A vicarious, one-pot synthesis of benzo- and naphthofurans: Applications to the syntheses of stereumene B and paeoveitols

Article abstract of DOI:10.1016/j.tetlet.2019.03.037

An interesting albeit unexpected deviation during attempted Tanabe γ-lactone annulation on 4-hydroxycyclohexanones has led to a general, one-pot synthesis of benzofurans and naphtho[2,3–b]furans from readily assembled precursors. The utility of this adaptable methodology has been demonstrated through concise syntheses of natural products, stereumene B, paeoveitol D and (±)-paeoveitol.

Full text of DOI:10.1016/j.tetlet.2019.03.037

Accepted Manuscript
A Vicarious, One-Pot Synthesis of Benzo- and Naphthofurans: Applications to
the Syntheses of Stereumene B and Paeoveitols
Showkat Rashid, Bilal A. Bhat, Goverdhan Mehta
PII:
S0040-4039(19)30253-9
https://doi.org/10.1016/j.tetlet.2019.03.037
TETL 50678
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
1 February 2019
13 March 2019
Please cite this article as: Rashid, S., Bhat, B.A., Mehta, G., A Vicarious, One-Pot Synthesis of Benzo- and
Naphthofurans: Applications to the Syntheses of Stereumene B and Paeoveitols, Tetrahedron Letters (2019), doi:
https://doi.org/10.1016/j.tetlet.2019.03.037
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
A Vicarious, One-Pot Synthesis of Benzo- and
Naphthofurans: Applications to the Syntheses of
Stereumene B and Paeoveitols
Leave this area blank for abstract info.
Showkat Rashid, Bilal A. Bhat and Goverdhan Mehta

1
Tetrahedron Letters
A Vicarious, One-Pot Synthesis of Benzo- and Naphthofurans: Applications to
the Syntheses of Stereumene B and Paeoveitols
Showkat Rashid,† ‡# Bilal A. Bhat†‡* and Goverdhan Mehta#*
†CSIR-Medicinal Chemistry Division, Indian Institute of Integrative Medicine, Sanatnagar-Srinagar, 190005
‡Academy of Scientific & Innovative Research (AcSIR), India
#
School of Chemistry, University of Hyderabad, Hyderabad 500046, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An interesting albeit unexpected deviation during attempted Tanabe -lactone
annulation on 4-hydroxycyclohexanones has led to a general, one-pot synthesis of
benzofurans and naphtho[2,3-b]furans from readily assembled precursors. The
utility of this adaptable methodology has been demonstrated through concise
syntheses of natural products, strereumene B, paeoveitol D and ()-paeoveitol.
Available online
Keywords:
Benzofuran
2009 Elsevier Ltd. All rights reserved.
Naphthofuran
Stereumene B
(±)-Paeoveitol
Benzofuran and naphthofuran segment is widely
benzofurans and naphthofurans has endured for decades both as a
platform for methodological advances and as a target driven
endeavor. A flavor of these developments, particularly those
reported during the past decade and involving one-pot operation
for the generation of benzofurans and naphthofurans are depicted
in Scheme 1.11-12 These have involved both metal- mediated as
well as acid or base-mediated cyclizations of pre-formed
substrates. Notwithstanding these efforts and the availability of a
plethora of earlier developed methods towards benzofurans12
there is room for alternate, simpler and efficient approaches to
this much-in-demand platform.
encountered in a range of bioactive natural products and synthetic
compounds exhibiting a broad spectrum of activities against key
biological targets.1-2Among the representative examples of
benzofuran and naphthofuran motif embodying bioactive
compounds are fungal sesquiterpenoid stereumene B3 (1), plant-
derived natural products including modified antioxidant
sesquiterpene, 13-hydroxy-14-nordehydrocacalohastine4 (2), nor-
diterpenoid paeoveitol5 (3), and anti-HIV oligostilbene malibatol
A6 (4). Additional notable examples of benzofuran bearing active
compounds are of marine-derived anti-cancer potent PI3K
inhibitor7-liphagal (5), -2-adrenergic blocker drug MK-9128 (6)
and anti-viral synthetic compound HCV-7969 (6), (Figure 1).
During a natural product total synthesis campaign in the
group, there was an occasion to carry out the reaction between
substituted cyclohexanones and 1,1-dimethoxyacetone in
presence of TiCl4-Bu3N to obtain -lactone annulated products
via one-pot cross Aldol condensation, Scheme 2. Such Tanabe
annulations13 are quite convenient to execute and have been
employed by us14 and others13 in diverse contexts to install -
lactone moiety. However, when Tanabe annulation protocol13a
was attempted on 4-hydroxy-cyclohexanone
8 with 1,1-
dimethoxy acetone, 3-methybenzofuran 9 was isolated as the
only product in 78% yield and the expected -lactone 8a was not
seen. Exclusive formation of 9 appeared to provide a new and
convenient entry to benzofurans that could be extended to
naphthofurans and other related frameworks. Further exploration
and scoping of this observation and its application in natural
product synthesis forms the subject matter of this
communication.
The outcome depicted in Scheme 2 was indicative of
the fact that the benzofuran product 9 arose through a deviant
pathway triggered by the presence of the additional 4-hydroxyl
group in the precursor ketone 8. Indeed, the formation of such
benzofurans was found to be quite general and could be
Figure 1. Benzofuran and naphtho[2,3-b]furan based bioactive natural
products and synthetic compounds
Given their structural diversity, ever-expanding
pharmacological activity profile and importance in medicinal
chemistry,10 it is hardly surprising that interest in the synthesis of

2
Tetrahedron
Table 1. Access to a wide range of substituted benzofurans
Scheme 1. Recently established approaches for the syntheses of benzofurans.
Scheme 2. Benzofuran annulation under Tanabe reaction conditions.
demonstrated on additional 4-hydroxyl bearing cyclohexanones
10-15 to furnish the corresponding 16a-21a in consistently good
yields. The benzofuran formation from cyclic hydroxyl ketones
10-13 under Tanabe reaction conditions also proceeded with 2,2-
dimethoxy acetaldehyde as cross-aldol partner with equal facility
to furnish benzofurans 16b-19b respectively, Table 1.
Plausible mechanistic considerations leading to the
unexpected formation of benzofurans under TiCl4-Bu3N exposure
are shown in Scheme 3 and indicated that the observed deviation
from the expected -lactone products could be attributed to
concurrent dehydration and introduction of a cyclohexene double
bond along with the aldol formation, which in turn facilitates
aromatization through subsequent elimination of TiCl3OH and
MeOH (Scheme 3).
Scheme 3: Plausible mechanism of the formation of benzofurans
Having observed a decent and efficient one-pot access
to diverse benzofurans, it was considered appropriate to probe
their deployability in natural product syntheses. As a first
demonstrator, recently reported sesquiterpenoid stereumene B
(1), isolated from the fungus Stereum sp.YMF1.041833 was
identified as the target and the benzofuran 16a as the starting
point. Vilsmeier-type formylation on 16a led to aldehyde 34
which was elaborated through Grignard addition of 1-bromo-2-
methylpropane to 35 and further DMP oxidation of 35 led to
stereumene B (1), spectroscopically identical to the natural
product, Scheme 4.
The above premise led to the prediction that a pre-
existing olefin or equivalent substitution in the cyclohexanone
precursors would also be serviceable to deliver the benzo- or
naphthofurans under Tanabe reaction conditions. Indeed, this
expectation has been realized and precursors 22-28 smoothly led
to the corresponding benzo- or naphthofurans 18a, 20, 29-33 and
further vouching for the generality of our approach, Table 2. It
may be noted that naphtho[2,3-b]furans 31-33 form a segment of
many natural products (including compound 2) and have been
previously accessed through multistep sequence.15

3
Table 2. Access to benzofurans and naphtho[2,3-b]furansfrom substrates with
preinstalled cyclohexene double bond.
Scheme 5: Hetero-Diels-Alder (4+2) cycloaddtion approach to ()-paeoveitol
We have applied the newly developed benzofuran
synthesis to rapidly assemble paeoveitol D 36 from commercially
available methylcyclohexenone 38 involving dihydroxylation to
39, direct furan annulations under Tanabe protocol to 40 and
further regioselective aromatic methyl oxidation to deliver
paeoveitol D 36, Scheme 6. Scandium triflate-mediated hetero-
[4+2]-cycloaddition between paeoveitol
D
36 and o-
quinodimethane precursor 41 delivered natural product (±)-
paeoveiticol 3 in excellent yield, Scheme 6.
Scheme 6: Total synthesis of paeoveitol D and ()-paeoveitol.
In short, we have stumbled upon an effective strategy
for accessing a range of functionalized benzo- and naphthofurans
from readily available cyclohexanone precursors via TiCl4
-
mediated Tanabe protocol. Efficacy and potential of this new
methodology are demonstrated through short syntheses of natural
poducts, stereumene B, paeoveitol D, and ()-paeoveitol.
Acknowledgments
SR and BAB thank CSIR-India for Senior Research
Fellowship support to SR. GM acknowledges the generous
research support from Dr. Reddy’s Laboratories and the award of
Dr. Kallam Anji Reddy Chair (IIIM Communication XXX).
References
(1) Reviews related to synthesis of benzofurans- (a) Abu-Hashem, A. A.;
Hussein, H. A. R.; Aly, A. S.; Gouda, M. A. Synth. Commun. 2014, 44, 2285-
231. (b) Heravi, M. J. Zadsirjan, V. Recent Advances in the Synthesis of
Benzo[b]furans. In Advances in Heterocyclic Chemistry, Scriven, E,
Ramsden, C, Eds.; Elsevier Academic Press Inc, 2015, 117, 261-376. (c)
Heravi, M. M.; Zadsirjan, V.; Hamidi, H.; Parvin Amiri, P. H. T. RSC Adv.
2017, 7, 24470-24521
(2) Selected references on bioactivity of benzo and naphthofurans (a) Monte,
A. P.; Marona-Lewicka, D.; Lewis, M. M.; Mailman, R. B.; Wainscott, D. B.;
Nelson, D. L.; Nichols, D. E. J. Med. Chem. 1998, 41, 2134-2145. (b)
Khanam, H.; Shamsuzzaman. Eur. J. Med. Chem.2015, 97, 483-504; (c)
Goyal, D.; Kaur, A.; Goyal, B. ChemMedChem, 2018, 13, 1275-1299.
(3) Yan, J. -M.; Wang, X.; Tian, M.-Q.; Liu, C.-M.; Zhang, K. -Q.; Li, G. -H.
Phytochemistry Lett. 2017, 22, 6-8.
Scheme 4: First total synthesis of stereumene B.
We next sought to validate the utility of our benzofuran
methodology with a more demanding natural product target. The
nor-diterpenoid paeoveitol 3, isolated along with a sibling
benzofuran, paeoveitol D 36 from the roots of Paeonia veitchii-a
plant widely mentioned in the traditional Chinese medicine for
diverse disorders, appeared to be a good proposition.16 The
biological activity of paeoveitol is of potential interest but fuller
explorations have been hampered in view of the limited
availability of the natural product. As a synthetic objective,
paeoveitol 3 has drawn immediate traction and three total
syntheses17 have been reported via a putative biomimetic route
involving hetero-Diels-Alder reaction between benzofuranoid
paeoveitol-D 36 and o-quinone methide 37, Scheme 5.
(4) Doe, M.; Shibue, T.; Haraguchi, H.; Morimoto, Y. Org. Lett. 2005, 7,
1765-1768.
(5) Liang, W. J.; Geng, C. A.; Zhang, X. M.; Chen, H.; Yang, C. Y.; Rong, G.
Q.; Zhao, Y.; Xu, H. B.; Wang, H.; Zhou, N. J; Ma, Y. B.; Huang, X. Y.;
Chen, J. J. Org. Lett. 2014, 16, 424-427.
(6) Dai, J. R.; Hallock, Y. F.; Cardellina, J. H.; Boyd, M. R. J. Nat.
Prod.1998, 61, 351-353.

4
Tetrahedron
(7) Marion, F.; Williams, D. E.; Patrick, B. O.; Hollander, I.; Mallon, R.;
Kim, S. C.; Roll, D. M.; Feldberg, L.; Soest, R. V.; Anderson, R. J. Org. Lett.
2006, 8, 321-324.
(8) Ortiz-Alonso, F. J.; Herman, W. H.; Gertz, B. J.; Williams, V. C.; Smith,
M. J.; Halter, J. B. Metabolism. 1991, 40, 1160-1167.
(9) Kneteman, N.; M.; Howe, A. Y. M.; Gao, T.; Lewis, J.; Pevear, D.; Lund,
G.; Douglas, D.; Mercer, D. F.; Tyrrell, D. L. J.; Immermann, F.; Chaudhary,
I.; Speth, J.; Villano, S. A.; O’Connell, J.; Collet, M. Hepatology, 2009, 49,
745-752.
(10) Reichstein, A.; Vortherms, S.; Bannwitz, S.; Tentrop, J.; Prinz, H.;
Müller K. J. Med. Chem.2012, 55, 7273-7284.
(11) (a) Eidamshaus, C.; Burch, J. D. Org. Lett. 2008, 10, 4211-4214. (b)
Wang, S.; Li, P.; Yu, L.; Wang, L. Org. Lett. 2011, 13, 5968-5971. (c) Reddy,
C. R.; Krishna, G.; Kavitha, N.; Latha, B.; Shin, D.-S. Eur. J. Org. Chem.
2012, 27, 5381-5388. (d) Wu, F.; Bai, R.; Gu, Y. Adv. Synth. Catal. 2016,
358, 2307-2316. (e) Alonso-Maranon, M.; Martínez, M. M.; Sarandeses, L.
A.; Gꢀmez-Bengoa, E.; Sestelo, J. P. J. Org. Chem. 2018, 83, 7970-7980.
(12) (a) Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald, S. L. J. Am.
Chem. Soc. 2006, 128, 10694-10695. (b) Luca, L. D.; Giacomelli, G.; Nieddu,
G. J. Org. Chem. 2007, 72, 3955-3957. (c) Shen, Z.; Dong, V. M. Angew.
Chem., Int. Ed. 2009, 48, 784-786. (d) Maimone, T. J. Buchwald, S. L. J. Am.
Chem. Soc. 2010, 132, 9990-9991. (e) Wang, W.; Huang, J.; Zhou, R.; Jiang,
Z. J.; Fu, H. Y.; Zheng, X. L.; Chen, H.; Li, R. -X. Adv. Synth. Catal. 2015,
357, 2442-2446. (f) Tharra, P.; Baire, B. Chem. Commun.2016, 52, 14290-
14293. (g) Sun, P.; Gao, S.; Yang, C.; Guo, S.; Lin, A.; Yao, H. Org. Lett.
2016, 18, 6464-6467. (h) Yang, K.; Pulis, A. P.; Perry, G. J. P.; Procter, D. J.
Org. Lett. 2018, 20, 7498-7503.
(13) (a) Tanabe, Y.; Mitarai, K.; Higashi, T.; Misaki, T.; Nishii, Y. Chem.
Commun. 2002, 2542-2543. (b) Ban, Y.; Ashida, Y.; Nakatsuji, H.; Tanabe,
Y. Molbank, 2016, 2016, M908.
(14) (a) Ramesh, S.; Mehta, G. Tetrahedron Lett. 2015, 56, 3941-3944. (b)
Ramesh, S.; Mehta, G. Tetrahedron Lett. 2015, 56, 5545-5548. (c) Rashid, S.;
Bhat, B. A.; Mehta, G. Tetrahedron Lett. 2017, 58, 3800-3802.
(15). Uchuskin, M. G.; Shcherbinin, V. A.; Butin, A. V. Chem. Heterocycl.
Comp. 2014, 50, 619-633.
(16) Liang, W. J.; Ma, Y. B.; Geng, C. A.; Huang, X. Y.; Xu, H. B.; Zhang,
X. M.; Chen, J. J. Fitoterapia 2015, 106, 36-40.
(17) (a) Xu, L.; Liu, F.; Xu, L.-W.; Gao, Z.; Zhao, Y.-M. Org. Lett. 2016, 18,
3698-3701. (b) Zhang, Y.; Guo, Y.; Li, Z.; Xie, Z. Org. Lett. 2016, 18, 4578-
4581. (c) Li, T. -Z.; Geng, C. -A.; Yin, X.-J.; Yang, T. -H.; Chen, X. -L.;
Huang, X.-Y.; Ma, Y.-B.; Zhang, X. -M.; Chen, J.-J. Org. Lett. 2017, 19,
429-431.

5
Highlights



A deviation to Tanabe -lactone annulation
is reported
This method provides one-pot access to
benzofurans and naphtho[2,3-b]furans
Concise synthesis of strereumene B,
paeoveitol
D
and ()-paeoveitol are
accomplished