Synthesis of Cyclic Peptidomimetics via a Pd-Catalyzed Macroamination Reaction

Article abstract of DOI:10.1021/acs.orglett.6b01961

A new method to access cyclic peptidomimetics via a Pd-catalyzed macroamination reaction is presented. Natural amino acid amines are revealed as proficient coupling partners in these transformations. With a commercially available CPhos G3 catalyst system and substrates bearing diverse amino acid and aryl halide backbones, the unique head to side-chain (or side-chain mimic) macrocycles are afforded with ring sizes from 11 to 23 members in yields up to 84%.

Full text of DOI:10.1021/acs.orglett.6b01961

Letter
pubs.acs.org/OrgLett
Synthesis of Cyclic Peptidomimetics via a Pd-Catalyzed
Macroamination Reaction
Brett A. Hopkins,* Graham F. Smith, and Nunzio Sciammetta*
Discovery Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States
S
* Supporting Information
ABSTRACT: A new method to access cyclic peptidomimetics
via a Pd-catalyzed macroamination reaction is presented.
Natural amino acid amines are revealed as proficient coupling
partners in these transformations. With a commercially
available CPhos G3 catalyst system and substrates bearing
diverse amino acid and aryl halide backbones, the unique head
to side-chain (or side-chain mimic) macrocycles are afforded with ring sizes from 11 to 23 members in yields up to 84%.
Scheme 1. Summary of This Work
eptide-based therapeutics are a major focus in drug
Pdiscovery as these molecules can disrupt difficult targets
with extended binding sites (e.g., protein−protein interactions)
while maintaining good target specificity and low toxicity
profiles.1,2 However, many peptide therapeutics have certain
limitations, notably poor cellular permeability, which often
restricts many of these agents to extracellular target space.2f
One way of improving the cellular permeability of peptide
therapeutics (to allow their interaction with desired intracellular
targets) is by constraining the amino acid sequence of interest
via the synthesis of a cyclic peptide (CP) or cyclic
peptidomimetic (CPM).2 Along with enhanced cellular
permeability, CPs and CPMs frequently possess other desired
druglike properties such as improved enzymatic stability and
target binding.2a,3
The Buchwald−Hartwig amination (BHA) is one of the
most widely utilized reactions in medicinal chemistry.16 This
transformation has been the key step in a variety of reactions,
including recent natural product applications and the synthesis
of advanced pharmaceutical intermediates.17 Despite this
widespread utility, macrocyclizations of amino acid sequences
via the BHA reaction have been limited to a single method that
only uses aniline nucleophiles and one aryl bromide.18 Even
with a limited use for CPM synthesis, we were interested in the
BHA reaction to access these molecules for two main reasons.
First, using the natural aliphatic amino acid amine as the
nucleophiles does not require special prefunctionalization. Also,
the wide availability of aminoaryl halides would allow facile
access to novel and diverse macrocyclic cores (Scheme 1).
For our initial experimentation, 3-bromophenethylamine was
used as a direct surrogate for the side chain in the amino acid
Phe and a weak base was used to limit epimerization concerns.
Under these conditions, a variety of catalyst systems were
tested for this macroamination reaction.19 The use of the
BINAP G3 precatalyst (P1) led to poor results with both 1a
and 1b, affording small amounts of product along with
substantial substrate reduction in the reaction with 1a (entries
Because of the importance of CPs and CPMs, methods to
access these molecules have been an area of extreme interest.4
Traditionally, cyclizations to afford CPs and CPMs have been
achieved via macrolactamization and macrolactonization
reactions,5 SNAr,6 and multicomponent reactions,7 among
others.8,9 Lately, there has been an increased interest in using
transition-metal-catalyzed reactions to access novel CPMs
(Figure 1) including Suzuki−Miyaura couplings,10 Cu-catalyzed
“click” reactions,11 and ring-closing metathesis,12 to name a
few.13,14 However, none of the aforementioned transition-
metal-catalyzed reactions utilize the natural amino acid amine
in their respective cyclization steps (Scheme 1).15
Received: July 6, 2016
Figure 1. Biologically relevant CPMs.
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.6b01961
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Letter
1 and 2).20 Other commonly employed precatalyst systems (P2
and P3, entries 3−6) provided a good yield of either product 2a
or 2b but were not general for both products. The CPhos G3
precatalyst (P4), which has been used in other hindered amine
amination reactions, and has been shown to diminish substrate
reduction,21 afforded a good yield of both products 2a and 2b
in our reaction (Table 1, entries 7 and 8).21 This precatalyst
Figure 2. Epimerization study. (I) Lowest energy conformer of 2c
(S,S) displaying the close spatial proximity of hydrogens a and b (all
hydrogens removed except the two of interest). (II) Diagram of key
couplings from ROESY spectrum.
a
Table 1. Initial Screen
With the optimal conditions for cyclization in hand, we
tested the scope of this head to side chain (Phe mimic)
macroamination reaction. Cyclizing with an N-Me secondary
amine, present in many biologically relevant molecules,26
provided product 2e in 60% yield (Scheme 2). Substitutions
a
Scheme 2. Substrate Scope
b
entry
substrate
precatalyst
NMR yield (%)
product
c
1
2
3
4
5
6
7
8
9
1a
1b
1a
1b
1a
1b
1a
1b
1c
1c
1d
P1
10 2a, reduced 1a
2a
2b
2a
2b
2a
2b
2a
2b
2c
2c
2d
d
P1
trace
P2
36
P2
65
P3
73
P3
43
P4
72 (62)
65 (60)
88 (84)
55
P4
P4
e
10
P4 (5%)
P4
11
77 (80)
a
Conditions: 1.0 equiv of 1a−d, 4 equiv of Cs2CO3, 10% precatalyst,
1,4-dioxane (0.025 M), 100 °C, 18 h. Reactions were conducted on a
b
1
0.05 mmol scale. Yields were based on H NMR with phenanthrene
as an internal standard. Yields in parentheses refer to isolated yields.
c
Product 2a was afforded along with 35% of 1a and reduction of 1a.
d
e
Mostly starting material. 5% of the CPhos ligand was used too.
also worked well with substrate 1c, providing the 15-membered
ring product 2c in excellent yield (entry 9). Lowering the
catalyst loading afforded product 2c in a reduced yield (entry
10).
a
We wondered if epimerization was occurring in this reaction,
since phenylalanine groups are particularly susceptible to
epimerization.22 Thus, we desired to see if the lowest energy
conformation of (S,S)-2c correlated with its NMR data.23 The
lowest energy conformation of 2c was generated with MOE
2015.10 using the Amber10:EHT force field,24 which revealed
hydrogens a and b to be in close proximity (only in the (S,S)
diastereomer, Figure 2). Further analysis of product 2c by
1H−1H ROESY NMR confirmed the spatial proximity of
hydrogens a and b (structure II, Figure 2), showing that the
stereochemistry was preserved.24 We also synthesized the
epimeric substrate 1d (Table 1, entry 11), and it afforded
product 2d with no trace of 2c. All of the above data suggest
that no epimerization was occurring in our reaction.25
Conditions: 1.0 equiv of 1e−p, 4 equiv of Cs2CO3, 10% P4, 1,4-
dioxane (0.025 M), 100 °C, 18 h. Reactions were conducted on a 0.05
b
mmol scale. A catalyst system composed of 10% BrettPhos G4 was
used for 2m and 2o.
in the backbone for different amino acids and different cyclizing
nitrogens were well tolerated (2f−l).27 An unprotected
heteroatom in the amino acid sequence was tolerated for the
indole ring in tryptophan (2g), although the oxygens in
tyrosine and threonine required protecting groups in this
reaction (2h and 2i). Extra amino acid residues in the backbone
worked as well, and products 2m, 2n, and 2p were afforded in
good yields. Substrates without a heterocyclic amino acid were
also synthesized. Under the reaction conditions, product 2o
B
DOI: 10.1021/acs.orglett.6b01961
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Letter
(S,R,S) was afforded in 42% yield. However, the epimer with an
(S,S,S) backbone was only observed in a trace amount.5c,27
The next aim was to expand the scope of the aryl bromide
linker. To start, a change in the linker by simply moving the aryl
bromide from the meta position to the ortho position was made.
As shown in Figure 3, the 11-membered ring product 2q and
*E-mail: nunzio.sciammetta@merck.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Lisa Nogle, Mark Pietrafitta, and David Smith for the
purification of the final CPM products and Adam Beard for
obtaining HRMS. We also thank Peter Fuller and Charles
Yeung for helpful suggestions during the preparation of this
manuscript and Hakan Gunaydin and Hai-Young Kim for
helpful discussions. We are grateful to the MRL Postdoctoral
Research Fellows Program for financial support of B.A.H.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01961.
■
S
Experimental procedures, characterization data for all
new compounds (starting material and final products),
́
(7) (a) Vasco, A. V.; Perez, C. S.; Morales, F. E.; Garay, H. E.;
1
and H and 13C NMR spectra along with LCMS spectra
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(UV and TIC) for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(8) (a) Jo, H.; Meinhardt, N.; Wu, Y.; Kulkarni, S.; Hu, X.; Low, K.
E.; Davies, P. L.; DeGrado, W. F.; Greenbaum, D. C. J. Am. Chem. Soc.
*E-mail: brett.hopkins@merck.com.
C
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D
DOI: 10.1021/acs.orglett.6b01961
Org. Lett. XXXX, XXX, XXX−XXX