Concise Redox Deracemization of Secondary and Tertiary Amines with a Tetrahydroisoquinoline Core via a Nonenzymatic Process

Article abstract of DOI:10.1021/jacs.5b06659

A concise deracemization of racemic secondary and tertiary amines with a tetrahydroisoquinoline core has been successfully realized by orchestrating a redox process consisted of N-bromosuccinimide oxidation and iridum-catalyzed asymmetric hydrogenation. This compatible redox combination enables one-pot, single-operation deracemization to generate chiral 1-substituted 1,2,3,4-tetrahydroisoquinolines with up to 98% ee in 93% yield, offering a simple and scalable synthetic technique for chiral amines directly from racemic starting materials.

Full text of DOI:10.1021/jacs.5b06659

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Communication
Concise Redox Deracemization of Secondary and Tertiary Amines
with Tetrahydroisoquinoline Core via Nonenzymatic Process
Yue Ji, Lei Shi, Mu-Wang Chen, Guang-Shou Feng, and Yong-Gui Zhou
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 14 Aug 2015
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Concise Redox Deracemization of Secondary and Tertiary
Amines with Tetrahydroisoquinoline Core via Nonenzymatic
Process
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Yue Ji,† Lei Shi,*†‡ MuꢀWang Chen,† GuangꢀShou Feng† and YongꢀGui Zhou*†
†State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, P. R. China
‡State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, P. R. China
Scheme 2. Chemically Catalytic Redox Deracemization
ABSTRACT: A concise deracemization of racemic secondary
and tertiary amines with tetrahydroisoquinoline core has been
successfully realized by orchestrating a redox process consistꢀ
ed of Nꢀbromosuccinimide oxidation and iridumꢀcatalyzed
asymmetric hydrogenation. This compatible redox combinaꢀ
tion enables oneꢀpot singleꢀoperation deracemization to generꢀ
ate chiral 1ꢀsubstituted 1,2,3,4ꢀtetrahydroisoquinolines with up
to 98% ee and 93% yield, offering a simple and scalable synꢀ
thetic technique for chiral amines directly from racemic startꢀ
ing materials.
Classical and kinetic resolution of a racemic mixture are the
widest methods used in largeꢀscale preparation of enantiomericalꢀ
ly pure compounds, but they are impeded by the fact that the theoꢀ
retical yield of the target chiral molecule is only 50% and at least
a half of starting material would be discarded.1 To overcome this
restriction, some enantiomerically convergent processes have
emerged to obtain single enantiomer from a racemate in theoretiꢀ
cally 100% yield, including dynamic kinetic resolution,2 dynamic
kinetic asymmetric transformation3 and deracemization.4 A raceꢀ
Deracemization reaction is comprised of two halfꢀreactions that
are opposite in reacting direction and completely distinct in mechꢀ
anistic pathways, at least one should operate enantioselectively.
Combination of oxidation with reduction is a common practice
through destroying and regenerating of the chirality of stereogenic
center. The main challenge of redoxꢀdriven deracemization is that
oxidants and reductants easily and directly quench each other in
single reactor, which usually is thermodynamically and kinetically
favorable. Sequential operation or physical isolation of oxidation
and reduction has been employed to overcome this problem. Two
reaction modes, linear and cyclic redox deracemizations, have
been built to achieve deracemization of a racemic mixture of chiꢀ
ral alcohols or amines (Scheme 1).5,6 However, deracemization
technique relies heavily on the utility of biological catalyst sysꢀ
tems till now. As the most representative one, monoamine oxidasꢀ
es (MAO) coupled with chemical reduction condition, such as
BH3ꢀNH3, metalꢀcatalyzed hydrogenation, etc., can lead to the
efficient formation of enantiomerically pure amines in cyclic deꢀ
racemization mode (Scheme 1).6 During biocatalyzed processes,
good compatibility between oxidation and reduction is probably
due to the active reacting site is shielded by protein or cell wall.
To the best of our knowledge, pure chemically catalytic deraceꢀ
mization is still very rare (Scheme 2). Williams and Nishibayashi
mic mixture can be completely converted into a single enantiomer
of the same compound through a deracemization process. Deracꢀ
emization is a highly efficient technology to obtain enantiomeriꢀ
cally pure compounds, especially when the substrate and the deꢀ
sired product possess an identical chemical structure. The addiꢀ
tional steps to remove the resolving agents from the products are
not needed. Thus, deracemization continues to attract considerable
research attention because of obvious atomꢀ and stepꢀeconomy.
Scheme 1. Linear and Cyclic Redox Deracemization
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independently developed elegant Ruꢀcatalyzed deracemization of
Next, a survey of solvent revealed that 1,2ꢀdichloroethane is
secondary alcohols.7 The reaction operated in discrete sequential
nonꢀselective or enantionselective oxidation and enantioselective
hydrogenation steps. Recently, a facile organocatalyzed deraceꢀ
mization of amines was reported by Toste group.8 Their brilliant
strategy of aqueous/organic /solid phase separation successfully
minimized the direct quenching of oxidant and reductant, which
enabled a oneꢀpot singleꢀoperation deracemization. Given current
wellꢀdeveloped catalytic oxidation/reduction reactions can proꢀ
vide a huge number of possibilities of redox combinations for
deracemization technique, as well as the scope of substrates
would be further widened under nonꢀenzyme conditions, pure
chemically catalytic deracemization is promising and highly deꢀ
sirable. Herein, we wish to report a concise deracemization of
secondary and tertiary amines with tetrahydroisoquinoline core by
orchestrating a redox process consisted of oxidation in situ and
highly enantioselective hydrogenation.
more suitable than others (Table 1, entries 1ꢀ5). Deracemization
of 1a performed well and offered high values of ee with most of
inorganic base (entries 5ꢀ8), while organic base triethylamine
showed a negative effect on enantioselectivity. A slight improveꢀ
ment in enantioselectivity was provided by reducing amount of
sodium carbonate (entry 9). Diverse arrays of commercially availꢀ
able ligands depicted in table 1 were tested to investigate the efꢀ
fect of the nature of ligand on deracemerization process. (R)ꢀ
SynPhos (L2), an electronꢀrich diphosphine ligand with axial
chirality, afforded the highest selectivity of 98% ee (entry 10).
Thus, we established the optimal condition for deracemization of
1ꢀphenylꢀ1,2,3,4ꢀtetrahydroisoquinoline 1a: using [Ir(cod)Cl]2/
(R)ꢀSynPhos as catalyst, 1.5 equiv. of NBS as oxidant, 0.55 equiv.
of sodium carbonate as base and 1,2ꢀdichloroethane as solvent to
perform reaction at 30 oC and at a hydrogen of 500 psi.
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Table 1. Optimization of Deracemization Conditionsa
In previous research work on iridiumꢀcatalyzed asymmetric hyꢀ
9
[Ir(cod)Cl]2/Ligand
drogenation reported by us and other groups, some oxidizing
NH
NH
agents containing halogen, such as iodine, TCCA (trichloroisocyꢀ
anuric acid) and NBS (Nꢀbromosuccinimide), can significantly
improve the performance of catalyst by elevating the valence state
of the center metal (Ir(I) to Ir(III)). Even using excess oxidants
would not affect the results of hydrogenation. On the other hand,
this kind of mild oxidants can also oxidize some racemic secondꢀ
ary amines into prochiral imines.10 Taking two facts together into
consideration, we envisaged that using this rare compatibility of
Irꢀcatalyzed hydrogenation condition with halogen oxidants
would realize a linear redox deracemization of some amines, parꢀ
ticularly those important motifs in natural alkaloids and pharmaꢀ
ceutical molecules such as tetrahydroisoquinoline.11 For this purꢀ
pose, two conditions have to be met. First, the direct quenching
between oxidant and reductant (metalꢀhydride) has to be much
slower than oxidation of amines; second, the oxidation should
take place in 100% conversion and faster than asymmetric hydroꢀ
genation.
NBS, Base, Solvent
H2 (500 psi), 30 oC, 24 h
Ph
Ph
rac
-1a
(R)-1a
recovery
(%)b
ee
entry
solvent
base (equiv.)
ligand
(%)c
1
2
DCM
Toluene
Dioxane
MeOH
DCE
Na2CO3 (0.75)
Na2CO3 (0.75)
Na2CO3 (0.75)
Na2CO3 (0.75)
Na2CO3 (0.75)
Cs2CO3 (0.75)
K3PO4 (0.50)
Et3N (1.50)
>95
86
93
ꢀ55
ꢀ48
ꢀ19
96
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
3
92
4
>95
>95
>95
>95
>95
>95
>95
>95
94
5
6
DCE
95
7
DCE
95
8
DCE
ꢀ14
97
9
DCE
Na2CO3 (0.55)
Na2CO3 (0.55)
Na2CO3 (0.55)
Na2CO3 (0.55)
Scheme 3. Effect of Oxidants on Deracemization of 1-
Phenyl-1,2,3,4-tetrahydroisoquinoline
10
11
12
DCE
98
DCE
95
DCE
85
a
Reaction conditions: 1a (0.2 mmol), [Ir(cod)Cl]2 (1 mol%), ligand (2.2
b
mol%), NBS (1.5 equiv.), base (0.55 equiv.), solvents 3 mL; Determined
Initially, 1ꢀphenylꢀ1,2,3,4ꢀtetrahydroisoquinoline 1a was seꢀ
lected as model compound to investigate deracemization condiꢀ
tion because it can be easily oxidized into imine by halogen reaꢀ
gents and also be enantioselectively furnished through hydrogenaꢀ
tion of cyclic imine.12 In the presence of 2 mol% chiral iridium
complex generated in situ from [Ir(cod)Cl]2/(R)ꢀMeOBiPhep and
0.5 equiv. of TCCA as oxidant, the deracemization of racemic 1a
was conducted in dichloromethane under hydrogen gas of 500 psi
(Scheme 3). After 24 hours, 1a could be recovered in 7% ee and
95% yield. This positive result confirmed our hypothesis and
encouraged us to further investigate the effect of the identity of
the oxidant on enantioselectivity. Surprisingly, when the oxidants
containing bromine were used, especially NBS, the value of ee
dramatically jumped up to 93%. This remarkable improvement is
probably due to dual roles of NBS in activating metal catalyst and
oxidizing substrate, respectively.
c
by 1H NMR; Determined by HPLC for the corresponding benzamide. cod
= 1,5ꢀcyclooctadiene.
The scope of this deracemization reaction was examined under
the optimized condition identified above. As depicted in Scheme
4, a series of 1ꢀaryl substituted tetrahydroisoquinolines could be
effectively deracemized into enantiomerically enriched forms
with up to 98% ee and good yields (> 90%). Notably, it was found
that the electronic property of substrates affects the enantioselecꢀ
tivity to a certain extent. Introduction of electronꢀdonating methꢀ
oxy group on isoquinoline core or 1ꢀphenyl resulted relatively
lower ees (1b, 1c and 1g), because some possible side reactions
might consume a part of oxidants. Those substrates containing an
electronꢀdeficient phenyl (1h, 1i and 1j) were deracemized with
excellent enantioselectivity (98% ee). With alkyl substituent at 1ꢀ
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position (1l, 1k), high yields and good enantioselectivities can still
be obtained, albeit ee values somewhat decreased.
To demonstrate the practical utility, deracemization of comꢀ
pound 1a was performed under the optimal condition in gram
scale, employing (S) instead of (R)ꢀSynPhos as ligand. (S)ꢀ1a was
prepared in 90% isolated yield and 97% ee (Scheme 6), which is
key intermediate for the synthesis of some drug molecules, such
as (+)ꢀSolifenacin14 and (+)ꢀFR115427.15 Besides, compound 3, a
potent noncompetitive AMPA receptor antagonist,12b,16 was effiꢀ
ciently synthesized via deracemization of 1m followed by acylaꢀ
tion with 90% ee and 84% overall yield (Scheme 7).
Scheme 4. Deracemization of 1-Substituted 1,2,3,4-Tetra-
hydroisoquinolines
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Scheme 6. Deracemization at Gram Scale and Applications
Scheme 7. Synthesis of AMPA Receptor Antagonist
Considering tertiary amines are widely popular in natural alkaꢀ
loids, we also explored the deracemization of Nꢀmethyl and Nꢀ
benzyl 1ꢀaryl substituted tetrahydroisoquinolines (Scheme 5, 2aꢀ
2h). To our delight, racemic tertiary amines with THIQ core can
be recovered in 87~95% yields with high ees (86~95%) after the
similar deracemization treatment. It is noteworthy that Nꢀbenzyl
group could be removed as temporary protected group. This is
very practical in multistep total synthesis of complex compound.
In contract with secondary amines, the enantioselectivity of deꢀ
racemization of these substrates is more sensitive with electronic
property of the chiral ligand used (see supporting information),
strong electronꢀdeficient L4 only give <50% ee. This phenomeꢀ
non should be resulted by two different reacting intermediates,
imine and iminium, produced by NBS oxidation of two kinds of
amines.10, 13
Next, to gain insight into the reaction mechanism, isotopic laꢀ
beling experiment was conducted under D2 gas (eq. 1). 1ꢀ
Deuterioꢀ1ꢀphenylꢀ1,2,3,4ꢀtetrahydroisoquinoline was formed
with 90% deuterium incorporation, which suggests that the raceꢀ
mic substrate was oxidized to imines firstly and C1 stereogenic
center regenerated by Irꢀcatalyzed enantioselective hydrogenation.
When imine 4 was subjected to the optimized reaction condition,
1a was obtained with 94% yield and 98% ee (eq. 2), which is
almost identical to the result of deracemization of 1a. This result
further confirmed the deracemization pathway involving an imine
intermediate. In addition, an interesting reaction of configuration
switch was carried out, and (S)ꢀ1a (97% ee) was able to be transꢀ
formed into (R)-1a (96% ee) with 88% yield after being treated
under deracemization condition (eq. 3).
Scheme 5. Deracemization of N-methyl and N-benzyl 1-
Substituted 1,2,3,4-Tetrahydroisoquinolinesa
By using an orchestrated redox process consisted of NBS oxiꢀ
dation and iridiumꢀcatalyzed asymmetric hydrogenation, we have
realized oneꢀpot oneꢀoperation deracemization of secondary and
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(b) Alexeeva, M.; Enright, A.; Dawson, M. J.; Mahmoudian, M.;
tertiary amines with tetrahydroisoquinoline core under pure chemꢀ
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chiral tetrahydroisoquinolines in 98% ee directly from the racemic
substrates with 100% theoretical yield, which is valuable for
preparation of some important drugs, including (+)ꢀsolifenacin,
(+)ꢀFR115427 and AMPA receptor antagonist. Further studies to
expand the scope to other amines or alcohols are ongoing in our
laboratory.
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ASSOCIATED CONTENT
Supporting Information
Procedures and spectral (NMR, HRMS, HPLC) data. This materiꢀ
al is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
shileichem@dicp.ac.cn; ygzhou@dicp.ac.cn
ACKNOWLEDGMENT
Financial support from the National Natural Science Foundation
of China (21472188, 21125208) and Youth Innovation Promotion
Association, Chinese Academy of Sciences (2014167).
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