One-Pot N-Deprotection and Catalytic Intramolecular Asymmetric Reductive Amination for the Synthesis of Tetrahydroisoquinolines

Article abstract of DOI:10.1002/anie.201611181

A one-pot N-Boc deprotection and catalytic intramolecular reductive amination protocol for the preparation of enantiomerically pure tetrahydroisoquinoline alkaloids is described. The iodine-bridged dimeric iridium complexes displayed superb stereoselectivity to give tetrahydroisoquinolines, including several key pharmaceutical drug intermediates, in excellent yields under mild reaction conditions. Three additives played important roles in this reaction: Titanium(IV) isopropoxide and molecular iodine accelerated the transformation of the intermediate imine to the tetrahydroisoquinoline product; p-toluenesulfonic acid contributed to the stereocontrol.

Full text of DOI:10.1002/anie.201611181

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201611181
German Edition: DOI: 10.1002/ange.201611181
Asymmetric Catalysis
One-Pot N-Deprotection and Catalytic Intramolecular Asymmetric
Reductive Amination for the Synthesis of Tetrahydroisoquinolines
Huan Zhou, Yuan Liu, Suhua Yang, Le Zhou, and Mingxin Chang*
Abstract: A one-pot N-Boc deprotection and catalytic intra-
molecular reductive amination protocol for the preparation of
enantiomerically pure tetrahydroisoquinoline alkaloids is
described. The iodine-bridged dimeric iridium complexes
displayed superb stereoselectivity to give tetrahydroisoquino-
lines, including several key pharmaceutical drug intermediates,
in excellent yields under mild reaction conditions. Three
additives played important roles in this reaction: Titanium(IV)
isopropoxide and molecular iodine accelerated the transfor-
mation of the intermediate imine to the tetrahydroisoquinoline
product; p-toluenesulfonic acid contributed to the stereocon-
trol.
Scheme 2. One-pot reductive amination for the preparation of tetrahy-
droisoquinolines. Boc=tert-butoxycarbonyl, TFA=trifluoroacetic acid.
S
tereogenic 1-substituted tetrahydroisoquinolines have
attracted great attention in life science owing to their
[
1]
[4]
biological activity. This structural motif is present ubiqui-
corresponding imines (Scheme 2), the approach of asym-
tously in natural products and pharmaceuticals, for example,
metric reductive amination bypasses the preparation of the
imine, and is thus more concise, more efficient, and more
promising.
[
2a]
in naturally occurring (+)-cryptostyline II,
norcoclauri-
[2b]
ne, and tubocurarine (the functional ingredient of arrow
poison used by South American native people centuries ago
The reductive amination reaction is one of the most
important CÀN bond-construction tools both in biological
[
2c]
[2d]
to hunt animals), in an AMPA receptor antagonist, and
[
2e]
[2f]
[5]
in the pharmaceutical drugs almorexant and solifenacin
Scheme 1). To satisfy the demand for enantiomerically pure
tetrahydroisoquinolines, many synthetic methods have been
systems and synthetic organic chemistry. Since the first
(
asymmetric reductive amination reaction reported by Blaser
et al. in 1999 for the production of the herbicide metola-
[3]
[6]
developed. As compared with the highly efficient asym-
metric hydrogenation and transfer hydrogenation of the
chlor, some progress has been made in the synthesis of chiral
amines through intermolecular asymmetric reductive amina-
[
7]
tion. As for the intramolecular reaction, only two examples
have been reported. In 2003, Wills and co-workers applied the
Noyori transfer-hydrogenation catalytic system in the first
intramolecular asymmetric reductive amination reaction to
prepare 1-methyl-6,7-dimethoxytetrahydroisoquinoline in
[8a]
8
5% yield with 88% ee.
Merck chemists successfully
utilized the same type of catalyst to construct the key
stereogenic center of suvorexant, a drug approved by the
FDA in 2014 for the treatment of insomnia, in 97% yield with
[8b]
9
5% ee.
Unlike the intermolecular counterpart, which
could be deliberately designed by selecting from various
nitrogen donors to accommodate the catalyst spatial and
electronic requirements for better stereocontrol, the substrate
for intramolecular reductive amination bears certain moiet-
ies, and difficulties may be encountered during the formation
of the imine intermediate and the following reduction process.
Owing to the limited advances yet promising utility of the
intramolecular asymmetric reductive amination reaction for
the synthesis of chiral amines, the development of this
reaction is challenging and highly desirable. Herein, we
report the highly efficient combination of N-Boc deprotection
and intramolecular hydrogenative asymmetric reductive
amination in a one-pot process for the preparation of
tetrahydroisoquinolines (Scheme 2). Catalyzed by iodine-
Scheme 1. Bioactive 1-substituted tetrahydroisoquinolines.
[
*] H. Zhou, Y. Liu, S. Yang, Prof. Dr. L. Zhou, Prof. Dr. M. Chang
Department of Chemistry and Chemical Engineering
Northwest A&F University
22 Xinong Road, Yangling, Shaanxi 712100 (PR China)
E-mail: mxchang@nwsuaf.edu.cn
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201611181.
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bridged dimeric iridium complexes and promoted by addi-
tives, this efficient reaction led to chiral tetrahydroisoquino-
lines in excellent yields with excellent enantioselectivity (up
to 99% ee).
Initially, the N-Boc protecting group of the standard
substrate tert-butyl 2-benzoylphenethylcarbamate (1a) was
removed under acidic conditions. After all volatile compo-
nents had been removed, the resulting substance underwent
asymmetric reductive amination with the iridium–BINAP
reaction yielded only imine intermediate 3. It is commonly
believed that Ti(OiPr) can promote the formation of the
4
[7]
imine intermediate during the reductive amination process.
Our study showed that it also accelerated the transformation
of imine 3 into product 2a (Table 1, entry 2). Although the
addition of iodine alone did not help the reaction, its
combination with Ti(OiPr) did enhance the reduction of
4
imine 3 as well as the enantioselectivity of the process.
Brønsted acids have manifested positive effects on asymmet-
[
6,10b–d]
ric reductive amination.
In our study, upon the addition
of p-toluenesulfonic acid, the ee value of the product was
improved to 40%. From solvent screening, a 4:1 tetrahydro-
furan/toluene mixture was found to provide the best yield and
enantioselectivity (Table 1, entry 9).
We then screened several commercially available chiral
phosphine ligands (Scheme 3). The doubly oxygenated atro-
pisomeric C -symmetric bisphosphine ligands SEGPHOS,
2
SynPhos, and DifluoroPhos, in conjunction with [{Ir-
(
cod)Cl} ], displayed good enantioselectivity in the asymmet-
2
ric reductive amination of 1a (Table 2, entries 2–4). The
[
a]
Table 2: Screening of chiral ligands.
[
b]
[c]
Entry
Ligand
Yield [%]
ee [%]
1
2
3
4
5
6
7
(R)-BINAP
(R)-SEGPHOS
(R)-Synphos
98
98
99
99
62
98
99
99
99
98
93
24
74
77
75
15
0
89
97
89
98
98
Scheme 3. Structures of chiral phosphine ligands.
(S)-DifluoroPhos
(S)-(R)-Josiphos
(R)-Monophos
(S,S)-f-Binaphane
(R)-SEGPHOS
(R)-SEGPHOS
(R)-SEGPHOS
(R)-SEGPHOS
(
Scheme 3) catalytic system. Iridium–diphosphine complexes
were chosen since iridium has displayed potential for imine
reduction in the presence of various additives as compared
[
[
d]
8
9
0
1
d,e]
[
4b,9]
with other transition metals.
Several additives were
[d,f]
[d,g]
1
1
[10]
examined (Table 1, entries 1–5). Without any additive, the
À
[
a] Reaction conditions: [Ir]L /I /1a (1:1:10:100), Ti(OiPr) (1.1 equiv),
2
4
TsOH (10 mol%), H (50 atm), 24 h. [b] Yields were calculated from
H NMR spectra. [c] The ee value was determined by HPLC on a chiral
Table 1: Study of additives and solvents for the reductive amination of
2
1
[
a]
1
a.
stationary phase after the product was converted into the corresponding
acetamide. [d] Complex A was the catalyst. [e] TFA (10 mol%) was used
instead of TsOH. [f] The H pressure was 20 atm. [g] The H pressure
2
2
was 10 atm.
[
b]
[c]
[c]
Entry
Solvent
Additives
2a/3
ee [%]
superior performance of those ligands might be related to
their smaller dihedral angles, as compared with that of
1
2
3
4
5
6
7
8
CH Cl2
–
1:99
40:60
1:99
68:32
19:81
98:2
95:5
72:28
98:2
–
15
–
22
40
16
15
25
24
2
CH Cl2
Ti(OiPr)4
I2
Ti(OiPr) , I2
Ti(OiPr) , I , TsOH
Ti(OiPr) , I , TsOH
4 2
Ti(OiPr) , I , TsOH
Ti(OiPr) , I , TsOH
Ti(OiPr) , I , TsOH
4 2
2
[11]
CH Cl2
BINAP, and their electronic properties.
Iodine-bridged
2
CH Cl2
dimeric iridium complexes, initially reported by GenÞt,
2
4
2
CH Cl2
4
2
Mashima, and co-workers,
[12]
showed outstanding perfor-
EtOAc
THF
toluene
toluene/THF
mance in our previous studies on the asymmetric hydro-
genation of 2-aryl 1-pyrrolines and 1-aryl 3,4-dihydroisoqui-
4
2
4
2
[
4c,13]
[
d]
nolines.
Therefore,
the
complex
[{Ir(H)[(R)-
9
+
À
SEGPHOS]} (m-I) ] I (A) was also prepared and examined
2
3
[a] Reaction conditions: [Ir]/(R)-BINAP/1a (1:1:100), H (50 atm), 13 h.
2
in the reaction of 1a. To our delight, the ee value of the
product, which was formed in 99% yield, was dramatically
improved to 97% (Table 2, entry 8). When trifluoroacetic
acid (TFA; 10 mol%) was used instead of p-toluenesulfonic
[b] Ti(OiPr) (1.1 equiv); TsOH=p-toluenesulfonic acid (10 mol%); I
4
2
(
10 mol%). [c] Ratios and ee values were determined by HPLC on a chiral
stationary phase after the products were converted into the corre-
sponding acetamides. [d] Toluene/THF (4:1).
2
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acid, the reaction remained quantitative, but the ee value
dropped to 89% (entry 9). At a H pressure of 20 atm, the
2
reaction proceeded without a noticeable difference. When the
H2 pressure was further decreased to 10 atm, the yield
dropped slightly to 93%, but the enantioselectivity was not
affected (Table 2, entries 10 and 11).
To explore the utility of the iodine-bridged dimeric
iridium–SEGPHOS complex A, we prepared a range of
2
-substituted tert-butyl benzoylphenethylcarbamate sub-
strates 1 and studied them under the optimized conditions
Scheme 4). The electronic properties of the substrates
(
exerted no evident effect on enantioselectivity or reactivity.
However, the steric properties of certain substrates influ-
enced their reactivity and the enantioselectivity of the
reaction. When the substituents on the phenyl ring were at
the para position (1b–g), the meta position (1h–k), or both
para and meta (1l) positions, all substrates were converted
into the corresponding tetrahydroisoquinoline alkaloids with
high enantioselectivity (ee values all above 95%), regardless
of the electronic nature of the substituents; for ortho-
substituted substrates 1m and 1n, the results varied. The
yield and ee value for 2m was limited to 83 and 85%,
respectively. Under the catalysis of complex A (1 mol%), 1n
was transformed into product 2n with high enantioselectivity
(
99% ee). When the iodine-bridged dimeric Ir–(S,S)-f-Bina-
phane complex B was applied, the 2-alkylcarbonyl substrate
o was converted into the corresponding product 2o in 95%
1
yield with 97% ee. We also tested substrates with substituents
on the aryl ring that forms part of the tetrahydroisoquinoline
backbone of 2 and found that substrate 1q with an electron-
withdrawing substituent underwent a more enantioselective
reaction than substrate 1p with an electron-donating sub-
stituent.
To further demonstrate the practical utility of the newly
developed method, we carried out the N-Boc deprotection
and asymmetric reductive amination of 1a on a gram scale.
Catalyzed by complex A prepared from (S)-SEGPHOS, the
reaction rendered the desired product (S)-1-phenyl-1,2,3,4-
tetrahydroisoquinoline (2a) in 97% yield with 97% ee.
Compound (S)-2a is the key intermediate for the pharma-
Scheme 4. Scope of the reaction. [a] The reaction was carried out with
mol% of complex A. [b] Complex B prepared from (S,S)-f-Binaphane
1
+
À
was used. [c] [{Ir(H)[(S)-SEGPHOS]} (m-I) ] I was used.
2
3
+
À
bridged dimeric [{Ir(H)[(R)-SEGPHOS]} (m-I) ] I com-
2
3
[
14]
ceutical
drugs
(+)-solifenacin
(Scheme 5). We also examined substrate
r. With complex A, the corresponding
(Scheme 1)
and
plexes A and B displayed excellent enantioselectivity and
reactivity. Use of the Lewis acid titanium(IV) isopropoxide,
[
15]
(+)-FR115427
1
acetamide 4, an AMPA receptor antagonist
Scheme 1), was obtained in 95% yield with
5% ee (Scheme 5). The iodine-bridged
dimeric iridium complex B, prepared from
(
7
(
(
S,S)-f-Binaphane (Scheme 3), afforded
S)-4 in 95% yield with 97% ee.
In summary, we have developed
a highly efficient and enantioselective pro-
tocol for the preparation of bioactive chiral
1
-substituted tetrahydroisoquinolines. By
this route, tert-butyl 2-benzoylphenethyl-
carbamates were effectively converted into
the corresponding tetrahydroisoquinolines
through N-Boc deprotection and direct
asymmetric intramolecular reductive ami-
nation in a one-pot process. The iodine- Scheme 5. Larger-scale reductive amination of 1a and synthesis of 4.
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acetamide, the ee value of which was determined by HPLC on a chiral
stationary phase.
Acknowledgements
We thank the National Natural Science Foundation of China
(
(
(
No. 21402155), Yangling Bureau of Science and Technology
No. 2016NY-25), and Northwest A&F University
Z109021521) for financial support. We thank Hongli Zhang
[
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Keywords: asymmetric catalysis · enantioselectivity · iridium ·
reductive amination · tetrahydroisoquinolines
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Manuscript received: November 15, 2016
Final Article published: && &&, &&&&
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Communications
Asymmetric Catalysis
H. Zhou, Y. Liu, S. Yang, L. Zhou,
M. Chang*
&&& — &&&
One-Pot N-Deprotection and Catalytic
Intramolecular Asymmetric Reductive
Amination for the Synthesis of
Tetrahydroisoquinolines
Cool combo: N-Boc deprotection was
combined with direct asymmetric intra-
molecular reductive amination in a one-
pot process for the preparation of bioac-
tive chiral 1-substituted tetrahydroiso-
quinolines (see scheme; Boc=tert-
butoxycarbonyl). The iodine-bridged
+
À
dimer [{Ir(H)[(R)-SEGPHOS]} (m-I) ] I
2
3
was a very effective catalyst for the
transformation, in which the additives
Ti(OiPr) , p-toluenesulfonic acid, and I
4
2
played important roles.
6
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