Total Synthesis of Selaginpulvilin C and D Relying on in Situ Formation of Arynes and Their Hydrogenation

Article abstract of DOI:10.1021/acs.orglett.6b03241

The total syntheses of selaginpulvilins C and D is described. The key strategy for the construction of the core fluorene moiety involves in situ formation of an aryne intermediate followed by its formal hydrogenation. The precursor tetraynes that undergo

Full text of DOI:10.1021/acs.orglett.6b03241

Letter
pubs.acs.org/OrgLett
Total Synthesis of Selaginpulvilin C and D Relying on in Situ
Formation of Arynes and Their Hydrogenation
Rajdip Karmakar and Daesung Lee*
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607, United States
S
* Supporting Information
ABSTRACT: The total syntheses of selaginpulvilins C and D is described. The key strategy for the construction of the core
fluorene moiety involves in situ formation of an aryne intermediate followed by its formal hydrogenation. The precursor
tetraynes that undergo aromatization via hexadehydro Diels−Alder reaction were prepared from readily available building blocks
through typical alkyne-coupling reactions.
elaginpulvilins A−D that contain a novel 9,9-diphenyl-1-
(phenylethynyl)-9H-fluorene framework were reported by
Scheme 1. Selaginpulvilin Retrosynthesis
S
Yin and co-workers in 2014.1 The structural assignment of
these tetraphenolic compounds was secured by spectroscopic,
chemical, and single-crystal X-ray diffraction analyses. These
unprecedented natural products were isolated from Selaginella
pulvinata (Hook. et Grev.) Maxim. (Selaginellaceae), which has
been widely used in traditional Chinese medicine.2 The activity-
guided bioassays of ethanolic extracts of S. pulvinata containing
selaginpulvilins A−D and other constituents showed significant
inhibitory activities (IC50 values of 0.11−5.13 μM) against
phosphodiesterase-4 (PDE4).
The important biological profiles of selaginpulvilins in
combination with their novel structural features make them
highly attractive targets for total synthesis, which will also
provide an opportunity to develop a range of related structures
for further biological activity−relationship studies. In terms of
designing an effective synthetic approach, we envision that 9,9-
diphenyl substituents on the central fluorene substructure3 of
selaginpulvilins can be installed via double Friedel−Crafts
arylations with precursor 1 (Scheme 1). In turn, the
phenylethynyl-9H-fluorenone structure can be constructed
from tetrayne 2 via a hexadehydro Diels−Alder reaction4−6
(HDDAR) to form an aryne7 intermediate followed by its
formal hydrogenation via either intramolecular hydride transfer
from a trialkylsilyl group followed by protonation5c or
hydrogen transfer from cyclooctane.4h Finally, tetrayne 2
would be accessed from readily available arene and alkyne
building blocks.
yl)acetylene, desilylation, and a Cadiot−Chodkiewicz coupling
with 4-bromo-2-methylbut-3-yn-2-ol followed by removal of
the acetone moiety to liberate a terminal alkyne under basic
conditions. Generation of an acetylide from 4 and its addition
to aldehyde 3 afforded alcohol 5.
Removal of the trimethylsilyl group from 5 followed by a
copper-catalyzed coupling with bromoalkynes delivered tet-
raynes 7a−e.
With these substrates for HDDAR in hand, we explored their
conversion to the projected fluorenones. On the basis of the
established protocol5c for intramolecular hydride transfer to an
The preparation of tetrayne 2 commenced with a
Sonogashira coupling of commercially available 2-bromo-5-
methoxybenzaldehyde with (trimethylsilyl)acetylene to gen-
erate 3 (Scheme 2).8 4-(Methoxyphenyl)-1,3-diyne 4 was also
prepared through a merger of 4-iodoanisole and (trimethylsil-
Received: October 28, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03241
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthesis of Tetraynes
Scheme 3. Total Synthesis of Selaginpulvilin D
aryne species catalyzed by a silver catalyst, tetrayne 7a was
treated with MnO2 at 25 °C in CH2Cl2 in the presence of
AgSbF6 (10 mol %) (Scheme 3). Unfortunately, substrate 7a
decomposed upon addition of AgSbF6. Next, 7b was oxidized
with MnO2 in cyclooctane as a source of hydrogen.4h
Gratifyingly, desired compound 9b was generated in 34%
overall yield as a mixture of two isomers in a 6:1 ratio, the
minor isomer of which was formed via the alternative mode of
HDDAR. On the other hand, the corresponding trimethylsilyl-
containing 7c provided 9c in 54% yield along with another
isomer in a 5:1 ratio. Addition of anisole-based Grignard
reagent 10 to ketone 9b provided an adduct tert-alcohol 11b,
which was directly subjected to the known Friedel−Crafts
arylation conditions to afford 12b in 51% overall yield from
9b.9,10 Subsequent removal of the triethylsilyl group from 12b
was found to be recalcitrant. Treating 12b with an excess
amount of Bu4NF at 90 °C afforded the corresponding
desilylated product 13b, O-trimethylselaginpulvilin D, in only
34% yield along with 22% recovered starting material 12b. In
stark contrast, the Friedel−Crafts arylation of trimethylsilyl-
containing compound 11c directly generated protodesilylated
compound 13b in 38% yield devoid of 12c under otherwise
identical conditions. The final cleavage of the methyl ethers
Scheme 4. Total Synthesis of Selaginpulvilin C
12
with Me3SiI11 or BBr3 afforded a mixture of several products
of incomplete demethylation After much experimentation, it
was found that treating 13b with MeMgI in neat at 160 °C
under reduced pressure delivered selaginpulvilin D.13
With the successful route in hand, synthesis of another
congener of the same family, selaginpulvilin C, was attempted.
The (trimethylsilyl)methyl-substituted tetrayne 7d was pro-
posed to be a good choice for this purpose. Treating 7d with
MnO2 in cyclooctane at room temperature afforded fluorenone
9d, which was reacted with Grignard reagent 10 to generate
11d (Scheme 4). Subsequently, with the established Friedel−
Crafts arylation protocol, 11d was converted to 12d in 86%
yield. Desilylation of 12d with TBAF quantitatively afforded
13d, a trimethyl-protected form of selaginpulvilin C. Finally,
global cleavage of the methyl ethers with methylmagnesium
iodide resulted in the formation of selaginpulvilin C in 69%
yield,13 which constitutes a short total synthesis of the natural
product.
B
DOI: 10.1021/acs.orglett.6b03241
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chem. 2015, 80, 11744−11754. (l) Chen, J.; Palani, V.; Hoye, T. R. J.
Am. Chem. Soc. 2016, 138, 4318−4321. (m) Wang, T.; Niu, D.; Hoye,
T. R. J. Am. Chem. Soc. 2016, 138, 7832−7835. (n) Wang, T.; Hoye, T.
R. J. Am. Chem. Soc. 2016, 138, 13870−13873.
(5) (a) Yun, S. Y.; Wang, K.-P.; Lee, N.-K.; Mamidipalli, P.; Lee, D. J.
Am. Chem. Soc. 2013, 135, 4668−4671. (b) Karmakar, R.; Mamidipalli,
P.; Yun, S. Y.; Lee, D. Org. Lett. 2013, 15, 1938−1941. (c) Mamidipalli,
P.; Yun, S. Y.; Wang, K.; Zhou, T.; Xia, Y.; Lee, D. Chem. Sci. 2014, 5,
2362−2367. (d) Lee, N.; Yun, S. Y.; Mamidipalli, P.; Salzman, R. M.;
Lee, D.; Zhou, T.; Xia, Y. J. Am. Chem. Soc. 2014, 136, 4363−4368.
(e) Karmakar, R.; Yun, S. Y.; Wang, K.; Lee, D. Org. Lett. 2014, 16, 6−
9. (f) Karmakar, K.; Ghorai, S.; Xia, Y.; Lee, D. Molecules 2015, 20,
15862−15880. (g) Karmakar, R.; Wang, K.-P.; Yun, S. Y.; Mamidipalli,
P.; Lee, D. Org. Biomol. Chem. 2016, 14, 4782−4788.
In summary, we have accomplished total syntheses of
selaginpulvilins C and D. The construction of the core fluorene
moiety of these natural products relies on a strategy that
involves in situ formation of an aryne intermediate via the
hexadehydro Diels−Alder reaction (HDDAR) followed by
formal hydrogenation of the aryne moiety. The required
tetrayne substrates for HDDAR were prepared efficiently via
repetitive use of alkyne-coupling reactions starting from readily
available building blocks. We are pursuing the synthesis of
selaginpulvilins A and B and other structurally diverse
analogues for structure−activity relationship studies on the
basis of HDDAR-based approaches, which will be reported in
due course.
(6) HDDA reaction related reviews: (a) Holden, C.; Greaney, M. F.
Angew. Chem., Int. Ed. 2014, 53, 5746−5749. (b) Li, W.; Zhou, L.;
Zhang, J. Chem. - Eur. J. 2016, 22, 1558−1571. (c) Karmakar, R.; Lee,
D. Chem. Soc. Rev. 2016, 45, 4459−4470.
ASSOCIATED CONTENT
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S
* Supporting Information
(7) Reviews on the chemistry of arynes: (a) Wenk, H. H.; Winkler,
M.; Sander, W. Angew. Chem., Int. Ed. 2003, 42, 502−528. (b) Dyke, A.
M.; Hester, A. J.; Lloyd-Jones, G. C. Synthesis 2006, 2006, 4093−4112.
(c) Sanz, R. Org. Prep. Proced. Int. 2008, 40, 215−291. (d) Chen, Y.;
Larock, R. C. In Modern Arylation Methods; Akermann, L., Ed.; Wiley-
VCH: Weinheim, 2009; pp 401−473. (e) Tadross, P. M.; Stoltz, B. M.
Chem. Rev. 2012, 112, 3550−3577. (f) Gampe, C. M.; Carreira, E. M.
Angew. Chem., Int. Ed. 2012, 51, 3766−3778. (g) Bhunia, A.; Yetra, S.
R.; Biju, A. T. Chem. Soc. Rev. 2012, 41, 3140−3152. (h) Wu, C.; Shi,
F. Asian J. Org. Chem. 2013, 2, 116−125.
(8) Rosillo, M.; Domínguez, G.; Casarrubios, L.; Amador, U.; Per
Castells, J. J. Org. Chem. 2004, 69, 2084−2093.
(9) Ward, S.; Messier, T.; Lukeman, M. Can. J. Chem. 2010, 88, 493−
499.
(10) Hasegawa, T.; Koyama, Y.; Seto, R.; Kojima, T.; Hosokawa, K.;
Takata, T. Macromolecules 2010, 43, 131−136.
(11) Anderson, J. C.; Denton, R. M.; Wilson, C. Org. Lett. 2005, 7,
123−125.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03241.
Detailed experimental procedures, characterization data,
1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dsunglee@uic.edu.
ORCID
́
ez-
Daesung Lee: 0000-0003-3958-5475
Notes
The authors declare no competing financial interest.
(12) Boger, D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.; Jin, Q.
J. Am. Chem. Soc. 1999, 121, 54−62.
(13) Mechoulam, R.; Braun, P.; Gaoni, Y. J. Am. Chem. Soc. 1972, 94,
6159−6165.
ACKNOWLEDGMENTS
■
We thank the NSF (CHE-1361620) and TACOMA Technol-
ogy for financial support of this work and the high school intern
Ms. Muskaan Gupta from Adlai E. Stevenson High School for
her contribution in preparing compounds 7b, 11b, and 12b.
The mass spectrometry facility at UIUC is greatly acknowl-
edged.
REFERENCES
■
(1) Liu, X.; Luo, H.-B.; Huang, Y.-Y.; Bao, J.-M.; Tang, G.-H.; Chen,
Y.-Y.; Wang, J.; Yin, S. Org. Lett. 2014, 16, 282−285.
(2) State Administration of Traditional Chinese Medicine of the
People’s Republic of China. Chinese Materia Medica (Zhong Hua Ben
Cao); Editorial Board of ‘Zhong Hua Ben Cao’; Shanghai Scientific and
Technical Publishers: Shanghai, 1999; Vol. 4, pp 387−389.
(3) A review on the synthesis of fluorenone and fluorine-containing
natural products: Shi, Y.; Gao, S. Tetrahedron 2016, 72, 1717−1735.
(4) (a) Miyawaki, K.; Suzuki, R.; Kawano, T.; Ueda, I. Tetrahedron
Lett. 1997, 38, 3943−3946. (b) Kimura, H.; Torikai, K.; Miyawaki, K.;
Ueda, I. Chem. Lett. 2008, 37, 662−663. (c) Bradley, A. Z.; Johnson, R.
P. J. Am. Chem. Soc. 1997, 119, 9917−9918. (d) Skraba-Joiner, S. L.;
Johnson, R. P.; Agarwal, J. J. Org. Chem. 2015, 80, 11779−11787.
(e) Tsui, J. A.; Sterenberg, B. T. Organometallics 2009, 28, 4906−4908.
(f) Hoye, T. R.; Baire, B.; Niu, D. W.; Willoughby, D. P. H.; Woods, B.
P. Nature 2012, 490, 208−212. (g) Baire, B.; Niu, D.; Willoughby, P.
H.; Woods, B. P.; Hoye, T. R. Nat. Protoc. 2013, 8, 501−508. (h) Niu,
D.; Willoughby, P. H.; Baire, B.; Woods, B. P.; Hoye, T. R. Nature
2013, 501, 531−534. (i) Willoughby, P. H.; Niu, D.; Wang, T.; Haj,
M. K.; Cramer, C. J.; Hoye, T. R. J. Am. Chem. Soc. 2014, 136, 13657−
13665. (j) Woods, B. P.; Baire, B.; Hoye, T. R. Org. Lett. 2014, 16,
4578−4581. (k) Marell, D. J.; Furan, L. R.; Woods, B. R.; Lei, X.;
Bendelsmith, A. J.; Cramer, C. J.; Hoye, T. R.; Kuwata, K. T. J. Org.
C
DOI: 10.1021/acs.orglett.6b03241
Org. Lett. XXXX, XXX, XXX−XXX