An Acid-Catalyzed Epoxide Ring-Opening/Transesterification Cascade Cyclization to Diastereoselective Syntheses of (±)-β-Noscapine and (±)-β-Hydrastine

Article abstract of DOI:10.1021/acs.orglett.9b02715

An acid-catalyzed stereoselective epoxide ring-opening/intramolecular transesterification cascade cyclization reaction and N-Boc deprotection was found to be a successful strategy to construct the phthalide tetrahydroisoquinoline skeleton in one pot. Based on this strategy, the unified and highly diastereoselective routes for the total syntheses of (±)-β-Noscapine and (±)-β-Hydrastine were exploited.

Full text of DOI:10.1021/acs.orglett.9b02715

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
An Acid-Catalyzed Epoxide Ring-Opening/Transesterification
Cascade Cyclization to Diastereoselective Syntheses of ( )-β-
Noscapine and ( )-β-Hydrastine
Jihui Li,†,# Yongxiang Liu,†,‡,§,# Xinjing Song,† Tianxiao Wu,† Jiaxin Meng,† Yang Zheng,†
Qiaohua Qin,† Dongmei Zhao,*,† and Maosheng Cheng†,§
†Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University,
Shenyang, 110016, China
‡Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, People’s Republic of China
§Institute of Drug Research in Medicine Capital of China, Benxi, 117000, People’s Republic of China
S
* Supporting Information
ABSTRACT: An acid-catalyzed stereoselective epoxide ring-opening/intramolecular transesterification cascade cyclization
reaction and N-Boc deprotection was found to be a successful strategy to construct the phthalide tetrahydroisoquinoline
skeleton in one pot. Based on this strategy, the unified and highly diastereoselective routes for the total syntheses of ( )-β-
Noscapine and ( )-β-Hydrastine were exploited.
11
12
́
́
Alternatively, Kerekes and Bognar and Szantay et al.
hthalide tetrahydroisoquinoline alkaloids, such as Nosca-
Hydrastine (2),2 Bicuculline (3),2a,3 and
Cordrastine (4),4 are known to possess interesting and diverse
biological properties (Figure 1).5 Structurally, the alkaloids
comprise a 1,2,3,4-tetrahydroisoquinoline and a phthalide ring
and these two units are linked together by two chiral centers at
their C-1 and C-3′ carbons to form either erythro- or threo-
isomer (Figure 1). (−)-α-Noscapine [(−)-α-1], originally
isolated from Papaver somniferum L.,6 is a classical non-
addictive antitussive agent without significant toxicity7a and
also displays other potential clinical utilities7 for the treatment
of stroke, anxiety, especially and cancer. Clinically used (−)-α-
1 can be provided through extraction from plant resources.8
For the intriguing structure and important bioactivity,
Noscapine (1) has become an attractive target for chemical
synthesis and much effort has been made toward the
development of efficient routes to Noscapine (1).4b,9−12 The
first route was reported by Robinson and Perkin,9 who
constructed a C-1−C-3′ bond through direct condensation
between Cortanine and Meconine, which were produced by
degradation of natural (−)-α-1. Based on Robinson−Perkin
strategy, several other approaches4b,10 were reported, such as
zinc-promoted4b coupling and electrochemical reductive
coupling.10
1
synthesized phthalide isoquinoline skeletons through the
Bischler−Napieralski reaction. Despite these remarkable
achievements, an inherent drawback associated with all of
the above-mentioned strategies was the lack of regioselectivity
and/or stereoselectivity. Thus, the development of novel
strategies for regioselective and stereoselective construction of
a phthalide tetrahydroisoquinoline core is still in great demand.
Recently, we proposed a unified acid-catalyzed epoxide ring-
opening/intramolecular transesterification cascade cyclization
strategy for the regioselective and stereoselective synthesis of
phthalide tetrahydroisoquinoline alkaloids, in which the C and
D rings are constructed simultaneously in one step (Scheme
1). Herein, we described the total syntheses of ( )-β-
Noscapine [( )-β-1] and ( )-β-Hydrastine [( )-β-2],
based on this cascade strategy.
Our retrosynthetic analysis of ( )-β-Noscapine was outlined
in Scheme 2. We envisioned that the phthalide tetrahydro-
isoquinoline core (5a) might be introduced by an acid-
catalyzed epoxide ring-opening/transesterification cascade
cyclization of the epoxide 6a, which could be derived from
(E)-stilbene 7a by epoxidation.13 Moreover, the stilbene 7a
Ppine (1),
Received: August 2, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02715
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Letter
might be constructed from monoiodide 8 and substituted
styrene 9 by a Pd-catalyzed Heck coupling reaction. The
monoiodide 8 could be synthesized by a selective monoiodiza-
tion of N-Boc protected phenethylamine 10, which could be
obtained from commercially available vanilline (11). In
addition, the styrene 9 could be afforded via the Wittig
reaction from 12, which could be derived from commercially
available 2,3-dimethoxybenzoic acid (13).14
Consequently, our synthetic studies commenced with the
preparation of monoiodide 8 (Scheme 3). The vanilline 11 was
Scheme 3. Synthesis of Monoiodide 8
Figure 1. Phthalide-tetrahydroisoquinoline-containing alkaloids and
erythro- and threo-form of Noscapine (1).
Scheme 1. Our Proposed Common Strategy To Form a
Phthalide Tetrahydroisoquinoline Skeleton
subjected to the I2/KI condition,15 leading to the formation of
iodovanilline 14 in 92% yield. A three-step sequence involving
the hydrolysis of iodide in 14, the subsequent dioxolane ring
closure with CH2Br2,15 and the Henry reaction,16 provided the
desired precursor 15 in 57% overall yield. The precursor 15
underwent a reduction of olefin and nitro group with BH3-
THF complex, followed by N-Boc protection to generate
carbamate 10 in 77% yield over two steps. Without further
purification, the selective monoiodination of compound 10
with I2/CF3COOAg17 was examined, but it failed to provide
the expected monoiodide 8; only the diiodination product at
both C-2 and C-6 was obtained in quantitative yield.
Alternatively, the temperature- and iodine-concentration-
controlled iodination was performed using 0.02 M I2 in
CH2Cl2 at −15 °C to generate monoiodide 8 regioselectively
in 75% isolated yield. Note that this seven-step sequence
required only one chromatographic purification, which allowed
the preparation of 8 with an overall yield of 30% in gram scale.
Next, we then turned our attention to synthesize the key
intermediate 9 (Scheme 4). The transformation of commer-
cially available 2,3-dimethoxybenzoic acid 13 to phthalide 16
was achieved by modified Pd(II)-catalyzed ortho alkylation of
benzoic acid with CH2Br218 in 66% yield. Two successive steps
Scheme 2. Retrosynthetic Analysis of ( )-β-Noscapine
Scheme 4. Synthesis of Substituted Styrene 9
B
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involving a radical bromination on benzyl position of 16 with
NBS and AIBN, and a hydrolysis in the presence of aqueous
KOH, thus yielded ortho-formyl functionalized product 17 in
75% yield. Methyl esterification of 17 was easily achieved by
treatment with SOCl2/MeOH in excellent yield. Finally, the
resulting 12 was converted to corresponding substituted
styrene 9 in 76% yield via the Wittig reaction.14 Notably,
compound 9 were readily prepared in gram scale through this
five-step sequence in 33% overall yield.
Table 1. Optimization of the Acid-Catalyzed Cascade
Cyclization and N-Boc Deprotection in One Pot
With substantial amounts of the key intermediates 8 and 9 in
hand, we moved on to install a phthalide tetrahydroisoquino-
line core (Scheme 5). The Pd-catalyzed Heck coupling
a
b
c
entry
acid
AlCl3
FeCl3
method
yield (%) diastereomeric ratio, dr
1
2
3
4
A
A
A
A
A
A
A
A
A
A
B
34
42
33
30
−
25
29
−
>99:1
>99:1
>99:1
>99:1
−
>99:1
>99:1
−
Scheme 5. Completion of the Synthesis of ( )-β-Noscapine
ZnCl2
Zn(OTf)2
RuCl3·xH2O
BF3·Et2O
TiCl4
Ti(i-PrO)4
Ti(n-BuO)4
CF3CO2H
CF3CO2H
CF3CO2H
d
5
6
7
d
8
d
9
−
−
−
−
e
10
11
12
0
ND
76
f
g
B
>99:1
a
Method A: (a) 6a (0.05 mmol), acid (0.2 equiv), CH2Cl2 (7.0 mL),
0 °C, 3.0 h; (b) acid (2.0 equiv), rt, 3.0 h. Method B: (a) 6a (0.05
mmol), CF3CO2H (5.0 equiv), CH2Cl2 (7.0 mL), 0 °C, 3.0 h; b)
b
c
CF3CO2H (20 equiv), rt, 3.0 h. Isolated yield. The dr (β/α or
d
e
1
threo/erythro) was determined by H NMR. No reaction. Starting
f
material was recovered. 6a was completely converted, the product
was N-Boc 5a (see Scheme SI-5 and Table S1 in the Supporting
g
Information). For entry 12, (a) CF3CO2H (30 equiv) was used; (b)
CF3CO2H (120 equiv) was used.
To further examine the scope of this cascade cyclization in
constructing the phthalide tetrahydroisoquinoline alkaloid,
( )-β-Hydrastine [( )-β-2] was synthesized by using a
similar strategy. As outlined in Scheme 6, commercially
available 3,4-methylenedioxyphenethylamine 18 was converted
to iodide 19 in 84% yield over two steps, namely, N-Boc
protection and I2/CF3COOAg-mediated iodination.17 Next,
the Pd-catalyzed Heck coupling reaction22 of 19 and 9 was
performed to generate (E)-stilbene 20 as the only stereo-
isomer, which was converted to the phthalide tetrahydroiso-
quinoline scaffold 21 as a pair of diastereomers [dr (α/β or
threo/erythro) = 4:1] by DMDO-mediated epoxidation13 and
the subsequent one-pot acid-catalyzed epoxide ring-opening/
intramolecular transesterification cascade cyclization and N-
Boc deprotection. Pleasingly, Eschweiler−Clarke methylation
of this mixture afforded easily chromatographically separable
Hydrastine in 57% yield, leading to the isolation of both
( )-α-Hydrastine [( )-α-2, 46%] and the desired ( )-β-
Hydrastine [( )-β-2, 11%] as the single diastereomers.
Finally, a late-stage epimerization of ( )-α-2 at C-3′ under
MeOK/MeOH conditions afforded its β-configured epimer
[( )-β-2] as a diastereomerically pure product in a yield of
65%. The structure and stereochemistry of ( )-β-Hydrastine
[( )-β-2] were confirmed by X-ray crystallographic analysis.
Mechanistically, as shown in Scheme 7, this pivotal cascade
reaction probably occurs via an acid-catalyzed regioselective
and stereoselective ring opening of epoxide in a SN1-like
mechanism19b,23 and transesterification sequence. Probably, in
the initial step, the proton will coordinate to the oxygen atom
in the trans-epoxide 6a (or 22) to form an oxonium ion 6a-I
reaction of the monoiodide 8 and substituted styrene 9 turned
out to be highly stereoselective, thus providing a 75% yield of
(E)-stilbene 7a as the only stereoisomer. Epoxidation of (E)-
alkene 7a with DMDO13 proceeded smoothly to give epoxide
6a. Inspired by the acid-catalyzed ring-opening reaction of
epoxides with amines19 and Lewis acid-mediated selective
deprotection of N-Boc,20 we expected that an acid-catalyzed
expoxide ring-opening/intramolecular transesterification cas-
cade cyclization reaction and the deprotection of N-Boc would
occur regioselectively and stereoselectively to install the
challenging phthalide tetrahydroisoquinoline core 5a in one
pot. Initially, we treated epoxide 6a with AlCl3 in CH2Cl2,
leading to the isolation of 5a as a single diastereomer (with a
diastereomeric ratio (dr) of >99:1) in 34% yield (see Table 1,
entry 1). Extensive screening of Lewis acids, such as FeCl3,
ZnCl2, Zn(OTf)2, RuCl3·xH2O, BF3·Et2O, TiCl4, Ti(i-PrO)4
and Ti(n-BuO)4 failed to improve the yield (see Table 1,
entries 2−9). Ultimately, trifluoroacetic acid (CF3CO2H)
proved to be effective to promote this cascade reaction to
afford 5a in 76% yield (see Table 1, entry 12). The N-
methylation of 5a occurred under classic Eschweiler−Clarke
reaction conditions,21 thus yielding ( )-β-1 in a yield of 75%
with unaltered diastereoselectivity (dr > 99:1). The structure
of ( )-β-1 was unambiguously confirmed by X-ray single-
crystal diffraction. Notably, without purification of 5a and 6a,
( )-β-1 was prepared from 7a in the three-step yield of 39%
(see the Supporting Information).
C
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6a-III is the main cause of the inability of 6a-II to epimerize to
produce its epimer 6a-III, thus resulting in ( )-β-5a as a
single diastereomer (dr > 99:1). However, the hydroxyl group
in 22-II is sterically less hindered to epimerize to produce its
epimer 22-III, thus resulting in the above-mentioned
diastereoselectivity (dr = 4:1). At the experimental stage, the
detectable intermediates 6a-II, 22-II, and 22-III, as well as the
easily chromatographically obtainable intermediates N-Boc
protected ( )-β-5a, ( )-α-21, and ( )-β-21 (see Scheme SI-
5 in the Supporting Information ) strongly supported our
proposed reaction mechanism.
Scheme 6. Completion of the Synthesis of ( )-β-Hydrastine
In summary, we have disclosed a diastereoselective synthetic
approach to form the phthalide tetrahydroisoquinoline
alkaloids ( )-β-Noscapine and ( )-β-Hydrastine. The syn-
thesis featured a novel and unprecedented acid-catalyzed
epoxide ring-opening/intramolecular transesterification cas-
cade annulation reaction and N-Boc deprotection in one pot
as the key step to construct the phthalide tetrahydroisoquino-
line scaffolds. The synthetic strategy applied in the present
synthesis offers a new access to those phthalide-tetrahydroi-
soquinoline-containing alkaloids. We anticipate that the
synthetic strategy described herein may find more applications
in the diastereoselective and/or enantioselective total
syntheses of other related natural products.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02715.
Scheme 7. Postulated Mechanism for Acid-Catalyzed
Cascade Cyclization and N-Boc Deprotection in One Pot
Experimental procedures, spectroscopic data, and X-ray
crystallographic data for ( )-β-1, ( )-α-2, and ( )-β-2
(PDF)
Accession Codes
CCDC 1944137 [( )-β-1], CCDC 1944152 [( )-α-2], and
CDCC 1944153 [( )-β-2] contain the supplementary
crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_
request/cif, or by emailing data_request@ccdc.cam.ac.uk, or
by contacting The Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44 1223
336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: medchemzhao@163.com.
ORCID
Yongxiang Liu: 0000-0003-0364-0137
Dongmei Zhao: 0000-0001-5156-6125
Author Contributions
#These authors contributed equally.
Notes
(or 22-I), which, in turn, undergoes rupture of the C−O bond
and intramolecular amino nucleophilic substitution from the si-
face to afford 6a-II (or 22-II). Such a syn-opening23,24
approach causes the retention of configuration at C-1. The
diastereoselectivity of this cascade reaction could be
interpreted as the epimerization of 6a-II and 22-II at C-3′.
Namely, the steric repulsion between hydroxyl and methoxyl in
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Program for Innovative
Research Team of the Ministry of Education and the Program
for Liaoning Innovative Research Team in University.
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