A silica-gel accelerated [4 + 2] cycloaddition-based biomimetic approach towards the first total synthesis of magterpenoid C

Article abstract of DOI:10.1016/j.tetlet.2019.151137

The first total synthesis of magterpenoid C has been realized via a silica gel accelerated biomimetic Diels-Alder reaction between β-myrcene and randaiol derived quinone. However, application of similar strategy towards magterpenoid B via a protective Diels-Alder reaction failed to deliver the natural product.

Full text of DOI:10.1016/j.tetlet.2019.151137

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A silica-gel accelerated [4+2] cycloaddition-based biomimetic approach to-
wards the first total synthesis of magterpenoid C
Dileep Kumar, Virendra Kumar, Abdus Salam, Tabrez Khan
PII:
S0040-4039(19)30905-0
DOI:
https://doi.org/10.1016/j.tetlet.2019.151137
TETL 151137
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Tetrahedron Letters
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9 September 2019
10 September 2019
Please cite this article as: Kumar, D., Kumar, V., Salam, A., Khan, T., A silica-gel accelerated [4+2] cycloaddition-
based biomimetic approach towards the first total synthesis of magterpenoid C, Tetrahedron Letters (2019), doi:
https://doi.org/10.1016/j.tetlet.2019.151137
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A silica-gel accelerated [4+2] cycloaddition-
based biomimetic approach towards the first
total synthesis of magterpenoid C
Leave this area blank for abstract info.
Dileep Kumar, Virendra Kumar, Abdus Salam and Tabrez Khan
O
O
OH
O
O
OH
OH
[O]
[H]
i) silica gel assisted
[4+2] cycloaddition
ii) oxidative aromatization
HO
magterpenoid C
OH
randaiol

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A silica-gel accelerated [4+2] cycloaddition-based biomimetic approach towards the
first total synthesis of magterpenoid C
Dileep Kumar, Virendra Kumar, Abdus Salam and Tabrez Khan
Organic Synthesis Laboratory, School of Basic Sciences, Indian Institute of Technology, Bhubaneswar, Khurdha-752050, Odisha, India.
———
ARTICLE INFO
ABSTRACT
 Corresponding author. Tel.: +91-674-713-5164; fax: +0-000-000-0000; e-mail: tabrez@iitbbs.ac.in
Article history:
Received
Received in revised form
Accepted
The first total synthesis of magterpenoid C has been realized via a silica gel accelerated
biomimetic Diels-Alder reaction between β-myrcene and randaiol derived quinone. However,
application of similar strategy towards magterpenoid B via a protective Diels-Alder reaction
failed to deliver the natural product.
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Diels-Alder reaction
meroterpenoids
oxidative aromatization
Traditional Chinese Medicine (TCM)
total synthesis
The barks of Magnolia officinalis var. biloba also known as
“Houpo” in Chinese, holds high significance in traditional
Chinese medicine (TCM) for treating a wide range of ailments
such as abdominal distention, nausea, vomiting, dyspepsia,
cough, and asthma.1 Also, the bark extracts of M. officinalis var.
biloba have been found to exhibit antibacterial, antioxidant, anti-
inflammatory, anti-anxiety, anti-gastric ulcer, antitumor,
neuroprotective, and cardiovascular protection activities.2 While
seconday metabolites such as neolignans, lignans, sesquiterpenes,
alkaloids, and phenylethanoid glycosides have found to be the
chemical constituents of the bark extract.3 Further, the recent
approval of the Magnolia extract as food additive has further
amplified their application beyond TCM.4 Intrigued by the huge
plethora of bioactive natural products isolated from Magnolia
officinalis var. biloba, very recently Zhang et al. through a
bioassay-guided study isolated three polycyclic meroterpenoids
with protein tyrosine phosphatase 1B (PTP1B) inhibitory activity
which they named as magterpenoids A-C (Figure 1).5
In view of the prospective of magterpenoids to serve as
potential leads for type 2 diabetes mellitus agents as well as our
ongoing interest in the synthesis of quinoid natural products and
cyclolignans6 we were motivated to embark on the synthesis of
magterpenoids with initial focus on magterpenoid B and C. In
this context we decided to explore the Zhang et.al. proposed
Diels-Alder (DA) cycloaddition based biosynthetic pathway
captured in Scheme 1.5 As per the proposed biogenesis,5 the
[4+2] cycloadditon of randaiol derived quinone (1) with β-
myrcene on the non-substituted double bond followed by
oxidative aromatization in the resultant cycloadduct 2 is
supposed to offer magterpenoid C. While, the same cycloadditon
on the phenylsubstituted double bond of 1 followed by the
hemiketal formation at the C-1 position of the resultant
cycloadduct 3 via
O
O
OH
O
O
-myrcene
-myrcene
[4+2] cycloaddition
[4+2] cycloaddition
O
OH
O
OH
O
3
2
O
HO
O
O
O
1
[O]
[O]
HO
H
O
O
O
O
OH
OH
OH
O
HO
HO
H
Magterpenoid A
Magterpenoid B
Magterpenoid C
O
OH
Figure 1. Bioactive meroterpenoids isolated from Magnolia officinalis.
magterpenoid C
magterpenoid B
randaiol
Magterpenoid A isolated in enantiomerically pure form
Scheme 1. Proposed biogenesis for magterpenoid B and C.
the nucleophilic attack of phenolic OH group is assumed to offer
magterpenoid B.
exhibits
a
unique 4,6,11-trioxatricyclo-[5.3.1.01,5]undecane
framework. On the other hand, magterpenoid B isolated in
racemic form possess an unprecedented 6/6/6/6 polycyclic ring
system while magterpenoid C was identified as a novel terpenoid
quinone with a C6-C3 unit which was also perhaps found to be
the most potent member among all the three for its PTP1B
inhibitory activity.
Towards the realization of the proposed biosynthetic route for
magterpenoid B & C, we commenced our synthetic journey as
highlighted in Scheme 2, with the synthesis of trimethyl ether
derivative of randaiol (10) from readily available starting

2
Tetrahedron
material. A 2-step process involving exhaustive bromination-
12 h
2c
3
debromination protocol on the commercially available 4-allyl
anisole (4) easily furnished 2-bromo-4-allyl anisole (5). Then,
subjection of 5 to nBuLi in presence of triisopropylborate
followed by acidic work-up offered the desired boronic acid 6.7
With 6 in hand we executed its Suzuki coupling with 2-bromo-
1,4-dimethoxybenzene (9)8 to access 10 in reasonably good
yield.9
Toluene, reflux,
12 h
Toluene, reflux,
12 h
1,4 Dioxane, reflux,
2 h
1,2 DCE, reflux, 4 h
DCM, DDQ,
reflux
--
DCM, MnO2,
reflux, 5 h
DCM, MnO2,
reflux, 5 h
DCM, MnO2,
reflux, 5 h
DCM, MnO2,
reflux, 5 h
DCM, MnO2,
reflux, 5 h
DCM, MnO2,
reflux, 5 h
DCM, MnO2,
reflux, 5 h
NA
72
34
65
73
61
70
59
4
5
OMe OH
B
OMe
OMe
6d
7
SiO2-gel, rt, 3 h
MeCN, reflux, 4 h
MeOH, reflux, 3 h
DCM, reflux, 4 h
Br
OH
i
ii
OMe
OMe
OMe
v
6
4
5
8
+
OH
OMe
OMe
10
Br
9
iv
iii
THF, reflux
HFIP, reflux, 3 h
NR
50
10
11
OH
7
OMe
8
OMe
9
DCM, MnO2,
reflux, 5 h
DCM, MnO2,
reflux, 5 h
Scheme 2. Reagents and conditions: (i) (a) Br2, CCl4, 0 °C, 12
h; (b) Zn dust, acetic acid, diethyl ether, 12 h, 96% over 2 steps;
(ii) n-BuLi, dry THF, triisopropyl borate 16 h, 86% (iii) K2CO3,
dimethyl sulphate, acetone, rt, 12 h, 70% (iv) Br2, glacial acetic
acid, 0 °C - r.t., 1 h, 92% (v) Pd(PPh3)4, Na2CO3, 1,2 dimethoxy
ethane, H2O, reflux, 6 h, 60%.
Neat, 80 °C, 2 h
56
12
aA solution of 11 (0.26 mmol) and β-myrcene (0.52 mmol) were
refluxed under N2 atm. in appropriate solvent for time indicated
c
in the table. bIsolated yield. No oxidation was observed on the
d
DA adduct. Reaction between 11 and β-myrcene was executed
With substantial access to intermediate 10 we next explored
its oxidative demethylation to access quinone 11. After scouting
different reagents for the desired task, phenyliodine
bis(trifluoroacetate) (PIFA) in aq. acetonitrile proved to be the
ideal reagent for arriving at the quinone 11 in satisfactory yield.
With quinone 11 in hand we next thought of exploring its key
[4+2] cycloaddition reaction with β-myrcene in various solvents
as well as on silica-gel (100-200 mesh size) surface in view of its
green quotient as well in light of its success history in efficiently
catalyzing many DA reaction because of its slight acidic nature.10
The detail list of conditions explored for the DA reaction of
quinone 11 with β-myrcene as well as the subsequent
aromatization of DA adduct 12 to access the methyl ether of
magterpenoid C (13) in a regioselective manner are as captured
in Table 1. To our delight, among the various investigated
condition, the cycloaddition reaction in refluxing toluene/on
SiO2-gel at rt (entry 3 & 6, Table 1) and subsequent oxidative-
aromatization of the resultant cycloadduct using MnO2 in dry
DCM proved to be the best conditions, by offering 13 in almost
on SiO2-gel surface at rt.
similar maximum yield of 73%. Also, the reaction was found to
be dramatically accelerated on silica-gel surface without affecting
the regioselectivity of the DA reaction, which was in consonance
with our earlier observation in context of acremine G synthesis10f
and by others.10a-e The notable regioselectivity observed in the
DA reaction could be accounted from frontier molecular orbital
(FMO) perspective through the interaction of the low-energy
LUMO of the unsubstituted C5=C6 double bond of quinone 11
having its largest LUMO coefficient at C5 position (in view of the
4-allylanisole substitution at the C2 position), with the HOMO of
β-myrcene having its largest HOMO coefficient at C1 position (in
view of the homoprenyl substitution at the C2 position).
A
detailed density functional theory analysis (which is beyond the
scope of the present paper) would perhaps better confirm the
presumption. In context of magterpenoid C, after access to 13 the
only task left was to deprotect the methyl ether. However, the
seemingly straightforward task on 13 turned out to be a tricky
proposition as all our investigated condition failed to accomplish
the desired methyl deprotection, thereby upsetting our plan to
access magterpenoid C.
4
3
O
2
OMe
OMe
OMe
OMe
O
5
6
2
1
6
5
i
-myrcene
4
1
1
4
2
After failing in our attempts to deprotect the methyl ether in
13, we next planned to synthesize randaiol from its already
synthesized trimethylether derivative 10. However, the
exhaustive demethylation on 10 under several investigated
condition failed to cleanly deliver randaiol thereby forcing us to
explore other intermediate. To our delight, the quinone 11 proved
be the right intermediate since a 2-step process as depicted in
Scheme 4 involving borohydride mediated reduction of quinone
11 followed by AlCl3 mediated demethylation on the resultant
quinol 14 smoothly furnished randaiol in decent yield. Finally,
exposure of randaiol to NaIO4 affected the desired oxidation to
offer quinone 1 in excellent yield.
Table 1
10
O
MeO
11
O
12
Table 1
O
O
O
13
O
MeO
HO
magterpenoid C
Scheme 3. Reagents and conditions: (i) PIFA, CH3CN:H2O
(2:1), 0 °C- rt, 2 h, 62%.
Table 1: Optimization of the DA reaction and subsequent
oxidative-aromatization.a
Entry
Cycloaddition
condition
Oxidative-
aromatization
condition
Yield of
13 b (%)
1c
Toluene, reflux,
DCM, DDQ, rt
--

3
OH
OH
OH
OMe
OH
OH
OMe
O
O
ii
i
OMe
OMe
O
O
O
OMe
O
O
H
H
H
H
14
11
randaiol
i
11
15
O
O
16
iii
ii
iii
O
O
O
OH
O
O
MeO
12
-myrcene

OMe
17
O
iv
1
HO
magterpenoid C
O
O
O
Scheme 4. Reagents and conditions: (i) NaBH4, ethanol, 0 °C,
10 min., 99 % (ii) AlCl3, Me2S, 0 °C-rt, 2 h, 50% (iii) NaIO4,
MeOH:H2O (2:1), 0 °C, 10 min, 95 %. (iv) a) SiO2-gel, 2.5 h (b)
MnO2, dry DCM, reflux, 4 h, 67% over 2 steps.
18
OMe
O
O
MeO
13
CCDC 1940335
Scheme 5. Reagents and conditions: (i) MeOH, 0 °C, 1 h, 85%
(ii) (a) toluene, reflux, 12 h (b) dry DCM, MnO2, 5 h, 40% over 2
steps (iii) xylene, reflux, 12 h, 55%.
Finally with quinone 1 we executed its DA reaction with β-
myrcene as well as subsequent aromatization of the resultant
cycloadduct in a single pot under the best condition mentioned in
Table 1 to finally accomplish the synthesis of magterpenoid C in
a regioselective manner. The NMR spectral data of the synthetic
sample was found to be in good agreement with those reported
for the natural product (refer Supporting Information).5
of magterpenoid B via a protective DA reaction couldn’t
materialize, we look forward for the development of an alternate
approach. Efforts in this direction are currently underway in our
laboratory.
Next, attention was turned towards magterpenoid B and for
accomplishing its synthesis via the biosynthetic route the first
synthetic demand was to subdue the reactivity of unsubstituted
quinone double bond in order to reverse the regioselectivity in
the DA reaction of β-myrcene with quinone 11/1. Therefore, in
this context we decided to use a protective DA reaction using
cyclopentadiene (CP) as the protective diene to block the more
reactive unsubstituted quinone double bond which can be
disposed off at later stage after executing the desired DA reaction
on the phenyl substituted double bond of quinone 11/1. To test
the viability of the synthetic tactic as captured in Scheme 5,
initially we chose quinone 11 for the DA reaction with CP to
arrive at the cycloadduct 15 in a highly regio- as well as
stereoselective manner. However, all our efforts to execute the
next DA reaction on 15 with β-myrcene at phenyl substituted
double bond were unfruitful, as the investigated thermal
condition only resulted in swapping of the CP protection with β-
myrcene through a retro DA reaction resulting in expulsion of CP
followed by addition of β-myrcene on the unsubstituted quinone
double bond to offer the cyloadduct 12 which on oxidative
aromatization offered the undesired 13. Also, our efforts to
execute the DA reaction on 15 with β-myrcene under typical
Lewis acid catalyzed condition involving AlCl3 as well as
BF3.OEt2 meet similar fate. Disappointed with the expulsion of
CP under drastic thermal DA reaction conditions as well as under
Lewis acid conditions which were explored for addition of β-
myrcene on the phenyl substituted double bond of quinone 11,
we next thought of replacing CP with anthracene. Indeed, the
reaction of 11 with anthracene was executed in refluxing xylene,
however to arrive at 18 instead of the desired cycloadduct 17.
Also, the structure of 18 was confirmed through its single crystal
X-ray diffraction studies.11 Although 18 was not serviceable in
context of further elaboration of the natural product, we tried the
DA reaction of β-myrcene with 18 but we again failed to arrive at
any cycloadduct. Henceforth, we look forward to explore an
alternative synthetic route to access magterpenoid B.
Acknowledgments
T. K. gratefully acknowledges the financial support from
CSIR, India (Sanction No. 02(0320)/17/EMR-II) as well as
SERB, DST, India (Sanction No. EMR/2014/000826). D.K. is
thankful to UGC, India for the SRF. V.K and A.S. are thankful to
MHRD and CSIR, India respectively for the financial support.
Also, IIT Bhubaneswar is thanked for the financial and
infrastructural support.
References and notes
1.
2.
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People's Republic China, China Medical Science Press, Beijing,
China, 2015; vol. 1, pp. 251–252.
(a) Greenberg, M.; Dodds, M.; Tian, M. J. Agric. Food. Chem.
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Chen, J. J. Phytochemistry 2013, 85, 153–160; (e) Maruyama, Y.,
Kuribara, H., Morita, M., Yuzurihara, M. & Weintraub, S. T. J.
Nat. Prod. 1998, 61, 135–138; (f) Watanabe, K. Gendai Toyo
Igaku 1986, 7, 54–59; (g) Liu, Y. et al. Scientific Reports 2013, 3,
3098–3105; (h) Lin, Y. R.; Chen, H. H.; Ko, C. H.; Chan, M. H.
Eur. J. Pharmacol. 2006, 537, 64–69; (i) Jennifer, H.; Ho, C. &
Hong, C. Y. J. Biomed. Sci. 2012, 19, 70–78.
3.
(a) Zhang, B. B.; Wang, H.; Chen, S. Z. J. Chi. Pharm. Sci. 2013,
22, 420–426; (b) Yahara, S.; Nishiyori, T.; Kohda, A.; Nohara, T.;
Nishioka, I. Chem. Pharm. Bull. 1991, 39, 2024–2036; (c) Yan, R.
Y.; Liu, H. L.; Zhang, J. Y.; Yang B. J. Asian Nat. Prod. Res.
2014, 16, 400–405; (c) Guo, Z. F.; Wang, X.-B.; Luo, J.-G.; Luo,
J.; Wang, J.-S.; Kong, L.-Y. Fitoterapia 2011, 82, 637–641; (d)
Yu, S. X., Yan, R. Y., Liang, R. X., Wang, W. & Yang, B.
Fitoterapia 2012, 83, 356–361.
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5.
6.
Greenberg, M., Urnezis, P. & Tian, M. J. Agric. Food Chem.
2007, 55, 9465–9469.
Li, C.; Li, C.-J.; Ma, J.; Chen, F.-Y.; Li, L.; Wang, X.-L.; Ye, F.;
Zhang, D.-M. Org. Lett. 2018, 20, 3682−3686.
Kumar, D.; Das, O.; Kaurav, M. S.; Khan, T. RSC Advances 2017,
7, 36844–36851.
In summary, we have successfully demonstrated the
implementation of the biomimetic DA approach for the first total
synthesis of magterpenoid C from cheap and readily accessible
starting material. As extension of similar approach for synthesis

4
Tetrahedron
7.
(a) Denton, R.M.; Scragg, J. T.Org. Biomol. Chem. 2012, 10,
5629-5635. (b) Denton, R.M.; Scragg, J.T. Synlett, 2010, No. 4,
0633-0635.
8.
9.
Iwanaga, K.; Kobayashi, J.; Kawashina, T.; Tetrahedron, 2007,
63, 10127-10132.
Johnson, M. M,; Ngwira, K. J.; Rousseau, A. L.; Lemmerer, A.; de
Koning, C. B.; Tetrahedron, 2018, 74, 12-18.
10. (a) Veselovsky, V. V.; Gybin, A. S.; Lozanova, A. V.;
Moiseenkov, A. M.; Smit, W. A.; Caple, R. Tetrahedron Lett.
1988, 29, 175-178; (b) Iwasawa, N.; Sakurada, F.; Iwamoto, M.
Org. Lett. 2000, 2, 871-873; (c) Reymond, S.; Cossy, J. Chem.
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T.; Iwagawa, T.; Furuno, H. Tetrahedron 2009, 65, 10709–10714;
(e) Wei, K.; Wang, S.; Liu, Z.; Du, Y.; Shi, X.; Qi, T.; Ji, S.
Tetrahedron Lett. 2013, 54, 2264–2266; (f) Mehta, G.; Khan, T.
B.; Kumar, Y. C. S. Tetrahedron Lett. 2010, 51, 5116-5119.
11. CCDC 1940335 contain the crystallographic information for the
crystals of 18. This data can be obtained free of charge from the
Cambridge Crystallographic Data Centre by emailing at
deposit@ccdc.cam.ac.uk or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
Supplementary Material
Experimental procedures and NMR spectral data. CIF file for 18.
Copies of 1H and 13C NMR spectral data.
 First total synthesis of Magterpenoid C.
 A
silica-gel
accelerated
[4+2]
cycloaddition-based biomimetic approach.
 Randaiol has been accessed with 18%
overall yield in 4 steps starting from easily
accessible starting materials.
 Magterpenoid C has been accessed with
12% overall yield in 6 linear steps.