Stereoselective total synthesis of (?)-zeylenol, a key intermediate for the synthesis of (+)-pipoxide, (?)-uvarigranol G and (?)-tonkinenin A

Article abstract of DOI:10.1016/j.tetlet.2017.02.003

Total synthesis of (?)-zeylenol, a key intermediate for the synthesis of (+)-pipoxide, (?)-uvarigranol G and (?)-tonkinenin A was achieved from commercially available starting material D-mannose. The key steps are mixed aldol condensation, Grignard reaction, ring closing metathesis and regioselective benzoylation.

Full text of DOI:10.1016/j.tetlet.2017.02.003

DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.02.003
TETL 48614
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 January 2017
31 January 2017
1 February 2017
Please cite this article as: Vinaykumar, A., Muniraju, C., Rao, B.V., Stereoselective total synthesis of (–)-zeylenol,
a key intermediate for the synthesis of (+)-pipoxide, (–)-uvarigranol G and (–)-tonkinenin A, Tetrahedron Letters
(2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.02.003
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
Stereoselective total synthesis of (–)-zeylenol, a key
intermediate for the synthesis of (+)-pipoxide,
(–)-uvarigranol G and (–)-tonkinenin A
Leave this area blank for abstract info.
Allam Vinaykumara, Chinthala Munirajua and Batchu Venkateswara Rao*a

Tetrahedron Letters
journal h omepage: www.els evier. com
Stereoselective total synthesis of (–)-zeylenol, a key intermediate for the synthesis
of (+)-pipoxide, (–)-uvarigranol G and (–)-tonkinenin A
Allam Vinaykumara, Chinthala Munirajua and Batchu Venkateswara Rao*a
a Organic & Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500 007, India.
* Corresponding author. Tel./ fax: +91 40 27193003; E-mail addresses: venky@iict.res.in , drb.venky@gmail.com.
ARTICLE INFO
ABSTRACT
Article history:
Received
Total synthesis of (–)-zeylenol, a key intermediate for the synthesis of (+)-pipoxide, (–)-
uvarigranol G and (–)-tonkinenin A was achieved from commercially available starting
material D-mannose. The key steps are mixed aldol condensation, Grignard reaction, ring
closing metathesis and regioselective benzoylation.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Zeylenol
Carbasugars
Benzoylation
Vinylation
Aldol condensation
4, ferrudiol 5 and uvaribonol A 6 (Figure 1) are some examples
Introduction
Polyoxygenated cyclohexene unit having benzoyloxy
belong to this class whose absolute configuration have been
established.5–14
methyl or hydroxyl methyl functionalities on a tertiary carbon is a
popular moiety present in many natural products. The first
example of this category is (–)-zeylenol 1. Interestingly zeylenol
exists in nature in both enantiomeric forms and both have shown
important biological activity. (–)-Zeylenol 1 was isolated by Cole
and Bates1 in 1981 from the plant uvaria zeylanica. The absolute
configuration of (–)-zeylenol was then confirmed by Ganem using
chemical correlation and circular dichroism spectroscopy.2 Also
there are some reports which describe the isolation of (–)-zeylenol
without determining the absolute configuration.3,4 Later, the
enantiomer (+)-zeylenol was also isolated from a natural source
kaempferia species6 and also from uvaria7 and piper.8 (+)-
Zeylenol shows selective cytotoxicity towards HL-60 leukemia
cells.6c (–)-Zeylenol 1 shows antitumor, antifeedant activity12 and
also anti-inflammatory activity. Moreover, (–)-zeylenol exhibits
moderate cytotoxic activity in human breast cancer cell lines
MDA-MB231 (IC50 54.22 μM) with SD 10.20 but with a lesser
extent in hepatocellular carcinoma HepG2.15 Numerous natural
products which are having zeylenol skeleton have been isolated
from different sources and are showing interest biological
activity.5-14 (–)-Uvarigranol G 2, (–)-tonkinenin A 3, (+)-pipoxide
Figure 1. Some natural products in the zeylenol family.
So far only Ogasawara et al. has reported both formal16a
and total16b,c enantiocontrolled synthesis of (–)-zeylenol 1 which
has been utilized for the synthesis of (–)-uvarigranol G 2, (–)-
tonkinenin A 3 and (+)-pipoxide 4. The key material for their
synthesis is the chiral cyclohexenoid building block which was
prepared from meso ene diol. Palframan et al17 synthesized (+)-
zeylenol and zeylenones from ipso, ortho diols using

photooxygenation of
a microbial arene and regioselective
Kornblum–DeLaMare Rearrangement. To the best of our
knowledge, nobody has synthesized these molecules from chiral
starting materials. For the past few years, we have been carrying
out the research in the synthesis of polyhydroxy cyclohexene
compounds which are commonly known as carbasugar by using
Table 1: Vinyl Grignard addition on compounds 10 and 11:
ring closing metathesis approach.18 Herein we report
a
Entry
Conditions
Temperature
(oC)
Time
(h)
Yield (%)
stereoselective approach to (–)-zeylenol starting from D-mannose.
In the present approach we have used mixed aldol
condensation19, Grignard reaction, ring closing metathesis20 and
regioselective benzoylation21 reactions as key steps for a short
synthesis of (–)-zeylenol in good overall yield.
(equivalents)
10
10
11
4
4
4
–78oC -r.t.
0oC -r.t.
12
12
12
N.R
N.R
–78oC -r.t.
75%
(dr : 1:3)a
NR = no reaction; [a] = dr ratio is shown as syn:anti and confirmed by 1H
NMR
The formation of major diastereomer 13 can be
explained via chelation controlled transition states A or B (Figure
2). In the seven membered transition state26 A, the TBDPS ether
group blocks one of the faces, so the nucleophile will attack from
the opposite face to give the major isomer 13 or addition may be
taking place via transition state B.
Scheme 1: Retrosynthetic Analysis
Results and Discussion:
Based on the retrosynthetic analysis (Scheme 1) we
have chosen D-mannose as a starting material which is a cheap
and commercially available. D-Mannose was converted to diol 7
in 97% yield by reported method.22 Application of Garregg’s
protocol23 on diol 7 yielded olefin compound 824. Deprotection of
acetate in 8 gave free lactol 924. Next step is the introduction of
hydroxymethyl group selectively at C-2. For this, Compound 9
was subjected to the mixed aldol reaction19 with formaldehyde in
presence of K2CO3 to yield 1025. (Scheme 2).
Figure 2: Chelation controlled transition state.
Ring closing metathesis reaction was carried out on 13
using Grubbs II generation catalyst27 to give substituted
cyclohexene 14. Cleavage of TBDPS ether in 14 with TBAF
resulted in the formation of 1, 3 diol 15. To achieve the selective
benzoylation in 15 it is required to mask primary and one of the
allylic hydroxyl groups in compound 15. For this, compound 15
was treated with 2, 2-DMP and p-TSA (cat.) to give acetal 16. The
allylic hydroxyl group in 16 was converted to benzoyl ester 17
with triethylamine, benzoyl chloride and DMAP(cat.). Selective
acetonide deprotection in 17 was achieved with 80% aq.AcOH to
furnish the diol 18. To complete the synthesis of (–)-zeylenol,
selective benzoylation of primary hydroxyl group has to be carried
out. For this conversion, bases like triethylamine and pyridine
were tried in the presence of benzoyl chloride at various
temperatures. All the time it gave only tri benzoate 19 as a sole
product (Scheme 3).
Scheme 2: Reagents and conditions: (i) see ref.22; (ii) imidazole,
TPP, I2, DCM, rt (80%); (iii) K2CO3, MeOH, rt (90%); (iv)
K2CO3, 37% aq.HCHO, MeOH, 80oC (90%).
To make diene precursor for RCM, we tried vinyl
Grignard addition on compound 10 which failed to give the
desired product and every time the starting material was
recovered. The inertness of substrate 10 towards Grignard addition
even with excess reagent might be due to the presence of free
hydroxyl group adjacent to the lactol. To circumvent this, we
protected the primary alcoholic group in 10 as TBDPS ether to get
1125 by treating with TBDPS-Cl, imidazole and DMAP (cat.).
Vinyl Grignard addition on 11 afforded two diastereomers syn 12
and anti 13 in 1:3 ratio which were separated by column
chromatography.

3. (a) Xu, Q. -M.; Zou, Z. -M.; Xu, L. -Z.;Yang, S. -L. Chem. Pharm. Bull.
2005, 53, 826–828; (b) Zhang, C. -R.; Yang, S. -P.; Liao, S. -G.; Wu, Y.;
Yue, J. -M. Helv. Chim. Acta 2006, 89, 1408–1416; (c) Xu, Q.-M.; Liu, Y.-L.
Chinese Traditional and Herbal Drugs 2007, 38, 1654–1656; (d) Zhang, C. -
R.; Wu, Y.; Yue, J. -M. Chinese J. Nat. Med. 2010, 8, 84–87.
4. Note that in ref. [3b], zeylenol isolated from Uvaria rufa is depicted as the (_)-
1 enantiomer, although no chiroptical data are presented. A subsequent report
on this same species assigned the isolate as (+)-1 on the basis of its positive
[α]D value; see ref. [6b].
5. (a) Kijjoa, A.; Bessa, J.; Pinto, M. M. M.; Anatachoke, C.; Silva, A. M. S.;
Eaton, G.; Herz, W. Phytochemistry 2002, 59, 543–549; (b) Wirasathien, L.;
Pengsuparp, T.; Moriyasu, M.; Kawanishi, K.; Suttirsi, R. Arch. Pharmacal
Res. 2006, 29, 497–502.
Scheme 3: Reagents and conditions: (i) G-II catalyst, toluene,
reflux (80%); (ii) TBAF, THF, rt (90%); (iii) 2,2-DMP, p-
TSA(cat.) (80%); (iv) BzCl, Et3N, DMAP (cat.), 0oC–rt (85%) (v)
80% aq. AcOH (80%). (vi) BzCl, pyridine, DMAP (cat.), 0oC–rt
(75%); (vii) BzCl, Et3N, DMAP (cat.), 0oC–rt (70%).
6. (a) Tuntiwachwuttikul, P.; Pancharoen, O.; Bubb, W. A.; Hambly, T. W.;
Taylor, W.C.; Reutrakul, V. Aust. J. Chem. 1987, 40, 2049–2061; (b)
Pancharoen, O.; Tuntiwachwuttikul, P.; Taylor, W. C. Phytochemistry 1989,
28, 1143–1148; (c) Tang, S. W.; Sukari, M. A.; Rahmani, M.; Lajis, N.H.;
Ali, A.M. Molecules 2011, 16, 3018–3028.
Finally, selective benzoylation was achieved by treating
with 1 equivalent of benzoyl chloride and 3 equivalents of
7. (a) Pan, X. -P.; Qiu, Y. -P.; Chen, R. -Y.; Yu, D. -Q. Acta Pharm. Sinica
1998, 3, 275–281; (b) Tudla, F. A.; Aguinaldo, A. M.; Krohn, K.; Hussain,
H.; Macabeo, A. P. G. Biochem. Syst. Ecol. 2007, 35, 45–47.
o
collidine20 in dry DCM at –78 C for 3 h and then at room
temperature for another 1 h to get 20. Deprotection of acetonide
under acidic conditions gave target molecule (–)-zeylenol 1 in
70% yield (Scheme 4).
8. Taneja, S. C.; Koul, S. K.; Pushpangadan, P.; Dhar, K. L.; Daniewski, W. M.;
Schilf, W. Phytochemistry 1991, 30, 871–874.
9. (a) Xu, Q. -M.; Zou, Z. -M.; Xu, L. -Z.; Yang, S. -L. Chem. Pharm. Bull.
2005, 53, 826–828; (b) Zhang, C. -R.; Yang, S. -P.; Liao, S. -G.; Wu, Y.;
Yue, J. -M. Helv. Chim. Acta 2006, 89, 1408–1416; (c) Xu, Q. -M.; Liu, Y. -
L. Chinese Traditional and Herbal Drugs 2007, 38, 1654–1656; (d) Zhang,
C. -R.; Wu, Y.; Yue, J. -M. Chinese J. Nat. Med. 2010, 8, 84–87.
10. Pan, X.-P.; Yu, D.-Q.; Lee, K.-H. Chin. Chem. Lett. 1996, 7, 241–244.
11. Yonghong, L.; Zhongmei, Z.; Jian, G.; Lizhen, X.; Min, Z.; Shilin, Y.; J.
Chin. Pharm. Sci. 2000, 9, 170–173.
Scheme 4: Reagents and conditions: (i) BzCl, collidine, DMAP
(cat.), –78oC–rt (80%); (ii) TFA, H2O, rt (70%).
Conversion of (–)-zeylenol 1 to (–)-uvarigranol G 2, (–)-
tonkinenin A 3, (+)-pipoxide 4 has already been reported by
Ogasawara’s group.16b
12. Stevenson, P. C.; Veitch, N. C.; Simmonds, M. S. J. Phytochemistry 2007,
68, 1579–1586.
13. (a) Singh, J.; Dhar, K. L.; Atal, C. K.; Tetrahedron 1970, 26, 4403–4406; (b)
Singh, J.; Dhar, K. L.; Atal, C. K. Indian J. Pharm. 1971, 31, 50–51; (c)
Joshi, B. S.; Gawad, D. H.; Fuhrer, H. Tetrahedron Lett. 1979, 20, 2427–
2430; (d) Sumathykutty, M. A.; Rao, J. M. Phytochemistry 1991, 30, 2075–
2076.
3. Conclusions :
In conclusion, we have successfully developed a strategy
for the synthesis of (–)-zeylenol 1 based on mixed aldol
condensation reaction, Grignard addition, ring closing metathesis
and regioselective benzoylation with an overall yield of 9%.
Compound 1 is also a common intermediate for making 2, 3 & 4.
14. Ma, Z. -J.; Meng, Z. -K.; Zhang, P. Fitoterapia 2009, 80, 374–376.
(b) Hongthong, S.; Kuhakarn, C.; Jaipetch, T.; Prabpai, S.; Kongsaeree, P.;
Piyachaturawat, P.; Jariyawat, S.; Suksen, K.; Limthongkul, J.; Panthong,
A.; Nuntasaen, N.; Reutrakul, V. Fitoterapia 2015, 106, 158–166.
15. Seangphakdee, P.; Pompimon, W.; Meepowpan, P.; Panthong, A.;
Chiranthanut, N.; Banjerdpongchai, R.; Wudtiwai, B.; Nuntasaen, N.;
Pitchuanchom, S. ScienceAsia 2013, 39, 610–614.
4. Acknowledgments:
A. V. K and C.M.R thanks, CSIR New Delhi for
financial support as part of XII Five Year plan programme under
title ORIGIN (CSC-0108) and Denova (CSC-0205). The authors
also thank Director, CSIR-IICT for the constant support and
encouragement.
16. (a) Ogawa, S.; Takagaki, T. J. Org. Chem. 1985, 50, 2356–2359; (b)
Hiroya, K.; Ogasawara, K. Chem. Commun. 1999, 2197–2198; (c) Hiroya,
K.; Honzumi, M.;
Kamikubo, T.; Nakashima, H.; Taniguchi, T.;
Ogasawara, K. Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 1999, 41,
331–336.
17. Palframan, M. J.; Kociok – kohn, G.; Lewis, S. E. Chem. Eur. J. 2012, 18,
4766–4774.
References:
18. (a) Ramana, G.V.; Rao, B. V. Tetrahedron Lett. 2005, 46, 3049–3051; (b)
Rao, J. P.; Rao, B. V. Tetrahedron: Asymmetry, 2010, 21, 930–935; (c)
Mishra, G. P., Rao, B. V. Tetrahedron Asymmetry, 2011, 22, 812–817; (d)
1. Jolad, S. D.; Hoffmann, J. J.; Schram, K. H.; Cole, J. R.; Tempesta, M. S.;
Bates, R. B. J. Org. Chem., 1981, 46, 4267–4274
2. Schulte, G. R.; Ganem, B. Tetrahedron Lett., 1982, 23, 4299–4302.

MuniRaju, C.; Rao, J. P.; Rao, B. V. Tetrahedron: Asymmetry, 2012, 23, 24. Vonlanthen, D.; Leumann. C. J. Synthesis. 2003, 1087–1090.
86–93.
25. Kumamoto, H.; Kobayashi, M.; Kato, N.; Balzarini, J.; Tanaka, H. Eur. J.
Org. Chem. 2011, 2685–2691.
19. Pak – Tsun Ho. Can. J. Chem. 1979, 57, 381–383.
20. Scholl, M.; Ding, S.; Lee, C.W.; Grubbs, R.H. Org. Lett. 1999, 1, 953–956.
21. Shing, T. K. M.; Tam. E. K. W. J. Org. Chem. 1998, 63, 1547–1554.
22. Ichiyanagi. T.; Sakamoto. N.; Ochi. K.; Yamasaki. R. J. Carbohydr. Chem.
2009, 53–63.
26. (a) Mekki, B.; Singh, G.; Wightman, R. H. Tetrahedron Lett., 1991, 32,
5143–5146. (b) Rajender, A.; Rao, J. P.; Rao, B. V. Eur. J. Org. Chem.
2013, 1749–1757.
27. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
23. Garegg, P. J.; Samuelsson, B. Synthesis. 1979, 469–470.

Highlights
ꢀ An efficient stereoselective total synthesis of (–)-zeylenol.
ꢀ (–)-zeylenol is a precursor of (+)-pipoxide, (–)-uvarigranol G & (–)-tonkinenin A.
ꢀ This strategy can be used in the synthesis of many zeylenol related compounds.