Total synthesis of actinophenanthroline A via double Doebner–Miller reaction

Article abstract of DOI:10.1016/j.tetlet.2016.06.045

Total synthesis of actinophenanthroline A, a marine actinomycete within the family of Streptomycetaceae (strain CNQ-149) is reported. Both the racemic and enantiopure actinophenanthroline A have been synthesized with good overall yields. Highlight of the synthesis contains the classical and economical double Doebner–Miller reaction to access the 1,7-phenanthroline core followed by a modified EDCI coupling.

Full text of DOI:10.1016/j.tetlet.2016.06.045

Accepted Manuscript
Total synthesis of Actinophenanthroline A via double Doebner–Miller reaction
Suman Kr Ghosh, Rajagopal Nagarajan
PII:
S0040-4039(16)30720-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.06.045
TETL 47772
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 May 2016
10 June 2016
12 June 2016
Please cite this article as: Ghosh, S.K., Nagarajan, R., Total synthesis of Actinophenanthroline A via double
Doebner–Miller reaction, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.06.045
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Total synthesis of Actinophenanthroline A via
double Doebner–Miller reaction
Suman Kr Ghosh and Rajagopal Nagarajan*

1
Tetrahedron Letters
Total synthesis of Actinophenanthroline A via double Doebner–Miller reaction
Suman Kr Ghosh and Rajagopal Nagarajan*
a
School of chemistry, University of Hyderabad, Hyderabad- 500046, India (+) 91 40 23012460
rnsc@uohyd.ernet.in
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Total synthesis of actinophenanthroline A, a marine actinomycete within the family of
Streptomycetaceae (strain CNQ-149) is reported. Both the racemic and enantiopure
actinophenanthroline A has been synthesized with good overall yields. Highlight of the synthesis
contains the classical and economical double Doebner-Miller reaction to access the 1, 7-
phenanthroline core followed by a modified EDCI coupling.
Available online
Keywords:
Total Synthesis
Natural product
1,7-phenanthroline
Double Doebner-Miller
In June 2015, Fenical et al. isolated1 some unprecedented
alkaloids actinobenzoquinoline and actinophenanthroline A- C
(Figure 1.) from a marine actinomycete within the family of
streptomycetaceae (strain CNQ-149). The core structures of both
the alkaloids were not known in the alkaloid literature previously.
Actinophenanthrolines A−C are the elementary examples of
natural products containing the 1,7-phenanthroline alkaloid core.
The synthetic phenanthrolines are already well established in
literature from ages, among them 1,7-, 1,10-, 4,7- are
predominantly common. Synthetic 1, 7-phenanthrolines were the
first phenanthroline to be prepared by Skarup et al. in 18822 and
later on, studies revealed their activities to induce the
biosynthesis of drug-metabolizing enzymes by binding to
metals.3 1, 10-Phenanthrolines are most well studied among all
the phenanthrolines as they exhibit properties like: inhibitors of
zinc metallopeptidases,4 antimalarial activities5, metal binding
capacity.6 Thus, the first naturally occurring alkaloids which
contains 1,7- phenanthroline core were indeed important from a
synthetic view point. This may open opportunity to reveal many
important biological or pharmaceutical properties. As, our group
is working on the total synthesis of different heterocyclic
alkaloids,7 this alkaloid actinophenanthroline A enticed us to
carry out the synthesis of it. Though there were many synthetic
strategies available in literature for 1, 7- phenanthroline core8 but
we planned our synthetic route for this alkaloid via the classic
and economic Doebner-Miller method.9 Very recently Lindsley
group reported the first total synthesis for this alkaloid starting
from 8-hydroxy-2-methylquinoline. Although their synthetic
route gave a good overall yield but it consists of isolation and
purification problems in every steps as author mentioned in their
manuscript.10 Thus, in this paper we report an easier and
economical total synthesis of actinophenanthroline A via double
Doebner-Miller reaction.
Figure. 1. Structures of Actinophenanthrolines
As depicted in scheme 1, our initial strategy for the
synthesis of 9 hinged on the deprotection of the hydroxyl groups
(aliphatic and aromatic) of compound 8 in two consecutive steps.
Compound 8 could be stemmed from compound 7 via a coupling
reaction with protected L-lactic acid. The amine (7) could be
generated through nitration followed by reduction on compound
5. To achieve the exact 1, 7 phenanthroline core (5), a repeated
Doebner-Miller reaction on 2-methoxy-5-nitroaniline would have
been the best pathway.

2
reached to compound 7, we were very eager to carry out the key
Scheme 1. Retrosynthetic analysis
coupling reaction between amine (7) and L-lactic acid using
EDCI.HCl as coupling agents that has already been reported for
benzene moieties,11 but unfortunately that was a failure. Thus, we
tried variety of conditions with different coupling agents
(EDCI.HCl, HBTU, HATU, TBTU, DCC, CID, CDI) along with
activating agents (DMAP, HOBt) at varied temperatures even
then we failed to obtain our desired coupled product 8 (see
Supporting Information, Table 1). We envisaged that it is the
free hydroxyl group of lactic acid which might be the culprit for
these consecutive failures. Thus, we protected the free hydroxyl
group of L-lactic acid with methoxy group. We prepared the (S)-
2-methoxypropanoic acid in three steps starting from L-lactic
acid by following ref. 12.
We commenced the forward synthesis with 2-methoxy-5-
nitroaniline (1a), where it was treated with crotonaldehyde in
Doebner-Miller reaction conditions at 90 °C with mixed acid
(AcOH and HCl) to produce the substituted 2-methylquinoline
(3) in 61 % yield. Exposure of this nitroquinoline (3) to a reflux
condition with Fe powder/NH4Cl, furnished the corresponding
amine product (4) which has been subjected to second Doebner-
Miller reaction with crotonaldehyde in same mixed acid
condition for 2 h at 90 °C to achieve the desired 1, 7-
phenanthroline core (5) in 71% yield. Next, selective introduction
of a nitro group at the C5 of the compound 5 can be achieved
only with the o and p directing substitution at C6. Thus, we had
an edge due to the methoxy group at C6 of compound 5. Hence,
we treated compound 5 with HNO3-H2SO4 at 0 °C to obtain the
corresponding nitro substituted compound (6) but unfortunately
yield was very poor.
Figure. 1. X-ray structure of 6-methoxy-2, 8-dimethyl-1,7-phenanthrolin-5-
amine (7)13
Next, we treated compound 7 and (S)-2-methoxypropanoic
acid (12) with EDCI.HCl in DCM at 0 °C- rt for 72 h then at 50
°C for another 24 h but still we were not able to obtain the
coupled product 13.
Scheme 3. Synthesis of enantiospecific Actinophenanthroline
A
Scheme 2. Forward Synthesis
We presume that it is not only the hydroxyl group but there
might be some other electronic or steric factors which plays a
vital role for this reaction. It is possibly that C5 amine on this
phenanthroline core that is less nucleophilic (in comparison with
simple benzene core) due to the presence of two electron
withdrawing pyridine rings. Hence, its nucleophilicity might not
be enough to displace the O-acyl lactic acid intermediate (which
forms in situ with EDCI and lactic acid) to form the desired
amide (8/13). Hence, we envisioned that, keeping an electron
withdrawing group at the α-/β position of the L-lactic acid might
increase the eletrophilicity of the lactic acid intermediate that
might be sufficient to form the desired coupled product (8/ 13).
From this perspective, we primarily started the venture for
synthesis of racemic actinophenanthroline A. We carried out the
reaction between compound 7 and pyruvic acid with coupling
agent EDCI. HCl in DCM at 0 °C for 1 h, followed by 30 mins at
rt to get the desired coupled product 14 with an excellent yield.
The keto group of compound 13 was next reduced to alcohol
using sodium borohydride in methanol at 0 °C which led to a
racemic compound 15. The methoxy deprotection of compound
Next, we tried to optimize the reaction using different conditions
with other nitrating agents like NO2BF4, AcONO2 and NaNO3-
H2SO4 to improve the yield of compound 6. Among them
NaNO3-H2SO4 condition at 0- 10 °C found to give a moderate
yield of compound 6. This nitro group of compound 6 was
reduced again to respective 5-amino-1, 7-phenanthroline (7) in
quantitative yields with Fe powder under reflux condition. As we

3
15 was then achieved using BBr3 in DCM at -78 °C to rt in a
highly diluted condition after 24 h. The NMR spectrum of
synthetic racemic actinophenanthroline A exactly matches with
the reported actinophenanthroline A. Thus, we successfully
completed the total synthesis of racemic actinophenanthroline A.
natural product along with the synthetic product (see
Supporting Information).
In conclusion, we have successfully achieved the synthesis of
both enantiopure actinophenanthroline A as well as the racemic
version. The easier, classical and economical methods had been
utilized to synthesize this alkaloid. This synthetic strategy
administers an easier route to synthesize the other analogue
alkaloids.
Scheme 4. Synthesis of racemic Actinophenanthroline A
Acknowledgments
We thank DST for financial support. S.K.G. also thanks UGC
for senior research fellowship.
Supplementary Material
Experimental procedure, NMR, HRMS and Crystallographic data
are available in supporting information.
References and notes
1.
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a
successful synthetic execution of racemic
2.
3.
Skraup, H.; Vortmann, G. Monatsh. Chem. 1882, 3, 572.
actinophenanthroline A we diverted our focus again towards the
enantiopure actinophenanthroline A. Thus, we protected the
hydroxyl group of L-lactic acid with acetyl group which indeed
became an electron withdrawing group to α of the acid group.
(S)-2-acetoxypropanoic acid was prepared via three steps, where
the acid group was first protected with benzyl group using benzyl
bromide in basic condition. Next, the acetoxylation was achieved
using acetic anhydride with DMAP (cat.) followed by
deprotection of the benzyl group using hydrogenation led to the
(S)-2-acetoxypropanoic acid (see Supporting Information).
a) Felber, J. P.; Coombs, T. L.; Vallee, B. L. Biochemistry 1962, 1,
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Scheme 5. Synthesis of enantiospecific Actinophenanthroline
A
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With desired acid in hand, we carried out the key coupling
reaction between the amine (7) and (S)-2-acetoxypropanoic acid
with EDCI. HCl in DCM. The reaction was very sluggish, after
72 h also it did not reach completion. Hence, we interrupted the
reaction and isolated the pure coupled product 19 along with
some unreacted starting amine (7). The cleavage of O-acetate
group of compound 19 was performed selectively using K2CO3 in
MeOH solvent at 0 °C, within 10 mins the reaction was
completed to give compound 20 in quantitative yields. On
treatment of compound 20 with BBr3 in DCM the deprotection of
methoxy group was achieved in 72 % yield to obtain the
enantiopure actinophenanthroline A. We accomplished the total
synthesis of racemic as well as enantiopure actinophenanthroline
A with overall 5.11% and 4.8% yields respectively. All spectral
data and HRMS data is consistent with the data of isolated
10. While compiling our manuscript the first synthesis of this alkaloid has
appeared in the following journal.
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Lett. 2016, 57, 2194–2196.
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5630–5631.
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Macromolecules 2014, 47, 5313−5319.
13. Molecular formula: C15H15N3O, unit cell parameters: a 12.1928(9), b
12.9524(10), c 16.6378(13); CCDC 1445332.

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Highlights:
 Total synthesis of a marine actinomycete Actinophenanthroline A is achieved.
 Both racemic and enantiopure actinophenanthroline A has been synthesized.
 The classical and economical double Doebner-Miller reaction is used as Key step.