Total synthesis of anithiactins A-C and thiasporine A

Article abstract of DOI:10.1016/j.tetlet.2019.01.038

The total syntheses of anithiactins A-C (1–3) and thiasporine A (4) have been achieved in good overall yields. The key reaction in the synthetic sequence was the Suzuki-Miyaura cross-coupling between 2-aminophenylboronic acid hydrochloride and methyl 2-bromothiazole-4-carboxylate forming the common intermediate methyl 2-(2-aminophenyl)thiazole-4-carboxylate (8), which could be further transformed by hydrolysis, alkylation, and aminolysis to give the four title natural products. This work represents the first total synthesis of anithiactin B (2) and C (3).

Full text of DOI:10.1016/j.tetlet.2019.01.038

Accepted Manuscript
Total synthesis of anithiactins A-C and thiasporine A
I. Caroline Vaaland, Emil Lindbäck, Magne O. Sydnes
PII:
S0040-4039(19)30067-X
https://doi.org/10.1016/j.tetlet.2019.01.038
TETL 50571
DOI:
Reference:
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
19 December 2018
17 January 2019
20 January 2019
Please cite this article as: Vaaland, I.C., Lindbäck, E., Sydnes, M.O., Total synthesis of anithiactins A-C and
thiasporine A, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.01.038
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Total synthesis of anithiactins A-C and thiasporine A Leave this area blank for abstract info.
I. Caroline Vaaland, Emil Lindbäck and Magne O. Sydnes
University of Stavanger

1
Tetrahedron
Total synthesis of anithiactins A-C and thiasporine A
a
a
a,
I. Caroline Vaaland , Emil Lindbäck and Magne O. Sydnes 
a
Faculty of Science and Technology, Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, NO-4036 Stavanger,
Norway
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The total syntheses of anithiactins A-C (1-3) and thiasporine A (4) have been achieved in good
overall yields. The key reaction in the synthetic sequence was the Suzuki-Miyaura cross-
coupling between 2-aminophenylboronic acid hydrochloride and methyl 2-bromothiazole-4-
carboxylate forming the common intermediate methyl 2-(2-aminophenyl)thiazole-4-carboxylate
(8), which could be further transformed by hydrolysis, alkylation, and aminolysis to give the
four title natural products. This work represents the first total synthesis of anithiactin B (2) and
C (3).
Available online
Keywords:
Natural product
Total synthesis
Thiazole
2
009 Elsevier Ltd. All rights reserved.
Suzuki-Miyaura cross-coupling
—
——

Corresponding author. Tel.: +47-51831761; fax: +47-51831750; e-mail: magne.o.sydnes@uis.no

2
Tetrahedron
1
. Introduction
Anithiactins A-C (1-3) (Fig. 1) was first reported by Kim and
co-workers isolated from Streptomyces sp. 10A085 samples
Figure 1. Structures of anithiactin A-C (1-3) and thiasporine
A (4).
collected from mudflat sediment on the southern coast of the
Korean peninsula. Shortly thereafter Fu and MacMillan reported
1
2. Results and Discussion
the isolation of anithiactin A (1) and C (3) from
Our synthesis was based on the preparation of the common
intermediate methyl 2-(2-aminophenyl)thiazole-4-carboxylate (8)
that could be further converted to all four products by either
conducting an alkylation, alkylation-hydrolysis or -aminolysis
sequence. Biaryl 8 was envisioned as being prepared by a
Actionomycetospora sp. SNC-032 collected from a mangrove
2
,3
4,5
swamp in Vava’u, Tonga, together with thiasporine A (4).
Compounds 1-3 showed moderate acetylcholinesterase inhibitory
activity, and anithiactin A (1) acted as a competitive inhibitor of
1
,6
8
monoamine oxidase A (K = 1.84 M). Thiasporine A (4)
i
Suzuki-Miyaura cross-coupling between 2-aminophenylboronic
displayed cytotoxicity against the non-small-cell lung cancer cell
acid hydrochloride (5) or the corresponding boronate 6 (see ESI)
and methyl 2-bromothiazole-4-carboxylate (7). The preparation
of compound 8 turned out to be quite challenging, at least partly
2
line H2122 (IC50 = 5.4 M), while compounds 1-3 showed no
1
significant cytotoxicity. Anithiactin A (1) has been prepared
9
synthetically by Kim and co-workers as part of their structure
due to sulfur being a catalyst poison. Therefore, laborious
1
7
elucidation work, and by the group of Hawkins. The syntheses,
which were three and four steps long, respectively, gave the
desired compound in 24% and 8% overall yield, respectively. As
optimization studies of the Suzuki-Miyaura cross-coupling
conditions were conducted, details of which can be found in
Table 1 and Table S1 in the ESI.
5
part of the structure revision of thiasporine A (4), the natural
Utilizing palladium-tetrakis(triphenylphosphine) as catalyst
and potassium carbonate as base in toluene/water (3:1) heated in
a microwave (MW) oven gave 14-15% of the desired cross-
coupling product (Table 1, entries 1 and 2). Further attempts to
improve this yield were unsuccessful. Switching the catalyst to
palladium(II) acetylacetonate and changing the reaction
conditions, which also included addition of XPhos, improved
matters slightly resulting in the formation of compound 8 in 26%
yield (Table 1, entry 3). However, turning to
product was prepared in a one-pot sequence from 2-
aminobenzonitrile in 37% yield. Herein, we report our total
syntheses of natural products 1-4, which also represents the first
total synthesis of anithiactin B (2) and anithiactin C (3).
4
tris(dibenzylideneacetone)dipalladium(0) as the catalyst and
utilizing XPhos as the ligand finally solved the problem (Table 1,
entries 4-9). 1,4-Dioxane (Table 1, entries 6-9) was found to be a
better solvent for the reaction than a mixture of ethanol and water
(
Table 1, entries 4 and 5).
In our hands the highest yield of the desired cross-coupling
product was obtained when treating boronic acid 5 and
bromothiazole 7 with Pd dba and XPhos using CsF as base in
2
3
1
0
1
,4-dioxane at reflux resulting in a 64% isolated yield of ester 8
(
Table 1, entry 8). An attempt to increase the reaction time did
not result in an increased yield most likely due to decomposition
of the product over time (Table 1, entry 9). In order to further
improve the yield of compound 8 boronate 6 was used instead of
boronic acid 5 (Table 1, entry 10), however, to our
disappointment the yield dropped.

3
Table 1. Optimization of the Suzuki-Miyaura cross-coupling of boronic acid 5 and 2-bromothiazole-4-carboxylate (7).
Entry
Catalyst
Ligand
Base
Solvent
Temp./condition
Time
0.5 h
1.5 h
0.75 h
1 h
Yield
14%
15%
26%
23%
54%
51%
35%
64%
53%
29%
a
o
1
Pd(PPh
Pd(PPh
3
3
)
4
4
(20 mol%)
(20 mol%)
(10 mol%)
(15 mol%)
(10 mol%)
(10 mol%)
(10 mol%)
(10 mol%)
(15 mol%)
(15 mol%)
-
K
2
CO
3
3
(4 equiv.)
(4 equiv.)
Toluene/H
Toluene/H
Dioxane
2
O (3:1)
O (3:1)
110 C, MW
b
o
2
)
-
K
2
CO
2
110 C, MW
a
o
3
Pd(acac)
2
XPhos (20 mol%)
XPhos (5 mol%)
XPhos (20 mol%)
XPhos (43 mol%)
XPhos (1 equiv.)
XPhos (43 mol%)
XPhos (43 mol%)
XPhos (43 mol%)
CsF (3.5 equiv.)
KOAc (3 equiv.)
150 C, MW
o
4
Pd
Pd
Pd
Pd
Pd
Pd
Pd
2
(dba)
2
(dba)
2
(dba)
2
(dba)
2
(dba)
2
(dba)
2
(dba)
3
3
3
3
3
3
3
EtOH/H
2
O (9:1)
O (9:1)
130 C, MW
c
o
5
KOAc (3.5 equiv.) EtOH/H
2
130 C, MW
1 h
b
o
6
CsF (3.5 equiv.)
CsF (3.5 equiv.)
CsF (4 equiv.)
CsF (4 equiv.)
Dioxane
150 C, MW
0.5 h
1.5 h
17 h
20 h
17 h
b
o
7
Dioxane
Dioxane
Dioxane
Dioxane
150 C, MW
a
8
Reflux
Reflux
a,d
9
e
1
0
CsF (4 equiv.)
Reflux
a
b
c
d
e
2
equiv. of boronic acid 5 was used; 1.5 equiv. of boronic acid 5 was used; 1.1 equiv. of boronic acid 5 was used; 0.1 equiv. of 18-crown-6 was added; 1.05
equiv. of boronate 6 was used.
Scheme 1. Synthesis of anithiactin A-C (1-3) and thiasporine A (4).
With the optimized cross-coupling conditions in hand, focus
then shifted towards the next challenge in the synthesis, namely
the alkylation of substrate 8. The monomethylation of compound
to give anithiactin A (1) has been proved to be non-trivial as
8
can be seen from the rather low yield obtained by Kim and co-
1
workers for this transformation (43%). Initially we treated
substrate 8 with formaldehyde (37% w in water) in ethanol under
a hydrogen atmosphere over Pd/C according to our previously

4
Tetrahedron
1
1
reported method. Unfortunately, this only resulted in the
of Bergen, for conducting MS analysis. Professor Tanaka,
formation of anithiactin A (1) in 30% yield. However, by
Okinawa Institute of Science and Technology Graduate
University, Okinawa, Japan is thanked for excellent working
conditions during a sabbatical stay.
modifying the reductive amination conditions reported by Kim
1
and co-workers by using sodium triacetoxyborohydride as the
reducing agent in the presence of 4 Å molecular sieves (MS) in
1
,2-dichloroethane (DCE) provided anithiactin A (1) in 70%
References and notes
isolated yield (Scheme 1), thus resulting in the formation of
anithiactin A (1) in 45% yield over the two steps.
1. Kim, H.; Yang, I.; Patil, R. S.; Kang, S.; Lee, J.; Choi, H.; Kim,
M.-S.; Nam, S.-J.; Kang, H. J. Nat. Prod. 2014, 77, 2716-2719.
2. Fu, P.; MacMillan, J. B. J. Nat. Prod. 2015, 78, 548-551.
Subjecting anithiactin A (1) to aminolysis using 4 M NH in
3
2
methanol utilizing a modified procedure reported in a patent by
3. In the isolation paper by Fu and MacMillan they named
1
2
anithiactin A (1) as thiasporine C and anithiactin C (3) as
Billedeau and co-workers gave anithiactin B (2) in 85% yield
thiasporine B presumably due to the fact that they were not aware
after a reaction time of 4 days (Scheme 1). This transformation
1
of the paper by Kim and co-workers, which at the time of
could also be conducted by using 2 M NH in methanol,
3
submission by Fu and MacMillan must have been in press.
Compounds 1 and 3 have since been referred to as anithiactin A
and anithiactin C, respectively.
however, the reaction was more sluggish and did not reach
completion over the course of 5 days. Under the latter conditions,
the target product was isolated in 71% yield in addition to
recovery of the starting material. Hydrolysis of natural product 1
upon treatment with aqueous sodium hydroxide in methanol at
room temperature gave anithiactin C (3) in 57% yield. Finally,
subjecting ester 8 to similar hydrolysis conditions as used for
compound 1 gave the final natural product, viz. thiasporine A (4),
in 95% yield. The spectroscopic data obtained for anithiactins A-
C (1-3) and thiasporine A (4) are in agreement with the data
reported for the isolated compounds (see ESI, Table S2 for
details).
4
5
.
.
Seitz, T.; Fu, P.; Haut, F.-L.; Adam, L.; Habicht, M.; Lentz, D.;
MacMillan, J. B.; Christmann, M. Org. Lett. 2016, 18, 3070-3073.
The structure of thiasporine A (4) was incorrectly assigned in the
2
original isolation paper. The structure was revised in 2016 as a
result of a collaboration between the groups of MacMillan and
4
Christmann.
6. Lee, H. W.; Jung, W. K.; Kim, H. J.; Jeong, Y. S.; Nam, S.-J.;
Kang, H.; Kim, H. J. Microbiol. Biotechnol. 2015, 25, 1425-1428.
7
8
.
.
Lamb, R. A.; Badart, M. P.; Swaney, B. E.; Gai, S.; Baird, S. K.;
Hawkins, B. C. Aust. J. Chem. 2015, 68, 1829-1833.
Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.
9. a) Bartholomew, C. H. Appl. Catal., A 2001, 212, 17-60; b)
Dunleavy, J. K. Platinum Met. Rev. 2006, 50, 110.
3
. Conclusion
1
0. a) Bannister, T. D.; Roush, W. R.; Choi, J. Y.; Nair, R.; Tsai, A.
S.; Mishra, J. K.; Cleveland, J. L. WO 2016118825, A1, 2016;
Chem. Abstr. 2016, 165, 224000; b) Yadav, M. R.; Nagaoka, M.;
Kashihara, M.; Zhong, R.L.; Miyazaki, T.; Sakaki, S.; Nakao, Y.
J. Am. Chem. Soc. 2017, 139, 9423-9426.
We have successfully prepared anithiactins A-C (1-3) and
thiasporine A (4) using a Suzuki-Miyaura cross-coupling reaction
as the key step forming methyl 2-(2-aminophenyl)thiazole-4-
carboxylate (8). Compound 8 was further elaborated giving the
four natural products 1-4 in good overall yield. This work
represents the first total synthesis of anithiactin B (2) and C (3).
1
1
1. Sydnes, M. O.; Isobe, M. Tetrahedron Lett. 2008, 49, 1199-1202.
2. Billedeau, R. J.; Kondru, R. K.; Lopez-Tapia, F. J.; Lou, Y.;
Owens, T. D.; Qian, Y.; So, S.-S.; Thkkar, K. C.; Wanner, J. WO
2
012156334, A1, 2012; Chem.Abstr. 2012, 157, 734758.
Supplementary Material
Acknowledgments
1
13
Supplementary material including H and C NMR charts of
compounds 1-4 and 8 can be found in the online version at
doi:…...
Financial support from the University of Stavanger and the
research program Bioactive is gratefully acknowledged. The
authors would also like to thank Dr. Bjarte Holmelid, University

5
Highlight
An efficient total synthesis of the natural products
anithiactin A-C and thiasporine A.