Annulated oxa-cage frameworks via Claisen rearrangement and ring-closing metathesis

doi:10.1016/j.tet.2020.131694

Tetrahedron

Volume 76, Issue 49, 4 December 2020, 131694

https://doi.org/10.1016/j.tet.2020.131694 Get rights and content

Highlights

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Oxa-cage compounds were synthesized via cycloadditions and ring closing metathesis (RCM).
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Transannular cyclization was observed in the Grignard addition.
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Novel dioxa cage compound was prepared by RCM.
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The target oxa-cage has been proven by single crystal X-ray diffraction studies.

Abstract

In our quest to design high-density fuels, we report a variety of structurally interesting new annulated oxa-cage frameworks. Here, we investigated a linear synthetic sequence, which relies on reductive C–C bond cleavage and ring-closing metathesis as key steps. For this purpose, we utilized inexpensive and readily available starting materials such as hydroquinone and endo-dicyclopentadiene. Transannular cyclization during Grignard addition played a significant role in the design of intricate caged compounds. The creation of these new oxa-cage systems is a challenging task by traditional methods. The structure of the target compound has been unambiguously established by single-crystal X-ray diffraction studies. These data indicate that density of the RCM compound is larger than the cubane density.

Graphical abstract

Introduction

Cage frameworks containing heteroatoms are useful in diverse areas of chemical sciences [1]. High symmetry, severe ring strain, rigid and compact architecture of the cage systems has been identified as suitable building blocks for the design of high-density fuels. Moreover, the high nitrogen content within the cage framework enriches its desirable energetic properties such as detonation performance; positive heats of formation, low ecological toxicity, good oxygen balance, high density, hydrolytic and good thermal stability along with low impact sensitivity and high burning rate [1]. Also with these valuable properties and lipophilicity of the cage moiety improve the biological properties [2].

Several oxygenated cage systems 1–6 incorporating pentacycloundecane (PCUD) framework are found to be beneficial as supramolecules, application in medicinal and pharmaceutical chemistry and also good ligands in the asymmetric catalysis (Fig. 1) [3]. Limited reports are available dealing with the syntheses of oxa-cage systems [4]. Interestingly, amino group present in the PCUD cage system 2, 5, and 6 shows an interesting activities against tuberculosis, neurodegenerative, and anti-viral diseases [[5], [6], [7]]. Additionally, pentacycloundecylamine 5 (NGP1-01) reveals both N-methyl-d-aspartate (NMDA) receptor channel blocking and L-type calcium channel antagonist activity [6,7].

NGP1-01 and similar types of aminated oxa-cage frameworks are examined as a promising candidates for neuroprotective agents [8]. PCUD containing tetra-amine oxa-cages show an excellent anti-TB activity against M-tuberculosis H37Rv (Fig. 1) [9]. Also, these studies have demonstrated that the crown ether-based oxa, aza, and thia-cage frameworks exhibit interesting cation-binding properties [10]. Marchand’s group assembled a series of bis annulated cage crown ethers and tested for alkali metal picrate extraction [11]. Interestingly, it was found that the oxa-cage crown ether moieties increase the lipophilicity and complexation properties of the host and these oxa-cage crown systems bind selectively with Li⁺ and Na⁺ ions (Fig. 1) [11]. Kruger’s group designed diverse oxa cage chiral bidentate ligands and studied their binding properties. These PCUD ligands work as an effective catalysts with good enantioselectivities [12].

Section snippets

Results and discussion

To expand the synthetic routes to oxa-cage systems, ozonolysis method has been used to design of tri-oxa, tetra-oxa, penta-oxa, acetal based oxa-cages, and oxa-peristylanes [13]. Other methods to oxygenated cage compounds include: iodine induced cyclization, hydride rearrangement, alkene-oxirane photocycloaddition, tandem cyclizations, transannular cyclizations, base promoted rearrangement, dehydration of diols, reduction of lactones, oxidation-based methodologies, intramolecular

Conclusions

In conclusion, we have successfully assembled new and interesting oxa-cage framework via a transannular cyclization and two-fold RCM protocol. The newly synthesized cage heterocyclic system holds tetrahydrofuran and oxepane rings. The methodology involved in this sequence is useful to design other highly functionalized heterocyclic cage compounds. The density of compound 15 as determined by X-ray studies and this value is comparable to cubane 29 although one bond and cyclopropane are missing as

General methods

Moisture-sensitive materials were transferred by using syringe-septum technique and the reactions were maintained under nitrogen atmosphere. The TLC (thin-layer chromatography) was performed on (7.5 × 2.5 cm) glass plates coated with Acme’s silica gel GF 254 (containing 13% calcium sulfate as a binder) by using a suitable mixture of EtOAc and petroleum ether for development. Column chromatography was accomplished by using Acme’s silica gel (100–200 mesh) with an appropriate mixture of EtOAc and

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

The authors are gratefully appreciate the Defense Research and Development Organization (DRDO, NO. ARDB/01/1041849/M/1), New Delhi-India, for the financial assistance. S. K. thanks Department of Science and Technology (DST, NO. SR/S2/JCB-33/2010), DST, New Delhi, India for the award of a J. C. Bose fellowship and Praj industries for Chair Professorship in Green Chemistry. S.R.C and U.N.C thanks University Grants Commission (UGC), New Delhi, India, for the award of a doctoral fellowship.

References (21)

M.D. Duque et al.
J. Med. Chem.
(2011)
O.K. Onajole et al.
Eur. J. Med. Chem.
(2009)
A.P. Marchand et al.
Tetrahedron
(1999)
A.P. Marchand et al.
Tetrahedron
(1999)
A.P. Marchand et al.
Tetrahedron
(1997)
A.P. Marchand et al.
J. Chem. Crystallogr.
(2002)
A.P. Marchand et al.
Tetrahedron Lett.
(1998)
S.M. Blair et al.
Anal. Chem.
(2000)
S.M. Blair et al.
J. Am. Soc. Mass Spectrom.
(2000)
W.J. Geldenhuys et al.
Med. Res. Rev.
(2005)
K.F. Biegasiewicz et al.
Chem. Rev.
(2015)
Q. Wu et al.
RSC Adv.
(2014)
E. Osawa et al.
Carbocyclic Cage Compounds
(1992)
G.A. Olah
Cage Hydrocarbons
(1990)
R.T. Vayalakkavoor et al.
Heterocycles
(1990)
S.J. Gharpure et al.
Org. Prep. Proced. Int.
(2013)
P.E. Eaton et al.
J. Am. Chem. Soc.
(1964)
A.K. Sikder et al.
J. Hazard Mater.
(2004)
A. Sankaranarayanan et al.
Fuel
(2019)
Q. Wu et al.
RSC Adv.
(2014)
L. Mallick et al.
New J. Chem.
(2017)
G. Ali mansoori
Adv. Chem. Phys.
(2007)
I.A. Levandovskiy et al.
Russ. Chem. Rev.
(2010)
D.I. Sharapa et al.
Curr. Org. Chem.
(2012)
K. Gerzon et al.
J. Med. Chem.
(1967)
K. Gerzon et al.
J. Med. Chem.
(1965)
K. Hayakawa et al.
J. Chem. Soc., Chem. Commun.
(1986)
T. Govender et al.
Struct. Chem.
(2008)
S.M. Williams et al.
Anal. Chem.
(2002)
C.L. Sherman et al.
ARKIVOC
(2005)
T.G. Levitskaia et al.
J. Am. Chem. Soc.
(2001)
D. Giomi et al.
J. Org. Chem.
(2000)
H.-C. Lin et al.
Tetrahedron
(2000)
M.-Y. Chang et al.
J. Chin. Chem. Soc.
(2001)
H.-J. Wu et al.
Tetrahedron
(1997)
F.A. Khan et al.
Tetrahedron Lett.
(2007)
N.C. Kong et al.
Tetrahedron
(2007)
S.I. Kozhushkov et al.
Eur. J. Org Chem.
(2006)
R. Sharma et al.
Molecules
(2018)
S.C. Suri
J. Org. Chem.
(1993)
A. Mdzinarishvili et al.
Neurosci. Lett.
(2005)
A. van Dijk et al.
Behav. Brain Res.
(2008)
J. Hao et al.
Brain Res.
(2008)
J. Joubert et al.
ChemMedChem
(2012)
C.J. Van der Schyf et al.
Neurotherapeutics
(2009)
J. Joubert et al.
Bioorg. Med. Chem. Lett
(2016)
A.O. Egunlusi et al.
ChemMedChem
(2015)
F.T. Zindo et al.
Eur. J. Med. Chem.
(2019)
O.K. Onajole et al.
Eur. J. Med. Chem.
(2012)
E. Grobler et al.
Bioorg. Med. Chem.
(2006)
H.J.R. Lemmer et al.
Med. Chem.
(2012)
O.K. Onajole et al.
Eur. J. Med. Chem.
(2009)
L.M. Young et al.
Arch. Pharm. Chem. Life Sci.
(2016)
L.H. Prins et al.
Eur. J. Med. Chem.
(2009)
J. Joubert et al.
Bioorg. Med. Chem.
(2011)
D.K. Wilkes et al.
Arch. Pharm.
(2009)

There are more references available in the full text version of this article.

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Annulated oxa-cage frameworks via Claisen rearrangement and ring-closing metathesis

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusions

General methods

Declaration of competing interest

Acknowledgements

J. Med. Chem.

Eur. J. Med. Chem.

Tetrahedron

Tetrahedron

Tetrahedron

J. Chem. Crystallogr.

Tetrahedron Lett.

Anal. Chem.

J. Am. Soc. Mass Spectrom.

Med. Res. Rev.

Chem. Rev.

RSC Adv.

Carbocyclic Cage Compounds

Cage Hydrocarbons

Heterocycles

Org. Prep. Proced. Int.

J. Am. Chem. Soc.

J. Hazard Mater.

Fuel

RSC Adv.

New J. Chem.

Adv. Chem. Phys.

Russ. Chem. Rev.

Curr. Org. Chem.

J. Med. Chem.

J. Med. Chem.

J. Chem. Soc., Chem. Commun.

Struct. Chem.

Anal. Chem.

ARKIVOC

J. Am. Chem. Soc.

J. Org. Chem.

Tetrahedron

J. Chin. Chem. Soc.

Tetrahedron

Tetrahedron Lett.

Tetrahedron

Eur. J. Org Chem.

Molecules

J. Org. Chem.

Neurosci. Lett.

Behav. Brain Res.

Brain Res.

ChemMedChem

Neurotherapeutics

Bioorg. Med. Chem. Lett

ChemMedChem

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Bioorg. Med. Chem.

Med. Chem.

Eur. J. Med. Chem.

Arch. Pharm. Chem. Life Sci.

Eur. J. Med. Chem.

Bioorg. Med. Chem.

Arch. Pharm.