A three-step total synthesis of goniothalesdiol A using a one-pot Sharpless epoxidation/regioselective epoxide ring-opening

Article abstract of DOI:10.1016/j.tetlet.2017.01.100

Using a one-pot Sharpless asymmetric epoxidation/regioselective epoxide ring-opening as a key step, the protecting-group-free total synthesis of goniothalesdiol A was accomplished in only three steps starting from commercially available trans-cinnamaldehy

Full text of DOI:10.1016/j.tetlet.2017.01.100

Accepted Manuscript
A three-step total synthesis of goniothalesdiol A using a one-pot Sharpless ep-
oxidation/regioselective epoxide ring-opening
Perla Ramesh, Yarram Narasimha Reddy
PII:
S0040-4039(17)30132-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.100
TETL 48603
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 January 2017
21 January 2017
25 January 2017
Please cite this article as: Ramesh, P., Reddy, Y.N., A three-step total synthesis of goniothalesdiol A using a one-
pot Sharpless epoxidation/regioselective epoxide ring-opening, Tetrahedron Letters (2017), doi: http://dx.doi.org/
10.1016/j.tetlet.2017.01.100
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Graphical Abstract
A three-step total synthesis of goniothalesdiol
A using a one-pot Sharpless
epoxidation/regioselective epoxide ring-
opening
Leave this area blank for abstract info.
Perla Ramesh, Yarram Narasimha Reddy

1
Tetrahedron Letters
A three-step total synthesis of goniothalesdiol A using a one-pot Sharpless
epoxidation/regioselective epoxide ring-opening
Perla Ramesh* and Yarram Narasimha Reddy
Natural Products Chemistry Division, Indian Institute of Chemical Technology, Uppal Road, Hyderabad-500007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Using a one-pot Sharpless asymmetric epoxidation/regioselective epoxide ring-opening as a key
step, the protecting-group-free total synthesis of goniothalesdiol A was accomplished in only
three steps starting from commercially available trans-cinnamaldehyde in 55.1% overall yield.
In 6 previously reported total syntheses, 6-11 steps were required.
Available online
Keywords:
Goniothalesdiol A
Sharpless epoxidation
Asymmetric synthesis
Protecting-group-free
Tetrahydropyran
2017 Elsevier Ltd. All rights reserved.
1. Introduction
30% overall yield.6 Recently, Sabitha and co-workers7 reported
the application of the Tandem α-aminoxylation–allylation
reaction, resulting in the concise synthesis of 1. Quite recently,8
Rakeshwar has described the last synthesis of 1 in six steps with
31% overall yield, starting from the commercially available 2-
deoxy-D-ribose. Most of these syntheses rely on the use of
protecting groups and as a consequence are lengthy sequences.
As part of our ongoing projects focused on improving the
efficiency of natural products synthesis,9 herein we describe the
asymmetric total synthesis of goniothalesdiol A (1) by a unified
strategy that requires no use of protecting groups.
The tetrahydropyran backbone is a ubiquitous heterocyclic
unit found in numerous bioactive natural products and
pharmaceutically active compounds. Studies on natural products
isolated from several species of the genus Goniothalamus have
led to the discovery of various secondary metabolites including
acetogenins, styryllactones, alkaloids, and flavonoids with
interesting biological properties, such as pesticidal, teratogenic
and cytotoxic.1 Goniothalesdiol A (1) (Figure 1), a new natural
3,4-dihydroxy 2,6-disubstituted tetrahydropyran derivative, was
isolated in 2006 from the stem of a southern Taiwan tree
Goniothalamus amuyon by Wu and co-workers. The gross
structure and relative stereochemistry of 1 were assigned on the
basis of
1H NMR, 13C NMR and HRMS experiments, and the absolute
configuration was confirmed by biosynthesis.2
Figure 1. The structure of goniothalesdiol A (1).
To date, there have been six reports describing elegant
synthetic efforts toward this natural product. In 2009, Yadav et
al.3 reported the first total synthesis of goniothalesdiol A (1) from
homopropargyl alcohol in 11 steps with 35.1% overall yield by
employing a Sharpless kinetic resolution and intramolecular oxa-
Michael addition for the construction of the pyran ring. More
recently, the same author has reported the synthesis of 1 that
proceeded in nine steps using an intramolecular oxa-Michael
reaction as a key step.4 Fadnavis et al.5 achieved the asymmetric
synthesis of 1 from (R)-2,3-O-cyclohexylidine glyceraldehyde in
11 steps with an overall yield of 22%. Protecting-group-free total
2. Results and discussion
Our first retrosynthetic analysis for the synthesis of 1 is shown
in Scheme 1. Goniothalesdiol A (1) would be obtained from triol
2 through an intramolecular oxa-Michael addition of the
hydroxyl group present at the active benzylic position. Triol 2
would be built by using a Sharpless asymmetric epoxidation
applied to compound 3, followed by a regioselective epoxide ring
opening with water to control the stereogenic centers at C2 and
C3. Finally, the α,β-unsaturated ester 3 would be synthesized
synthesis of 1 was accomplished by She et al. in six steps with
———
 Corresponding authors. Tel.: +91-40-27191631; fax: +91-40-27160512; e-mails: perlaramesh@yahoo.co.in (P. Ramesh);
nyarram20@gmail.com (Y. Narasimha Reddy)

2
Tetrahedron Letters
from commercially available trans-cinnamaldehyde 4 using an
asymmetric allylation followed by an olefin cross-metathesis.
Scheme1. First retrosynthetic analysis to goniothalesdiol A (1).
Scheme 2. End-game: first attempt.
The synthesis of goniothalesdiol A (1) started with the known
homoallylic alcohol 5,9d,e which is readily available in high
enantiomeric excess from (E)-cinnamaldehyde by an asymmetric
allylation. Chemoselective olefin cross-metathesis (OCM)10 of
compound 5 with methyl acrylate in the presence of second-
generation Grubbs catalyst provided the desired (E)-α,β-
unsaturated ester 3 in 91% yield as a single stereoisomer (judged
1
by H NMR analysis). Sharpless asymmetric epoxidation11 of
allylic alcohol 3 using (+)-diethyl tartrate as a chiral ligand
proceeded efficiently to produce epoxy alcohol 6 in 90% yield.
Regioselective epoxide ring opening of epoxy alcohol 6 using hot
o
water under the catalyst-free condition at 60 C provided triol
2,12,9e which was then subjected to intramolecular oxa-Michael
addition using the acid catalyst. At this stage, we anticipated that
a desired THP product 1 would be obtained from triol 2 through
an intramolecular 1,4-addition of the hydroxyl group present at
the active benzylic position on the unsaturated ester.
Unfortunately, when compound 2 was treated with TBAF in dry
Scheme 3. Second retrosynthetic analysis for 1.
As delineated in scheme 4, the synthesis of 1 commenced with
methyl(S,E)-5-hydroxy-3-oxo-7-phenylhept-6-enoate (11), which
o
THF at 0 C, an excellent yield in the unexpected intramolecular
1,4-addition product trans-THF 7 was obtained with 97:3
diastereomeric ratio.13 The 2,5-trans configuration of the
tetrahydrofuran ring in undesired product 2 was confirmed by
NOE data (Scheme 2).
is
a
known intermediate easily available from trans-
cinnamaldehyde by an asymmetric Mukaiyama aldol
reaction.14 As we reported previously,14a the stereoselective syn
reduction of 11 under Narasaka’s conditions15 using
Et2BOMe/NaBH4 in THF-MeOH (4:1) at −78 °C gave syn-diol 9,
which was then subjected to Sharpless asymmetric epoxidation
using (+)-diethyl tartrate as a chiral ligand. Surprisingly, under
Sharpless conditions, asymmetric epoxidation (formation of 8)
and concomitant cyclization via intramolecular regioselective
Due to the first strategy failure, a second strategy was then
envisaged, utilizing asymmetric reactions in order to reduce the
number of steps. In this strategy (Scheme 3), the required cis-
THP 1 would be achieved from 8 by using an intramolecular
regioselective epoxide ring opening at the active benzylic
position. Compound 8 would be emerged from 9 by a Sharpless
asymmetric epoxidation, while 9 would be derived from
commercially available trans-cinnamaldehyde by the successful
implementation of asymmetric aldol addition followed by 1,3-syn
reduction.
epoxide ring opening proceeded smoothly to form
a
tetrahydropyran ring, and the desired cis-THP product (1) was
obtained in 84% yield for a single step. Goniothalesdiol A (1)
was identical in all respect with the spectral data (1H NMR, 13C
NMR and HRMS) and the specific rotation reported previously.2-
8 It is noteworthy that this three-step synthesis of 1 compares well
with those reported in the literature that ranges in length from 6
to 11 steps.

3
Scheme 4. Synthesis of goniothalesdiol A (1).
4.
5.
6.
7.
8.
9.
Yadav, J. S.; Nageshwar Rao, R.; Somaiah, R.; Harikrishna, V.;
Subba Reddy, B. V. Helv. Chim. Acta 2010, 93, 1362–1368.
Venkataiah, M.; Somaiah, P.; Reddipalli, G.; Fadnavis, N. W.
Tetrahedron: Asymmetry 2009, 20, 2230–2233.
Li, J.; Zheng, H.; Su, Y.; Xie, X.; She, X. Synlett 2010, 2283–
2284.
Sabitha, G.; Rammohan Reddy, T.; Yadav, J. S. Tetrahedron Lett.
2011, 52, 6550–6553.
Pallavi, T.; Kumaraswamy, B.; Raji, R. G.; Rakeshwar B.; Khagga
M. Tetrahedron: Asymmetry 2012, 23, 659–661.
(a) Ramesh, P.; Raju, A.; Fadnavis, N. W. Tetrahedron:
Asymmetry 2015, 26, 1251-1255; (b) Ramesh, P. Synthesis 2016,
48, 4300-4304; (c) Ramesh, P.; Anjibabu, R.; Raju, A.
Tetrahedron Lett. 2016, 57, 2100-2102; (d) Ramesh, P.
ChemistrySelect, 2016, 1, 3244-3246; (e) Ramesh, P.; Rao, T. P. J.
Nat. Prod. 2016, 79, 2060-2065; (f) Ramesh, P; Reddy, Y. N;
Reddy, T. N; Srinivasu, N. Tetrahedron: Asymmetry 2017, DOI:
org/10.1016/j.tetasy.2017.01.005.
3. Conclusions
In summary, two approaches of the goniothalesdiol A (1) were
examined. One of them failed in the formation of the cis-THP
ring, utilizing an intramolecular oxa-Michael addition of active
benzylic hydroxyl group on an unsaturated ester. On the contrary,
the second approach allowed us to minimize the number of steps
by using a one-pot Sharpless epoxidation/regioselective epoxide
ring-opening strategy. This highly concise synthesis relied on the
use of a key one-pot Sharpless epoxidation/regioselective
epoxide ring-opening reaction to rapidly construct the unique six-
membered cis-tetrahydropyran ring and two continuous
stereocenters in
a single step. In contrast to previous
approaches,2-8 this protocol is atom economical, step-economical
and devoid of any protecting group manipulations. Our route to
goniothalesdiol A (1) is significantly shorter than the previous
approaches, requiring only three steps instead of 6-11 steps.
10. Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42,
1900–1923.
11. Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda,
M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237-6240.
12. Wang, Z.; Cui, Y. T.; Xu, Z. B.; Qu, J. J. Org. Chem. 2008, 73,
2270-2274.
Acknowledgments
We thank CSIR New Delhi for financial support under XII
Five Year Plan CSC0108-ORIGIN.
13. Jun-Ling, C.; Zheng-Wei, Y.; Feng-Ling, Q. J. Fluorine Chem.
2013, 155, 143–150.
14. (a) Ramesh, P.; Raju, A.; Paramesh, J.; Ramisetti, A. Tetrahedron
Lett. 2016, 57, 1087-1089; (b) Brownbridge, P.; Chan, T. H.;
Brook, M. A.; Kang, G. J. Can. J. Chem. 1983, 61, 688-693; (c)
Rayala, N. K.; Meshram, H. M. Tetrahedron Lett. 2011, 52, 1003-
1007; (d) Xu, Q.; Yu, J.; Han, F.; Hu, J.; Chen, W.; Yang, L.
Tetrahedron: Asymmetry 2010, 21, 156-158; (e) Ramesh, P.; Raju,
A.; Fadnavis, N. W. Helv. Chim. Acta 2016, 99, 70-72.
15. (a) Narasaka, K.; Pai, F.-C. Tetrahedron 1984, 40, 2233-2238. (b)
Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro,
M. J. Tetrahedron Lett. 1987, 28, 155-158.
References and notes
1.
(a) Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z. M.; He, K.;
Mc Laughlin, J. L. Nat. Prod. Rep. 1996, 13, 275-306; (b) Din, L.
B.; Colegate, S. M.; Razak, D. A. Phytochemistry 1990, 29, 346-
348; (c) Omar, S.; Chee, C. L.; Ahmad, F.; Ni, J. X.; Jaber, H.;
Huang, J.; Nakatsu, T. Phytochemistry 1992, 31, 4395-4397; (d)
Sam, T. W.; Chew, S. Y.; Matsjeh, S.; Gan, E. K.; Razak, D.;
Mohamed, A. L. Tetrahedron Lett. 1987, 28, 2541-2544; (e) Fang,
X.-P.; Anderson, J. E.; Chang, C. J.; McLauglin, J. L. Tetrahedron
1991, 4, 9751-9758.
Supplementary Material
2.
3.
Lan, Y.-H.; Chang, F.-R.; Yang, Y.-L.; Wu, Y.-C. Chem. Pharm.
Bull. 2006, 54, 1040–1043.
Yadav, J. S.; Rami Reddy, N.; Harikrishna, V.; Subba Reddy, B.
V. Tetrahedron Lett. 2009, 50, 1318–1320.
1H and 13C spectra of all compounds have been provided in a
separate electronic file as a supplementary data.

Tetrahedron
4
Highlights:
 The protecting-group-free total synthesis of goniothalesdiol A is described.
 Only three steps starting from trans-cinnamaldehyde in 55.1% overall yield.
 A one-pot Sharpless epoxidation/regioselective epoxide opening is a key step.

Atom economical, step-economical and devoid of protecting group manipulations.