediones, naphthoquinones, thiazinones, and diazepinones which w

Full text of DOI:10.1002/1521-3773(20021004)41:19<3677::AID-ANIE3677>3.0.CO;2-Y

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of libraries∫[6] of scaffolds resembling evolution-selected
molecules like natural products or drugs.
Generation of Libraries of Pharmacophoric
Structures with Increased Complexity and
Diversity by Employing Polymorphic Scaffolds
Libraries are mainly based on a core molecule that is
subjected to functional group manipulation which leads to a
number of derivatives with the same central structure. Several
versatile molecules that were key intermediates used by
traditional medicinal chemists, for example, Corey©s lactone,
the Wieland Miescher ketone, and the Prelog Djerassi
lactone, could lead to a variety of apparently unrelated
pharmacophoric frameworks. These starting materials are
small molecules equipped with many reactive sites and
functionalities, which can undergo both skeletal rearrange-
ments and functional group interconversions. The use of such
a polymorphic compound as the cornerstone of a library
would be of great advantage since: 1) Many known synthetic
key intermediates lead to medicinally important or ™privi-
leged∫ scaffolds; 2) they possess high potential for both
structural and functional diversification; 3) their chemical
transformations and modifications in solution are well docu-
Elias A. Couladouros* and Alexandros T. Strongilos
During the last decade we have witnessed the emergence of
combinatorial chemistry as a tool for the discovery of new
lead compounds.[1] Outstanding examples of sophisticated
directed libraries have been reported, including pharmaco-
phoric scaffolds,[2] bioactive metabolites,[2] designed ™unnatu-
ral∫, diversity-oriented, pharmacophore-like, rigid, and ver-
satile structures,[3] and even natural products with highly
complex architectures.[4] The state-of-the-art in this field
combines three main features: 1) suitably functionalized
druglike ™privileged structures∫[5] having specific spatial
architecture and rigidity, 2) short synthetic pathways compris-
ing reliable, clean, and high-yielding reactions, and 3) an
overall ™diversification strategy∫ resulting ideally in ™libraries
aminosugars, thiosugars, sugaryl amino-
monosaccharides, KDO liposaccha-
acids, azasugars (e.g. indolizidines)
rides, glycosides, antibiotics (e.g.vineo-
mycin, aclacinomycin, nogalamycin)
OH
OH
R1
R2
R3
R1
R2
R3
NHR5
O
O
O
OH
R1
R2
O
annulated pyranosides
e.g. antibiotics
actinobolin and forskolin
penicillic acid
derivatives
OR4
OR4
O
OR4
(Wittig coupling)
Reaction with Michael
and/or sugaryl donors
O
O
chrysan-
themo
carboxylic
acids
R1
R2
R3
R1
X
R3
Other
reactions
Reaction with
dienes
R'
R''
O
O
O
antimicrobials
O
OR4
(cyclopropanation)
antifungals
R3
Conversion
R1
R2
anticoccidials
antitumors
Conversion
to levoglu-
cosenones
to other
synthetic
building
blocks
cardiac steroids
pesticides
O
1
herbicides
OR4
frontalin, multistriatin,
dissaccharides,
antibiotics
Conversion
to pyrones
Conversion to
polyhydroxyl-
ated chains
(e.g. tirantamycin)
O
Other
R1
R2
R3
R3
natural
R1
products
O
OH
O
O
O
O
O
OR4
cyclopentenones
R1
R2
R3
OH
R1
Prelog-Djerassi
lactone
R1
O
R2
e.g. mono-
crotalic acid
e.g. pseudomonic acid,
styryl lactones, asperlin,
spirolactone pheromones
and antibiotics
O
benzodiazepinones,
thiazepinones, etc.
macrolide and
ionophoric
antibiotics
O
butenolides
Figure 1. Representative reported derivatizations and applications of pyranone 1.
[*] Prof. Dr. E. A. Couladouros, A. T. Strongilos
Chemistry Laboratories, Agricultural University of Athens
Iera Odos 75, Athens 118 55 (Greece)
Fax : (þ 30)10-677-7849
mented; and 4) the pharmacological activity of their descend-
ing structures is well precedented.
To demonstrate the above concept, 2H-pyran-3(6H)-one
(1)[7,8] was selected from among several synthetic key inter-
mediates listed in the literature. As shown in Figure 1,
derivatives of pyranone 1 exhibit significant biological
activities, including antibacterial, antifungal, anticoccidial,
antiinflamatory, and anticancer properties. Besides serving as
intermediates in several natural product syntheses, such
E-mail: ecoula@chem.demokritos.gr
and
Organic and Bioorganic Chemistry Laboratory
NCSR ™Demokritos∫
153 10 Ag. Paraskevi, Athens (Greece)
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
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compounds have also acted as templates for the synthesis of
monosaccharides and glycosides. In addition, they undergo
skeletal rearrangements to yield a wide range of structures
ranging from polyhydroxylated chains and benzodiazepines to
butenolides and anthraquinones.
The primary concern and prerequisite for the effective use
of this molecule in combinatorial chemistry is the identifica-
tion of a suitable linker to attach the pyranone core on the
resin (9, Scheme 1). This linker should be able to withstand a
variety of chemical transformations, be cleavable under
specific, relatively mild conditions, and be compatible with
many functionalities. We tested several possibilities before we
selected an oxidatively cleavable aromatic ether (linker L,
Scheme 1). This linker was designed[9] to tolerate basic and
mildly acidic or oxidative conditions and be cleaved rapidly
upon treatment with DDQ or TFA. In the optimum loading
procedure the respective furyl alcohol (pyranone precursor)
was coupled with the linker and then loaded on Merrifield
resin by using Cs2CO3 (Scheme 1). Thus, furyl alcohol 3 was
prepared by conversion of allyl ether 2 into the corresponding
aldehyde, followed by addition of furyllithium. This alcohol,
after oxidation and subsequent derivatization with Grignard
reagents, was transformed into tertiary alcohols 4 (route A).
The latter, after desilylation, were loaded on the resin to
afford supported furyl alcohols 6, which were oxidized to 2H-
pyran-3(6H)-ones 9 in high yields following a slightly
modified reported protocol.[7c] Secondary alcohol 3 could also
be loaded on the resin in the same fashion after protection of
the hydroxy group (route B). Complicated substrates could
also be loaded by using an additional ™handle∫ on the side
chain (e.g., route C). Most of the compounds were cleaved
efficiently and isolated in satisfactory yields and purity;
cleavage conditions, yields, and purity are presented in
Table 1.
For the practical demonstration of the use of 2H-pyran-
3(6H)-ones 9 as key intermediates with great potential for
diversification we carried out a significant number of deriva-
tizations and transformations (Scheme 2). Upon treatment
with isocyanates they were converted into carbamates 10,
scaffolds known to show anticoccidial and antimicrobial
activities.[8a,b] These carbamates were treated with further
alcohols to give bioactive ethers 11 by using catalytic HClO4
or, under alkaline conditions, quantitatively converted into
pharmacophoric oxazolediones 12.[10] A patented procedure
was applied to convert substrates 12 into angiogenesis
inhibitor 13,[8k] albeit in low yield.
Further oxidation of substrate 9 with the Dess Martin
reagent afforded pyrones 14, which were transformed, after
reduction with NaBH4, into lactones 15. The latter may serve
as the core structures for the generation of new libraries since
they have many reactive sites for derivatization with either
nucleophilic or electrophilic reagents, as well as with dienes.
Moreover, pyrone 14, after treatment with several binucleo-
philes,[11] was transformed into medicinally important hetero-
cycles such as thiazinones 16, benzothiazinones 17, and
diazepinones 18. Pyranone 9 was also directly esterified (to
give 19) or etherified (to give 21). These classes of compounds
are known for their antimicrobial (against both Gram-positive
and Gram-negative bacteria), antifungal, pesticidal, and
anticoccidial activities.[8] Acetate 19 (R3 ¼ CH3) served as a
model glycosyl acceptor and was efficiently glycosylated with
6-O-methyl-2,3,4-triacetylglycopyranoside.[12] Methyl ether 21
(R5 ¼ CH3) was used as a Michael acceptor to yield deoxy-
sugar derivatives 22 and 23. The same substrate (21) was
reduced with NaBH4 and subsequently epoxidized to afford
epoxide 24, which was further derivatized to give sugar
derivatives 25.[7b,8l]
Scheme 1. Loading of pyranone precursors on resin. Reagents and
conditions: a) OsO4/NaIO4, THF/H2O 1:1; b) furyllithium, Et2O, 0 8C;
c) SO3¥py, DMSO/Et3N/CH2Cl2, 08C; d) RMgX, Et2O, 0 8C; e) Merrifield
resin, Cs2CO3, Bu4NI, CH2Cl2, 5 d; f) TBAF, THF, 08C; g) Ac2O, Et3N,
DMAP, CH2Cl2; h) MeONa, THF/MeOH 4:1, 258C, 8 h; i) Cs2CO3, Bu4NI,
608C, DMF; j) LiOH(aq)/THF/MeOH 1:1:1; k) NBS, THF/H2O 4:1 , !0
258C, 1h; l) DDQ, CH 2Cl2/H2O 18:2, 258C, 2 3 h, then aqueous ascorbic
acid or CH2Cl2/TFA 6:1, 258C, 8 10 h. TBS ¼ tert-butyldimethylsilyl, py ¼
pyridine, DDQ ¼ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, TBAF¼ tet-
rabutylammonium fluoride, DMAP ¼ 4-dimethylaminopyridine, NBS ¼ N-
bromosuccinimide, TFA ¼ trifluoroacetic acid.
Application of additional known transformations already
listed in Figure 1should lead efficiently to further structurally
diversified substrates. Furthermore, new reactions and novel
transformations might be applied on these highly reactive
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Table 1. Structures, cleavage conditions, yields, and purity of selected members of the library.
Substrate
Cleavage[a]
Structure
Substituents
Yield [%} (Purity [%])[b]
O
9
9
A
A
R ¼ Ph
95 (95)
85 (80)
R ¼ (CH2)9CH3
HO
O
R
R
R
O
O
O
OH
O
11
1
1
A
R ¼ Ph, R2 ¼ CH3
90 (85)
1
1
1
¼ Ph, R2 ¼ Bn
A
A
A
75 (80)
85 (85)
85 (85)
¼ Ph, R2 ¼ (CH2)7CH3
1
¼ (CH2)9CH3, R2 ¼ CH3
OR2
O
1
1
1
2
2
2
A
A
A
R ¼ Ph, R9 ¼ Bn
¼ Ph, R9 ¼ CH3R
90 (90)
90 (90)
90 (90)
HO
9
R9
¼ (CH2)9CH3, RR¼ CH3
N
O
O
1
1
6
6
B
B
H
N
R ¼ Ph
75 (pur.)
65 (pur.)
O
O
¼ (CH2)9CH3
R
R
HO
S
R OH
1
1
7
7
B
B
R ¼ Ph
¼ (CH2)9CH3
70 (pur.)
67 (pur.)
H
N
O
O
HO
O
S
R OH
O
1
1
1
1
1
9
9
9
9
9
A
A
A
A
A
R ¼ Ph, R3 ¼ C6H5
95 (95)
95 (95)
95 (95)
80 (85)
80 (85)
¼ Ph, R3 ¼ pNORC6H4
2
R
¼ Ph, R3 ¼ CH3R
O
3
¼ (CH2)9CH3, RR¼ pNO2C6H4
O
O
R3
3
¼ (CH2)9CH3, RR¼ C6H5
O
21A
21A
21A
R ¼ Ph, R5 ¼ CH3
95 (95)
90 (95)
85 (95)
R
R
¼ Ph, R5 ¼ CH2CH3
¼ (CH2)9CH3, R5 ¼ CH3
O
HO
HO
R
R
R
O
O
O
OR5
O
22
22
A
A
R ¼ Ph, R5 ¼ CH3, R6 ¼ S(CH2)3CH3
90 (95)
90 (95)
R ¼ (CH2)9CH3, R5 ¼ CH3, R6 ¼ S(CH2)3CH3
R6
OR5
OH
23
26
A
B
R ¼ Ph, R5 ¼ CH3, R6 ¼ N3
70 (80)
R6
R5
O
MeO OH OR5
O
R ¼ Ph, R5 ¼ CH3
80 (pur.)
R
OH
MeO OH O
[a] For details on the cleavage conditions and compound characterization see the Supporting Information. Method A: DDQ, CH2Cl2/H2O 18:2, 258C, 2 3 h;
then ascorbic acid. Method B: CH2Cl2/TFA 6:1, 258C, 8 10 h. [b] Yields and purities (HPLC) pertain to the mixture after cleavage before any purification
unless (purity) is stated.
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In conclusion, we have demonstrated that a polymorphic
synthetic key intermediate can be used as the core structure of
a directed library leading through structural modifications to
well-defined classes of compounds, each of which may
subsequently serve as the intermediate for the construction
of new directed libraries of medicinally important molecules.
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Scheme 2. Construction of a library from 9. Reagents and conditions: a) R1NCO, Et3N, 0!258C, 2 h; b) R2OH, THF, cat. HClO4 70%, 258C, 1h; c) DBU,
CH2Cl2, 258C, 12 h; d) for R9 ¼ H: R10COCl, Et3N, CH2Cl2, 258C, 6 h; e) Dess Martin reagent, CH2Cl2, 258C, 12 h; f) NaBH4, THF/H2O 1:4, 25 8C, 0.5 h;
g) binucleophile, CH2Cl2, 258C, 10 h; h) R3COCl, Et3N, 25 8C, 12 h; i) glycosyl donor, BF3¥Et2O, CH2Cl2, 58C, 6 h; j) CH(OR5)3, BF3¥Et2O, THF, 08C, 1h;
k) R6SH, Et3N, CH2Cl2, 258C, 2 h or NaN3(aq), CH3COOH, pH 5, 258C, 1h; l) NaBH 4, THF/H2O 1:4, 258C, 2 h; m) mCPBA, CH2Cl2, 258C, 6 h;
n) nucleophile, CH2Cl2, 258C, 8 h; o) 4,7-dimethoxy-3-oxodihydroisobenzofuran-1-carbonitrile, LDA, THF, ꢀ78!08C, 4 h. DBU ¼ 1,8-diazabicy-
clo[5.4.0]undec-7-ene, mCPBA ¼ m-chloroperoxybenzoic acid, LDA ¼ lithium diisopropylamide.
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