Stereoselective synthesis of vittarilide-A

Article abstract of DOI:10.1016/j.tetlet.2015.02.028

A facile and stereoselective synthesis of vittarilide-A, having promising antioxidant property was accomplished in 12 linear synthetic steps with an overall yield of 6.34% using a chiral pool approach from naturally available diethyl tartrate. The key rea

Full text of DOI:10.1016/j.tetlet.2015.02.028

Accepted Manuscript
Stereoselective synthesis of vittarilide-A
Jhillu Singh Yadav, Vijaya Vardhan Chinnam, Bendapudi Bala Murali Krishna,
Kundeti Lakshmi Srinivasa Rao, Saibal Das
PII:
S0040-4039(15)00287-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.02.028
TETL 45896
Reference:
Tetrahedron Letters
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Revised Date:
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19 December 2014
6 February 2015
8 February 2015
Please cite this article as: Yadav, J.S., Chinnam, V.V., Krishna, B.B.M., Rao, K.L.S., Das, S., Stereoselective
synthesis of vittarilide-A, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.02.028
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Stereoselective synthesis of vittarilide-A
Jhillu Singh Yadav,*a Vijaya Vardhan Chinnam,a Bendapudi Bala Murali Krishna,a Kundeti Lakshmi
Srinivasa Rao,a and Saibal Das*a
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A facile and stereoselective synthesis of vittarilide–A, having promising antioxidant property was
accomplished in 12 linear synthetic steps with an overall yield of 6.34% using a chiral pool approach
from naturally available diethyl tartarate. The key reactions employed were diastereoselective
vinylation, Sharpless asymmetric dihydroxylation, (2,2,6,6-tetramethylpiperidin-1-yl)oxy radical
(TEMPO), bis(acetoxy)iodo-benzene (BAIB) mediated tandem oxidation followed by lactonization
and finally esterification under Yamaguchi conditions.
Available online
2014 Elsevier Ltd. All rights reserved.
Keywords:
Vittarilide-A
Natural Product
Vinylation
Sharpless Asymmetric Dihydroxilation
In the year 2005, Wu et al. reported1 the isolation of 20 known
and 12 new natural products from the crude methanol extract of
whole plant Vittaria anguste-elongata Hayata. This plant belongs
to Vittariaceae natural products family, is a unique linear grass-
like fern which grows on moss covered rocks and trees of low
altitude forests and it is aboriginal to Taiwan. This report also
revealed that the crude plant extract displays moderate
cytotoxicity against human lung cancer, gastric and nasopharynx
carcinoma cell lines. One of the constituent from the newly
isolated lot, vittarilide-A, a optically active colourless syrup
(Figure 1) exhibited moderate antioxidant property with IC50
value of 91µM.1 The unique structural features and bioactivity
signifies its importance but poor natural abundance demands a
concise and scalable synthetic approach, as true for many natural
products. To date only one report is available by Yoda et al.2
Wherein, absolute stereochemistry at C5 was establishment along
with the total synthesis from D-gluconolactone in 17 steps. As
part of our ongoing reserach on the synthesis of natural products
in line with cytotoxic and anti-cancer activity recently3,
vittarilide-A attracted our attention and herein we disclose our
successful 12 step linear synthetic approach utilizing
accessed from L-(+)-diethyltartarate 4 by utilising standard
synthetic transformations known in the literature.4
Figure 1. Structure of Vittarilide-A (1)
We commenced our synthesis towards intermediate 3 (Scheme 2)
starting from inexpensive L-(+)-diethyl tartarate 4, which was
protected as its di-Methoxymethyl ether which inturn on
reduction with Lithium aluminium hydride (LAH) in THF
furnished the corresponding diol, which was further converted to
mono benzyl ether 5.
diastereoselective
vinylation,
Sharpless
asymmetric
dihydroxylation, tandem oxidation followed by lactonization and
esterification reactions.
Accordingly we have designed a retrosynthetic analysis
(Scheme 1) utilising a chiral pool approach. We envisaged the
esterification reaction between an acid 2 and an alcohol 3, for the
construction of desired compound 1. The alcohol 3 can be easily
_______________________
* Corresponding author. Tel.: +91-40-2719 3737; Fax: +91-40-
27160512. E-mail: yadavpub@iict.res.in
Scheme 1. Retrosynthesis for Vittarilide-A (1)

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Then, the primary alcohol of 5 was oxidized by Dess–Martin
alcohol in 7 was protected as its benzyl ether and the terminal
olefin 8 was subjected to Sharpless asymmetric dihydroxylation
(SAD) conditions employing potassium osmate (5 mol%) and
potassium ferricyanide as a co-oxidant in the presence of a
(DHQ)2PHAL ligand (10 mol%) to furnish the corresponding
diol allyltributyl 9 in 85% yield and 92% de.6
periodinane (DMP) to obtain the corresponding aldehyde 6. A
chelation controlled diastereoselective vinyl Grignard reaction of
6 was performed in presence of MgBr2.Et2O at –78 °C producing
the desired syn-alcohol 7 in satisfactory 89% yield with high
diastereomeric excess (de = >95%).5 Subsequently, the allyl
Scheme 2. Synthesis of lactone intermediate (3)
Scheme 3. Synthesis of Vittarilide-A (1)
The resulting diol 9 was then protected as its di-silyl ether 10
with TBSOTf7 and subsequent deprotective hydrogenolysis of the
benzyl groups in the presence of palladium hydroxide on carbon2
afforded the desired diol 11 in 83% yield. It was further subjected
to (2,2,6,6-tetramethylpiperidin-1-yl)oxy radical (TEMPO),
spectroscopic data and optical rotation of our synthetic
compound is in good agreement with the natural as well as the
previously synthesized natural product.
In conclusion, we have accomplished the stereoselective
bis(acetoxy)iodo-benzene
(BAIB)
mediated
tandem
synthesis of vittarilide-A (1) in a concise manner using
oxidation/lactonization8 producing the awaited gluconate 12. A
regio selective cleavage of the primary TBS ether with
camphorsulfonic acid (CSA) in MeOH9 furnished the required
alcohol intermediate 3 in 70% yield.
diastereoselective
dihydroxylation,
vinylation,
BAIB/TEMPO
Sharpless
mediated
asymmetric
tandem
oxidation/lactonization and esterification under Yamaguchi
conditions as key steps. The implementation of present strategy
in synthesizing the other five and six membered polyhydroxy
lactone natural products are underway and results will be
communicated in details, in near future.
The coupling of di-TBS protected trans-caffoeyl moiety 22 onto
the hydroxy group of gluconate 3 was successfully achieved
under Yamaguchi conditions10 (Scheme 3) obtained as protected
ester-lactone moiety 13 in 82% yield. Finally the removal of all
the MOM and TBS groups using 6 N HCl in THF3d furnished the
targeted natural product vittarilide-A (1) in 60% yield. The

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(c) Yadav, J. S.; Haldar, A.; Maity, T. Eur. J. Org. Chem.
Acknowledgements
2013, 15, 3076-3085 (d) Yadav, J. S.; Mandal, S. S. Synlett 2011, 19,
2803–2806;
C. V. V, B. B. M. K and K. L. S. R thanks CSIR, New Delhi,
India for fellowship. The authors thank CSIR, New Delhi for
financial support through Project ORIGIN under 12th Five Year
Plan and J. S. Y. thank Department of Science and Technology
(DST), New Delhi for the award of Bhatnagar and J. C. Bose
Fellowships.
4
(a) Kaseda, T.; Kikuchi, T.; Kibayash, C. Tetrahedron Lett. 1989, 30,
4539–4542; (b) Iida, H.; Yamazaki, N.; Kibayashi, C. Tetrahedron Lett.
1985, 26, 3255–3258.
5
6
Venkatesan, K.; Srinivasan, K. V. Tetrahedron: Asymmetry 2008, 19,
209–215.
aKolb, ) H. C.; VanNieuwenhze , M. S.; Barry Sharpless, K. Chem. Rev.
1994, 94, 2483–2547; b) Lin, Chia-I.; Sasaki, E.; Zhong, Aoshu.; Liu, H.
J. Am. Chem. Soc. 2014, 136, 906−909.
7
8
Yadav, J. S.; Mandal, S. S. Tetrahedron Lett. 2011, 52, 5747–5749.
Yadav, J. S.; Lakshmi, K. A.; Reddy, N. M.; Prasad, A. R.; Ghamdi, A.
A. K. A. Synthesis 2012, 44, 2595–2600. (b) Hansen T. M.; Florence G.
J.; Lugo-Mas P.; Chen J.; Abrams J. N.; Forsyth C. J.; Tetrahedron Lett.
2003, 44, 57.
Supplementary data
1
Experimental procedures, spectral data and Copies of H NMR
and 13C NMR spectra are available under supporting information.
9
Sun, J.; Fan, S.; Wang, Z.; Zhang1, G.; Bao K.; Zhang, W. Beilstein J.
Org. Chem. 2013, 9, 2620–2624.
References and notes
10 Yadav, J. S.; Pattanayak, M. R.; Das, P. P.; Mohapatra, D. K. Org. Lett.
2011, 13, 1710.
1
2
3
Wu, P. L.; Hsu, Y. L. C.; Zao, W.; Damu, A. G.; Wu, T. S. J. Nat. Prod.
2005, 68, 1180–1184.
Takahashi, M.; Murata, Y.; Hakamata, Y.; Suzuki, K.; Sengoku, T.;
Yoda, H. Tetrahedron 2012, 68, 7997–8002.
(a) Yadav, J. S.; Vardhan, V.; Das, S. Synthesis 2014, 46, 2347–2352.
(b) Yadav, J. S.; Nayak, S.; Sabitha, G. RSC Adv. 2013, 3, 21007-21015.

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Stereoselective synthesis of vittarilide A
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Jhillu Singh Yadav,*a Vijaya Vardhan Chinnam,a Bendapudi Bala Murali Krishna,a Kundeti Lakshmi Srinivasa
Rao,a and Saibal Das*a
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.