Design, synthesis, and evaluation of proline and pyrrolidine based melanocortin receptor agonists. A conformationally restricted dipeptide mimic approach

Article abstract of DOI:10.1021/jm060384p

The design, synthesis, and structure-activity relationships (SAR) of a series of novel proline and pyrrolidine based melanocortin receptor (MCR) agonists are described. To validate a conformationally constrained Arg-Nal dipeptide analogue strategy, we fir

Full text of DOI:10.1021/jm060384p

J. Med. Chem. 2006, 49, 4745-4761
4745
Design, Synthesis, and Evaluation of Proline and Pyrrolidine Based Melanocortin Receptor
Agonists. A Conformationally Restricted Dipeptide Mimic Approach
Xinrong Tian,* Timothy B. Field, Adrian G. Switzer, Adam W. Mazur, Frank H. Ebetino, John A. Wos, Steve M. Berberich,
Lalith R. Jayasinghe, Cindy M. Obringer, Martin E. Dowty, Beth B. Pinney, Julie A. Farmer, Doreen Crossdoersen, and
Russell J. Sheldon
Procter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Road, Mason, Ohio 45040
ReceiVed March 31, 2006
The design, synthesis, and structure-activity relationships (SAR) of a series of novel proline and pyrrolidine
based melanocortin receptor (MCR) agonists are described. To validate a conformationally constrained Arg-
Nal dipeptide analogue strategy, we first synthesized and evaluated a test set of cis-(2R,4R)-proline analogues
(21a-g). All of these compounds showed significant binding and agonist potency at the hMC1R, hMC3R,
and hMC4R. Potent cis-(2S,4R)-pyrrolidine based MCR agonists (35a-g) were subsequently developed by
means of this design approach. A SAR study directed toward probing the effect of the two chiral centers in
the pyrrolidine ring on biological activity revealed the importance of the (S) absolute configuration at the
2-position for binding affinity, agonist potency, and receptor selectivity. Among the four sets of the pyrrolidine
diastereomers investigated, analogues with the (2S,4R) configuration were the most potent agonists across
the three receptors, followed by those possessing the (2S,4S) configuration.
The melanocortin receptors (MCRs)a are a family of five
seven-transmembrane G-protein-coupled receptors (MC1R-
MC5R) that have been identified and cloned. These receptors
are activated by endogenous peptide ligands, R,â,γ-melanocyte
stimulating hormones (MSH), and adrenocorticotropin (ACTH),
which are derived from a common precursor protein, proopi-
omelanocortin (POMC), by post-translational cleavage.1,2 All
of these ligands feature a conserved tetrapeptide sequence, His-
Phe-Arg-Trp, which has been identified as the minimal peptide
fragment necessary for activating the receptors.3,4 In addition,
two endogenous antagonists, namely, the agouti protein and
agouti-related peptide (AgRP),5 of the melanocortin receptor
family have been discovered. The MCRs mediate a variety of
physiological responses that include skin pigmentation (MC1R),6
inflammation (MC1R),7-9 steroidogenesis (MC2R),10,11 feeding
behavior (MC3R and MC4R),12-14 sexual function (MC4R),15
and exocrine gland secretion (MC5R).16,17 Consequently, the
melanocortin system has become an attractive therapeutic target
for drug development. Over the past decade, significant progress
has been made toward the design of peptidic and nonpeptidic
ligands as potential therapeutic agents for treatment of melano-
cortin-mediated diseases.18-20 The MC4R, in particular, has
attracted an enormous level of attention as a potential therapeutic
target for obesity, sexual dysfunction, and involuntary weight
loss associated diseases.21,22 Recently, many research groups
have disclosed their efforts in the design of potent and selective
nonpeptidic small-molecule MC4 agonists23-35 and antago-
nists.36-42
optimization of the initial lead 2, which was derived by the
coupling of a dipeptide to a spiroindoline privileged structure,
a key component of the growth hormone secretagogue MK-
0677.43,45 The effectiveness of this design concept has also been
demonstrated in the discovery of a number of potent and
selective piperazine-based MC4R agonists.42,46,47 The initial lead
compound containing an arylsulfonamide unit (3) in the series
was identified through iterative directed screening of several
libraries generated by employing a GPCR privileged structure,
an aryl piperazine scaffold. In fact, piperidine and piperazine
cores have been the key structural templates for the majority of
the potent MC4 agonists reported to date. In another distinct
approach, Fostch and co-workers48 used a set of low-energy
structures derived from NMR data for the peptide ligand to
identify ring systems that could position key functional groups
in proximity to the side chains of the D-Phe-Arg-Trp tripeptide,
which led to the synthesis of a 1,4-diaminocyclohexyl ring
containing peptidomimetic MCR agonist with single-nanomolar
potency at MC4R.
During the course of our efforts to develop peptidomimetic
MCR agonists with significantly reduced peptide character on
the basis of the tetrapeptide leads derived from His-D-Phe-Arg-
Trp, we have explored a conceptually different strategy. It
involves the incorporation of conformational constraint between
two adjacent amino acids through the ring formation. A key
objective of this approach would be to identify the appropriate
constraining mode and cyclic scaffold that could enhance
receptor binding and functional potency while allowing for both
replacement of the amide bonds and truncation of the peptide
terminus.
One successful approach in the design and synthesis of MC4R
agonists has been the use of privileged structures.43,44 The first
potent and selective small-molecule MC4R agonist 1 (Figure
1), reported by Sebhat and co-workers,35 resulted from the
Our early work in the design of melanocortin ligands by
means of the Tyr-D-Phe dipeptide mimic approach provided
preliminary evidence for the validity for the strategy described
above. The use of proline as a cyclic scaffold to conformation-
ally restrict two phenyl rings intended to mimic the D-Phe and
Tyr side chains produced dipeptide mimic 4 (Figure 2).49 The
coupling of 4 with a capped Arg residue led to the discovery
of a series of ligands that displayed significant binding affinity
at the MC4R. As exemplified by 5, these analogues are
* To whom correspondence should be addressed. Phone: +1-513-622-
1444. Fax: +1-513-622-1195. E-mail: tian.x@pg.com.
a Abbreviations used: MCR, melanocortin receptor; ECDI, ethyldi-
methylaminopropyl carbodiimide; HOBt, 1H-benzotriazole; NMM, 4-meth-
ylmorpholine; DMEM, Dulbecco’s modified Eagel’s medium; BSA, bovine
serum albumin. MK-0677, (R)-2-amino-N-(3-(benzyloxy)-1-(1-(methylsul-
fonyl)spiro[indoline-3,4′-piperidine]-1′-yl)-1-oxopropan-2-yl)-2-methylpro-
panamide.
10.1021/jm060384p CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/24/2006

4746 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15
Tian et al.
Figure 1. Piperidine and piperazine scaffolds identified through the privileged structure approach.
As illustrated in Figure 3, the constrained dipeptide surrogates
we identified were derived by inserting a methylene group
between the two amide nitrogen atoms (7) and subsequently
substituting the amide bond between two amino acids with a
CH2-CH2 linkage and deleting the C-terminus (8). While the
C-2 guanidine side chain was used for mimicking the Arg
residue, the naphthyl ring was employed to mimic the 2-Nal
and Trp residues. It has been demonstrated by Haskell-Luevano
and co-workers that replacement of the Trp in tetrapeptide 9
with 2-Nal maintained agonist potency across MC1R, MC3R,
and MC4R.50 We also found that substitution of the Trp-NH2
residue of 9 for 2-Nal-NHCH3 (10) resulted in ∼8-fold and
3-fold better affinity at MC4R and MC1R, respectively (Table
1). Moreover, the selectivity for MC4R over MC1R was
dramatically enhanced by replacing the His of 7 with Tyr (11).
In addition to the beneficial effect on potency, the use of a
2-naphthyl ring provided a significant synthetic advantage due
to its chemical inertness compared to the indole ring of the Trp
moiety. The absolute stereochemistry depicted at C-2 of the five-
membered ring of 8 correlates with the (S) configuration of
L-Arg. Inversion of this chirality would provide the correspond-
Figure 2. Proline based Tyr-D-Phe dipeptide mimic.
structurally different from the tetrapeptide templates. Subsequent
efforts directed toward conformationally constraining the two
C-terminal amino acids (Arg-2-Nal) of the tetrapeptide lead
resulted in the identification of a privileged constraining mode
for the design of novel peptidomimetics as potent melanocortin
agonists. Herein, we report the design and synthesis of both
proline and pyrrolidine based Arg-2-Nal dipeptide mimics and
their use in the development of melanocortin agonists.
Figure 3. Design of five-membered ring constrained Arg-2-Nal dipeptide mimetics.
Table 1. Binding Affinity and Agonist Potency for Tetrapeptides 9-11

Melanocortin Receptor Agonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15 4747
Scheme 1a
it was difficult to separate 23a and 23b by chromatography on
silica gel, a mixture of two isomers was treated with sodium
hydride and bromomethylnaphthalene to alkylate the C-4
hydroxyl group of the pyrrolidine ring. Subsequent hydrobo-
ration of the olefins, 24a and 24b, afforded a mixture of
diastereomers 25 and 26, which could be separated readily by
column chromatography. Both alcohols were converted to the
azides 28 and 37 by means of a two-step sequence. Mesylate
formation from isomer 25 followed by treatment with sodium
azide at 70 °C in DMSO produced the azide 28, which was
then deprotected. The coupling of 29 with Boc-D-Phe-OH
followed by cleavage of the Boc group generated the amine
31, which was reacted with acids (ROH) to give the dipeptide
32. The selective reduction of the azido group of 32 was
accomplished with Pd/C (10 wt %) in the presence of pyridine
while leaving the naphthyl ether intact. Guanidination of 33
followed by removal of the Boc group from the guanidine
moiety or (R) amino acids afforded the desired analogues 35.
The transformation of trans isomer 26 to the targeted (2R,4R)-
pyrrolidine analogues 42a-e was carried out using the same
sequence of reactions as illustrated for the synthesis of cis
isomers.
Alternatively, the key intermediate 25 could be prepared from
4-(naphthalen-2-ylmethoxy)proline 13 by means of two-carbon
chain elongation (Scheme 3). The coupling of 5 with Meldrum’s
acid under EDCI activation produced 43, which was deoxy-
genated with sodium borohydride in the presence of acetic acid
to afford 44. The attempted cleavage and decarboxylation of
44 in the presence of Cu in pyridine under reflux52 gave the
desired methyl ester 45 in a low yield, with extensive decom-
position of 44 being observed upon prolonged heating. We
found, however, that heating 44 in a mixture of toluene/EtOH
(5:1) at 100 °C promoted smooth ring opening to give the ethyl
ester 46, which underwent decarboxylation when heated in
toluene at reflux to yield 47. Reduction of 47 with lithium
aluminum hydride afforded 25, which was identical in every
respect to that prepared using the route shown in Scheme 1,
thus allowing for the assignment of the stereochemistry for
isomers 25 and 26. The stereochemistry for diastereomers 23a
and 23b and diastereomers 24a and 24b was also established
by converting pure 23a to 25 via an alkylation and hydroboration
sequence.
a Reagents and conditions: (a) sodium hydride, 2-bromomethyl naph-
thalene, DMF; (b) NH2CH2CH2NH(Cbz), HOBt, EDCI, NMM, DMF; (c)
TFA, CH2Cl2; (d) BOC-D-Phe-OH, HOBt, EDCI, NMM, DMF; (e) TFA,
CH2Cl2; (f) acids (ROH), EDCI, HOBt, NMM, DMF; (g) H2, pyridine,
Pd/C, CH3OH; (h) 1,3-bis(tert-butoxycarbonyl)2-methyl-2-thiopseudourea,
HgCl2, Et3N, DMF; (i) TFA/anisole/CH2Cl2.
ing configuration of a D-Arg mimic at this position. On the other
hand, the C-4 chiral center was created by replacing the amide
nitrogen with a carbon and was thus not related to the chirality
of Nal or Trp. The stereochemical requirement at C-4 of the
ring could not be defined by a topographical comparison with
the tetrapeptide counterpart or computer modeling. Therefore,
both (R) and (S) isomers at this position were synthesized and
investigated in response to the potential critical impact of this
chiral center on biological activity.
Chemistry
The cis-proline analogues were prepared from (2R,4R)-Boc-
4-hydroxyproline using the route shown in Scheme 1. Alkylation
of the 4-hydroxyl group of 12 by treatment with sodium hydride
and bromomethylnaphthalene yielded 4-naphthyl methyl ether
13, which was then coupled with N-1-Cbz-1,2-diaminoethane
to give 14. Removal of the Boc group with TFA followed by
EDCI-mediated coupling of the amine with Boc-D-Phe-OH
afforded dipeptide 17, which was then deprotected and coupled
with appropriate acids chosen to answer specific SAR questions.
Selective cleavage of the Cbz group was accomplished by means
of hydrogenation with 10 wt % Pd/C in the presence of a
catalytic amount of pyridine. It was found that the addition of
pyridine to the reaction mixture was critical for the desired
transformation because concomitant cleavage of the naphthyl
methyl ether and the Cbz group was observed without pyridine.
The guanidination of the resulting amines 19 with 1,3-bis(tert-
butoxycarbonyl)-2-methyl-2-thiopseudourea and HgCl2 pro-
duced the protected guanidines 20, which were then treated with
TFA to give the desired target compounds 21.
The (2R,4S) isomers 56a-e and (2S,4S) isomers 60a-e were
prepared from (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate
(48) using the reaction sequences shown in Scheme 2 (Scheme
4).
Results and Discussion
All analogues were purified by reverse-phase preparative
HPLC (purity >98%) and screened in binding and functional
assays against the human MC1R, MC3R, and MC4R. Binding
affinity (calculated as IC50 and Ki values) was determined by
measuring the displacement of a constant concentration of
europium labeled NDP-R-MSH with competing unlabeled
ligands. The agonist activity of the MCR analogues was
evaluated at three human MCRs using a cell-based assay that
is specific for each subtype of MCR (MC1R, MC3R, MC4R).
Each subtype was stably transfected into HEK293 cells. The
MCR expressing cells were stably transfected with a reporter
system consisting of a cyclic-AMP responsive element (CRE)
coupled to a luciferase reporter gene. Responses were compared
to the effect of NDP-MSH (MT-I) and expressed as a percentage
of maximum activity. The detailed procedures are provided in
the Experimental Section.
The synthetic route developed for cis-(2S,4R)-pyrrolidine
analogues is outlined in Scheme 2. The synthesis began with
(R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (22). Allyla-
tion of 22 using the procedure reported by Gallagher and co-
workers51 gave a mixture of 23a and 23b in a ∼1:1 ratio. Since

4748 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15
Tian et al.
Scheme 2a
a Reagents and conditions: (a) s-BuLi, -78 °C; TMEDA, allyl bromide, THF; (b) NaH, 2-bromomethylnaphthalene, DMF; (c) BH3-THF, H2O2, THF,
NaOH, H2O; (d) MsCl, Et3N, CH2Cl2; (e) NaN3, DMSO, 70 °C; (f) TFA, CH2Cl2; (g) BOC-D-Phe-OH, HOBt, EDCI, NMM, DMF; (h) TFA, CH2Cl2; (i)
acids (ROH), EDCI, HOBt, NMM, DMF; (j) H2, pyridine, Pd/C, CH3OH; (k) 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea, HgCl2, Et3N, DMF;
(l) TFA/anisole/CH2Cl2.
Scheme 3a
a Reagents and conditions: (a) Meldrum’s acid, EDCI, DMAP, CH2Cl2; (b) NaBH4, acetic acid, CH3OH; (c) Cu, pyridine, CH3OH; (d) toluene/EtOH
(5:1), 100 °C; (e) toluene, reflux; (f) LAH, THF; (g) NaH, 2-(bromomethyl)naphthalene, THF; (h) BH3-THF, H2O2, NaOH, H2O, THF.
Proline Analogues. As an initial proof of concept study, we
set out to synthesize and evaluate a series of synthetically
accessible proline analogues that would demonstrate the validity
of our design strategy. Table 2 summarizes a list of initial
proline-based target compounds along with their corresponding
binding affinity and functional activity at MC1R, MC3R, and

Melanocortin Receptor Agonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15 4749
Scheme 4a
a Reagents and conditions: (a) s-BuLi, -78 °C; TMEDA, allyl bromide, THF; (b) NaH, 2-bromomethylnaphthalene, DMF; (c) BH3-THF, H2O2, THF,
NaOH, H2O; (d) MsCl, Et3N, CH2Cl2; (e) NaN3, DMSO, 70 °C; (f) TFA, CH2Cl2.
Table 2. Binding Affinity and Agonist Potency of cis-Proline Analogues 21a-ga
a The data represent the mean of the at least three experiments ( SEM.
MC4R. We were delighted to find that 21a showed single-
nanomolar agonist potency (EC50, 3 nM) at MC1R with a Ki of
13 nM, comparable to those of the corresponding linear analogue
9. Constrained analogue 21a, however, exhibited a significantly
improved selectivity for MC1R over MC4R (∼120-fold, on the
basis of binding affinity). In addition, the noncapped His

4750 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15
Tian et al.
analogue 21b showed binding affinity at MC1R and MC3R
similar to those of analogue 21a and 2-fold better affinity at
MC4R than 21a. The permeability of 21a was also measured
across the Caco-2 cell monolayer. It appeared to be passively
absorbed at a permeability rate lower than that of mannitol
(absorptive and exsorptive permeability coefficients of 0.6 ×
10-4 and 0.3 × 10-4 cm/min, respectively, vs 1.3 × 10-4 and
1.1 × 10-4 cm/min of mannitol, respectively).
five-membered ring proline analogue 35f showed comparable
binding affinity and functional potency profiles to those of six-
membered ring piperidine 35e.
In comparison with the Tyr analogue 35b, the Phe analogue
35g showed ∼2-fold to 3-fold reduced affinity at the MC1R
and MC4R, suggesting that the hydroxyl group on the aromatic
ring of the Tyr moiety plays a role in binding either by forming
a hydrogen bond with receptors or by sterically affecting a key
receptor pocket. However, deletion of the N-terminal group
(-NHAc) from the Phe moiety 35g led to a ∼2-fold to 3-fold
loss in binding affinity. This structural change was more
detrimental to agonist potency at the MC3R and MC4R, and
the resulting analogue 35h became a partial agonist at these
two receptors. A similar trend was also seen with the acetyl
analogue 35i, which was a partial agonist at MC3R and MC4R
but retained significant binding affinity across the three recep-
tors. Nevertheless, acetyl analogue 35i showed significantly
improved Caco-2 permeability than the His analogue 21a
(absorptive and exsorptive permeability coefficients of 4.5 ×
10-4 and 3.7 × 10-4 cm/min, respectively, vs 0.6 × 10-4 and
0.3 × 10-4 cm/min of 21a, respectively). These results clearly
indicated the importance of the N-terminus for agonist potency
at all three receptors. To better understand the effect of capping
the NH2 group of the D-Phe residue with an amino acid or a
simple acid, the tripeptidomimetic 38 was also evaluated. While
38 showed significantly reduced binding affinity and functional
potency than analogues containing a D-Phe-Xaa dipeptide as
the top side chain, it was a full agonist across all three receptors
with EC50 values of 151 and 291 nM, respectively, at MC1R
and MC4R. On the other hand, the corresponding linear
tripeptide D-Phe-Arg-2-Nal-NHCH3 (61) was inactive at MC1R
and MC3R and had a Ki of 2013 nM at MC4R, compared to
305 nM of 38. The discovery of these (2S,4R)-pyrrolidine
analogues with high binding affinity and agonist potency at
MC1R and MC4R provided further compelling evidence sup-
porting our strategy of designing conformationally restricted
Arg-2-Nal dipeptide mimics.
Encouraged by these promising preliminary results, we moved
on to explore other amino acids in place of the His residue to
gain insight into the structure-activity relationship of the top
side chain appended to the constrained proline based dipeptide
mimic (Table 2). In general, all other amino acids surveyed in
this work to replace the His residue produced analogues that
demonstrated significant binding and functional activity across
all three receptors. However, because of the significantly reduced
binding and agonist potency at MC1R observed with these
analogues compared to the His analogue 21a, the selectivity
for MC1R over MC4R was markedly reduced. Among these
compounds, the Tyr analogue 21c showed the weakest affinity
at MC1R but was ∼4-fold selective for MC4R over MC1R. In
comparison with 21a, 21c had a ∼300-fold reduced affinity at
MC1R but exhibited 3-fold better affinity at MC4R and
comparable affinity at MC3R. The use of a constrained Phe
analogue (Tic) gave an analogue (21d) exhibiting ∼4-fold
selectivity for MC4R over MC1R and MC3R. The aromatic
ring of the Tic moiety of 21d seems to have an impact on the
receptor selectivity because the Pip analogue 21e exhibited
3-fold better binding affinity at MC1R and ∼2-fold decreased
affinity at MC4R compared to 21d. An R-amino acid capping
group of the D-Phe residue was important but not obligatory
for biological activity. Moving the piperidine nitrogen from the
2 (21e) to the 4 position (21f) led to a ∼4-fold increase in
binding and agonist potency for MC1R and a marginal decrease
in potency at MC3R and MC4R. The analogue 21g, containing
linear amino acid Gln, also had Ki values below 900 nM at
MC1R and MC4R and was a full agonist of these two receptors.
To further explore the pyrrolidine based Arg-Trp dipeptide
mimetics, we next focused on the effect of stereochemistry at
the two chiral centers of the pyrrolidine ring on binding affinity,
functional activity, and receptor selectivity profile across the
MC1R, MC3R, and MC4R. A study of stereochemical modi-
fication of tetrepeptide 9 and tripeptide Ac-D-Phe-Arg-Trp-NH2
has demonstrated the importance of the chirality related to the
amino acid residues for binding affinity and functional activity.53
To this end, we set out to synthesize and evaluate three other
sets of (2R,4R)-, (2R,4S)-, (2S,4S)-pyrrolidine diastereomers by
using His, Tyr, Tic, Pip, and Gln as the capping groups of the
D-Phe moiety as depicted in Figure 4.
The initial studies with the proline scaffold validated our
constrained dipeptide analogue approach and motivated us to
further explore this design strategy by using other heterocyclic
templates. As a next step, we expanded our effort to include
pyrrolidine analogues illustrated in Figure 3. To this end, a series
of (2S,4R)-pyrrolidine analogues bearing a guanidine moiety
at the 2-position and a naphthyl ring at the 4-position were
synthesized and screened. It was remarkable to find that a
seemingly minor change, replacing of the amide bond of the
C-2 side chain with a methylene group, had such a profound
effect on binding affinity and functional activity across the
MC1R, MC3R, and MC4R, as shown by the data listed in Table
3. The His analogue 35a showed subnanomolar affinity (0.65
nM) and agonist potency (0.3 nM) at MC1R, representing a
20-fold and 10-fold improvement over the proline His analogue
21a. Moreover, 35a had ∼90-fold and ∼30-fold better binding
affinity at MC4R and MC3R, respectively, than 21a. These
dramatic increases in binding affinity and functional potency
across all three receptors were also achieved with Tyr, Tic, Pip,
and Gln analogues within this class. In contrast with the
corresponding proline counterparts, all four analogues had potent
functional activity at the three receptors. In addition, moderate
selectivity for MC4R over MC1 was seen with the Tyr analogue
35b (∼4-fold) and the Tic analogue 35d (∼8-fold). The removal
of the aromatic moiety from the Tic residue of 35d slightly
reduced affinity at the MC4R while maintaining affinity at the
MC1R (35e), thus decreasing the MC4/MC1 selectivity. The
The binding affinity and agonist potency of three sets of
diastereomers are listed in Table 4. The potent and selective
MC1R agonists were identified within the trans (2R,4R) series.
With the exception of the Tyr analogue 42a, all four of the
other compounds showed significant affinity and agonist potency
at MC1R and weak affinity on MC3R and MC4R. The His
analogue 42b had a Ki value of 4.7 nM and an EC50 value of
8.2 nM at MC1R with 3100- and 1480-fold selectivity for MC1R
over MC3R and MC4R, respectively. These data indicated that
inverting the C-2 chirality of cis-pyrrolidine 35a resulted in a
∼60-fold increase in selectivity for MC1R over MC4R.
Similarly, the Tic analogue 42c also exhibited high affinity (Ki,
19 nM) and functional potency (EC50, 19 nM) as well as
excellent selectivity (>200-fold) for MC1R over MC4R.
Within the trans (2S,4S) series, five analogues exhibited

Melanocortin Receptor Agonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15 4751
Table 3. Binding Affinity and Agonist Potency of (2R,4R)-Pyrrolidine Analoguesa
a The data represent the mean of the at least three experiments ( SEM.
Figure 4. Pyrrolidine analogues with (2R,4R), (2R,4S), and (2S,4S) configurations.
moderate to good binding affinity and functional potency across
the three MCRs. In comparison with the corresponding cis
(2S,4R) analogues, compounds from this series (56a-e) were
only slightly less potent and possessed similar receptor selectiv-
ity profiles. These results might suggest that an (S) configuration
at the C-2 position is critical for significant binding affinity and
agonist potency while both (R) and (S) configurations at the
C-4 position are tolerated.
functional potency across all three receptors, with the exception
of the His analogue 60b. Within this series, the most notable
SAR observation was that the His analogue 60b exhibited a Ki
of 14 nM and an EC50 of 9 nM and was >150-fold and >100-
fold selective for MC4 over MC1R and MC3R, respectively.
The importance of the stereochemistry at the C-4 position was
further revealed by comparing 60b with the His analogue 42b
from the (2R,4R) series; inversion of the (R) configuration of
60b to (S)-(42b) converted a potent and selective MC4R agonist
to a potent and selective MC1R agonist.
In contrast with the corresponding cis (2S,4R) analogues, the
cis (2R,4S) analogues showed significantly reduced affinity and

4752 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15
Tian et al.
Table 4. Binding Affinity and Agonist Potency of 42a-e, 56a-e, and 60a-ea
a The data represent the mean of the at least three experiments ( SEM.
Conclusions
Experimental Section
General. Unless otherwise indicated, all reagents were purchased
from commercial suppliers and used without further purification.
TLC analyses were carried out on precoated silica gel plates
(Diamond MK6F). Flash column chromatography was performed
on Merck silica gel 60A (230-400) mesh. Reverse-phase prepara-
tive HPLC purification was carried out using a Varian 320 and a
Varian-A 10 µm (250 mm × 500 mm) column. Analytical HPLC
was performed using an Agilent Polaris C18-A 3 µm column with
15 min linear gradient from 95:5 to 1:99 0.1% H3PO4/CH3CN at a
We have designed and synthesized a series of novel proline
and pyrrolidine based Arg-Nal dipeptide mimics in which two
specific amino acid side chains, the guanidine and naphthyl
moieties, are conformationally restricted by a five-membered
ring template. The coupling of pyrrolidine-derived dipeptide
mimics with a variety of Xaa-D-Phe dipeptides led to the
discovery of a number of potent peptidomimetic MCR agonists.
The stereochemistry at the two chiral centers of the pyrrolidine
ring has been demonstrated to play an important role in affinity,
agonist potency, and selectivity profiles across the MC1R,
MC3R, and MC4R. Among four sets of diastereomers inves-
tigated, cis (2S,4R) analogues showed the best binding affinity
and agonist potency at the three receptors and trans (2S,4S)
analogues displayed moderate to good affinity and agonist
potency. On the other hand, (2R,4S) and (2R,4R) analogues
exhibited significantly reduced potency at MC1R, MC3R,
MC4R compared to the other two sets of analogues with the
(S) configuration at the 2-position of the pyrrolidine ring, with
the exception of the His analogues. The His analogue 42b within
the (2R,4R) series was a potent and selective MC1R agonist,
while the corresponding stereoisomer 60b in the (2R,4S) series
was a potent and selective MC4R agonist. The SAR insights
described in this paper established the viability of the constrained
dipeptide (Arg-Nal) mimic approach for designing peptidomi-
metic melanocortin agonists. These constrained dipeptide mimics
could serve as novel templates for the development of small-
molecule melanocortin agonists as potential therapeutic agents.
Our subsequent efforts at further optimization of the constrained
dipeptide (Arg-Nal) mimic demonstrated that the bulky naphthyl
group could be replaced with a phenyl group, thus offering an
additional opportunity for further reduction of molecular weight.
These results and the extension of the design strategy described
above to other cyclic scaffolds will be reported in due course.
1
flow rate of 1 mL/min with UV detection at 215 and 254 nm. H
NMR spectra were recorded on a Varian INOVA-300 NMR
spectrometer and were reported as parts per million (ppm) relative
to Me4Si as internal reference. Mass spectra data were determined
on a Micromass ZMD-4000. Elemental analyses (C, H, N) were
performed on a LECO CHNS-932 elemental analyzer.
Binding and Functional Assays. The agonist activity of MCR
ligands was evaluated at three human MCR using a cell based assay
that is specific for each subtype of MCR (MC1R, MC3R, MC4R).
Each subtype of receptor was stably transfected into HEK293 cells.
The MCR expressing cells were next stably transfected with a
reporter system consisting of a cyclic-AMP responsive element
(CRE) coupled to a luciferase reporter gene. Agonist activity was
determined by assaying cells in 96-well plates. Cells were seeded
at 2 × 104/well in 200 µL of DMEM containing 10% FBS, 1%
amino acids, 0.1% L-glutamine and incubated at 37 °C plus 5%
CO2. The next day the media was removed from the cells and
replaced with 100 µL of diluted compound in DMEM containing
0.01% BSA. After plates were incubated for 4 h at 37 °C and 5%
CO2, the compounds were removed and 30 µL of Steady Glo
luciferase reagent (Promega E 2650) was added to each well. After
20 min at room temperature, the luciferase luminescence was
determined on a Wallac TriLux reader. Responses were compared
to the effect of NDP-MSH (MT-I) and expressed as a percentage
of maximum activity of MT-1 (Emax). MT-1 is considered to be
a full agonist at each of the three MCR subtypes.
Binding activity was measured using a cell based assay specific
for each subtype of MCR (MC1R, MC3R, MC4R) stably expressed

Melanocortin Receptor Agonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15 4753
in HEK293 cells. Cells were seeded in 96-well poly-L-lysine coated
plates as described above. The media were removed from the cells
the next day and replaced with 100 µL of diluted compound in
DMEM, 10% SeaBlock (Pierce 37527), and 10 nM of NDP-MSH-
EU (Perkin-Elmer CR339-100). Plates were incubated at room
temperature for 90 min and washed four times with PBS. An
amount of 100 µL of enhancement solution (Wallac 1244-105)
was added, and plates were shaken for 20 min at room temperature.
Europium fluorescence was detected using time-resolved fluorom-
etry on Wallac Victor. Binding activity (calculated as IC50 and Ki
values) was determined by measuring the displacement of a constant
concentration of europium labeled NDP-R-MSH with competing
unlabeled ligands.
(2R,4R)-1-(tert-Butoxycarbonyl)-4-(naphthalen-2-ylmethoxy)-
pyrrolidine-2-carboxylic Acid (13). To a solution of Boc-cis-4-
hydroxy-D-proline (7.25 g, 31.4 mmol) in THF (50 mL) was added
sodium hydride (60% in oil, 2.76 g, 69.0 mmol) in portions at 0
°C. The reaction mixture was stirred for 45 min, and a solution of
2-(bromomethyl)naphthalene (15.6 g, 70.6 mmol) in THF (20 mL)
was slowly added. The mixture was stirred at room temperature
for 20 h, quenched with H2O (100 mL), and extracted with Et2O.
The aqueous layer was acidified with 6 N HCl and extracted with
CH2Cl2. The extract was dried over MgSO4 and concentrated to
give a pale-yellow oil (8.1 g), which was used for the next reaction
without further purification. 1H NMR (300 MHz, CDCl3) δ 7.65-
7.90 (m, 4H), 7.30-7.60 (m, 3H), 4.30-4.80 (m, 3H), 4.13 (m,
1H), 3.45-3.80 (m, 2H), 2.00-2.80 (m, 2H), 1.48 (d, 9H); MS
(ESI) m/z 272 (M + H).
mmol) in CH2Cl2 (20 mL) was added TFA (5 mL), and the reaction
mixture was stirred for 3.0 h. It was then concentrated, and the
residue was dried under high vacuum to give amine 17 as a pale-
yellow oil in a quantitative yield. 1H NMR (300 MHz, CD3OD) δ
7.70-7.90 (m, 4H), 7.20-7.55 (m, 13H), 5.04-5.10 (m, 2H),
4.40-4.70 (m, 3H), 4.26 (m, 1H), 3.00-4.10 (m, 9H), 1.60-2.50
(m, 2H); MS (ESI) m/z 596 (M + H).
Benzyl 2-((2R,4R)-1-((R)-2-((S)-2-Acetamido-3-(1-trityl-1H-
imidazol-4-yl)propanamido)-3-phenylpropanoyl)-4-(naphthalen-
2-ylmethoxy)pyrrolidine-2-carboxamido)ethylcarbamate (18a).
To a solution of amine 17 (347 mg, 0.49 mmol) in DMF (3 mL)
were added Ac-His(1-Trt)-OH (258 mg, 0.59 mmol), HOBt (149
mg, 1.10 mmol), NMM (303 mg, 3.00 mmol), and EDCI (105 mg,
0.59 mmol) consecutively, and the reaction mixture was stirred for
3.0 h. It was quenched with aqueous NH4Cl and extracted with
EtOAc. The extract was dried over Na2SO4, filtered, and concen-
trated. The residue was chromatographed (silica gel, eluent CH2-
Cl2/acetone, 15:1) to give 18a as a white solid (180 mg, 36% yield).
1H NMR (300 MHz, CDCl3) δ 6.40-8.40 (m, 34H), 2.70-5.10
(m, 18H), 2.40-2.70 (m, 1H), 1.90-2.10 (m, 4H); MS (ESI) m/z
1016 (M + H).
N-(tert-Butoxycarbonyl)-1-trityl-L-histidyl-D-phenylalanyl-
(4R)-N-(2-{[(benzyloxy)carbonyl]amino}ethyl)-4-(2-naphthyl-
methoxy)-D-prolinamide (18b). 18b was synthesized from 17 as
described for preparation of 18a in 69% yield as a white solid. 1H
NMR (300 MHz, CD3OD) δ 7.10-8.00 (m, 34H), 4.90-5.10 (m,
2H), 4.10-4.70 (m, 4H), 2.20-4.10 (m, 14H), 1.30-1.42 (m, 9H);
MS (ESI) m/z 1074 (M + H).
(2R,4R)-tert-Butyl 2-(2-(Benzyloxycarbonylamino)ethylcarbam-
oyl)-4-(naphthalen-2-ylmethoxy)pyrrolidine-1-carboxylate (14).
To a solution of 13 (8.1 g, 21.8 mmol) in DMF (80 mL) were
added N-1-CBZ-1,2-diaminoethane‚HCl (4.75 g, 20.6 mmol), HOBt
(5.06 g, 37.5 mmol), NMM (10.7 g, 105.5 mmol), and EDCI (4.44
g, 23.1 mmol) consecutively, and the reaction mixture was stirred
for 3.5 h. It was quenched with aqueous NH4Cl and extracted with
EtOAc. The extract was dried over Na2SO4, filtered, and concen-
trated. The residue was chromatographed (silica gel, eluent CH2-
Cl2/acetone, 8:1) to give the amide 14 as a viscous oil (5.8 g, 34%
Benzyl 2-((2R,4R)-1-((R)-2-((S)-2-Acetamido-3-(4-hydroxy-
phenyl)propan-amido)-3-phenylpropanoyl)-4-(naphthalen-2-yl-
methoxy)pyrrolidine-2-carboxamido)ethylcarbamate (18c). 18c
was synthesized from 17 as described for preparation of 18a in
1
31% yield as a foam. H NMR (300 MHz, CD3OD) δ 7.60-7.90
(m, 4H), 6.60-7.50 (m, 17H), 5.00-5.10 (m, 2H), 4.40-4.90 (m,
4H), 2.60-4.30 (m, 12H), 1.30-2.50 (m, 5H); MS (ESI) m/z 800
(M + H).
(S)-tert-Butyl 3-((R)-1-((2R,4R)-2-(2-(Benzyloxycarbonylami-
no)ethylcarbamoyl)-4-(naphthalen-2-ylmethoxy)pyrrolidin-1-yl)-
1-oxo-3-phenylpropan-2-ylcarbamoyl)-3,4-dihydroisoquinoline-
2(1H)-carboxylate (18d). 18d was synthesized from 17 as described
for preparation of 18a in 30% yield as a foam. 1H NMR (300 MHz,
CDCl3) δ 7.00-8.00 (m, 21H), 4.20-5.20 (m, 10H), 2.70-4.00
(m, 10H), 1.20-2.70 (m, 11H); MS (ESI) m/z 854 (M + H).
(S)-tert-Butyl 2-((R)-1-((2R,4R)-2-(2-(Benzyloxycarbonylami-
no)ethylcarbamoyl)-4-(naphthalen-2-ylmethoxy)pyrrolidin-1-yl)-
1-oxo-3-phenylpropan-2-ylcarbamoyl)piperidine-1-carboxyl-
ate (18e). 18e was synthesized from 17 as described for preparation
1
yield over two steps). H NMR (300 MHz, CDCl3) δ 7.70-7.90
(m, 4H), 7.20-7.60 (m, 8H), 5.10-5.40 (m, 1H), 5.05 (s, 2H),
4.50-4.70 (m, 2H), 4.37 (m, 1H), 4.16 (m, 1H), 3.00-4.10 (m,
6H), 2.40-2.90 (m, 1H), 2.10-2.40 (s, 1H), 1.46 (s, 9H); MS (ESI)
m/z 548 (M + H).
Benzyl 2-((2R,4R)-4-(Naphthalen-2-ylmethoxy)pyrrolidine-2-
carboxamido)ethylcarbamate (15). To a solution of 14 (2.47 g,
4.52 mmol) in CH2Cl2 (10 mL) was added TFA (2 mL), and the
reaction mixture was stirred for 3.0 h. It was then concentrated
and further dried under high vacuum to give a pale-yellow oil, which
was used for the next reaction without further purification (2.40
1
of 18a in 31% yield as a foam. H NMR (300 MHz, CDCl3) δ
7.10-8.00 (m, 17H), 4.4 0-5.00 (m, 6H), 2.80-4.20 (m, 12H),
2.64 (m, 1H), 1.20-2.30 (m, 16H); MS (ESI) m/z 806 (M + H).
tert-Butyl 4-((R)-1-((2R,4R)-2-(2-(Benzyloxycarbonylamino)-
ethylcarbamoyl)-4-(naphthalen-2-ylmethoxy)pyrrolidin-1-yl)-1-
oxo-3-phenylpropan-2-ylcarbamoyl)piperidine-1-carboxylate (18f).
18f was synthesized from 17 as described for preparation of 18a
in 34% yield as a foam. 1H NMR (300 MHz, CDCl3) δ 7.10-8.00
(m, 12H), 4.90-5.10 (m, 2H), 4.30-4.60 (m, 3H), 3.60-4.20 (m,
5H), 3.30-3.50 (m, 1H), 2.90-3.30 (m, 8H), 1.20-2.30 (m, 16H);
MS (ESI) m/z 806 (M + H).
1
g). H NMR (300 MHz, CDCl3) δ 8.00 (m, 1H), 7.70-7.85 (m,
4H), 7.25-7.54 (m, 8H), 5.05 (s, 2H), 4.66 (d, J ) 12.2 Hz, 2H),
4.56 (d, J ) 12.2 Hz, 1H), 3.82 (dd, J ) 9.6, 3.0 Hz, 1H), 3.42 (m,
1H), 3.12-3.30 (m, 5H), 2.42-2.56 (m, 2H), 2.14 (m, 1H); MS
(ESI) m/z 448 (M + H).
N-(tert-Butoxycarbonyl)-D-phenylalanyl-(4R)-N-(2-{[(benzyl-
oxy)carbonyl]amino}ethyl)-4-(2-naphthylmethoxy)-D-prolinamide
(16). To a solution of the TFA salt of amine 15 (2.40 g, 4.39 mmol)
in DMF (10 mL) were added BOC-D-Phe-OH (1.44 g, 5.43 mmol),
HOBt (1.34 g, 9.92 mmol), NMM (2.30 g, 22.68 mmol), and EDCI
(1.04 g, 5.43 mmol) consecutively, and the reaction mixture was
stirred for 3.0 h. It was quenched with aqueous NH4Cl solution
and extracted with EtOAc. The extract was dried over Na2SO4,
filtered, and concentrated. The residue was chromatographed (silica
gel, eluent CH2Cl2/acetone, 15:1) to give the amide 16 as a pale-
Benzyl 2-((2R,4R)-1-((R)-2-((S)-2-Acetamido-5-amino-5-oxo-
pentanamido)-3-phenylpropanoyl)-4-(naphthalen-2-ylmethoxy)-
pyrrolidine-2-carboxamido)ethylcarbamate (18g). 18g was syn-
thesized from 17 as described for preparation of 18a in 37% yield
1
as a foam. H NMR (300 MHz, CDCl3) δ 6.80-8.00 (m, 17H),
4.20-5.20 (m, 7H), 2.70-4.10 (m, 9H), 1.20-2.70 (m, 9H); MS
(ESI) m/z 765 (M + H).
1
yellow oil (2.95 g, 96% yield). H NMR (300 MHz, CDCl3) δ
7.10-8.00 (m, 17 H), 5.40-5.70 (m, 2H), 4.90-5.20 (m, 2H),
4.00-4.80 (m, 4H), 2.80-4.00 (m, 9H), 2.58 (m, 1H), 1.90-2.10
(m, 1H), 1.20-1.50 (m, 9H); MS (ESI) m/z 695 (M + H).
Benzyl 2-((2R,4R)-1-((R)-2-Amino-3-phenylpropanoyl)-4-
(naphthalen-2-ylmethoxy)pyrrolidine-2-carboxamido)ethylcar-
bamate (17). To a solution of the BOC substrate 16 (2.95 g, 4.25
(2R,4R)-1-((R)-2-((S)-2-Acetamido-3-(1-trityl-1H-imidazol-4-
yl)propanamido)-3-phenylpropanoyl)-N-(2-aminoethyl)-4-(naph-
thalen-2-ylmethoxy)pyrrolidine-2-carboxamide (19a). To a so-
lution of the Cbz substrate 18a (180 mg, 0.18 mmol)) in methanol
(5 mL) were added Pd/C (70 mg) and pyridine (0.02 mL, 0.26
mmol), and the reaction mixture was stirred for 3.0 h. The mixture

4754 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15
Tian et al.
was then filtered through a short pad of Celite, and the filtrate was
concentrated to give the title compound (140 mg, 89% yield) as a
white solid, which was used for the next reaction without further
purification. 1H NMR (300 MHz, CDCl3) δ 7.00-8.40 (m, 29 H),
2.80-5.10 (m, 16H), 1.80-2.50 (m, 5H); MS (ESI) m/z 882 (M +
H).
NMR (300 MHz, CD3OD) δ 6.60-8.00 (m, 16H), 3.90-4.80 (m,
5H), 2.60-3.80 (m, 11H), 1.30-2.60 (m, 23H); MS (ESI) m/z 908
(M + H).
(S)-tert-Butyl 3-((R)-1-((2R,4R)-2-(2-((Z)-2,3-Bis(tert-butoxy-
carbonyl)guanidino)ethylcarbamoyl)-4-(naphthalen-2-ylmethoxy)-
pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-ylcarbamoyl)-3,4-di-
hydroisoquinoline-2(1H)-carboxylate (20d). 20d was synthesized
tert-Butyl (S)-1-((R)-1-((2R,4R)-2-(2-Aminoethylcarbamoyl)-
4-(naphthalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpro-
pan-2-ylamino)-1-oxo-3-(1-trityl-1H-imidazol-4-yl)propan-2-
ylcarbamate (19b). 19b was synthesized from 18b as described
1
from 19d as described for 20a in 55% yield as a white solid. H
NMR (300 MHz, CDCl3) δ 7.00-8.00 (m, 16H), 2.80-5.00 (m,
18H), 1.20-2.70 (m, 29H); MS (ESI) m/z 962 (M + H).
1
for 19a in 96% yield as a white solid. H NMR (300 MHz, CD3-
(S)-tert-Butyl 2-((R)-1-((2R,4R)-2-(2-((Z)-2,3-Bis(tert-butoxy-
carbonyl)guanidino)ethylcarbamoyl)-4-(naphthalen-2-ylmethoxy)-
pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-ylcarbamoyl)piperidine-
1-carboxylate (20e). 20e was synthesized from 19e as described
for 20a in 49% yield as a white solid. 1H NMR (300 MHz, CDCl3)
δ 7.10-8.00 (m, 12H), 4.30-5.00 (m, 4H), 2.50-4.30 (m, 12H),
1.20-2.40 (m, 35H); MS (ESI) m/z 914 (M + H).
tert-Butyl 4-((R)-1-((2R,4R)-2-(2-((Z)-2,3-Bis(tert-butoxycar-
bonyl)guanidino)ethylcarbamoyl)-4-(naphthalen-2-ylmethoxy)-
pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-ylcarbamoyl)piperidine-
1-carboxylate (20f). 20f was synthesized from 19f as described
for 20a in 55% yield as a white solid. 1H NMR (300 MHz, CDCl3)
δ 7.20-8.00 (m, 12H), 3.90-4.60 (m, 6H), 2.40-3.80 (m, 11H),
1.20-2.40 (m, 34H); MS (ESI) m/z 914 (M + H).
OD) δ 7.10-8.00 (m, 29H), 4.20-4.70 (m, 4H), 2.10-4.20 (m,
14H), 1.36-1.46 (m, 9H); MS (ESI) m/z 940 (M + H).
(2R,4R)-1-((R)-2-((S)-2-Acetamido-3-(4-hydroxyphenyl)pro-
panamido)-3-phenylpropanoyl)-N-(2-aminoethyl)-4-(naphthalen-
2-ylmethoxy)pyrrolidine-2-carboxamide (19c). 19c was synthe-
1
sized from 18c as described for 19a in 96% yield as a foam. H
NMR (300 MHz, CD3OD) δ 6.60-8.00 (m, 16H), 2.50-4.90 (m,
16H), 1.20-2.50 (m, 5H); MS (ESI) m/z 666 (M + H).
(S)-tert-Butyl 3-((R)-1-((2R,4R)-2-(2-Aminoethylcarbamoyl)-
4-(naphthalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpro-
pan-2-ylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)carboxyl-
ate (19d). 19d was synthesized from 18d as described for 19a in
1
79% yield as a foam. H NMR (300 MHz, CDCl3) δ 7.00-8.00
(m, 16H), 4.00-5.00 (m, 6H), 2.50-4.00 (m, 12H), 1.20-2.40 (m,
11H); MS (ESI) m/z 720 (M + H).
(Z)-tert-Butyl 1-((2R,4R)-1-((R)-2-((S)-2-Acetamido-5-amino-
5-oxopentanamido)-3-phenylpropanoyl)-4-(naphthalen-2-yl-
methoxy)pyrrolidin-2-yl)-10,10-dimethyl-1,8-dioxo-9-oxa-2,5,7-
triazaundecan-6-ylidenecarbamate (20g). 20g was synthesized
(S)-tert-Butyl 2-((R)-1-((2R,4R)-2-(2-Aminoethylcarbamoyl)-
4-(naphthalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpro-
pan-2-ylcarbamoyl)piperidine-1-carboxylate (19e). 19e was syn-
thesized from 18e as described for 19a in 90% yield as a foam. 1H
NMR (300 MHz, CDCl3) δ 7.10-8.00 (m, 12H), 4.30-5.00 (m,
4H), 2.80-4.40 (m, 12H), 1.10-2.50 (m, 16H); MS (ESI) m/z 672
(M + H).
1
from 19g as described for 20a in 74% yield as a white solid. H
NMR (300 MHz, CD3OD) δ 7.70-7.90 (m, 4H), 7.20-7.60 (m,
8H), 4.00-4.80 (m, 5H), 2.90-3.90 (m, 9H), 1.20-2.60 (m, 27H);
MS (ESI) m/z 775 (M + H).
(2R,4R)-1-((R)-2-((S)-2-Acetamido-3-(1H-imidazol-4-yl)pro-
panamido)-3-phenylpropanoyl)-N-(2-guanidinoethyl)-4-(naph-
thalen-2-ylmethoxy)pyrrolidine-2-carboxamide (21a). To a so-
lution of the Boc substrate 20a (230 mg, 0.19 mmol) in CH2Cl2 (5
mL) was added trifluoroacetic acid (2 mL), and the reaction mixture
was stirred for 4.0 h. It was then concentrated, and the residue was
subjected to reverse-phase HPLC purification to give a TFA salt
tert-Butyl 4-((R)-1-((2R,4R)-2-(2-Aminoethylcarbamoyl)-4-
(naphthalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-
2-ylcarbamoyl)piperidine-1-carboxylate (19f). 19f was synthe-
1
sized from 18f as described for 19a in 99% yield as a foam. H
NMR (300 MHz, CDCl3) δ 7.00-8.00 (m, 12H), 4.30-4.70 (m,
2H), 3.30-4.30 (m, 7H), 2.40-3.30 (m, 8H), 1.20-2.40 (m, 16H);
MS (ESI) m/z 672 (M + H).
1
of the title compound (65 mg). H NMR (300 MHz, CD3OD) δ
8.30-8.90 (m, 1H), 7.70-7.90 (m, 4H), 7.00-7.60 (m, 9H), 4.30-
4.80 (m, 5H), 4.00-4.20 (m, 1H), 3.60-3.80 (m, 2H), 2.80-3.30
(m, 8H), 1.40-2.60 (m, 5H); MS (ESI) m/z 682 (M + H). Anal.
(C34H41N9O4‚3.2CF3CO2H) C, H, N.
(S)-2-Acetamido-N1-((R)-1-((2R,4R)-2-(2-aminoethylcarbam-
oyl)-4-(naphthalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenyl-
propan-2-yl)pentanediamide (19g). 19g was synthesized from 18g
as described for 19a in 99% yield as a foam. 1H NMR (300 MHz,
CD3OD) δ 7.00-8.00 (m, 12H), 2.70-4.90 (m, 14H), 1.20-2.70
(m, 9H); MS (ESI) m/z 631 (M + H).
(2R,4R)-1-((R)-2-((S)-2-Amino-3-(1H-imidazol-4-yl)propan-
amido)-3-phenylpropanoyl)-N-(2-guanidinoethyl)-4-(naphthalen-2-
ylmethoxy)pyrrolidine-2-carboxamide (21b). 21b was synthesized
(Z)-tert-Butyl 1-((2R,4R)-1-((R)-2-((S)-2-acetamido-3-(1-trityl-
1H-imidazol-4-yl)propanamido)-3-phenylpropanoyl)-4-(naph-
thalen-2-ylmethoxy)pyrrolidin-2-yl)-10,10-dimethyl-1,8-dioxo-
9-oxa-2,5,7-triazaundecan-6-ylidenecarbamate (20a). To a solution
of amine 19a (140 mg, 0.31 mmol) in DMF (2 mL) were added N,
N′-di-Boc-(S)-methylisothiourea (56 mg, 0.19 mmol), HgCl2 (54
mg, 0.20 mmol), and triethylamine (49 mg, 0.48 mmol) consecu-
tively, and the reaction mixture was stirred for 3.0 h. It was filtered
through a short pad of Celite, and the filtrate was concentrated.
The residue was subjected to column chromatography (silica gel,
CH2Cl2/acetone, 15:1) to give the amide 20a (120 mg, 69% yield).
1H NMR (300 MHz, CDCl3) δ 7.00-8.40 (m, 29 H), 2.90-5.10
(m, 16H), 1.40-2.60 (m, 23H); MS (ESI) m/z 1125 (M + H).
N-(tert-Butoxycarbonyl)-1-trityl-L-histidyl-D-phenylalanyl-
(4R)-N-[2-({(Z)-[tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)-
imino]methyl}amino)ethyl]-4-(2-naphthylmethoxy)-D-prolin-
amide (20b). 20b was synthesized from 19b as described for 20a
in 63% yield as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.10-
8.00 (m, 29H), 4.20-4.70 (m, 4H), 2.10-4.10 (m, 14H), 1.30-
1.60 (m, 27H); MS (ESI) m/z 1182 (M + H).
1
from 20b as described for 21a. H NMR (300 MHz, CD3OD) δ
8.70-8.90 (m, 1H), 7.70-7.95 (m, 4H), 7.20-7.60 (m, 9H), 4.10-
4.80 (m, 6H), 3.50-3.90 (m, 2H), 2.20-3.40 (m, 10H); MS (ESI)
m/z 640 (M + H). Anal. (C34H41N9O4‚4.3CF3CO2H) C, H, N.
(2R,4R)-1-((R)-2-((S)-2-Acetamido-3-(4-hydroxyphenyl)pro-
panamido)-3-phenylpropanoyl)-N-(2-guanidinoethyl)-4-(naph-
thalen-2-ylmethoxy)pyrrolidine-2-carboxamide (21c). 21c was
1
synthesized from 20c as described for 21a. H NMR (300 MHz,
CD3OD) δ 7.70-7.90 (m, 4H), 7.15-7.60 (m, 10H), 6.60-6.80
(m, 2H), 4.20-4.70 (m, 5H), 4.00-4.20 (m, 1H), 3.50-3.75 (m,
2H), 2.60-3.40 (m, 8H), 1.30-2.50 (m, 5H); MS (ESI) m/z 708
(M + H). Anal. (C39H45N7O6‚1.6CF3CO2H) C, H, N.
(S)-N-((R)-1-((2R,4R)-2-(2-Guanidinoethylcarbamoyl)-4-(naph-
thalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-
yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (21d). 21d was
1
synthesized from 20d as described for 21a. H NMR (300 MHz,
CD3OD) δ 7.70-7.90 (m, 4H), 7.20-7.50 (m, 12H), 4.00-4.90
(m, 8H), 2.90-3.80 (m, 10H), 1.50-2.60 (m, 2H); MS (ESI) m/z
662 (M + H). Anal. (C38H43N7O4‚3.0CF3CO2H) C, H, N.
(Z)-tert-Butyl 1-((2R,4R)-1-((R)-2-((S)-2-Acetamido-3-(4-hy-
droxyphenyl)propanamido)-3-phenylpropanoyl)-4-(naphthalen-
2-ylmethoxy)pyrrolidin-2-yl)-10,10-dimethyl-1,8-dioxo-9-oxa-
2,5,7-triazaundecan-6-ylidenecarbamate (20c). 20c was synthesized
(S)-N-((R)-1-((2R,4R)-2-(2-Guanidinoethylcarbamoyl)-4-(naph-
thalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-
yl)piperidine-2-carboxamide (21e). 21e was synthesized from 20e
as described for 21a. H NMR (300 MHz, CD3OD) δ 7.70-8.00
(m, 3H), 7.15-7.60 (m, 9H), 4.30-5.00 (m, 4H), 2.80-4.30 (m,
1
1
from 19c as described for 20a in 84% yield as a white solid. H

Melanocortin Receptor Agonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15 4755
12H), 1.20-2.40 (m, 8H); MS (ESI) m/z 614 (M + H). Anal.
(C34H43N7O4‚3.0CF3CO2H) C, H, N.
the addition of aqueous NaOH solution (3.0 M, 7.3 mL) and 33%
H2O2 (5.0 mL). The mixture was stirred for 2 h and extracted with
EtOAc (50 mL). The organic layer was then dried over Na2SO4,
filtered, and evaporated to a yellow oil. The oil residue was purified
by chromatography (silica gel, eluent hexanes/EtOAc, 1:1) to give
25 (712 mg, 25% yield) and 26 (879 mg, 33% yield) as clear oils.
cis-25. 1H NMR (300 MHz, CDCl3) δ 7.80-7.90 (m, 4H), 7.45-
7.55 (m, 3H), 4.70 (s, 2H), 4.18 (m, 1H), 3.93 (m, 1H), 3.72 (m,
2H), 3.49 (dd, J ) 12.2, 2.8 Hz, 1H), 1.90-2.25 (m, 3H), 1.50-
1.80 (m, 3H), 1.49 (s, 9H); MS (ESI) m/z 386 (M + 1).
N-((R)-1-((2R,4R)-2-(2-Guanidinoethylcarbamoyl)-4-(naph-
thalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-
yl)piperidine-4-carboxamide (21f). 21f was synthesized from 20f
1
as described for 21a. H NMR (300 MHz, CDCl3) δ 7.10-8.00
(m, 12H), 4.50-4.80 (m, 4H), 4.00-4.20 (m, 1H), 2.80-3.80 (m,
12H), 1.30-2.80 (m, 7H); MS (ESI) m/z 614 (M + H). Anal.
(C34H43N7O4‚2.5CF3CO2H) C, H, N.
(S)-2-Acetamido-N1-((R)-1-((2R,4R)-2-(2-guanidinoethylcar-
bamoyl)-4-(naphthalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-
phenylpropan-2-yl)pentanediamide (21g). 21g was synthesized
1
trans-26. H NMR (300 MHz, CDCl3) δ 7.78-7.90 (m, 4H),
7.40-7.55 (m, 3H), 4.72 (d, J ) 11.8 Hz, 1H), 4.66 (d, J ) 11.8
Hz, 1H), 4.19 (m, 1H), 4.03 (m, 1H), 3.65-3.78 (m, 3H), 3.44
(dd, J ) 11.8, 4.9 Hz, 1H), 1.40-2.30 (m, 15H); MS (ESI) m/z
386 (M + 1).
1
from 20g as described for 21a. H NMR (300 MHz, CD3OD) δ
7.70-7.90 (m, 4H), 7.00-7.50 (m, 8H), 4.00-4.80 (m, 5H), 2.90-
3.40 (m, 9H), 1.20-2.80 (m, 9H). MS (ESI) m/z 673 (M + H).
Anal. (C35H44N8O6‚1.9CF3CO2H) C, H, N.
(2S,4R)-tert-Butyl 2-(3-Azidopropyl)-4-(naphthalen-2-ylmeth-
oxy)pyrrolidine-1-carboxylate (28). To a stirred solution of 25
(712 mg, 1.85 mmol) in dichloromethane (6 mL) were added
triethylamine (0.39 mL, 2.77 mmol) and methanesulfonyl chloride
(0.215 mL, 2.77 mmol) at 0 °C, and the reaction mixture was stirred
at room temperature for 0.75 h. The reaction was quenched with
saturated aqueous NaHCO3 solution and extracted twice with
dichloromethane (25 mL). The combined organic layers were dried
over Na2SO4, filtered, and evaporated to give 27 as an oil that was
sufficiently pure for the next reaction without further purification.
Sodium azide (361 mg, 5.50 mmol) was added to a solution of
27 (856 mg) in DMSO (7 mL), and the reaction mixture was stirred
at 70 °C for 3 h. The reaction was quenched with H2O and extracted
with EtOAc (30 mL). The extract was dried over Na2SO4, filtered,
and evaporated to an orange oil. The oil residue was purified by
chromatography (silica gel, eluent hexanes/EtOAc, 3:1) to give 28
(2S,4R)-tert-Butyl 2-Allyl-4-hydroxypyrrolidine-1-carboxylate
(23a) and (2R,4R)-tert-Butyl 2-Allyl-4-hydroxypyrrolidine-1-
carboxylate (23b). To a solution of 4-hydroxylpyrrolidine 22 (3.0
g, 16.0 mmol) and TMEDA (6.4 mL, 40.1 mmol) was added a
solution of sec-butyllithium (1.3 M, 50 mL) in cyclohexanes at
-78 °C with stirring. The resultant orange mixture was warmed to
-40 °C and stirred for 2.75 h. The mixture was then cooled to
-78 °C, and allyl bromide (3.1 mL, 35.3 mmol) was added. The
reaction mixture was slowly warmed to room temperature with
stirring over 4.5 h. It was quenched with aqueous NH4Cl solution
and extracted with ethyl acetate (150 mL). The organic layer was
dried over Na2SO4, filtered, and concentrated. The oil residue was
purified by chromatography (silica gel, eluent CH2Cl2/acetone, 4:1)
to give a mixture of 23a and 23b (2.1 g, 58% yield) as a clear oil.
The small amount of the mixture was purified by preparative
reverse-phase HPLC to give pure isomers 23a and 23b for
characterization.
1
(584 mg, 78%) as a colorless oil. H NMR (300 MHz, CDCl3) δ
7.80-7.90 (m, 4 H), 7.40-7.55 (m, 3H), 4.71 (s, 2H), 4.18 (m,
1H), 3.85 (m, 1H), 3.71 (dd, J ) 12.0, 5.4 Hz, 1H), 3.49 (dd, J )
12.0, 3.0 Hz, 1H), 3.31 (m, 2H), 2.10-2.30 (m, 1H), 1.80-2.05
(m, 2H), 1.60-1.80 (m, 3H), 1.50 (s, 9H); MS (ESI) m/z 411 (M
+ 1).
1
cis-23a. H NMR (300 MHz, CDCl3) δ 5.80 (m, 1H), 5.12 (m,
2H), 4.44 (m, 1H), 3.88 (m, 1H), 3.70 (dd, J ) 11.9, 5.6 Hz, 1H),
3.32 (ddd, J ) 11.9, 3.3, 1.2 Hz, 1H), 2.68 (m, 1H), 2.45 (m, 1H),
2.18 (m, 1H), 1.80-1.98 (m, 2H), 1.50 (s, 9H); MS (ESI) m/z 172
(M + H - 56).
(2R,4R)-tert-Butyl 2-(3-Azidopropyl)-4-(naphthalen-2-ylmeth-
oxy)pyrrolidine-1-carboxylate (40). 40 was synthesized from 24b
as described for preparation of 28. 1H NMR (300 MHz, CDCl3) δ
7.75-7.90 (m, 4H), 7.40-7.55 (m, 3H), 4.68 (m, 2H), 4.18 (m,
1H), 3.99 (m, 1H), 3.78 (d, J ) 12.0 Hz, 1H), 3.40 (dd, J ) 12.0,
4.8 Hz, 1H), 3.32 (m, 2H), 2.20-2.30 (m, 1H), 1.75-2.00 (m, 2H),
1.40-1.70 (m, 12H); MS (ESI) m/z 411 (M + 1).
(2S,4R)-2-(3-Azidopropyl)-4-(naphthalen-2-ylmethoxy)pyrro-
lidine (29). The Boc analogue 28 (2.85 g, 6.95 mmol) was dissolved
into a prepared solution of TFA/H2O/CH2Cl2 (1:0.1:1, 20 mL), and
1
trans-23b. H NMR (300 MHz, CDCl3) δ 5.73 (m, 1H), 5.11
(m, 2H), 4.41 (m, 1H), 4.03 (m, 1H), 3.57 (m, 1H), 3.40 (dd, J )
11.9, 3.8 Hz, 1H), 2.53 (m, 1H), 2.31 (m, 1H), 2.05 (m, 1H), 1.89
(m, 1H), 1.50 (s, 9H); MS (ESI) m/z 172 (M + H - 56).
(2S,4R)-tert-Butyl 2-Allyl-4-(naphthalen-2-ylmethoxy)pyrro-
lidine-1-carboxylate (24a) and (2R,4R)-tert-Butyl 2-Allyl-4-
(naphthalen-2-ylmethoxy)pyrrolidine-1-carboxylate (24b). To a
stirred solution of 23 (2.0 g, 8.8 mmol) in DMF (10 mL) was added
sodium hydride (408 mg, 11.5 mmol) in portions at 0 °C, and the
reaction mixture was stirred for 20 min. A solution of 2-(bromom-
ethyl)naphthalene (2.9 g, 13.2 mmol) in DMF (5 mL) was then
added, and the resulting solution was stirred for 5.0 h at room
temperature. The reaction mixture was quenched with aqueous NH4-
Cl solution and extracted with ethyl acetate. The extract was dried
over Na2SO4, filtered, and evaporated to a yellow oil. The oil residue
was purified by chromatography (silica gel, eluent hexanes/EtOAc,
4:1) to give a mixture of 24a and 24b (2.7 g, 84%) as a clear oil.
the reaction mixture was stirred for 1.0 h. The mixture was
concentrated to give 29 (3.0 g, 100%) as a TFA salt. The crude oil
was carried forward for the next reaction without further purifica-
tion.
1H NMR (300 MHz, CDCl3) δ 7.75-8.00 (m, 4H), 7.40-
7.60 (m, 3H), 4.60-4.80 (m, 2H), 4.33 (m, 1H), 3.68 (m, 1H),
3.51 (m, 1H), 3.39 (m, 3H), 2.30-2.50 (m, 1H), 1.60-2.20 (m,
6H); MS (ESI) m/z 311 (M + H).
(2R,4R)-2-(3-Azidopropyl)-4-(naphthalen-2-ylmethoxy)pyrro-
lidine (41). 41 was synthesized from 40 as described for preparation
1
cis-24a. H NMR (300 MHz, CDCl3) δ 7.80-7.90 (m, 4H),
1
7.45-7.60 (m, 3H), 5.83 (m, 1H), 5.14 (m, 2H), 4.71(m, 2H), 4.17
(m, 1H), 3.50-4.00 (m, 3H), 2.60-2.80 (m, 1H), 2.47 (m, 1H),
2.10 (m, 2H), 1.52 (s, 9H); MS (ESI) m/z 368 (M + H).
of 29. H NMR (300 MHz, CDCl3) 7.75-7.90 (m, 4H), 7.40-
7.60 (m, 3H), 4.60-4.80 (m, 2H), 4.34 (m, 1H), 3.88 (m, 1H),
3.82 (m, 2H), 3.34 (t, J ) 6.3 Hz, 2H), 2.40 (dd, J ) 13.6, 5.6 Hz,
1H), 1.50-2.00 (m, 5H); MS (ESI) m/z 311 (M + 1).
1
trans-24b. MS (ESI) m/z 368 (M + H); H NMR (300 MHz,
CDCl3) δ 7.80-7.90 (m, 4H), 7.45-7.60 (m, 3H), 5.77 (m, 1H),
5.13 (m, 2H), 4.00-4.20 (m, 2H), 3.40-4.00 (m, 2H), 2.40-2.70
(m, 1H), 2.00-2.40 (m, 2H), 1.93 (m, 1H), 1.53 (s, 9H); MS (ESI)
m/z 368 (M + H).
(2S,4R)-tert-Butyl 2-(3-Hydroxypropyl)-4-(naphthalen-2-yl-
methoxy)pyrrolidine-1-carboxylate (25) and (2R,4R)-tert-Butyl
2-(3-Hydroxypropyl)-4-(naphthalen-2-ylmethoxy)pyrrolidine-1-
carboxylate (26). To a solution of 24 (2.70 g, 7.36 mmol) in THF
(15 mL) was added slowly a solution of borane-tetrahydrofuran
complex in THF (1.0 M, 11.0 mL), and the reaction mixture was
stirred for 0.5 h. Water (4.1 mL) was added dropwise followed by
tert-Butyl (R)-1-((2S,4R)-2-(3-Azidopropyl)-4-(naphthalen-2-
ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-ylcarbam-
ate (30). To a solution of 29 (1.0 g, 2.36 mmol) in DMF (9.4 mL)
were added Boc-D-Phe-OH (625 mg, 2.36 mmol), HOAt (641 mg,
4.72 mmol), NMM (0.8 mL, 7.07 mmol), and EDCI (506 mg, 2.83
mmol) consecutively, and the reaction mixture was stirred for 1.25
h. The reaction was quenched with saturated aqueous NH4Cl
solution and extracted with EtOAc (75 mL). The organic layer was
washed with H2O (100 mL) and brine (100 mL), dried over Na2-
SO4, filtered, and evaporated to a brown oil. The crude oil residue
was purified by column chromatography (silica gel, eluent hexanes/

4756 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15
Tian et al.
1
EtOAc, 3:2) to give 30 (986 mg, 75%) as a white solid. H NMR
(300 MHz, CD3OD) δ 7.70-7.90 (m, 4H), 7.00-7.60 (m, 13H),
4.40-4.90 (m, 4H), 3.80-4.20 (m, 2H), 2.70-3.40 (m, 8H), 1.70-
2.10 (m, 6H), 1.35-1.55 (m, 3H); MS (ESI) m/z 647 (M + H).
N-((R)-1-((2S,4R)-2-(3-Azidopropyl)-4-(naphthalen-2-ylmeth-
oxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl)-3-phenylpropan-
amide (32h). 32h was synthesized from 31 and 3-phenylpropanoic
(300 MHz, CDCl3) δ 7.10-7.95 (m, 12H), 4.45-4.75 (m, 3H),
3.50-4.20 (m, 3H), 2.90-3.40 (m, 5H), 1.40-2.10 (m, 15H); MS
(ESI) m/z 558 (M + H).
(R)-2-Amino-1-((2S,4R)-2-(3-azidopropyl)-4-(naphthalen-2-yl-
methoxy)pyrrolidin-1-yl)-3-phenylpropan-1-one (31). The Boc
analogue 30 (986 mg, 1.77 mmol) was dissolved into a prepared
solution of TFA/CH2Cl2/H2O (1:1:0.1, 10 mL), and the reaction
mixture was stirred for 1.0 h. It was then concentrated to give a
TFA salt of 31 (1.0 g, 99%) as a clear oil, which was sufficiently
pure for the next reaction without purification. 1H NMR (300 MHz,
CDCl3) 7.10-7.95 (m, 12H), 4.30-4.70 (m, 3H), 3.50-4.20 (m,
3H), 3.00-3.50 (m, 5H), 1.40-2.10 (m, 6H); MS (ESI) m/z 458
(M + H).
(S)-2-Acetamido-N-((R)-1-((2S,4R)-2-(3-azidopropyl)-4-(naph-
thalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-
yl)-3-(4-hydroxyphenyl)propanamide (32b). To a solution of
amine 31 (1.5 g, 2.63 mmol) in DMF (8.8 mL) were added Ac-
Tyr-OH (586 mg, 2.63 mmol), HOBt (709 mg, 5.25 mmol), NMM
(0.9 mL, 7.88 mmol), and EDCI (564 mg, 3.15 mmol) consecu-
tively, and the reaction mixture was stirred for 1.0 h. The reaction
was quenched with aqueous NH4Cl and extracted twice with EtOAc
(75 mL). The combined organic layers were washed with H2O (80
mL) and brine (80 mL), dried over Na2SO4, filtered, and evaporated
to an oil. The oil residue was purified by column chromatography
(silica gel, eluent acetone/CH2Cl2, 3:2) to give 32b (1.03 g, 60%
1
acid as described for 32b in 85% yield as a foam. H NMR (300
MHz, CD3OD) δ 7.75-7.90 (m, 4H), 7.40-7.60 (m, 3H), 7.00-
7.30 (m, 10H), 4.40-4.80 (m, 3H), 3.80-4.20 (m, 2H), 2.80-
3.60 (m, 8H), 2.53 (q, J ) 7.8 Hz, 2H), 1.70-2.10 (m, 3H), 1.30-
1.55 (m, 3H); MS (ESI) m/z 590 (M + H);
N-((R)-1-((2S,4R)-2-(3-Azidopropyl)-4-(naphthalen-2-ylmeth-
oxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl)acetamide (32i).
32i was synthesized from 31 and acetic acid in 88% yield as an
1
oil. H NMR (300 MHz, CDCl3) δ 7.10-8.00 (m, 12H), 4.80-
5.10 (m, 1H), 4.50-4.70 (m, 2H), 2.80-4.20 (m, 8H), 1.40-2.30
(m, 9H); MS (ESI) m/z 500 (M + H).
(S)-2-Acetamido-N-((R)-1-((2S,4R)-2-(3-aminopropyl)-4-(naph-
thalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-
yl)-3-(4-hydroxyphenyl)propanamide (33b). A solution of 32b
(1.03 g, 1.56 mmol) and pyridine (0.07 mL, 0.78 mmol) in methanol
(5.0 mL) was purged with argon, and palladium on carbon (10%
by wt, 500 mg) was then added. This reaction mixture was stirred
at a hydrogen atmosphere for 5.0 h. It was filtered through a short
pad of Celite, and the filtrate was concentrated under the reduced
pressure to yield 33b (871 mg, 88%) as a white solid, which was
1
1
yield) as a white solid. H NMR (300 MHz, CD3OD) 7.70-8.00
used directly for the next reaction without further purification. H
(m, 4H), 7.00-7.60 (m, 10H), 6.74 (m, 2H), 4.40-4.80 (m, 4H),
3.80-4.20 (m, 2H), 2.70-3.40 (m, 8H), 1.75-2.10 (m, 6H), 1.40-
1.55 (m, 3H); MS (ESI) m/z 663 (M + H).
NMR (300 MHz, CD3OD) δ 7.70-8.00 (m, 4H), 7.40-7.60 (m,
3H), 7.00-7.30 (m, 7H), 6.74 (m, 2H), 4.50-4.80 (m, 4H), 3.85-
4.20 (m, 2H), 2.55-3.40 (m, 8H), 1.75-2.10 (m, 6H), 1.40-1.55
(m, 3H); MS (ESI) m/z 637 (M + 1).
(S)-2-Acetamido-N-((R)-1-((2S,4R)-2-(3-aminopropyl)-4-(naph-
thalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-
yl)-3-(1-trityl-1H-imidazol-4-yl)propanamide (33a). 33a was
synthesized from 32a as described for 33b in 97% yield as a foam.
1H NMR (300 MHz, CD3OD) δ 7.00-8.00 (m, 29H), 4.50-4.80
(m, 4H), 3.90-4.20 (m, 2H), 2.60-3.50 (m, 8H), 1.70-2.10 (m,
6H), 1.30-1.60 (m, 3H); MS (ESI) m/z 853 (M + H).
(S)-2-Acetamido-N1-((R)-1-((2S,4R)-2-(3-aminopropyl)-4-(naph-
thalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl-
)pentanediamide (33c). 33c was synthesized from 32c as described
from 33b in 98% yield as a foam. 1H NMR (300 MHz, CD3OD) δ
7.70-7.90 (m, 4H), 7.00-7.60 (m, 8H), 4.35-4.80 (m, 4H), 3.90-
4.20 (m, 2H), 2.60-3.80 (m, 6H), 1.40-2.40 (m, 13H); MS (ESI)
m/z 602 (M + H).
(S)-2-Acetamido-N-((R)-1-((2S,4R)-2-(3-azidopropyl)-4-(naph-
thalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-
yl)-3-(1-trityl-1H-imidazol-4-yl)propanamide (32a). 32a was
synthesized from 31 and Ac-His-(1-Trt)-OH as described for 32b.
1H NMR (300 MHz, CD3OD) δ 7.00-8.00 (m, 29H), 4.40-4.80
(m, 4H), 3.80-4.20 (m, 3H), 2.70-3.50 (m, 8H), 1.70-2.10 (m,
6H), 1.30-1.55 (m, 3H); MS (ESI) m/z 901 (M + Na).
(S)-2-Acetamido-N1-((R)-1-((2S,4R)-2-(3-azidopropyl)-4-(naph-
thalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl-
)pentanediamide (32c). 32c was synthesized from 31 and Ac-Gln-
OH in 60% yield as a foam. 1H NMR (300 MHz, CD3OD) δ 7.70-
7.90 (m, 4H), 7.00-7.60 (m, 8H), 4.30-4.80 (m, 4H), 3.85-4.20
(m, 2H), 2.90-3.60 (m, 6H), 1.70-2.20 (m, 13H); MS (ESI) m/z
628 (M + H).
(S)-tert-Butyl 3-((R)-1-((2S,4R)-2-(3-Azidopropyl)-4-(naphtha-
len-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-ylcar-
bamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (32d). 32d
was synthesized from 31 and BOC-Tic-OH as described for 32b
(S)-tert-Butyl 3-((R)-1-((2S,4R)-2-(3-Aminopropyl)-4-(naph-
thalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl-
carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (33d).
33d was synthesized from 32d as described for 33b in 95% yield
1
in 64% yield as a foam. H NMR (300 MHz, CD3OD) δ 7.70-
1
7.90 (m, 4H), 7.00-7.60 (m, 12H), 4.40-4.80 (m, 5H), 2.80-
4.20 (m, 11H), 1.20-2.00 (m, 15H); MS (ESI) m/z 717 (M + H).
(S)-tert-Butyl 2-((R)-1-((2S,4R)-2-(3-Azidopropyl)-4-(naphtha-
len-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-ylcar-
bamoyl)piperidine-1-carboxylate (32e). 32e was synthesized from
31 and BOC-Pip-OH as described for 32b in 75% yield as a foam.
1H NMR (300 MHz, CD3OD) δ 7.75-7.90 (m, 4H), 7.40-7.55
(m, 3H), 7.00-7.30 (m, 5H), 4.50-4.90 (m, 4H), 3.45-4.25 (m,
4H), 2.90-3.40 (m, 6H), 1.10-2.20 (m, 21H); MS (ESI) m/z 669
(M + H).
as a foam. H NMR (300 MHz, CD3OD) δ 7.70-7.90 (m, 4H),
7.00-7.60 (m, 12H), 4.40-4.90 (m, 5H), 2.60-4.20 (m, 11H),
1.20-2.00 (m, 15H); MS (ESI) m/z 691 (M + H).
(S)-tert-Butyl 2-((R)-1-((2S,4R)-2-(3-Aminopropyl)-4-(naph-
thalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl-
carbamoyl)piperidine-1-carboxylate (33e). 33e was synthesized
1
from 32e as described for 33b in 97% yield as a foam. H NMR
(300 MHz, CD3OD) δ 7.75-7.90 (m, 4H), 7.40-7.55 (m, 3H),
7.10-7.35 (m, 5H), 4.50-5.00 (m, 4H), 3.80-4.30 (m, 3H), 2.90-
3.60 (m, 7H), 1.10-2.20 (m, 21H); MS (ESI) m/z 643 (M + H).
(S)-tert-Butyl 2-((R)-1-((2S,4R)-2-(3-Aminopropyl)-4-(naph-
thalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl-
carbamoyl)pyrrolidine-1-carboxylate (33f). 33f was synthesized
(S)-tert-Butyl 2-((R)-1-((2S,4R)-2-(3-Azidopropyl)-4-(naphtha-
len-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-ylcar-
bamoyl)pyrrolidine-1-carboxylate (32f). 32f was synthesized from
31 and BOC-proline as described for 32b in 72% yield as a foam.
1H NMR (300 MHz, CD3OD) δ 7.70-7.90 (m, 4H), 7.40-7.55
(m, 3H), 7.00-7.30 (m, 5H), 4.56 (m, 2H), 3.80-4.30 (m, 3H),
2.80-3.60 (m, 9H), 1.10-2.20 (m, 19H); MS (ESI) m/z 655 (M +
H).
1
from 32f as described for 33b in 96% yield as a foam. H NMR
(300 MHz, CD3OD) δ 7.70-7.90 (m, 4H), 7.40-7.55 (m, 3H),
7.10-7.35 (m, 5H), 4.58 (m, 2H), 3.80-4.30 (m, 3H), 3.10-3.70
(m, 5H), 2.50-3.10 (m, 4H), 1.60-2.30 (m, 7H), 1.20-1.60 (m,
12H); MS (ESI) m/z 629 (M + H).
(S)-2-Acetamido-N-((R)-1-((2S,4R)-2-(3-azidopropyl)-4-(naph-
thalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-
yl)-3-phenylpropanamide (32g). 32g was synthesized from 31 and
Ac-Tyr-OH as described for 32b in 62% yield as a foam. 1H NMR
(S)-2-Acetamido-N-((R)-1-((2S,4R)-2-(3-aminopropyl)-4-(naph-
thalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-
yl)-3-phenylpropanamide (33g). 33g was synthesized from 32g
as described for 33b in 99% yield as a foam. 1H NMR (300 MHz,

Melanocortin Receptor Agonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15 4757
CD3OD) δ 7.70-7.90 (m, 4H), 7.00-7.60 (m, 13H), 4.40-5.00
(m, 4H), 3.80-4.20 (m, 2H), 2.60-3.60 (m, 8H), 1.30-2.10 (m,
9H); MS (ESI) m/z 621 (M + H).
δ 7.70-8.00 (m, 4H), 7.10-7.60 (m, 8H), 4.50-5.00 (m, 3H),
3.80-4.30 (m, 3H), 2.80-3.60 (m, 9H), 1.20-2.30 (m, 37H); MS
(ESI) m/z 871 (M + H).
N-((R)-1-((2S,4R)-2-(3-Aminopropyl)-4-(naphthalen-2-ylmeth-
oxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl)-3-phenylpropan-
amide (33h). 33h was synthesized from 32h as described for 33b
(Z)-tert-Butyl (3-((2S,4R)-1-((R)-2-((S)-2-Acetamido-3-phenyl-
propanamido)-3-phenylpropanoyl)-4-(naphthalen-2-ylmethoxy)-
pyrrolidin-2-yl)propylamino)(tert-butoxycarbonylamino)meth-
ylenecarbamate (34g). 34g was synthesized from 33g as described
1
in 96% yield as a foam. H NMR (300 MHz, CD3OD) δ 7.75-
1
7.90 (m, 4H), 7.00-7.60 (m, 13H), 4.40-4.80 (m, 3H), 3.80-
4.20 (m, 2H), 2.80-3.60 (m, 6H), 2.40-2.70 (m, 4H), 1.70-2.10
(m, 3H), 1.30-1.50 (m, 3H); MS (ESI) m/z 564 (M + H).
N-((R)-1-((2S,4R)-2-(3-Aminopropyl)-4-(naphthalen-2-ylmeth-
oxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl)acetamide (33i).
33i was synthesized from 32i as described for 33b in 91% yield as
a foam. 1H NMR (300 MHz, CD3OD) δ 7.70-7.90 (m, 4H), 7.00-
7.60 (m, 8H), 4.40-5.00 (m, 3H), 2.70-4.30 (m, 8H), 1.20-2.20
(m, 9H); MS (ESI) m/z 474 (M + H).
for 34b in 76% yield as a white solid. H NMR (300 MHz, CD3-
OD) δ 7.70-7.90 (m, 4H), 7.00-7.60 (m, 13H), 4.50-5.00 (m,
4H), 3.80-4.20 (m, 2H), 2.70-3.70 (m, 8H), 1.40-2.10 (m, 27H);
MS (ESI) m/z 863 (M + H).
(Z)-tert-Butyl (tert-Butoxycarbonylamino)(3-((2S,4R)-4-(naph-
thalen-2-ylmethoxy)-1-((R)-3-phenyl-2-(3-phenylpropanamido)-
propanoyl)pyrrolidin-2-yl)propylamino)methylenecarbamate (34h).
34h was synthesized from 33h as described for 34b in 64% yield
1
as a white solid. H NMR (300 MHz, CD3OD) δ 7.75-7.90 (m,
4H), 7.35-7.60 (m, 3H), 7.00-7.30 (m, 10H), 4.50-4.90 (m, 3H),
3.80-4.20 (m, 2H), 2.80-3.60 (m, 8H), 2.55 (q, J ) 7.60 Hz,
2H), 1.70-2.10 (m, 3H), 1.30-1.60 (m, 21H); MS (ESI) m/z 807
(M + H).
(Z)-tert-Butyl (3-((2S,4R)-1-((R)-2-((S)-2-Acetamido-3-(4-hy-
droxyphenyl)propanamido)-3-phenylpropanoyl)-4-(naphthalen-
2-ylmethoxy)pyrrolidin-2-yl)propylamino)(tert-butoxycarbon-
ylamino)methylenecarbamate (34b). To a solution of amine 33b
(125 mg, 0.20 mmol) in DMF (2.0 mL) were added 1,3-bis(tert-
butoxycarbonyl)-2-methyl-2-thiopseudourea (57 mg, 0.2 mmol),
triethylamine (0.1 mL, 0.59 mmol), and mercury(II) chloride (64
mg, 0.24 mmol), and the reaction mixture was stirred at 0 °C for
1.0 h. It was then diluted with EtOAc and filtered through a short
pad of Celite. The filtrate was concentrated under the reduced
pressure to give an oil residue, which was purified by column
chromatography (silica gel, eluent CH2Cl2/methanol,14:1) to give
(Z)-tert-Butyl (3-((2S,4R)-1-((R)-2-Acetamido-3-phenylpro-
panoyl)-4-(naphthalen-2-ylmethoxy)pyrrolidin-2-yl)propylami-
no)(tert-butoxycarbonylamino)methylenecarbamate (34i). 34i
was synthesized from 33i as described for 34b in 59% yield as a
1
white solid. H NMR (300 MHz, CD3OD) δ 7.70-8.00 (m, 4H),
7.10-7.60 (m, 8H), 4.40-5.00 (m, 3H), 3.80-4.30 (m, 2H), 2.80-
3.70 (m, 6H), 1.20-2.20 (m, 27H); MS (ESI) m/z 716 (M + H).
(S)-2-Acetamido-N-((R)-1-((2S,4R)-2-(3-guanidinopropyl)-4-
(naphthalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-
2-yl)-3-(4-hydroxyphenyl)propanamide (35b). The Boc analogue
34b (170 mg, 0.19 mmol) was dissolved into a prepared solution
of TFA/CH2Cl2/anisole (40:55:5, 3.0 mL), and the reaction mixture
was stirred for 3.0 h. It was then concentrated, and the residue was
purified by reverse-phase preparative HPLC to give 35b (57 mg,
1
34b (170 mg, 98%) as a white solid. H NMR (300 MHz, CD3-
OD) δ 7.70-7.90 (m, 4H), 7.00-7.60 (m, 10H), 6.74 (m, 2H),
4.45-4.80 (m, 4H), 3.85-4.20 (m, 2H), 2.70-3.60 (m, 8H), 1.40-
2.00 (m, 18H); MS (ESI) m/z 879 (M + H).
(Z)-tert-Butyl (3-((2S,4R)-1-((R)-2-((S)-2-Acetamido-3-(1-tri-
tyl-1H-imidazol-4-yl)propanamido)-3-phenylpropanoyl)-4-(naph-
thalen-2-ylmethoxy)pyrrolidin-2-yl)propylamino)(tert-butoxy-
carbonylamino)methylenecarbamate (34a). 34a was synthesized
1
44% yield) as a white powder. H NMR (300 MHz, CD3OD) δ
7.70-7.90 (m, 4H), 7.40-7.60 (m, 3H), 7.00-7.30 (m, 7H), 6.74
(m, 2H), 4.50-4.80 (m, 4H), 3.85-4.20 (m, 2H), 2.70-3.30(m,
8H), 1.40-2.10 (m, 9H); MS (ESI) m/z 679 (M + H). Anal.
(C39H46N6O5‚2.5CF3CO2H) C, H, N.
1
from 33a as described for 34b in 65% yield as a white solid. H
NMR (300 MHz, CD3OD) δ 7.70-8.00 (m, 4H), 7.00-7.60 (m,
25H), 4.50-4.80 (m, 4H), 3.90-4.30 (m, 2H), 2.80-3.60 (m, 8H),
1.80-2.10 (m, 6H), 1.30-1.60 (m, 12H); MS (ESI) m/z 1095 (M
+ H).
(S)-2-Acetamido-N-((R)-1-((2S,4R)-2-(3-guanidinopropyl)-4-
(naphthalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-
2-yl)-3-(1H-imidazol-4-yl)propanamide (35a). 35a was synthe-
sized from 34a as described for 35b as a TFA salt. 1H NMR (300
MHz, CD3OD) δ 7.70-8.00 (m, 4H), 7.40-7.60 (m, 3H), 7.10-
7.35 (m, 7H), 4.50-4.90 (m, 4H), 3.90-4.30 (m, 3H), 2.90-3.60
(m, 8H), 1.80-2.20 (m, 6H), 1.40-1.60 (m, 3H); MS (ESI) m/z
653 (M + H). Anal. (C36H44N8O4‚3.3CF3CO2H) C, H, N.
(S)-2-Acetamido-N1-((R)-1-((2S,4R)-2-(3-guanidinopropyl)-4-
(naphthalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-
2-yl)pentanediamide (35c). 35c was synthesized from 34c as
described for 35b as a TFA salt (white solid). 1H NMR (300 MHz,
CD3OD) δ 7.70-7.90 (m, 4H), 7.10-7.60 (m, 8H), 4.30-4.80 (m,
4H), 3.90-4.25 (m, 2H), 2.90-3.80 (m, 6H), 1.75-2.40 (m, 10H),
1.40-1.60 (m, 3H); MS (ESI) m/z 644 (M + H). Anal.
(C35H45N7O5‚2.8CF3CO2H) C, H, N.
(S)-N-((R)-1-((2S,4R)-2-(3-Guanidinopropyl)-4-(naphthalen-
2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl)-1,2,3,4-
tetrahydroisoquinoline-3-carboxamide (35d). 35d was synthe-
sized from 34d as described for 35b as a TFA salt. 1H NMR (300
MHz, CD3OD) δ 7.70-7.90 (m, 4H), 7.10-7.60 (m, 12H), 4.92
(m, 2H), 4.68 (m, 2H), 4.40 (m, 2H), 4.00-4.30 (m, 4H), 2.90-
3.50 (m, 6H), 1.80-2.20 (m, 3H), 1.58 (m, 3H); MS (ESI) m/z
633 (M + H). Anal. (C38H44N6O3‚2.5CF3CO2H) C, H, N.
(S)-N-((R)-1-((2S,4R)-2-(3-guanidinopropyl)-4-(naphthalen-2-
ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl)piperidine-
2-carboxamide (35e). 35e was synthesized from 34e as described
for 35b as a TFA salt (white solid). 1H NMR (300 MHz, CD3OD)
δ 7.75-8.00 (m, 4H), 7.10-7.60 (m, 8H), 4.50-5.00 (m, 4H),
3.90-4.30 (m, 2H), 2.90-3.85 (m, 8H), 1.30-2.20 (m, 12H); MS
(ESI) m/z 886 (M + H). Anal. (C34H44N6O3‚2.8CF3CO2H) C, H,
N.
(Z)-tert-Butyl (3-((2S,4R)-1-((R)-2-((S)-2-Acetamido-5-amino-
5-oxopentanamido)-3-phenylpropanoyl)-4-(naphthalen-2-yl-
methoxy)pyrrolidin-2-yl)propylamino)(tert-butoxycarbonylamino)-
methylenecarbamate (34c). 34c was synthesized from 33c as
1
described for 34b in 53% yield as a white solid. H NMR (300
MHz, CD3OD) δ 7.70-7.90 (m, 4H), 7.35-7.60 (m, 3H), 7.10-
7.30 (m, 5H), 4.30-4.80 (m, 4H), 3.90-4.20 (m, 2H), 2.60-3.80
(m, 7H), 1.75-2.49 (m, 14H), 1.40-1.70 (m, 17H); MS (ESI) m/z
866 (M + Na).
(S)-tert-Butyl 3-((R)-1-((2S,4R)-2-(3-((E)-2,3-Bis(tert-butoxy-
carbonyl)guanidino)propyl)-4-(naphthalen-2-ylmethoxy)pyrro-
lidin-1-yl)-1-oxo-3-phenylpropan-2-ylcarbamoyl)-3,4-dihydroiso-
quinoline-2(1H)-carboxylate (34d). 34d was synthesized from 33d
as described for 34b in 41% yield as a white solid. 1H NMR (300
MHz, CD3OD) δ 7.70-7.90 (m, 4H), 7.00-7.60 (m, 12H), 4.40-
4.90 (m, 5H), 2.80-4.20 (m, 11H), 1.20-2.00 (m, 33H); MS (ESI)
m/z 933 (M + H).
(S)-tert-Butyl 2-((R)-1-((2S,4R)-2-(3-((Z)-2,3-Bis(tert-butoxy-
carbonyl)guanidino)propyl)-4-(naphthalen-2-ylmethoxy)pyrro-
lidin-1-yl)-1-oxo-3-phenylpropan-2-ylcarbamoyl)piperidine-1-
carboxylate (34e). 34e was synthesized from 33e as described for
1
34b in 51% yield as a white solid. H NMR (300 MHz, CD3OD)
δ 7.75-8.00 (m, 4H), 7.40-7.60 (m, 3H), 7.10-7.35 (m, 5H),
4.50-5.00 (m, 4H), 3.80-4.30 (m, 3H), 2.90-3.60 (m, 7H), 1.10-
2.20 (m, 39H); MS (ESI) m/z 886 (M + H).
(S)-tert-Butyl 2-((R)-1-((2S,4R)-2-(3-((Z)-2,3-Bis(tert-butoxy-
carbonyl)guanidino)propyl)-4-(naphthalen-2-ylmethoxy)pyrro-
lidin-1-yl)-1-oxo-3-phenylpropan-2-ylcarbamoyl)pyrrolidine-1-
carboxylate (34f). 34f was synthesized from 33f as described for
1
34b in 62% yield as a white solid. H NMR (300 MHz, CD3OD)

4758 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15
Tian et al.
(S)-N-((R)-1-((2S,4R)-2-(3-Guanidinopropyl)-4-(naphthalen-
2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl)pyrro-
lidine-2-carboxamide (35f). 35f was synthesized from 34f as
described for 35b as a TFA salt (white solid). 1H NMR (300 MHz,
CD3OD) δ 7.75-8.00 (m, 4H), 7.10-7.60 (m, 8H), 4.63 (m, 2H),
4.30 (m, 2H), 2.90-4.20 (m, 10H), 2.36 (m, 1H), 1.20-2.20 (m,
9H); MS (ESI) m/z 571 (M + H). Anal. (C33H42N6O3‚2.7CF3CO2H)
C, H, N.
(S)-2-Acetamido-N-((R)-1-((2S,4R)-2-(3-guanidinopropyl)-4-
(naphthalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-
2-yl)-3-phenylpropanamide (35g). 35g was synthesized from 34g
as described for 35b as a TFA salt. 1H NMR (300 MHz, CD3OD)
δ 7.70-8.00 (m, 4H), 7.00-7.60 (m, 13H), 4.50-5.00 (m, 4H),
3.80-4.20 (m, 2H), 2.70-3.70 (m, 8H), 1.60-2.10 (m, 6H), 1.48
(m, 3H); MS (ESI) m/z 663 (M + H). Anal. (C39H46N6O4‚2.7CF3-
CO2H) C, H, N.
N-((R)-1-((2S,4R)-2-(3-Guanidinopropyl)-4-(naphthalen-2-yl-
methoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl)-3-phenyl-
propanamide (35h). 35h was synthesized from 34h as described
for 35b as a TFA salt (white solid). 1H NMR (300 MHz, CD3OD)
δ 7.75-7.90 (m, 4H), 7.10-7.60 (m, 13H), 4.50-4.90 (m, 3H),
3.80-4.20 (m, 2H), 2.80-3.60 (m, 8H), 2.56 (m, 2H),), 1.70-
2.10 (m, 3H), 1.30-1.60 (m, 3H); MS (ESI) m/z 606 (M + H).
Anal. (C37H43N5O3‚1.3CF3CO2H) C, H, N.
N-((R)-1-((2S,4R)-2-(3-Guanidinopropyl)-4-(naphthalen-2-yl-
methoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl)acetam-
ide (35i). 35i was synthesized from 34i as described for 35b as a
TFA salt (white solid). 1H NMR (300 MHz, CD3OD) δ 7.70-8.00
(m, 4H), 7.10-7.60 (m, 8H), 4.40-5.00 (m, 3H), 3.90-4.30 (m,
2H), 2.90-3.70 (m, 6H), 1.20-2.20 (m, 9H); MS (ESI) m/z 516
(M + H). Anal. (C30H37N5O3‚1.6CF3CO2H) C, H, N.
2.60-3.80 (m, 8H), 1.80-2.40 (m, 3H), 1.30-1.70 (m, 3H); MS
(ESI) m/z 633 (M + H). Anal. (C38H44N6O3‚3.0CF3CO2H) C, H,
N.
(S)-N-((R)-1-((2R,4R)-2-(3-Guanidinopropyl)-4-(naphthalen-
2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl)piperi-
dine-2-carboxamide (42d). White solid; 1H NMR (300 MHz,
CD3OD) δ 7.80-8.00 (m, 4H), 7.40-7.60 (m, 3H), 7.10-7.40 (m,
5H), 2.80-5.00 (m, 14H), 1.20-2.30 (m, 12H); MS (ESI) m/z 585
(M + H). Anal. (C34H44N6O3‚2.4CF3CO2H) C, H, N.
(S)-2-Acetamido-N1-((R)-1-((2R,4R)-2-(3-guanidinopropyl)-4-
(naphthalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-
2-yl)pentanediamide (42e). White solid; 1H NMR (300 MHz,
CD3OD) δ 7.70-7.90 (m, 4H), 7.10-7.60 (m, 8H), 4.10-4.90 (m,
6H), 2.80-3.80 (m, 6H), 1.20-2.20 (m, 13H); MS (ESI) m/z 644
(M + H). Anal. (C35H45N7O5‚1.4CF3CO2H) C, H, N.
(2R,4S)-tert-Butyl 2-allyl-4-hydroxypyrrolidine-1-carboxylate
(49a) and (2S,4S)-tert-Butyl 2-allyl-4-hydroxypyrrolidine-1-
carboxylate (49b). To a solution of 3-(S)-hydroxypyrrolidine-1-
carboxylic acid tert-butyl ester (48) (3.0 g, 16.0 mmol) in THF
(50 mL) were added TMEDA (6.4 mL, 40.1 mmol) and a solution
of sec-butyllithium in THF (1.3 M, 31 mL) at -78 °C, and the
resultant orange mixture was warmed to -40 °C and stirred at that
temperature for 2.75 h. The mixture was then cooled to -78 °C,
and allyl bromide (3.1 mL, 35.3 mmol) was added. This mixture
was stirred and warmed to 0 °C over 4.5 h. The reaction was
quenched with aqueous NH4Cl solution and extracted with ethyl
acetate (150 mL). The organic layer was dried over Na2SO4, filtered,
and evaporated to a brown oil. The oil residue was purified by
column chromatography (silica gel, eluent CH2Cl2/acetone, 4:1) to
give a mixture of 49a and 49b (2.2 g, 61%) as a clear oil. A small
amount of the mixture was purified using reverse-phase preparative
HPLC to give pure 49a and 49b for characterization.
tert-Butyl (R)-1-((2S,4R)-2-(3-Aminopropyl)-4-(naphthalen-
2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-ylcar-
bamate (36). 36 was synthesized from 30 as described for 33b in
1
cis-49a. H NMR (300 MHz, CDCl3) δ 5.80 (m, 1H), 5.12 (m,
2H), 4.44 (m, 1H), 3.88 (m, 1H), 3.70 (dd, J ) 11.70, 5.70 Hz,
1H), 3.32 (ddd, J ) 12.0, 3.3, 1.2 Hz, 1H), 2.68 (m, 1H), 2.45 (m,
1H), 2.10-2.30 (m, 2H), 1.84 (m, 1H), 1.50 (m, 9H); MS (ESI)
m/z 172 (M + H - 56).
1
94% yield as a foam. H NMR (300 MHz, CD3OD) δ 7.70-7.90
(m, 4H), 7.00-7.60 (m, 8H), 3.20-4.90 (m, 6H), 2.60-3.20 (m,
5H), 1.10-2.10 (m, 15H); MS (ESI) m/z 532 (M + H).
1
Di-tert-butyl[(Z)-({3-[(2S,4R)-1-[N-(tert-butoxycarbonyl)-D-
phenylalanyl]-4-(2-naphthylmethoxy)pyrrolidin-2-yl]propyl}-
amino)methylylidene]biscarbamate (37). 37 was synthesized from
trans-49b. H NMR (300 MHz, CDCl3) δ 5.73 (m, 1H), 5.11
(m, 2H), 4.40 (m, 1H), 4.02 (m, 1H), 3.57 (m, 2H), 3.40 (dd, J )
11.8, 3.8 Hz, 1H), 2.53 (m, 1H), 2.31 (m, 1H), 2.04 (m, 1H), 1.89
(m, 1H), 1.49 (m, 9H); MS (ESI) m/z 172 (M + H - 56).
(2R,4S)-tert-Butyl 2-Allyl-4-(naphthalen-2-ylmethoxy)pyrro-
lidine-1-carboxylate (50a) and (2S,4S)-tert-Butyl 2-Allyl-4-
(naphthalen-2-ylmethoxy)pyrrolidine-1-carboxylate (50b). So-
dium hydride (458 mg, 11.45 mmol) was added in portions to a
stirred solution of 49 (2.0 g, 8.81 mmol) in DMF (18 mL) at 0 °C.
After the reaction mixture was stirred for 20 min, 2-(bromomethyl)-
naphthalene (2.9 g, 13.22 mmol) in DMF (5 mL) was added, and
the resulting solution was stirred overnight at room temperature.
The reaction was quenched with aqueous NH4Cl solution and
extracted twice with ethyl acetate. The extract was dried over Na2-
SO4, filtered, and evaporated. The residue was purified by chro-
matography (silica gel, eluent hexanes/EtOAc, 6:1) to give 50 (2.7
g, 84% yield) as a clear oil. A small amount of the mixture was
purified using reverse-phase preparative HPLC to give pure 50a
and 50b for characterization.
1
36 as described for 34b in 30% yield as a white solid. H NMR
(300 MHz, CD3OD) 7.70-8.00 (m, 4H), 7.10-7.60 (m, 8H), 4.40-
5.00 (m, 3H), 3.80-4.30 (m, 2H), 2.80-3.70 (m, 6H), 1.20-2.20
(m, 33H); MS (ESI) m/z 774 (M + H).
1-(3-((2S,4R)-1-((R)-2-Amino-3-phenylpropanoyl)-4-(naphtha-
len-2-ylmethoxy)pyrrolidin-2-yl)propyl)guanidine (38). 38 was
synthesized from 37 as described for 35b as a TFA salt (white
solid). 1H NMR (300 MHz, CD3OD) δ 7.70-8.00 (m, 4H), 7.10-
7.60 (m, 8H), 4.00-4.80 (m, 4H), 2.70-3.80 (m, 7H), 1.20-2.20
(m, 6H); MS (ESI) m/z 474 (M + H). Anal. (C28H35N5O2‚2.6CF3-
CO2H) C, H, N.
(S)-2-Acetamido-N-((R)-1-((2R,4R)-2-(3-guanidinopropyl)-4-
(naphthalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-
1
2-yl)-3-(4-hydroxyphenyl)propanamide (42a). White solid; H
NMR (300 MHz, CD3OD) δ 7.70-7.90 (m, 4H), 7.30-7.50 (m,
3H), 7.00-7.30 (m, 5H), 6.95 (d, J ) 8.4 Hz, 2H), 6.68 (d, J )
8.4 Hz, 2H), 4.10-4.80 (m, 6H), 2.90-3.70 (m, 5H), 2.50-2.90
(m, 3H), 1.60-2.20 (m, 6H), 1.30-1.60 (m, 3H); MS (ESI) m/z
679 (M + 1). Anal. (C39H46N6O5‚2.5CF3CO2H) C, H, N.
1
cis-50a. H NMR (300 MHz, CDCl3) δ 7.70-7.90 (m, 4H),
7.40-7.60 (m, 3H), 5.81 (m, 1H), 5.11 (m, 2H) 4.69 (m, 2H), 4.16
(m, 1H), 3.89 (m, 1H), 3.70 (m, 1H), 3.50 (m, 1H), 2.66 (m, 1H),
2.43 (m, 1H), 2.07 (m, 2H), 1.49 (m, 9H); MS (ESI) m/z 368 (M
+ H).
(S)-2-Acetamido-N-((R)-1-((2R,4R)-2-(3-guanidinopropyl)-4-
(naphthalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-
1
1
2-yl)-3-(1H-imidazol-4-yl)propanamide (42b). White solid; H
trans-50b. H NMR (300 MHz, CDCl3) δ 7.75-7.90 (m, 4H),
NMR (300 MHz, CD3OD) δ 7.00-8.90 (m, 14H), 4.10-4.90 (m,
6H), 2.80-3.80 (m, 8H), 1.80-2.30 (m, 6H), 1.20-1.70 (m, 3H);
MS (ESI) m/z 653 (M + 1). Anal. (C36H44N8O4‚3.2CF3CO2H) C,
H, N.
(S)-N-((R)-1-((2R,4R)-2-(3-Guanidinopropyl)-4-(naphthalen-
2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl)-1,2,3,4-
tetrahydroisoquinoline-3-carboxamide (42c). White solid; 1H
NMR (300 MHz, CD3OD) δ 7.80-7.90 (m, 4H), 7.42-7.54 (m,
3H), 7.10-7.40 (m, 9H), 4.60-5.00 (m, 3H), 4.10-4.50 (m, 5H),
7.40-7.60 (m, 3H), 5.75 (m, 1H), 5.10 (m, 2H), 4.69 (m, 2H),
3.40-4.20 (m, 4H), 2.10-2.70 (m, 3H), 1.92 (m, 1H), 1.51 (m,
9H); MS (ESI) m/z 368 (M + H).
(2S,4S)-tert-Butyl 2-(3-Hydroxypropyl)-4-(naphthalen-2-yl-
methoxy)pyrrolidine-1-carboxylate (51) and (2R,4S)-tert-Butyl
2-(3-Hydroxypropyl)-4-(naphthalen-2-ylmethoxy)pyrrolidine-1-
carboxylate (52). To a solution of 50 (2.7 g, 7.36 mmol) in THF
(15 mL) was slowly added 1.0 M solution of borane-tetrahydro-
furan complex in THF (11.0 mL), and the reaction mixture was

Melanocortin Receptor Agonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15 4759
stirred for 0.5 h. Water (4.1 mL) was then added dropwise followed
by the addition of aqueous NaOH (3.0 M, 7.3 mL) and 33% H2O2
(5.0 mL). The mixture was stirred for 2.0 h and extracted with
EtOAc (150 mL). The organic layer was then dried over Na2SO4,
filtered, and concentrated. The residue was purified by chroma-
tography (silica gel, eluent hexanes/EtOAc, 1:1) to afford 51 (1.1
g) and 52 (1.0 g) as clear oils.
(S)-N-((R)-1-((2S,4S)-2-(3-Guanidinopropyl)-4-(naphthalen-
2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl)piperi-
dine-2-carboxamide (56d). White solid; 1H NMR (300 MHz,
CD3OD) δ 7.80-7.95 (m, 4H), 7.45-7.60 (m, 3H), 7.20-7.40 (m,
5H), 4.60-5.10 (m, 4H), 4.00-4.40 (m, 3H), 2.80-3.90 (m, 7H),
1.10-2.30 (m, 12H); MS (ESI) m/z 585 (M + H). Anal.
(C34H44N6O3‚3.0CF3CO2H) C, H, N.
(S)-2-Acetamido-N1-((R)-1-((2S,4S)-2-(3-guanidinopropyl)-4-
(naphthalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-
2-yl)pentanediamide (56e). White solid; 1H NMR (300 MHz,
CD3OD) δ 7.70-7.90 (m, 4H), 7.42-7.60 (m, 3H), 7.10-7.30 (m,
5H), 4.60-4.80 (m, 2H), 4.00-4.50 (m, 4H), 2.90-3.80 (m, 6H),
1.10-2.40 (m, 13H). MS (ESI) m/z 644 (M + H). Anal.
(C35H45N7O5‚1.4CF3CO2H) C, H, N.
1
trans-51. H NMR (300 MHz, CDCl3) δ 7.78-7.90 (m, 4H),
7.40-7.60 (m, 3H), 4.60-4.80 (m, 2H), 4.19 (m, 1H), 4.05 (m,
1H), 3.60-3.95 (m, 3H), 3.46 (m, 1H), 3.09 (m, 1H), 2.25 (m,
1H), 1.80-2.00 (m, 2H), 1.40-1.70 (m, 12H); MS (ESI) m/z 386
(M + 1).
cis-52. 1H NMR (300 MHz, CDCl3) δ 7.80-7.90 (m, 4H), 7.45-
7.55 (m, 3H), 4.70 (s, 2H), 4.17 (m, 1H), 3.92 (m, 1H), 3.70 (m,
2H), 3.49 (dd, J ) 12.0, 3.3 Hz, 1H), 1.90-2.25 (m, 3H), 1.40-
1.80 (m, 12H); MS (ESI) m/z 386 (M + 1).
(S)-2-Acetamido-N-((R)-1-((2R,4S)-2-(3-guanidinopropyl)-4-
(naphthalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-
(2S,4S)-tert-Butyl 2-(3-Azidopropyl)-4-(naphthalen-2-ylmeth-
oxy)pyrrolidine-1-carboxylate (54). 54 was synthesized from 51
as described for 28 in 83% yield as a clear oil. 1H NMR (300 MHz,
CDCl3) δ 7.75-7.90 (m, 4H), 7.45-7.55 (m, 3H), 4.69 (m, 2H),
4.18 (m, 1H), 3.40 (m, 1H), 3.77 (m, 1H), 3.25-3.50 (m, 2H),
2.25 (m, 1H), 1.40-2.00 (m, 14H); MS (ESI) m/z 433 (M + Na).
(2R,4S)-tert-Butyl 2-(3-Azidopropyl)-4-(naphthalen-2-ylmeth-
oxy)pyrrolidine-1-carboxylate (58). 58 was synthesized from 52
1
2-yl)-3-(4-hydroxyphenyl)propanamide (60a). White solid; H
NMR (300 MHz, CD3OD) δ 7.70-7.70 (m, 4H), 7.40-7.60 (m,
3H), 7.10-7.40 (m, 5H), 7.10 (m, 2H), 6.74 (m, 2H), 4.40-4.90
(m, 4H), 2.70-4.20 (m, 10H), 1.40-2.10 (m, 9H). MS (ESI) m/z
679 (M + H). Anal. (C39H46N6O5‚1.7CF3CO2H) C, H, N.
(S)-2-Acetamido-N-((R)-1-((2R,4S)-2-(3-guanidinopropyl)-4-
(naphthalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-
1
2-yl)-3-(1H-imidazol-4-yl)propanamide (60b). White solid; H
1
as described for 28 in 78% yield as a colorless oil. H NMR (300
NMR (300 MHz, CD3OD) δ 7.75-7.90 (m, 4H), 7.40-7.60 (m,
3H), 7.10-7.35 (m, 7H), 4.40-4.90 (m, 5H), 2.80-4.30 (m, 9H),
1.40-2.20 (m, 9H); MS (ESI) m/z 652 (M + H). Anal.
(C36H44N8O4‚4.2CF3CO2H) C, H, N.
MHz, CDCl3) δ 7.80-8.00 (m, 4H), 7.40-7.70 (m, 3H), 4.70 (s,
2H), 4.18 (m, 1H), 3.87 (m, 1H), 3.70 (m, 1H), 3.49 (m, 1H), 3.30
(m, 2H), 1.90-2.30 (m, 3H), 1.20-1.90 (m, 12H); MS (ESI) m/z
411 (M + 1).
(S)-N-((R)-1-((2R,4S)-2-(3-Guanidinopropyl)-4-(naphthalen-
2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl)-1,2,3,4-
tetrahydroisoquinoline-3-carboxamide (60c). White solid; 1H
NMR (300 MHz, CD3OD) δ 7.70-7.90 (m, 4H), 7.40-7.60 (m,
3H), 7.10-7.40 (m, 9H), 4.60-4.80 (m, 2H), 4.38 (s, 2H), 3.90-
4.30 (m, 3H), 2.80-3.90 (m, 9H), 1.40-2.10 (m, 6H); MS (ESI)
m/z 633 (M + H). Anal. (C38H44N6O3‚3.2CF3CO2H) C, H, N.
(S)-N-((R)-1-((2R,4S)-2-(3-Guanidinopropyl)-4-(naphthalen-
2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl)piperi-
dine-2-carboxamide (60d). White solid; 1H NMR (300 MHz,
CD3OD) δ 7.70-7.90 (m, 4H), 7.40-7.60 (m, 3H), 7.20-7.40 (m,
5H), 2.80-4.90 (m, 14H), 1.20-2.30 (m, 12H); MS (ESI) m/z 585
(M + H). Anal. (C34H44N6O3‚3.5CF3CO2H) C, H, N.
(S)-2-Acetamido-N1-((R)-1-((2R,4S)-2-(3-guanidinopropyl)-4-
(naphthalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-
2-yl)pentanediamide (60e). White solid; 1H NMR (300 MHz,
CD3OD) δ 7.70-7.90 (m, 4H), 7.42-7.60 (m, 3H), 7.10-7.30 (m,
5H), 4.60-4.80 (m, 2H), 2.90-4.50 (m, 10H), 1.10-2.40 (m, 13H);
MS (ESI) m/z 644 (M + 1). Anal. (C35H45N7O5‚1.3CF3CO2H) C,
H, N.
(2S,4S)-2-(3-Azidopropyl)-4-(naphthalen-2-ylmethoxy)pyrro-
lidine (55). 55 was synthesized from 54 as described for 29 in a
quantitative yield as a TFA salt, which was used directly for the
next reaction without further purification. 1H NMR (300 MHz, CD3-
OD) δ 7.80-8.00 (m, 4H), 7.45-7.55 (m, 3H), 4.71 (s, 2H), 4.39
(m, 1H), 3.83 (m, 1H), 3.30-3.60 (m, 4H), 2.47 (dd, J ) 6.0, 1.4
Hz, 1H), 1.60-2.00 (m, 6H); MS (ESI) m/z 311 (M + H).
(2R,4S)-2-(3-Azidopropyl)-4-(naphthalen-2-ylmethoxy)pyrro-
lidine (59). 59 was synthesized from 58 as described for 29 in a
quantitative yield as a TFA salt, which was used directly for the
1
next reaction without further purification. H NMR (300 MHz,
CDCl3) δ 7.40-8.00 (m, 7H), 4.72 (m, 2H), 4.35 (m, 1H), 3.20-
3.90 (m, 5H), 1.30-2.60 (m, 6H); MS (ESI) m/z 311 (M + H).
(S)-2-Acetamido-N-((R)-1-((2S,4S)-2-(3-guanidinopropyl)-4-
(naphthalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-
2-yl)-3-(4-hydroxyphenyl)propanamide (56a). 56a was synthe-
sized from (Z)-tert-butyl (3-((2S,4S)-1-((R)-2-((S)-2-acetamido-3-
(4-hydroxyphenyl)propanamido)-3-phenylpropanoyl)-4-(naphtha-
len-2-ylmethoxy)pyrrolidin-2-yl)propylamino)(tert-butoxycarbon-
ylamino)methylenecarbamate as described for 35b. 1H NMR (300
MHz, CD3OD) δ 7.80-7.90 (m, 4H), 7.40-7.55 (m, 3H), 6.90-
7.30 (m, 7H), 6.72 (m, 2H), 4.50-4.90 (m, 4H), 2.60-4.20 (m,
11H), 1.10-2.20 (m, 9H); MS (ESI) m/z 679 (M + H). Anal.
(C39H46N6O5‚1.6CF3CO2H) C, H, N.
Acknowledgment. The authors thank Marsha Peasley of the
Analytic Department of Procter & Gamble Pharmaceuticals for
performing elemental analyses.
(S)-2-Acetamido-N-((R)-1-((2S,4S)-2-(3-guanidinopropyl)-4-
(naphthalen-2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-
2-yl)-3-(1H-imidazol-4-yl)propanamide (56b). 56b was synthe-
sized from (Z)-tert-butyl (3-((2S,4S)-1-((R)-2-((S)-2-acetamido-3-
(1-trityl-1H-imidazol-4-yl)propanamido)-3-phenylpropanoyl)-4-(naph-
thalen-2-ylmethoxy)pyrrolidin-2-yl)propylamino)(tert-butoxycarbonyl-
Supporting Information Available: Experimental procedures
and analytical data for analogues 42a-e, 43-47, 56a-e, 60a-e
and elemental analysis results for final compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
amino)methylenecarbamate as described for 35b. White solid; H
NMR (300 MHz, CD3OD) δ 8.70-8.90 (m, 1H), 7.80-8.00 (m,
5H), 7.40-7.55 (m, 3H), 7.20-7.40 (m, 5H), 4.60-5.00 (m, 4H),
2.80-4.20 (m, 11H), 1.10-2.30 (m, 9H); MS (ESI) m/z 653 (M +
H). Anal. (C36H44N8O4‚2.2CF3CO2H) C, H, N.
(S)-N-((R)-1-((2S,4S)-2-(3-Guanidinopropyl)-4-(naphthalen-
2-ylmethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl)-1,2,3,4-
tetrahydroisoquinoline-3-carboxamide (56c). White solid; 1H
NMR (300 MHz, CD3OD) δ 7.80-8.00 (m, 4H), 7.20-7.60 (m,
12H), 4.76 (m, 2H), 4.00-4.50 (m, 6H), 2.80-3.40 (m, 8H), 2.24
(m, 1H), 1.80-2.00 (m, 2H), 1.10-1.65 (m, 3H); MS (ESI) m/z
633 (M + H). Anal. (C38H44N6O3‚2.3CF3CO2H) C, H, N.
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