Enantioselective Formal Synthesis of the Cytotoxic Topoisomerase II Inhibitor Deoxythysanone, Catalyzed by Chiral Spiroborate Ester

Article abstract of DOI:10.1134/S1070428020040181

Abstract: Bioactive pyranonaphthoquinone analogs, (1R,3S)-deoxythysanone,(1R,3S)-thysanone, and (1R,3S)-demethoxythysanone can be efficientlysynthesized from a common intermediate product, (S)-3-methyl-3,4-dihydro-1H-isochromene-5,8-dione. We have develop

Full text of DOI:10.1134/S1070428020040181

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 4, pp. 693–697. © Pleiades Publishing, Ltd., 2020.
Enantioselective Formal Synthesis of the Cytotoxic
Topoisomerase II Inhibitor Deoxythysanone,
Catalyzed by Chiral Spiroborate Ester
M. U. Chopadea,b,*, M. D. Nikaljeb, H. S. Patilc, and A. U. Chopaded
a Department of Chemistry, Sant Dnyaneshwar Mahavidyalaya, Soegaon, Aurangabad, 431120 India
b Department of Chemistry, Savitribai Phule University, Pune, 411007 India
c Department of Chemistry, Moreshwar College, Bhokardan, 431114 India
d Dahiwadi College, Dahiwadi, 415508 India
*e-mail: chopademanojkumar@gmail.com; chopadeau@yahoo.co.in
Received September 26, 2019; revised February 20, 2020; accepted February 25, 2020
Abstract—Bioactive pyranonaphthoquinone analogs, (1R,3S)-deoxythysanone, (1R,3S)-thysanone, and
(1R,3S)-demethoxythysanone can be efficiently synthesized from a common intermediate product, (S)-3-meth-
yl-3,4-dihydro-1H-isochromene-5,8-dione. We have developed a short synthetic route to pyranonaphthoquinone
antibiotics, which involves enantioselective reduction of homobenzylic ketone in the presence of a chiral
spiroborate catalyst with 87% enantiomeric excess as the key step. The subsequent oxa-Pectet–Spengler
reaction, followed by oxidative demethylation, afforded deoxythysanone.
Keywords: homobenzylic ketone, spiroborate esters, asymmetric reduction, alcohol, deoxythysanone
DOI: 10.1134/S1070428020040181
Compounds of the pyranonaphthoquinone family
are of microbial origin and are used as antibiotics
against pathogenic microorganisms like bacteria, fungi,
yeasts, and viruses [1, 2]. Their basic skeleton consists
of the naphtha[2,3-c]pyran-5,10-dione ring system in
which the naphthoquinone moiety is fused to dihydro-
pyran ring; an additional γ-lactone ring fused to the di-
hydropyran moiety is present in some members [3, 4].
Pyranonaphthoquinone skeleton is one of the most im-
portant pharmacophores constituting various bioactive
natural products such as thysanone, deoxythysanone,
ventiloquinone L, isoeleutherin, and eleutherin [5–9]
(Fig. 1). Thysanone is a fungal isolate from Thysano-
phora penicilloides; it inhibits human rhinovirus 3C
protease. Deoxythysanone showed in vivo growth in-
hibition of Saccharomyces cerevisiae with an IC50
value of 15 μM. Deoxythysanone also exhibited cyto-
toxicity against P388 murine leukemia cell lines with
O
OH
OH
O
OH
OH
O
OH
O
O
O
Me
HO
Me
O
MeO
Me
O
O
O
Deoxythysanone
Thysanone
Ventiloquinone L
OMe
Me
OMe
O
O
Me
O
O
Me
Me
O
Isoeleutherin
Eleutherin
Fig. 1. Structures of some pyranonaphthoquinone antibiotics.
693

CHOPADE et al.
694
Scheme 1.
R1
O
O
OH
O
OMe
OMe
Me
Me
O
O
OH
R2
Me
O
6
4
OMe
OMe
OMe
OMe
NO2
Me
CHO
2
1
Deoxythysanone: R1 = R2 = H; thysanone: R1 = R2 = OH; demethoxythysanone: R1 = OH, R2 = H.
an IC50 value of 5–10 μM [10, 11]. The wide range of
bioactivity of pyranonaphthoquinone antibiotics made
them interesting synthetic targets. There have been
several published reports on the synthesis of deoxy-
thysanone and thysanone. The reported syntheses are
based on the chiral pool approach [12], Sharpless
asymmetric dihydroxylation [13], CBS reduction [14],
enzymatic resolution [15], and asymmetric α-amino-
oxylation [16], but these protocols have drawbacks like
several reaction steps, low yield, and low enantioselec-
tivity. Hence, there is a need of a common synthetic
approach that would combine efficient strategy with
short time and high yield compared to the reported
methods.
The objective of the present investigation is to
develop a very short route for the synthesis of deoxy-
thysanone via asymmetric reduction of intermediate
ketone as the key stage. In addition, the syntheses of
the ketone by modified Nef reaction are also described
[17]. Retrosynthetic analysis of deoxythysanone
(Scheme 1) showed that the creation of stereocenters at
C1 and C3 is the main challenge [15]. Our synthetic
strategy (Scheme 2) utilized 2,5-dimethoxybenzalde-
hyde (1) as a starting material for the synthesis of de-
Scheme 2.
OMe
OMe
OMe
OMe
CHO
NO2
Me
Me
i
ii
iii
Me
O
OH
OMe
OMe
OMe
OMe
1
2
3
4
OMe
OMe
O
O
R1
O
OH
9
Me
Me
10
5
1
8
7
iv
v
O
3
O
O
R2
Me
6
4
O
5
6
7, deoxythysanone (R1 = R2 = H)
Me
H2
N
O
Me
Catalyst =
B
Ph
Ph
O
O
Reagents and conditions: i: EtNO2, t-BuNH2, tolulene, reflux, 84%; ii: Fe, AcOH, 1h, 82%; iii: BH3·SMe2, catalyst, THF, 25°C,
30 min, 95%; iv: ZnCl2 (30 mol %), MeOCH2Cl, Et2O, 0°C to r.t., 4 h, 82%; v: CAN, MeCN/H2O, 0°C to r.t., 25 min.
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ENANTIOSELECTIVE FORMAL SYNTHESIS
695
oxythysanone. The nitroaldol condensation of 2,5-di-
methoxybenzaldehyde (1) with nitroethane in the pres-
ence of tert-butylamine as a base gave (E)-1,4-di-
methoxy-2-(2-nitroprop-1-en-1-yl)benzene (2) which
was purified by column chromatography to isolate
a yellow solid with 84% yield. The nitro group of 2
was subjected to modified Nef reaction with iron metal
in acetic acid for 3 h at 60°C in order to obtain
homobenzylic ketone 3 as a colorless liquid with 82%
yield. Ketone 3 was reduced with oxazaborolidine
catalyst at 25°C in 85% yield and 40% ee. Raising the
temperature to 40°C increased enantiomeric excess to
50%, but the yield decreased to 80% [18]. Further
reduction of 3 ketone was performed at 0°C using
BH3·SMe2 in the presence of spiroborate ester catalyst
prepared from chiral diphenylvalinol [19]; in this case,
60% ee and 90% yield were achieved. Optimization
results showed that both enantiomeric excess and yield
significantly increased (87% ee, 95% yield) when the
reaction was carried out by slowly adding homoben-
zylic ketone 3 at a constant rate at room temperature.
ical shifts were measured relative to tetramethylsilane
(1H) or CDCl3 (δC 77.00 ppm). The IR spectra were
recorded on a Shimadzu FTIR-8400 spectrometer with
samples loaded as thin films on KBr plates. The optical
rotations were determined on a Jasco P-2000 polarim-
eter using 10-mm cells. Gas chromatographic/mass
spectrometric analyses were run on an Agilent 5975
mass selective detector interfaced with an Agilent 7890
gas chromatograph (HP-5 capillary column, 30 m×
0.32 mm×0.25 μm, J & W Scientific). The LC/MS
(ESI) data were obtained with a Waters H-Class HPLC
system (Milford, MA) coupled to an ion trap mass
spectrometer with an electrospray ionization source
(Finnigan MAT, San Jose, CA). The melting points
were taken with a Büchi 560 apparatus and are uncor-
rected. HPLC analysis was performed by using Waters
HPLC system with an UV-Vis detector and an analy-
tical X-Bridge C18 column (4.6×250 mm, 5 μm) at
a flow rate of 1 mL/min. All reactions were carried out
in dry solvents, unless otherwise stated. The reaction
progress was monitored by TLC on silica gel plates
(Kieselgel 60 F254, Merck). Visualization of spots on
TLC plates was achieved either by UV light or by
staining the plates in 2,4-dinitrophenylhydrazine/anis-
aldehyde and charring on a hot plate.
The resulting chiral alcohol, (S)-1-(2,5-dimethoxy-
phenyl)propan-2-ol (4) was purified by flash chroma-
tography. Alcohol 4 was then subjected to oxa-Pictet–
Spengler cyclization with methoxymethyl chloride in
the presence of ZnCl2 (30 mol %) in anhydrous diethyl
ether to afford (S)-5,8-dimethoxy-3-methyl-3,4-dihy-
dro-1H-2-benzopyran (5) with 82% yield. Oxidative
demethylation of 5 was carried out by the action of
ceric ammonium nitrate (CAN) in aqueous acetonitrile
to furnish the target quinone. Thus, we have success-
fully completed the synthesis of (+)-(S)-3-methyl-3,4-
dihydro-1H-2-benzopyran-5,8-dione (6) in six steps
with high optical purity (87% ee) and overall yield of
49.2%. The two-step conversion of 6 to (1R,3S)-deoxy-
thysanone (7a) has been reported in [20]. Initially,
quinone 6 reacted with 1-acetoxy-1,3-butadiene at
room temperature in toluene for 48 h, followed by
treatment with 1% aqueous solution of sodium carbon-
ate in ethanol at room temperature for 5 h. Purification
gave 7a in 85% yield, and all its characteristics
matched the reported data.
(S)-1-(2,5-Dimethoxyphenyl)propan-2-ol (4) [16].
A solution of BH3–DMS complex (10 M, 0.5 mL,
5.0 mmol) was added with stirring over a period of
30 min at 25°C under argon to a mixture of chiral
spiroborate ester (0.5 mmol) and anhydrous THF
(15 mL). A solution of compound 3 (931 mg,
5.0 mmol) in anhydrous THF (5 mL) was than added
over a period of 1 h using an infusion pump. After
30 min, compound 3 was completely consumed (TLC).
The mixture was stirred at 25°C for an additional 1 h,
cooled to 0°C, and slowly quenched with methanol
(5 mL). After stirring for 1 h at room temperature, the
solvent was removed under reduced pressure. The
residue was dissolved in methylene chloride (20 mL),
washed with a saturated solution of ammonium
chloride (15 mL) and water (10 mL), and dried over
Na2SO4. The solvent was evaporated under reduced
pressure, and the crude product was purified by flash
chromatography (15% EtOAc/hexane) to afford 4
(935 mg) as colorless oil.
All isolated intermediate compounds were charac-
1
terized by spectroscopic data (IR, H and 13C NMR).
The enantiomeric excess of (S)-4 was determined by
HPLC analysis using a chiral AD-H column
(250 mm×4.6 mm; particle size 5 μm) [21].
1,4-Dimethoxy-2-(2-nitroprop-1-en-1-yl)benzene
(2). Yield 84%, yellow solid. mp 64–62°C. IR spec-
trum (KBr), cm–1: 2999, 2357, 2056, 1645, 1504, 1321,
EXPERIMENTAL
1
1298, 1118, 1041, 860, 705, 482. H NMR spectrum
1
The H and 13C NMR spectra were recorded on
(300 MHz, CDCl3), δ, ppm: 8.21 s (1H), 7.91–6.82 m
a Varian Mercury 300 MHz spectrometer; the chem-
(3H), 3.82 s (3H, OCH3), 3.78 s (3H, OCH3) 2.38 s
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 4 2020

CHOPADE et al.
696
(3H). 13C NMR spectrum (75 MHz, CDCl3), δC, ppm:
153.58, 153.17, 147.75, 129.61, 116.08, 115.84,
113.36, 110.44, 55.87, 56.07, 14.13. Mass spectrum:
m/z 223.
(3H, J = 6.0 Hz, CH3). 13C NMR spectrum (75 MHz,
CDCl3), δC, ppm: 186.0, 185.7, 145.2, 139.5, 136.3,
136.0, 69.4, 62.7, 28.8, 21.1.
ACKNOWLEDGMENTS
1-(2,5-Dimethoxyphenyl)propan-2-one (3). Yield
82%, colorless liquid. IR spectrum (KBr), cm–1: 3400,
3273, 2843, 1712, 1500, 1356, 1280, 1226, 1222, 1159,
The authors are thankful to Department of Science and
Technology and Department of Chemistry, University of
Pune, for financial support and infrastructural facility;
M. Chopade thanks the Ajintha Education Society for
infrastructural facility.
1
810, 707, 526. H NMR spectrum (300 MHz, CDCl3),
δ, ppm: 6.79–6.70 m (3H), 3.76 s (3H, OCH3), 3.75 s
(3H, OCH3) 3.64 s (2H, CH2), 2.13 s (3H). 13C NMR
spectrum (75 MHz, CDCl3), δC, ppm: 206.43, 153.13,
151.25, 124.30, 117.03, 112.40, 111.13, 55.70, 55.40,
45.44, 29.11. Mass spectrum: m/z 194.
FUNDING
This study was performed under financial support by the
BCUD Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad.
1-(2,5-Dimethoxyphenyl)propan-2-ol (4). Yield
95%, white solid, mp 55–57°C, 96% ee, [α]D25
=
+11.21° (c = 1, MeOH) [16], [α]D23 = +14.8° (c = 1.01,
MeOH). IR spectrum (KBr), cm–1: 3410, 2949, 1500,
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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