Efficient one-pot synthesis of enantiomerically pure: N -protected-α-substituted piperazines from readily available α-amino acids

Article abstract of DOI:10.1039/c7nj04039c

A new pathway towards enantiomerically pure 3-substituted piperazines, bearing a benzyl protecting group, has been developed in good overall yields (83-92%), starting from commercially available N-protected amino acids. The methodology represents an efficient and simple one-pot procedure, employing a synthetic sequence consisting of an Ugi-4 component reaction, a Boc-deprotection, an intramolecular cyclisation reaction and a final reduction (UDCR). From the benzyl protected precursors, the 2-substituted piperazines bearing a Boc-protecting group could consequently also be obtained via a simple protection and deprotection step of the corresponding piperazines. The practical utility of this methodology was demonstrated for chiral drug synthesis.

Full text of DOI:10.1039/c7nj04039c

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ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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Efficient one-pot synthesis of enantiomerically pure N-protected-
α-substituted piperazines from readily available α-amino acids
Mouhamad Jidaa* and Steven Balleta*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A new pathway towards enantiomerically pure 3-substituted lipophilicity.14 For these reasons, the synthesis of piperazines
piperazines, bearing
a benzyl protecting group, has been
bearing a substitution at C2 is of particular significance and several
methods have been developed to this end. Commonly, chiral α-
substituted piperazines are prepared by reduction of substituted
mono- and diketopiperazines, which are obtained by i) classical
developed in good overall yields (83-92%), starting from
commercially available N-protected amino acids. The
methodology represents an efficient and simple one-pot
procedure, employing a synthetic sequence consisting of an Ugi-4
component reaction,
a Boc-deprotection, an intramolecular resolution, ii) using chiral building blocks, or iii) via asymmetric
synthesis employing a chiral auxiliary.15
cyclisation reaction and a final reduction (UDCR). From the benzyl
protected precursors, the 2-substituted piperazines bearing a Boc-
protecting group could consequently also be obtained via a simple
protection and deprotection step of the corresponding
piperazines. The practical utility of this methodology was
demonstrated for chiral drug synthesis.
CF3
N
HN
N
OH
OH
N
H
N
N
N
O
N
CF3
N
N
O
O
-BuNH
t
F
Vestipitant
Mirtazapine
Indinavir
Piperazine rings are deployed in a plethora of medicinal
chemistry applications, as they represent important structural
motifs in pharmacologically active compounds. Within these
molecules they play the role of a linker,1 a pharmacophoric group,2
or a modulator of pharmacokinetics.3 Moreover, the α-substituted
piperazine scaffold is considered to be a privileged structure in drug
discovery,4 and it has served for the development of several
Figure 1. Examples of marketed drugs containing chiral α-substituted piperazines.
Interestingly, Guercio and co-workers have reported a route
towards chirally pure arylpiperazines, based on a dynamic kinetic
resolution with an overall yield of 60% over nine steps.16
Alternatively, Franzyk and co-workers have described
a new
a
NK-1 antagonist,5
efficient method to synthesize chiral 2-substituted piperazines via
ring-opening of optically pure nosylamide-activated aziridines with
ω-amino alcohols, followed by Fukuyama-Mitsunobu cyclization
(Scheme 1).17 Recently, O’Biren and co-workers have also reported
marketed drugs such as Vestipitant,
Mirtazapine, an antidepressant agent,6 and Indinavir, an HIV
protease inhibitor (Figure 1).7 In addition, a variety of natural
products with a broad spectrum of biological activities, such as
safracin B,8 ectenascidin 743,9 TAN-125A,10 and dragmacine,11
contain a chiral piperazine ring as part of their structure. To
complement piperazine use in medicinal chemistry, several groups
have also examined their efficiency as chiral catalysts and ligands in
asymmetric catalysis.12 It is widely recognized that the presence of
substituents, adjacent to one of the nitrogens in the piperazine ring,
has a significant influence on the biological acitivity. Hence, the
ability to prepare substituted piperazines is crucial during the
optimization of such compounds, as it impacts on pKa13 and
a
synthetic route to enantiomerically enriched 2-substituted
piperazines, by asymmetric lithiation−subsꢀtuꢀon of an α-
methylbenzyl functionalized N-Boc piperazine using s-BuLi/(−)-
sparteine or (+)-sparteine surrogates (Scheme 1).18 In this context,
we have previously published an efficient method for the
stereoselective synthesis of optically pure N-Boc-3-arylpiperazines
via the Meyers lactamization condensation in 22-45% yield over 8
steps.19 In pursuit of this work, and in an attempt to reduce the
number of reaction steps, with concomitantly an increase in yield,
we have previously reported a new methodology to prepare
racemic N-benzyl-2-substituted piperazine derivatives in 4 steps via
the formation of the intermediate 2,5-diketopiperazines (DKPs)
under microwave irradiation (in acetic acid at 180 °C for 10 min),
followed by final reduction of the corresponding piperazines.20
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However, the above methods often require multistep syntheses convertible isocyanide for the Ugi-4CR. It allows, for instance, a
that need chromatographic purifications, and suffer from harsh one-pot procedure the synthesis of optically pure 1-methyl-3-
conditions, low enantioselectivity and the use of toxic and corrosive phenylpiperazine (88 % yield, >98 % ee), an advanced intermediate
reagents. Thus, the development of a fast and simple protocol for for the preparation of (S)-Mirtazapine (vide infra). In an attempt to
the construction of enantiomerically pure, N-protected 2- or 3- minimize high reagent cost and to increase the synthetic efficacy,
substituted piperazines in a minimal number of steps, purifications we used in the current work, the readily available and cheap tert-
and reagents, remains a significant challenge.
butyl isocyanide as an alternative relative to the more expensive
In search for a new alternative to prepare chiral piperazines in a isocyanides cited above.22 Moreover, in our case the cleaved tert-
straightforward manner, the Ugi four-component reaction (Ugi- butyl amine group can be removed by evaporation while cleaved n-
4CR) represents an efficient route to rapidly build pseudo-dipeptide butyl- and cyclohexenyl amine removal requires silica gel
scaffolds and even heterocyclic templates by means of convertible purification. In contrast, our strategy allows the easy isolation of the
isocyanides via post-condensation procedures.21 Hulme and co- desired piperazines with excellent yields and in an enantiopure
workers have reported an Ugi-4CR/deprotection/cyclization form.
sequence (UDC) to form heterocyclic cores and have applied it to
In order to find the best reaction conditions for the synthesis of
the synthesis of DKPs derivatives.21r,s They used either the the prototype piperazine derivatives, N-Boc-L-phenylalanine, (S)-1-
expensive Armstrong cleavable isocyanide at room temperature methyl benzylamine, paraformaldehyde and tert-butyl isocyanide
under acidic conditions,21r or n-butylisonitrile as a convertible were chosen as model substrates to study the feasibility and the
isocyanide under acidic conditions and microwave irradiation at enantioselectivity of the proposed protocol (Table 1).
high temperature.21s These reported conditions furnished the
Table 1. Optimization of acidic conditions for the lactamization step.
desired DKP products in low to moderate yields accompanied by
the formation of side products (e.g., deprotected Ugi products,
carboxamide21r and trifluoroacetylated derivatives21s).
First, the Ugi-4CR reaction was carried out at room temperature
in MeOH for 6 h, affording the classical Ugi products in excellent
conversion and purity as judged by HPLC and LCMS analysis.
Thereafter, in vacuo evaporation of MeOH followed by AcOH-
promoted Boc removal and intramolecular cyclisation of the
deprotected Ugi products was carried out using previously
optimized conditions (entry 1, Table 1),20 yielding the desired
diketopiperazine (DKP) with good overall yield as a mixture of 2
diastereomers (78% yield, 65/35 dr). This result is consistent with
the results reported by Karasavin, who describes the racemization
of substituted DKP through enolization under microwave heating-
irradiation conditions.21k As expected, decreasing the reaction time
or temperature of the microwave irradiation leads to incomplete
conversion of the lactamization step. However, the reaction did not
proceed when using Hulme’s conditions for the formation of DKP
(i.e. use of 10% TFA in dichloroethane in instead of AcOH).21s
A
mixture of the Deboc-Ugi product, accompanied by the formation
of secondary products in the reaction mixture was observed by
LCMS (entry 2, Table 1). To optimize the acidic lactamization
conditions, we turned our attention to classical heating in a sealed
vial (AcOH, 0.17 M), as alternative conditions. Of note, the
microwave heating-irradiation process is also not easy to scale up.
When the reaction was carried out under heating in sealed vial at
120 °C, only a limited conversion was observed after 20 min. To our
Scheme 1. Examples of methods employed for the synthesis of chiral N-protected α-
substituted piperazines.
In this communication, we report a facile and efficient one-pot
process to synthesize (R)- and (S)-2- or 3-substituted piperazines in
an enantiopure form, starting from readily available amino acids,
and by employing an Ugi-4CR/deprotection/cyclization/reduction
(UDCR) synthetic sequence using tert-butyl isocyanide as
a
2 | J. Name., 2012, 00, 1-3
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satisfaction, more of the desired product was observed upon mixture under vacuum and the crude DKPs were then dissolved in
further increase of the reaction time and temperature. THF, and reduced in the presence of 4 equivalents of LiAlH4 to
A
temperature increase from 120 °C to 160 °C and prolonged reaction afford the corresponding enantiomerically pure 3-substituted DKPs,
time of 20 min to 120 min, afforded total conversion to the desired bearing a benzyl protecting group on nitrogen atom 1 in excellent
chiral N-protected 3-substituted DKP (100% conversion, 91% overall yield (87-92 %). In our case the benzylamine was used as a
isolated yield, > 99 % de, entry 3, Table 1). Gratifyingly, only a single precursor of the N-benzyl protected piperazine. This protecting
diastereomer was observed by RP-HPLC and characterized by NMR. group can be selectively removed via Pd-catalyzed hydrogenolysis
However, this procedure is interesting as it shows that, although under mild conditions. Yet its presence allows a differentiation of
both conventional heating and microwave heating give way to high the two nitrogen atoms in subsequent reactions. Next, these
conversions, only the first allows the preparation of the desired DKP optimal conditions were chosen to explore the substituent scope of
in an enantiopure form.
this methodology. Table 2 details the array of enantiopure N-
protected 3-substituted piperazines scaffolds that were obtained.
First, we tested various optically active and commercially available
N-Boc-(S)-α-amino acids 1 under the optimized conditions. In most
cases, the corresponding enantiopure 3-substituted piperazines (2a-
m) were isolated with excellent yields and diastereo- or
enantioselectivity (entries 1-13). The electronic proprieties of the
substituent in α position were well-tolerated and have no influence
on the yield and diastereomeric excess of the reaction.
Furthermore, to check that no racemization takes place during the
Table 2. Substrate Scope.
cyclization step,
a reaction in the presence of (S)-methyl
benzylamine and (R)-methyl benzylamine was carried out. Only one
diastereomer was observed by 1H NMR and HPLC (entries 10-13,
Table 2), and the compounds (2J-m) were isolated in an
enantiopure form. The reaction with (R)-phenylalanine was also
realized, and the targeted products were isolated in excellent yield
(83-87 %) (entries 8, 12 and 13). However, the use of N-Boc-(S)-
glutamine as a carboxylic acid derivative to be engaged in the Ugi-
4CR reaction, proved to be inappropriate and lead mainly to
degradation of the Ugi product, maybe because of the low solubility
of the starting materials and synthetic intermediates (entry 14).
It is straightforward that the incorporation of substituted
piperazine fragments in pharmaceuticals often requires a selective
protection at one of the two nitrogens. For this reason, an
orthogonal protection of compound 2g was carried out (Scheme 2).
The protection of nitrogen atom 4 by a Boc group was achieved
using (Boc)2O in the presence of Et3N in dichloromethane at room
temperature. The N,N-diprotected α-substituted piperazine 3 was
obtained in excellent yield (96%) starting from 2g. Next, a selective
deprotection of the Bn group on nitrogen atom 1 was realized in
the presence of catalytic amounts of Pd-C (10 wt%) in methanol at
room temperature, delivering the desired N-Boc-protected-2-
substituted piperazines 4 quantitatively. In this way, one can easily
choose how to introduce the piperazine moiety into more complex
structures.
aIsolated yields after workup (see the Supporting Information). bOne diastereomer was
observed by 1H and 13C NMR spectra and HPLC. cIsolated yields from Boc-(D)-Phe-OH.
After establishing the optimal conditions for the lactamization step
(entry 3, Table 1), the acetic acid was removed from the reaction
Scheme 2. Orthogonal protection and deprotection of piperazine 2g
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To demonstrate applicability of the described methodology, a
key intermediate of Mirtazepine was prepared. In general,
Mirtazapine is used as a racemate for the treatment of depression.
But more recent studies on both enantiomers of Mirtazapine
revealed excellent biological activity for the (S)-enantiomer only,
which was used in the treatment of climacteric symptoms and
insomnia.6 The key intermediate to prepare the (S)-Mirtazapine is 1-
methyl-3-phenylpiperazine 6. Generally, low yield and selectivity
were obtained for this compound due to the multistep synthesis
and multiple chromatographic purifications.6 More recently, Zhou
and co-workers have reported the synthesis of 1-methyl-3-
phenylpiperazine in six steps with a 47 % overall yield and 90 % of
enantiomeric excess.15j Herein, we describe an efficient three-steps
one-pot procedure to prepare intermediate 6 with an overall yield
of 86 % and excellent enantioselectivity (> 98% ee), starting from
cheap and readily available enantiopure N-Boc-L-phenylglycine 5
and methylamine hydrochloride as amine component for the Ugi
reaction (Scheme 3).
Acknowledgements
SB gratefully acknowledges the Strategic Research Program –
Growth Funding of the Vrije Universiteit Brussel for the financial
support.
Notes and references
1
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s
t proces
One-po
1) MeOH, r.t., 6 h
NH2.HCl
NC
2) AcOH, sealed vial,
160 °C, 2 h
ref. 6
N
(
S
)-Mirtazapine
O
H
(S)
(S)
N
N
H
3) THF, LiAlH4,
0 °C (1h), r.t. (1h)
CH2
O
Boc
OH
5
(6, 86 %)
Scheme 3. Synthesis of the advanced intermediate 6 of (S)-Mirtazapine.
To confirm that there is no epimerization at the stereogenic
center of (S)-phenylglycine 5 during the cyclization step, to form
intermediate 6, a reaction between (S)-phenylglycine 5 and (S)-
methyl benzylamine was achieved. Only one diastereoisomer of
diketopiperazine 7 was observed by NMR and HPLC analysis
(Scheme 4).
5
6
7
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have developed an easy and efficient methodology for the
preparation of various optically pure mono-N-protected α-
substituted piperazines, bearing a protecting group on nitrogen
atom 4 or 1. These chiral products were prepared by a one-pot Ugi-
4CR/Deprotection/Cyclisation/Reduction sequence (UDCR), using
cheap and readily available tert-butyl isocyanide. This original
procedure is suitable for the synthesis of valuable drug
intermediates in an enantiomerically pure form, and it should prove
to be useful for the synthesis of combinatorial libraries with a wide
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