Synthetic approach to seco-tetracenomycin natural products saccharothrixone A–C

Article abstract of DOI:10.1016/j.tetlet.2018.04.031

Design and development of first synthetic approach to the functionalized tetracyclic framework of structurally novel seco-tetracenomycin natural products saccharothrixones A–C has been reported. A thermal dehydro Diels-Alder reaction of an arenyne-alkyne

Full text of DOI:10.1016/j.tetlet.2018.04.031

Accepted Manuscript
Synthetic Approach to seco-Tetracenomycin Natural Products Saccharothrix-
one A–C
Bhavani Shankar Chinta, Harikrishna Sanapa, Kamala Prasad Vasikarla,
Beeraiah Baire
PII:
S0040-4039(18)30488-X
https://doi.org/10.1016/j.tetlet.2018.04.031
TETL 49894
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
10 March 2018
11 April 2018
12 April 2018
Please cite this article as: Shankar Chinta, B., Sanapa, H., Prasad Vasikarla, K., Baire, B., Synthetic Approach to
seco-Tetracenomycin Natural Products Saccharothrixone A–C, Tetrahedron Letters (2018), doi: https://doi.org/
1
0.1016/j.tetlet.2018.04.031
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Synthetic Approach to seco-Tetracenomycin
Natural Products Saccharothrixone A–C
Bhavani Shankar Chinta, Sanapa, Kamala Prasad Vasikarla and Beeraiah Baire*
Leave this area blank for abstract info.
[a]
[b]
[b]
Department of Chemistry, Indian Institute of Technology Madras, Chennai-36, Tamilnadu, India.
This manuscript describes the first synthesis of tetracyclic framework of the novel seco-tetracenomycin natural products
saccharothrixone A–C

1
Tetrahedron Letters
Synthetic Approach to seco-Tetracenomycin Natural Products Saccharothrixone A–C
[
a]
[b]
[b]
[a]
Bhavani Shankar Chinta, Harikrishna Sanapa, Kamala Prasad Vasikarla and Beeraiah Baire*
Department of Chemistry, Indian Institute of Technology Madras, Chennai-600036, Tamilnadu, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Design and development of first synthetic approach to the functionalized tetracyclic framework of
structurally novel seco-tetracenomycin natural products saccharothrixones A–C has been reported. A
thermal dehydro Diels-Alder reaction of an arenyne-alkyne unit has been utilized as the key synthetic
step. This strategy has been extended for the generation of a small library of diversely functionalized
tetracyclic systems of seco-tetracenomycins. An approach for the synthesis of poly-hydroxyl
tetracyclic system has also been described. This report represents the first synthetic approach to the
tetracenomycin natural products saccharothrixones A–C.
Available online
Keywords:
Alkynes
2009 Elsevier Ltd. All rights reserved.
Cycloadditions
Natural products
Phthalides
Total synthesis
The Aromatic polyketides are a class of natural products
possessing a broad spectrum of bioactivities, such as
The structural novelty associated with the bioactivities
attracted our attention. To the best of our knowledge so far, there
are no reports appeared in the literature on the development of
synthetic approaches to either for the synthesis of partial
frameworks or for the total synthesis of these novle seco-
tetracenomycin natural products (saccharothrixones A-C). Here
in we report a first synthetic approach to this family of natural
products. This strategy is rapid (3 steps) and diversity oriented to
generate the functionalized derivatives of saccharothrixones A-C.
antibacterial, antifungal, and anticancer. Recently, a screening
program by Xiao et al., to identify potential aromatic polyketide-
producing microorganisms led to the identification of the marine-
derived actinomycete Saccharothrix sp.. Tetracenomycins (tcm)
are a family of tetracyclic naphthacenequinones with a highly
hydroxylated cyclohexenone moiety and significant antitumor
1
activity. The tetracenomycin X, an aromatic polyketide
antibiotic, was identified as a major metabolite from the
actinomycete Saccharothrix sp. 10-10. An extensive
investigation of the secondary metabolite resulted in the isolation
of three novel polyketide seco-tetracenomycins,
saccharothrixones A–C, along with saccharothrixone D, which is
a new tetracenomycin analogue possessing opposite
configurations at all of the stereogenic centres. The
saccharothrixones A–C represent first examples of seco-
tetracenomycins where the quinone ring B is cleaved and re-
formed into a furanone ring. These structures were elucidated by
spectroscopic analyses and electronic circular dichroism
calculations. Saccharothrixone D showed in vitro cytotoxic
activity against the HepG2 cancer cell line with an IC50 value of
7.5 μM
Figure 1. seco-Tetracenomycin natural products saccharothrixones A-C
[
a] Department of Chemistry, Indian Institute of Technology Madras, Chennai-
00036, INDIA
b] Denisco Chemicals Pvt. Ltd. Hyderabad, INDIA
Email: beeru@iitm.ac.in
6
We employed an arenyne-alkyne based dehydro Diels-alder
reaction as the key step for the construction of the tetracyclic
framework 1 of saccharothrixones A-C. According to our retro
synthetic analysis (Scheme 1), the carbocylic system 1 of
saccharothrixones A-C can be generated from the enyne-alkyne 2
[
*
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.xxxx/ejoc.2017xxxxx.

2
Tetrahedron Letters
via an aromatic tetradehydro Diels-Alder (Ar-TDDA) reaction.
But, according to our design, the synthesis of carbocyclic
framework, i.e., the linear naphthofuranone 1, of
This ester 2 can be obtained from the secondary propargylic
alcohol 3 via DCC mediated esterification. The alcohol 3 can be
efficiently prepared from cyclohexane-carbaldehyde 4.
saccharothrixones A-C involves an Ar-TDDA reaction.
Therefore, initially, we performed an optimization study (Table
1) to find out a suitable reaction condition for the selective
generation of linear naphthofuranone derivative 14a from the
arenyne-alkyne 5a.
Accordingly, initially the arenyne-alkyne 5a was heated as
1
5
,2-dichlorobenzene solution at 110 °C (entry 1, Table 1). After
1 h, an inseparable (0.15:1) mixture of linear and angular
furanone derivatives 14a and 15a was isolated in 73% combined
yield. Next, performing the reaction in presence of phenol (10
4b
equiv) at 110 °C (entry 2) resulted in the formation of the linear
furanone 14a as the exclusive product in 71% yield. Increasing
the temperature to 130 °C (entry 3) resulted in the reduced
reaction time (21 h) and gave the 70% of 14a. Further increase of
temperature to 150 °C (entry 4) gave both reduced reaction time
Scheme 1. Our retrosynthetic plan for the generation of carbocylic system of
seco-tetracenomycin natural products saccharothrixones A-C
(2 h) as well yield (58%) of the product 14a.
Results and Discussion
To understand the feasibility and ease of the proposed TDDA
reaction, we performed a model study. Our synthetic approach
begins with the preparation of the model substrate an arenyne-
alkyne 5a. Addition of the lithium phenylacetylide to the
cyclohexane-carbaldehyde 6 at 0 °C in THF gave the secondary
alcohol 7 in 85% yield after 2 h. The coupling of this alcohol 7
with the propiolic acid in presence of dicyclohexylcarbodiimide
(DCC) and (4-dimethylamino)pyridine (DMAP) at 0 °C to RT
afforded the arenyne-alkyne ester 5a in moderate yield (48%).
Table 1. Optimization study
Scheme 2. Synthesis of model arenyne-alkyne substrate for TDDA reaction
2
The tetradehydro Diels-Alder reaction (TDDA), is a [4+2]
3
cycloaddition between an enyne (4π) and alkyne (2π) 8, and
would result in arene 9 via a [1,5]H shift of the initially formed
cyclic allene intermediate 10 (Scheme 3). In case of arenyne-
4
alkyne 11, the Ar-TDDA reaction would result in the formation
of two isomeric products, linear and angular naphthalene
derivatives 12 and 13.
Table 2. Synthesis of structurally divergent, functionalized tetracyclic
Scheme 3. The tetradehydro Diels-Alder (TDDA) and Ar-TDDA reactions
systems of saccharothrixones A-C

3
After finding an optimized condition (entry 3, Table 1) for the
efficient formation of tricyclic lactones, we further extended this
strategy to generate library of structurally divergent analogues
frameworks (Table 2). Accordingly, various arenyne-alkynes 5b-
e have been employed under standard reaction conditions (1,2-
DCB, PhOH (10 equiv) and 130 °C). All these substrates
underwent smooth Ar-TDDA cyclization (20-28 h) to provide
access to the corresponding linear naphthofuranone derivatives
4
the olefin present in 22 with OsO and NMO followed by the
acetonide protection of the resultant vicinal diol 23 with 2,2-
dimethoxypropane and pTSA at 60 °C afforded the ester 24 in
7
excellent yield (77%). Reduction of the ester group in 24 with
LiAlH
4
followed by the oxidation of the resultant primary alcohol
gave an inseperable (1:0.24) diastereomeric
25 with PCC-SiO
2
mixture of aldehydes 21.
14b-e in moderate yields (56-64%). There was no detection of
any traces of their angular counter parts.
Next, we aimed for functionalized cyclohexane bearing
analogues of saccharothrixones A-C. Therefore, 2-
bromocyclohexene-1-carbaldehyde 16 was chosen as the starting
5
material. Addition of phenylacetylide to the aldehyde 16 at ice
cold temperature resulted in the formation of secondary alcohol
17, in 74% yield. Initially, the reaction of alcohol 16 with
propiolic acid in presence of DCC and DMAP failed to give any
of the expected products. Instead it gave an unidentifiable
product mixture after 3 h at 0 °C. So therefore, we planned to
synthesize an analogous ether derivative 20. Propargylation of
the hydroxyl group present in 17 with NaH and propargyl
bromide in THF at rt gave the bispropargylether 18 in 71% yield
after 12 h. At this stage, heating the 1,2-DCB solution of
arenyne-alkyne 18 at 130 °C as well as 150 °C, in presence of
phenol resulted in the complex mixture of unidentifiable
products. This may be due to the fact that the alkyne partner is
inactivated. Disappointed by this outcome, we next prepared an
Scheme 5. Synthesis of poly-oxygenated cyclohexane-carbaldehyde 21
We further proceeded with this mixture. Phenylacetylide
addition to the aldehyde 21 at 0 °C gave a mixture of four
diastereomeric seondary propargylic alcohols. To our delight,
this time we could seperate two sets 26a (major) and 26b
activated arenyne-alkyne substrate 19 from 18. Treatment of the
(minor), each containing two diastereomers (1:0.22) and (1:0.3)
n
1
8 with BuLi in THF at 0 °C followed by trapping the resultant
respectivley. Initially, The major mixture 26a was taken further
to complete the synthesis of respective tetracyclic framework.
Coupling of the 26a with propiolic acid in presence of DCC and
acetylide by ethyl chloroformate gave the alkynoate 19 (55%).
Upon subjection to standard reaction conditions, 19 gave the
corresponding cyclised product 20 in moderate (50%) yield after
2 2
DMAP in CH Cl at 0 °C gave the corresponding ester 27a
3
h.
(1:0.22) in 67% yield.
Scheme 4. Synthesis of functionalized linear isonaphthofuran
Subsequently, we focused on the synthesis of a poly-
oxygenated, polychiral centred derivative of saccharothrixones
A-C in its racemic form. Accordingly, our synthetic approach
began with the preparation of the corresponding cyclohexane
carbaldehyde 21 (Scheme 5). The Diels-Alder reaction between
Scheme 6. Synthesis of poly-oxygenated tetracyclic isonaphthofuranone
framework
Heating a solution of 27a in 1,2-DCB and phenol at 130 °C for
18 h, underwent the anticipated Ar-TDDA cyclization to generate
the linear naphthofuranone derivatives. To our surprise, a single
diastereomeric linear naphthofuranone 28 was isolated as the
furan and methyl acrylate in presence of BF
3
.Et
2
O at 0 °C gave
6
the endo-ester 22 as the major in 40% yield. Dihydroxylation of

4
Tetrahedron Letters
product in moderte yield (40%). We could not identify any
References and notes
traces of other diastereomeric cyclic product. The relative
streochemistry of the isolated tetracyclic product 28 is not
known. On the other hand, when we employed the another set of
secondary propargylic alcohols 26b in coupling with propiolic
acid, the entire reaction mixture was decomposed to
unidentifiable complex mixture.
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In summary, we have developed a synthetic strategy for the first
synthesis of functionalized tetracyclic frameworks of the natural
products saccharothrixone A–C. We employed the aromatic
tetradehydro Diels-Alder reaction between an arenyne and alkyne
as the key step. We further extended this strategy for the
generation of highly oxygenated tetracyclic framework of the
natural products saccharothrixone A–C.
3
.
Acknowledgments
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We thank We thank Department of Chemistry, IIT Madras for
infrastructure facility. We acknowledge financial support from
CSIR-INDIA (No.02(0209)/14/EMR-II) and Denisco Chemicals
Pvt. Ltd. Hyderabad (RB/16-17/CHY/002/DENI/BEER). We
thank Ms. Keerthana for helping BS for the characterizations of
few compounds. BS thanks IIT Madras for HTRA fellowship.
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Supplementary data ( H, C NMR spectra for all new
synthesized compounds and experimental procedures) (PDF)
associated with this article can be found in the online version, at
http:// dx.doi.org/xxxxxxxxxx.
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Highlights of the manuscript:
) This report represents the first synthetic approach to the
tetracenomycin natural products saccharothrixones A–C.
) Generation of a small library of diversely functionalized
tetracyclic systems of seco-tetracenomycins
) Mild and short synthetic approach for the frame work
generation (4-5 steps)
) A thermal dehydro Diels-Alder reaction of an arenyne-alkyne
unit has been utilized as the key synthetic step.
) An approach for the synthesis of poly-hydroxyl tetracyclic
system has also been described
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