The first synthesis of biatriosporin D

Article abstract of DOI:10.1016/j.tetlet.2018.04.027

Biatriosporin D was synthesized in six steps from 3,5-dimethoxyphenol. The key step was an intramolecular Friedel-Crafts cyclization of an acyl imidazolide to form an ortho-quinone.

Full text of DOI:10.1016/j.tetlet.2018.04.027

Accepted Manuscript
The First Synthesis of Biatriosporin D
Shuai Wang, George A. Kraus
PII:
S0040-4039(18)30485-4
DOI:
https://doi.org/10.1016/j.tetlet.2018.04.027
TETL 49890
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
22 March 2018
3 April 2018
10 April 2018
Please cite this article as: Wang, S., Kraus, G.A., The First Synthesis of Biatriosporin D, Tetrahedron Letters (2018),
doi: https://doi.org/10.1016/j.tetlet.2018.04.027
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Shuai Wang, George A. Kraus

1
Tetrahedron Letters
The First Synthesis of Biatriosporin D
a
a,
Shuai Wang , George A. Kraus 
a
Department of Chemistry, Iowa State University, Ames, IA 50010, U.S.A.
ARTICLE INFO
ABSTRACT
Article history:
Received
Biatriosporin D was synthesized in six steps from 3,5-dimethoxyphenol. The key step was an
intramolecular Friedel-Crafts cyclization of an acyl imidazolide to form an ortho-quinone.
Received in revised form
Accepted
Available online
Keywords:
Biatriosporin D
Friedel-Crafts cyclization
Ortho-quinone
The biatriosporins are a group of heptaketide metabolites
1
isolated from the endolichenic fungus Biatrospora sp. They have
been reported to exhibit antifungal activity. Recently, Lou and
coworkers reported that biatriosporin D (1) shows anti-virulence
activity by a mechanism leading to the reduction of intracellular
2
3
cAMP levels. In the context of our program in antimicrobials,
we needed a sample of biatriosporin D and herein report a direct
synthetic route to 1.
Scheme 1. Friedel-Crafts reaction with oxalyl chloride.
Next, we explored the reaction between 4 and ethyl
5
chlorooxoacetate catalyzed by AlCl as shown in Scheme 2. The
3
Figure 1. Biatriosporins
reaction resulted in two products in approximately equal yields.
The structure of compound 7 was supported by the strong NOE
between the furan hydrogen and the methyl group on the furan
ring. The structure of compound 6 was supported by the
symmetry observed in both the proton NMR spectra. Although
compound 7 could have been converted into 1, the yield of 7 was
low. Therefore, this strategy was abandoned in favor of the plan
described in Scheme 3.
Our initial approach focused on creating the ortho-quinone
subunit in 1 via a Friedel-Crafts reaction with oxalyl chloride
Scheme 1). We obtained the requisite aryl furan from the
palladium mediated coupling of the triflate of 3,5-
dimethoxyphenol (3) with 5-methylfuran. While Lewis acid
mediated acylations with oxalyl chloride had been reported to
(
4
give low yields, more recent papers reported good yields. Our
key acylation with oxalyl chloride was not selective, providing
several decomposition products. Various Lewis acids (BF3,
AlCl , TiCl , SnCl ) were tried but none of them afforded the
3
4
4
desired product in good yield. Despite changes in reaction
parameters such as solvent (CH Cl , THF, 1,4-dioxane),
2
2
temperature and the addition of reagents to capture HCl
propylene oxide) the best yield was only 10% with titanium
tetrachloride in methylene chloride at -78 °C.
(
Scheme 2. Friedel-Crafts reaction with ethyl chlorooxoacetate.
—
——

Corresponding author. Tel.: +1-515-294-7794; e-mail: gakraus@iastate.edu

2
Tetrahedron Letters
Electronic Devices 2016, 4, 2269-2273. e) Gao, Z.; Chen, Y.;
Meng, B.; Kong, M.; Wang, S. Shenyang Huagong Xueyuan
Xuebao. 2009, 23, 213-216, 249.
5
6
7
8
9
.
.
.
.
.
Richter, C.; Ernsting, N.P.; Mahrwald, R. Synthesis. 2016, 48,
1
217-1225.
Kraus, G.A.; Gupta, V.; Kempenma, A. Synlett. 2012, 23, 385-
88.
3
Yoshikawa, N.; Doyle, A.; Tan, L.; Murry, J.A.; Akao, A.;
Kawasaki, M.; Sato, K. Org. Lett. 2007, 9, 4103-4106.
Bernard, A.M.; Ghiani, M.R.; Piras, P.P; Rivoldini, A. Synthesis.
1
989, 287-289.
General Experimental Procedure for the cyclization and the
demethylation. To a solution of acid 10 (145 mg, 1.0 equiv) in
CH Cl (3.0 mL) was added carbonyldiimidazole (162 mg, 2.0
2 2
equiv). The reaction mixture was stirred at room temperature
overnight. The resulting solution was added into a solution of
TiCl
reaction mixture was stirred at -10 °C for 5 hours and quenched by
addition of HCl (2.0 M) and then was extracted twice with CH
The combined organic solution was washed with sat NaHCO
water and brine. The organic solution was dried by Na SO . The
4 2 2
(380 mg, 4.0 equiv) in CH Cl (2.0 mL) at -10 °C. The
2
Cl2.
3
,
2
4
solvent was evaporated in vacuo and red solid 5 was obtained (87
mg, 63 %). To a solution of solid 5 (54.4 mg, 1.0 equiv) in DMF
Scheme 3. Synthesis of 1 in six steps.
(6.0 mL) was added LiCl (50.4 mg, 6.0 equiv). The reaction
mixture was heated under reflux for 2 hours and was cooled down.
DMF was removed by distillation under reduced pressure. And the
residue was acidified by HCl (2.0 M) and then was extracted three
times by EtOAc. The combined organic solution was washed with
water, brine. The organic solution was dried by Na SO . The
2 4
solvent was evaporated in vacuo and the residue was purified by
Our second route began with the reaction of 3,5-
dimethyoxyphenol with ethyl chlorooxalate and titanium
tetrachloride to produce the phenol, which could be readily
6
converted into triflate 8 in 93% yield. Coupling of 8 with 5-
methylfuranyl boronic acid afforded furan 9 in 94% isolated
yield. Hydrolysis with NaOH in ethanol-water provided the keto
acid 10 in 99% yield. Conversion of the keto acid 10 into ortho-
quinone 5 proved to be difficult. Reaction with trifluoroacetic
anhydride and tin tetrachloride produced 12-20% yields of 5.
column chromatography on silica gel and product 1 was obtained
1
as red solid (47.4 mg, 92 %). H NMR (400 MHz, CDCl
3
) δ =
1
1
1
2.43 (s, 1H), 6.74 (d, J=2.3, 1H), 6.41 (s, 1H), 6.31 (d, J=2.3,
13
H), 3.90 (s, 3H), 2.40 (s, 3H). C NMR (100 MHz, CDCl
3
) δ =
82.12, 175.37, 169.22, 168.20, 158.14, 156.31, 129.59, 122.78,
7
Fortunately, a procedure recently reported by Yoshikawa using
106.82, 105.39, 104.44, 101.26, 56.31, 13.78. HRMS (ESI-QTOF)
+
carbonyl diimidazole (CDI) followed by titanium tetrachloride at
calcd for [M + H ]: 259.0601, found: 259.0597.
-10 °C afforded a 63% isolated yield of 5 as a sparingly soluble
red solid. Attempted deprotection using boron trichloride, boron
tribromide or aluminum chloride returned recovered starting
material. Finally, lithium chloride in boiling DMF for two hours
8
produced the demethylation product 1 in 92 % yield.
Ortho-quinone 1 was synthesized in six steps from 3,5-
dimethoxyphenol. This route is scalable, providing 300
miligrams of 1. This three-component synthetic approach will
allow for considerable flexibility in the design of synthetic
analogs of 1.
Acknowledgments
We thank the Department of Chemistry for partial support of
Shuai Wang.
A. Supplementary data
Supplementary data associated with this article can be found,
in the online version, at
References and notes
1
2
.
.
Zhou, Y.; Zhang, M.; Zhu, R.X.; Zhang, J.Z.; Xie, F.; Li, X.B.;
Chang, W.Q.; Wang, X.N.; Zhao, Z.T.; Lou, H.X. J. Nat. Prod.
2
016, 79, 2149-2157.
Zhang, M.; Chang, W.Q.; Shi, H.Z.; Zhou, Y.H.; Zheng, S.; Li,
Y.; Li, L.; Lou, H.X. Toxicology and Applied Pharmacology.
2
017, 322, 104-112.
3
4
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Guney, T.; Kohles, S.A.; Thompson, V.L.; Philips, G.J.; Kraus,
G.A. Tetrahedron. 2015, 71, 3115-3119.
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Granoth, I.; Pownall, H.J. J. Org. Chem. 1975, 40, 2088-2091. c)
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Huang, W. J. Materials Chem. C: Materials for Optical and

3
Highlights
1
. An efficient synthesis of Biatriosporin D
2
. Cyclization of an acyl imidazolide to produce an
ortho-quinone
3
. Selective demethylation using LiCl in DMF