Direct, Enantioselective, and Nickel(II) Catalyzed Reactions of N-Azidoacetyl Thioimides with Trimethyl Orthoformate: A New Combined Methodology for the Rapid Synthesis of Lacosamide and Derivatives

Article abstract of DOI:10.1002/chem.202001057

A direct and highly enantioselective reaction of N-azidoacetyl-1,3-thiazolidine-2-thione with trimethyl orthoformate catalyzed by Tol-BINAPNiCl₂ in the presence of TESOTf and 2,6-lutidine is reported. The heterocyclic scaffold can be easily removed by addition of a wide array of amines to give the corresponding enantiomerically pure 2-azido-3,3-dimethoxypropanamides in high yields. Appropriate manipulation of the N-benzyl amide derivative provides an efficient access to the antiepileptic agent lacosamide through a new enantioselective C?C bond-forming process. DFT computational studies uncover clues for the understanding of the remarkable stereocontrol of the addition of a nickel(II) enolate to a putative oxocarbenium intermediate from trimethyl orthoformate.

Full text of DOI:10.1002/chem.202001057

Accepted Article
Accepted Article
Title: Direct, Enantioselective, and Nickel(II) Catalyzed Reactions of
N-Azidoacetyl Thioimides with Trimethyl Orthoformate. A New
Combined Methodology for the Rapid Synthesis of Lacosamide
and Derivatives
Authors: Pedro Romea, Saul F. Teloxa, Stuart C. D. Kennington, Marc
Camats, Fèlix Urpí, Gabriel Aullón, and Mercè Font-Bardia
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To be cited as: Chem. Eur. J. 10.1002/chem.202001057
Link to VoR: https://doi.org/10.1002/chem.202001057
01/2020

10.1002/chem.202001057
Chemistry - A European Journal
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Direct, Enantioselective, and Nickel(II) Catalyzed Reactions of N-
Azidoacetyl Thioimides with Trimethyl Orthoformate. A New
Combined Methodology for the Rapid Synthesis of Lacosamide
and Derivatives
Saul F. Teloxa,[a] Stuart C. D. Kennington,[a] Marc Camats,[a] Pedro Romea,*[a] Fèlix Urpí,*[a] Gabriel
Aullón,[b] and Mercè Font-Bardia[c]
Dedicated to Prof. Sergio Castillón
[a]
S. F. Teloxa, S. C. D. Kennington, M. Camats, P. Romea, F. Urpí
Department of Inorganic and Organic Chemistry, Section of Organic Chemistry
Universitat de Barcelona
Carrer Martí i Franqués 1-11, 08028 Barcelona (Catalonia, Spain)
E-mail: pedro.romea@ub.edu; felix.urpi@ub.edu
Homepage: http://www.qo.ub.edu/grups/SSNP/en/qui_som_presentacio.html
G. Aullón
Department of Inorganic and Organic Chemistry, Section of Inorganic Chemistry
Universitat de Barcelona
[b]
[c]
Carrer Martí i Franqués 1-11, 08028 Barcelona (Catalonia, Spain)
M. Font-Bardia
X-Ray Difraction Unity. CCiTUB
Universitat de Barcelona
Carrer Solé i Sabarís 1-3, 08028 Barcelona (Catalonia, Spain)
Supporting information for this article is given via a link at the end of the document.
Abstract: A direct and highly enantioselective reaction of N-
azidoacetyl-1,3-thiazolidine-2-thione with trimethyl orthoformate
catalyzed by Tol-BINAPNiCl2 in the presence of TESOTf and 2,6-
lutidine is reported. The heterocyclic scaffold can be easily removed
by addition of a wide array of amines to give the corresponding
enantiomerically pure 2-azido-3,3-dimethoxypropanamides in high
yields. Appropriate manipulation of the N-benzyl amide derivative
provides an efficient access to the antiepileptic agent lacosamide
through a new enantioselective C–C bond-forming process. DFT-
Computational studies uncover clues for the understanding of the
remarkable stereocontrol of the addition of a nickel(II) enolate to a
putative oxocarbenium intermediate from trimethyl orthoformate.
plethora of cationic reagents using 1–5 mol% of robust and easy
to handle [(R)-DTBM-SEGPHOS]NiCl2.[6] Particularly, the direct
addition to trimethyl orthoformate activated by TESOTf produces
a single enantiomer of the corresponding adduct in 90% yield
(Scheme 1A). Furthermore, former evidence on similar reactions
based on chiral N-acyl 1,3-thiazolidine-2-thiones catalyzed by
(Me3P)2NiCl2 indicated that the N-azidoacetyl counterpart was
particularly suitable to provide highly stereocontrolled
transformations (Scheme 1B),[7] which resulted in being especially
appealing due to the well known instability of metal enolates from
those substrates.[8–10] In view of such results, we envisaged that
the azido group might be used as a masked amino group to
synthesize enantiomerically pure -amino acids or derivatives in
a straightforward manner.[11] Thus, aiming to expand the scope of
such processes, we launched a project to develop direct,
enantioselective, and nickel(II) catalytic reactions of N-
azidoacetyl thioimides with carbenium and oxocarbenium
intermediates.
Introduction
Despite the tremendous advancements in the asymmetric and
catalytic construction of carbon–carbon bonds achieved during
the last years, there is still a need for versatile methods that will
We hereby describe our first results on the enantioselective
addition of N-azidoacetyl thioimides to trimethyl orthoformate and
the application of this method to the synthesis of lacosamide[12,13]
and several related compounds as a proof of concept (Scheme
1C).
enable the synthesis of
a
broad range of molecular
architectures.[1–3] In this context, Evans[4] and Shibasaki[5] have
convincingly established that both thiazolidinethione and
azaindoline are suitable scaffolds to carry out direct and highly
enantioselective aldol reactions catalyzed by chiral nickel(II) and
copper(I) complexes respectively. Inspired by such studies, we
have recently reported that simple N-propanoyl-1,3-thiazinane-2-
thione is a valuable platform from which to carry out direct and
enantioselective carbon–carbon bond forming reactions with a
1
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Scheme 2. Synthesis of N-azidoacetyl scaffolds.
Then, we evaluated the reactivity of 1–5 with trimethyl
orthoformate and commercially available (Me3P)2NiCl2. Taking
advantage of our former experience, TESOTf was chosen to both
activate the nickel(II) complex via ligand exchange and to create
the required oxocarbenium electrophile from the trimethyl
orthoformate.[14] Then, the addition of N-azidoacetyl derivatives
1–5 to trimethyl orthoformate in the presence of 2,6-lutidine and
TESOTf was initially tested with 2.5 mol% of achiral (Me3P)2NiCl2
for a relatively short reaction time of 2.5 h to better grasp the
differences between the scaffolds. The results are summarized in
Table 1.
Scheme 1. Direct and stereoselective reactions from N-acyl thioimides
catalyzed by nickel(II) complexes.
Table 1. Direct and nickel(II) catalyzed addition of N-azidoacetyl derivatives to
trimethyl orthoformate.
Results and Discussion
Direct and Ni(II) catalyzed addition of N-azidoacetyl
thioimides to trimethyl orthoformate
Our experience from the carbon–carbon bond forming reactions
of N-propanoyl thioimides indicated that the 6-membered
thiazinanethione was slightly more selective and active than the
5-membered thiazolidinethione counterpart.[6] Unfortunately, we
were unable to synthesize the corresponding N-azidoacetyl-1,3-
thiazinane-2-thione. The use of both azidoacetic acid and EDC as
a coupling agent or azidoacetyl chloride and triethylamine at 0 °C
under conditions previously described led to a complex mixture
and no presence of the desired product. Conducting the reaction
at –20 °C showed signs of product formation (the solution turned
yellow as expected along with a new TLC spot) but when either
warmed or quenched the solution turned black and the product
could not be detected in the crude mixture. These results suggest
that whilst the N-azidoacetyl thiazinanethione might be initially
formed at –20 °C it is unstable at room temperature and therefore
not viable.
For that reason, we moved to evaluate various 5-membered
scaffolds. Five different heterocycles were chosen to assess the
influence of the heteroatoms as well as geminal dimethyl groups
in the direct addition to trimethyl orthoformate. Importantly, all
candidates were acylated smoothly and the ensuing N-
azidoacetyl derivatives 1–5 shown in Scheme 2 were completely
stable and could be satisfactorily isolated in a pure form.
Entry
Starting Material
X
O
S
S
S
S
Y
O
O
S
O
S
R
Product
Yield [%] [a]
< 5
1
2
3
4
5
1
2
3
4
5
H
6
H
7
39
H
8
61
Me
Me
9
< 10
< 10
10
[a] Isolated yield.
As expected, oxazolidinone 1 gave low conversion in the nickel
catalyzed reaction and the starting material was recovered
unaltered (entry 1 in Table 1), which further confirmed the need
for an exocyclic sulphur atom (X = S in Table 1). The endocyclic
sulfur (Y = S in Table 1) also held a key importance as the isolated
yield from thiazolidinethione 3 was considerably higher than that
attained from oxazolidinethione 2 (compare entry 2 and 3 in Table
1). This concurred with previous results making the sulphur–
sulphur combination (X, Y = S in Table 1) superior.[14] Eventually,
it was thought that the introduction of geminal dimethyl groups at
C4 in 4 and 5 might improve the stereochemical outcome of the
addition, but the conversion observed for both compounds was
too low to be deemed useful (entry 4 and 5 in Table 1). Therefore,
these results pointed to the N-azidoacetyl-1,3-thiazolidine-2-
thione (3) as the most appropriate substrate to conduct the
enantioselective trimethyl orthoformate reaction.
2
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Table 3. Direct and enantioselective addition of thioimide 3 to trimethyl
orthoformate catalyzed by [(R)-TolBINAP] NiCl2.
Direct, enantioselective, and Ni(II) catalyzed addition of N-
azidoacetyl-1,3-thiazolidine-2-thione
orthoformate
to
trimethyl
Having chosen the scaffold from which to carry out the desired
addition, we next screened the chiral ligands necessary to
achieve the highest enantioselectivity. The ligands tested were
the traditional DIOP as well as the BINAP and SEGPHOS families.
The required chiral complexes L*NiCl2 were prepared via the
simple reflux of the chiral diphosphine ligand and NiCl2 in
acetonitrile. These were compared to the achiral (Me3P)2NiCl2
and both the enantioselectivity and efficiency were evaluated,
which is summarized in Table 2.
Entry
n (mol%)
3.0
T (°C)
–20
–20
–20
–20
0
Yield [%] [a]
1
2
3
4
5
6
81
80
82
69
59
53
2.5
2.0
1.5
2.0
2.5
20
[a] Isolated yield.
Table 2. Influence of nickel(II) ligands on the addition of N-azidoacetyl thioimide
3 to trimethyl orthoformate.
Once established the main framework of the reaction, we focused
our attention to the synthesis of lacosamide (vide infra). Since
exploratory studies indicated that the required configuration was
the opposite to that provided by [(R)-Tol-BINAP]NiCl2 we moved
to use the (S) enantiomer. Then, we tackled the scale-up of the
reaction and a comprehensive analysis of the experimental
conditions. Importantly, the progressive increase of the reaction
from 1, to 3, and up to 6 mmol of N-azidoacetyl thiazolidinethione
3 with trimethyl orthoformate in the presence of 2 mol% [(S)-Tol-
BINAP]NiCl2 showed that ent-8 could be isolated with an 85%
yield and 96% ee at 6 mmol scale by stirring the reaction mixture
at –20 °C for 2.5 h (Scheme 3).[15]
Entry
L*
Yield [%] [a]
61
ee [%] [b]
1
2
3
4
5
6
7
(Me3P)2
–
(+)-DIOP
< 5
nd
94
96
92
88
94
(R)-BINAP
78 [c]
80 [c]
72 [c]
61 [d]
52 [d]
(R)-Tol-BINAP
(R)-Xyl-BINAP
(R)-SEGPHOS
(R)-DTBM-SEGPHOS
[a] Isolated yield. [b] Established by chiral HPLC analysis. [c] Full conversion.
[d] Incomplete conversion, ca 85%.
Initially, DIOP gave almost no conversion and was therefore
discarded (entry 2 in Table 2). The BINAP family performed much
better in terms of activity and gave full conversion and good yields
in all cases (entry 3–5 in Table 2). Importantly, the
enantioselectivity was high, especially with Tol-BINAP, which
gave an 80% yield (entry 4 in Table 2). Instead, the SEGPHOS
family gave worse results with respect to conversion, yield, and
selectivity (entry 6 and 7 in Table 2) and provided the desired
adduct 8 in modest yields (52–61%) with a somewhat eroded
stereocontrol (ee 88–94%). The conclusion of the ligand
screening left Tol-BINAP as the most selective diphosphine and
highest yielding and therefore [(R)-Tol-BINAP]NiCl2 was selected
as the complex of choice for this reaction.
We next analyzed the catalytic loading and temperature to
complete the optimization of the reaction conditions. As shown in
Table 3, the catalyst loading could be decreased to 2 mol%
without adverse effects; further reduction showed incomplete
conversion and a decrease in the yield of 8. In turn, raising the
temperature led to the formation of a side product resulting from
the nucleophilic attack of the exocyclic sulphur atom of the
thiazolidinethione heterocycle on the oxocarbenium species,
which leads to an S-methyl alkylation product. Interestingly, we
had previously observed a similar reaction when working with the
N-propanoyl thiazinanethione scaffold (see Scheme 1),[6] whose
nucleophilic character was more pronounced and the reaction
had to be conducted at –40 °C. Alongside this study, the (S)–C2
configuration of the resultant adduct 8 was initially established
through chemical correlation.
Scheme 3. Direct and enantioselective addition of N-azidoacetyl thioimide 3 to
trimethyl orthoformate catalyzed by [(S)-Tol-BINAP]NiCl2.
Mechanistically, this reaction may be occurring via an SN1-like
pathway, in which the TESOTf plays a key role.[16] Indeed, the silyl
triflate activates the chiral nickel(II) complex, [(S)-Tol-BINAP]NiCl2,
to form the true catalytic species, [(S)-Tol-BINAP]Ni(OTf)2, shown
in Scheme 4. Complexation with the thioimide in the presence of
2,6-lutidine triggers the formation of a nickel(II) Z-enolate, able to
+
add to an oxocarbenium intermediate, HC(OMe)2 , generated in
situ by the reaction of TESOTf with methyl orthoformate. The
approach of such an electrophile to the Re face of the enolate
leads to the formation of the carbon–carbon bond and the further
release of the desired adduct allows for the regeneration of the
active nickel(II) complex to start a new catalytic cycle.[17]
3
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DFT Calculations
Taking into account the mechanism described in Scheme 4, we
carried out computational studies for an accurate understanding
of the outstanding stereocontrol provided by the Tol-BINAP
catalyst. Assuming that the reaction proceeds through the
addition of
azidoacetyl-1,3-thiazolidine-2-thione]+
oxocarbenium intermediate from trimethyl orthoformate,
a
nickel(II) Z-enolate of [{(R)-Tol-BINAP}Ni(N-
(Figure 1) to an
a
theoretical study has been carried out. Importantly, NMR spectra
of [(R)-Tol-BINAP]NiCl2 were an undeniable proof for its
diamagnetic character and molecular geometries for the Z-
enolate have therefore been calculated in the singlet ground state.
Several conformations have been optimized for S,O-chelate and
thiazolidinethione rings with a nickel environment closer to
square-planar coordination, resulting in a range of 8 kcal·mol–1 for
Gibbs free energies in solution. Taking the most stable one, it
shows an important deviation for the planarity evaluated by
continuous shape measures (SSQ-4 = 3.7), and P–Ni–S and P–Ni–
O angles are 159º and 160º, respectively, clearly influenced by
the P–Ni–P bite angle of the diphosphine ligand (97º).
Scheme 4. Proposed mechanism for the reaction.
0.0 kcal mol–1
+0.78 kcal mol–1
+1.20 kcal mol–1
I.a (1C)
I.b (1A)
I.c (1B)
+3.09 kcal mol–1
+1.69 kcal mol–1
+4.24 kcal mol–1
II.b (2B)
II.a (2C)
II.c (2A)
Figure 1. Addition of a Z-nickel(II) enolate to an oxocarbenium intermediate
4
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+
To understand the reaction between HC(OMe)2 and [{(R)-Tol-
BINAP}Ni(N-azidoacetyl-1,3-thiazolidine-2-thione)]+, we have
analyzed the corresponding energy profile. Since the electrophilic
oxocarbenium can be approached by two π-faces of the nickel
enolate (I and II), and it can also present three different relative
orientations for the methoxy groups, six transition states were
proposed and fully characterized. They are shown in Figure 1,
together with the corresponding relative Gibbs free energies in
dichloromethane solution. Several transition states present
energies included within a range of less than 1 kcal·mol–1, and we
could anticipate the reaction evolving by different pathways. In the
three first transition states (I.a, I.b, and I.c), the electrophile is
approached on the same side of the nickel(II) enolate from the N-
bond. Hence, seeing the potential for an enantioselective
synthesis with the utility of easily accessible derivatives without
any methodological changes, we envisaged that the
retrosynthetic analysis depicted in Scheme 5, based on our newly
developed orthoformate reaction and the easy removal of the
thiazolidinethione scaffold[22,23] might allow us to gain access to
lacosamide and a wide array of structurally related compounds
keeping the C3 methyl ether that is apparently essential to their
antiepileptic activity.
azidoacetyl-1,3-thiazolidine-2-thione
giving
the
same
stereoisomer with different orientations for the methyl groups, but
their small differences suggest that the three pathways all
participate in the reaction (calculated values are about 74, 16, and
7%, respectively). However, the three transition states for the
opposite side, and therefore the other enantiomer (II.a, II.b, and
II.c), are higher in energy and their contributions clearly become
smaller. According to the energetic distribution of the six transition
states, estimation for the ratio of final products at –20 ºC would be
97:3, in excellent agreement to experimental data (er 98:2).
These results can be explained by the steric hindrance caused by
the (R)-Tol-BINAP diphosphine. The optimized conformation of
the nickel-complex presents two π–π stacking interaction
between p-tolyl and naphthyl aromatic rings (3.2–3.6 Å), whereas
another p-tolyl substituent is aligned at ~3.8 Å to the planar
methine group of the nickel-complex (see Supporting Information).
This situation is also reproduced for other conformations of the
reactant blocking only one π-face for reaction pathway (< 3.5
kcal·mol–1). Consequently, those transition states in which the
oxocarbenium is approaching from the external region become
more stable than those from the internal one by geometric
requirements (I and II, respectively). In the first cases, geometries
for nickel remain closer to reactant, while the latter becomes the
most planar environment. Thus, the excellent stereocontrol
observed for such a reaction hinges on the position of one of the
p-tolyl substituents blocking the Re π-face of the nickel(II) Z-
enolate.
Scheme 5. Retrosynthetic analyses of lacosamide.
With a fully optimized procedure in hand and a complete
understanding of the keys for the remarkable stereocontrol, the
attention was then paid to the synthesis of lacosamide.
Preliminary Studies
With the asymmetric reaction fully optimized, we turned our
attention toward the removal of the 1,3-thiazolidine-2-thione
moiety with an amine to form the amide group present in
lacosamide and its derivatives. We started the assessment using
benzylamine as a model, which would form the required N-benzyl
amide for lacosamide, in two differing routes. One would involve
the displacement of the scaffold from the purified product with
benzylamine, while an advanced one-pot process would be based
on the quenching of the carbon–carbon bond forming reaction
with benzylamine to directly furnish the desired amide (Scheme
6).
Both steps of the sequential approach proceeded smoothly
(Scheme 6). Indeed, the desired N-benzylpropanamide 11a was
isolated with a 73% overall yield using a stoichiometric amount of
benzylamine (a). In turn, the one–step process needed an excess
of amine and a careful monitoring by TLC to make sure that the
starting N-azidoacetyl thiazolidine 3 had completely reacted
before adding the amine. This is a key requirement. If full
conversion is not achieved before the addition of the amine it can
Lacosamide
Retrosynthetic Analysis
The development of new enantioselective carbon–carbon bond
forming reactions from N-azidoacetyl thioimides may offer a
lucrative route towards biologically active α-amino acid
derivatives. One of such compounds is the antiepileptic agent
lacosamide (Scheme 5). First synthesized in 1996, lacosamide[12]
and structurally related compounds show an important
anticonvulsant activity[18] for which they have recently received
great attention.[13] Despite such an interest, most of the synthetic
approaches reported up to now rely on the appropriate treatment
of D-serine or other starting materials from the chiral pool.[18,19]
Alternatively, a few syntheses involve kinetic resolution steps[20]
or are based on asymmetric reactions applied to substrates
containing the required carbon backbone.[21] However, none of
them hinge on the enantioselective construction of the C2–C3
5
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Scheme 7. Amide-like derivatives prepared by treatment of the reaction mixture
with primary and secondary amines.
lead to the formation of the corresponding N-azidoacetyl amide,
which is difficult to separate from the product. Taking into account
such premises, the one-pot process allowed an increase in the
yield over the sequential process and produced benzylamide 11a
with an 88% overall yield and ee 96% at a 3 mmol scale (Scheme
6).
Importantly, X-ray analysis of crystals from amide 11c confirmed
the configuration of the new Cα stereocenter (Figure 2).
Figure 2. X-Ray of amide 11c.
Scheme 6. First steps towards lacosamide.
The reduction of the dimethyl acetal to the corresponding methyl
ether with TiCl4 and Et3SiH was the next step in the synthetic
pathway towards lacosamide.[24,25] First, the reaction was
examined using the benzylamide derivative 11a as a model. Low
conversion was observed when using only 1.5 equivalents of both
TiCl4 and Et3SiH (entry 1 in Table 4). Furthermore, it became clear
that the reaction needed temperatures above 0 °C to function
(compare entry 2–4 in Table 4). Therefore, the addition of 2.5
equivalents of TiCl4 and Et3SiH was tested via two routes. We
found that the addition of an extra equivalent of both TiCl4 and
Et3SiH after 4 h led to an increase in the conversion and yield
(entry 5 in Table 4), while the initial use of 2.5 equivalents at the
beginning of the reaction provided full conversion and a 57% yield
(entry 6 in Table 4). Using these conditions, we were able to run
this reaction on 9 mmol scale with a comparable yield (entry 7 in
Table 4).
Six more amines (b–g) were then applied in this transformation
and the results are summarized in Scheme 7. Different reaction
times were required for each substrate; however, they only varied
between 1 h and 3 h to reach full conversion. The methodology
supported various primary amines, alkyl and aromatic variants
both gave excellent results (11a–d, 11g); furthermore, the use of
chiral amines provided the corresponding amides as a single
diastereomer (11c and 11g). Secondary amines were also
tolerated, with a slight decrease in the yield, and the pyrrolidine
amide 11e as well as the morpholine amide 11f were both
obtained with good yields. Furthermore, the displacement with a
chiral amino ester derived from leucine afforded the
diastereomerically pure peptidic product 11g with a remarkable
79% yield.
Table 4. Acetal reduction of N-benzyl amide 11a
Entry
Equiv
TiCl4
1.5
Equiv
Et3SiH
1.5
T (°C)
t (h)
Yield [%] [a]
ee [%] [b]
1
–20
–20
0
6
< 5
< 5
< 5
27
nd
nd
nd
nd
nd
96
96
2
2.0
2.0
16
16
16
4+12
16
16
3
2.0
2.0
4
5 [c]
2.0
2.0
20
20
20
20
1.5+1
2.5
1.5+1
2.5
46
6
7 [d]
57
2.5
2.5
54
[a] Isolated yield. [b] Established by chiral HPLC analysis. [c] Initial loading of
1.5 equiv of TiCl4 and Et3SiH followed by 1 equiv of both reagents 4 h later. [d]
Addition at 9 mmol scale.
With the model compound optimized, we strove to expand the
scope to the amides 11b–g. Unfortunately, the use of these
reaction conditions on N-hexyl amide 11b led to incomplete
conversion and the corresponding methyl ether 12b was isolated
6
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in 42% yield. Thus, we conducted a finetuning of the optimization
to achieve a more general protocol. The use of 4 equivalents of
TiCl4 and Et3SiH led to full conversion, but with a yield lower than
expected (entry 1 in Table 5). This made us suspect that some of
the product was not being liberated in the workup, possibly due to
the formation of titanium complexes, which led us to scrutinize the
quench of the reaction mixture.[26] We found that the yield
improved when the mixture was left stirring for 3.5 h after the
quench (compare entry 1 and 2 in Table 5). Moreover, the use of
NH4F instead of NH4Cl provided a 60% yield of product 12b after
3.5 h (entry 4 in Table 5); no further improvement was observed
at longer times (compare entry 4 and 5 in Table 5).
The final step in the synthesis of lacosamide and its derivatives
involved the conversion of the azido group into an acetamide
using a Staudinger reaction and subsequent in situ acylation
(Scheme 9).[27] Such a transformation proved very reliable and
lacosamide (13a) was isolated as planned with a yield of 86%.
The application of such a one-pot reduction and protective
sequence gave also excellent results when applied to other
amides 12 and afforded the desired acetamido derivatives in 80–
90% yields for all of the examples except 12g. This decrease is
unsurprising owing to the complexity of the molecule compared to
the other examples and so a yield of 70% is very respectable.
Again, the tolerance for the method was wide, with the primary,
secondary, alkyl and aryl amides all giving excellent yields.
Table 5. Work-up of the reaction.
Entry
Quenching reagent
sat NH4Cl
t (h) [a]
0.15
3.5
Yield of 12b [%] [b]
1
2
3
4
5
42
50
47
60
57
sat NH4Cl
25% w/w NH4F
25% w/w NH4F
25% w/w NH4F
0.5
3.5
7
[a] Stirring time after quench. [b] Isolated yield.
This advance combined with the use of four equivalents of TiCl4
and Et3SiH provided a general procedure for the reduction of the
acetal that was applied to the remaining amides 11. Unfortunately,
the morpholine amide 11f turned out to be unsuitable and gave a
considerably lower yield of product 12f that was inseparable from
the starting material (Scheme 8). In turn, the peptide fragment 11g
provided the corresponding product 12g with a slightly lower yield
of 46%, which can be attributed to its higher complexity. Apart
from these cases, the tolerance of the reaction to these conditions
was high and the majority of the β-methoxy amides 12 were
isolated with yields of around 60%, as shown in Scheme 8.
Scheme 9. Azide reduction and acylation of amides 12.
This completed the synthesis of lacosamide as summarized in
Scheme 10. The final route consists of five reactions in a three–
step synthetic sequence with an overall yield of 43% and
complete optical purity after recrystallization, making it a highly
efficient process. Furthermore, due to the development of the
adaptable methodology we were able to synthesize five other
derivatives of lacosamide without any significant change in the
reaction conditions. The number of derivatives able to be made
by this method are considerably larger due to there being three
points of divergence in the synthesis: the ortho ester addition, the
amine displacement of the scaffold, and the protection of the
Staudinger product. By changing either the ortho ester, amine, or
acyl agent a new derivative can thus be synthesized with ease.
Scheme 8. Acetal reduction of amides 11.
7
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Computational methods
ONIOM calculations were carried out using the Gaussian09 package.[28]
High quantum layer is defined by nickel, phosphorous and the N-
azidoacetyl-1,3-thiazolidine-2-thione together the electrophile in the
reaction pathway, while low layer includes organic frameworks of
diphosphane ligand (excluding phosphorous atoms) by treated by
universal field force (UFF).[29] The hybrid density functional known as
B3LYP was applied.[30] The all-electron basis sets having triple-ς quality
with an extra polarization function were used for all elements (TZVP).[31]
The geometries were fully optimized without restrictions and transition
states were confirmed by vibrational analysis. Solvent effects of
dichloromethane were taken into account by PCM algorithm,[32] keeping
the optimized geometry for the gas phase (single-point calculations).
Continuous shape measures were calculated with the SHAPE program,[33]
that provides quantitative information of how much the environment is
deviated from an ideal polyhedron.
Scheme 10. Lacosamide synthesis.
Conclusion
Acknowledgements
A direct, catalytic, and highly enantioselective addition of N-
azidoacetyl-1,3-thiazolidine-2-thione to trimethyl orthoformate
has been reported. Interestingly, the reaction proceeds through a
nickel(II) enolate from Tol-BINAPNiCl2 in which the α-azido group
remains stable, which provides facile access to a variety of
enantiomerically pure α-amino acid derivatives. Theoretical
calculations have uncovered the origin of such an outstanding
stereocontrol. Furthermore, the thiazolidinethione scaffold may be
easily removed by a wide array of amines to give enantiomerically
pure 2-azido-3,3-dimethoxyamides through a simple reaction in
which the heterocycle acts as a coupling reagent. The synthetic
potential of such an approach is demonstrated by converting the
N-benzyl amide into the antiepileptic agent lacosamide based on
a novel C2–C3 bond forming reaction and the synthesis of several
previously unsynthesized derivatives.
Financial support from the Spanish Ministerio de Ciencia,
Innovación
y
Universidades (MCIU)/Agencia Estatal de
Investigación (AEI)/Fondo Europeo de Desarrollo Regional
(FEDER, UE) (Grant No. CTQ2015-65756-P, Grant No.
PGC2018-094311-B-I00, and Grant No. PGC2018-093863-B-
C21), and the Generalitat de Catalunya (2017SGR 271 and
2017SGR 1289) as well as doctorate studentships to S. F. T.
(CONACYT–México, Grant Number 438357) and S. C. D. K. (FI,
Generalitat de Catalunya).
Keywords: Asymmetric synthesis • C–C bond forming reactions
• Catalysis • Lacosamide • Synthetic methods
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Chemistry - A European Journal
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9
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Entry for the Table of Contents
A direct, enantioselective, and catalytic approach to the synthesis of α-amino acids in which an achiral 1,3-thiazolidine-2-thione is
used for the sake of attaining high yields is reported. Such a scaffold also acts as coupling reagent to give in a single step
enantiomerically pure amide derivatives, which can then be converted into biologically active compounds as lacosamide in a rapid
and straightforward manner.
10
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