An efficient and concise synthesis of Indiacen A and Indiacen B

Article abstract of DOI:10.1016/j.tetlet.2017.03.002

A novel total synthesis of antimicrobial prenyl indoles, Indiacen A and its chloro analogue Indiacen B has been accomplished by using Horner-Wadsworth-Emmons olefination for terminal conjugated enynes, carboalumination, chlorination and Vilsmeier-Haack formylation as the key transformations.

Full text of DOI:10.1016/j.tetlet.2017.03.002

Accepted Manuscript
An efficient and concise synthesis of Indiacen A and Indiacen B
Kishore Kumar Anantoju, Baquer Syed Mohd, Thirumala Chary Maringanti
PII:
S0040-4039(17)30290-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.03.002
TETL 48703
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
3 January 2017
24 February 2017
1 March 2017
Please cite this article as: Anantoju, K.K., Mohd, B.S., Maringanti, T.C., An efficient and concise synthesis of
Indiacen A and Indiacen B, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.03.002
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Graphical Abstract
An efficient and concise synthesis of Indiacen
A and Indiacen B
a,b
Kishore Kumar Anantoju , Baquer Syed Mohd. *, Thirumala Chary Maringanti
Leave this area blank for abstract info.
a
b
+
+

1
Tetrahedron Letters
journal homepage: www.els evier.com
An efficient and concise synthesis of Indiacen A and Indiacen B
a a,∗
Kishore Kumar Anantoju , Baquer Syed Mohd , Thirumala Chary Maringanti
b
a
Department of Medicinal Chemistry, GVK Biosciences Pvt. Ltd., Survey Nos: 125 (part) & 126, IDA, Mallapur, Hyderabad 500076, India.
Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad, 500 085, India.
b
ARTICLE INFO
ABSTRACT
Article history:
Received
A novel total synthesis of antimicrobial prenyl indoles, Indiacen A and its chloro analogue
Indiacen B has been accomplished by using Horner-Wadsworth-Emmons olefination for
terminal conjugated enynes, carboalumination, chlorination and Vilsmeier-Haack formylation as
the key transformations.
Received in revised form
Accepted
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Total Synthesis
Natural Product
Antimicrobial
Carboalumination
Formylation
Introduction
1
chlorination followed by formylation would give the desired
Indiacen analogues.
Indiacen A and B (Figure 1), prenyl indoles are the first
reported secondary metabolites isolated from the bacterium
Sandaracinus amylolyticus belonging to a new species of
2
myxobacteria. These secondary metabolites Indiacen A and its
chloro analogue Indiacen B have been reported to present
antimicrobial activity. These were found to be active against
Gram-positive and Gram-negative bacteria as well as the fungus
Mucor hiemalis. Indiacen A (1) is a 3-formylindole derivative
bearing an isoprene like diene side chain and Indiacen B (2) is a
3
Lindel, T and co-workers have reported the first total synthesis of
-formylindole derivative bearing a dienyl chloride side chain.
3
Indiacen B, but the synthesis of Indiacen A has not been
reported so far.
In our ongoing interest in the synthesis of biologically active
compounds, the structural uniqueness and similarity in the
structure prompted us to undertake the total synthesis of these
compounds. We describe herein a first total synthesis of Indiacen
A and an efficient, novel route to its chloro analogue Indiacen B.
The synthesis features carboalumination, chlorination and
Vilsmeier-Haack formylation as the key transformations.
Figure 1: Structure of Indiacen A and Indiacen B
Results and Discussion
Our synthetic efforts (scheme 2) commenced with 4-bromo-1H-
indole 3 as a commercially available, suitable starting material.
N-Boc-indole-4-carboxaldehyde 5 was prepared from 3 following
Retrosynthetic analysis (scheme 1) revealed 4-formyl indole
derivative as the suitable starting material, which upon Wittig
Horner-Wadsworth Emmons reaction with the phosphonate 6
would install the desired ene-yne. Subsequent carboalumination-
4
the protocol as reported in the literature. Treatment of 5 with
freshly
prepared
5
diethyl
(3-trimethylsilyl-2-propynyl)
phosphonate 6 gave the silylated conjugated enyne 7 as
exclusively E-isomer in 72% yield. Removal of the silyl group
—
——
∗
Corresponding author. Tel.: +91 040 6748 3456; fax: +91 40 6748 3400; e-mail: baquer@gvkbio.com

2
Tetrahedron Letters
with K CO in methanol gave the terminal conjugated enyne 8 in
quantitative yield. The enyne 8 was then employed as a common
intermediate for the preparation of Indiacen A (1) and B (2).
2
3
carboalumination, chlorination and formylation as the key
transformations. In addition, chlorination of the terminal enyne to
give the desired dienyl chloride was achieved.
6
Carboalumination of the (E)-enyne 8 with trimethylaluminium
2 2
in the presence of zirconocene dichloride (Cp ZrCl ) followed by
aqueous work up gave the diene 9 in 46% yield with the
concomitant cleavage of the Boc group. The compound 9 was
found to be unstable at rt and thus it was immediately formylated
8
under Vilsmeier-Haack conditions to afford Indiacen A in 58 %
9
yield as a white solid. The spectral data was found to be well in
1
agreement with the data reported for the natural product.
Scheme 1: Retrosynthetic strategy of Indiacen A and Indiacen
B
Our next endeavor was the installation of dienyl chloride side
chain as in Indiacen B (2) from the enyne 8. Following a similar
6
,7
literature report for the preparation of the dienyl iodide
derivatives, the enyne 8 was similarly treated with trimethyl
aluminium in the presence of zirconocene dichloride to give the
dienyl alane 10 which upon chlorination with N-
chlorosuccinimide (NCS) gave the desired dienyl chloride 11 as
the major product (scheme 2) along with a minor amount of the
3
-chlorinated indole derivative. To our knowledge this
transformation has not been reported previously. Attempts to
purify the dienyl chloride 11 over silica gel proved futile as it
resulted in the decomposition of the product. Completion of the
synthesis then required formylation. The mixture of products was
used as such for the formylation step in anticipation to purify it in
the final stage. Subsequent formylation under Vilsmeier-Haack
conditions successfully delivered Indiacen B as a white solid in
Scheme 2: Synthesis of Indiacen A and Indiacen B
3
2 % yield over two steps. The geometry of the double bond was
ascertained as E-isomer after the formylation step by nOe
experiment of 1HNMR spectroscopy. The spectral data of the
prepared compound was found consistent with those of the
reported values. Thus, we have accomplished the synthesis of
Indiacen A (1) and its chloro analogue Indiacen B (2).
Acknowledgments
1
0
The authors are thankful GVK Biosciences Pvt. Ltd. for the
financial support and for the laboratory facilities. The assistance
from the analytical department is greatly acknowledged.
In summary, a first total synthesis of Indiacen A (1) and a
novel route to its chloro analogue Indiacen B (2) has been
accomplished in a divergent way starting from commercially
available starting materials. In this approach, the terminal enyne
References and notes
1. Steinmetz, H.; Mohr, K. I.; Zander, W.; Jansen R.; Gerth, K.; and
Müller, R. J. Nat. Prod. 2012, 75, 1803.
8
was employed as a key intermediate while using
2
.
Weissman, K. J.; Müller, R. Bioorganic & Medicinal Chemistry,
009, 17, 2121.
2

3
3
4
5
6
.
.
.
.
Marsch, N.; Jones, P. G.; and Lindel, T. Beilstein J. Org. Chem.
015, 11, 1700.
Moyer, M. P; Shiurba, J. F.; Rapoport, H. J. Org. Chem, 1986, 51,
106
CH), 9.91 (s, 1H, CHO), 11.36 (br s, 1H, NH); δ
acetone-d ) δ 13.3, 112.4, 118.9, 119.3, 121.6, 124.0, 124.9, 128.7,
131.6, 132.5, 139.5, 140.0, 143.0, 184.4. HRMS (ESI) calcd for
C
(100 MHz,
2
6
o
5
14
C H13 N O Cl [M+H] 246.0686, found 246.0699. mp 132-135 C
Gibson, A.W.; Humphrey, G. R.; Kennedy, D. J.; Wright, S. H. B.
Synthesis, 1991, 414
(a) Negishi, E.; Van Horn, D. E; Yoshida, T.; J. Am. Chem. Soc.,
1985, 107, 6639 (b) Baker R. and Brimble, A. M. Tetrahedron.
Lett., 1986, 27, 3311
Tohdo, K., Hamada Y., Shioiri T., Tetrahedron. Lett., 1992, 33,
7
.
2
5
031; Vaz, B; Alvarez, R; de Lera, A. R. J. Org. Chem. 2002, 67,
040.
8
.
Lauchli R.; Shea, K. J. Org. Lett., 2006, 8, 5287
Indiacen A (1): IR (KBr) 3496, 3183, 2918, 1642, 1402, 1293,
9
.
-1
1
139, 975, 852, 746 cm . δ
CH ), 5.03-5.16 (m, 2H, CH
.25-7.31 (m, 1H, CH), 7.45 (d, J=7.82 Hz, 1H, CH), 7.60 (d,
J=7.82 Hz, 1H, CH), 8.28 (s, 1H, CH), 8.49 (d, J=16.14 Hz, 1H,
CH), 9.92 (s, 1H, CHO), 11.33 (br s, 1H, NH); δ (100 MHz,
acetone-d ) 19.3, 112.2, 116.4, 119.1, 121.7, 124.0, 124.9, 131.6,
32.1, 133.0, 140.0, 142.6, 144.5, 184.3. HRMS (ESI) calcd for
H
(400 MHz, acetone-d
6
) 2.14 (s, 3H,
3
2
), 6.97 (d, J=16.14 Hz, 1H, CH),
7
C
6
1
C
o
14
H14NO [M+H] 212.1075, found 212.1079. mp 159-162 C
1
0. Indiacen B (2): IR (KBr) 3727, 3167, 2921, 1636, 1404, 1368,
-1
1
145, 975, 795, 746, 642 cm . δH(400 MHz, acetone-d
s, 3H, CH ), 6.47 (s, 1H, CH), 6.97 (d, J=16.14 Hz, 1H, CH),
.24-7.33 (m, 1H, CH), 7.47 (d, J=7.82 Hz, 1H, CH), 7.59 (d,
6
) δ 2.21
(
3
7
J=7.34 Hz, 1H, CH), 8.31 (s, 1H, CH), 8.63 (d, J=16.14 Hz, 1H,
Highlights:
•
•
•
A novel synthesis of antimicrobial metabolites
Indiacen A and Indiacen B is achieved.
An indole derivative with terminal enyne group
was employed as a common intermediate.
The key reactions are olefination, carbo-
alumination and chlorination.