Rapid Synthesis of Boc-2′,6′-dimethyl- l -tyrosine and Derivatives and Incorporation into Opioid Peptidomimetics

Article abstract of DOI:10.1021/acsmedchemlett.5b00344

The unnatural amino acid 2′,6′-dimethyl-l-tyrosine has found widespread use in the development of synthetic opioid ligands. Opioids featuring this residue at the N-terminus often display superior potency at one or more of the opioid receptor types, but the availability of the compound is hampered by its cost and difficult synthesis. We report here a short, three-step synthesis of Boc-2′,6′-dimethyl-l-tyrosine (3a) utilizing a microwave-assisted Negishi coupling for the key carbon-carbon bond forming step, and employ this chemistry for the expedient synthesis of other unnatural tyrosine derivatives. Three of these derivatives (3c, 3d, 3f) have not previously been examined as Tyr¹ replacements in opioid ligands. We describe the incorporation of these tyrosine derivatives in a series of opioid peptidomimetics employing our previously reported tetrahydroquinoline (THQ) scaffold, and the binding and relative efficacy of each of the analogues at the three opioid receptor subtypes: mu (MOR), delta (DOR), and kappa (KOR).

Full text of DOI:10.1021/acsmedchemlett.5b00344

Letter
pubs.acs.org/acsmedchemlett
Rapid Synthesis of Boc-2′,6′-dimethyl‑L‑tyrosine and Derivatives and
Incorporation into Opioid Peptidomimetics
Aaron M. Bender,† Nicholas W. Griggs,‡ Chao Gao,‡ Tyler J. Trask,‡ John R. Traynor,‡
and Henry I. Mosberg*,†,§
†Interdepartmental Program in Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109,
United States
‡Department of Pharmacology, School of Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States
§Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
S
* Supporting Information
ABSTRACT: The unnatural amino acid 2′,6′-dimethyl-L-
tyrosine has found widespread use in the development of
synthetic opioid ligands. Opioids featuring this residue at the N-
terminus often display superior potency at one or more of the
opioid receptor types, but the availability of the compound is
hampered by its cost and difficult synthesis. We report here a
short, three-step synthesis of Boc-2′,6′-dimethyl-L-tyrosine (3a)
utilizing a microwave-assisted Negishi coupling for the key
carbon−carbon bond forming step, and employ this chemistry
for the expedient synthesis of other unnatural tyrosine
derivatives. Three of these derivatives (3c, 3d, 3f) have not
previously been examined as Tyr1 replacements in opioid
ligands. We describe the incorporation of these tyrosine
derivatives in a series of opioid peptidomimetics employing
our previously reported tetrahydroquinoline (THQ) scaffold, and the binding and relative efficacy of each of the analogues at the
three opioid receptor subtypes: mu (MOR), delta (DOR), and kappa (KOR).
KEYWORDS: Negishi coupling, microwave synthesis, opioid peptidomimetics, tetrahydroquinoline, 2′,6′-dimethyl-L-tyrosine
he unnatural amino acid 2′,6′-dimethyl-L-tyrosine (Dmt)1
the desired L stereochemistry is the asymmetric hydrogenation
of (Z)-2-acetamido-3-(4-acetoxy-2,6-dimethylphenyl)-2-prope-
Thas found widespread use in the synthesis of opioid
peptides and small molecules.2−5 Typically, opioid ligands
containing Dmt in place of tyrosine (Tyr) at the N-terminus
noate, using the expensive chiral catalyst [Rh(1,5-COD)(R,R-
DIPAMP)]BF4.16 Other strategies involve the alkylation of a
Ni(II) complex of the chiral Schiff base derived from glycine
and (S)-o-[N-(N-benzylprolyl)amino]benzophenone17 and a
stereocontrolled alkylation of a chiral 2,5-diketopiperazine
synthon.18 Although these routes are synthetically viable, we
sought to develop a shorter and more direct approach for the
expedient synthesis of Dmt and other novel unnatural Tyr
derivatives. Additionally, we were interested in developing a
synthesis in which the desired L stereochemistry is incorporated
from the beginning and does not need to be installed with the
use of a chiral auxiliary or catalyst.
Jackson and colleagues have disclosed that the use of
Pd2(dba)3 and SPhos in a 1:2 molar ratio is a highly efficient
precatalyst for the Negishi coupling of aryl halides with an
organozinc reagent derived from iodoalanine intermediate 1.19
This strategy was shown to be effective for both aryl iodides
display increased affinity for the mu opioid receptor
(MOR),6−8 and many Dmt-containing ligands reported in the
literature are potent and efficacious analgesics in preclinical
pain models.9,10 Additionally, Dmt is a component of Dmt-Tic,
a delta opioid receptor (DOR) antagonist pharmacophore that
is incorporated in many biologically active compounds.11 Dmt
is also an important building block for the synthesis of the
mixed mu-delta opioid ligand Eluxadoline, a small molecule
opioid recently approved for the treatment of irritable bowel
syndrome.12,13 Moreover, it has recently been shown that small,
Dmt-conjugated peptides can be taken up by plant host cells
and help mitigate oxidative stress.14 Other studies with peptides
containing this amino acid have also highlighted the antioxidant
properties of Dmt.15 The increasingly common use of this
unnatural amino acid in peptide chemistry has rendered the
availability of this compound extremely valuable for medicinal
chemists.
Received: August 20, 2015
Accepted: October 19, 2015
Several synthetic routes to Dmt have previously been
published. In one such synthesis, the key step for installing
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.5b00344
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Letter
and bromides, as well as aryl halides featuring unprotected
phenols and ortho substitutions. Given the synthetic utility of
this approach, we reasoned that a Negishi coupling between 1
and commercially available 3,5-dimethyl-4-iodophenol was a
feasible approach toward the synthesis of Dmt.
Iodoalanine intermediate 1 was synthesized under Appel
conditions as previously reported starting from commercially
available Boc-protected L-serine methyl ester (Boc-Ser-OMe)
(Scheme 1).20 With intermediate 1 in hand, we sought to
cross coupling reaction for the synthesis of other unnatural
tyrosine and phenylalanine derivatives (Scheme 2).
2′-Methyl-L-tyrosine (Mmt), analogue 3b, has been
previously reported in synthetic endomorphin23 and DALDA-
based24 peptides and showed comparable binding affinity at
MOR relative to the Dmt counterpart compounds. 2′,6′-
Dimethyl-L-phenylalanine (Dmp), analogue 3e, has also been
incorporated into the endomorphin scaffold and has been
shown to improve binding affinity at MOR and DOR compared
to the naturally occurring endomorphins when substituted at
the third position.25 Additionally, phenylalanine and derivatives
can sometimes serve as suitable replacements for the N-
terminal tyrosine in opioid peptides, while still maintaining
biological activity.26,27 To our knowledge, compounds 3c, 3d,
and 3f have not been examined as Tyr replacements in opioid
ligands. The synthesis of all analogues using the microwave-
assisted Negishi coupling proved straightforward. Most yields
were comparable to that of 2a, although in the case of analogue
2d, the observed lower yield of 16% was likely a result of the
additional halogen substitutions on the aromatic ring in
combination with the steric hindrance of the system. In the
case of analogue 2d, aryl iodide 5 was synthesized from 3,5-
dichloroanisole as previously described (Scheme 3).28 In the
a
Scheme 1. Synthesis of Boc-2′,6′-dimethyl-L-tyrosine
a
Reagents and conditions: (a) I2, PPh3, imidazole, DCM, r.t.; (b) Zn
dust, catalytic I2, 3,5-dimethyl-4-iodophenol, Pd2(dba)3, SPhos, DMF,
110 °C, microwave irradiation; (c) LiOH, THF, H2O, r.t.
a
Scheme 3. Synthesis of Aryl Iodide 5
determine the optimal conditions for the Negishi coupling with
3,5-dimethyl-4-iodophenol. Jackson and colleagues observed
that the best yields for the coupling of mono-ortho-substituted
aryl halides with 1 were obtained by using 2.5 mol % of
Pd2(dba)3 and 5 mol % of SPhos with stirring at room
temperature overnight. For the coupling between 1 and 3,5-
dimethyl-4-iodophenol, these conditions led to the formation
of desired product 2a in 16% yield. We reasoned that the
additional steric hindrance of our system contributed to the
observed low yield and sought to determine a more efficient
approach.
a
Reagents and conditions: (f) I2, Ag2SO4, MeCN, r.t.
case of analogue 2f, aryl bromide 6 was synthesized via
halogenation and aromatization of commercially available 7-
bromo-3,4-dihydronaphthalen-1(2H)-one (Scheme 4). After
The use of microwave-assisted synthesis has been shown to
be highly effective for challenging Negishi cross-coupling
reactions,21,22 and we next ran the reaction under microwave
irradiation at 110 °C (Discover S-class (CEM) microwave
reactor in a closed vessel with a maximum power input of 300
W) for 2 h to give 2a in 34% yield. Increasing the mol % of
Pd2(dba)3 and SPhos to 5% and 10%, respectively, under these
conditions gave 2a in 56% yield. Subsequent methyl ester
hydrolysis gave Boc-2′,6′-dimethyl-L-tyrosine 3a. We then
turned our attention to using the microwave-assisted Negishi
a
Scheme 4. Synthesis of Aryl Bromide 6
a
Reagents and conditions: (g) NBS, CCl4, reflux; (h) LiBr, Li2CO3,
DMF, 140 °C
a
Scheme 2. Synthesis of Analogues 4a−f
a
Reagents and conditions: (a) Zn dust, catalytic I2, aryl iodide or aryl bromide, Pd2(dba)3, SPhos, DMF, 110 °C, microwave irradiation; (b) LiOH,
THF, H2O, r.t.; (c) 7, PyBOP, 6-Cl-HOBt, DIPEA, DMF, r.t.; (d) TFA, DCM, r.t.; (e) BBr3, DCM, r.t. (for intermediate 3d only).
B
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ACS Medicinal Chemistry Letters
Letter
a
Table 1. Opioid Receptor Binding Affinities of Analogues 4a−f
a
Binding affinities (Ki) were obtained by competitive displacement of radiolabeled [3H]diprenorphine in membrane preparations expressing MOR,
b
DOR, or KOR. All values are expressed as the mean SEM of three separate assays performed in duplicate. Data from ref 9.
LiOH-mediated methyl ester hydrolysis, all analogues were
coupled to chiral amine salt 729 under standard amide coupling
conditions (Scheme 2) to give final tetrahydroquinolines 4a−f
after Boc-deprotection, and in the case of 4d, after an additional
deprotection of the aryl methoxy group with BBr3 (Scheme 2).
Chiral HPLC analysis indicated high enantiomeric ratios for
derivatives 3a−f, and no significant racemization of final
compounds was observed by HPLC during the coupling of 7 to
the Boc-protected amino acid derivatives. Final analogues were
then purified by semipreparative RP-HPLC and lyophilized to
give enough material for in vitro testing.
Binding affinities for compounds 4a−f (Ki) were measured
by the competitive displacement of radiolabeled [3H]-
diprenorphine (a nonselective opioid antagonist) in C6 cells
stably expressing MOR or DOR, or Chinese Hamster Ovary
(CHO) cells stably expressing KOR (Table 1). EC50 and %
stimulation data were obtained by agonist-stimulated [35S]-
GTPγS binding in the same cell types (Table 2).30,31
As seen in Table 1, MOR binding affinity is reduced by
approximately an order of magnitude for analogues 4b and 4c
in which the 2′-methyl group is maintained, and the second aryl
methyl is either deleted (4b) or moved to the 5′ position (4c).
MOR affinity for 2′,6′-dichloro analogue 4d is comparable to
C
DOI: 10.1021/acsmedchemlett.5b00344
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ACS Medicinal Chemistry Letters
Letter
a
Table 2. Opioid Receptor Potencies and Relative Efficacies of Analogues 4a−f
EC50 (nM)
% stimulation
compd
MOR
DOR
KOR
MOR
DOR
KOR
b
b
b
b
b
b
4a
4b
4c
4d
4e
4f
1.6 0.3
44 20
110
dns
6
540 72
81
2
6
8
3
8
16
2
22
41
22
32
38
nt
2
8
6
4
5
2400 80
370 200
1200 290
4800 1100
nt
69
89
83
86
nt
dns
53
39
33
8
4
5900 2200
8
dns
dns
nt
dns
dns
nt
280 50
nt
a
Efficacy data were obtained using agonist induced stimulation of [35S]GTPγS binding in membrane preparations expressing MOR, DOR or KOR.
Efficacy is represented as EC50 (nM) and percent maximal stimulation relative to standard agonist DAMGO (MOR), DPDPE (DOR), or U69,593
(KOR) at 10 μM. All values are expressed as the mean SEM of three separate assays performed in duplicate. dns = does not stimulate; nt = not
b
tested, due to low binding affinity (Table 1). Data from ref 9.
Funding
the parent compound 4a, which is not entirely surprising given
the similar size of the methyl and chloro substituents.
Analogues 4e and 4f display a more pronounced decrease in
MOR binding, and analogues 4c, 4e, and 4f lose significant
binding affinity at DOR. The data in Table 2 show that
analogues 4b−e all maintain a high level of agonist efficacy (as
measured by [35S]GTPγS binding) compared to DAMGO at
MOR, but with reduced potency as compared to 4a. The 2′,5′-
dimethyl analogue 4c displays reduced potency at DOR as
compared to 4a, but with higher maximal stimulation (53%
compared to the full agonist DPDPE). The naphthol analogue
4f shows a significant decrease in binding affinity for all three
receptors and thus was not evaluated in the [35S]GTPγS assay.
The results observed with 4d merit special mention.
Compared with the lead compound 4a, 4d, which replaces
the 2′, 6′ methyls of Dmt with metabolically less labile chloro
substituents, maintains the high MOR affinity observed for 4a,
while providing considerable selectivity over DOR and KOR.
While in this particular example, 4d shows 20-fold lower
potency in the [35S]GTPγS assay compared to 4a, the results
suggest that 2′,6′-dichloro-L-tyrosine may prove useful for the
development of opioids with improved metabolic stability
toward benzylic oxidation.
This study was supported by NIH grant DA003910 (H.I.M.
and J.R.T.). N.W.G. was supported by the Pharmacological
Sciences Training Program administered by NIGMS: T32
GM007767.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Mary Clark and Alisha Griffin are thanked for additional in
vitro contributions.
ABBREVIATIONS
■
B o c , t e r t - b u t y l o x y c a r b o n y l ; P d 2 ( d b a ) 3 , t r i s -
(dibenzylideneacetone)dipalladium(0); SPhos, 2-dicyclohexyl-
phosphino-2′,6′-dimethoxybiphenyl; DCM, dichloromethane;
DMF, N,N-dimethylformamide; THF, tetrahydrofuran;
PyBOP, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexa-
fluorophosphate; 6-Cl-HOBt, 6-chloro-1-hydroxybenzotriazole;
DIPEA, diisopropylethylamine; TFA, trifluoroacetic acid;
MeCN, acetonitrile; NBS, N-bromosuccinimide
In this report we have described a short, convenient synthesis
of Boc-2′,6′-dimethyl-L-tyrosine for the more expedient
production of this important unnatural amino acid. We have
also demonstrated the utility of this chemistry for the synthesis
of new Tyr derivatives and have shown that the incorporation
of 3b and 3e and the previously unexplored derivatives 3c, 3d,
and 3f into our THQ scaffold yields novel opioids with
interesting in vitro profiles at MOR, DOR, and KOR. These
and future Tyr analogues should find use in the development of
new Tyr-containing peptides and small molecules.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.5b00344.
Experimental procedures and NMR data for all
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: him@med.umich.edu. Phone: (734) 764-8117.
D
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