Pd-catalyzed dimethylation of tyrosine-derived picolinamide for synthesis of (S)-N-Boc-2,6-dimethyltyrosine and its analogues

Article abstract of DOI:10.1021/acs.orglett.6b03548

A short and efficient synthesis of (S)-N-Boc-2,6-dimethyltyrosine utilizing palladium-catalyzed directed C-H functionalization is described. This represents the first general method for the ortho-dimethylation of tyrosine derivatives and offers a practical approach for preparing this synthetically important building block. Notably, throughout the reaction sequence no racemization occurs at the susceptible a-chiral centers.

Full text of DOI:10.1021/acs.orglett.6b03548

Letter
pubs.acs.org/OrgLett
Pd-Catalyzed Dimethylation of Tyrosine-Derived Picolinamide for
Synthesis of (S)‑N‑Boc-2,6-dimethyltyrosine and Its Analogues
Xuning Wang,† Songtao Niu,† Lanting Xu,‡ Chao Zhang,‡ Lingxing Meng,‡ Xiaojing Zhang,*,†
and Dawei Ma*,‡
†Shenyang Pharmaceutical University, 103 Wenhua Lu, Shenyang 110016, China
‡State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Lu, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A short and efficient synthesis of (S)-N-Boc-
2,6-dimethyltyrosine utilizing palladium-catalyzed directed C−
H functionalization is described. This represents the first
general method for the ortho-dimethylation of tyrosine
derivatives and offers a practical approach for preparing this
synthetically important building block. Notably, throughout the reaction sequence no racemization occurs at the susceptible α-
chiral centers.
he H-Tyr-Tic-OH dipeptide 1a (Figure 1, Tic: (S)-1,2,3,4-
tetrahydro-isoquinoline-3-carboxylic acid) is the smallest
1).5c,d In both approaches, tetra-substituted benzene starting
materials are not conveniently available, and expensive reagents
T
Scheme 1. Previous and Present Routes for Assembling (S)-N-
Boc-2,6-dimethyltyrosine
Figure 1. Structures of some potent δ-opioid receptor antagonists.
peptide fragment that still retained potent δ-opioid receptor
antagonist properties.1 Replacement of the tyrosine residue in
this dipeptide with (S)-2,6-dimethyltyrosine (DMT), a con-
formationally restricted unnatural amino acid, gave improved δ-
opioid affinity and selectivity.2 Since the discovery of H-Dmt-
Tic-OH (1b),2 thousands of its analogues have been designed
and synthesized for developing drugable opioid receptor
modulators.3 This campaign has resulted in the discovery of
Eluxadoline (2), an orally administered, first-in-class drug for the
treatment of diarrhea-predominant irritable bowel syndrome
(IBS-D) in adults.4
Although the structure of (S)-2,6-dimethyltyrosine is simple,
its 2,6-dimethyl substituents make the assembly of this unnatural
amino acid to be rather challenging.5 To date, two major
approaches have been developed for preparing (S)-2,6-
dimethyltyrosine and its derivatives. One is alkylation of
protected (2,6-dimethyl-4-hydroxy)benzyl halides with glycine-
derived chiral synthons,5a,b while another one is asymmetric
hydrogenation of (Z)-2-acetamido-3-(4-acetoxy-2,6-dimethyl-
phenyl)-2-propenoate 4 to afford enantioenriched 5 (Scheme
or catalysts are required to achieve asymmetric control. Although
the asymmetric hydrogenation approach allows for the synthesis
of (S)-N-Boc-2,6-dimethyltyrosine (6) on a large scale,5c the
required catalyst is expensive, which results in high costs. During
the studies on direct functionalization of conveniently available
amino acid derivatives to obtain high value-added products via
metal catalyzed C−H bond activation,6 we found that Pd-
catalyzed dimethylation of tyrosine derivative 7 could give 8 in
Received: November 28, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03548
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
about 90% yield, and thereby providing an inexpensive method
for synthesizing 6. Herein we wish to detail our results.
Table 1. Pd-Catalyzed ortho-Methylation of Amide 7 under
Different Reaction Conditions
a
The ortho-alkylation of acetanilides under the action of
stoichiometric amounts of palladium acetate was initially
reported by Tremont and Rahman in 1984.7 In this reaction
the acetoamido group was believed to coordinate with Pd and
thereby serve as a directing group. In recent years, this idea was
refreshed by employing more powerful picolinamide (PA)
directing group.8 Under the assistance of this group, direct ortho-
alkylation of the amides generated from a number of benzyl-
amines proceeded under the catalysis of 10 mol % Pd(OAc)2.8a
The key for this reaction was using NaOTf as the additive, t-
AmylOH as the solvent, and oxygen as the oxidant.8a The major
drawback of this transformation is it can not completely stop at
the monoalkylation stage, and therefore, only ortho- and meta-
substituted substrates gave single monoalkylation products. This
problem may result from that monoalkylation products are more
reactive than the corresponding substrates toward Pd-catalyzed
C−H bond activation, which has been seen in several metal-
catalyzed ortho-functionalizations of benzylamine-derived
amides.9−12 We envisioned that this special feature could turn
to be an advantage for assembling (S)-2,6-dimethyl-tyrosine
derivatives. Indeed, in their subsequent study Chen group has
discovered that Pd(OAc)2-catalyzed double methylation of a
phenylalanine-derived picolinamide could be achieved under the
action of 2 equiv of Ag2CO3.8b However, direct use of these
conditions to prepare the (S)-N-Boc-2,6-dimethyltyrosine 6
from the tyrosine derivative 7 would not be cost-effective, mainly
because using 2 equiv of silver salt not only increases the cost but
also gives difficulty for recovery of more expensive Pd catalyst.
Thus, we planned to discover more practical conditions for
double methylation.
b
yield (%)
entry atmosphere
base
solvent
t-AmyOH
7/8/9
c
1
O2
O2
O2
air
Ar
air
air
air
air
air
air
air
air
air
air
air
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
60/1/13
65/2/15
0/86/12
0/85/12
36/25/37
7/50/42
78/5/17
75/5/18
42/9/48
0/80/9
2
t-AmyOH
3
toluene/t-AmyOH (9:1)
toluene/t-AmyOH (9:1)
toluene/t-AmyOH (9:1)
4
5
6
KHCO3 toluene/t-AmyOH (9:1)
7
KOAc
K3PO4
toluene/t-AmyOH (9:1)
toluene/t-AmyOH (9:1)
8
9
Na2CO3 toluene/t-AmyOH (9:1)
10
11
12
13
14
15
16
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
ClCH2CH2Cl
dioxane
33/11/26
60/5/27
67/8/25
0/88/10
0/95/0
MeCN
toluene/t-AmyOH (1:1)
toluene
d
e
toluene
toluene
7/72/21
a
General conditions: 7 (0.2 mmol), Pd(OAc)2 (0.01 mmol), base (0.6
b
mmol), 0.2 M, 110 °C, 24 h. The yield was determined by 1H NMR
analysis of crude products using 1,3,5-trimethoxy-benzene as the
internal standard. Using NaOTf as the additive. At 120 °C. At 120
c
d
e
°C, 2.5 mol % Pd(OAc)2 was used.
As demonstrated in Table 1, we started our investigation by
conducting ortho-methylation of the amide 7 (preparing from
(S)-tyrosine in 3 steps and 88% overall yield) under Chen’s
conditions.8a It was found that reaction occurred at 110 °C, but
gave poor conversion and monomethylation product 9 as the
major product (entry 1). Removal of the additive NaOTf gave a
similar result (entry 2). Interestingly, a great improvement was
observed by using mixed toluene and t-AmyOH as the reaction
media. The similar phenomenon has been observed in Chen’s
study.8b In this case, reaction completed and gave the desired
dimethylation product 8 as the major product (entry 3).
Changing oxygen to air provided a similar but reproducible
result (entry 4). It seemed that oxygen is important to this
reaction because under Ar the conversion was significantly
decreased (entry 5). After having failed to increase the yield of 8
by changing the bases (entries 6−9), we further explored the
solvent effect. While 1,2-dichloroethane gave complete con-
version (entry 10), dioxane and acetonitrile led to incomplete
conversions (entries 11 and 12). Changing the ratio of toluene
and t-AmyOH gave a worse result (entry 13). However, using
toluene alone could slightly improve the yield of 8 (entry 14).
The best result was observed when the reaction was carried out at
120 °C in toluene, which led to exclusive formation of 8 in about
95% yield (entry 15). Under the same conditions, an
unsatisfactory result was obtained if the catalytic loading was
reduced to 2.5 mol % (entry 16).
were tested under the standard conditions (Scheme 2).
Unfortunately, none of them gave improved results in either
toluene or 1,2-dichloroethane.
As outlined in Scheme 3, we also checked some analogues of 7
with different substituents at the 4-position. Benzoxyl substituted
analogue 18a gave the dimethylation product in 85% yield.
However, poor yields were observed in case of chloro and ester
substituted analogues 18b and 18c as the substrates. These
results implied that electron-rich aryl compounds are more
reactive toward Pd-catalyzed dimethylation. Interestingly, in the
case of chloro substituted analogue 18b, an excellent yield was
obtained when 1,2-dichloroethane was used as the solvent. The
chloride functionality in the products can be functionalized
through a variety of transformations, thus providing a divergent
route to access a library of medicinally relevant scaffolds.
Furthermore, aryl chlorides can also be easily convert to the
amide group, which will result in the core intermediate en route
to the synthesis of Eluxadoline (2).4,13
Next, we turned our attention to scaling up the dimethylation
of 7 from a milligram to a multigram scale. Gratifyingly, we found
that the optimized conditions were also equally effective on a
large scale synthesis. When 20.7 g (50.0 mmol) of 7 was
subjected to the dimethylation conditions, the desired product 8
was formed in 90% yield with 99.7% ee (Scheme 4). The
deprotection of the amino and phenolic hydroxy groups using
HCl, and subsequent Boc protection of the amino group with
Boc anhydride, was achieved in a one-pot manner, giving 6 in a
93% yield without loss of enantiomeric excess. The overall yield,
enantiomeric excess and atom-economy of this sequence was
We then proceeded to investigate the effect of directing group
on the efficiency of the reaction. Accordingly, amides 10, 12, 14,
and 16 that were generated from quinaldic acid,10 2-
pyrazinecarboxylic acid,11 2-[bis(1-methylethyl)-amino]-2-oxo-
acetic acid,12 and 2-methoxyiminoacetic acid,6a,b respectively,
B
DOI: 10.1021/acs.orglett.6b03548
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In summary, we have demonstrated a novel, operationally
simple strategy for the practical synthesis of (S)-N-Boc-2,6-
dimethyltyrosine via Pd-catalyzed double C−H methylation.
The present reaction sequence is very general, straightforward,
easily scalable, and worked under mild reaction conditions for
various tyrosine derivatives. Additionally, the use of commer-
cially available amino acid derivatives eliminated the need of
expensive reagents or catalysts, further facilitating the synthesis
of these classes of molecules. Finally, this approach can also be
extended to other enantiomerically pure α-substituted tyrosine
derivatives, thus providing a facile route to access a library of
analogues for practical application in drug discovery and
development.
Scheme 2. Pd-Catalyzed ortho-Dimethylation of Other
Tyrosine-Derived Amides
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03548.
Experimental procedures, spectra data, and copies of all
new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: madw@mail.sioc.ac.cn.
*E-mail: xiaojinzhang62@163.com.
ORCID
Dawei Ma: 0000-0002-1721-7551
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to Chinese Academy of Sciences
(supported by the Strategic Priority Research Program, grants
XDB20020200 and QYZDJ-SSW-SLH029) and the National
Natural Science Foundation of China (grant 21132008) for their
financial support.
Scheme 3. Pd-Catalyzed ortho-Dimethylation of Analogues of
7
REFERENCES
■
(1) For a review, see: Bryant, S. D.; Salvadori, S.; Cooper, P. S.; Lazarus,
L. H. Trends Pharmacol. Sci. 1998, 19, 42−46.
(2) Salvadori, S.; Attila, M.; Balboni, G.; Bianchi, C.; Bryant, S. D.;
Crescenzi, O.; Guerrini, R.; Picone, D.; Tancredi, T.; Temussi, P. A.;
Lazarus, L. H. Mol. Med. 1995, 1, 678−689.
Scheme 4. Large-Scale Synthesis of 8 and Its Conversion to 6
(3) For selected references, see: (a) Bai, L.; Li, Z.; Chen, J.; Chung, N.;
Wilkes, B. C.; Li, T.; Schiller, P. W. Bioorg. Med. Chem. 2014, 22, 2333−
2338. (b) Lee, Y. S.; Agnes, R. S.; Cain, J. P.; Kulkarni, V.; Cai, M.;
Salibay, C.; Ciano, K.; Petrov, R.; Mayorov, A.; Vagner, J. Biopolymers
2008, 90, 433−438. (c) Toth, G.; Keresztes, A.; Tomboly, C.; Peter, A.;
Fulop, F.; Tourwe, D.; Navratilova, E.; Varga, E.; Roeske, W. R.;
Yamamura, H. I. Pure Appl. Chem. 2004, 76, 951−957. (d) Harrison, B.
A.; Pasternak, G. W.; Verdine, G. L. J. Med. Chem. 2003, 46, 677−680.
(e) Lu, Y.; Nguyen, T. M. D.; Weltrowska, G.; Berezowska, I.; Lemieux,
C.; Chung, N. N.; Schiller, P. W. J. Med. Chem. 2001, 44, 3048−3053.
́
(f) Page, D.; Naismith, A.; Schmidt, R.; Coupal, M.; Labarre, M.;
Gosselin, M.; Bellemare, D.; Payza, K.; Brown, W. J. Med. Chem. 2001,
44, 2387−2390.
(4) Garnock-Jones, K. P. Drugs 2015, 75, 1305−1310.
(5) (a) Soloshonok, V. A.; Tang, X.; Hruby, V. J. Tetrahedron 2001, 57,
6375−6382. (b) Balducci, D.; Contaldi, S.; Lazzari, I.; Porzi, G.
Tetrahedron: Asymmetry 2009, 20, 1398−1401. (c) Praquin, C. F. B.; de
Koning, P. D.; Peach, P. J.; Howard, R. M.; Spencer, S. L. Org. Process Res.
Dev. 2011, 15, 1124−1129. (d) Imamoto, T.; Tamura, K.; Zhang, Z.;
Horiuchi, Y.; Sugiya, M.; Yoshida, K.; Yanagisawa, A.; Gridnev, I. D. J.
thus better than the previously reported synthetic routes for
preparing (S)-N-Boc-2,6-dimethyltyrosine.
C
DOI: 10.1021/acs.orglett.6b03548
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Am. Chem. Soc. 2012, 134, 1754−1769. (e) Lin, L.; Fu, X.; Ma, X.;
Zhang, J.; Wang, R. Synlett 2012, 23, 2559−2562. (f) Bender, A. M.;
Griggs, N. W.; Gao, C.; Trask, T. J.; Traynor, J. R.; Mosberg, H. I. ACS
Med. Chem. Lett. 2015, 6, 1199−1203.
(6) (a) Fan, M.; Ma, D. Angew. Chem., Int. Ed. 2013, 52, 12152−12155.
(b) He, Y.-P.; Zhang, C.; Fan, M.; Wu, Z.; Ma, D. Org. Lett. 2015, 17,
496−499. (c) Xu, L.; Zhang, C.; He, Y.; Tan, L.; Ma, D. Angew. Chem.,
Int. Ed. 2016, 138, 495−499. (d) Xu, L.; Tan, L.; Ma, D. J. Org. Chem.
2016, 81, 10476−10483.
(7) Tremont, S. J.; Rahman, H. U. J. Am. Chem. Soc. 1984, 106, 5759−
5710.
(8) (a) Zhao, Y.; Chen, G. Org. Lett. 2011, 13, 4850−4853. (b) Zhang,
S.-Y.; He, G.; Nack, W. A.; Zhao, Y.; Li, Q.; Chen, G. J. Am. Chem. Soc.
2013, 135, 2124−2127.
(9) (a) Ackermann, L.; Hofmann, N.; Vicente, R. Org. Lett. 2011, 13,
1875−1877. (b) Bedford, R. B.; Haddow, M. F.; Mitchell, C. J.; Webster,
R. L. Angew. Chem., Int. Ed. 2011, 50, 5524−5527. (c) Chan, K. S. L.;
Wasa, M.; Wang, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2011, 50, 9081−
9084. (d) Han, J.; Liu, P.; Wang, C.; Wang, Q.; Zhang, J.; Zhao, Y.; Shi,
D.; Huang, Z.; Zhao, Y. Org. Lett. 2014, 16, 5682−5685. (e) He, G.;
Zhao, Y.; Zhang, S.; Lu, C.; Chen, G. J. Am. Chem. Soc. 2012, 134, 3−6.
(f) Lu, C.; Zhang, S.-Y.; He, G.; Nack, W. A.; Chen, G. Tetrahedron
2014, 70, 4197−4203. (g) Nack, W. A.; He, G.; Zhang, S.-Y.; Lu, C.;
Chen, G. Org. Lett. 2013, 15, 3440−3443. (h) Vickers, C. J.; Mei, T.-S.;
Yu, J.-Q. Org. Lett. 2010, 12, 2511−2513. (i) Wang, Q.; Han, J.; Wang,
C.; Zhang, J.; Huang, Z.; Shi, D.; Zhao, Y. Chemical Science 2014, 5,
4962−4967. (j) Wang, X.; Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2009,
131, 7520−7521. (k) Zhao, Y.; He, G.; Nack, W. A.; Chen, G. Org. Lett.
2012, 14, 2948−2951.
(10) Huang, L.; Sun, X.; Li, Q.; Qi, C. J. Org. Chem. 2014, 79, 6720−
6725.
(11) (a) Li, Q.; Zhang, S.-Y.; He, G.; AI, Z.; Nack, W. A.; Chen, G. Org.
Lett. 2014, 16, 1764−1767.
(12) (a) Guan, M.; Chen, C.; Zhang, J.; Zeng, R.; Zhao, Y. Chem.
Commun. 2015, 51, 12103−12106. (b) Wang, C.; Chen, C.; Zhang, J.;
Han, J.; Wang, Q.; Guo, K.; Liu, P.; Guan, M.; Yao, Y.; Zhao, Y. Angew.
Chem., Int. Ed. 2014, 53, 9884−9888.
(13) Panahi, F.; Jamedi, F.; Iranpoor, N. Eur. J. Org. Chem. 2016, 2016,
780−788.
D
DOI: 10.1021/acs.orglett.6b03548
Org. Lett. XXXX, XXX, XXX−XXX