Visible-Light-Driven C?H Oxidation of Cyclic Tertiary Amines: Access to Synthetic Strychnos Alkaloids with Antiviral Activity

Article abstract of DOI:10.1002/chem.201900078

Air and visible light have been used in facile direct C?H oxidation of cyclic tertiary amines at ambient conditions, employing organic dyes as photocatalysts and LED. Tolerance of this new environmentally compatible protocol to various side-chain derivati

Full text of DOI:10.1002/chem.201900078

A Journal of
Accepted Article
Title: Visible-Light-Driven C-H Oxidation of Cyclic Tertiary Amines:
Access to Synthetic Strychnos Alkaloids with Antiviral Activity
Authors: Anton A. Guryev, Friedrich Hahn, Manfred Marschall, and
Svetlana B. Tsogoeva
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Visible-Light-Driven C-H Oxidation of Cyclic Tertiary Amines:
Access to Synthetic Strychnos Alkaloids with Antiviral Activity
Anton A. Guryev,[a] Friedrich Hahn,[b] Manfred Marschall[b] and Svetlana B. Tsogoeva*[a]
Abstract: Air and visible light have been used in facile direct C-H
oxidation of cyclic tertiary amines at ambient conditions, employing
organic dyes as photocatalysts and LED. Tolerance of this new
environmentally compatible protocol to various side-chain
derivatizations of tryptoline and tetrahydroisoquinoline substrates was
demonstrated. The developed method provides a straightforward and
sustainable route towards -lactams, which feature strong antiviral
properties (EC50 down to 4.6±1.8ꢀμM) against human
cytomegalovirus (HCMV). The obvious advantages, which are easily
available and inexpensive reagents, organic dyes, visible light, air/O2
and atom efficiency, make this system highly appealing for synthesis
of versatile Strychnocarpine alkaloid derivatives with antiviral activity.
catalyst and ligand, or long reaction times and tedious workup
procedures. Recently, a Cu-catalyzed synthetic method for direct
oxidation of cyclic tertiary amines towards substituted
dihydroisoquinolones was reported (Figure 1b), which, however
requires vitamin B1 analogue as co-catalyst.[17] In other reported
Au-, Fe-, Co-catalyzed methods, -lactam formation was merely
an accompanying side process.[18]
Visible-light photocatalysis became a useful tool for organic
synthesis due to the fact that light is an inexpensive, nontoxic,
widely abundant and easy to handle reagent.[19] Visible-light-
mediated catalysis has been already successfully applied to a
large range of important organic transformations[20] as
visible-light-driven reactions occur under mild conditions and are
considered green chemical processes.[21]
Within the realm of chemical synthesis, amide bond formation
remains one of the most important endeavours in organic
chemistry.[1] This is because amides are ubiquitous in biologically
significant compounds, biopolymers (e.g., peptides, proteins) and
pharmaceuticals (like penicillin). In particular, cyclic amides have
attracted much attention due to their appearance as
antimicrobials,[2] antidiabetics,[3] antibiotics,[4] drugs addressing
the central nervous system (CNS)[5] and as important building
blocks for synthesis of biologically active molecules.[6] Particularly,
dihydroisoquinolone and dihydrocarbolinone frameworks can be
found in various natural and synthetic compounds,[7] most of
which exhibit significant biological activities.[8] For example,
compound I (Figure 1a), based on the dihydroisoquinolinone motif,
possesses of potent in vitro antimalarial activity against drug
resistant malaria parasites.[9] Dihydrocarbolinone compound II is
a plant alkaloid strychnocarpine,[10] which is a muscle relaxant
and 5-hydroxytryptamine receptor stimulant, while synthetic
dihydrocarbolinone derivative III is a potent and specific inhibitor
of the oncogenic death-associated protein kinase 3 (DAPK3
kinase) and is a potential anticancer agent.[11] Furthermore, such
subunits are important for the construction of active ingredients
(AI) for fragment-based drug discovery (FBDD).[12] Thereby
efficient methods for the synthesis of such extremely versatile
structures are highly desirable.
Traditionally, lactams are synthesized via lactamization of
lactones with amines[13] or by cyclization of aminoalcohols[14] or of
amidoalkenes.[15] However, these and related known cyclization
methods[16] require harsh reaction conditions, large amounts of
Figure 1. a) Selected examples of dihydroisoquinolones (I) and of
dihydrocarbolinones (II, III) as subunits of natural products and synthetic
bioactive compounds. b) Survey of the direct C-H oxidation of cyclic amines.
[a]
A. A. Guryev, Prof. Dr. S. B. Tsogoeva
Organic Chemistry Chair I and Interdisciplinary Center for Molecular
Materials (ICMM), Friedrich-Alexander University of Erlangen-
Nürnberg, Nikolaus-Fiebiger-Straße 10,
91058 Erlangen, Germany
e-mail: svetlana.tsogoeva@fau.de
In some recently reported Ru-, Ir- and Pt-catalyzed
photoredox additions of various acceptors to in situ generated
[b]
Dr. F. Hahn, Prof. Dr. M. Marschall
dihydroisoquinoline-derived
-amino
radicals,
the
Institute for Clinical and Molecular Virology, Friedrich-Alexander
University of Erlangen-Nürnberg, Schlossgarten 4, 91054 Erlangen,
Germany
dihydroisoquinolone 1b was obtained as a by-product (Figure
1b).[22] In comparison to metal-based photocatalysts, organic dyes
Supporting information for this article is given via a link at the end of
the document.
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lactam 1b was obtained with yield of 58% in shorter reaction time
(Table 1, Entry 2). Switching to DMSO as a solvent (Table 1, Entry
3) and varying additive, photocatalyst and its loading, as well as
reaction time (Table 1, Entries 4-9), allowed to improve product
yield to 72% (Entry 9). While several organic dyes in combination
with LED of a color corresponding to match the absorption
maximum of the dye and other commercially available bases were
screened, the combination of Rose Bengal (5 mol%) with NaOAc
(2 equiv.) was found optimal for this oxidation reaction (Table 1,
Entry 9). Furthermore, several background experiments were
performed to confirm importance of the “dye-light-additive”
sequence for reaction outcome (Table 1, Entries 10-12). It was
also found that concentration of molecular oxygen in the reaction
vessel and the nature of substrate have a strong influence on
reaction outcome (Figure 2). Thus, performing reaction under a
flow of pure oxygen from a balloon generally reduced the reaction
time and 2b was obtained with 45% yield. In order to further
increase the yield we examined several halides as additives, as it
was previously shown that halogen anions can accelerate the
oxidation[27] (see Supporting Information). To our delight, in
presence of 5 mol% of tetrabutylammonium chloride (TBAC),
57% yield of 2b was observed. However, while applying the same
reaction conditions to 1a led to lower yield of 1b (43%), the use of
air as oxidizing agent without TBAC resulted in 1b with higher
yield (72%, Figure 2).
are cheap, not moisture-sensitive, environmentally compatible
and easier to modify.[23] Surprisingly, the utilization of organic
dyes for oxidation of tertiary amines is still extremely rare. A single
successful example was reported by Das and co-workers very
recently.[24] However, to our knowledge, no synthetic methods for
direct oxidation of substituted tryptolines towards highly versatile
and potentially bioactive dihydrocarbolinones are known to date.
In the present work we describe the development of visible-
light-mediated direct C-H oxidation of cyclic N-substituted amines
towards corresponding bioactive -lactams in presence of organic
dyes as photocatalysts and using air/oxygen as economic and
green oxidant. Furthermore, for the first time we demonstrate a
facile direct access to new derivatives of Strychnos alkaloids
showing antiviral activity.
We started our investigation by exploring a selected model
reaction of N-phenyl-tetrahydroisoquinoline 1a towards
corresponding -lactam 1b (Table 1). According to the absorption
maximum of Rose Bengal (RB) (λ=558 nm in CH3CN)[25] and
previously reported visible-light-mediated transformations, where
RB was successfully applied as a photocatalyst,[23] green LED
was chosen for irradiation. The oxidation reaction in DMF in the
presence of RB (2 mol%) as a photocatalyst at room temperature
delivered desired product in 18% yield (Table 1, Entry 1).
Table 1: Optimization of the reaction conditions.
Organic dye,
mol%
Additive
(2 equiv.)
Figure 2. Study of the role of the oxygen and halogen anion for the reaction
outcome. Conditions: Rose Bengal (RB) (0.05 equiv.), green LED (λ=560 nm),
NaOAc (2 equiv.), DMSO (0.1 M). [a] TBAC (0.05 equiv.).
Entry
Time, h
Yield[a] [%]
1
2
Rose Bengal, 2
Rose Bengal, 2
Rose Bengal, 2
Fluorescein, 2
Rhodamine 6G, 2
Rose Bengal, 2
Rose Bengal, 2
Rose Bengal, 2
Rose Bengal, 5
Rose Bengal, 5
Rose Bengal, 5
-
-
48
18
18
18
18
18
18
72
18
18
18
18
18[b]
58[b]
71
These findings and promising results inspired us to expand our
oxidation method to a series of tetrahydroisoquinolines 3a-9a and
tryptolines 10a-15a to study substrate tolerance, and the obtained
results are summarized in Figure 3. A correlation between
outcome of reaction and substituent at nitrogen in the six
membered ring, was observed. Thus, presence of electron-
donating groups at the N-phenyl substituent generally decreased
the yield (2b, 3b), while presence of electron-withdrawing groups
increased it (4b, 5b). Quite the same trend was observed when
tryptolines 12a and 15a were applied as substrates. Though, use
of substituted dihydroisoquinolines 8a and 9a did not provide a
remarkable difference in comparison with results obtained for 1a
and 6a. In reaction of benzyl substituted amine 7a, no oxidation
of the exocyclic benzylic methylene was observed and relatively
low yield for compound 7b can be explained by possible
overoxidation of 7a.[28]
The essential role of oxygen as a terminal oxidant can be
described according to the proposed mechanism for generation
of α-aminoradicals.[29] An excited state of Rose Bengal (RB*)
delivered by irradiation of the dye under visible light from a low-
power source undergoes a single electron transfer (SET) with
amine A to form radical cation B and deactivated catalyst (RB•‾)
(Figure 4).
NaOAc
NaOAc
NaOAc
NaOAc
Li2CO3
KHCO3
NaOAc
NaOAc
-
3
4
56[c]
9[d]
46
5
6
7
-
8
76
9
72
10
11
12
35
NaOAc
NaOAc
7[d,e]
6[d]
[a] Isolated yield. [b] Reaction was performed in DMF. [c] Under blue light
irradiation (λ=450 nm). [d] Determined by NMR. [e] In absence of light.
We next performed the same reaction in presence of NaOAc, as
it was previously shown that α-amine radical formation can be
sufficiently accelerated in presence of base.[26] To our delight, -
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Figure 3. Substrate scope includes various amines 1a-15a. Reported yields were highest isolated yields of products 1b-15b. Conditions: Rose Bengal (RB) (0.05
equiv.), green LED (λ=560 nm), NaOAc (2 equiv.), DMSO (0,1 M). [a] Under air for 18 h. [b] Under flow of oxygen for 5 h in presence of TBAC (0.05 equiv.) as
additive. [c] Under flow of oxygen for 5 h. [d] Under oxygen atmosphere for 18 h.
•
•
Superoxide radical anion (O2 ‾), formed during regeneration of
Alternatively, the superoxide radical anion (O2 ‾) can react with the
RB•‾ by back electron transfer (BET) to molecular oxygen,[22c] can
react with radical cation B to form α-aminoradical C (path 1). This
deprotonation step is mediated by NaOAc, used as a base
additive. The α-aminoradical C could further react with the
generated peroxide radical (HOO•) to form hydroperoxyde
intermediate E (Figure 4).
-amino radical cation B to generate an iminium ion D (path 2),
which can then be attacked by the formed hydroperoxide anion
(HOO‾) to give intermediate E, similar to a previously reported
proposed mechanism.[30] Base mediated water elimination in E
finishes the reaction on both paths.
DFT computations for the selected transformation 1a1b
at the B3LYP/6-31G* level with inclusion of solvent effects by the
polarizable continuum model confirmed the above mechanistic
proposal. Formation of C from B by path 1 (with a reaction free
energy of -28.5 kcalmol-1) is strongly preferred over formation of
iminium ion D from B via path 2 (with a reaction free energy of -
15.7 kcalmol-1).
Notably, α-aminoradical C, formed via path 1, may easily be
transferred in situ to iminium ion D through reaction with oxygen
or with RB*. Indeed, according to the DFT calculations, radical C
may undergo further a distinctly exergonic follow-up reaction with
molecular oxygen to give iminium ion D (Figure 4) with a reaction
free energy of -20.7 kcalmol-1. As a consequence, species D is
much more abundant than C in the reaction mixture, which means
that hydroperoxide E is more likely to be formed from D than from
C. In line with this interpretation, observed correlation between
outcome of reaction and substituent at nitrogen in the six
membered ring (Figure 3) can readily be explained by reactivity
of iminium ion D (Figure 4). According to frontier molecular orbital
(FMO) theory, presence of electron-withdrawing groups at the N-
phenyl substituent lowers energy of the lowest unoccupied
molecular orbital (LUMO). This makes iminium ion D more
Figure 4. Proposed mechanism for RB-catalysed direct oxidation of cyclic
amines under visible light irradiation.
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electrophilic and increases product yield (e.g., compounds 4b, 5b,
15b). In contrast, iminium ions with electron-donating groups at
the N-phenyl substituent have a LUMO at higher energy and are
therefore less reactive towards weakly nucleophilic hydroperoxide
anion, which results in lower yields of desired products (e.g.,
compounds 2b, 3b, 12b).
Experimental Section
For detailed synthetic procedures, 1H, 19F and 13C NMR, mass-
spectroscopic data of all synthesized compounds, see the Supporting
Information.
Because of our ongoing interest to identify new efficient
antiviral agents, we analyzed selected cyclic tertiary amines 2a
and 15a and their corresponding C-H oxidation products 2b and
15b for their inhibitory activity against human cytomegalovirus
(HCMV). Interestingly, compared to antiviral activity of reference
drug ganciclovir (EC50 = 2.6 ± 0.5 µM), in use for standard
treatment of HCMV infections,[31] cyclic amine compounds 2a and
15a were inactive, while corresponding -lactams 2b (EC50 = 4.6
± 1.8 µM) and 15b (EC50 = 9.0 ± 0.2 µM) exerted strong anti-
HCMV activity in the absence of cytotoxicity (HFFs CC50 >100 µM)
(Table 2). These results underline the attractiveness of this C-H
photooxidation method allowing easy and direct generation of
highly bioactive compounds from poorly active or inactive
precursors.
Acknowledgements
S.B.T. and M.M. gratefully acknowledge the financial support from
the Deutsche Forschungsgemeinschaft (DFG) by grants TS
87/15-1, TS 87/17-1, TS 87/16-3, MM 1289/7-3, MM 1289/11-1
and from the Wilhelm Sander-Stiftung by grants Nr. 2014.019.1
and Nr. 2018.121.1. S.B.T. also thanks the Interdisciplinary
Center for Molecular Materials (ICMM) and Emerging Fields
Initiative (EFI) “Chemistry in Live Cells” supported by Friedrich-
Alexander-Universität Erlangen-Nürnberg for funding.
Keywords: cyclic amine • lactam • organic dye • metal-free C-H
oxidation • aerobic photooxidation • antiviral alkaloids
Table 2: EC50 values of anti-HCMV activity (AD169-GFP) determined in primary
HFFs
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In conclusion, we demonstrated that substituted tryptolines
and tetrahydroisoquinolines can be directly oxidized efficiently via
a
visible-light-mediated photocatalytic process towards
corresponding -lactams under ambient conditions using organic
dye Rose Bengal as photocatalyst and molecular oxygen as
oxidant. The visible-light-driven mild C-H oxidation protocol allows
to easily generate new highly functionalized Strychnocarpine
alkaloid derivatives. The modulated bioactive properties of -
lactams were demonstrated by the example of a strong antiviral
activity in vitro against HCMV (EC50 down to 4.6±1.8ꢀμM).
Moreover, the cytotoxicity of -lactams for primary HFFs (CC50)
was undetectable at concentrations up to 100ꢀμM. Thus, the
obtained products can be regarded as selective, which is one
of the most important aspects in drug design. All new -lactams
are currently under further biological investigation so that further
results will be reported elsewhere.
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Entry for the Table of Contents
COMMUNICATION
Light as air: Visible light and air
were used as easily available and
inexpensive reagents for direct
metal-free C-H photooxidation of
cyclic tertiary amines towards new
antiviral -lactams at ambient
conditions. This facile and atom
efficient method is highly appealing
A. A. Guryev, F. Hahn, M.
Marschall, S. B. Tsogoeva*
Page No. – Page No.
Visible-Light-Driven C-H
Oxidation of Cyclic Tertiary
Amines: Access to Synthetic
Strychnos Alkaloids with
Antiviral Activity
for
synthesis
of
versatile
Strychnocarpine alkaloid derivatives.
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