Asymmetric synthesis of isoquinolinonaphthyridines catalyzed by a chiral Br?nsted acid

Article abstract of DOI:10.1039/c7ob01527e

A catalytic asymmetric method for the synthesis of chiral isoquinolinonaphthyridines has been developed. A chiral disulfonimide catalyzes a redox cyclization reaction between 2-methyl-3-aldehydeazaarenes and 1,2,3,4-tetrahydroisoquinolines to deliver a range of isoquinolinonaphthyridines with good to high yields (up to 91%) and up to 92:8 er.

Full text of DOI:10.1039/c7ob01527e

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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DOI: 10.1039/C7OB01527E
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Asymmetric Synthesis of Isoquinolinonaphthyridines Catalyzed by
a Chiral Brønsted Acid
Jianjun Li,a Yiwei Fu,a Cong Qin,a Yang Yu,a Hao Li,*a and Wei Wang*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
catalytic asymmetric method for the synthesis of chiral
isoquinolinonaphthyridines has been developed. chiral
A
disulfonimide catalyzes a redox cyclization between 2-methyl-3-
aldehydeazaarenes and 1,2,3,4-tetrahydroisoquinolines to deliver
a range of isoquinolinonaphthyridines with good to high yields (up
to 91%) and up to 92:8 e.r..
Tetrahydroprotoberberines (THPBs) containing a quinolizine
core possess
a broad spectrum of appealing biological
properties.1 They display antifungal,2 antimicrobial,3
antiepileptic,4 anti-inflammatory,5 antihypertensive,6 antiviral,7
antitumor8 bioactivities. Therefore, the synthesis of THPB
analogues has been a long-standing interest to synthetic and
medicinal community. The classic approaches to THPBs employ
the Bischler-Napieralski9 and the Pictet-Spengler reactions.10
Recently, the THPBs derivatives containing N, O and S atoms
have been efficiently synthesized from readily accessible
tetrahydroisoquinolines with 2-hetreoatom (eg., N, O and S)
substituted benzaldehydes via redox cyclization strategy,
significantly contributed from Seidel and his team.11 Reactions
involving C-C bond instead of C-heteroatom bond formation
representing direct approach to the tetrahydroisoquinoline
scaffold also have been elegantly realized by the same group
(Scheme 1, eq 1).12 In these studies, easily enolizable
melanonate, keto- or nitroalkyl aldehydes have been used for
effective transformations. In addition, it is noted that these
processes are carried out in a non-asymmetric manner or by
employing chiral substrates to make chiral products. Catalytic
Scheme 1. Brønsted acid catalyzed enantioselective redox Mannich cyclization
reaction of inert arylmethyl aldehydes with tetrahydroisoquinolines.
enantioselective process is particularly appealing for the
synthesis of chiral tetrahydroisoquinolines, but remains elusive.
Recently, we have developed a non-classic class of carbon
centered nucleophiles for asymmetric organocatalysis.13 We
successfully implemented inert aryl methane as nucleophiles
for chiral amine catalyzed Michael addition and cascade
reactions (Scheme 1, eq. 2).13a Very recently, we developed a
Lewis acid catalyzed annulation for the synthesis of achiral
tetrahydroisoquinolines.14,15 In our continuing efforts on
advancing the useful chemistry, herein we report a chiral
Brønsted acid catalyzed redox cyclization method16 for the
a.State Key Laboratory of Bioengineering Reactor, Shanghai Key Laboratory of New
Drug Design, and School of Pharmacy, East China University of Science and
Technology, 130 Meilong Road, Shanghai 200237, China
Email: hli77@ecust.edu.cn
b.Department of Chemistry and Chemical Biology
University of New Mexico, Albuquerque, NM 87131-0001, USA
Email: wwang@unm.edu
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
synthesis of chiral tetrahydroisoquinolines
3 (eq. 3). In this new
process, we successfully imple-mented 2-methyl-3-
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Table 1. Catalyst screening for the asymmetric annulation reactionsa
Table 2. Solvent Screening for the asymmetric annulation reactionsa
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DOI: 10.1039/C7OB01527E
Entry
Solvent
toluene
t (d)
0.75
2.5
2.5
1.5
14
Yieldb (%)
e.r.c
1
2
3
4
5
6
91
62
70
87
60
71
86:14
79:21
78:22
76:24
63:37
75:25
o-xylene
p-xylene
chlorobenzene
DCE
Yieldb (%)
e.r.c
77:23
-
dioxane
4
Entry
cat.
I
t (d)
1.5
2.5
2.5
2.5
4
7
8
9d
EtOH
DMF
toluene
6
50
trace
81
58:42
50:50
83:17
1
2
3
4
5
51
trace
42
30
0.75
II
III
IV
V
55:45
53:47
75:25
50
a Unless specified, a mixture of 1a (0.1 mmol) and VII (30 mol%) in the solvent (1.0
mL) was stirred for 30 min at rt. Then 3Å MS, 2a (0.13 mmol) was added before the
reaction was carried out at 60 oC. b Isolated yields. c Determined by chiral HPLC
analysis. d 0.5 mL toluene was used.
40
6
7
8
9d
VI
VII
VIII
VII
2.5
0.75
2.5
55
91
20
72:28
86:14
71:29
-
H8-BINOL-based disulfonimide V, had no significant influence on this
reaction with only 40% yield and 75:25 e.r. (entry 5). It is well known
that the introduction of bulky and electron-deficient groups into the
3,3’-positions of the BINOL structure could result in a sterically
demanding environment.17 Then we screened more hindered DSIs
(VI-VIII) to improve reaction yields and enantioselectivities. DSI VI,
with even more electron deficient aryl substituents, gave worse
results than I (55% yield, 72:28 e.r., entry 6). Gratifyingly, when
bulkier DSI VII was employed, product 3a was produced with a
dramatic increase in the enantioselectivity and higher yield (86:14
e.r., 91%, entry 7). However, more sterically demanding DSI VIII gave
much lower yield and poor enantioselectivity (21%, 71: 29 e.r., entry
8). We also found that lower reaction temperature (40 oC)
diminished the reaction efficiency (entry 9). When the catalyst
loading was reduced to 15 mol%, the reaction became sluggish with
loss of yield (7.5 d, 50%, entry 10). Therefore, the high catalyst
loading is the limitation of this reaction.
2.5
trace
10e
VII
7.5
50
82:18
a Unless specified, a mixture of 1a (0.1 mmol) and cat. (30 mol%) in toluene (1.0
mL) was stirred for 30 min at rt. Then 3Å MS, 2a (0.13 mmol) was added
sequentially before the reaction was carried out at 60 oC. Isolated yields.
b
c
Determined by chiral HPLC analysis. d The reaction mixture was stirred at 40 oC.
e
VII (15 mol%) was used.
aldehydeazaarenes
with tetrahydroisoquinolines
In searching suitable chiral activators for the newly proposed
process, we feel that chiral Brønsted acids may be of possible
choice.17 An acid promotes the formation of imine
1 as a new coupling partner for reacting
2
.
A
from
1 and
2
to form the corresponding substrate-Brønsted acid complexes,
such as the well-explored catalyst-iminium ions,18,19 and
subsequent redox neutral process to generate chiral dipolar
complex B with a chiral Brønsted acid,12c which undergoes an
intramolecular Mannich reaction to give chiral products 3. The
Moreover, the solvent screening results were listed in Table
2. The reactions in less polar solvents, such as o-xylene, p-xylene
and chlorobenzene, gave the products with lower reaction
yields and enantioselectivities than that in toluene (entries 2-4). The
reaction gave much lower enantioselectivity when dichloroethane
(DCE) was used as solvent (entry 5). The reaction in dioxane afforded
the product with similar result as that in p-xylene (entry 6).
However, the reactions gave almost racemic products when the
polar solvents were used (entries 7 and 8). Interestingly, only
trace amount of racemic product was achieved when the
reaction was carried out in DMF. When the reaction
concentration was enhanced, the lower reaction yield was
achieved (entry 9). The solvent screening revealed that toluene was
the choice for this reaction in both reaction yield and enantiocontrol.
With the optimal reaction conditions in hand, the structural
generality and limitation of 2-methylquinoline-3-carbaldehydes
was then investigated. As shown in Scheme 2, 6-Br substituent
chiral Brønsted acid play a dual role in this process: promoting
the reaction and forming chiral complex with positively charged
“N” to control enantioselectivity.
To demonstrate the feasibility of the designed process, 2-
methylquinoline-3-carbaldehyde (1a) and 1,2,3,4-tetrahydro-6,7-
dimethoxy-isoquinoline (2a) were selected as the model substrates.
Initially, the reaction was performed in the presence of 30 mol% of
DSI I20 and 3 Å molecular sieves (MS) in toluene at 60 oC for 1.5 d. To
our delight, the desired product 3a was obtained in 51% yield with a
promising 77:23 e.r. (Table 1, entry 1). Next, different kinds of chiral
Brønsted acids (II-V) were screened. When the commercially
available chiral phosphoric acid II18 was probed, the reaction failed
to give the desired product even after longer reaction time (2.5 d,
entry 2). N-Triflyl phosphoramide III21 and disulfurylimide (JINGLE)
IV22 could provide the product 3a in moderate yields (42% and 50%)
but low enantiomeric ratios (55:45 and 53:47 e.r., entries 3 and 4).
Enlightened by these results, we turned our attention to chiral DSIs.
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Next, we probed the reaction scope by variation of amines
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DOI: 10.1039/C7OB01527E
components (Scheme 3). 1,2,3,4-Tetrahydroisoquinoline 2b
enabled to afford the product 3i with both moderate yield and
enantioselectivity (75% yield, 73:27 e.r.). Slightly better results
for the formation of product 3j (84%, 76:24 e.r.) were obtained
with 6-methoxy 2c. 6,7-Dioxolo 1,2,3,4-tetrahydroisoquinoline
2d gave similar efficiency but requiring portion addition of 2d
and longer reaction time. Tetrahydroisoquinoline 2e bearing
electron-withdrawing 6-bromo group was tolerated with the
moderate yield and low enantioselectivity (55% yield, 62:38 e.r.).
Finally, more pharmaceutically relevant indole derived
tetrahydroisoquinoline 2m was applicable for this reaction and
gave the desired product 3m in 62% yield and with 63:37 e.r).
a
Scheme 2. Scope of 2-methylquinoline-3-carbaldehydes.a Reaction conditions:
unless otherwise specified, see footnote a of Table 1 and the Experimental Section
b
c
in the Supporting Information. Isolated yields. Determined by chiral HPLC
d
e
analysis. The reaction mixture was stirred for 2 d. The reaction mixture was
stirred for 4 d.
product 3b was obtained in both good yield and
enantioselectivity (88% yield, 90:10 e.r.). Interestingly, 6-Cl
substituent 1c delivered product 3c with similar
enantioselectivity but in much lower yield (87:13 e.r., 41%).
When the electron-donating methoxy group was introduced at
the 6-position of quinoline, the enantioselectivity dropped
dramatically but without loss of yield after much longer reaction
time (86% yield, 66:34 e.r., 2 d). A similar result was obtained
for 6-phenyl quinoline 1e, giving product 3e in high yield but
poor enantiocontrol (81%, 76:24 e.r.). A branched 3,5-
bis(trifluoromethyl)-phenyl group at the 6-position furnished
product 3f with good enantioselectivity but lower yield (88:12
Scheme 4. X-Ray crystalstructure of compound 3b
.
The absolute configuration of the products was determined
to be S on the basis of single-crystal X-ray diffraction analysis of
compound 3b (Scheme 4).23
Conclusions
We have developed the first chiral Brønsted acid promoted
enantioselective
reaction
of
2-methylquinoline-3-
carbaldehydes with 1,2,3,4-tetrahydroisoquinolines. A range of
substituted 2-methylquinoline-3-carbaldehydes and 1,2,3,4-
tetrahydroisoquinoline derivatives are tolerated for the process
with good to high yields (up to 91%) and up to 92:8 e.r.. The
structures of the produced products are highly close to those of
biologically interesting tetrahydroprotoberberines. Therefore,
exploration of their biological activities and the catalysis
strategy for further improving enantioselectivity of the process
and new organic transformations are under investigation in our
laboratories.
e.r.,
43%).
When
more
rigid
substrate
2-
methylbenzo[g]quinoline-3-carbaldehyde 1g was examined,
both high yield and enantioselectivity were obtained (84% yield,
92:8 e.r.). Moreover, we evaluated a less reactive substrate 2-
methylnicotinaldehyde (1h). Not surprisingly, the cyclization
reaction went sluggishly and only gave a trace amount of
product after 4 d.
This work was supported by the National Science
Foundation of China (21372073, 21572054 and 21572055), the
Fundamental Research Funds for the Central Universities and
the China 111 Project (Grant B07023).
Notes and references
1
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a
Scheme 3. Scope of secondary amines.a Reaction conditions: unless otherwise
specified, see footnote a of Table 1. b Isolated yields. c Determined by chiral HPLC
d
analysis. 2d (0.05 mmol) was added every 2 d, and the reaction mixture was
2
Y. Han, and J. H. Lee, Biol. Pharm. Bull., 2005, 28, 541.
stirred for 14 d. e The reaction mixture was stirred for 5 d.
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