Synthesis of 2,4,5-trisubstituted tetrahydropyrans as peptidomimetic scaffolds for melanocortin receptor ligands.

Article abstract of DOI:10.1021/ol027281v

[reaction: see text] We have synthesized a series of 2,4,5-trisubstituted tetrahydropyran derivatives to determine the utility of this scaffold as a peptidomimetic platform. The key synthetic steps involved a palladium-mediated cross-coupling reaction of

Full text of DOI:10.1021/ol027281v

ORGANIC
LETTERS
2003
Vol. 5, No. 8
1163-1166
Synthesis of 2,4,5-Trisubstituted
Tetrahydropyrans as Peptidomimetic
Scaffolds for Melanocortin Receptor
Ligands
Anna Kulesza, Frank H. Ebetino, Rajesh K. Mishra, Doreen Cross-Doersen, and
Adam W. Mazur*
Procter and Gamble Pharmaceuticals, Health Care Research Center,
Mason, Ohio 45040
mazur.aw@pg.com
Received November 14, 2002
ABSTRACT
We have synthesized a series of 2,4,5-trisubstituted tetrahydropyran derivatives to determine the utility of this scaffold as a peptidomimetic
platform. The key synthetic steps involved a palladium-mediated cross-coupling reaction of a dihydropyran-4-one moiety to introduce R
2
followed by a sequential regio- and diastereoselective reduction of sp2 carbon centers. Selected compounds have shown biological activity
at melanocortin receptors, indicating that this scaffold may be useful in the design of peptidomimetics relating to a tripeptide structure.
Creation of structures that can be used as peptide surrogates
in drug discovery is a vibrant area of organic chemistry. Of
particular interest are the constrained scaffolds that allow
for a wide-ranging display of substituents in both regio- and
stereochemical fashion. Analogues having a specific spatial
distribution of substituents are useful in defining a preferred
conformational state of receptor ligands for activity. The
ready opportunity for a choice of substitutions and stereo-
chemical characteristics of the substituted tetrahydropyran
moiety makes this scaffold an interesting target in petido-
mimetic research. Herein we present one class of such
compounds comprising 2,4,5-trisubstituted tetrahydropyran
derivatives. Figure 1 shows that 3 can be viewed as a
transformation of an amide bond 1 in which nitrogen and
oxygen atom sites are constrained in a six-membered ring.
In this sense, the construct 3 is also related to the known
amide bond hydroxyethylene isostere 2.1
We were therefore interested in the study of structure 3
to understand if it actually would show some biological
properties of a tripeptide molecule. To verify this concept,
we selected, in conjunction with our ongoing research in the
melanocortin receptor area,2,3 a benchmark tripeptide, H-
Figure 1. Correlation between amide bond 1, amide bond isostere
2, and the tetrahydropyran moiety 3.
(1) Patani, G. A.; LaVoie, E. J. Chem. ReV. 1996, 96, 3147-3176.
10.1021/ol027281v CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/18/2003

DPhe-Arg-Trp-NH2. This peptide is a truncated version of
the agonist message sequence His-Phe-Arg-Trp at the mel-
anocortin receptor-4 (MC4R)4 that was proposed as a target
for the treatment of obesity5,6 and sexual dysfunction.7 For
designing the synthetic targets, we chose 2-naphthylalanine,
a bioisosteric replacement of tryptophane, because, for
synthetic reasons, we preferred to introduce the naphthyl
moiety rather than an indole into the anticipated mimetics.
Inspection of H-DPhe-Arg-Trp-NH2 reveals that if R is
considered to be the benzyl group in 3, then R1 and R2 should
correspond to the side-chains of naphthylalanine and arginine.
The melanocortin literature also indicated that the guanidine
group might not be essential in MC4R nonpeptide agonists
if a heterocyclic substituent is present in a proper position.8
Furthermore, a halo atom in the phenylalanine moiety has
been reported to modify agonist potency or produce an
antagonist at MCR.9 We incorporated these elements into
our synthetic plan.
Scheme 1
It should be noted that our definition of peptidomimetics
is more functional than structural even though the design of
2,4,5-trisubstituted pyran analogues was based on the model
peptide structure. While one may find certain structural
similarities between the peptide and the structures presented
later in this paper, we cannot prove that these compounds
relate to any conformations of the peptide. In fact, there is
no general definition of peptidomimetics, as their structures
encompass a broad range of variations10 and ligands can bind
to different conformational ensembles of the target recep-
tor.11,12
The first part of our synthesis, shown in Scheme 1,
involved a formation of the 5-bromo dihydropyran-4-one
derivatives 6a and 6b, providing 4- and 5-positions activated
for further derivatization. En route to these products, we
obtained dihydropyran-4-ones 5a and 5b using a known
hetero Diels-Alder reaction of aldehydes13 4a and 4b,
respectively. The latter materials were derived from D-
phenylalanine, which represents the N-terminus of the model
tripeptide. The major isomer of each dihydropyran-4-one was
produced in a 5:1 excess over its diastereoisomer, in
agreement with published data.13
A halide at C5 was important as an activator for a
palladium-mediated cross-coupling reaction14 that we envi-
sioned for introduction of aromatic substituents in this po-
sition. In a similar system, cis-2,3-disubstituted dihydropyran-
4-one,15 5-iodo derivatives were used in this reaction. On
the other hand, both bromo and iodo derivatives were used
in cross-coupling reactions involving benzopyranones.16,17
We were not able to obtain stable 5-iodo derivatives from
4a and 4b, and we turned our attention to 5-bromo dihydro-
pyranes 6a and 6b. A traditional method of enone bromi-
nation using Br2/Et3N18 proved to be very effective, with 5a
and 5b giving the corresponding bromides in good yields.
In contrast, attempts to make 6a and 6b with PhI(OAc)2/
TMSBr as reported for cis-2,3-disubstituted dihydropyran-
4-one15 led to a mixture of unidentified byproducts.
With 5-bromo dihydropyran-4-ones 6a and 6b in hand,
we explored two variants of cross-coupling methodology to
introduce R1. First, we tried to utilize the trimethylstannane
derivative15 of pyranone 7, since a large number of heteroaryl
halides (Het-X) were readily available for further cross-
coupling reactions. Unfortunately, low yields of 7 discour-
aged us from further explorations of this route and we
employed the 5-bromo dihyropyran-4-one 5a and heteroaryl
stannanes as the cross-coupling components to make 8a-c.
The 2-naphthyl derivative 9, on the other hand, was obtained
by a Suzuki-type reaction involving 2-naphthyl boronic acid.
The results of these reactions are reported in Table 1.
The next crucial aspect of our investigation was to
determine if reduction of the double bond and the ketone
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1164
Org. Lett., Vol. 5, No. 8, 2003

Scheme 3a
Table 1. Transformations of 5-Bromo Dihydropyran-4-one 6a
and 6b and Related Compounds
a Reagents and conditions. 10a-d: L-Selectride, THF, -78 °C.
11a-d: L-Selectride, THF, -78 °C. 12a-c: (i) 2-bromomethylene-
naphthalene, NaH, Bu4NI, THF; (ii) TFA, DCM.
a De values were determined by NMR and HPLC. b Yield for two steps.
products 11a-d was based on the X-ray structure of 11a
(Figure 2) and their nuclear magnetic resonance spectra.
group could be performed in a sequential chemoselective
and diastereoselective manner. We were particularly inter-
ested in reducing the double bond first because it would allow
for keeping an active carbonyl for further modifications. The
chemoselective reductions of this bond in pyrane-4-ones have
been reported by means of hydrogenation19-25 and L-
selectride for the unsubstituted 5-position.26 We chose
L-selectride with the hope that it could provide chemo-
selectivity for double-bond reduction in the first case and
diastereoselectivity in both cases (Scheme 3).
Scheme 2a
Figure 2. Model of 11a generated from its X-ray structure.
a Reagents and conditions. (a) (Me3Sn)2, PhMe, Pd(Ph3P)4, 85
°C, 3 h (10%). (b) 8a-c: R′′-A, Pd(PPh3)4, DMF, 100 °C, 6 h. 9:
R′′-A, Na2CO3, Pd(PPh3)4, benzene, reflux 3 h. See Table 1 for
yields.
Alkylation of 11a-c to the corresponding 12a-c con-
cluded the synthesis of this series of potential tripeptide
mimetics.
Scheme 4 shows the synthesis of structures in which the
guanidylethyl moiety at C4 and 2-naphthyl at C4 correspond
to the arginine and naphthylalanine sites in H-DPhe-Arg-
(2-Nal)-NHCH3.
Indeed, as shown in Table 1, the reactions are both chemo-
and diastereoselective. The stereochemistry assignment of
The guanidyl substituent was introduced in a sequence
involving a Horner-Emmons reaction27 and a reduction of
the resulting olefin as the key steps. The latter reaction was
performed using a palladium catalyst formed in situ by
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28
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Org. Lett., Vol. 5, No. 8, 2003
1165

Scheme 4a
Table 2. Biological Activity of Selected Tetrahydropyran
Analogues at the Melanocortin Receptor-4 (MC4R)a
compd
Ki [nM]
EC50 [nM], (Emax [%])
H-DPhe-Arg-Trp-NH2
1188
2803 (49)
>50 000 (0)
>50 000 (0)
9235 (32)
>50 000 (0)
>50 000 (0)
>50 000 (0)
>50 000 (0)
12a
12b
12c
14a
14b
16a
16b
>25 000
>25 000
9930
>25 000
>25 000
2801
4960
a For assay procedures, see Supporting Information.
In view of the recent report about the existence of
nonspecific interactions in the biological assay mixtures,
resulting in the discovery of “artificial” hits,29 it may be
important to address this question whenever novel actives
are found that deviate significantly from the established and
validated ligands. In our case, compounds 12a, and in
particular 12b, are structurally close to 12c but do not show
any activity at MC4R. Furthermore, significantly increased
receptor binding occurs with 16a and 16b upon transforma-
tion of the cyano group of 14a and 14b into a hydrophilic
guanidine functionality. These results argue against the
possibility that potential effects of nonspecific association
bias the screening results in this class of compounds. It
should also be pointed out that comparison of both binding
and functional response in the cellular assays involving
G-protein-coupled receptors limits the possibility of non-
specific interactions and, therefore, is less likely to produce
artifacts than the enzyme inhibition assays.
a Reagents and conditions. (a) (EtO)2OPCH2CN, NaH, THF. (b)
H2, NaBH4, PdCl2, MeOH. (c) (i) H2, Ni/Ra, MeOH/NH4OH (1:
4); (ii) BocHNC(dNBoc)SMe, HgCl2, Et3N, DMF; (iii) TFA,
DCM.
isomers in a 1:1 ratio. The diastereomers were separated on
a silica column. We assigned structure 13b to the faster
moving compounds on the basis of the presence of small
coupling values for the signals at about 3.4 ppm. We
postulate that this coupling belongs to two equatorial cis
protons H-4 and H-5. The NMR spectrum of 13a shows only
large coupling values at this chemical shift, and this should
correspond to trans H-4 and H-5 (see expanded spectral
regions in Supporting Information). Each diastereoisomer
was carried out separately through the next steps, giving 16a
and 16b.
The results in Table 2 show the results of in vitro testing
2,4,5-trisubstituted tetrahydropyrane analogues for binding
and functional activity at MC4R in the cell-based assays.
Compared to the model tripeptide H-DPhe-Arg-Trp-NH2, 12c
is a weak partial agonist as judged by EC50 and Emax values.
On the other hand, 16a and 16b bind to MC4R with
somewhat lower potency than the tetrapeptide but do not
trigger the functional response of the receptor.
Our data indicate that this peptidomimetic design based
on the 2,4,5-trisubstituted tetrahydropyrane structures can
indeed lead to the biologically active molecules. Presumably,
this scaffold meets some of the conformational requirements
of the melanocortin receptors. This approach allows for
significant departure from analogues with peptidic character
and is amenable to diastereoselective synthesis from readily
available materials.
Supporting Information Available: Experimental details
and characterization of compounds as well as biological assay
procedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL027281V
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J. Med. Chem. 2000, 43, 4051-4062.
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Chem. 2002, 45, 1712-1722.
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