Total synthesis of diaportheone A

Article abstract of DOI:10.1016/j.tetlet.2018.11.055

Diaportheone A (1), a chromone natural product was previously isolated from the endophytic fungi Diaporthe sp. P 133. Its structure was established by spectroscopic methods, however, its absolute configuration remained undefined. This study dealt on the total synthesis of diaportheone A (1) utilizing the cyclization and in situ thermal syn-elimination of a β-ketosulfoxide. The C-1R absolute configuration of the natural product was established by X-ray crystallography of the synthetic diaportheone A (1) (>99% ee) and comparison with the optical rotation.

Full text of DOI:10.1016/j.tetlet.2018.11.055

Accepted Manuscript
Total synthesis of diaportheone A
Mario A. Tan, Patrik Peter Züger, Silvio Roggo
PII:
S0040-4039(18)31404-7
https://doi.org/10.1016/j.tetlet.2018.11.055
TETL 50440
DOI:
Reference:
Tetrahedron Letters
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15 September 2018
16 November 2018
22 November 2018
Please cite this article as: Tan, M.A., Züger, P.P., Roggo, S., Total synthesis of diaportheone A, Tetrahedron
Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.11.055
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Graphical Abstract
Total synthesis of diaportheone A
Leave this area blank for abstract info.
Mario A. Tan, Patrik Peter Züger, Silvio Roggo
OH
O
OH
O

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Total synthesis of diaportheone A
Mario A. Tana,*, Patrik Peter Zügerb, Silvio Roggob
aResearch Center for the Natural and Applied Sciences and College of Science, University of Santo Tomas, Espana, Manila, Philippines 1015
bInstitute for Biomedical Research, Novartis Pharma, Basel, Switzerland
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Diaportheone A (1), a chromone natural producte, was previously isolated from the endophytic
fungi Diaporthe sp. P 133. Its structure was established by spectroscopic methods, however, its
absolute configuration remained undefined. This study dealt on the total synthesis of
diaportheone A (1) utilizing the cyclization and in situ thermal syn-elimination of a -
ketosulfoxide. The C-1R absolute configuration of the natural product was established by X-ray
crystallography of the synthetic diaportheone A (1) (> 99% ee) and comparison with the optical
rotation.
Available online
Keywords:
Chromone
2009 Elsevier Ltd. All rights reserved.
Diaportheone
Pandanus
X-ray crystallography
Introduction
Results and discussion
Chromones are benzoannelated-pyrone (4H-chromen-4-one,
4H-1-benzopyran-4-one) heterocyclic class of natural products
which are widely distributed in nature. Secondary metabolites
possessing the chromone structure showed diverse
pharmacological properties such as anti-inflammatory,
antimicrobial, antitumor, antidiabetic, antiallergy, diuretics,
hypoglycemic, hypolipidemic, and antioxidant.1 Their structural
diversity and synthetic accessibility have made the compounds
with the chromone scaffold excellent targets in organic synthesis
and play an important role in drug discovery and medicinal
chemistry.1a
Inspired by the synthesis of related benzopyrones4, the
synthesis of 1 (Fig. 2) started from the mono-demethylation of
the commercially available methyl-2,6-dimethoxybenzoate 3
using BCl3 in 97% yield. The mono-demethylated benzoate 4
was converted to -ketosulfoxide5 5 in 67.2% yield as yellow
crystals using sodium methylsulfinylmethide (5 eq. NaH / 25 eq.
DMSO, toluene, 70 °C, 1h). One-pot cyclization and in situ
thermal syn-elimination by treating 5 with 37% succinaldehyde
and catalytic amount of methyl piperidine led to the benzopyrone
compound 6 in 86% yield.6
At this stage, benzopyrone 6 was subjected to chiral
separation7 using preparative SFC method to obtain (+)-(S)-6a
([α]D 25 = +110o (c. 1.0, CHCl3)) and (-)-(R)-6b ([α]D 25 = 126o (c.
1.0, CHCl3)). Both enantiomers were obtained in >99% ee. The
absolute configuration of both enantiomers was determined by X-
ray crystallography (Fig. 3).
Diaportheone A (1) and B (2) (Fig. 1) are chromones isolated
from the endophytic fungi Diaporthe sp. P133 of Pandanus
amaryllifolius. Significant minimum inhibitory concentration
(MIC90) against the virulent strain of Mycobacterium tuberculosis
H37Rv was observed for 1 (MIC 101 µM) and 2 (3.5 µM).2 The
natural product 2 and its enantiomer have been synthesized
including the determination of its absolute configuration.3
However, the absolute configuration of 1 remained to be
determined. This paper describes the synthesis of diaportheone A
and determination of the absolute configuration of the natural
product.
OH O
OH O
OH
OH
H
1
3
Benzopyrone 6a
Benzopyrone 6b
O
O
H
Fig. 3. X-ray crystallography of 6a and 6b.
2
Diaportheone B,
1
Diaportheone A,
Fig. 1. Structures of chromones isolated from Diaporthe sp.
P133.

2
Tetrahedron
Completion of the synthesis involved the demethylation of
6. To a solution of 5 (180 mg, 0.789 mmol) in DMF (0.7 mL)
was added 37% aq. succinaldehyde (0.917 mL, 3.94 mmol) and
catalytic methyl piperidine (0.2 mL). The mixture was stirred at
140 °C for 5h. The mixture was cooled to RT and quenched with
water. The mixture was extracted with DCM (3x) and the
combined organic layer was washed with brine, dried with
anhydrous sodium sulfate, and concentrated under reduced
pressure. The crude mixture was purified by normal phase
column chromatography by MPLC using EtOAc in cyclohexane
(0 to 50%) to obtain the target material 6 in 86% yield (158.3
mg).
benzopyrone 6 using BCl3 to afford the racemic diaportheone A8
in 82% yield. Chiral separation by preparative HPLC9 obtained
the enantiomers (+)-(S)-1a (ent-diaportheone A) ([α]D 25 = +130o
(c. 1.0, CHCl3)) and ()-(R)-1 (diaportheone A) ([α]D 25 = 130o
(c. 1.0, CHCl3)) in 99% ee. Unambiguous determination of the
absolute configuration of the ()-(R)-1 was done by X-ray
crystallography (Fig. 4).
1H NMR (400 MHz, CDCl3) δ 7.53 (t, J = 8.4 Hz, 1H), 7.04 (dd,
J = 8.5, 1.0 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 5.43 (ddd, J = 7.8,
4.0, 1.5 Hz, 1H), 3.98 (s, 3H), 3.05 (dddd, J = 17.8, 9.7, 4.4, 1.5
Hz, 1H), 2.82 (ddd, J = 17.8, 9.3, 5.7 Hz, 1H), 2.50 (dddd, J =
13.7, 9.1, 7.8, 4.3 Hz, 1H), 2.00 (dddd, J = 13.7, 9.7, 5.6, 4.0 Hz,
1H).
7. The chiral separation of rac-6 was done by preparative SFC
method using Chiralpak IG column (5 μm, 250 x 30 mm) using
CO2:[MeOH+0.1%NH3] 45:55 (v:v) as mobile phase. The
flowrate was set at 1.00 mL/min and UV detection at 220 nm.
Both enantiomers were separated in >99% ee. The specific
rotation of 6a was found to be []D 25 = +110o (c. 1.0, CHCl3) and
6b is []D 25 = 126o (c. 1.0, CHCl3).
Fig 4. X-ray crystallography of synthetic 1.
1
8. H NMR (400 MHz, CDCl3) δ 12.40 (s, 1H), 7.49 (t, J = 8.3
Based on these results, the absolute configuration of the
Hz, 1H), 6.90 (dd, J = 8.4, 0.9 Hz, 1H), 6.80 (dd, J = 8.2, 0.9 Hz,
1H), 5.46 (ddd, J = 7.7, 3.4, 1.4 Hz, 1H), 3.14 (dddd, J = 18.2,
9.4, 5.2, 1.5 Hz, 1H), 2.85 (ddd, J = 18.2, 9.4, 4.9 Hz, 2H), 2.52
(dddd, J = 14.3, 9.4, 7.6, 5.1 Hz, 1H), 2.05 (dddd, J = 14.1, 9.2,
4.9, 3.3 Hz, 1H).
9. The chiral separation of rac-diaportheone A was done by
preparative HPLC method using Chiralpak AY-H column (5 μm,
250 x 30 mm) using Heptane : EtOH 85:15 as mobile phase. The
flowrate was set at 1.00 mL/min and UV detection at 220
nm.Both enantiomers were separated in 99% ee. The specific
rotation of 2 was found to be []D 25 = +130o (c. 1.0, CHCl3) and 2
is []D 25 = 130o (c. 1.0, CHCl3).
25
natural diaportheone A ([]D = 52o (c. 0.08, CHCl3))2 was
determined to be R in comparison of the optical rotation of the
synthetic enantiomers with the natural product. The NMR data
including the high resolution spectrometric data is in excellent
agreement with the natural product diaportheone A. The
synthesis of diaportheone A was completed in four steps and
46% over-all yield.
Conclusion
The total synthesis and elucidation of the absolute configuration
of enantiopure diaportheone A (1) was completed. All chiral
compounds (benzopyrones 6a and 6b, and diaportheone A (1)
and ent-diaportheone
A
(1a) were obtained in >99%
enantiomeric excess. The absolute configuration of diaporthone
A was established to be C-1R.
Acknowledgments
The Global Scientific Capabilities Centre of Excellence in Global
Drug Development, Novartis Pharma, the Global Health Office
in Novartis Institutes for BioMedical Research, Basel,
Switzerland, X-ray crystallography unit, and the Separations
Laboratory, NIBR GDC are gratefully acknowledged.
References and notes
1. (a) Gaspar A, Matos MJ, Garrido J, Uriarte E, Borges F.
Chem. Rev. 2014; 114: 4960-4992; (b) Reis J, Gaspar A,
Milhazes N, Borges F. J. Med. Chem. 2017; 60: 7941-7957
2. Bungihan M, Tan MA, Kitajima M, Kogure N, Franzblau S,
dela Cruz, TE, Takayama H, Nonato MG. J. Nat. Med. 2011; 65:
606-609.
3. Swaroop P, Raut G, Gonnade R, Verma P, Gokhale R,
Srinivasa Reddy D. Org. Biomol. Chem. 2012; 10: 5385-5394.
4. Mori K, Audran G, Monti H. Synlett. 1998; 259-260
5. Klutchko S, Cohen M-P, Shavel J-R, Von Strandtmann M. J.
Heterocyclic Chem. 1974; 11: 183-188.

3
OCH3
CO2CH3
OCH3
CO2CH3
OCH3O
O
S
1.1 eq. BCl3, CH2Cl2
y. 97%
Highlights
5 eq. NaH, 25 eq. DMSO, Toluene
y. 67.2%
OH
OCH3
OH
3
4
5
Total synthesis of diaportheone A
OCH3O
OH
O
O
OH
OH
Mario A. Tan,37P%aSturcickinPaldeehtyedre,ZDMügF,er, Silvio Roggo
4 eq. BCl3, CH2Cl2
y. 82%
cat. methylpiperidine, 140 oC
O
y. 86%
rac-1
1. This the first total synthesis and
rac-6
determination of the absolute configuration of
Chiral Separation
Chiral Separation
diaportheone A.
2. The absolute configuration was
unambiguously determined by X-ray
crystallography.
OCH3O
OH
OCH3O
OH
O
OH
O
OH
OH
OH
3. The synthesis was accomplished in four
O
steps and 46% over-all yield.
O
O
O
6a
6b
1a
1
Graphical abstract
Fig 2. Synthesis scheme of diaportheone A (1).
Total synthesis of diaportheone A
Mario A. Tan, Patrik Peter Züger, Silvio Roggo
OH
O
O
OH