First total synthesis of parvistone C and its C8-epimer

Article abstract of DOI:10.1080/00397911.2017.1354381

Diastereoselective first total synthesis of parvistone C 1 and C8-epimer 1a are described. The key features of our synthesis include Sharpless asymmetric dihydroxylation, stereoselective aryl Grignard reactions, Still–Gennari olefination, and intramolecul

Full text of DOI:10.1080/00397911.2017.1354381

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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First Total Synthesis of Parvistone C and it's C8-
epimer
Ranjith Jala, Rajesh Nomula & Palakodety Radha Krishna
To cite this article: Ranjith Jala, Rajesh Nomula & Palakodety Radha Krishna (2017):
First Total Synthesis of Parvistone C and it's C8-epimer, Synthetic Communications, DOI:
10.1080/00397911.2017.1354381
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Date: 22 July 2017, At: 12:55

First total synthesis of parvistone C and it’s C8-epimer
Ranjith Jala
Discovery Laboratory, Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of
Chemical Technology, Hyderabad, India
Rajesh Nomula
Discovery Laboratory, Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of
Chemical Technology, Hyderabad, India
Palakodety Radha Krishna*
Discovery Laboratory, Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of
Chemical Technology, Hyderabad, India
*Address correspondence to Palakodety Radha Krishna, D-211, Discovery Laboratory, Organic
and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology,
Hyderabad 500 007, India. Tele: + 91-40-27193158. Fax: 91-40-27160387. E-mail:
prkgenius@iict.res.in
Please see Supporting Information for the spectral data of selected compounds.
ABSTRACT
Diastereoselective first total synthesis of parvistone C 1 and C8-epimer 1a are described
The key features of our synthesis include Sharpless asymmetric dihydroxylation, stereoselective
aryl Grignard reactions, Still-Gennari olefination and intramolecular cyclization.
1

GRAPHICAL ABSTRACT
KEYWORDS: intramolecular cyclization, parvistones, sharpless asymmetric dihydroxylation,
still-gennari olefination, styryl lactones
Introduction
Over the past few decades styryl lactones are evergreen target compounds both in the
isolation as well as in the synthesis since they were found to be exhibit significant biological
activities[1] in addition to exigent structural features such as α,β-unsaturated δ-lactone moiety in
conjunction with flanking sterocenters. In this locale, recently parvistones A-E,[2] a new class of
6S-styryl lactones are isolated from methanolic extract of Polyalthia parviflora leaves and found
to be posses potent anti-inflammatory and cytotoxic activity. From the SAR studies of these
compounds in an in vitro anti-inflammatory assay revealed that 6S-styryl-lactones to be more
potent than 6R derivatives. Recently Perla Ramesh et al. reported the total synthesis of
parvistones A[3a], B[3b] and D-E.[3c] To the best of our knowledge no one reported the total
synthesis of parvistones C. Impressed by the attractive bio-profile of these compounds, coupled
with our interest in the synthesis of styryl lactone containing natural products,[4] we embarked on
the total synthesis of parvistone C and C8-epimer (Figure 1).
Results and Discussions
2

Herein, we report the total synthesis of 1 and 1a ( Scheme 1) in a linear pathway for the
creation of hydroxy stereocenters. Accordingly, the hypothesized retrosynthetic analysis
indicates 1 could be realized from Z-α,β-unsaturated ester 2 on cyclization[5] using Bronsted acid
(p-TSA), in turn compound 2 could be derived from benzylic alcohal 3 upon few transformations
involving methylation and oxidative cleavage of PMB ether followed by Still-Gennari
olefination.[4d,6] On the other hand the another target compound 1a maybe assembled from 3a
using the same synthetic sequence adpoted for 1 from 3. Compound 3 and 3a could be accessed
from dihydroxy ester 4[7] by a diastereoselective aryl Grignard reaction of corresponding
aldehyde afforded from 4. Compound 4 could be achieved from 1,3-propane diol using Sharpless
asymmetric dihydroxylation[8] to garner the stereogenic centers (6S,7R) and other sequential
transformations.
Syntheisis of parvistone C and it’s C8-epimer
Accordingly, the synthesis of parvistone C started from the known E-α,β-unsaturated
ester 5[7] which was readily accessed from commerically available 1,3-propanediol (Scheme 2).
Next, compound 5 on Sharpless asymmetric dihydroxylation[8] {AD mix-α/t-BuOH–H2O (1:1),
MeSO2NH2} gave syn-diol 4[7] as a single isomer in 90% yield. Subsequent acetonide protection
of the hydroxyl groups gave 6, followed by the ester reduction with DIBAL-H resulted in
primary hydroxyl compound 7 (92%). Next, alcohol 7 on oxidation under Swern conditions
afforded the corresponding aldehyde which on Grignard addition with phenyl
magnesiumbromide[4b] (PhMgBr/THF/0oC to rt) furnished the chromatographically separable
benzylic alcohols 3 and 3a as a diasteromeric mixture in 3:2 ratio. Both the isomeric alcohols
were purified by column chromatography and taken up for further transformations individually.
In continuation, the purified major diastereomer 3 was then converted into its methyl ether
3

(MeI/NaH/THF/0oC to rt) to furnish the methoxy benzylic alcohol 8 (85%). Next, oxidative
cleavage of PMB group under DDQ conditions (DDQ/CH2Cl2/0oC to rt) led to the primary
hydroxyl compound 9 (88%). Oxidation of alcohol 9 under DMP conditions to its corresponding
aldehyde and subsequent chain elongation with Still-Gennari reagent[4d,6] afforded the
chromatographically separable Z-α,β-unsaturated ester 2 (75%) along with traces of E-isomer.
Finally, tandem deprotection and an in situ cyclization process of ester 2 were achieved on
treating with p-TSA (cat.) in benzene to afford the target molecule 1. Similarly, 8-epi parvistone
1a was realized from 3a, adopting the same set of reactions that were employed for the synthesis
of 1 from 3.
Compounds 1 and 1a were fully characterized from their spectral data. From the
meticulous spectral analysis of compound 1 it was found that the NMR data (1H and 13C) was in
good agreement with the reported data.[2] whereas in the case of optical rotation synthetic 1
{[]D25 -204.3 (c 0.4, CHCl3)} are identical with the reported data[2] []D22 -216 (c 0.2, CH2Cl2).
Likewise, in the case of 1 the spectral data matched with the reported data.[2] For instance
1
in the H NMR spectrum of synthetic 1, H6 appeared at δ 4.95 ppm as a ddd, H7 appeared at δ
3.62 ppm as a dt and H8 appeared at δ 4.38 ppm as a doublet which is a good agreement with the
reported data for the same H6 at δ 4.95 ppm as a ddd, H7 appeared at δ 3.61 ppm as a dt and H8
appeared at δ 4.38 ppm as a doublet. In the 13C spectra characteristic peaks of C6, C7, C8
appeared at δ 76.1, 74.8, 81.9 ppm, correspondingly the reported signals[2] appeared at δ 76.1,
74.8, 81.9 ppm as a perfect match.
Conclusion
4

In summary, we have reported the first total synthesis of more potent 6S styryl lactones
parvistone C and it’s C8-epimer in a stereoselective manner that involves Sharpless asymmetric
dihydroxilation, aryl Grignard reaction, Still-Gennari olefination and intramolecular cyclizations
as key steps. The synthetic protocol is general and convenient for the the preparation of isosteres
or analogs.
Experimental Section
General: NMR spectra were recorded in CDCl3 with 300, 400 and 500 MHz
spectrometers at ambient temperature. The chemical shifts (δ) are reported relative to TMS as the
internal standard and by using the signal patterns indicated as follows: s, singlet; d, doublet; dd,
doublet of doublets; td, triplet of doublets; t, triplet; m, multiplet; br. s, broad singlet. Optical
rotations were measured at 25oC with a Horiba high sensitive polarimeter, m/z ratios are reported
as values in atomic mass units. Melting points recorded herein are uncorrected. All the reagents
and solvents were reagent grade and were used without further purification. Technical grade
ethyl acetate and petroleum ether used for column chromatography were distilled prior to use.
Column chromatography was carried out using silica gel (Acme’s, 60-120 mesh) packed in glass
columns. All the reactions were performed under an atmosphere of nitrogen in flame- or oven-
dried glassware with magnetic stirring.
Experimental procedure for synthesis of Parvistone C (1)
To a solution of compound 2 (0.100 g, 0.31 mmol) in distilled benzene was added a cat.
p-TSA, and the mixture was stirred at rt. for 4 h. Solid NaHCO3 (0.02 g) was added to quench
the p-TSA, and the mixture was extracted with EtOAc (2 x 10 mL). The combined organic layer
5

was dried (Na2SO4), concentrated and purified by column chromatography (Silica gel, 60-120
mesh, EtOAc:n-hexane, 7:3) to afford lactone 1 (0.030 g, 82%) as a colorless crystal.
Data
25
mp 98.5-101oC; [] = -204.3 (c 0.4, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.44-7.32
D
(m, 5H), 6.97 (ddd, J = 9.6, 6.2, 2.0 Hz, 1H), 6.05 (ddd, J = 9.7, 2.8, 0.8 Hz, 1H), 4.95 (ddd, J =
12.8, 3.9, 1.5 Hz, 1H), 4.38 (d, J = 8.9 Hz, 1H), 3.62 (dt, J = 7.9, 1.1 Hz, 1H), 3.23 (s, 3H), 2.84
(ddt, J = 18.4, 12.8, 2.8, 1H), 2.26 (ddd, J = 18.2, 6.2, 3.9, 1H); 13C NMR (125 MHz, CDCl3): δ
164.0, 145.9, 138.4, 128.6, 128.5, 127.7, 120.8, 81.9, 76.1, 74.8, 56.7, 26.1; ESI-MS: m/z
+
+
C14H20O4N [M + NH4] : 266; HRMS (ESI): m/z [M + NH4] calcd C14H20O4N: 266.1386:
found: 266.1383.
Experimental procedure for synthesis of 8-epi parvistone C (1a)
Same as compound 1 (colorless crystal)
Data
25
mp 98.2-103 oC; []
-26.8 (c 1.4, CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.44-7.32
=
D
(m, 5H), 6.86 (ddd, J = 9.4, 6.2, 1.8 Hz, 1H), 5.95 (dd, J = 9.8, 2.4 Hz, 1H), 4.56 (d, J = 8.6 Hz,
1H), 4.00 (dd, J = 12.2, 3.5 Hz, 1H), 3.67 (d, J = 8.5 Hz, 1H), 3.28 (s, 3H), 2.93 (ddt, J = 18.3,
13
12.4, 2.0, 1H), 2.10 (dt, J = 18.8, 5.8, 4.5, 1H); C NMR (100 MHz, CDCl3): δ 163.7, 145.6,
137.2, 128.6, 128.5, 127.6, 120.6, 83.3, 75.7, 75.6, 56.7, 25.7; ESI-MS: m/z C14H20O4N [M +
NH4] +: 266; HRMS (ESI): m/z [M + NH4] + calcd C14H20O4N: 266.1386: found: 266.1382.
Acknowledgments
6

The authors (J.R. and N.R.) thank CSIR, New Delhi, India for the financial support in the
form of fellowships.
References
[1](a) Mu, Q.; Tang, W. D.; Liu, R. Y.; Li, C. M.; Lou, L. G.; Sun, H. D.; Hu, C. O. Planta Med.
2003, 69, 826; (b) Pihie, A. H.; Stanslas, J.; Din, L. B. Anticancer Res. 1998, 18, 1739.
[2]Liou, J. R.; Wu, T. Y.; Thang, T. D.; Hwang, T. L.; Wu, C. C.; Cheng, Y. B.; Chiang, M. Y.;
Lan, Y. H.; Shazly, M. E.; Wu, S. L.; Beerhues, l.; Yuan, S. S.; Hou, M. F.; ChEn, S. L.;
Chang, F. R.; Wu, Y. C. J. Nat. Prod. 2014, 77, 2626.
[3](a) Ramesh, P.; Reddy, Y. N.; Reddy, T. N.; Srinivasu, N. Tetrahedron: Asymmetry 2017, 28,
246; (b) Ramesh, P. Chemistry Select. 2016, 1, 3244; (c) Ramesh, P.; Rao, T. P. J. Nat.
Prod. 2016, 79, 2060.
[4](a) Radha Krishna, P.; Reddy, P. V. N. Tetrahedron Lett. 2006, 46, 6676; (b) Radha Krishna,
P.; Shivakumar, E. Tetrahedron Lett. 2009, 50, 6676; (c) Radha Krishna, P.; Alivelu, M.
Helv. Chim. Acta 2011, 94, 1102; (d) Radha Krishna, P.; Kunde, R.; Ramakrishna, K. V.
S. Tetrahedron Lett. 2015, 56, 1344.
[5](a) Wender, P. A.; Koehler, M. F. T.; Sendzik, M. Org. Lett. 2003, 5, 4549; (b) Radha
Krishna, P.; Srinivas, P. Tetrahedron Lett. 2010, 51, 2295; (c) Radha Krishna, P.;
Nomula, R.; Kunde, R. Synthesis 2014, 46, 307.
[6]Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
[7]Zhou, B.; Li, Y. Tetrahedron Lett. 2012, 53, 502.
[8]Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispinio, G. A.; Hartung, J.; Jeong, K. S.;
Kwong, H. L.; Morikawa, K.; Wang, Z. M.; Xu, D.; Zhang, X. L. J. Org. Chem. 1992,
57, 2768.
7

Figure 1. Structures of target styrylpyrones.
8

Scheme 1. Retrosynthetic analysis of target compounds 1 and 1a.
9

Scheme 2. Syntheisis of parvistone C and it’s C8-epimer. Reagents and conditions. (a) Ref. [7];
(b) Ad mix-, t-BuOH:H2O (1:1), MeSO2NH2, 0C, 10h,90%; (c) 2,2-DMP, p-TSA, CH2Cl2,
0C to rt, 3 h, 82%; (d) DIBAL-H, CH2Cl2, 0C to rt, 3 h, 92%; (e) (i) (COCl)2, DMSO, Et3N,
CH2Cl2, -78C, 1 h; (ii) PhBr, Mg, THF, 0C to rt, 3 h, 86% (over two steps); (f) MeI, NaH,
THF, 0C to rt, 1 h; (g) DDQ, CH2Cl2:H2O (19:1), 0C to rt, 3 h; (h) (i) DMP, CH2Cl2, 0C to rt,
3 h; (ii) (F3CCH2O)2POCH2CO2Me, NaH, THF, -78C, 1h; (i) p-TSA, benzene, rt, 3 h.
10