Asymmetric total synthesis of (+)-asenapine

Article abstract of DOI:10.1039/c9ob00178f

Asymmetric total synthesis of (+)-asenapine, an atypical antipsychotic drug, used for treating schizophrenia and acute mania associated with bipolar disorder, is reported. The key steps are the organocatalytic Michael addition of aldehydes to trans-nitroa

Full text of DOI:10.1039/c9ob00178f

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: P. Szczeniak, O.
Staszewska-Krajewska and J. Mlynarski, Org. Biomol. Chem., 2019, DOI: 10.1039/C9OB00178F.
This is an Accepted Manuscript, which has been through the
Volume 14 Number
1 7 January 2016 Pages 1–372
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021PAlsepaosseePdtyoLtnd.ot adjust margins
Page 1 of 7
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C9OB00178F
Journal Name
ARTICLE
Total Asymmetric Synthesis of (+)-Asenapine.
Piotr Szcześniak,*a Olga Staszewska-Krajewska b and Jacek Mlynarski b
Received 00th January 20xx,
Accepted 00th January 20xx
Total, asymmetric synthesis of (+)-Asenapine an atypical antipsychotic drug, used for treating schizophrenia and acute
mania associated with bipolar disorder is reported. The key steps are organocatalytic Michael addition of aldehydes to
trans-nitroalkenes and subsequent reductive cyclization.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
N
Schizophrenia and bipolar disorder (BD) are two potentially
debilitating psychiatric illnesses that produce negative
consequences in the lives of millions people all over the world,
and an additional hundreds of thousands are diagnosed with
the above-mentioned disorders every year.1 Schizophrenia
affects an estimated 1.1% of the world's population, and it is
most commonly diagnosed between the ages of 16 to 25.
Schizophrenia and its treatment has an enormous effect on
the economy, costing between $32.5-$65 billion each year.2
Bipolar disorder is another complex, multifaceted, multisystem
psychiatric illness, affecting up to 1% of the world’s
population.3 Characterized primarily by manic, hypomanic, and
depressive mood episodes, it remains one of the most
disabling illnesses worldwide.4,5
Asenapine 1 is an active ingredient of Saphris® (USA),
Sycrest® (Europe), which is approved by FDA for treatment of
schizophrenia and acute manic or mixed episodes associated
with bipolar disorders.6,7,8 The mechanism of asenapine action,
as with other drugs having efficacy in schizophrenia and
bipolar disorder, is unknown. It has been suggested that the
efficacy of asenapine in schizophrenia is mediated through a
combination of antagonist activity at D2 (dopamine) and 5-
HT2A (serotonin) receptors, which has been shown to enhance
dopamine (DA) and acetylcholine (Ach) efflux in rat brains.9
Although it was approved for medical treatment in the U.S.
and Europe in 2009, worldwide net sales strongly increase year
by year. The sales of Saphris were estimated at $134.1 million
in 2012. By 2022, GlobalData projects these sales to grow
marginally to $154.9 million, with a compound annual growth
rate (CAGR) of 1.45%.10
Cl
O
(1)
Asenapine
Because of the medicinal importance of 1, the synthesis of
this pyrrolidine derivative has attracted many researchers at
academia11 as well as in industry.12 Given that the FDA has
approved the market launch of racemic asenapine, most
patented and public domain protocols involve the total
synthesis of asenapine in the racemic form. However, studies
of the metabolism and pharmacokinetics of the individual
enantiomers of asenapine revealed that (+)-isomer had shown
a better plasma concentration in mice, rats, and rabbits
compared to (–)-isomer.13 For this reason, the development of
an efficient and stereoselective strategy of the synthesis of
enantiomerically pure (+)-asenapine is highly desirable. In
2016 Chandrasekhar and co-workers reported the first
asymmetric synthesis of (+)-asenapine based on Julia
olefination and the Ireland–Claisen rearrangement as the key
steps.14 The enantiopure product was obtained in overall 4.6%
yield and 93.8% ee. The main drawback of this approache
results from relatively long and complicated synthetic
sequence requiring the use of reagents that are not acceptable
in industrial production, such as diazomethane or osmium
tetroxide. Since the strategies for asenapine preparation
developed so far suffer from drawbacks, it is necessary to find
an alternative and improved process for asenapine
manufacturing that would be more competitive and cost-
efficient.
a. Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Kraków,
Poland. E-mail:alchemik_84@tlen.pl
Very recently, we demonstrated that functionalized,
optically active cyclic nitrones or pyrrolidines can be obtained
in a simple and highly efficient manner via organocatalytic
Michael addition of aldehydes to trans-nitroalkenes and
b. Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-
224 Warsaw, Poland.
† Electronic Supplementary Information (ESI) available: Copies of 1H, 13C NMR,
NOE, HPLC spectra. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021PAlsepaosseePdtyoLtnd.ot adjust margins
Organic & Biomolecular Chemistry
Page 2 of 7
ARTICLE
Journal Name
subsequent reductive cyclization.15,16 The methodology was asenapine framework could be disconnected at the biaryl
View Article Online
DOI: 10.1039/C9OB00178F
successfully applied to the first asymmetric synthesis of ether to synthon 2, which could be built from 3 via reductive
Methdilazine a phenothiazine compound with antihistaminic cyclization. In turn synthon
3 could be realised via
activity and BZN molecule exhibits interesting binding to HIV-1 organocatalytic Michael addition of aldehydes 4 to trans-
protease.
Considering the chemical structure of (±)-asenapine as a
nitroalkene 5 (Scheme 1).
tetracyclic framework, wherein the N-methylpyrrolidine ring
fuses at the 3rd and 4th positions with chlorophenyl, phenyl
ether in a trans geometry, conceptually, we visualized that the
Br
5
Cl
organocatalytic
N
Michael
addition
Ulmmann
cyclization
reductive
Br cyclization
N
NO2
HO
OMe
NO2
+
O
Cl
O
Cl
Br
3
O
Cl
2
OMe
1
4
(+)-Asenapine ( )
Scheme 1 Retrosynthetic Analysis of (+)-Asenapine (1).
was performed in chloroform in the presence of 10 mol% of
the Hayashi-Jørgensen catalyst cat. I. and benzoic acid (20
mol%) as an additive, at ambient temperature.
With this strategy in mind, we thought of synthesizing one of
the desired isomers (+) in an optically pure form. The
application of the (S)-α,α-diphenylprolinol trimethylsilyl ether
(Hayashi-Jørgensen catalyst cat.I) as a catalyst for Michael
addition reaction should establish the correct configuration of
the stereogenic center in (+)-asenapine. The successful
execution of this strategy will naturally allow one to synthesize
(–)-asenapine by simply switching of the catalyst.
Br
Br
a)
O
NO2
5
O
Cl
Cl
Cl
c)
b)
O
O
OH
OMe
OMe
Results and discussion
6
4
Scheme 2 Reagents and condtions: a) i. MeNO2 (10 equiv), N,N,N,N-
tetramethylguanidine (10 mol%), toluene, –10 C, 90 min; ii. MsCl
(1.5 equiv), Et3N (1.5 equiv), –10 C, 40 min, 86% (2 steps); b) K2CO3
(2.0 equiv), MeI (1.33 equiv), DMF, rt, 48 h, 98%; c) i.
(methoxymethyl)triphenylphosphonium chloride (1.2 equiv), n-BuLi
The study started with the preparation of nitroalkene 5 and
aldehyde 4 – acceptor and donor in Michael addition reaction
(Scheme 2). The corresponding nitroalkene 5 was obtained
from commercially available 2-bromobenzaldehyde in a Henry
reaction with nitromethane and catalytic amount of N,N,N,N-
tetramethylguanidine in toluene. Subsequent addition of
methanesulfonyl chloride and triethylamine to the
intermediate nitro alcohol effected elimination to give the
desired nitro olefin 5 in good overall yield 86%. In turn,
aldehyde 4 was prepared from commercially available 5-
chlorosalicylaldehyde in three steps involves: protection of the
phenolic hydroxyl group with a methyl group leading to
aldehyde 6 in 98% yield. Then, a methylene-unit homologation
of the aldehyde moiety was performed via Wittig reaction
using phosphonium salt, followed by acidic hydrolysis,
affording aldehyde 4 in 66% yield in two steps.
̊
̊
(1.6 M)(1.2 equiv), THF, 0
h, 66% (2 steps).
̊C to rt, overnight; ii. HCl (5 M), THF, bp, 1
The reaction was complete within
4 h, providing γ-
nitroaldehyde 3 in excellent yield (95%) and stereoselectivity
(syn/anti ratio 8:1 and 96% ee.)(Scheme 5). The optimization
attempts revealed that in order to maintain the high
diastereomeric ratio (syn/anti 8:1), two equiv of the aldehyde
4 relatively to nitro olefin 5 should be used. Moreover the
catalyst has to be removed from the reaction mixture after
complete conversion of 5. These requirements arise from
nature of α-substituted γ-nitroaldehydes, witch can undergo
epimerization in the presence of the catalyst during Michael
addtion reaction. The isomerization process occurs, when the
product remains in contact with the catalyst for an extended
period of time. The γ-nitroaldehyde with high syn:anti ratio
With the desired Michaele acceptor 5 and donor 4 in hand,
we initiated the study of the organocatalytic Michaele addition
reaction leading to γ-nitroaldehyde 3. Based on our
experience, the reaction between nitro olefin 5 and aldehyde 4
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Page 3 of 7
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
reacts with the catalyst, a low steady-state concentration of
ARTICLE
An additional 1H-NMR experiment in deuterated chloroform
View Article Online
DOI: 10.1039/C9OB00178F
the enamine is rapidly established, and the equilibration confirmed that the isomerization process of the γ-nitroaldehyde 3
beetwen syn and anti continues until thermodynamic ratio is occurs in the Michael addition of aldehyde 4 to nitro olefin 5
reached (Scheme 3). This effect, has been intensively studied catalyzed by the Hayashi-Jørgensen catalyst cat. I (Scheme 4). The
and explained by Blackmond.17
progress of the isomerization is very fast and difficult to control,
when 1.2 equiv of the aldehyde 4 is used. This drawback was
overcome by using the excess of the aldehyde 4. We did not
observe the diastereomeric ratio decrease significantly, when the
reaction was performed with 2.0 equiv of the aldehyde 4. Moreover
the reaction was easy to monitor.
Ph
Ph
Ph
OTMS
cat. I
Ph
OTMS
N
N
Cl
H
H
cat. I
OMe
+
+
N
Cl
NO2
Br
Cl
After finding the suitable conditions, we were ready to exploit
the Michael reaction in the synthesis of (+)-asenapine 1. Obtained
γ-nitroaldehyde 3 with syn:anti ratio 8:1 was subjected reductive
cyclizaton to pyrrolidine 7.
Ph
Ph
OTMS
OMe
OMe
O
O
NO2
Br
NO2
Br
enamine
3
-syn
3
2-epi- -anti
Scheme 3 Reversible enamine formation between cat. 1, 3-syn, and
2-epi-3-anti.
OTMS
Ph
H
N
Cl
Cl
O
Ph
Br
OMe
OMe
H(B)
cat. I
(10 mol%)
O
O
+
+
OMe
NO2
Br
NO2
Br
PhCO2H (20 mol%)
NO2
H(c)
H(D)
H(A)
CDCl3, rt
Cl
5
4
(1.2 equiv)
(1.0 equiv)
3
3
2-epi- -anti
-syn
Scheme 4 1H-NMR analysis of syn/anti equilibration in the Michael addition of aldehyde 4 (1.2 equiv) to nitro olefin 5 (2.0 equiv)
catalyzed by 10 mol% of the Hayashi-Jorgensen catalyst cat. I.; selected signals are presented.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins