Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines

Article abstract of DOI:10.1021/acscatal.0c00211

The development of a general method utilizing a hydroxymethyl directing group for asymmetric hydrogenation of 1,3-disubstituted isoquinolines to provide chiral 1,2,3,4-tetrahydroisoquinolines is reported. The reaction, which utilizes [Ir(cod)Cl]₂ and a commercially available chiral xyliphos ligand, proceeds in good yield with high levels of enantioselectivity and diastereoselectivity (up to 95% ee and >20:1 dr) on a range of differentially substituted isoquinolines. Directing-group studies demonstrate that the hydroxymethyl functional group at the C1 position is more efficient at enabling hydrogenation in comparison to other substituents, although high levels of enantioselectivity were conserved across a variety of polar and nonpolar functional groups. By utilization of the generated chiral β-amino alcohol as a functional handle, the synthetic utility is further highlighted via the synthesis of 1,2-fused oxazolidine, oxazolidinone, and morpholinone tetrahydroisoquinolines in one step. Additionally, a non-natural analogue of the tetrahydroprotoberberine alkaloids was successfully synthesized.

Full text of DOI:10.1021/acscatal.0c00211

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Article
Iridium-Catalyzed Enantioselective and Diastereoselective
Hydrogenation of 1,3-Disubstituted Isoquinolines
Alexia Kim, Aurapat Ngamnithiporn, Eric R Welin, Martin Daiger, Christian
Grünanger, Michael D. Bartberger, Scott C Virgil, and Brian M. Stoltz
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c00211 • Publication Date (Web): 10 Feb 2020
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Iridium-Catalyzed Enantioselective and Diastereoselective
Hydrogenation of 1,3-Disubstituted Isoquinolines
Alexia N. Kim,‡,a Aurapat Ngamnithiporn,‡,a Eric R. Welin,a Martin T. Daiger,a Christian U.
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Grünanger,a Michael D. Bartberger,b Scott C. Virgil,a Brian M. Stoltz*,a
aWarren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena, California 91125, United States
b1200 Pharma LLC, 844 East Green Street, Suite 204, Pasadena, California, 91101, United States
KEYWORDS: hydrogenation, asymmetric catalysis, heterocycles, isoquinolines, tetrahydroisoquinolines
ABSTRACT: The development of a general method utilizing a hydroxymethyl directing group for asymmetric hydrogenation of
1,3-disubstituted isoquinolines to provide chiral 1,2,3,4-tetrahydroisoquinolines is reported. The reaction, which utilizes
[Ir(cod)Cl]2 and a commercially available chiral xyliphos ligand, proceeds in good yield with high levels of enantioselectivity and
diastereo-selectivity (up to 95% ee and >20:1 dr) on a range of differentially substituted isoquinolines. Directing group studies
demonstrate that the hydroxymethyl functional group at the C1-position is more efficient at enabling hydrogenation than other
substituents, although high levels of enantioselectivity were conserved across a variety of polar and non-polar functional groups. By
utilizing the generated chiral -amino alcohol as a functional handle, the synthetic utility is further highlighted via the synthesis of
1,2-fused oxazolidine, oxazolidinone, and morpholinone tetrahydroisoquinolines in one step. Additionally, a non-natural analog of
the tetrahydroprotoberberine alkaloids was successfully synthesized.
INTRODUCTION
The stereocontrolled synthesis of nitrogen-containing
heterocycles remains a challenge of great importance, as it
provides direct access to chiral compounds that are prevalent
structural motifs in many biologically active molecules.1 As a
result, the asymmetric hydrogenation of various hetero-
aromatic compounds has been extensively explored as a direct,
efficient synthesis of enantiopure cyclic amines.2 Despite
recent progress made toward the asymmetric hydrogenation of
N-heterocycles such as quinolines, quinoxalines, and
pyridines, the synthesis of 1,2,3,4-tetrahydroisoquinolines
(THIQs) from isoquinolines remains significantly under-
developed (Figure 1A).2 This is due in part to the stronger
basicity and coordinating ability of the THIQ products
compared to those of other heterocycles (e.g., quinolines),
leading to catalyst deactivation, as well as the overall lower
reactivity of isoquinoline substrates.3 Although a few effective
strategies toward the asymmetric hydrogenation of substituted
isoquinolines have been reported, these typically require
preparation of the isoquinolinium salt, substrate activation
with halogenides, and harsher hydrogenation reaction
conditions (Figure 1B).4 Furthermore, previous to our
research, there were only 2 catalytic systems describing
efficient methods to access chiral 1,3-disubstituted tetrahydro-
c,e,g
isoquinolines,4
a more complex and sterically challenging
Figure 1. (a) Limitations in enantioselective hydrogenation of
N-heterocycles. (b) Previous examples of iridium-catalyzed
enantioselective and diastereoselective hydrogenation of
mono-, and di-substituted isoquinolines.
system that generates two stereogenic centers. In addition, the
limited substrate scope from these reports demonstrates the
low tolerance of additional Lewis basic functionalities, such as
alcohols or heteroaryl-substituted isoquinolines, which limit
the applicability of these methodologies in synthesis. Since
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1,3-disubstituted tetrahydroisoquinolines with Lewis basic
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moieties are ubiquitous motifs present in a wide range of
natural products, such as the saframycin, naphthyridinomycin,
and quinocarcin families,5 a general method for highly
enantioselective and diastereoselective hydrogenation of
neutral disubstituted isoquinolines under mild reaction
conditions would be a significant advancement toward the
preparation of chiral amine-containing cyclic molecules.
RESULTS AND DISCUSSION
Substrate Syntheses. Due to a limited number of
methods for the syntheses of 1,3-disubstituted isoquinolines,7
we first established a simple and divergent sequence to access
a
wide variety of 1-(hydroxymethyl)-3-arylisoquinoline
substrates (i.e., 7, Scheme 1). Utilizing Pd-catalyzed arylation
of ester enolates reported by Donohoe and coworkers,8
monoarylated tert-butyl acetate 4 was isolated in an excellent
92% yield. Cyclization to isoquinoline triflate 5 was then
achieved via hydrolysis of the ketal, followed by isoquinoline
annulation with aqueous ammonium hydroxide, and alcohol
triflation.9 At this stage, different aryl or heteroaryl groups
could be coupled with intermediate 5 using Suzuki coupling
conditions to deliver a wide range of 1,3-disubstituted
isoquinolines (i.e., 6), highlighting the divergent synthesis of
our synthetic route. Finally, SeO2 oxidation to the aldehyde
and subsequent NaBH4 reduction provided our desired
isoquinoline starting materials 7a–r. It is worth noting that this
sequence allows for an introduction of various aryl and
heteroaryl groups at the C3-position of isoquinolines, as well
as different substituents with varied electronics on the
isoquinoline carbocycle (e.g., 9a–f, vide infra, Scheme 4).
Currently in the literature, the 1,3-disubstituted isoquinoline
motif is typically accessed via transition-metal-catalyzed
tandem C–H activation/annulation of arenes with alkynes.10
These methods have shown limited success in producing C3-
heteroaryl isoquinolines.11
Recently, our group has successfully completed the total
synthesis of jorumycin and jorunnamycin A, two bis-
tetrahydroisoquinoline natural products that exhibit potent
antiproliferative activity, as well as strong Gram-positive and
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Gram-negative
antibiotic
character.6
Through
an
unprecedented, nonbiomimetic synthetic route, we were
successful in harnessing catalysis to allow expedient access to
these natural products, as well as a diverse range of non-
natural analogs that are otherwise inaccessible using prior
biomimetic synthetic approaches. One of the key steps of this
synthesis involves a catalytic enantioselective hydrogenation
of bis-isoquinoline 1 to afford the THIQ motif, a crucial
intermediate that forms the pentacyclic carbon skeleton 2 in
one step by further hydrogenation of the second isoquinoline
and eventual amide ring closure (Figure 2). Considering the
ubiquity of the hydroxymethyl group at the C1 position, and
the amino alcohol functionality in a large number of natural
products, we envision that this synthetic method could access
a wide variety of THIQs as well as chiral amino alcohols, both
highly valuable pharmacophores. Following the successful
development of our asymmetric hydrogenation technology for
bis-isoquinolines, herein we disclose a mild, general method
for the enantioselective and diastereoselective hydrogenation
of 1,3-disubstituted isoquinolines.
Scheme 1. Syntheses of 1-(hydroxymethyl)-3-aryl
Isoquinoline Substratesa
Jorumycin Synthesis: A Key Enantioselective Hydrogenation Step
Me
Me
MeO
OMe
MeO
OMe
[Ir(cod)Cl]2 (5 mol %)
BTFM-xyliphos
(12 mol %)
Me
Me
H2 (60 bar), TBAI
60 °C, 18 h
then 80 °C, 24 h
N
CO2Me
N
CO2Me
N
NH
MeO
MeO
OMe
OMe
OH
OH
1
OMe
Me
Me
MeO
OMe
H
N
aConditions: (a) t-butyl acetate (2 equiv), LiHMDS (2.5 equiv),
Pd2(dba)3 (5 mol %), P(t-Bu3)•HBF4 (10 mol %), toluene, 23 °C,
18 h, 92% yield. (b) 33% TFA in CH2Cl2, 23 °C, 2 h; then aq.
NH4OH, MeCN, 70 °C, 12 h; then Tf2O (2 equiv), pyridine,
CH2Cl2, 0 °C, 1 h, 38% yield over 3 steps. (c) aryl/heteroaryl
boronic acid (1.5 equiv), XPhos Pd G3 (2 mol %), 2:1
K3PO4:THF, 40 °C, 2 h, 77–95% yield. (d) SeO2 (2 equiv), 1,4-
dioxane, 110 °C, 2 h; then NaBH4 (1 equiv), 4:1 CH2Cl2:MeOH,
10 min, 25–97% yield.
Me
OMe
H
NH
Me
N
CO2Me
H
H
MeO
NH
OH
MeO
OMe
O
OH
OMe
2
This Research:
• 30 examples of 1,3-disubstituted isoquinolines
• General method for a variety of substitution patterns
Ar/Het
Ir/L*
Ar/Het
*
R
R
H2
• No need for prior activation
• Mild reaction conditions
• Additional Lewis basic
functionalities tolerated
N
X
NH
X = H, OH, OR1, NR2
*
Reaction Optimization. With a divergent sequence to
X
access 1,3-disubstituted isoquinolines, we began our
hydrogenation
studies
with
1-(hydroxymethyl)-3-
Figure 2. Our research on iridium-catalyzed enantioselective and
phenylisoquinoline (7a) as our model substrate, using slightly
diastereoselective
isoquinolines.
hydrogenation
of
1,3-disubstituted
modified conditions from our previously reported
hydrogenation
on
the
bis-isoquinoline system (Table 1). An initial experiment,
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employing 1.25 mol % [Ir(cod)Cl]2 and 3 mol % of the diastereoselectivity and enantioselectivity (entries 9 and 11).
The absence of AcOH resulted in low conversion,12 while
further exploration of different additives (e.g., LiI, NaI, KI,
etc.) demonstrated that TBAI is the optimal additive (see
Supporting Information). Finally, we were excited to observe
that lowering the temperature to 23 °C and H2 pressure to 20
bar maintained excellent levels of conversion, diastereo-
selectivity, and enantioselectivity (entry 12). To the best of our
knowledge, these are the mildest reaction conditions reported
for isoquinoline hydrogenation to afford chiral THIQs to date.4
1
2
3
4
5
6
7
8
BTFM-xyliphos ligand (L1), gave high conversion of the
substrate but surprisingly modest enantioselectivity (49% ee,
entry 1). Seeking to improve the ee, we surveyed a wide
variety of chiral ligand scaffolds (see Supporting Information)
and found the xyliphos ligand framework to be optimal. By
exploring different electronics of this ligand scaffold, we
observed that replacing the 3,5-bistrifluoromethylphenyl
(BTFM) with more electron-rich aryl groups provided the
product with both excellent conversion and higher enantio-
selectivity (entries 1–5). Ligand L5, which features
4-methoxy-3,5-dimethylphenyl (DMM) substituted phosphine
delivers the product with the highest ee of 89%, albeit with a
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Scheme 2. Substrate Scope of Different Aryl Substituentsa
low 2:1 diastereoselectivity (entry 5). Interestingly,
a
background reaction was observed in the absence of the chiral
ligand, providing the product in excellent conversion and
diastereoselectivity (entry 6). From this finding, we obtained
all racemic hydrogenated products by simply performing the
hydrogenation in the absence of ligand, affording the cis-
product as a single diastereomer.
Table 1. Optimization of the Enantioselective
Hydrogenation of Isoquinolines to afford THIQsa
Ph
Ph
[Ir(cod)Cl]2 (1.25 mol %)
ligand (3 mol %)
NH
OH
N
H2 (60 bar), TBAI (7.5 mol %)
solvent (0.02 M)
60 °C, 18 h
OH
7a
8a
% conversionb
cis:transb
entry
% ee of cisc
ligand
Solvent
1
2
L1
L2
L3
L4
L5
–
PhMe:AcOH
PhMe:AcOH
PhMe:AcOH
PhMe:AcOH
PhMe:AcOH
PhMe:AcOH
CH2Cl2:AcOH
dioxane:AcOH
THF:AcOH
>95
>95
66
>20:1
3.2:1
4.5:1
4.9:1
2.0:1
>20:1
1.5:1
5.5:1
9.7:1
>20:1
9.5:1
– 49d
84
63
3
3
4
92
5
>95
>95
>95
66
89
0
6
7
L5
L5
L5
L5
L5
84
87
90
88
90
8
9
>95
38
10
11
CPME:AcOH
2-MeTHF:AcOH
>95
12e
L5
THF:AcOH
>95
15.7:1
92
L1: Ar = BTFMd
L2: Ar = Ph
P(Xyl)2
P(Ar)2
L4: Ar = furyl
L5: Ar = DMM
aReactions performed on a 0.2 mmol scale. bReaction
performed at 60 °C and 60 bar H2. CH2Cl2 cosolvent used to
improve substrate solubility.
Fe
Me
L3: Ar = 2-napthyl
c
aConditions: 0.04 mmol 7a, 1.25 mol % [Ir(cod)Cl]2,
3 mol % ligand, 7.5 mol % TBAI, 60 bar H2 in 2.0 mL 9:1
Substrate Scope. With optimized reaction conditions
identified, we explored the general substrate scope for this
transformation (Scheme 2). Gratifyingly, a wide variety of aryl
substituents at the 3-position of the isoquinoline are well
tolerated under the mild reaction conditions of 20 bar H2 at
ambient temperature. Substitution at the para-position of the
3-aryl ring delivered the hydrogenated products 8a–g in
consistently high yields and enantioselectivity. Electron-rich
substrates such as the 3-(p-tert-butylphenyl)isoquinoline (7b)
and the p-methoxyphenyl (7d) afforded chiral THIQs with
excellent yields, diastereoselectivity, and enantioselectivity,
similar to 7a. Interestingly, however, a general trend of lower
diastereoselectivity was observed with electron-withdrawing
substituents both at the para- and meta- positions (8f–i). We
envision that the observed lower diastereoselectivity arises
from the weaker coordinating ability of the nitrogen to the
b
1
solvent:AcOH. Determined from crude H NMR using 1,3,5-
c
trimethoxybenzene as standard. Determined by chiral SFC
analysis of Cbz-protected product. Opposite enantiomer of
ligand used. Reaction performed on a 0.2 mmol scale at
d
e
23 °C, 20 bar H2, and 0.1 M concentration of 7a.
Investigation of different solvents with L5 as the optimal
ligand reveals that while the use of CH2Cl2 provided similar
results to toluene (entry 7), the diastereoselectivity could be
improved with the use of ethereal solvents (entries 8–11).
Although bulkier ethereal solvents proved to worsen
conversion (entries 8 and 10), we were delighted to find that
THF and the more sustainable solvent 2-MeTHF delivered the
product in excellent conversion with high levels of
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iridium catalyst in electron-poor substrates, discouraging
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Het
Het
[Ir(cod)Cl]2 (1.25 mol %)
L5 (3 mol %)
coordination to the catalyst in a bidentate fashion,13 and thus
resulting in poorer facial selectivity in the second hydride
addition step. However, at this time, we still cannot rule out
the possibility that epimerization in situ also influences the
trend seen in diastereoselectivity.14 Investigation of steric
effects revealed that more sterically encumbered isoquinolines
such as the 3-napthyl and 3-xylyl substrates furnished the
products (8j–k) in excellent isolated yields with similarly high
enantioselectivity (95% and 92% ee, respectively) as a single
diastereomer. The most sterically demanding substrate 7m,
bearing an ortho-tolyl substituent, provided product 8m in a
modest 64% yield with lower enantioselectivity (49% ee),
1
2
3
4
5
6
7
8
N
NH
OH
H2 (60 bar), TBAI (7.5 mol %)
9:1 THF:AcOH (0.1 M)
60 °C, 18 h
OH
7n– r
8n– r
O
S
S
NH
NH
NH
OH
OH
OH
9
8o
94% yield
3.5:1 dr, 90% ee
8p
49% yield
7.3:1 dr, 89% ee
8n
74% yield
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3.0:1 dr, 92% ee
albeit still with
a
high 10.1:1 diastereoselectivity.
Me
N
Additionally, we were pleased to find that the nitrile and nitro
functional groups as well as the napthyl substituent were not
reduced (8g, 8h, and 8j), highlighting the chemoselectivity of
this catalytic process.
N
N
NH
OH
NH
OH
Pleased to find the reaction tolerable to a range of 3-aryl
substituted isoquinolines, we sought to further extend the
scope of the transformation by exploring heteroaryl-
substituted isoquinolines (Scheme 3). Although performing
the hydrogenation at 23 °C and 20 bar H2 resulted in lower
conversion, partially due to solubility issues, we found that
heterocyclic substituents including furan, thiophene, pyrazole,
and pyridine were well tolerated at 60 °C and under higher
pressure of 60 bar H2, producing THIQs 8n–r. We also
observed that the substitution pattern on the heteroaryl groups
strongly affects the reaction conversion. For instance, an
isoquinoline with a 3-substituted thiophene proceeded with a
significantly lower conversion than the 2-thiophene substrate
(8o and 8p). Similarly, no conversion was observed with
3- and 4-pyridyl substrates, whereas 2-pyridyl THIQ 8r was
isolated in 48% yield under the same reaction conditions. We
speculate that this may be due to the competitive binding of
the catalyst by the more distal heteroatom of 3- and
4-substituted heterocycles that inhibits directed hydrogenation
of the isoquinoline ring. From product 8p we were successful
in obtaining an X-ray crystal structure to confirm the relative
and absolute stereochemistry of our hydrogenation product.
8q
98% yield
2.9:1 dr, 87% ee
8r
48% yield
2.5:1 dr, 85% ee
X-ray of 8p
aReactions performed on a 0.2 mmol scale.
Furthermore, we were interested in exploring the
substrate scope of isoquinolines with different electronics and
substitution patterns on the isoquinoline carbocycle (Scheme
4). Electron-poor fluorinated isoquinolines with varied
electronics at the 3-position provided THIQs in high yields
(77–94%) with high diastereoselectivity and enantioselectivity
under our standard conditions (10a–c). It should be noted that
these electron-poor THIQs would be difficult to access
utilizing electrophilic aromatic substitution strategies,
a
classical method for the syntheses of THIQs. On the other
hand, the electron-rich dioxolane-appended isoquinolines
(9d–e) afforded lowered conversion under the same reaction
conditions, due in part to the poor solubility of the substrates
in THF. Nevertheless, executing the reaction at 60 °C and 60
bar H2 with CH2Cl2 as cosolvent improved the solubility and
conversion to yield products 10d–e with high diastereo-
selectivity.15 Interestingly, we observed significantly lower
enantioselectivity for the dioxolane THIQs, which is observed
in other reports as well.4a,g Finally, the napthyl-fused THIQ 10f
was obtained with high diastereoselectivity and enantio-
selectivity, despite its extended aromatic system and larger
steric hindrance. Although we observed modest conversion for
these highly decorated isoquinolines, we were pleased to see
that we were able to isolate unreacted starting material after
column chromatography to obtain 80%, 99%, and 79% yield,
respectively, of 10d–f based on recovered starting material.
Consistent with our results for THIQs 8j and 8r, we observed
that only the ring with the least degree of aromatic
stabilization was reduced for 10f.
Scheme 3. Substrate Scope of Heterocyclic Substituentsa
Scheme 4. Substrate Scope of IQ Backbone Substituentsa
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aReactions performed on
performed at 60 °C and 60 bar H2. CH2Cl2 cosolvent used to
improve substrate solubility.
a
0.2 mmol scale. bReaction
c
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Directing Group Studies. Having demonstrated that this
aReactions performed on
a
0.2 mmol scale. bReaction
transformation is general for
a wide variety of 1,3-
performed at 60 °C and 60 bar H2. cRelative and absolute
stereochemistry determined by experimental and computed VCD
and optical rotation, see Supporting Information.16
disubstituted isoquinolines, we then turned our attention to
investigate the effects of different “directing” groups at the
C1-position (Scheme 5). Isoquinolines bearing other polar
groups such as an ester (12a), ethers (12b–c), and a
Boc-protected amine (12d) delivered the products in lower
yields than the hydroxy-directed substrate at 23 °C and 20 bar
H2. However, to our delight, by increasing the temperature and
H2 pressure, these yields could be improved with no erosion of
enantioselectivity and diastereoselectivity.
Synthetic Utility of the Hydrogenated Products.
Overall, the broad application of our hydrogenation
technology to afford chiral THIQs provides access to a range
of decorated analogs that are difficult to synthesize via
biomimetic
approaches (e.g., Pictet-Spengler, Bischler-Napieralski). These
often require electron-rich substrates to undergo
cyclization (eq 1).17
Additionally, we found that aldehyde 11f was reduced to
the alcohol in situ, affording the hydroxymethyl THIQ 8a in
comparable yield, enantioselectivity, and diastereoselectivity
to that of the hydroxy-directing substrate 7a (vide supra).
Interestingly, an isoquinoline lacking a potential directing
group (12e) also afforded chiral THIQs with no erosion of
enantioselectivity (90% ee),16 although elevated temperature
and pressure are needed to obtain a synthetically useful yield
(64%). While the hydroxy-directing aspect is the enabling
feature in the context of our total synthesis of jorumycin, we
are pleased to find that we can obviate this requirement in our
developed hydrogenation technology. Nevertheless, surveying
a variety of different directing groups demonstrates the
importance of a functional group for directed hydrogenation,
with the hydroxy functionality acting as the best directing
group for mild and efficient asymmetric hydrogenation.
Notably, this is the first asymmetric hydrogenation method of
isoquinolines in which additional Lewis basic functionalities
are tolerated. It is also the first report investigating the effects
of different directing groups in enantioselective hydrogenation
of isoquinolines.
With the scope of the transformation established, we
sought to demonstrate the synthetic utility of the produced
chiral THIQs toward more complex scaffolds that could be
applicable to natural products. Additionally, we envisioned
taking advantage of the chiral β-amino alcohol that is
generated in our product as a building block to forge more
complex enantioenriched heterocyclic scaffolds (Scheme 6).18
Scheme 6. Derivatization of a Hydrogenated Producta
Scheme 5. Substrate Scope of Different Directing Groupsa
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high levels of diastereoselectivity and enantioselectivity. The
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reaction conditions tolerate a wide range of substitution on the
1-, 3-, 6-, 7-, and 8-position of the isoquinoline core. To date,
this report represents the broadest scope and highest tolerance
of Lewis-basic functionality of any asymmetric isoquinoline
reduction technology currently known. Furthermore, this
method is amenable to the production of electron-deficient
THIQs that are difficult to obtain through the classical
Pictet-Spengler approach. In order to demonstrate the
synthetic utility of the hydrogenated products, we utilize the
hydroxyl directing group as a functional handle for further
synthetic manipulations. As a result, we have completed the
syntheses of various tricyclic and pentacyclic skeletons that
are of potential medicinal interest. Further exploration of the
mechanism, and other applications of this technology are
currently underway.
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aConditions: (a) 37% aq. CH2O (1.85 equiv), DCE, 23 °C, 15
min, 93% yield. (b) CDI (4 equiv), THF, 50 °C, 15 h, 84% yield.
(c) 40% aq. glyoxal (20 equiv), DCE, 23 °C, 18 h, 41% yield. (d)
60% aq. 2,2-dimethoxyacetaldehyde (1.85 equiv), DCE, 23 °C, 18
h; then Eaton’s Reagent (4 equiv), CH2Cl2, 23 °C, 3 h, 38% yield.
AUTHOR INFORMATION
Prior to our investigation into the synthetic utilitiy of
THIQ products, we performed the hydrogenation of
isoquinoline 7l on a larger scale (1 mmol). We were pleased to
find that the hydrogenated product 8l was still obtained in
good yield (91% isolated yield) with excellent selectivity
(>20:1 dr, 88% ee). With an ample amount of 8l in hand, we
subjected THIQ 8l to aqueous fomaldehyde solution and found
that the tricyclic 1,2-fused oxazolidine THIQ 13 was formed
rapidly via the cyclization of the alcohol onto the
iminium generated in situ. Furthermore, the reaction of amino
alcohol 8l with carbonyldiimidazole (CDI) afforded
oxazolidinone-fused THIQ 14 in 84% yield.19 To our delight,
we found that these 6,6,5-tricyclic systems are conserved
structural motifs in a number of natural products such as
Corresponding Author
*stoltz@caltech.edu
Author Contributions
‡These authors contributed equally to this work and are listed
alphabetically.
ASSOCIATED CONTENT
Supporting Information Available. Detailed experimental
procedures, compound characterization data, and computational
analysis. This material is available free of charge via the Internet
at http://pubs.acs.org.
ACKNOWLEDGMENT
quinocarcin, tetrazomine, and bioxalomycin.5 Lastly,
a
We thank NIH-NIGMS (R01GM127972A) and Caltech for the
support of our research program. A. N. thanks the Royal Thai
Government Scholarship Program. E. R. W. was supported by a
Postdoctoral Fellowship (PF-16-011-01-CDD) from the American
Cancer Society. C.U.G. was supported by a Feodor Lynen
Research Fellowship from the Alexander von Humboldt
Foundation. We thank Dr. David VanderVelde (Caltech) and
Maximilian B. Kaiser for NMR expertise, and Dr. Michael
Takase (Caltech) for assistance with X-ray analysis.
different tricyclic scaffold containing fused morpholinone (15)
can be isolated in 41% yield by the addition of excess glyoxal
to 8l at room temperature.20 Being able to access a variety of
complex heterocyclic scaffolds in one step from our
hydrogenated THIQs further highlights the advantages of the
hydroxymethyl functionality at the C1 position, beyond
directing hydrogenation.
In addition to the tricyclic scaffold, we were pleased to
find that an analog of tetrahydroprotoberberine alkaloids, a
family of natural products with a tetracyclic bis-THIQ core,21
can be synthesized via a 2-step sequence. First, reaction of 8l
with glyoxal dimethyl acetal delivered the oxazolidine-fused
intermediate with a dimethoxy acetal substituent at the
carbinol-amine carbon. Subsequently, exploration of both
Brønsted and Lewis acid-mediated Pomeranz-Fritsch reaction
revealed that the use of Eaton’s reagent22 delivered pentacyclic
THIQ 16 in 38% yield as a single diastereomer. This complex
scaffold could be of medicinal interest, as previous studies
have shown that tetrahydroprotobeberine derivatives possess a
ABBREVIATIONS
ee, enantiomeric excess; dr, diastereomeric ratio; THIQ, 1,2,3,4-
tetrahydroisoquinoline; BTFM, 3,5-bistrifluoromethylphenyl;
DMM, 4-methoxy-3,5-dimethylphenyl; TBAI, tetrabutyl-
ammonium iodide; CPME, cyclopentyl methyl ether; Boc, tert-
butoxycarbonyl; DCE, 1,2-dichloroethane; CDI, carbonyldi-
imidazole; VCD, vibrational circular dichroism.
REFERENCES
(1) (a) Tayor, R. D.; MacCoss, M.; Lawson, A. D. G. Rings in
Drugs. J. Med. Chem. 2014, 57, 5845. (b) Vitaku, E.; Smith, D. T.;
Njardarson, J. T. Analysis of the Structural Diversity, Substitution
Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA
Approved Pharmaceuticals. J. Med. Chem. 2014, 57, 10257–10274.
(c) Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland:
Increasing Saturation as an Approach to Improving Clinical Success.
J. Med. Chem. 2009, 52, 6752–6756. (d) Lovering, F. Escape from
Flatland 2: Complexity and Promiscuity. Med. Chem. Commun. 2013,
4, 515–519. e) Roughley, S. D.; Jordan, A. M. The Medicinal
Chemist’s Toolbox: An Analysis of Reactions Used in the Pursuit of
Drug Candidates. J. Med. Chem. 2011, 54, 3451–3479.
,23
wide array of interesting biological activities.17
CONCLUSIONS
We have developed a general, efficient enantioselective
hydrogenation reaction of 1,3-disubstituted isoquinolines
toward the syntheses of chiral THIQs. Key to the success of
this reaction is the installation of a directing group at the C1-
position that facilitates hydrogenation to reduce a variety of
isoquinolines under mild reaction conditions. The
developed method affords chiral THIQs in good yields, with
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(2) (a) Zhou, Y.-G. Asymmetric Hydrogenation of Heteroaromatic
Reaction for the Synthesis of Isoquinolines. Org. Biomol. Chem.
2016, 14, 1065–1090.
Compounds. Acc. Chem. Res. 2007, 40, 1357–1366. (b) Wang, D.-S.;
Chen, Q.-A.; Lu, S.-M.; Zhou, Y.-G. Asymmetric Hydrogenation of
Heteroarenes and Arenes. Chem. Rev. 2012, 112, 2557–2590.
(3) (a) Zhao, D.; Glorius, F. Enantioselective Hydrogenation of
Isoquinolines. Angew. Chem. Int. Ed. 2013, 52, 9616–9618. (b)
Wiedner, E. S.; Chambers, M. B.; Pitman, C. L.; Bullock, R. M.;
Miller, A. J. M.; Appel, A. M. Thermodynamic Hydricity of
Transition Metal Hydrides. Chem. Rev. 2016, 116, 8655–8692.
(4) For Ir-catalyzed asymmetric hydrogenation of isoquinolines,
see (a) Lu, S. M.; Wang, Y. Q.; Han, X. W.; Zhou, Y.-G. Asymmetric
Hydrogenation of Quinolines and Isoquinolines Activated by
Chloroformates. Angew. Chem. Int. Ed. 2006, 45, 2260–2263. (b) Shi,
L. Ye, Z.-S.; Cao, L. L.; Guo, R. N.; Hu, Y.; Zhou, Y.-G. Enantio-
selective Iridium-Catalyzed Hydrogenation of 3,4-Disubstituted
Isoquinolines. Angew. Chem. Int. Ed. 2012, 51, 8286–8289. (c)
Iimuro, A.; Yamaji, K.; Kandula, S.; Nagano, T.; Kita, Y.; Mashima,
K.Asymmetric Hydrogenation of Isoquinolinium Salts Catalyzed by
Chiral Iridium Complexs: Direct Synthesis for Optically Active
1,2,3,4-Tetrahydroisoquinolines. Angew. Chem. Int. Ed. 2013, 52,
2046–2050. (d) Ye, Z.-S.; Guo, R.-N.; Cai, X.-F.; Chen, M.-W.; Shi,
L.; Zhou, Y.-G. Enantioselective Iridium-Catalyzed Hydrogenation of
1- and 3-Substituted Isoquinolinium Salts. Angew. Chem. Int. Ed.
2013, 52, 3685–3689. (e) Kita, Y.; Yamaji, K.; Higashida, K.;
Sathaiah, K.; Iimuro, A.; Mashima, K. Enhancing Effects of Salt
Formation on Catalytic Activity and Enantioselectivity for
Asymmetric Hydrogenation of Isoquinolinium Salts by Dinuclear
Halide-Bridged Iridium Complexes Bearing Chiral Diphosphine
Ligands. Chem. Eur. J. 2015, 21, 1915–1927. (f) Guo, R.-N.; Cai,
X.-F.; Shi, L.; Ye, Z.-S.; Chen, M.-W.; Zhou, Y.-G. An Efficient
Route to Chiral N-Heterocycles Bearing a C–F Stereogenic Center via
Asymmetric Hydrogenation of Fluorinated Isoquinolines. Chem.
Commun. 2013, 49, 8537–8539. (g) Chen, M.-W.; Ji, Y.; Wang, J.;
Chen, Q.-A.; Shi, L.; Zhou, Y.-G. Asymmetric Hydrogenation of
Isoquinolines and Pyridines Using Hydrogen Halide Generated in Situ
as Activator. Org. Lett. 2017, 19, 4988–4991. For Ru-Catalyzed
Enatioselective Hydrogenation of Isoquinolines, see (h) Wen, J.; Tan,
R.; Liu, S.; Zhao, Q.; Zhang, X. Strong Brønsted Acid Promoted
Asymmetric Hydrogenation of Isoquinolines and Quinolines
Catalyzed by a Rh-Thiourea Chiral Phosphine Complex via Anion
Binding. Chem. Sci. 2016, 7, 3047–3051.
(5) (a) Scott, J. D.; Williams, R. M. Chemistry and Biology of
Tetrahydroisoquinoline Antitumor Antibiotics. Chem. Rev. 2002, 102,
1669–1730. (b) Siengalewicz, P.; Rinner, U.; Mulzer, Recent Progress
in the Total Synthesis of Napthyridinomycin and Lemonomycin
Tetrahydroisoquinoline Antitumor Antibiotics (TAAs). J. Chem. Soc.
Rev. 2008, 37, 2676–2690.
(6) Welin, E. R.; Ngamnithiporn, A.; Klatte, M.; Lapointe, G.;
Pototschnig, G. M.; McDermott, M. S. J.; Conklin, D.; Gilmore, C.
D.; Tadross, P. M.; Haley, C. K.; Negoro, K.; Glibstrup, E.;
Grünanger, C. U.; Allan, K. M.; Virgil, S. C.; Slamon, D. J.;
Stoltz, B. M. Concise Total Syntheses of (–)-Jorunnamycin A and
(–)-Jorumycin Enabled by Asymmetric Catalysis. Science. 2019, 363,
270–275.
(7) For C–H activation/annulation strategy, see (a) Zhang, Z.-W.;
Lin, A.; Yang, J. Methyl Ketone Oxime Esters as Nucleophilic
Coupling Partners in Pd-Catalyzed C–H Alkylation and Application
in the Synthesis of Isoquinolines. J. Org. Chem. 2014, 79, 7041–7050.
For ketone enolate-arylation/annulation, see (b) Donohoe, T. J.;
Pilgrim, B. S.; Jones, G. R.; Bassuto, J. A. Synthesis of Substituted
Isoquinolines Utilizaing Palladium-Catalyzed -Arylation of
Ketones. Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 11605–11608. For
benz-annulation of isocoumarins, see (c) Manivel, P. Probakaran, K.;
Khan, F. N.; Jin, J. S. Facile Benzannulation of Isocoumarins in the
Efficient Synthesis of Diversified 1,3-Disubstituted Isoquinolines.
Res. Chem. Intermed. 2012, 38, 347–357.
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2
3
4
5
6
7
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(9) Allan, K. M.; Hong, B. D.; Stoltz, B. M.; Expedient Synthesis
of 3-Hydroxyisoquinolines and 2-Hydroxy-1,4-Napthoquinones via
One-Pot Aryne Acyl-Alkylation/Condensation. Org. Biomol. Chem.
2009, 7, 4960–4964.
( 0) For example of transition-metal-catalyzed tandem C–H
activation/annulation of arenes and alkynes, see (a) Zhu, Z.; Tang, X.;
Li, X.; Wu, W.; Deng, G.; Jiang, H. Palladium-Catalyzed C–H
Functionalization of Aromatic Oximes: A Strategy for the Synthesis
of Isoquinolines. J. Org. Chem. 2016, 81, 1401–1409. (b) Zhou, S.;
Wang, M.; Wang, L.; Chen, K.; Wang, J.; Song, C.; Zhu, J. Bidentate
Directing-Enabled, Traceless Heterocycle Synthesis: Cobalt-
Catalyzed Access to Isoquinolines. Org. Lett. 2016, 18, 5632–5635.
(c) Chinnagolla, R. K.; Pimparkar, S.; Jeganmohan, M. Ruthenium-
Catalyzed Highly Regioselective Cyclization of Ketoximes with
Alkynes by C–H Bond Activation: A Practical Route to Synthesize
Substituted Isoquinolines. Org. Lett. 2012, 14, 3032–3035. (d) Zhao,
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D.;
Lied,
F.;
Glorius,
F.
Rh(III)-Catalyzed
C–H
Functionalization/Aromatization Cascade with 1,3-Dienes: A Redox
Neutral and Regioselective Access to Isoquinolines. Chem. Sci. 2014,
5, 2869–2873.
(1 ) (a) Chu, H.; Sun, S.; Yu, J.-T.; Cheng, J. Rh-Catalyzed
Sequential Oxidative C–H Activation/Annulation with Geminal-
Substituted Vinyl Acetates to Access Isoquinolines. Chem. Commun.
2015, 51, 13327. (b) Arambasic, M.; Hooper, J. F.; Willis, M. C.
Activating Group Recycling in Action:
A Rhodium-Catalyzed
Carbothiolation Route to Substituted Isoquinolines. Org. Lett. 2013,
15, 5162–5165.
( 2) See Supporting Information for additional results using other
acids. Although further studies are required to fully understand the
role of acid, we speculate that the acid helps promoting a) the
tautomerization of enamine to imine prior to the second reduction and
b) the dissociation of THIQ product from Ir-complex through
protonation.
( 3) In a similar Ir-xyliphos system, it is reported that the alpha-
alkoxy imine binds to the catalyst complex in a bidentate fashion, see
(a) Dorta, R.; Broggini, D.; Stoop, R.; Rüegger, H. Spindler, F.;
Togni, A. Chiral Xyliphos Complexes for the Catalytic Imine
Hydrogenation Leading to the Metolachlor Herbicide: Isolation of
Catalyst-Substrate Adducts. Chem. Eur. J. 2004, 10, 267–278. (b)
Dorta, R.; Broggini, D.; Kissner, R.; Togni, A. Iridium-Imine and –
Amine
Complexes Relevant to the (S)-Metolachlor Process: Structures,
Exchanges Kinetics, and C–H Activation by IrI Causing
Racemization. Chem. Eur. J. 2004, 10, 4546–4555.
( 4) Hopmann, K. H.; Bayer, A. On the Mechanism of Iridium-
Catalyzed Asymmetric Hydrogenation of Imines and Alkenes: A
Theoretical Study. Organometallics. 2011, 30, 2483–2497.
( 5) Increasing the catalyst loading to 2.5 mol % of [Ir(cod)Cl]2 and
6 mol % of L5 does not improve the conversion any further.
( 6) The absolute stereochemistry of product 12e was determined
via the combination of measured and computed vibrational circular
dichroism (VCD) spectra and optical rotations. The configuration of
12e (R, R) was found to be analogous to that determined for
hydroxymethyl product 8a and also observed crystallographically for
8p. See Supporting Information.
( 7) (a) Chrzanowska, M. Grajewska, A.; Rozwadowska, M. D.
Asymmetric Synthesis of Isoquinoline Alkaloids: 2004–2015. Chem.
Rev. 2016, 116, 12369–12465. (b) Carrillo, L.; Badia, D.; Dominguez,
E.; Anakabe, E.; Osante, I.; Tellitu, I.; Vicario, J. L. Chiral Amino
Alcohols As Intermediates in the Stereocontrolled Synthesis of
1,3-Disubstiuted Tetrahydroisoquinolines and Protoberbertines. J.
Org. Chem. 1999, 64, 115–1120.
( 8) Haftchenary, S.; Nelson, S. D.; Furst, L.; Dandapani, S.;
Ferrara, S. J.; Bošković, Z. V.; Lazú, S. F.; Guerrero, A. M.; Serrano,
J. C.; Crews, D. K.; Brackeen, C.; Mowat, J.; Brumby, T.; Bauser, M.;
Schreiber, S. L.; Phillips, A. J. Efficient Routes to a Diverse Array of
Amino Alcohol-Derived Chiral Fragments. ACS. Comb. Sci. 2016, 18,
569–574.
(8) Pilgrim, B. S.; Gatland, A. E.; Esteves, C. H. A.; McTernan, C.
T.; Jones, G. R.; Tatton, M. R. Procopiou, P. A.; Donohoe, T. J.
Palladium-Catalyzed Enolate Arylation as a Key C–C Bond-Forming
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( 9) Alternatively, the oxazolidinone-fused product 7b could be
(22) Thimmaiah, S.; Ningegowda, M.; Shivananju, N. S.;
synthesized utilizing a 2-step sequence. First is the Boc-protection of
the amine. The Boc-protected product was subsequently cyclized to
afford oxazolidinone-fused THIQ 7b under the Appel reaction
conditions. See Supporting Information for experimental details.
(20) Zhang, G.-L.; Chen, C.; Xiong, Y.; Zhang, L.-H.; Ye, J.; Ye,
X.-S. Synthesis of N-Substituted Iminosugar Derivatives and Their
Immunosuppresive Activities. Carbohydrate Research. 2010, 345,
780–786.
Ningegowda, R.; Siddaraj, R.; Priya, B. S. Eaton’s Reagent Catalysed
Alacritous Synthesis of 3-Benzazepinones. Eur. J. Chem. 2016, 7,
391–396.
(23) Guo, D.; Li, J.; Lin, H.; Zhou, Y.; Chen, Y.; Sun, H.; Zhang,
D.; Li, H.; Shoichet, B. K.; Shan, L.; Xie, X.; Jiang, H.; Liu, H.
Design, Synthesis, and Biological Evaluation of Novel
Tetrahydroprotoberberine Derivatives (THPBs) as Selective 1A-
Adrenoceptor Antagonists. J. Med. Chem. 2016, 59, 9489–9502.
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(2 ) Gadhiya, S. V.; Giri, R.; Cordone, P.; Karki, A.; Harding, W.
W. Diverse Approaches and Recent Advances in the Synthesis of
Tetrahydroprotoberberines. Curr. Org. Chem. 2018, 22, 1893–1905.
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(1) (a) Tayor, R. D.; MacCoss, M.; Lawson, A. D. G. Rings in Drugs. J. Med. Chem. 2014, 57, 5845. (b) Vitaku, E.; Smith, D. T.; Njardarson, J.
T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved
Pharmaceuticals. J. Med. Chem. 2014, 57, 10257–10274. (c) Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland: Increasing Saturation as
an Approach to Improving Clinical Success. J. Med. Chem. 2009, 52, 6752–6756. (d) Lovering, F. Escape from Flatland 2: Complexity and
Promiscuity. Med. Chem. Commun. 2013, 4, 515–519. e) Roughley, S. D.; Jordan, A. M. The Medicinal Chemist’s Toolbox: An Analysis of
Reactions Used in the Pursuit of Drug Candidates. J. Med. Chem. 2011, 54, 3451–3479.
(2) (a) Zhou, Y.-G. Asymmetric Hydrogenation of Heteroaromatic Compounds. Acc. Chem. Res. 2007, 40, 1357–1366. (b) Wang, D.-S.; Chen,
Q.-A.; Lu, S.-M.; Zhou, Y.-G. Asymmetric Hydrogenation of Heteroarenes and Arenes. Chem. Rev. 2012, 112, 2557–2590.
(3) (a) Zhao, D.; Glorius, F. Enantioselective Hydrogenation of Isoquinolines. Angew. Chem. Int. Ed. 2013, 52, 9616–9618. (b) Wiedner, E. S.;
Chambers, M. B.; Pitman, C. L.; Bullock, R. M.; Miller, A. J. M.; Appel, A. M. Thermodynamic Hydricity of Transition Metal Hydrides. Chem.
Rev. 2016, 116, 8655–8692.
(4) For Ir-catalyzed asymmetric hydrogenation of isoquinolines, see (a) Lu, S. M.; Wang, Y. Q.; Han, X. W.; Zhou, Y.-G. Asymmetric
Hydrogenation of Quinolines and Isoquinolines Activated by Chloroformates. Angew. Chem. Int. Ed. 2006, 45, 2260–2263. (b) Shi, L. Ye, Z.-S.;
Cao, L. L.; Guo, R. N.; Hu, Y.; Zhou, Y.-G. Enantioselective Iridium-Catalyzed Hydrogenation of 3,4-Disubstituted Isoquinolines. Angew. Chem.
Int. Ed. 2012, 51, 8286–8289. (c) Iimuro, A.; Yamaji, K.; Kandula, S.; Nagano, T.; Kita, Y.; Mashima, K.Asymmetric Hydrogenation of
Isoquinolinium Salts Catalyzed by Chiral Iridium Complexs: Direct Synthesis for Optically Active 1,2,3,4-Tetrahydroisoquinolines. Angew. Chem.
Int. Ed. 2013, 52, 2046–2050. (d) Ye, Z.-S.; Guo, R.-N.; Cai, X.-F.; Chen, M.-W.; Shi, L.; Zhou, Y.-G. Enantioselective Iridium-Catalyzed
Hydrogenation of 1- and 3-Substituted Isoquinolinium Salts. Angew. Chem. Int. Ed. 2013, 52, 3685–3689. (e) Kita, Y.; Yamaji, K.; Higashida, K.;
Sathaiah, K.; Iimuro, A.; Mashima, K. Enhancing Effects of Salt Formation on Catalytic Activity and Enantioselectivity for Asymmetric
Hydrogenation of Isoquinolinium Salts by Dinuclear Halide-Bridged Iridium Complexes Bearing Chiral Diphosphine Ligands. Chem. Eur. J. 2015,
21, 1915–1927. (f) Guo, R.-N.; Cai, X.-F.; Shi, L.; Ye, Z.-S.; Chen, M.-W.; Zhou, Y.-G. An Efficient Route to Chiral N-Heterocycles Bearing a C–
F Stereogenic Center via Asymmetric Hydrogenation of Fluorinated Isoquinolines. Chem. Commun. 2013, 49, 8537–8539. (g) Chen, M.-W.; Ji, Y.;
Wang, J.; Chen, Q.-A.; Shi, L.; Zhou, Y.-G. Asymmetric Hydrogenation of Isoquinolines and Pyridines Using Hydrogen Halide Generated in Situ
as Activator. Org. Lett. 2017, 19, 4988–4991. For Ru-Catalyzed Enatioselective Hydrogenation of Isoquinolines, see (h) Wen, J.; Tan, R.; Liu, S.;
Zhao, Q.; Zhang, X. Strong Brønsted Acid Promoted Asymmetric Hydrogenation of Isoquinolines and Quinolines Catalyzed by a Rh-Thiourea
Chiral Phosphine Complex via Anion Binding. Chem. Sci. 2016, 7, 3047–3051.
(5) (a) Scott, J. D.; Williams, R. M. Chemistry and Biology of Tetrahydroisoquinoline Antitumor Antibiotics. Chem. Rev. 2002, 102, 1669–
1730. (b) Siengalewicz, P.; Rinner, U.; Mulzer, Recent Progress in the Total Synthesis of Napthyridinomycin and Lemonomycin
Tetrahydroisoquinoline Antitumor Antibiotics (TAAs). J. Chem. Soc. Rev. 2008, 37, 2676–2690.
(6) Welin, E. R.; Ngamnithiporn, A.; Klatte, M.; Lapointe, G.; Pototschnig, G. M.; McDermott, M. S. J.; Conklin, D.; Gilmore, C. D.; Tadross,
P. M.; Haley, C. K.; Negoro, K.; Glibstrup, E.; Grünanger, C. U.; Allan, K. M.; Virgil, S. C.; Slamon, D. J.; Stoltz, B. M. Concise Total Syntheses
of (–)-Jorunnamycin A and (–)-Jorumycin Enabled by Asymmetric Catalysis. Science. 2019, 363, 270–275.
(7) For C–H activation/annulation strategy, see (a) Zhang, Z.-W.; Lin, A.; Yang, J. Methyl Ketone Oxime Esters as Nucleophilic Coupling
Partners in Pd-Catalyzed C–H Alkylation and Application in the Synthesis of Isoquinolines. J. Org. Chem. 2014, 79, 7041–7050. For ketone
enolate-arylation/annulation, see (b) Donohoe, T. J.; Pilgrim, B. S.; Jones, G. R.; Bassuto, J. A. Synthesis of Substituted Isoquinolines Utilizaing
Palladium-Catalyzed -Arylation of Ketones. Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 11605–11608. For benzannulation of isocoumarins, see (c)
Manivel, P. Probakaran, K.; Khan, F. N.; Jin, J. S. Facile Benzannulation of Isocoumarins in the Efficient Synthesis of Diversified 1,3-
Disubstituted Isoquinolines. Res. Chem. Intermed. 2012, 38, 347–357.
(8) Pilgrim, B. S.; Gatland, A. E.; Esteves, C. H. A.; McTernan, C. T.; Jones, G. R.; Tatton, M. R. Procopiou, P. A.; Donohoe, T. J. Palladium-
Catalyzed Enolate Arylation as a Key C–C Bond-Forming Reaction for the Synthesis of Isoquinolines. Org. Biomol. Chem. 2016, 14, 1065–1090.
(9) Allan, K. M.; Hong, B. D.; Stoltz, B. M.; Expedient Synthesis of 3-Hydroxyisoquinolines and 2-Hydroxy-1,4-Napthoquinones via One-Pot
Aryne Acyl-Alkylation/Condensation. Org. Biomol. Chem. 2009, 7, 4960–4964.
(10) For example of transition-metal-catalyzed tandem C–H activation/annulation of arenes and alkynes, see (a) Zhu, Z.; Tang, X.; Li, X.; Wu,
W.; Deng, G.; Jiang, H. Palladium-Catalyzed C–H Functionalization of Aromatic Oximes: A Strategy for the Synthesis of Isoquinolines. J. Org.
Chem. 2016, 81, 1401–1409. (b) Zhou, S.; Wang, M.; Wang, L.; Chen, K.; Wang, J.; Song, C.; Zhu, J. Bidentate Directing-Enabled, Traceless
Heterocycle Synthesis: Cobalt-Catalyzed Access to Isoquinolines. Org. Lett. 2016, 18, 5632–5635. (c) Chinnagolla, R. K.; Pimparkar, S.;
Jeganmohan, M. Ruthenium-Catalyzed Highly Regioselective Cyclization of Ketoximes with Alkynes by C–H Bond Activation: A Practical Route
to Synthesize Substituted Isoquinolines. Org. Lett. 2012, 14, 3032–3035. (d) Zhao, D.; Lied, F.; Glorius, F. Rh(III)-Catalyzed C–H
Functionalization/Aromatization Cascade with 1,3-Dienes: A Redox Neutral and Regioselective Access to Isoquinolines. Chem. Sci. 2014, 5,
2869–2873.
(11) (a) Chu, H.; Sun, S.; Yu, J.-T.; Cheng, J. Rh-Catalyzed Sequential Oxidative C–H Activation/Annulation with Geminal-Substituted Vinyl
Acetates to Access Isoquinolines. Chem. Commun. 2015, 51, 13327. (b) Arambasic, M.; Hooper, J. F.; Willis, M. C. Activating Group Recycling
in Action: A Rhodium-Catalyzed Carbothiolation Route to Substituted Isoquinolines. Org. Lett. 2013, 15, 5162–5165.
(12) See Supporting Information for additional results using other acids. Although further studies are required to fully understand the role of
acid, we speculate that the acid helps promoting a) the tautomerization of enamine to imine prior to the second reduction and b) the dissociation of
THIQ product from Ir-complex through protonation.
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(13) In a similar Ir-xyliphos system, it is reported that the alpha-alkoxy imine binds to the catalyst complex in a bidentate fashion, see (a) Dorta,
R.; Broggini, D.; Stoop, R.; Rüegger, H. Spindler, F.; Togni, A. Chiral Xyliphos Complexes for the Catalytic Imine Hydrogenation Leading to the
Metolachlor Herbicide: Isolation of Catalyst-Substrate Adducts. Chem. Eur. J. 2004, 10, 267–278. (b) Dorta, R.; Broggini, D.; Kissner, R.; Togni,
A. Iridium-Imine and –Amine Complexes Relevant to the (S)-Metolachlor Process: Structures, Exchanges Kinetics, and C–H Activation by IrI
Causing Racemization. Chem. Eur. J. 2004, 10, 4546–4555.
(14) Hopmann, K. H.; Bayer, A. On the Mechanism of Iridium-Catalyzed Asymmetric Hydrogenation of Imines and Alkenes: A Theoretical
Study. Organometallics. 2011, 30, 2483–2497.
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(15) Increasing the catalyst loading to 2.5 mol % of [Ir(cod)Cl]2 and 6 mol % of L5 does not improve the conversion any further.
(16) The absolute stereochemistry of product 12e was determined via the combination of measured and computed vibrational circular dichroism
(VCD) spectra and optical rotations. The configuration of 12e (R, R) was found to be analogous to that determined for hydroxymethyl product 8a
and also observed crystallographically for 8p. See Supporting Information.
(17) (a) Chrzanowska, M. Grajewska, A.; Rozwadowska, M. D. Asymmetric Synthesis of Isoquinoline Alkaloids: 2004–2015. Chem. Rev. 2016,
116, 12369–12465. (b) Carrillo, L.; Badia, D.; Dominguez, E.; Anakabe, E.; Osante, I.; Tellitu, I.; Vicario, J. L. Chiral Amino Alcohols As
Intermediates in the Stereocontrolled Synthesis of 1,3-Disubstiuted Tetrahydroisoquinolines and Protoberbertines. J. Org. Chem. 1999, 64, 115–
1120.
(18) Haftchenary, S.; Nelson, S. D.; Furst, L.; Dandapani, S.; Ferrara, S. J.; Bošković, Z. V.; Lazú, S. F.; Guerrero, A. M.; Serrano, J. C.; Crews,
D. K.; Brackeen, C.; Mowat, J.; Brumby, T.; Bauser, M.; Schreiber, S. L.; Phillips, A. J. Efficient Routes to a Diverse Array of Amino Alcohol-
Derived Chiral Fragments. ACS. Comb. Sci. 2016, 18, 569–574.
(19) Alternatively, the oxazolidinone-fused product 7b could be synthesized utilizing a 2-step sequence. First is the Boc-protection of the amine.
The Boc-protected product was subsequently cyclized to afford oxazolidinone-fused THIQ 7b under the Appel reaction conditions. See Supporting
Information for experimental details.
(20) Zhang, G.-L.; Chen, C.; Xiong, Y.; Zhang, L.-H.; Ye, J.; Ye, X.-S. Synthesis of N-Substituted Iminosugar Derivatives and Their
Immunosuppresive Activities. Carbohydrate Research. 2010, 345, 780–786.
(21) Gadhiya, S. V.; Giri, R.; Cordone, P.; Karki, A.; Harding, W. W. Diverse Approaches and Recent Advances in the Synthesis of
Tetrahydroprotoberberines. Curr. Org. Chem. 2018, 22, 1893–1905.
(22) Thimmaiah, S.; Ningegowda, M.; Shivananju, N. S.; Ningegowda, R.; Siddaraj, R.; Priya, B. S. Eaton’s Reagent Catalysed Alacritous
Synthesis of 3-Benzazepinones. Eur. J. Chem. 2016, 7, 391–396.
(23) Guo, D.; Li, J.; Lin, H.; Zhou, Y.; Chen, Y.; Sun, H.; Zhang, D.; Li, H.; Shoichet, B. K.; Shan, L.; Xie, X.; Jiang, H.; Liu, H. Design,
Synthesis, and Biological Evaluation of Novel Tetrahydroprotoberberine Derivatives (THPBs) as Selective 1A-Adrenoceptor Antagonists. J.
Med. Chem. 2016, 59, 9489–9502.
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