An Alternative Approach to the Synthesis of Parvistone C

Article abstract of DOI:10.1002/jhet.3455

A stereoselective total synthesis of parvistone C, an oxygenated natural styryllactone, has been accomplished in excellent overall yield by employing asymmetric aldol reaction, asymmetric epoxidation and regioselective epoxide ring opening as the key steps. Our synthetic strategy is very simple, concise and no use of protecting groups.

Full text of DOI:10.1002/jhet.3455

Month 2019
An Alternative Approach to the Synthesis of Parvistone C
Ramakrishnam Raju Addada,a,b Venkata Reddy Regalla,a,b Sivarami Reddy Gangireddy Venkata,b
b
a
*
Venkata Naresh Vema, and Venkateswara Rao Anna
aDepartment of Chemistry, Koneru Lakshmaiah Education Foundation, Green fields, Vaddeswaram, Guntur, Andhra
Pradesh 522502, India
bMedicinal Chemistry Division, GVK Biosciences Private Limited, 28A, Nacharam, Hyderabad, Telangana 500076, India
*E-mail: avrchemistry@gmail.com
Received July 27, 2018
DOI 10.1002/jhet.3455
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
A stereoselective total synthesis of parvistone C, an oxygenated natural styryllactone, has been accom-
plished in excellent overall yield by employing asymmetric aldol reaction, asymmetric epoxidation and re-
gioselective epoxide ring opening as the key steps. Our synthetic strategy is very simple, concise and no
use of protecting groups.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
RESULTS AND DISCUSSION
Chiral lactone rings are widely distributed in many
biologically active natural products [1]. Particularly,
α,β-unsaturated δ-lactone gained the great attention of
The retrosynthetic pathway of parvistone C (1b) is
presented in Scheme 2. The key step is a Mukaiyama
asymmetric aldol reaction to install lactone stereogenic
center. The remaining two chiral centers could then be
introduced by asymmetric epoxidation reaction followed
by regioselective epoxide ring opening with methanol.
As shown in Scheme 3, our synthesis started with
Mukaiyama asymmetric aldol reaction. Thus, trans-
cinnamaldehyde 3 was allowed to react with Chan’s
diene 4 using catalytic amounts of Ti (OiPr)4/(S)-BINOL
complex (10 mol%). This gave δ-hydroxy-β-ketoester 5
as a >95% enantiomeric excess (Chiral HPLC analysis)
researchers due to
a
variety of pharmaceutical
properties including antitumor, antifungal, antibacterial,
and immunosuppressive properties [2]. A series of new
6S-styryllactones parvistone A-E were isolated from a
methanolic extract of Polyalthia parviflora leaves by
Liou et al. in 2014 [3]. Their structures were
elucidated on the basis of NMR spectroscopy and
single-crystal X-ray analysis. These compounds exhibit
potent anti-inflammatory and cytotoxic properties.
Parvistone C (1b) is structurally related to parvistone
B (1a) and differs in the stereochemical configurations
(Figure 1).
Recently, asymmetric total syntheses of parvistone A-E
natural products have been reported in the literature [4].
Very recently, Radha Krishna et al. [4e] disclosed the
first total synthesis of parvistone C (1b) starting from
commercially available 1,3-propane diol in 13 steps with
Figure 1. Structures of parvistone B (1a) and C (1b).
13% overall yield. They employed
a
Sharpless
asymmetric dihydroxylation, stereoselective aryl Grignard
reactions, Still–Gennari olefination, and intramolecular
cyclization as the key steps (Scheme 1). Herein, we
report a five-step total synthesis of parvistone C (1b)
from commercially available, inexpensive trans-
cinnamaldehyde using a protecting group-free strategy.
Scheme 1. Previous synthetic approach to parvistone C (1b).
© 2019 Wiley Periodicals, Inc.

R. R. Addada, V. R. Regalla, S. R. Gangireddy Venkata, V. N. Vema, and V. R. Anna
Vol 000
Scheme 2. Retrosynthetic analysis of parvistone C (1b).
via hydrolysis of ester followed by intramolecular
lactonization in 62% yield over two steps [6]. The
elimination of hydroxyl group in β-hydroxy-δ-lactone 2
was performed smoothly to furnish the desired
α,β-unsaturated δ-lactone (6) in 76% yield [7]. Next, the
compound 6 was subjected to Han’s reaction conditions
[8] using (+)-(R,R)-salen-Mn (III) as the catalyst and
Oxone as the oxidant at 0°C to furnish the desired
goniothalamin oxide 7 with excellent regioselectivity and
diastereoselectivity (dr, 98:2) in 81% yield. Finally, the
in 75% yield [5]. The aldol adduct 5 was then subjected to
a carbonyl reduction with NaBH4 to give the diol as the
product. After, we have converted the diol to lactone 2
Scheme 3. Synthesis of parvistone C (1b).
Table 1
Comparison of 1H-NMR and 13C-NMR data of natural parvistone C and synthetic 1b.
1H-NMR
13C-NMR
H
Natural
Synthetic
(Δδ)N,S
C
Natural
Synthetic
(Δδ)N,S
2
3
4
5
164.0
120.8
146.0
26.2
164.0
120.8
145.9
26.1
0.0
0.0
3
4
5
6.05 (dd, 9.5, 2.4)
6.97 (dt, 9.5, 6.4, 2.4)
2.26 (ddd, 18.2, 6.4, 4.0)
2.84 (ddt, 18.2, 13.2, 2.4)
4.95 (ddd, 12.6, 4.0, 1.2)
3.61 (dt, 8.4, 1.2)
6.04 (ddd, 9.6, 2.7, 0.8)
6.97 (ddd, 9.6, 6.1, 2.1)
2.25 (dddd, 18.1, 6.1, 3.7, 0.7)
2.83 (ddt, 18.1, 12.7, 2.1)
4.95 (ddd, 12.7, 3.8, 1.5)
3.61 (dd, 9.0, 1.5)
À0.01
0.00
À0.01
À0.01
0.00
À0.1
À0.1
6
7
6
7
76.1
74.8
76.1
74.8
0.0
0.0
0.00
8
4.38 (d, 8.4)
4.38 (d, 8.8)
0.00
8
81.9
81.9
0.0
Ph
OMe
7.41–7.36 (m, 5H)
3.22 (s)
7.44–7.31 (m, 5H)
9
138.5
127.8
128.7
128.5
128.7
127.8
56.7
138.5
127.8
128.6
128.5
128.6
127.8
56.7
0.0
0.0
3.22 (s)
0.00
10
11
12
13
14
OMe
À0.1
0.0
À0.1
0.0
0.0
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
An Alternative Approach to the Synthesis of Parvistone C
stereoselective and regioselective epoxide ring-opening of
goniothalamin oxide 7 with methanol in the presence of
Lewis acid Eu (OTf)3 provided the target natural product
compound 8 (40 mg, 0.18 mmol) in methanol (1 mL)
was added Eu (OTf)3 (12.2 mg, 0.02 mmol) at room
temperature and stirred for 12 h. The methanol was
removed under vacuum, and the residue was purified by
flash column chromatography (hexane: EtOAc, 6:4) to
provide parvistone C (1b) (43 mg, 95%) as a white solid.
[α]2D5 = À219 (c 0.5, CHCl3), HRESIMS m/z 271.0936
[M + Na]+ (Calcd for C14H16O4Na, 271.0940).
1
parvistone C (1b) in 95% yield with 96:4 dr. The H-
NMR and 13C-NMR data of natural parvistone C were
well agreed with our synthetic compound 1b (Table 1).
CONCLUSIONS
The protecting group-free stereoselective total synthesis
of lactone natural product parvistone C (1b) was achieved
in simple five steps without using any protecting group
from readily available starting material trans-
cinnamaldehyde with 27% overall yield. Key
transformations of our synthetic scheme include an
asymmetric aldol reaction and asymmetric epoxidation
and regioselective epoxide ring opening.
Acknowledgments. R. K. R. thanks K L University for constant
encouragement during this research program. R. K. R. is also
grateful to GVK Biosciences for providing basic research facility.
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General.
Solvents were dried over standard drying
agents and freshly distilled prior to use. All moisture-
sensitive reactions were carried out under nitrogen.
Organic solutions were dried over anhydrous MgSO4 and
concentrated below 40°C in vacuo. All column
chromatographic separations were performed on silica gel
1
of 60–120 mesh. H-NMR and 13C-NMR spectra were
recorded in CDCl3 solvent at 300, 400, 500 MHz, and
75, 100, 125 MHz, respectively, using tetramethylsilane
as internal standard. Optical rotations were measured with
a digital polarimeter at 25°C. Mass spectra were recorded
on a mass spectrometer by electrospray ionization (ESI-
MS). High-resolution mass spectra (ESI-HRMS) were
recorded on an ESI-QTOF mass spectrometer.
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hydroxy-2-methoxy-2-phenylethyl)-5,6-dihydro-2H-pyran-2-
one (Parvistone C) (1b).
To a stirred solution of
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet