FeCl3 catalyzed Prins-type cyclization for the synthesis of highly substituted indenes: Application to the total synthesis of (±)-jungianol and epi-jungianol

Article abstract of DOI:10.1021/ol3032347

A novel approach was developed for the synthesis of highly substituted indene derivatives, using an FeCl₃ catalyzed Prins-type cyclization reaction which was further applied in the total synthesis of jungianol and epi-jungianol.

Full text of DOI:10.1021/ol3032347

ORGANIC
LETTERS
2013
Vol. 15, No. 3
429–431
FeCl3 Catalyzed Prins-Type Cyclization
for the Synthesis of Highly Substituted
Indenes: Application to the Total
Synthesis of (()-Jungianol and
epi-Jungianol
Dattatraya H. Dethe* and Ganesh Murhade
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur-208016, India
ddethe@iitk.ac.in
Received November 23, 2012
ABSTRACT
A novel approach was developed for the synthesis of highly substituted indene derivatives, using an FeCl3 catalyzed Prins-type cyclization
reaction which was further applied in the total synthesis of jungianol and epi-jungianol.
Indanes are compounds of great interest as they are
encountered in many biologically active natural products1
and are also used as building blocks for pharmaceutical2
and material chemistry3 (Figure 1). Thus development of
new pentannulation reactions of aromatic rings remains
to be an important quest in synthetic organic chemistry.4
The development of new methodologies to gain access to
various indene derivatives has steadily increased in recent
years. There are various methods reported in the literature
for the synthesis of indenes; recently Sarpong,4b Nolan,4e
and Wang4g independently reported the metal catalyzed
cyclopentannulation of aromatic rings. In fact the past
decade has witnessed a variety of synthetic methods for the
formation of indene rings.5 Very recently Tian and co-
workers4n have reported the FeCl3 catalyzed synthesis of
indenes from arylallenes.
(1) (a) Huffman, J. W.;Padgett, L. W. Curr. Med. Chem. 2005, 12, 1395.
(b) Gao, H.; Katzenellenbogen, J. A.; Garg, R.; Hansch, C. Chem. Rev.
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Jarry, C.; Rault, S. Bioorg. Med. Chem. 2002, 10, 1043. (e) Molteni, V.;
Rhodes, D.; Rubins, K.; Hansen, M.; Bushman, F. D.; Siegel, J. S.
J. Med. Chem. 2000, 43, 2031.
(4) Selected other types of metal-catalyzed pentannulation reactions
on aromatic rings: (a) Miki, K.; Ohe, K.; Uemura, S. J. Org. Chem. 2003,
68, 8505. (b) Prasad, B. A. B.; Yoshimoto, F. K.; Sarpong, R. J. Am.
Chem. Soc. 2005, 127, 12468. (c) Shintani, R.; Okamoto, K.; Hayashi, T.
J. Am. Chem. Soc. 2005, 127, 2872. (d) Yamabe, H.; Mizuno, A.;
Kusama, H.; Iwasawa, N. J. Am. Chem. Soc. 2005, 127, 3248. (e)
ꢀ
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Marion, N.; Dıez-Gonzalez, S.; de Fremont, P.; Noble, A. R.; Nolan,
S. P. Angew. Chem., Int. Ed. 2006, 45, 3647. (f) Malona, J. A.; Colbourne,
J. M.; Frontier, A. J. Org. Lett. 2006, 8, 5661. (g) Peng, L.; Zhang, X.;
Zhang, S.; Wang, J. J. Org. Chem. 2007, 72, 1192. (h) Soriano, E.;
Marco-Contelles, J. J. Org. Chem. 2007, 72, 1443. (i) Nakanishi, Y.;
Miki, K.; Ohe, K. Tetrahedron 2007, 63, 12138. (j) Nie, J.; Zhu, H.-W.;
Cui, H.-F.; Hua, M.-Q.; Ma, J.-A. Org. Lett. 2007, 9, 3053. (k) Saito, A.;
Umakoshi, M.; Yagyu, N.; Hanzawa, Y. Org. Lett. 2008, 10, 1783. (l)
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Chem., Int. Ed. 2009, 48, 8757. (m) Vaidya, T.; Atesin, A. C.; Herrick,
I. R.; Frontier, A. J.; Eisenberg, R. Angew. Chem., Int. Ed. 2010, 49,
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r
10.1021/ol3032347
2013 American Chemical Society
Published on Web 01/14/2013

is a well-known method for preparation of aromatic com-
pounds,9 regio- and chemoselectivity still remain a problem.
Scheme 1. Retrosynthetic Analysis of Jungianol, 1
Figure 1. Selected examples of natural products that contains
the indane framework.
In this context, herein we report inexpensive and envir-
onmentally benign6 FeCl3 catalyzed Prins-type cyclization
for the synthesis of various 1,3-disubstituted indenes and
transformation of suitably substituted indene derivatives
into natural product jungianol 1. Jungianol 1 was isolated
in 1977 from a South American plant, Jungia malvaefolia,
by Bolhmann et al.7 Structurally it is composed of an
indane moiety containing a trisubstituted phenol substruc-
ture having methyl and isobutene side chains on the 1 and 3
position of the indane five-member ring respectively. In-
itial stereochemical assignments of side chains by isolation
group was later revised by Hashmi et al. unambiguously
by first total synthesis of jungianol and its epimer;8 prior to
their work Ho et al. reported the total synthesis and revision
of another isomeric natural product mutisianthol in 19971b
that differs only in the position of the phenolic hydroxyl
group. Although the biological activity of jungianol is not
known, its isomer mutisianthol 2 exhibits moderate anti-
tumor activity.1e
Scheme 2. Synthesis of Diene Ester 13a
Retrosynthetically jungianol 1 could be obtained from
allylic alcohol 5 by Lewis acid catalyzed Prins-type cycliza-
tion followed by regio- and stereoselective hydrogenation
of an endocyclic double bond thus formed. Compound 5
could be prepared from ester 6 by a Grignard reaction.
Ester 6 in turn could be synthesized from aldehyde 7 using
a Wittig reaction (Scheme 1). Regioselective synthesis of
highly substituted aromatic rings is a challenging task in
organic synthesis. Altough cyclotrimerization of alkynes
In this regard we have exploited the previously reported
aromatization of carvone 8. In 1953 Treibs et al. reported
the aromatization of carvone 8 at 140 °C using stoichio-
metric Hg(OAc)2 and acetic acid.10 We modified and
optimized this reaction for the preparation of highly
substituted aromatic diene ester 6 as shown in Scheme 2.
Thus treatment of (()-carvone 8 with LDA at À78 °C
followed by quenching of the kinetic enolate thus gener-
ated by ethyl cyanoformate produced the diastereomeric
mixture of β-ketoesters 9.11 Having the ketoester 9 in hand,
the stage was set for the aromatization reaction; after
several different conditions were tried, ketoesters 9 using
stoichiometric Hg(OAc)2 in toluene under reflux condi-
tions gave a 64% yield of the desired phenol 10. Our efforts
to replace the toxic mercury reagent with DDQ (3 equiv)
for the aromatization reaction also resulted in the forma-
tion of phenol 10, but in only 30% yield. Reduction of ester
(5) For selected reports on indene formation, see: (a) Xi, Z.; Guo, R.;
Mito, S.; Yan, H.; Kanno, K.-i.; Nakajima, K.; Takahashi, T. J. Org.
Chem. 2003, 68, 1252. (b) Lautens, M.; Marquardt, T. J. Org. Chem.
2004, 69, 4607. (c) Chang, K.-J.; Rayabarapu, D. K.; Cheng, C.-H.
J. Org. Chem. 2004, 69, 4781. (d) Madhushaw, R. J.; Lo, C.-Y.; Hwang,
C.-W.; Su, M.-D.; Shen, H.-C.; Pal, S.; Shaikh, I. R.; Liu, R.-S. J. Am.
Chem. Soc. 2004, 126, 15560. (e) Shi, M.; Xu, B.; Huang, J.-W. Org. Lett.
2004, 6, 1175. (f) Nakamura, I.; Mizushima, Y.; Gridnev, I. D.; Yamamoto,
Y. J. Am. Chem. Soc. 2005, 127, 9844. (g) Kuninobu, Y.; Kawata, A.; Takai,
K. J. Am. Chem. Soc. 2005, 127, 13498. (h) Zhang, D.; Yum, E. K.; Liu, Z.;
Larock, R. C. Org. Lett. 2005, 7, 4963. (i) Basavaiah, D.; Reddy, K. R. Org.
Lett. 2007, 9, 57. (j)Xu, T.;Yang, Q.;Li, D.;Dong, J.;Yu, Z.;Li, Y.Chem.;
Eur. J. 2010, 16, 9264.
(6) For reviews on the iron Lewis acid catalysis, see: (a) Padron, J. I.;
Martın, V. S. Top. Organomet. Chem. 2011, 33, 1. (b) Bolm, C.; Legros,
J.; Paih, J. L.; Zani, L. Chem. Rev. 2004, 104, 6217.
(9) Agenet, N.; Buisine, O.; Slowinski, F.; Gandon, V.; Aubert, C.;
Malacria, M. Org. React. 2007, 68, 1.
(10) Treibs, W.; Lucius, G.; Kogler, H.; Breslauer, H. Justus Liebigs
(7) Bohlmann, F.; Zdero, C. Phytochemistry 1977, 16, 239.
(8) Hashmi, A. S. K.; Ding, L.; Bats, J. W.; Fischer, P.; Frey, W.
Chem.;Eur. J. 2003, 9, 4339.
Ann. Chem. 1953, 581, 59.
(11) Cuthbertson, J. D.; Godfrey, A. A.; Taylor, R. J. K. Synlett
2010, 2805.
430
Org. Lett., Vol. 15, No. 3, 2013

using LAH followed by PCC oxidation and Wittig olefina-
tion of the resultant aldehyde using Ph3PdCHCO2Et
generated the key intermediate diene ester 6 in 60% yield,
along with a substantial amount of lactone 11 (20%).
To avoid the formation of lactone byproduct, phenol 10
was protected as its methyl ether. Reduction of ester using
DIBAL-H produced aldehyde 12 in 82% yield, which upon
Wittig olefination produced the diene ester13a in very good
yield.
Finally treatment of diene ester 13a with excess MeMgI
generated the key intermediate allylic tert-alcohol 14a in
89% yield. With 14a in hand, the stage was set for the key
cyclization reaction. Several different conditions were tried
such as TFA (40 mol %), Sc(OTf)3 (10 mol %), Yb(OTf)3
It was envisioned that jungianol could be generated by
stereoselective hydrogenation of indene derivative 15a,
obtained earlier by Prins-type cyclization of tertiary alco-
hol 14a. Hoping that hydrogenation would be regioselec-
tive, indene derivative 15a was hydrogenated using 10%
Pd/C. Interestingly the hydrogenation reaction turned out
to be highly regio- and stereoselective to give the indane
16a in very good yield (Scheme 4). Cis stereochemistry was
assigned based on the assumption that the approach of
hydrogen would be opposite to that of the isobutenyl
group generating 1,3 cis substituted indane, which was
confirmed by deprotection of indane 15a using thioethanol
in the presence of sodium hydride and matching the
spectral data with those of epi-jungianol 17. Finally after
trying several different reduction conditions, chemoselec-
tive reduction of the benzylic double bond of 15a using
Li/liq NH3 resulted in a 1:1 inseparable mixture of cis and
trans isomers 16a,b. Deprotection of phenol followed by
careful column chromatography of the mixture of isomers
furnished jungianol 1 and epi-jungianol 17 whose spectral
(10mol%),Cu(OTf)2 (10 mol %), and BF3 OEt2 (20mol%)
using CH2Cl2 as solvent which resulted in the formation of
3
15a in poor to moderate yield via Prins-type cyclization.
TFA and BF3 OEt2 afforded 15a in 30% and 44% yield,
3
while Sc(OTf)3, Yb(OTF)3, and Cu(OTf)2 resultedin 41%,
45%, and 39% yield respectively. Interestingly tertiary
alcohol 14a on treatment with 10 mol % anhydrous FeCl3
using CH2Cl2 as solvent underwent smooth cyclization to
afford 15a in 79% yield. Under the optimized conditions
(10 mol % FeCl3, CH2Cl2, rt), we explored the substrate
scope of the reaction. Compound 14b was synthesized by
treatment of 13a with an excess of EtMgBr. Compounds
14cÀd and 14fÀi were prepared from corresponding car-
vone derivatives in a similar manner as shown in Scheme 2
(see Supporting Information). Scheme 3 shows the results
1
data (IR, H, 13C, and HRMS) were in complete agree-
ment with those reported in literature.7,8
Scheme 4. Total Synthesis of Jungianol (1) and epi-Jungianol (17)
Scheme 3. Intramolecular Prins-Type Cyclization for Synthesis
of Indenes
In conclusion, syntheses of various highly substituted
indenes were achieved using FeCl3 catalyzed Prins-type
cyclization, which was further applied in the total synthesis
of natural product jungianol, 1 (8.15% overall yield), and
its epimer, 17 (18.75% overall yield); in the process, known
Hg(OAc)2 mediated aromatization of carvone was exploited
for the development of regioselective synthesis of highly
substituted aromatic rings.
Acknowledgment. We thank Prof. Vinod K. Singh Di-
rector, IISER Bhopal, for allowing us to use laboratory
facilities. G.M. thanks CSIR, New Delhi, for the award of
a research fellowship. Financial support from IIT Kanpur
is gratefully acknowledged.
of the conversions of allylic tertiary alcohols 14aÀj to
corresponding indene derivatives 15aÀj. Several sub-
stitution patterns on the aromatic ring were tolerated
and provided good yields of the desired indene deriva-
tives 15aÀi. To check the effect of the ortho-methoxy
group on this cyclization we prepared compound 14e (see
Supporting Information) which also underwent smooth
cyclization to generate the desired product 15e in 81%
yield using 10 mol % FeCl3, showing that the reaction is
quite general and has a larger substrate scope.
Supporting Information Available. Synthetic proce-
dures and characterization data for all the new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 3, 2013
431