Oxetanyl peptides: Novel peptidomimetic modules for medicinal chemistry

Article abstract of DOI:10.1021/ol501590n

The synthesis of novel oxetanyl peptides, where the amide bond is replaced by a non-hydrolyzable oxetanylamine fragment, is reported. This new class of pseudo-dipeptides with the same H-bond donor/acceptor pattern found in proteins expands the repertoire

Full text of DOI:10.1021/ol501590n

Letter
pubs.acs.org/OrgLett
Open Access on 07/28/2015
Oxetanyl Peptides: Novel Peptidomimetic Modules for Medicinal
Chemistry
Martin McLaughlin, Ryo Yazaki, Thomas C. Fessard, and Erick M. Carreira*
Department of Chemistry and Applied Biosciences, Laboratorium fu
̈
̈
r Organische Chemie, Vladimir-Prelog-Weg 3, Eidgenossische
Technische Hochschule Zurich, CH-8093 Zurich, Switzerland
̈
̈
*
S Supporting Information
ABSTRACT: The synthesis of novel oxetanyl peptides, where
the amide bond is replaced by a non-hydrolyzable oxetanyl-
amine fragment, is reported. This new class of pseudo-
dipeptides with the same H-bond donor/acceptor pattern
found in proteins expands the repertoire of peptidomimetics.
ith over 50 marketed drugs and an estimated $13 billion
susceptibility to enzymatic amide bond cleavage at the site of
substitution (Figure 1b).
W
market in 2010, peptide drugs are important players in
1
pharmaceuticals. This is however, a relatively small share of the
Peptidomimicry has long sought to provide alternative
structural building blocks for fragments or the whole of
biologically relevant peptides in an effort to generate
compounds with improved pharmacokinetic profiles. A number
of creative approaches have been demonstrated including β-
peptides and δ-peptide oligomers, peptoids, alkene isosteres,
total pharmaceuticals market given the broad range of
biological activities displayed by this class of compounds. The
discrepancy arises from some inherent limitations of peptides in
1a,2
the drug development process,
including short lifetimes in
the stomach, intestine, and plasma, which often result in less
than optimal pharmacokinetic profiles. However, the high
specificity and potency as well as low toxicity of certain peptide3s
along with advances in drug delivery have led to a renaissance.
Thus, there are currently dozens of peptide drugs in clinical
5
and oligo o-substituted aromatics, and expanding the portfolio
of peptidomimetics is of continued interest in drug discovery.
In previous work we have suggested that 3,3-disubstituted
oxetanes can be perceived as useful surrogates for carbonyl
groups in small heterocycles, leading to analogs of lactams and
4
development in a broad range of therapeutic areas. As part of
6
our ongoing interest in new building blocks for medicinal
chemistry, we report herein a novel approach based upon the
use of a 3-amino oxetane as a surrogate for a peptide bond
Figure 1a). The strategy aims at expanding the scope of
peptidomimetics that display H-bond donor/acceptor patterns
analogous to that of the parent amide bonds, without attendant
ketones with improved physico-chemical properties. Because a
primary pathway for degradation of peptides is amide bond
hydrolysis, we reasoned that replacement of the amide carbonyl
by an oxetane would result in a fragment with increased
stability while at the same time give access to novel regions of
chemical space. We aimed at developing a strategy for the use
of oxetanyl peptides compatible with modern practices in
(
7
peptide synthesis. Two strategies were considered for their
preparation, which differ in the tactics employed to introduce
the amino oxetane residues (Figure 1c).
The first approach (A) would utilize monomeric oxetanyl
building blocks while the second (B) would rely on the use of
prefabricated dipeptides with embedded oxetanes. Although the
former parallels standard peptide synthesis methods, it would
require optimization of the coupling conditions for each
fragment. In approach B the coupling reactions leading to chain
extension involve amide bond formation. In either case, the
synthetic challenges include the identification of suitable
reactions for the preparation of the building blocks and
compatible coupling conditions for their incorporation into
larger peptides without suffering unwanted side reactions.
Received: June 3, 2014
Published: July 28, 2014
Figure 1. Analysis and research plan.
©
2014 American Chemical Society
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dx.doi.org/10.1021/ol501590n | Org. Lett. 2014, 16, 4070−4073

Organic Letters
Letter
In the initial design of the approach toward surrogate
dipeptides (approach B in Figure 1c), we favored the 1,4-
addition of amino acids to oxetanyl-substituted nitroolefins.
NaHCO in 4:1 THF/H O) using 1 atm of H consistently
3
2
2
produced a protected amine in a single operation in good
8
,9
yield. This protocol has proven to be remarkably general and
allows for the formation of enantiopure oxetanyl dipeptides
using inexpensive amino esters from the chiral pool (Table 1).
Simple alkyl-substituted Boc-protected dimers derived from
glycine, L-alanine, L-leucine, L-valine, and L-phenylalanine are
formed in high yield (Table 1, entries 1−5). Compounds
bearing tBu ethers and esters (7−9), as well as trityl-protected
amides 10 and Boc-protected amines 11, all generated products
in 57%−82% yield (entries 6−9, 12). The derivatives of L-
histidine and L-tryptophan furnished 28 and 29 in 49 and a
Subsequent NO -group reduction would lead to terminal
2
primary amines. We first examined the synthesis of dimers
1
2
(
H NAA -AA CO H) incorporating the glycine surrogate in
2 ox 2
1
position AA (Table 1). In practice, simple mixing of 1 and H-
ox
Table 1. Synthesis of Dipeptides with Oxetanyl Glycine at
1
AA
ox
6
9% overall yield, respectively. To accommodate sulfur-bearing
side chains, zinc/HCl was selected as a reducing agent (27).
Dipeptides were also substrates for this process, with H-Leu-
Phe-OnPr (31, Table 1) affording 32 in 62% yield (two steps).
Preliminary results also showed that direct addition of
unprotected amino acids to nitro-olefin 1 is possible (Table 2).
Table 2. Synthesis of Dipeptides with Oxetanyl Glycine at
1
AA
ox
Indeed, mixing a (orthogonally protected) free amino acid with
1
in THF/H O in the presence of NaHCO afforded nitro-acid
2
3
adducts 33−36. Crude mixtures were subjected to reduction of
the nitro group with Raney Nickel and H , followed by
2
filtration and treatment with CbzCl or FmocOSu to afford N-
protected amino acid dimers 37−40 in 27%−44% yield over
three steps. This result constitutes, to the best of our
knowledge, the first example of conjugate addition of
unprotected amino acids to unsaturated nitro compounds, as
well as a direct approach to dimers ready for further coupling.
Ala-OnPr in DMSO at 23 °C resulted in clean 1,4-addition to
afford 3 in 74% yield (entry 2). This reaction proved successful
with other α amino esters, with products resulting from the
addition of glycine, L-leucine, L-valine, L-proline, and L-
phenylalanine formed in 52%−95% yield. The mild reaction
conditions were compatible with many of the standard side-
chain protecting groups used in modern solid-phase peptide
syntheses. The reaction of tBu-protected L-tyrosine, L-serine, L-
glutamic acid, and trityl protected L-asparagine with 1 afforded
nitro alkanes 7, 8, 9, and 10 in 71%−87% yield. N-Trityl
protected L-histidine and Boc-L-tryptophan furnished products
Through minor modifications of this protocol, other oxetanyl
1
ox
amino acid residues were incorporated at the AA position.
The synthesis of these compounds is exemplified in Table 3.
The sequence begins with the Et N-promoted addition of the
3
10
nitro alkanes 41−45 to oxetan-3-one. After conversion of
nitro alcohols obtained to the corresponding mesylates, in situ
treatment with glycine propyl ester then afforded nitro alkanes
46−51, which were in turn transformed to oxetanyl dipeptides
52−57. The transient formation of tetrasubstituted nitro
alkenes was advantageous because of their tendency otherwise
to undergo cyclization to the corresponding isoxazole under
13 and 14 in 60% and 76% yield, respectively. N-Boc-protected
11
L-lysine gave the nitroalkane 11 in 66% yield, and the L-
methionine-containing nitro alkane 12 was formed in 98%
yield.
basic conditions. The sequence proved to be high-yielding
and efficient with a variety of substituted nitro alkanes featuring
the side chains of leucine (41), O-tert-butyl tyrosine (42),
glutamine tert-butyl ester (43), N-Boc lysine (44), and Ts-
tryptophan (45). This process entails six synthetic trans-
formations and is carried out with purification of only one
intermediate.
We next investigated NO -group reduction and the
2
protection of the resulting amine. Raney nickel proved to be
the most practical reducing agent, leading to a procedure where
reduction in the presence of either (Boc) O or CbzOSu (aq
2
4
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Organic Letters
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1
Table 3. Synthesis of Oxetanyl Dipeptides with AA ≠ Gly
reductive, and oxidative reaction conditions. Further studies to
establish the physicochemical and biological properties, as well
as enzymatic stability, of these new building blocks are ongoing
and will be reported in due course.
ASSOCIATED CONTENT
Supporting Information
■
*
S
Experimental procedures and full spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: carreira@org.chem.ethz.ch.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the NIH (USA) through a Ruth L.
Kirschstein National Research Service Award to M.M.
GM090547), the Japan Society for Promotion of Science for
a fellowship to R.Y., and ETH (TH 10-07-03) is acknowledged.
SpiroChem AG is acknowledged for a generous gift of oxetan-
■
Using the strategy described above, the synthesis of complex
oxetanyl peptide surrogates substituted at both Cα and Cα′
positions was possible in a sequence requiring minimal
chromatographic purification (52−57, Table 3). However, the
ease of separation of the diastereomeric oxetanyl dipeptides
generated was substrate-dependent. This constitutes a current
limitation, and efforts are ongoing to devise a workable
approach to this problem.
(
3
-one and nitromethyleneoxetane.
REFERENCES
■
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2
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