Directed diversity-oriented synthesis. Ring-fused 5- to 10-membered rings from a common peptidomimetic 2-pyridone precursor

Article abstract of DOI:10.1016/j.tetlet.2012.08.100

A variety of ring-fused 2-pyridone-based central fragments were prepared using a strategy inspired by diversity-oriented synthesis. The produced compounds are diverse, yet focused, analogs of biologically active peptidomimetic 2-pyridones.

Full text of DOI:10.1016/j.tetlet.2012.08.100

Tetrahedron Letters 53 (2012) 6022–6024
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Tetrahedron Letters
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Directed diversity-oriented synthesis. Ring-fused 5- to 10-membered rings
from a common peptidomimetic 2-pyridone precursor
⇑
Magnus Sellstedt, G. Krishna Prasad, K. Syam Krishnan, Fredrik Almqvist
Department of Chemistry, Umeå University, 901 57 Umeå, Sweden
Umeå Centre for Microbial Research, Umeå University, 901 57 Umeå, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of ring-fused 2-pyridone-based central fragments were prepared using a strategy inspired by
diversity-oriented synthesis. The produced compounds are diverse, yet focused, analogs of biologically
active peptidomimetic 2-pyridones.
Received 19 June 2012
Revised 7 August 2012
Accepted 24 August 2012
Available online 1 September 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Diversity-oriented synthesis
Medium-sized rings
Peptidomimetics
2-Pyridone
2-Pyridones are privileged structures in medicinal chemistry,1
and many biologically active ring-fused 2-pyridones exist, for
example, the natural product derived anti-cancer drug, topotecan,2
and the acetylcholinesterase inhibitor, huperzine A.3 The ring-
fused 2-pyridones 1 and 2 (Fig. 1) belong to a class of compounds
designed as peptidomimetics.4 This type of thiazolo ring-fused 2-
pyridone has various biological effects depending on their substi-
tution pattern, for example, as antibacterials—targeting bacterial
virulence,5,6 and as modulators of the fibrillation of amyloid pro-
teins, such as Alzheimer b-peptides7 and the Parkinson’s associated
Figure 1. Biologically active thiazolo ring-fused 2-pyridones with peptidomimetic
backbones (highlighted).
a
-synuclein.8 Previous synthetic efforts to improve, or to alter the
biological activity of these compounds have focused on variation of
the substituents9 as well as changes of the central fragment it-
self.10,11 Here, we report the synthesis of a series of central frag-
ment analogs of compounds 1 and 2 using a strategy inspired by
the concepts of diversity-oriented synthesis (DOS).12,13
The aim with DOS is to prepare compound collections with
widely diverse central fragments to find biologically active sub-
stances without having a pre-determined target.14 Considering
the diverse biological activities of the thiazolo ring-fused 2-pyri-
dones, we believe that further exploration of the chemical space
around this class will generate many new compounds that are ac-
tive in a variety of biological assays. In efforts toward this goal, we
have developed a strategy involving directed diversity-oriented
synthesis, where the produced compounds are relatively close to
compounds 1 and 2 in the chemical space, but still considerably
more varied than what is usually achieved by substituent variation.
Inspired by the use of a 2-fluorobenzene sulfonyl chloride as a two-
sited electrophile in the preparation of a DOS-library,15 compound
3
was prepared in analogy with previously prepared com-
pounds,16,17 and then formylated18 to give compound 4, which
contains two different electrophilic sites (Scheme 1). This key
starting material allowed the synthesis of compounds with large
variations of the left-hand side of the peptidomimetic 2-pyridone
by orthogonally reacting the two electrophilic groups to form var-
ious ring-structures.
To start with, two new heteroaromatic scaffolds were prepared.
Heteroaromatics are often easily functionalized and give rigid com-
pounds, which can be beneficial for biological activity.19 Ring-fused
pyrroles have been prepared from other compounds with two elec-
trophilic sites,20,21 and reaction of 4 with primary amines under
basic conditions gave the pyrroles 5 and 6 (Scheme 2A).
The corresponding ring-fused thiophene 7 was obtained by
reaction with potassium thioacetate followed by cleavage of the
⇑
Corresponding author.
E-mail address: fredrik.almqvist@chem.umu.se (F. Almqvist).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.100

M. Sellstedt et al. / Tetrahedron Letters 53 (2012) 6022–6024
6023
structural planarity, which typically improves aqueous solubility.25
By preparing medium-sized rings with saturated carbons, less pla-
nar compounds with restricted flexibility were created. To synthe-
size the seven-membered carbamates 14 and 15, compound 4 was
reduced to the alcohol 11, reacted with an amine, and then ring-
closed with triphosgene (Cl3COCOOCCl3) (Scheme 4).
Cl
O
Cl
oxalyl chloride
DMF, MeCN
80 oC, 4 h
S
S
N
N
CO2Me
4 54%
CO2Me
O
O
3
Two compounds containing eight-membered rings were syn-
thesized by nucleophilic substitution of the chloride followed by
reductive amination of the aldehyde (Scheme 5). Thus, Boc-pro-
tected cysteine methyl ester was reacted with 4 and then deprotec-
ted with trifluoroacetic acid. Ring-closure to compound 16 was
accomplished with sodium borohydride in methanol. The use of
non-protected cysteine gave several by-products. Triazole 17 was
prepared by displacement of the chloride with sodium azide fol-
lowed by reductive amination with N-methyl propargylamine. A
thermal intramolecular Huisgen cyclization26,27 then gave the
ring-closed product 17. During the first step in the synthesis of
17, small amounts of the ring-fused pyrrolidone 18 were formed.
This type of transformation usually requires acidic conditions
and is then regarded an intramolecular Schmidt rearrangement,28
but in our case acid did not promote the formation of 18. However,
it was found that slightly elevated temperatures and longer reac-
tion times increased the amount of this product and allowed its
isolation in 62% yield.
Scheme 1. Preparation of a 2-pyridone with two electrophilic sites.
A
B
Scheme 2. Ring-fused five-membered heteroaromatics.
We planned to prepare a nine-membered ring system by ring-
closing metathesis.29 To introduce the alkenes for the metathesis,
Ph
O
Ph
O
A
R1CHO, R2NH2
MeOH:MeCN
Cl
Cl
R1
R2
RNH2
S
S
NaBH4
S
S
K2CO3
N
AcOH
air, rt
N
N
N
N
MeCN
MeCN
N
N
MeOH
CO2Me
CO2Me
AcO
O
CO2Me
CO2Me
11 79%
O
O
O
OH O
8
4
B
R
NH
Ph
S
R
Triphosgene
Et3N, CH2Cl2
N
S
S
N
PhCHO, RNH2
O
Cl
N
N
O
MeOH:MeCN
AcOH
CO2Me
9 61%
O
O
O
S
CO2Me
CO2Me
R = H
OH
MW, 80 oC
10 min
N
14 R = Me 57%
12 R = Me 59%
15 R = Bn 61%
13 R = Bn 64%
CO2Me
Ph
O
O
S
4
Scheme 4. Synthesis of seven-membered carbamates.
N
CO2Me
10 74%
Cl
R = Me
1) N-Boc-Cys-OMe
K2CO3, MeCN
S
Scheme 3. Improved syntheses of naphthyridones and naphthyridonium salts.
S
2) TFA:CH2Cl2
N
3) NaBH4
MeOH
MeO2C
acetyl group and dehydration in a one-pot procedure (Scheme 2B).
The use of sodium sulfide instead of potassium thioacetate gave
significant amounts of a dimeric compound (according to LC–MS).
We previously described a three-component reaction that pro-
duced dihydronaphthyridones from methyl and formyl substituted
2-pyridones such as 8. Subsequent oxidation with air, or more gen-
erally, with chloranil, gave naphthyridones and naphthyridonium
salts (Scheme 3A).22 Compound 4 participated in similar reactions
when reacted with aldehydes and amines under mildly acidic con-
ditions (Scheme 3B). The naphthyridone 9 and the naphthyridoni-
um salt 10 were formed without the need of an extra oxidation
step, thus providing a more straightforward route to these types
of compounds.
N
CO2Me
16 22%
H
O
O
O
1) NaN3
N
N
N
Cl
O
MeCN:MeOH
MW, 80 oC, 10 min
S
S
2)
N
N
N
N
H
N
NaBH(OAc)3
CO2Me
17 37%
CO2Me
O
3) 1,4-dioxane
100 oC, 24 h
4
NaN3
MeCN:MeOH
S
HN
MW, 100 oC
30 min
O
CO2Me
18 62%
Although new heteroaromatic scaffolds are valuable in medicinal
chemistry,23 compounds with a higher proportion of sp3-carbons
and stereochemical complexity often interact more specifically with
proteins.24 A higher proportion of saturated carbons also decreases
Scheme 5. Synthesis of eight-membered rings and
a pyrrolidone ring-fused
compound.

6024
M. Sellstedt et al. / Tetrahedron Letters 53 (2012) 6022–6024
In conclusion, we have applied a strategy of directed diversity-
Cl
O
Cl
oriented synthesis to prepare a series of 5- to 10-membered ring-
fused structural peptidomimetics starting from a chloromethyl and
formylated compound. This type of two-sited electrophile can
potentially be used to construct a wide range of ring-fused hetero-
cycles. The compounds produced here are diverse analogs of bio-
logically active 2-pyridones that will be evaluated in a variety of
biological assays in the near future.
TMS
.
S
S
BF3 Et2O
1,4-dioxane
rt, overnight
N
N
CO2Me
CO2Me
O
OH
O
4
19 73%, 3.7:1 dr
Scheme 6. Hosomi-Sakurai allylation of 4.
Acknowledgments
Cl
NH
We gratefully thank the Swedish Natural Research Council
(Grant 621-2010-4730), the Knut and Alice Wallenberg Founda-
tion, and JC Kempe Foundation (SJCKMS) for financial support.
allylamine
S
S
K2CO3, MeCN
MW, 100 oC, 1 h
N
N
CO2Me
CO2Me
20 83%
OH
O
OH O
Supplementary data
19
1) Ac2O
Supplementary data (experimental procedure and spectral
data) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2012.08.100.
Ac
N
2) 5% Grubbs'
S
2nd gen. cat.
N
PhMe, 100 oC
overnight
CO2Me
21 72%
OH
O
References and notes
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Next, compound 19 was reacted with allylamine to introduce
the second alkene needed for the metathesis. The resulting amine
20 was then N-acylated, and the ring-closing metathesis was real-
ized by the use of Grubbs’ second generation catalyst31 in toluene
(20 mM) to give 21 in 72% yield (Scheme 7).
For the 10-membered case, we considered a lactone ring-clo-
sure. Although medium-sized lactones are often difficult to prepare
because of competing formation of dimeric species,32 substrates
with rigidifying elements such as Z-double bonds can give efficient
reactions.33 The 10-membered lactone 23 was prepared from the
alcohol 11, which was first reacted with the allyl ester of N-
methyl-c-aminobutyric acid to give 22. This product was then sub-
jected to palladium-catalyzed deallylation, followed by lactoniza-
tion to give 23 using PyBOP as the coupling reagent34 (Scheme
8). The ring-closure proceeded well using modest dilute conditions
(50 mM) without the need for slow addition of the substrate.