Three-Step Total Synthesis of Ramelteon via a Catellani Strategy

Article abstract of DOI:10.1002/cctc.201901355

Ramelteon is the first medicine in human history that treat insomnia as a melatonin receptor agonist. Herein, we report an efficient three-step synthetic route to access it from commercially available 2,3-dihydrobenzofuran-4-amine, which represents as the shortest racemic synthesis to date with a 26 % overall yield. Key to the success is the application of the intermolecular Catellani-type alkylation and intramolecular redox-relay Heck cyclization cascade for preparation of the key indane-containing aldehyde. The unique primary amide-involved reductive amination of aldehyde is another feature of this route. New process of ramelteon can be developed based on this chemistry.

Full text of DOI:10.1002/cctc.201901355

Accepted Article
Title: Three-Step Total Synthesis of Ramelteon via a Catellani Strategy
Authors: Shijun Gao, Guangyin Qian, Hao Tang, zuo Yang, and
Qianghui Zhou
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ChemCatChem
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Three-Step Total Synthesis of Ramelteon via a Catellani Strategy
Shijun Gao, Guangyin Qian, Hao Tang, Zuo Yang and Qianghui Zhou*[a][b]
Abstract: Ramelteon is the first medicine in human history that treat
insomnia as a melatonin receptor agonist. Herein, we report an
efficient three-step synthetic route to access it from commercially
available 2,3-dihydrobenzofuran-4-amine, which represents as the
shortest racemic synthesis to date with a 26% overall yield. Key to
the success is the application of the intermolecular Catellani-type
alkylation and intramolecular redox-relay Heck cyclization cascade
for preparation of the key indane-containing aldehyde. The unique
primary amide-involved reductive amination of aldehyde is another
feature of this route. New process of ramelteon can be developed
based on this chemistry.
Introduction
Ramelteon (Rozerem™, 1), as a famous sleep agent, was
developed by Takeda and approved by FDA in 2005. Known as
the first selective agonist for melatonin MT1/MT2 receptors in
suprachiasmatic nucleus (SCN), ramelteon is primarily used for
the treatment of insomnia.[1] With negligible affinity for MT3
receptors,[2] ramelteon nearly has no adverse effects, such as
Figure 1. Representitive Approaches to Access Ramelteon
drug dependence and cognitive impairment that associated with
benzodiazepine-class drugs.[3] This stunning feature makes it the
unavailable bromoenolate substrate to afford a reasonable yield.
only prescription sleep medication that is not labeled as a
In 2015, Xiao and co-workers reported a short approach to access
controlled substance by the US Drug Enforcement Administration.
As shown in Figure 1A, ramelteon possesses a unique
tricyclic core scaffold that includes a dihydrobenzofuran and an
1 involving a nucleophilic addition of the carbonyl group and
catalytic hydrogentation as the key reactions. Nevertheless,
seven steps were required to prepare the aryl dibromide starting
indane subunit, as well as a S-configurated stereogenic center at
material (Figure 1B-3).[6] Other alternative synthetic routes were
the benzylic position. The synthesis of ramelteon has been
also repored.[7] However, these existing routes commonly
intensively studied in the past two decades.[4-7] For instance, in
suffered from long synthetic sequences from commercial sources
2012, the Zhang group[4] reported an enantioselective approach
and low overall synthetic efficiency. Thus, efficient syntheses of
to ramelteon, featuring a Heck reaction and an organocatalysis-
ramelteon are highly desirable.
enabled asymmetric Michael addition. However, this eleven-step
route was based on a very expensive starting material 4-bromo-
The Catellani reaction, firstly introduced by Catellani and co-
workers in 1997,[8] now has become a powerful method that
2,3-dihydrobenzofuran and suffered from a low overall yield
permits expeditious synthesis of highly substituted arenes.[9] The
(Figure 1B-1). In 2013, the Chen group[5a] reported a fifteen-step
application of Catellani reaction in total synthesis of natural
synthesis utilizing the elegant Catellani reaction and a chiral
products has been practised elegantly by the group of Bach,[10]
auxiliary-assisted asymmetric Michael addition as the key steps
Lautens,[11] Gu,[12] Dong,[13] and others.[14] Our group is also
(Figure 1B-2). Later on, they improved the synthesis[5b] with a
interested in developing novel Catellani-type strategies for the
modified Catellani strategy developed by the Lautens group,[5c]
efficient total synthesis of bioactive natural products and
which required excessive (5.0 equivalents) commercially
pharmaceuticals.[15] Recently, we developed
a convergent
synthetic method that allowed the construction of
tetrahydronaphthalenes and indanes through consecutive
Catellani-type otho C-H alkylation and ipso-intramolecular redox-
relay Heck reaction of aryl iodides.[16] Through a careful structure
analysis, we envisioned the application of this method for the
synthesis of ramelteon. The retrosynthetic analysis was shown in
Figure 2A. We surmised that 1 could be obtained from aldehyde
2 through a reductive amination. The key indane motif-based
aldehyde 2 could be assembled through our Catellani strategy,
with aryl iodide 3 and bromide 4 as the reactants. As to the
[a]
[b]
S. Gao, G. Qian, H. Tang, Z. Yang, Prof. Dr. Q. Zhou
Sauvage Center for Molecular Sciences, Engineering Research Cen
ter of Organosilicon Compounds & Materials (Ministry of Education),
College of Chemistry and Molecular Sciences, Wuhan University,
Wuhan, 430072 (China)
E-mail: qhzhou@whu.edu.cn
Prof. Dr. Q. Zhou
Institute for Advanced Studies, Wuhan University, Wuhan, 430072
(China)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/cctc.201901355
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preparation of 3, a Sandmeyer reaction of the commercially
available 2,3-dihydrobenzofuran-4-amine (5) is just needed.[17]
Table 1. Optimization of reaction conditions[a]
Meanwhile, (E)-5-bromopent-2-en-1-ol (4) is
a
known
compound.[18] Thus, a very short synthesis of ramelteon can be
expected.
As can be seen, the key step of this synthetic plan is the
preparation of 2 from 3 and 4 through a Catellani-type tandem
process. The detail of this transformation is outlined in Figure 2B.
Aryl iodide 3 and bromide 4 would engage in consecutive
Catellani-type ortho C-H alkylation (intermediate A to D) and
redox-relay migration Heck-type cyclization (intermediate D to
product 2). Such a sequence would enable the formation of the
core indane motif and the installation of an aldehyde functionality
for further transformation.
Yield of 2
[%][b]
Entry
[NBE]
Solvent
MeCN
MeCN
1
2
N1
8[c]
N2
N3
N4
N4
N4
N4
N4
N4
N4
9
6
3
4
MeCN
MeCN
NMP
DMF
DMF
DMF
DMF
DMF
14
28
40
42
49
53
63[h]
5
6
7[d]
8[d,e]
9[d,e,f]
10[d,e,f,g]
[a] The reaction was performed on a 0.1 mmol scale. [b] GC yield with biphenyl
as an internal standard. [c] 2′ was isolated in 40% yield. [d] 50 mol% of N4
was applied. [e] The concentration of 3 was 0.05 M. [f] The reaction
temperature was 60 oC. [g] The reaction time was 19 h. [h] Isolated yield. NMP
= N-methyl-2-pyrrolidinone, DMF = N,N-dimethylformamide.
loading of N1 to 2.5 equiv and employing KI (1.0 equiv) as the
additve, the yield of 2 was increased to 8% (entry 1). Considering
the central role NBE-type mediator taken in Catellani reactions,
subsequent studies were focused on finding the optimal mediator.
An array of readily available NBE derivatives were screened,
including norbornene (N2), the diester derivative N3, bisamide
derivative N4 and others (see SI for details) (entries 1-4).[19] N4
was among the best to provide 2 in 14% yield (entry 4). Further
optimization revealed a significant solvent effect of this reaction.
The switching of MeCN for more polar NMP or DMF provided 2 in
a significantly increased yield (28% and 40% respectively)
(entries 5 and 6). In contrast, only trace amount of 2 was obtained
while nonpolar solvent such as toluene was used (see Table S1
of the Supporting Information). Therefore, DMF was selected as
the optimal reaction solvent. Interestingly, following studies
showed that reducing the loading of the mediator could have a
positive effect on the reaction efficiency. For instance, the use of
50 mol % of N4 provided 2 in 42% yield (entry 7). Additional
optimization regarding the palladium catalyst, phosphine ligand,
base, and the amount of 4 did not provide obvious improvement
in the reaction efficiency (see Table S1 of the Supporting
Information for details). However, a lower concentration and
reaction temperature as well as a shorter reaction time were
determined to be beneficial (entries 8-10).[20] Thus, entry 10 was
identified as the optimal conditions, which delivered 2 in 63% yield
(entry 10).
Figure 2. Retrosynthetic analysis of 1 and the key reaction design
In this communication, we report a very efficient three-step
synthesis of ramelteon from commercially available starting
materials, with the Catellani-type cascade reaction and a
subsequent reductive amination as the key steps. Optimization of
this key Catellani-type cascade reaction is also included.
Results and Discussion
Our efforts commenced with the preparation of substrates 3
and 4 for the key Catellani reaction. As mentioned previously, 3
was readily synthesized in just one step from the commercially
available starting material 2,3-dihydrobenzofuran-4-amine (5)[17]
in 70% yield through the Sandmeyer reaction. Meanwhile, 4 was
facilely prepared by cross-metathesis of 4-bromo-1-butene and
cis-2-butene-1,4-diol, according to the reported procedure[18] (see
the Supporting Information for details).
Next, the key Catellani reaction was investigated (Table 1).
Subjecting substrates 3 and 4 to our previously identified standard
reaction conditions[16] ([Pd(C3H5)Cl]2 as the catalyst, Xphos as the
ligand, N1 as the mediator, K2CO3 as the base, and MeCN as the
solvent), only trace amount of the desired product 2 was detected.
Delightly, after careful modifications including increasing the
Alongside optimization of the reaction conditions, the side
products of this process were also probed. One obvious side
reaction was the palladium-promoted oxidation of the allylic
alcohol motif in 4 into conjugated aldehyde,[21] which necessitated
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10.1002/cctc.201901355
ChemCatChem
COMMUNICATION
synthesis of ramelteon was achieved in 26% overall yield starting
from 5. Similarly, aldehyde 7 could be transformed into the
methylated ramelteon through the same reductive amination. It is
expected that other ramelteon analogs for new drug discovery can
also be facilely prepared using this chemistry.
In summary, we have developed a very efficient three-step
synthesis of melatonin receptor agonist ramelteon from
commercially available compound 2,3-dihydrobenzofuran-4-
amine (5), which represents as the shortest racemic synthetic
route to date. Key to the success is the application of the
intermolecular Catellani-type alkylation and intramolecular redox-
relay Heck cyclization cascade for preparation of the key indane-
containing aldehyde from two readily available substrates. The
unique primary amide-involved reductive amination of aldehyde is
another feature of this route. Efforts to develop the asymmetric
version of the Catellani-type annulation for the enantioselective
synthesis of ramelteon are underway in our laboratory.
Figure 3. (A) Proposed mechanism of generating 2 and 2′. (B) A Control
experiment.
the requirement of 4 in excess. However, a lower substrate
concentration and reaction temperature could prohibit this side
reaction to some extent, as demonstrated in Table 1. Another
identified major side product was 2-(1,6-dihydro-2H-indeno[5,4-
b]furan-8-yl)ethan-1-ol (2′), which was isolated in 40% yield from
entry 1 of Table 1. The structure of 2′ was confirmed through 1D-
and 2D-NMR as well as HRMS analysis (see the Supporting
Information for details). In order to rationalize the formation of 2′,
we further dug into the procedure regarding the formation of 2
from intermediate D (Figure 2B). As shown in Figure 3A, the first
Experimental Section
Synthesis of Ramelteon: The aldehyde 2 (20.2 mg, 0.1 mmol) and
propionamide (21.9 mg, 0.3 mmol) in toluene was added HSiEt3 (47.8 μL,
0.3 mmol) and TFA (21.5 μL, 0.25 mmol). Then the resulting mixture was
stirred at 80 ℃ for 24 h. The reaction mixture was cooled to room
temperature and washed with saturated NaHCO3 solvent and brine, dried
over anhydrous Na2SO4. The solvent was removed under reduced
pressure and the crude product was purified by preparative thin layer
chromatography (PE:EtOAc = 1:1) to give the desired product 1 (14.0 mg,
54% yield). Physical state: white solid. Melting point: 89 – 92 ºC. IR (KBr
pellet): ν 3316, 2921, 2851, 1646, 1541, 1459, 1234, 1132, 1076, 801 cm-
migration insertion of
D would lead to intermediate F.
Subsequently, there’s two options for the following β-H-
elimination: H1 (path A)and H2 (path B). Path A led to intermediate
G which was finally transformed to 2 through the redox-relay
migration of the [Pd-H] species driven by thermodynamic force
towards the alcohol side.[22] On the contrary, path B generated
intermediate H which led to 2′ through the redox-relay migration
of the [Pd-H] species driven by steric hindrance. In addition, the
extended conjugate system of H and 2′ might also favor this side
reaction. In our previous study, this type of byproduct was not
observed since the corresponding alkyl bromides possessed a
methyl substitution on the olefin, which dictated the direction of
the redox-relay only towards the alcohol side.[16] A control
experiment employing olefinic bromide 6 as the reaction partner
of 3 was conducted to provide aldehyde 7 as the sole cyclized
product in 55% yield, which supported the above rationale (Figure
3B).
1
1. H NMR (400 MHz, CDCl3) δ 6.94 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 7.9
Hz, 1H), 5.47 (brs, 1H), 4.61 – 4.47 (m, 2H), 3.40 – 3.30 (m, 2H), 3.28 –
3.06 (m, 3H), 2.92 – 2.85 (m, 1H), 2.80 – 2.72 (m, 1H), 2.32–2.23 (m, 1H),
2.17 (q, J = 7.6 Hz, 2H), 2.07 – 1.97 (m, 1H), 1.86 – 1.79 (m, 1H), 1.67 –
1.58 (m, 1H), 1.13 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 173.90,
159.45, 143.20, 135.92, 123.50, 122.30, 107.55, 71.30, 42.27, 38.16,
33.56, 31.84, 30.80, 29.90, 28.69, 10.03. HRMS (ESI-TOF): calc’d for
C16H22O2N [M+H+] 260.1645, found 260.1644.
Acknowledgements
Based on understanding of this key Catellani-type cascade
process, we were able to conducted a 6.5 mmol scale operation
to obtain 0.89 gram of 2 (68% yield) (Scheme 1). Next, by
adopting a unique primary amide-involved reductive amination of
aldehyde for C-N bond formation reported by Dubé and co-
workers,[23] ramelteon 1 was directly accessed from 2 in 54% yield
(Scheme 1). The analytical data of the synthetic 1 were identical
to those of the reported. [4,5a,6] The obtained moderate yield of 1
was attribute to the instability of 2 under current reductive
amination conditions. Further optimization would be conducted to
enhance the efficiency of this step. Therefore, the three-step total
We are grateful to the National Natural Science Foundation of
China (nos 21602161, 21871213, 21801193), the National “1000
Youth Talents Plan”, Funding of College Students Innovation and
Entrepreneurship Project (no 201810486032), start-up funding
from Wuhan University, and the China Postdoctoral Science
Foundation (nos 2016M602339, 2018M642894) for financial
support. We thank Prof. W.-B. Liu (WHU) and Prof. H.-D. Tang
(WHU) for sharing their instruments.
Keywords: ramelteon • indane • Catellani reaction • redox-relay
Heck reaction • reductive amination
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Scheme 1. Synthesis of ramelteon
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Shijun Gao, Guangyin Qian, Hao Tang,
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Three-Step Total Synthesis of
Ramelteon via a Catellani Strategy
An efficient three-step synthetic route to access the anti-insomnia medicine
ramelteon from commercially available 2,3-dihydrobenzofuran-4-amine was
developed, which represents as the shortest racemic synthesis to date.
This article is protected by copyright. All rights reserved.