Asymmetric synthesis of α,β-substituted γ-amino acids via conjugate addition

Article abstract of DOI:10.1016/j.tetlet.2019.05.060

The first conjugate addition reaction of organocuprates to N-enoyl oxazolidinone where a N-protected γ-nitrogen atom and an α-methyl group are present into α, β-unsaturated system is described. This reaction gave anti-products in moderate yields and high diastereomeric ratios. The anti-products have two contiguous stereogenic centers, one formed by the conjugate addition reaction and the other by a diastereoselective protonation reaction. The removal of chiral oxazolidinone moiety and N-deprotection of amino group furnished chiral α, β-disubstituted γ-amino acids.

Full text of DOI:10.1016/j.tetlet.2019.05.060

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric synthesis of
addition
a
,b-substituted
c-amino acids via conjugate
a
a
b
a
a
Rocío Sabala , Salomon Assad , Ángel Mendoza , Jacqueline Jiménez , Estibaliz Sansinenea ,
Aurelio Ortiz
a
a,
⇑
Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Pue. 72570, Mexico
Instituto de Ciencias, de la Benemérita Universidad Autónoma de Puebla, Puebla, Pue. 72570, Mexico
b
a r t i c l e i n f o
a b s t r a c t
Article history:
The first conjugate addition reaction of organocuprates to N-enoyl oxazolidinone where a N-protected c-
nitrogen atom and an a-methyl group are present into a, b-unsaturated system is described. This reaction
gave anti-products in moderate yields and high diastereomeric ratios. The anti-products have two con-
tiguous stereogenic centers, one formed by the conjugate addition reaction and the other by a diastere-
oselective protonation reaction. The removal of chiral oxazolidinone moiety and N-deprotection of amino
Received 6 May 2019
Revised 21 May 2019
Accepted 28 May 2019
Available online xxxx
group furnished chiral a, b-disubstituted c-amino acids.
Keywords:
Ó 2019 Elsevier Ltd. All rights reserved.
a, b-Disubstituted c-amino acids
Conjugate addition
Oxazolidinone
Organocuprates
(S)-Pregabalin is marketed as pharmaceutical for the treatment
rated system. The removal of chiral oxazolidinone from conjugate
of diseases accompanied with GABA recepors [1]. (S)-Pregabalin
has potent and robust activity in preclinical models predictive of
clinical efficacy in anxiety [2], epilepsy [3] and neuropathic pain
addition product and N-deprotection of nitrogen atom in amino
group produced the a, b-disubstituted c-amino acids.
The synthesis began with the development of the (E)-4-(diben-
[
2
4] since the molecule interacts with a -d subunit of calcium chan-
zylamino)-2-methylbut-2-enoic acid. The tiglic acid 1 was treated
nels [5] and is a substrate of the L transporter system [6]. The pre-
cise mechanism through which, pregabalin exhibits its
pharmacological action has been the subject of many studies in
recent years. It is noteworthy that (R)-pregabalin lacks antiepilep-
tic, analgesic or anxiolytic activity in vivo animal models, since it
2 4
with concentrated H SO and EtOH, which was used both as sol-
vent as reagent, at reflux for 7 h to give the ethyl tiglate 2 in
91%, as shown in Scheme 1. Ester 2 was exposed to allylic bromi-
nation reaction conditions according to the Pronin’s protocol, treat-
ing 2 with LDA solution (1 M, THF) and TMSCl in the presence of
NBS at À78 °C to furnish the brominated compound 3 in 40% yield
[9]. The brominated compound 3 was coupled with dibenzylamine
in THF for 12 h at room temperature to yield (E)-ethyl-4-(dibenzy-
lamino)-2-methylbut-2-enoate 4 as yellow liquid in 80% yield [10].
Ester 4 was hydrolyzed using an aqueous solution 5 N of NaOH
has significantly weaker affinity for
The -substituted -amino acid has reduced affinity for both the
-d and the system L transporter [7]. This structure-activity rela-
tionship has led to put more emphasis on stereoselective synthesis
of -, b-substituted -amino acid derivatives. However, to date the
methodologies to achieve , b-disubstituted -amino acids are
restricted [8]. Wustrow [7] described the synthesis of -amino
2
a -d and system L transporter.
a
c
a
2
a
c
a
c
2
in MeOH/H O at room temperature for 12 h affording (E)-4-(diben-
c
zylamino)-2-methylbut-2-enoic acid 5 as a white solid in 95%
yield, as shown in Scheme 2 [11]. This compound 5 was trans-
formed to its respective anhydride using pyvaloyl chloride in the
acids analogs to pregabalin adding methyl group at position along
the pregabalin backbone and determined the structure-activity
relationship with their affinity for
a
2
-d subunit and the system L
presence of Et
3
N in anhydrous THF, for 15 min at À78 °C and sub-
transporter (biological activity) (Fig. 1). We report herein, the first
diastereoselective conjugate addition reaction of organocuprates
to chiral N-enoyl oxazolidinone, where the methyl group and pro-
sequent stirring at 0 °C for 45 min to give compound 6 in a quan-
titative yield. This anhydride 6 was used in the next reaction
without purification. The chiral oxazolidinone 7 was treated with
a solution of n-butyllithium (2.5 M, hex.) in anhydrous THF at
À78 °C for 15 min followed by the addition of anhydride 6 in anhy-
drous THF. The reaction mixture was stirred at room temperature
tected nitrogen atom have been incorporated into the a, b-unsatu-
⇑
Corresponding author.
E-mail address: aurelioom@yahoo.com (A. Ortiz).
https://doi.org/10.1016/j.tetlet.2019.05.060
040-4039/Ó 2019 Elsevier Ltd. All rights reserved.
0
Please cite this article as: R. Sabala, S. Assad, Á.Mendoza et al., Asymmetric synthesis of
Letters, https://doi.org/10.1016/j.tetlet.2019.05.060
a,b-substituted c-amino acids via conjugate addition, Tetrahedron

2
R. Sabala et al. / Tetrahedron Letters xxx (xxxx) xxx
Scheme 3. Reaction conditions to conjugate addition.
Fig. 1. Analog compounds to Pregabalin.
Scheme 1. Incorporation of N-protected amino group to a, b-unsaturated system.
Scheme 4. Anti-products from conjugate addition.
mixture. The products were isolated by silica gel column chro-
matography with hexane:ethyl acetate 97:3 as eluent. The stereo-
chemistry of the major product 9a was possible to establish from
the structure achieved by X-ray diffraction and the configuration
at newly formed chiral centers is (R, R). The major product 9a cor-
responds to the anti-product, as shown in Fig. 2. High diastereose-
lectivity was observed, when the N-enoyloxazolidinone 8 was
treated under the same conjugate addition reaction conditions
using other organocuprates (Et, n-Pr, vinyl) to give the anti-prod-
ucts 10, 11 and 12 with 75–76% yields and diastereomeric ratios
(
98:2) which were determined by NMR of crude reaction mixtures,
as shown in Scheme 4.
The stereoselectivity of the major anti-products 9a-12 can be
rationalized when N-enoyloxazolidinone 8 adopts syn-s-cis confor-
Scheme 2. Coupling reaction of c-amino acid and chiral oxazolidinone.
mation, where the organocuprate reagent attacks at C b of
a, b-
unsaturated system by the less hindered side, on the opposite side
to the phenyl group, and a diastereoselective protonation reaction
is carried out for the same side of the phenyl group, as shown in
Scheme 5.
for 2 h to give N-enoyl oxazolidinone 8 in 80% yield [12], as a white
solid.
N-enoyloxazolidinone 8 was treated under conjugate addition
reaction conditions [12]. The Gilman’s reagent was achieved from
the reaction of CuI-DMS complex and methyl magnesium bromide
at À45 °C to provide the respective diorganocuprate, which was
added to N-enoyloxazolidinone 8 in anhydrous THF, as shown in
Scheme 3. The reaction mixture was stirred for 1 h at À45 °C and
for 1 h at room temperature to provide a mixture of diastereoiso-
mers 9a/9b in 80% yield and with 87/13 diastereomeric ratio
The removal of chiral oxazolidinone moiety of compounds 9a-
12 was carried out with Evans’ protocol using LiOH, H
2 2
O in THF-
H
2
O at room temperature to give N-protected -amino acids 13–
c
16 in good yields (85–90%) and recovering chiral oxazolidinone
in 80% yield [13], as shown in Scheme 6.
For the N-deprotection of amino group, the compounds 13–16
were exposed to hydrogenation reaction conditions using a cat-
alytic amount of Pd/C in EtOH at room temperature for 16 h to
(Scheme 4), which was determined by NMR of crude reaction
Please cite this article as: R. Sabala, S. Assad, Á.Mendoza et al., Asymmetric synthesis of
Letters, https://doi.org/10.1016/j.tetlet.2019.05.060
a,b-substituted c-amino acids via conjugate addition, Tetrahedron

R. Sabala et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Fig. 2. Molecular structure of the compound 9a. Summary of Data CCDC 1916099.
Scheme 5. The stereoselectivity can be rationalized by this possible transition
state.
Scheme 7. Chiral a, b-disubstituted c-amino acids.
nitrogen atom and
a
-methyl group are presents into
a
,b-unsatu-
rated system. The reaction furnished the anti-products in moder-
ated yields and with high diastereomeric ratios (98:2). The
addition products have two contiguous stereogenic centers, one
formed by the conjugate addition reaction and the other by a
diastereoselective protonation reaction. The removal of the chiral
oxazolidinone moiety and N-deprotection produced
a, b-substi-
tuted -amino acids. Our research is ongoing to study the role that
c
nitrogen atom and methyl group are playing in transition state of
the conjugate addition.
Scheme 6. Chiral oxazolidinone moiety removal.
Acknowledgments
deliver
a, b-disubstituted
c
-amino acids 17–19 in quantitative
We thank VIEP and CONACyT (251512).
yields (93–94%). The compound 16 was exposed to hydrogenation
conditions, and both N-deprotection of the amino group and vinyl
group double bond hydrogenation were carried out giving the
disubstituted -amino acid 18 in 90% yield, as shown in Scheme 7.
In conclusion, we have described the first conjugate addition
reaction of organocuprates to N-enoyloxazolidinone, where
a
, b-
Appendix A. Supplementary data
c
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.05.060.
c
-
Please cite this article as: R. Sabala, S. Assad, Á.Mendoza et al., Asymmetric synthesis of
Letters, https://doi.org/10.1016/j.tetlet.2019.05.060
a,b-substituted c-amino acids via conjugate addition, Tetrahedron

4
R. Sabala et al. / Tetrahedron Letters xxx (xxxx) xxx
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Please cite this article as: R. Sabala, S. Assad, Á.Mendoza et al., Asymmetric synthesis of
Letters, https://doi.org/10.1016/j.tetlet.2019.05.060
a,b-substituted c-amino acids via conjugate addition, Tetrahedron