Enantioselective synthesis of levomilnacipran

Article abstract of DOI:10.1039/c2cc33743f

A novel approach for the asymmetric synthesis of the active (1S,2R)-enantiomer of the antidepressant milnacipran is reported. The two stereogenic centers borne by the cyclopropane ring were sequentially installed starting from phenylacetic acid.

Full text of DOI:10.1039/c2cc33743f

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Enantioselective Synthesis of Levomilnacipran†‡
Julien Alliot,a Edmond Gravel,a Florence Pillon,a David-Alexandre Buisson,a Marc Nicolas,b and Eric
Doris*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A novel approach for the asymmetric synthesis of the active
(1S,2R)-enantiomer of the antidepressant milnacipran is
reported. The two stereogenic centers borne by the
cyclopropane ring were sequentially installed starting from
10 phenylacetic acid.
Levomilnacipran 1 ((1S,2R)-milnacipran) is an antidepressant
currently in phase III clinical trials1 for the treatment of major
depressive disorders.2 Levomilnacipran is the most active
enantiomer of milnacipran and a selective dual serotonin-
15 norepinephrine reuptake inhibitor.3 While several strategies have
already been developed for the synthesis of milnacipran and
analogous cyclopropanes in their racemic form,4 enantioselective
routes to the title compound are scarce.
35
Scheme 2 Retrosynthetic approach to optically active key lactone 2
of the lactone ring followed by interconversion of the resulting
alcohol into the corresponding primary amine, finally afforded
optically active milnacipran.
40
In this paper we report an alternative route to levomilnacipran
from (2S)-phenylpent-4-enoic acid 3 (Scheme 1, Path C). The
latter compound could be easily converted to cis-γ-lactone 4 by
iodolactonization prior to methanolysis of the lactone ring and
concomitant epoxide 5 formation via ring closure of the transient
Approaches that have been devised so far relied on the
20 asymmetric construction of the key cyclopropane-fused lactone 2
where absolute configuration of the two stereogenic centers is
controled (Scheme 1).5 For example, the nucleophilic addition of
phenylacetonitrile to optically active epichorohydrin under basic
conditions provided efficient access to 2 through a two-step
25 sequence (Scheme 1, Path A).6 Also, the rhodium(II)-catalyzed
asymmetric intramolecular cyclopropanation of allyl phenyl-
diazoacetate efficiently promoted the formation of the key
intermediate 2 (Scheme 1, Path B).7 Although the latter approach
45 halohydrin (Scheme 2). Tandem cyclopropanation by SN2 ring
opening of the γ,δ-epoxide and in situ lactonization would then
deliver the optically active target lactone 2.
Our synthesis thus commenced with the preparation of (2S)-
phenylpent-4-enoic acid
3 which was obtained with high
50 enantioselectivity using the elegant methodology recently
developed by Zakarian et al.8 (Scheme 3). The process involved
the enantioselective alkylation of phenylacetic acid using a
tetramine as traceless chiral auxilary. Using the above procedure,
optically active (2S)-phenylpent-4-enoic acid 3 was obtained in
provided
a concise pathway to lactone 2, the obtained
30 enantiomeric excesses were moderate (≤ 68% ee) regardless of
the rhodium-based catalytic system. Further transformation of 2
by diethylaminolysis
55
Scheme 3 Enantioselective Approach to the Key Lactone
Scheme 1 Enantioselective routes to milnacipran
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steric interactions, each enolate evolves selectively to provide
83% yield and 88% ee. Subsequent iodolactonisation of 3 with
molecular iodine in diethyl ether afforded lactone 4.9
preferential access to one of the cyclopropane forms (for a model,
Iodoactonization selectively provided the γ-butyrolactone as the 55 see Figure S1 in the ESI).
only
product
(92%
yield)
and
with
satisfactory
At this stage, we had formally synthesized levomilnacipran
considering that lactone 2, wherein the two stereogenic centers
are irreversibly set, is the classical intermediate in the known
syntheses of the title compound. The preparation of
5
diastereoselectivity since the expected cis-isomer was formed
preferentially over the trans-form (cis/trans 70:30). The
lactonization step thus proceeded with high 1,3-asymmetric
induction which permitted to control the absolute configuration of 60 levomilnacipran was nevertheless continued (Scheme 4) by
the C5 position. The major cis-isomer 4 was recovered by column
diethylaminolysis of the lactone in the presence of AlCl3 to afford
the cyclopropyl amide-alcohol 7 in 90% yield.10
10 chromatography and chiral HPLC measurements indicated no
erosion of the optical purity since iodolactone 4 exhibited the
same enantiomeric excess (88% ee) as that of the starting
phenylacetic acid derivative 3. The lactone ring of 4 was
thereafter methanolyzed in the presence of potassium carbonate.
15 Although complete epimerization of the centre adjacent to the
ester was observed under the mildly basic conditions, chiral
information borne by C5 was fully retained during the ring
closure step of the halohydrin intermediate into epoxide 5.
Absolute stereochemistry of the epoxide unit is a key element in
20 our overall strategy towards the asymmetric synthesis of lactone
2 as the cyclopropanation step is expected to proceed by second
order nucleophilic substitution of the epoxide with inversion of
configuration. The stage was thus set for the intramolecular
cyclopropanation of the γ,δ-epoxy ester 5 by SN2 nucleophilic
25 ring opening of the oxirane.
Scheme 4 Completion of the Synthesis of Levomilnacipran
65 The alcohol group was then converted into a leaving group for
the ensuing introduction of the primary amine. Compound 7 was
hence reacted with thionyl chloride to give halogenated derivative
Table 1 Optimization of the Cyclopropanation Conditions
8
before potassium phtalimide was added. Nuleophilic
entry solvent
temp
cis/transa
conv (%)a
displacement of the chlorine atom by potassium phtalimide
70 permitted efficient introduction of the amine precursor (9) whose
deprotection with ethanolamine finally afforded levomilnacipran
1 in 89% yield.
1
2
3
4
THF
THF
rt
30:70
45:55
55:45
70:30
92
90
87
89
rflx
rflx
rflx
THF/HMPA (9:1)
Dioxane/HMPA (9:1)
Spectral data (1H and 13C NMR) of 1 are consistent with those of
authentic milnacipran and optical rotation measurements gave an
75 [α]D value of −88.3 (c 1.0, CHCl3). Noteworthy that while
compound 1 is levorotatory, levomilnacipran hydrochloride is
dextrorotatory ([α]D +72.5 (c 0.7, CHCl3)). However, the optical
rotation sign of 1·HCl matches that reported in the literature for
(1S,2R)-milnacipran hydrochloride ([α]D +72.8 (c 0.95, CHCl3),
80 96% ee).6a Enantiomeric excess of 1 was ultimately measured by
chiral HPLC which revealed a steady ee value of 88%. These
results unambiguously indicate that the initial stereochemical
information of the starting α-substituted phenylacetic acid 3 was
fully transferred throughout our synthesis of levomilnacipran.
85 The strategy we have developed to meet the synthetic challenge
of the asymmetric synthesis of levomilnacipran may also be
viewed as a general route for the preparation of optically active
substituted cyclopropanes.
a Based on 1H NMR analysis of the crude reaction mixture.
30
Attempts to run the reaction at room temperature and under
various basic conditions afforded majoritarily the unwanted
trans-cyclopropane (Table 1, Entry 1). LDA was however
selected as a base and the reaction conditions were optimized to
promote the preferential formation of the cis-isomer 6. We found
35 that by rising the reaction temperature to refux, the ratio of the
cis-isomer was increased up to nearly 50% (Entry 2). The
addition of HMPA also had a beneficial effect on the selective
formation of 6 as the latter was now produced as the major
product (Entry 3). Best results were obtained when the
40 intramolecular nucleophilic displacement was conducted in a
higher boiling point solvent such as dioxane and in the presence
of HMPA. Indeed, the expected cis-cyclopropane 6 was obtained
in good yield and with a cis/trans ratio of 70:30 (Entry 4). The
cis-cyclopropane was not isolated from the crude mixture but
45 treated in situ with HCl to induce clean formation of the key
lactone 2 in 55% yield (over two steps) and 88% ee. Although not
fully understood yet, the diastereoselectivity observed for the
cyclopropanation step in the presence or in the absence of HMPA
may originate from selective deprotonation of the ester. The
50 process, which is governed by lithium coordination between the
carbonyl and the epoxide, can give rise to cis or trans-enolate
intermediates depending on the reaction conditions. Owing to
In summary, we reported here an efficient enantioselective
90 synthesis of levomilnacipran from phenylacetic acid. Our approch
involved the asymmetric preparation of the central lactone
intermediate 2 using three key reactions: i) the enantioselective
synthesis of (2S)-phenylpent-4-enoic acid, ii) its selective
iodolactonisation, and iii) the intramolecular cyclopropanation of
95 epoxy ester 5. The enantiomeric excess of the starting
phenylpentenoic acid 3 was preserved throughout the developed
synthetic pathway, thus permitting efficient access to
levomilnacipran 1 with 88% ee.
2
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Notes and references
a CEA, iBiTecS, Service de Chimie Bioorganique et de Marquage, 91191
Gif-sur-Yvette, France. Fax: +33-169 08 79 91; Tel: +33-169 08 80 71;
E-mail: eric.doris@cea.fr
5
b Les Laboratoires Pierre Fabre, Centre de Développement de Chimie
Industrielle, 16 rue Jean Rostand, 81600 Gaillac, France.
† Electronic Supplementary Information (ESI) available: Experimental
procedures, copies of 1H/13C NMR spectra of all compounds, and a model
10 for the selective cyclopropanation step. See DOI: 10.1039/b000000x/
‡ This paper is dedicated to the memory of Charles Mioskowski who
initiated this work. J.A. thank the CEA and “Les Laboratoires Pierre
Fabre” for a CTCI PhD grant. The Service de Chimie Bioorganique et de
15 Marquage belongs to the Laboratory of Excellence in Research on
Medication and Innovative Therapeutics (LabEx LERMIT).
1
2
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TOC Graphic
The asymmetric synthesis of Levomilnacipran is reported starting from phenylacetic acid.