A novel approach to oxoisoaporphine alkaloids via regioselective metalation of alkoxy isoquinolines

Article abstract of DOI:10.3762/bjoc.13.156

Oxoisoaporphine alkaloids are conveniently prepared via direct ring metalation of alkoxy-substituted isoquinolines at C-1, followed by reaction with iodine. Subsequent Suzuki cross-coupling of the resulting 1-iodoisoquinolines to methyl 2-(isoquinolin-1-y

Full text of DOI:10.3762/bjoc.13.156

A novel approach to oxoisoaporphine alkaloids via
regioselective metalation of alkoxy isoquinolines
Benedikt C. Melzer and Franz Bracher*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 1564–1571.
Department für Pharmazie - Zentrum für Pharmaforschung,
Ludwig-Maximilians Universität München, Butenandtstr. 5-13,
D-81377 Munich, Germany
doi:10.3762/bjoc.13.156
Received: 24 May 2017
Accepted: 28 July 2017
Published: 08 August 2017
Email:
Franz Bracher* - Franz.Bracher@cup.uni-muenchen.de
Associate Editor: D. J. Dixon
* Corresponding author
© 2017 Melzer and Bracher; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
directed ortho/remote metalation; Eaton’s reagent; isoquinolines;
Suzuki cross-coupling
Abstract
Oxoisoaporphine alkaloids are conveniently prepared via direct ring metalation of alkoxy-substituted isoquinolines at C-1, fol-
lowed by reaction with iodine. Subsequent Suzuki cross-coupling of the resulting 1-iodoisoquinolines to methyl 2-(isoquinolin-1-
yl)benzoates and intramolecular acylation of the corresponding carboxylic acids with Eaton’s reagent afforded five alkaloids of the
oxoisoaporphine type. The yield of the cyclization step strongly depends on the electrophilic properties of ring B. An alternative
cyclization protocol via directed remote metalation of ester and amide intermediates was investigated thoroughly, but found to be
not feasible. Two of the alkaloids showed strong cytotoxicity against the HL-60 tumor cell line.
Introduction
Benzylisoquinoline alkaloids represent a very large group of several truncated chemotypes like aristolactams and azafluoran-
plant secondary metabolites, which includes about 2,500 known thenes, and is of considerable pharmacological interest due to
structures. Besides simple benzylisoquinolines, more complex the significant cytotoxicity of numerous representatives [3]. A
tetracyclic ring systems like aporphines, protoberberines, cular- unique subclass of the aporphinoid alkaloids are the oxoisoapor-
ines, pavines, as well as pentacyclic morphinane-type alkaloids phines (7H-dibenzo[de,h]quinolin-7-ones, e.g., menisporphine,
belong to this class. Biosynthetically, all of these chemotypes (2)), which at the first glance appear to be not derived from
are derived from the 1-benzyltetrahydroisoquinoline (S)-norco- 1-benzyltetrahydroisoquinoline intermediates, albeit a hypoth-
claurine. The structures, biosynthesis and pharmacology of esis of Kunitomo postulates a biosynthesis from a benzyliso-
benzylisoquinoline alkaloids have been reviewed recently by quinoline precursor involving a rearrangement (Figure 1) [4].
Hagel and Facchini [1].
Menisporphine (2), first isolated from Menispermum dauricum
The subgroup of aporphinoid alkaloids [2] consists of the apor- DC [4], shows antiangiogenic activity. Some, partly synthetic,
phines and oxoaporphines (e.g., liriodenine (1)), as well as oxoisoaporphine-like analogues were found to have strong
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using polyphosphoric acid (Scheme 1). In the course of this
cyclization, the methoxy group at C-6 is typically hydrolized to
the phenol, subsequent O-methylation gives the 6-methoxy de-
rivatives menisporphine (2) and dauriporphine (3). Recently,
Zhang et al. [20] described an alternative approach starting from
an isoquinoline bearing an ester group at C-8. In a photoredox-
catalyzed direct C–H arylation a 4-methoxyphenyl residue from
a methoxyphenyldiazonium salt was introduced at C-1, and
after ester hydrolysis intramolecular Friedel–Crafts acylation
afforded menisporphine (2).
In continuation of our recent work on the synthesis of poly-
cyclic aromatic alkaloids like pyridoacridine, benzylisoquino-
line-type and oxoaporphine alkaloids using direct ring metala-
tions of heterocycles as vital step [13,21] we intended to
develop a novel and more flexible access to oxoisoaporphine
alkaloids. Again we were inspired by Knochel’s reports on the
direct metalation of isoquinoline [22] and 6,7-dimethoxyiso-
quinoline [23] as well as by our own results for the metalation
of various alkoxyisoquinolines [13] at C-1 with the
Knochel–Hauser base TMPMgCl·LiCl. Transmetalation of the
intermediate organomagnesium species with ZnCl2 should lead
to at C-1 zincated isoquinolines, which could undergo Negishi
cross-coupling reactions with appropriately substituted
methyl 2-bromobenzoates to give methyl 2-(isoquinolin-1-
yl)benzoates. These would again open an access to oxoisoapor-
phine alkaloids via intramolecular acylation following
Kunitomo’s strategy. Main advantage of this approach should
be that the laborious introduction of the carboxy residue at a
late stage of the total synthesis is circumvented. Alternatively,
Figure 1: Prominent oxoaporphine and oxoisoaporphine alkaloids:
liriodenine (1), menisporphine (2), dauriporphine (3), 6-O-demethyl-
menisporphine (4), dauriporphinoline (5), and bianfugecine (6).
DNA binding affinity and therefore high cytotoxicity [5] as well quenching of the 1-magnesiated alkoxyisoquinolines with
as antiplasmodial activity [6]. Besides menisporphine (2), the iodine should lead to 1-iodoisoquinolines, which were expected
related oxoisoaporphine alkaloids dauriporphine (3), 6-O- to be versatile substrates for Suzuki cross-coupling reactions
demethylmenisporphine (4), dauriporphinoline (5) and with appropriate phenylboronic acids to gain methyl
bianfugecine (6) were isolated from Menispermum dauricum 2-(isoquinolin-1-yl)benzoates as the central intermediates
DC, among a few other plants [1,7,8].
(Scheme 1).
A number of approaches to the oxoaporphine ring system has Results and Discussion
been published, typically involving the synthesis of 1-benzyl/ As we reported previously, metalation of 6,7-dimethoxyiso-
1-benzoylisoquinoline intermediates, followed by cyclization quinoline (7a) and 5,6,7-trimethoxyisoquinoline (7b) with
under intramolecular biaryl synthesis, utilizing either photo- 1.5 equivalents of the Knochel–Hauser base (TMPMgCl∙LiCl)
chemical [9-13], radical [14] or Pd-catalyzed [15,16] reactions. exclusively occurs at C-1. Trapping with appropriate benzalde-
hydes opened an access to benzylisoquinoline and oxoapor-
In contrast, only minute work has been published on the synthe- phine-type alkaloids [13]. Here we describe the extension of
sis of oxoisoaporphines. The approaches are mainly based on this approach to the synthesis of oxoisoaporphines.
Kunitomo’s total syntheses of menisporphine (2) [7] and dauri-
porphine (3) [17], which start with the synthesis of 1-(2- By using our modification (1.5 equivalents of TMPMgCl∙LiCl
bromoaryl)isoquinolines using Bischler–Napieralski chemistry, over 4 h at room temperature) [13] of Knochel’s [23] protocol
followed by tedious replacement of the bromine substituent by for the metalation of isoquinolines, the alkoxy-substituted
cyanide (for modern variants, see ref. [18,19]), and subsequent isoquinolines 7a,b were metalated at C-1, as shown before, and
conversion to a carboxylate and Friedel–Crafts-type cyclization this method could conveniently be extended to 6-methoxyiso-
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Scheme 1: Previously reported [7,17] and new approach to oxoisoaporphine alkaloids.
quinoline (7c). Unfortunately, transmetalation with ZnCl2 at applied, since the alkaloids of interest all bear the methoxy
0 °C followed by palladium-catalyzed (5 mol % Pd(dba)2/ group at C-9. Suzuki cross-coupling reaction of the iodinated
10 mol % P(2-furyl)3 or 1 mol % Pd2(dba)3/2 mol % RuPhos) isoquinolines 8a–c with this boronate under Pd(PPh3)4 cataly-
Negishi cross-coupling reaction with methyl 2-bromo-5- sis gave the desired 1-arylisoquinolines 10a–c in moderate to
methoxybenzoate did not lead to the expected methyl 2-(iso- good isolated yields (65–77%, Scheme 3). Up to 20% of the
quinolin-1-yl)benzoates 10 after up to 72 h at room temperature starting materials 8a–c were typically recovered, but all
or 60 °C [22]. Starting materials were recovered almost quanti- attempts to achieve complete conversion (longer reaction times,
tatively. However, quenching with iodine gave the 1-iodoiso- other catalysts and bases) were in vain.
quinolines 8a [23], 8b, and 8c in good yields (53–67%,
Scheme 2).
The esters 10a–c are valuable intermediates for the further
conversion to the target oxoisoaporphines, and in previous
For the introduction of ring D of the oxoisoaporphine protocols [7,17] the esters were typically converted into the cor-
alkaloids one common building block, (4-methoxy-2-(methoxy- responding carboxylic acids, and then cyclized using polyphos-
carbonyl)phenyl)boronic acid pinacol ester (9) [24], could be phoric acid. Previously we found that esters can directly be sub-
Scheme 2: Synthesis of iodinated isoquinolines 8a–c from alkoxy-substituted isoquinolines 7a–c.
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Scheme 3: Synthesis of methyl 2-(isoquinolin-1-yl)benzoates 10a–c from 1-iodoisoquinolines 8a–c.
jected to this type of intramolecular Friedel–Crafts-type acyl- phinoline (5) was synthesized in 58% yield using the same
ations, and trifluoromethanesulfonic acid [25] is superior to protocol starting from the methyl ester 10b, once again under
polyphosphoric acid [26,27] for the synthesis of polycyclic ke- hydrolysis of the 6-methoxy group.
tones. Unfortunately, direct cyclization of esters 10a–c using
In order to explore the scope of this new cyclization methodolo-
gy, we further investigated the synthesis of the alkaloid
bianfugecine (6, Scheme 4), which contains only one methoxy
group at ring B. Until now, only one partial synthesis of this
alkaloid is described in the literature. Kunitomo et al. [30] ob-
tained alkaloid 6 by hydrogenolytic demethoxylation of alka-
loid menisporphine (2) with H2/PtO2 in acetic acid. Unfortu-
nately, upon cyclization of the carboxylic acid 11c, obtained by
acidic hydrolysis of ester 10c, with Eaton’s reagent alkaloid 6
could be isolated in only very poor yield (7%). Other estab-
lished cyclization methods starting from methyl ester 10c were
tested in order to increase the yield. As described above,
attempted direct intramolecular Friedel–Crafts-type cyclization
of 10c catalyzed by trifluoromethanesulfonic acid [25] failed
completely. Also, generation of an acid chloride from 11c with
thionyl chloride, followed by the reaction with AlCl3 did not
even give traces of bianfugecine (6).
this reagent failed completely, despite numerous variations of
the reaction conditions. As an alternative reagent for the acyl-
ation of arenes with esters Eaton’s reagent (phosphorus
pentoxide, 7.7 wt % in methanesulfonic acid) has been de-
scribed in the literature [28,29]. Eaton’s reagent has advantages
over polyphosphoric acid as it is an easy to handle, non-viscous
and freely measurable liquid, and therefore more suitable for
small-scale synthesis. However, attempted direct cyclization of
ester 10a with Eaton’s reagent to menisporphine (2) failed.
Consequently, we had to come back to Kunitomo’s approach
[7,17] via carboxylate intermediates. Carboxylic acid 11a was
conveniently obtained by hydrolysis of the methyl ester 10a
with concentrated hydrochloric acid. The crude carboxylic acid
11a underwent cyclization to 6-O-demethylmenisporphine (4)
with Eaton’s reagent in 45% yield over both steps (Scheme 4).
In accordance with Kunitomo’s observations [7,17], we also ob-
served demethylation of the methoxy group at C-6. Dauripor-
Scheme 4: Synthesis of the alkaloids 6-O-demethylmenisporphine (4), dauriporphinoline (5), and bianfugecine (6).
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Taken all of these results together, intramolecular sively at C-6 of the benzamide moiety (Scheme 6). It is known
Friedel–Crafts-type cyclization aimed at the construction of the for decades [33] that cooperative effects of directing groups
oxoisoaporphine scaffold is a very challenging conversion, and lead to directed ortho-metalation (DoM) at their common ortho-
the electronic properties of the ring to be attacked (ring B) position (C-6 in this case, located ortho to both the amide and
strongly determine the outcome of this reaction.
the methoxy group). Nevertheless, under reversible metalation
conditions, typically existing when amide bases like LDA are
Inspired by a report from the Snieckus group [31] on the appli- employed, kinetically controlled DoM can be followed by an
cation of the directed remote metalation (DreM) methodology equilibration to give a thermodynamically controlled DreM
for generation of carbanionic Friedel–Crafts equivalents (gener- product [34]. This has been demonstrated by Tilly et al. [35] in
ating acridones from diarylamine carboxamides), we converted the synthesis of fluorenones by treatment of N,N-dialkyl
methyl ester 10c into the corresponding diethyl amide 12. For biphenyl-2-carboxamides with LDA. In our case, however,
this purpose, ester 10c was reacted in a Weinreb amidation [32] initial metalation at C-6 of the benzamide moiety was not fol-
with a mixture of trimethylaluminium and diethylamine to give lowed by an equilibration giving the desired 8’-metalated inter-
the amide 12 in 31% yield (Scheme 5). The diethyl amide mediate (which in turn should be trapped by the amide group to
moiety was designated to promote a directed remote metalation give the tetracyclic ketone 6). Probably, the DreM at C-8’ is
by lithium diisopropylamide (LDA) at C-8 of the isoquinoline prevented, since the amide moiety forms a chelate with a lithi-
ring, which should be followed by an intramolecular trapping of um ion and N-2 of the isoquinoline moiety, thus is kept away
the amide group to give the oxoisoaporphine bianfugecine (6, from C-8’. In contrast, we found in previous investigations on
Scheme 5). However, only starting material 12 was recovered the synthesis of the pyridoacridone alkaloid demethyldeoxyam-
from this reaction.
phimendine [21], that an ester group located at a comparable
position (suitable for forming a chelate in cooperation with a
A D2O quenching experiment after the metalation period pyridine nitrogen), can very well promote a directed remote
(4 equiv LDA, 1 h, 25 °C) was performed in order to identify metalation.
the position(s) of ring metalation of 12. In recovered (about
80%) educt, deuterium incorporation (about 40%; calculated To test our hypothesis, we performed two more D2O quenching
from integrals of the 1H NMR spectrum) was observed exclu- experiments with naphthalene analogues of esters 10 and amide
Scheme 5: Attempted synthesis of bianfugecine (6) via directed remote metalation and subsequent trapping of the carboxamide group.
Scheme 6: Outcome of a D2O quenching experiment after metalation of amide 12.
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12. The methyl ester analogue 15 was obtained by Suzuki cross- further attempts to initialize the cyclization of arylisoquinolines
coupling of naphthalene-1-boronic acid (13) and methyl 10c and 12 to the oxoisoaporphine alkaloid bianfugecine (6,
2-bromo-5-methoxybenzoate (14) in 68% yield. Methyl ester 15 Scheme 5) by a DreM did not appear to be promising.
was converted into the corresponding diethyl amide 16 in 58%
yield by Weinreb amidation following the protocol described Finally, the alkaloids 6-O-demethylmenisporphine (4) and
above for the synthesis of 12 (Scheme 7).
dauriporphinoline (5) were converted into their corresponding
6-methoxy derivatives, the oxoisoaporphine alkaloids menis-
Incubation of methyl ester 15 with LDA (4 equiv LDA, 25 °C) porphine (2) and dauriporphine (3). Using Kunitomo’s [7,17]
over a period of 1 h, followed by D2O quenching resulted in protocol (methyl iodide in the presence of silver oxide), phenols
complete decomposition. In contrast, metalation of amide 16 4 and 5 were converted into the alkaloids 2 and 3 in 33 and 49%
under the same conditions and quenching with D2O led to the yields (Scheme 9). In accordance to Kunitomo’s observations,
formation of the benzo[c]fluoren-7-one 17 in 38% yield. In the isomeric methoxy compounds 18 and 19 were obtained as
recovered (about 20%) educt 16, deuterium incorporation byproducts in significant yields (Scheme 9). In order to find a
(about 20%; calculated from integrals of the 1H NMR spec- more convenient methylation protocol, we explored diazome-
trum) was exclusively observed at C-6 of the benzamide moiety thane, but no conversion was observed at all.
(Scheme 8). These data show no indication for a DreM at the
peri-position C-8’, since neither a 8’-deuterated arylnaphtha- Finally, all of the synthesized alkaloids were tested for their
lene nor a benzo[de]anthracen-7-one was detected. This obser- cytotoxic potential in a MTT assay on the HL-60 cell line.
vation is in accordance with results from the Snieckus group Except for menisporphine (2) and bianfugecine (6, both
[36] on the remote metalation/cyclization of a 2-(1- IC50 values > 50 µM), all of the described oxoisoaporphine
naphthyl)benzamide, which gave exclusively benzo[c]fluo- alkaloids and the isomers 18 and 19 showed significant cyto-
renone (analogue of 17 lacking the methoxy group), and not the toxic activity. IC50 values of alkaloid 3 and of compounds 18
benzo[de]anthracen-7-one. This clearly indicates that remote and 19 are ranging from 3–6 µM. Very strong cytotoxicity was
metalation, if any, occurs only in the ortho-position to the benz- determined for 6-O-demethylmenisporphine (4) with an
amide residue (C-2 of the naphthalene ring system), but not in IC50 value of 0.06 µM and for dauriporphinoline (5) with
the peri-position (C-8 of the naphthalene). Consequently, 0.23 µM. So, at least in the HL-60 cell line, oxoisoaporphines
Scheme 7: Synthesis of 1-arylnaphthalene analogues 15 and 16.
Scheme 8: Outcome of a D2O quenching experiment after metalation of amide 16 with LDA.
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Scheme 9: Synthesis of the alkaloids menisporphine (2) and dauriporphine (3) by O-methylation of the alkaloids 6-O-demethylmenisporphine (4) and
dauriporphinoline (5).
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