Stereoselective synthesis of oxa- and aza-angular triquinanes using tandem radical cyclization to vinylogous carbonates and carbamates

Article abstract of DOI:10.1021/ol302557a

Tandem radical cyclization to vinylogous carbonates and carbamates is developed for a new, highly stereoselective synthesis of heterocyclic angular triquinanes. The strategy is also useful to gain access to oxa- and azatriquinanes, which incorporate the spiroindoline moiety. The method is further extended to the synthesis of lactone-bearing as well as uracil-fused angular triquinanes.

Full text of DOI:10.1021/ol302557a

ORGANIC
LETTERS
2012
Vol. 14, No. 21
5476–5479
Stereoselective Synthesis of Oxa- and
Aza-Angular Triquinanes Using Tandem
Radical Cyclization to Vinylogous
Carbonates and Carbamates
Santosh J. Gharpure,*,§,†,‡ P. Niranjana,† and Suheel K. Porwal†
Department of Chemistry, Indian Institute of Technology Madras,
Chennai 600036, Tamil Nadu, India, and Department of Chemistry,
Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
sjgharpure@iitb.ac.in
Received September 17, 2012
ABSTRACT
Tandem radical cyclization to vinylogous carbonates and carbamates is developed for a new, highly stereoselective synthesis of heterocyclic
angular triquinanes. The strategy is also useful to gain access to oxa- and azatriquinanes, which incorporate the spiroindoline moiety. The method
is further extended to the synthesis of lactone-bearing as well as uracil-fused angular triquinanes.
The stereoselective synthesis of triquinanes has attracted
considerableattention due to theubiquity ofthisimportant
framework in challenging natural products.1 Triquinanes
are typically classified into three types depending on the
fusion pattern of the five-membered rings as linear-,
angular-, and propellane-type triquinanes (Figure 1). Sig-
nificant effort has been directed to the synthesis of triqui-
nanes bearing an all-carbon framework as they constitute
the core of many sesquiterpene natural products. In con-
trast, the heteroatom-substituted triquinanes have attracted
much less attention from the synthetic community.2 The
majority of the strategies developed to date give access to
either aza- or oxa-triquinanes; however, methods incorporat-
ing both oxygen and nitrogen in the same molecule are
uncommon. This is surprising as heteroatom-substituted
triquinanes not only serve as important intermediates
in the synthesis of carbocyclic triquinanes, but were
also suggested to be responsible for bioactivity of many
natural products.3 Thus, a general, rapid, and stereo-
selective access to heterocyclic angular triquinanes is
highly desirable.
† Indian Institute of Technology Madras.
‡ Indian Institute of Technology Bombay.
§ Indian Institute of Technology Bombay.
(1) For reviews, see: (a) Mehta, G.; Srikrishna, A. Chem. Rev. 1997,
97, 671. (b) Singh, V.; Thomas, B. Tetrahedron 1998, 54, 3647. (c)
Marchand, A. P. Synlett 1991, 73.
(2) Selected examples. Oxa-triquinanes: (a) Yadav, J. S.; Kumar,
P. T. K.; Gadgil, V. R. Tetrahedron Lett. 1992, 33, 3687. (b) Woltering,
T. J.; Hoffmann, H. M. R. Tetrahedron 1995, 51, 7389. (c) Singh, V.;
Alam, S. Q. Bioorg. Med. Chem. Lett. 2000, 10, 2517. (d) Ader, T. A.;
Champey, C. A.; Kuznetsova, L. V.; Li, T.; Lim, Y.-H.; Rucando, D.;
Sieburth, S. McN. Org. Lett. 2001, 3, 2165. (e) Gurjar, M. K.;
Ravindranadh, S. V.; Kumar, P. Chem. Commun. 2001, 917. (f) Singh,
V.; Alam, S. Q.; Praveena, G. D. Tetrahedron 2002, 58, 9729. (g)
Kaliappan, K. P.; Nandurdikar, R. S. Chem. Commun. 2004, 2506.
(h) Kaliappan, K. P.; Nandurdikar, R. S.; Shaikh, M. M. Tetrahedron
2006, 62, 5064. (i) Ramakrishna, K.; Kaliappan, K. P. Synlett 2011,
2580. (j) Liao, J.-H.; Maulide, N.; Augustyns, B.; Marko, I. E. Org.
Biomol. Chem. 2006, 4, 1464. (k) Mascal, M.; Hafezi, N.; Meher, N. K.;
Fettinger, J. C. J. Am. Chem. Soc. 2008, 130, 13532. Aza-triquinanes:
(l) Clive, D. L. J.; Cole, D. C.; Tao, Y. J. Org. Chem. 1994, 59, 1396. (m)
Hext, N. M.; Hansen, J.; Blake, A. J.; Hibbs, D. E.; Hursthouse, M. B.;
Shishkin, O. V.; Mascal, M. J. Org. Chem. 1998, 63, 6016. (n) Li, Y.;
Meng, Y.; Meng, X.; Li, Z. Tetrahedron 2011, 67, 4002. (o) Zancanella,
M. A.; Romo, D. Org. Lett. 2008, 10, 3685. (p) Kudryavtsev, K. V.
Heterocycles 2011, 83, 323. (q) Bandaru, A.; Kaliappan, K. P. Synlett
2012, 1473.
(3) (a) Huang, J.-M.; Yokoyama, R.; Yang, C.-S.; Fukuyama, Y.
Tetrahedron Lett. 2000, 41, 6111. (b) Huang, J.-M.; Yang, C.-S.;
Tanaka, M.; Fukuyama, Y. Tetrahedron 2001, 57, 4691.
r
10.1021/ol302557a
Published on Web 10/25/2012
2012 American Chemical Society

Our proposed synthesis of heteroatom-substituted an-
gular triquinane is depicted in Figure 2. It was envisaged
that cyclopentene 1 bearing an appropriate radical pre-
cursor and tethered vinylogous functional group, upon
being subjected to radical conditions, will first undergo a
5-exo-trig cyclization to generate the radical 2. This inter-
mediate 2 will further react with a vinylogous functional
group in a 5-exo-trig fashion generating radical 3, which
will undergo reduction to generate angularly fused cyclic
system 4. One of the heteroatoms of the triquinane will
come from the tether used for attaching radical precursor
to cyclopentene moiety, whereas the other heteroatom
would be the part of the initial vinylogous carbonate or
carbamate.
Figure 1. Carbocyclic and heterocyclic triquinanes and
spiroindoline.
Scheme 1
Vinylogous carbonates and carbamates have come to
the forefront as excellent radical acceptors, and they
have been used in the stereoselective synthesis of tetra-
hydrofurans (THFs) and piperidines, respectively.4,5
However, their utility in the synthesis of heteroatom
substituted triquinanes is conspicuous by its absence. In
a program directed at using vinylogous functional
groups in the synthesis of oxa- and aza-cyclic frame-
works,6 herein we report for the first time a strategy for
the stereoselective construction of the heterocyclic an-
gular triquinanes using tandem radical cyclization to
vinylogous carbonates and carbamates.7
In order to test the proposed strategy, synthesis of iodide
5 was undertaken. Thus, known BaylisÀHilmann adduct8
6 was reacted with ethyl propiolate in the presence of
N-methylmorpholine (NMM) to furnish the vinylogous
carbonate 7. Luche reduction9 of the enone 7 followed by
(5) Some selected examples, see: (a) Navarro-Vazquez, A.; Garcia,
A.; Dominguez, D. J. Org. Chem. 2002, 67, 3213. (b) Berlin, S.; Ericsson,
C.; Engman, L. J. Org. Chem. 2003, 68, 8386. (c) Chakraborty, T. K.;
Samanta, R.; Roy, S.; Sridhar, B. Tetrahedron Lett. 2009, 50, 3306. (d)
Lee, E.; Kang, T. S.; Joo, B. J.; Tae, J. S.; Li, K. S.; Chung, C. K.
Tetrahedron Lett. 1995, 36, 417. (e) Macdonald, S. J. F.; Mills, K.;
Spooner, J. E.; Upton, R. J.; Dowle, M. D. J. Chem. Soc., Perkin Trans.
1 1998, 3931.
(6) (a) Gharpure, S. J.; Reddy, S. R. B. Org. Lett. 2009, 11, 2519. (b)
Gharpure, S. J.; Shukla, M. K.; Vijayasree, U. Org. Lett. 2009, 11, 5466.
(c) Gharpure, S. J.; Reddy, S. R. B. Tetrahedron Lett. 2010, 51, 6093. (d)
Gharpure, S. J.; Sathiyanarayanan, A. M. Chem. Commun. 2011, 47,
3625. (e) Gharpure, S. J.; Nanda, L. N.; Shukla, M. K. Eur. J. Org.
Chem. 2011, 6632. (f) Gharpure, S. J.; Prasath, V. J. Chem. Sci. 2011,
123, 943. (g) Gharpure, S. J.; Vijayasree, U.; Reddy, S. R. B. Org.
Biomol. Chem. 2012, 10, 1735. (h) Gharpure, S. J.; Porwal, S. K. Synlett
2008, 242. (i) Gharpure, S. J.; Porwal, S. K. Tetrahedron Lett. 2009, 50,
7162.
(7) For selected reviews on tandem radical cyclizations, see: (a)
McCarroll, A. J.; Walton, J. C. Angew. Chem., Int. Ed. 2001, 40, 2224.
(b) Malacria, M. Chem. Rev. 1996, 96, 289. (c) Ryu, I.; Sonoda, N.;
Curran, D. P. Chem. Rev. 1996, 96, 177.
(8) (a) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52,
8001. (b) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003,
103, 811. (c) Guerra, K. P.; Afonso, C. A. M. Tetrahedron 2011, 67, 2562.
(9) (a) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226. (b) Gemal,
A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454.
(10) Recent reviews: (a) Kumara Swamy, K. C.; Bhuvan Kumar,
N. N.; Balaraman, E.; Pavan Kumar, K. V. P. Chem. Rev. 2009, 109,
2551. (b) But, T. Y. S.; Toy, P. H. Chem. Asian J. 2007, 2, 1340.
Figure 2. Tandem radical cyclization to vinylogous functional
group for heterocyclic angular triquinanes.
(4) For some selected examples, see: (a) Lee, E.; Tae, J. S.; Lee, C.;
Park, M. C. Tetrahedron Lett. 1993, 34, 4831. (b) Ko, H. M.; Lee, C. W.;
Kwon, H. K.; Chung, H. S.; Choi, S. Y.; Chung, Y. K.; Lee, E. Angew.
Chem., Int. Ed. 2009, 48, 2364. (c) Matsuo, G.; Kadohama, H.; Nakata,
T. Chem. Lett. 2002, 31, 148. (d) Evans, P. A.; Murthy, V. S.; Roseman,
J. D.; Rheingold, A. L. Angew. Chem., Int. Ed. 1999, 38, 3175. (e) Evans,
P. A.; Roseman, J. D. J. Org. Chem. 1996, 61, 2252. (f) Leeuwenburgh,
ꢀ
M. A.; Litjens, R. E. J. N.; Codee, J. D. C.; Overkleeft, H. S.; Van der
Marel, G. A.; Van Boom, J. H. Org. Lett. 2000, 2, 1275. (g) Sibi, M. P.;
Patil, K.; Rheault, T. R. Eur. J. Org. Chem. 2004, 372. (h) Pandey, G.;
Hajra, S.; Ghorai, M. K.; Ravi Kumar, K. J. Org. Chem. 1997, 62, 5966.
(i) Chakraborty, T. K.; Samanta, R.; Ravikumar, K. Tetrahedron Lett.
2007, 48, 6389 and references therein.
Org. Lett., Vol. 14, No. 21, 2012
5477

AIBN in refluxing benzene indeed gave the desired dioxa-
triquinane 10 in good yield with excellent diastereoselectivity.
After successfully demonstrating the feasibility of the
tandem radical cyclization to vinylogous carbonates for
the construction of dioxatriquinane, attention was turned
toward expanding the scope of this reaction to the synthe-
sis of oxa- and azatriquinanes. To this end, the radical
precursors 11À20 bearing vinylogous carbonates or car-
bamates as radical acceptors were synthesized following a
strategy similar to that described for the iodide 5 (see the
Supporting Information). These vinylogous carbonates
and carbamates were subjected to cyclization reaction
using the standard radical conditions. The results are
summarized in the Table 1.
Table 1. Scope of the Tandem Radical Cyclization to
Vinylogous Carbonates and Carbamates for the Synthesis
of Oxa- and Aza-triquinaes
Various radical precursors could be successfully em-
ployed in this reaction. Thus, the iodide derived from
iodophenol, iodonaphthol, and protected iodoaniline also
participated efficiently in this tandem radical cyclization
(Table 1, entries 1À6). Not only aryl iodides but also the
alkynes could act as radical precursors and furnished the
triquinanes bearing tributylstannyl substitution (Table 1,
entries 7À10). The proto-destanylation of angular triqui-
nanes 22, 25, 28, and 30 could be rather easily achieved by
simply stirring them with either silica gel or PTSA to
furnish the corresponding olefins 31À34, respectively
(Scheme 2). Having a gem-dimethyl substitution on the
cyclopentene ring did not affect the reactivity of the
reaction, and oxa- and aza-triquinanes were formed in
comparable efficiencies with variety of radical precursors
(Table 1, entries 1, 2, 4À6, 9À10). In general, vinylogous
carbonates proved to be better acceptors in this tandem
radical cyclization process than the vinylogous carbamates,
and the yields were better in the former cases.11 Heterocyclic
triquinanes 26 and 29 are particularly noteworthy as they
incorporate the spirocyclic indoline moiety, which is part of
the structure of many bioactive molecules.12
In all the cases, the triquinane formation proceeded with
excellent diastereoselectivity. This stereochemical outcome
was established on the basis of the 1H NMR data as well as
single-crystal X-ray diffraction studies on the hetereocyclic
triquinanes 23, 27, 29, 32, and 33.13 As can be noticed, the
product oxa- and azatriquianes 21À30 had the hydrogens
on C3 and C3a syn to each other.
Scheme 2
a Isolated yield. b In all the cases, dr was determined on the crude
reaction mixtures by 1H NMR.
Mitsunobu reaction10 on the alcohol 8 with 2-iodophenol
(9) yielded the iodide 5 (Scheme 1). Reaction of the iodide 5
with n-Bu3SnH in the presence of catalytic amount of
(11) The lower yields for vinylogous carbamates are partly due to the
difficulties associated with purification.
5478
Org. Lett., Vol. 14, No. 21, 2012

Scheme 3
Figure 3. Transition-state structures for the tandem radical
cyclization reaction.
vinylogous urea as the functional group. When the uracil
derivative 38 was indeed subjected to the standard radical
cyclization conditions developed in this study, the aza-
oxatriquinane 39fused tothe uracil moiety wasobtainedin
good yield and excellent diastereoselectivity (Scheme 4).
This is an example which demonstrated that not only
vinylogous carbonates and carbamates but also vinylo-
gous ureas can be used as acceptors in tandem radical
cyclization for the synthesis of angular triquinanes.
The stereochemical outcome of this reaction can be
rationalized on the basis of the mechanism of this reaction.
The first 5-exo-trig radical cyclization generated the diqui-
nane with cis fusion of the two five-membered rings as
expected. In the second step of the tandem radical cycliza-
tion, there is a possibility of formation of two diastereo-
mers, the one in which the two hydrogens on C3 and C3a
are syn (the product formed) or the other where these two
hydrogens are anti to each other. It is apparent that the
transition-state structure B leading to the anti product
suffers from steric interaction between the aryl ring/
olefin moiety and the incipient carbethoxymethyl group
(Figure 3). No such interaction is present in the transition
state structure A leading to the syn product, and hence, it is
formed preferentially.
Scheme 4
In order to test this hypothesis, a substrate 35 devoid
of any olefin or aryl ring on the radical precursor
was conceived. The tandem radical cyclization using so-
dium cyanoborohydride, tributyltin chloride and catalytic
AIBN in refluxing t-BuOH followedby Jones’oxidation of
the intermediate acetal 36 indeed furnished the dioxatri-
quinane 37 as a 4:1 mixture of diastereomers (Scheme 3).14
This clearly suggested that the steric interaction between
aryl ring/olefin moiety and the incipient carbethoxymethyl
group arising from vinylogous carbonates/carbamates is
important for getting good diastereoselectivity. The triqui-
nane 37 is also particularly interesting as it gave an entry
into lactone-bearing oxatriquinanes.
In conclusion, we have disclosed the first examples of
tandem radical cyclizations to vinylogous carbonates and
carbamates for the synthesis of heterocyclic angular tri-
quinanes. In general, the reactions were found to be good
yielding, and in most cases, the diastereoselectivities ob-
tained were excellent. The method gave access to lactone-
bearing oxatriquinanes. Further, conformationally con-
strained uracil fused angular triquinanes could be synthe-
sized using this protocol.
We envisioned that synthesis of uracil-fused oxatriqui-
nane would be challenging and further highlight the utility
of this method.15 Toward this end, we decided to replace
the vinylogous carbamate with a uracil moiety bearing
Acknowledgment. We thank DST, New Delhi, for fi-
nancial support and Mr. V. Ramkumar of the Department
of Chemistry, IIT Madras, for the crystallographic data.
We thank CSIR, New Delhi, for the award of research
fellowships to P.N. and S.K.P.
(12) Some recent reviews: (a) Trost, B. M.; Brennan, M. K. Synthesis
2009, 3003. (b) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed.
2007, 46, 8748. (c) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003,
2209.
(13) See the Supporting Information.
Supporting Information Available. Characterization
data of products. This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) Only a trace amount of triquinane 36 was obtained using
n-Bu3SnH and AIBN, with simple reduction without cyclization being
the major product.
(15) (a) Evans, P. A.; Lai, K. W.; Zhang, H. R.; Huffman, J. C. Chem.
Commun. 2006, 844. (b) Evans, P. A.; Manangan, T.; Rheingold, A. L.
J. Am. Chem. Soc. 2000, 122, 11009 and refrences cited therein.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 21, 2012
5479