Synthesis of Chiral α,β-Unsaturated γ-Amino Esters via Pd-Catalyzed Asymmetric Allylic Amination

Article abstract of DOI:10.1021/acs.orglett.7b01904

A Pd-catalyzed asymmetric allylic amination of 4-substituted 2-acetoxybut-3-enoates with amines has been developed for the regiospecific synthesis of chiral α,β-unsaturated γ-amino esters. The desired chiral aminated products can be obtained in up to 98%

Full text of DOI:10.1021/acs.orglett.7b01904

Letter
pubs.acs.org/OrgLett
Synthesis of Chiral α,β-Unsaturated γ‑Amino Esters via Pd-Catalyzed
Asymmetric Allylic Amination
Chao Xia,† Jiefeng Shen,† Delong Liu,*,† and Wanbin Zhang*,†,‡
‡
†School of Pharmacy and School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road,
Shanghai 200240, P. R. China
S
* Supporting Information
ABSTRACT: A Pd-catalyzed asymmetric allylic amination of
4-substituted 2-acetoxybut-3-enoates with amines has been
developed for the regiospecific synthesis of chiral α,β-
unsaturated γ-amino esters. The desired chiral aminated
products can be obtained in up to 98% yield, and 99% ee
and can be conveniently transformed to chiral γ-amino acid/
alcohol derivatives and chiral γ-lactams, which can then be
subjected to the synthesis of several types of chiral drugs and
drug candidates. The preferential formation of chiral γ-amino esters may be attributed to the bulky substituents on the right side
of the allyl substrates. This work provides an efficient strategy for the synthesis of chiral α,β-unsaturated γ-amino esters and their
derivatives.
hiral α,β-unsaturated γ-amino esters are of considerable
Csignificance due to their use as versatile building blocks
for chemical and biological synthesis.1 They can be converted
to chiral γ-amino amides (of which some are efficient β-
secretase inhibitors),2a chiral γ-amino alcohols for the synthesis
of the antidepressant drug cis-(+)-sertraline,2b or chiral γ-
lactams for the synthesis of other biologically active
compounds, such as a bioactive tankyrase inhibitor,2c etc.
(Scheme 1).
By using enantioenriched allylic substrates, Lee synthesized two
chiral α,β-unsaturated γ-amino esters via an Ir-catalyzed allylic
amination.3a Norrby demonstrated an enantioconvergent
synthesis of only one chiral α,β-unsaturated γ-amino ester by
utilizing an asymmetric HWE reaction and a stereoselective Pd-
catalyzed allylic substitution.3b Sharma3c and Ohshima3d
independently reported a Pd- or Pt-catalyzed stereoselective
opening of chiral vinyl epoxides with amine nucleophiles. Just
recently, Terada employed an efficient Pd-catalyzed decarbox-
ylative rearrangement of enantioenriched allylic carbamates for
the synthesis of chiral γ-amino-α,β-unsaturated esters; slightly
loss in enantioselectivities of aminated products was observed.3e
Although several elegant methodologies have been developed, a
direct catalytic asymmetric synthesis of chiral α,β-unsaturated γ-
amino esters from various racemic allyl substrates and
nucleophiles has yet to be explored.
Scheme 1. Chiral α,β-Unsaturated γ-Amino Esters as Drug
(Intermediates) and Building Blocks
Pd-catalyzed allylic substitution is a powerful synthetic tool
for the formation of C−C and C−X bonds (X = N, O, S, etc.).4
Recently, we have developed several metal-catalyzed asym-
metric allylic alkylations for the construction of biologically
active chiral molecules which possess excellent catalytic
behavior.5 Among them, a hydrogen-bond-directed regioselec-
tive Pd-catalyzed asymmetric allylic alkylation has been
developed, providing “branched” chiral α-amino acids in high
yields and excellent selectivities.5e
Herein, we disclose an efficient pathway for the preparation
of α,β-unsaturated γ-amino esters via a Pd-catalyzed asymmetric
allylic amination of functionalized allyl substrates and amine
nucleophiles (Scheme 2).
Generally, chiral α,β-unsaturated γ-amino esters can be
prepared readily via a Wittig-type olefination of N-protected α-
amino aldehydes. However, chiral aldehydes that are used in
the reactions are sensitive to air, and their preparation requires
a tedious multistep process. Few examples have emerged for
the direct construction of chiral α,β-unsaturated γ-amino esters
using chiral source-induced asymmetric synthesis (Scheme 1).3
Received: June 22, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01904
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Organic Letters
Letter
a
Scheme 2. Reported Examples and Our Project
Scheme 3. Scope of Substrates 1
The effect of solvent, base, additive, and ligand on the Pd-
catalyzed asymmetric allylic amination of methyl (E)-2-acetoxy-
4-phenylbut-3-enoate (1a) with benzylamine (2a) was
examined in details, and the optimal reaction conditions are
as follows: using a catalyst system consisting of [Pd(η3-
C3H5)Cl]2 and (R)-DTBM-SegPHOS in the presence of Et3N
and CsF in THF at rt for 12 h.6
With the optimized reaction conditions in hand, reaction
scope with regard to the allylic substrates 1 was investigated
(Scheme 3). First, substrates bearing different ester groups were
investigated and 3a with a Me group gave the best result (3a−
d). Next, 1 bearing different substituted Ar groups was
examined. The ee of the desired products decreased for
substrates bearing electron-donating groups on the phenyl rings
(3e−j). However, 3k bearing a bulky ortho-substituted i-Pr
group was obtained in 96% ee. Both good to high yields and
excellent enantioselectivities were obtained for substrates with
electron-withdrawing groups on phenyl groups (3l−p).
Substrates bearing two electron-withdrawing groups on the
phenyl rings all gave their corresponding products with good
yields and excellent enantioselectivities (with >99% ee in
several cases, 3q−t). Excellent enantioselectivities were retained
when the electron-withdrawing groups were replaced by phenyl
rings (3u and 3v). Replacing the phenyl ring with naphthalene
groups had little influence on the reaction outcomes (3w and
3x). A substrate bearing a furyl ring was used in the reaction,
with the desired product also being obtained in excellent
enanioselectivity but only moderate yields (3y). Finally, the
reactions were carried out with substrates by replacing Ar
a
Reactions of 1 (0.1 mmol) and 2a (2 equiv) were carried out using a
catalyst system consisting of [Pd(η3-C3H5)Cl]2 (5 mol %) and (R)-
DTBM-SegPHOS (10 mol %) in the presence of Et3N (2 equiv) and
CsF (1.2 equiv) in THF (2 mL) at rt for 12 h; isolated yields and ee’s
were determined by chiral HPLC using a chiral OJ-H or OD-H
column; the absolute configuration of products was determined by the
NOESY spectrum of 3a6 and transforming 3a to its corresponding
chiral γ-lactam derivative and comparing the sign of its optical rotation
with reported data.7 The reaction was carried out on a large scale with
1 mmol of 1a.
b
groups with aliphatic substituents. However, only racemic
products 3z and 3aa were obtained in moderate yields.
Subsequently, a number of different amines (2) were
investigated in the asymmetric amination (Scheme 4). Primary
amines provided good to excellent yields and excellent
enantioselectivities (3ab−af). As a comparison, secondary
amines, both cyclic and acyclic, gave their respective products
in excellent yields with moderate to good enantioselectivities
(3ag−am).
B
DOI: 10.1021/acs.orglett.7b01904
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Organic Letters
Letter
a
chiral ligand, was treated with magnesium in MeOH and then
with LiAlH4, to afford the corresponding alcohol 7 in high yield
without loss in enantioselectivity. Compound 7 is a key
intermediate for the synthesis of chiral drug cis-(+)-sertraline,
an effective antidepressant (Scheme 6).2b
Scheme 4. Scope of Nucleophilic Amines 2
Scheme 6. Synthesis of Chiral γ-Amino Alcohol 7
The chiral α,β-unsaturated γ-amino esters can also be
converted to chiral γ-lactams, which are challenging to
synthesize via conventional means but are widely used for the
synthesis of both drugs and natural products.8 Thus, the chiral
γ-lactam 8 can be obtained readily in good yield and with
excellent enantioselectivity from 3ad via a Pd/C-catalyzed
hydrogenation and subsequent cyclization (Scheme 7).
a
Using the optimal reaction conditions shown in Scheme 3; isolated
yields and ee’s were determined by chiral HPLC using a chiral OJ-H or
OD-H column; the absolute configuration of products was determined
by comparing the sign of the optical rotations with 3a.
Scheme 7. Synthesis of Chiral γ-Lactam 8 and 13
In order to determine the origin for the preferential
formation of γ-aminated products over α-aminated products,
substrates 4 bearing Me, Et and i-Pr groups, respectively,
instead of ester groups, were subjected to the above reaction
conditions (Scheme 5). When 4c bearing a bulky i-Pr group
Scheme 5. Control Experiments
was used in the above reaction under the optimal reaction
conditions, the corresponding aminated product 6 was obtained
in high yield. However, substrates 4a and 4b bearing the less
bulky groups, gave the unexpected “α-substituted” products in
94% yields. Obviously, the steric hindrance of the left aryl
groups have no effect on the regioselectivity of the reaction (see
the data in Scheme 3). The bulky substituents on the right side
of the allyl substrates (ester groups and i-Pr versus Me and Et)
may be responsible for the preferential formation of the γ-
substituted products.
To prove the usefulness of the chiral aminated products, the
product (S)-3aj produced using (S)-DTBM-SegPHOS as the
C
DOI: 10.1021/acs.orglett.7b01904
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Serafino, R.; Strathdee, C. A.; Turci, S. M.; Wilson, C.; DiMauro, E. F.
J. Med. Chem. 2013, 56, 4320.
Compound 8 can be used as a key intermediate for the
construction of several biologically active compounds, such as
the cannabinoid receptor 1 inhibitor 9,9a the TNF activity
moderator 10,9b the bioactive tankyrase inhibitor 11,2c and the
plant growth regulating compound 12.9c
(3) For the synthesis of chiral α,β-unsaturated γ-amino esters, see:
(a) Lee, J. H.; Lee, S.-G. Chem. Sci. 2013, 4, 2922. (b) Pedersen, T. M.;
Hansen, E. L.; Kane, J.; Rein, T.; Helquist, P.; Norrby, P.-O.; Tanner,
D. J. Am. Chem. Soc. 2001, 123, 9738. (c) Srikanth, G.; Ramakrishna,
K. V. S.; Sharma, G. V. M. Org. Lett. 2015, 17, 4576. (d) Zhang, M.;
Watanabe, K.; Tsukamoto, M.; Shibuya, R.; Morimoto, H.; Ohshima,
T. Chem. - Eur. J. 2015, 21, 3937. (e) Kondoh, A.; Kamata, Y.; Terada,
M. Org. Lett. 2017, 19, 1682.
To further explore the utility of chiral γ-lactams in organic
synthesis, 3ae bearing a para-substituted bromine atom on the
phenyl ring was converted to its corresponding chiral γ-lactam
13 in high yield (Scheme 7). Compound 13 could be further
transformed to 14 (a candidate for the treatment of
inflammatory disorders)10a or a hydroxamate-based inhibitor
of deacetylases B 15 following literature procedures.10b
In summary, we have developed a Pd-catalyzed asymmetric
allylic amination of 4-substituted 2-acetoxybut-3-enoates with
different amines for the synthesis of chiral α,β-unsaturated γ-
amino esters. The desired products can be obtained in up to
98% yield and with more than 99% ee and can be transformed
to chiral γ-amino acid/alcohol derivatives and chiral γ-lactams,
which can be further applied to the synthesis of several types of
chiral drugs and drug candidates. The preferential formation of
γ-amino esters over α-amino esters has been discussed. This
work provides an efficient strategy for the synthesis of chiral γ-
substituted α,β-unsaturated γ-amino esters.
(4) Selected reviews of Pd-catalyzed asymmetric allylic substitutions,
see: (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395.
(b) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336. (c) Trost,
B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921. (d) Lu, Z.; Ma, S.
Angew. Chem., Int. Ed. 2008, 47, 258. (e) Trost, B. M.; Zhang, T.;
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(5) Selected our recent papers, see: (a) Zhao, X.; Liu, D.; Guo, H.;
Liu, Y.; Zhang, W. J. Am. Chem. Soc. 2011, 133, 19354. (b) Quan, M.;
Butt, N.; Shen, J.; Shen, K.; Liu, D.; Zhang, W. Org. Biomol. Chem.
2013, 11, 7412. (c) Huo, X.; Quan, M.; Yang, G.; Zhao, X.; Liu, D.;
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Liu, D.; Liu, Y.; Gridnev, I. D.; Zhang, W. Angew. Chem., Int. Ed. 2014,
53, 6776. (e) Wei, X.; Liu, D.; An, Q.; Zhang, W. Org. Lett. 2015, 17,
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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/acs.or-
glett.7b01904.
(6) See details in the Supporting Infromation.
(7) Yuan, Q.; Liu, D.; Zhang, W. Org. Lett. 2017, 19, 1886.
(8) (a) Bellesia, F.; Clark, A. J.; Felluga, F.; Gennaro, A.; Isse, A. A.;
Roncaglia, F.; Ghelfi, F. Adv. Synth. Catal. 2013, 355, 1649. (b) Fenster,
E.; Hill, D.; Reiser, O.; Aube, J. Beilstein J. Org. Chem. 2012, 8, 1804.
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(c) Tan, D. Q.; Atherton, A. L.; Smith, A. J.; Soldi, C.; Hurley, K. A.;
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Experimental procedures, characterization details, and
additional data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(9) (a) Alexander, R. P.; Brace, G. N.; Brown, J. A.; Calmiano, M. D.;
Chovatia, P. T.; Deligny, M.; Gallimore, E. O.; Heer, J. P.; Jackson, V.
E.; Kroeplien, B.; Maccoss, M.; Quincey, J. R.; Sabnis, Y. A.; Swinnen,
D. L. L.; Zhu, Z. Fused tricyclic imidazole derivatives as modulators of
TNF acitivity. EP 2014076884, 2015. (b) Villedieu-PerCheron, E.;
Lachia, M. D.; De Mesmaeker, A.; Wolf, H. C.; Jung, P. J. M.; Lanfer-
Meijer, F.; Van Den Wijingaard, P.; Screpanti, C. Plant growth
regulating compounds. EP 2013060470, 2013. (c) Liu, H.; He, X.;
Phillips, D.; Yang, K.; Lau, T.; Wu, B.; Xie, Y.; Nguyen, T. N.; Wang,
X. Compounds and compositions as inhibitors of Cannabinoid
receptor 1 activity. US 2007087230, 2010.
(10) (a) Kozlowski, J. A.; Yu, W. S.; Wong, M. K. C.; Kim, S.-H.;
Tong, L.; Lavey, B. J.; Shankar, B. B.; Yang, D. Y.; Feltz, R.; Kosinski,
A. M.; Zhou, G. W.; Rizvi, R. K.; Dai, C. Y.; Fire, L.; Girijavallabhan, V.
M.; Li, D. S.; Popovici-Muller, J.; Richard, J. E.; Kristin, K. E.; Siddiqui,
M. A.; Yang, L. P. Compounds for the treatment of inflammatory
disorders. WO 2010054279 A1, 2010. (b) Shultz, M.; Chen, C. H.-T.;
Cho, Y. S.; Jiang, L.; Fan, J. M.; Liu, G.; Majumdar, D. Hydroxamate-
based inhibitors of deacetylases. WO 2009118305 A1, 2009.
*E-mail: dlliu@sjtu.edu.cn.
*E-mail: wanbin@sjtu.edu.cn.
ORCID
Wanbin Zhang: 0000-0002-4788-4195
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by the National Natural
Science Foundation of China (Nos. 21372152, 21402117,
21672142, and 21232004), the Basic Research Foundation of
Shanghai Committee of Science and Technology
(15JC1402200), and the Instrumental Analysis Center of
SJTU for characterization. We also thank Prof. Ilya Gridnev and
Masahiro Terada of Tohoku University, Japan, for their helpful
discussions.
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DOI: 10.1021/acs.orglett.7b01904
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