Rapid Assembly of Protoilludane Skeleton through Tandem Catalysis: Total Synthesis of Paesslerin A and Its Structural Revision

Article abstract of DOI:10.1021/acs.orglett.9b01089

A multicomponent domino reaction involving three mechanistically distinct Tf₂NH-catalyzed reactions was developed. The reaction cascade enables the assembly of a skewed 5/6/4 tricyclic motif with migration of the reactive site with the assistan

Full text of DOI:10.1021/acs.orglett.9b01089

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rapid Assembly of Protoilludane Skeleton through Tandem
Catalysis: Total Synthesis of Paesslerin A and Its Structural Revision
Yuzo Mogi,†,§ Kazato Inanaga,‡,§ Hidetoshi Tokuyama,‡ Masataka Ihara,‡ Yousuke Yamaoka,†
Ken-ichi Yamada,†,¶ and Kiyosei Takasu*,†
†Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
‡Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Sendai 980-8578, Japan
S
* Supporting Information
ABSTRACT: A multicomponent domino reaction involving
three mechanistically distinct Tf2NH-catalyzed reactions was
developed. The reaction cascade enables the assembly of a
skewed 5/6/4 tricyclic motif with migration of the reactive site
with the assistance of a catalyst. The tricyclic product was used
to achieve the first total synthesis of cytotoxic paesslerin A by
regioselective C−H insertion of the sulfonyl carbenoid and
base-promoted olefin isomerization. Our results led to the
revision of the originally proposed tricyclic structure of
paesslerin A.
variety of organic substances, including structurally
Acomplex molecules, are found in Nature. Their biosyn-
thesis occurs within living organisms and is generally catalyzed
by enzymes. In some cases, enzyme complexes such as fatty
acid, polyketide, and polypeptide synthases catalyze more than
two mechanistically distinct reactions sequentially.1 Therefore,
high-order molecular structures can be efficiently formed from
simpler materials, accompanied by the formation of several
covalent bonds and stereogenic centers. In synthetic chemistry,
domino reactions2 and related processes such as multi-
component3 and one-pot reactions4 are attractive as
complementary methods to biosynthesis, because they can
Figure 1. Examples for a typical domino bond-formation reaction
(path a) and for domino reaction with migration of a reactive site
during the bond-formation reaction cascade (path b).
be used to build structurally complex molecules in one
operation. Major advantages of such procedures include
operational simplicity, time and cost savings, atom economy,
environmental benignancy, and applicability to diversity-
which bond-forming reaction(s) and rearrangement of the
reactive functional group were sequentially activated by the
same catalyst would achieve the difficult goal: a rapid assembly
of more-complex molecules in one operation.
We reported a catalytic multicomponent cycloaddition, a
domino [4 + 2]−[2 + 2] cycloaddition, starting with 2-
siloxybutadiene and two molecules of an α,β-unsaturated ester
(see Figure 2).6
In the reaction cascade, the formation of new C−C bonds in
the second [2 + 2] cycloaddition stage occurs directly at the
reactive silyl enol ether, which is generated by the first [4 + 2]
cycloaddition. By using this reaction as a key step, a rapid
synthesis of the proposed structure of paesslerin A (1), which
was isolated from the sub-Atrantic soft coral Alcyonium
oriented synthesis and combinatorial chemistry. Their catalytic
variants have also been investigated to identify more-efficient
processes. In typical domino and/or multicomponent reac-
tions, a potential bond-forming reactive site (functionality) of
an intermediate, which is produced in the preceding step, is
directly used in the subsequent bond-forming reaction (Figure
1, path a). The chemoselectivity, regioselectivity, and stereo-
selectivity arising during the reaction cascade to the product is
usually defined by the nature of the substrates. However, if the
reactive site moves to another position during the domino
reaction, with the assistance of a catalyst, the construction of
diverse and complex structures is possible (Figure 1, path b).
Recently, tandem catalysis has attracted much interest as an
efficient synthetic strategy.5 The term “tandem catalysis” is
defined as one or more compatible catalysts that independently
promote two or more mechanistically distinct reactions in a
cascade. We envisioned that a tandem catalysis strategy in
Received: March 28, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01089
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
smoothly in the presence of Tf2NH.13 It has been reported that
the same catalyst also activates Diels−Alder type [4 + 2]
cycloaddition of enones with 2-siloxydiene14 and [2 + 2]
cycloaddition of silyl enol ethers with acrylate.15 We chose
cyclopentenone 3,16 siloxydiene 4,17 and methyl acrylate (5) as
the components for the synthesis of the protoilludane skeleton.
A mixture of 3, 4, and 5 in CH2Cl2 was treated with a catalytic
amount of Tf2NH, which resulted in the production of a
complex mixture. The mass spectrum of the crude mixture
indicated the formation of three-component adducts. Careful
optimization of the reaction conditions showed that a one-pot
procedure afforded the desired tricyclo[6.3.0.02,5]undecanone
8 as the major product (Scheme 1). The reaction of 3 with 4
Figure 2. Catalytic domino [4 + 2]−[2 + 2] cycloaddition for the
synthesis of the originally reported structure of paesslerin A.
Scheme 1. Assembly of Tricyclic Intermediate
paessleri,7 and which displays antitumor activity against human
cancer cell lines, was accomplished.6a However, the spectro-
scopic data of synthetic 1 were not consistent with those of the
natural compound. Based on reassignment of one-dimensional
(1D) and two-dimensional (2D) NMR signals of the isolated
natural product, it was suspected that the possible structure of
the natural paessrerin A would be an acetyl derivative of
protoilludenol (2b),8 whose core skeleton is tricyclo-
[6.3.0.02,5]undecane. The skewed 5/6/4 tricyclic system is
found in Nature as the core structure of protoilludane
sesquiterpens, which were mainly isolated as fungal metabo-
lites.9 A variety of oxidized metabolites of protoilludanes and
their derivatives have been isolated, and several of these show
promising biological activities.10 It is known that the hydroxy
substituent at the 6/4 ring juncture would be important for the
biological activity from the structure−activity relationship
analysis. Because of the characteristic tricyclic structure of
protoilludanes, many researchers have investigated the
synthetic studies.11 Most of these are directed to the synthesis
protoilludanes having no hydroxy group at the 6/4 ring
juncture. In contrast, the synthetic studies toward proto-
illudanes with a hydroxy group at the 6/4 ring juncture are
rare;12 the total synthesis was recently accomplished only by
Sheidt’s group.12b We envisaged that the key structure could be
constructed in a single operation if the silyl enol ether was
isomerized using a tandem catalyst in a multicomponent
reaction cascade (Figure 3). Here, we describe a catalytic
(1.1 equiv) in the presence of Tf2NH (2 mol %) was
performed at −40 °C, and then 5 (2.5 equiv) and Tf2NH (3
mol %) were added at the same temperature, when monitoring
via thin-layer chromatography (TLC), showed completion of
isomerization of cycloadduct 6 to the thermodynamically
favored silyl enol ether 7. The desired tricyclic adduct 8 was
obtained in 34% yield as the major isomer. In the reaction, no
regioisomer was observed and a trace amount of diastereomers
was detected. It was found that the E/Z ratio of 4 did not
influence the yield and stereoselectivity of 6. The structure of 8
was determined by X-ray crystallography, after hydrolysis to 9;
8 had the core structure of protoilludane sesquiterpenes. It is
worth noting that the preparation of a multigram quantity of 9
(12 g), which can be easily purified simply by recrystallization,
was also successful from 3 (15 g) without isolation of ester 8
(18%−30% overall yield, 23% average). The domino reaction
involving isomerization, which affords the skewed 5/6/4
tricyclic adduct 8, is clearly complementary to the domino
reaction with EtAlCl2, which does not activate isomerization of
the silyl enol ether. In the presence of EtAlCl2, instead of the
formation of the skewed tricycle 8, linear 5/6/4 tricycle 10 was
observed.
Figure 3. Domino process for production of skewed skeleton for
synthesis of newly suggested structure of paesslerin A (2a).
three-component reaction consisting of [4 + 2] cycloaddition,
isomerization, and [2 + 2] cycloaddition. We also report the
first total synthesis of the cytotoxic sesquiterpenoid paesslerin
A, and its structural revision.
Recently, we found that isomerization of kinetically favored
silyl enol ethers to thermodynamically stable ones occurs
A key issue in accomplishing the synthesis of 2 from 9 is the
installation of a methyl group at the C(2) position. We
expected that either the ketocarbonyl, tert-hydroxy, or carboxyl
group of 9 would be used as a directing group for
functionalization of the inactive C−H bond at the C(2) or
C(3) position. Although various direct and indirect C−H
B
DOI: 10.1021/acs.orglett.9b01089
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Introduction of One-Carbon Unit at the C(2) Position
a
Legend: HOTT, S-(1-oxido-2-pyridinyl)-1,1,3,3-tetramethylthiouronium hexafluorophosphate; DTMBP, 2,6-di-tert-butyl-4-methylpyridine; and
Rh2Oct4, dirhodium(II) tetrakis(octanoate).
activation reactions were attempted (see the Supporting
Information), decomposition of the fused 6/4 system was
observed in many cases, because of the high reactivity of the
tert-cyclobutanol moiety under acidic, basic, or radical
conditions.18 Finally, we found that an intramolecular
carbenoid insertion19 directed by the tert-hydroxy group was
promising. The substrate 15 for the carbene insertion was
prepared from 9 in six steps, as shown in Scheme 2. Reductive
decarboxylation of 9 was performed using a modified Barton’s
decarboxylative reagent, S-(1-oxido-2-pyridinyl)-1,1,3,3-tetra-
methylthiouronium hexafluorophosphate (HOTT),20 to afford
11. Enol triflation of 11, followed by hydrogenation, afforded
alkene 1321 in high yield. After stereoselective reduction of 13,
using a rhodium/carbon catalyst under a high pressure of
hydrogen gas (H2), desilylation of the resulting product
provided alcohol 14 in 90% yield (two steps). Installation of
the silicon-tethered diazoacetate into 14 was conducted using
diisopropylsilyl bis(trifluoromethanesulfonate) and ethyl diaz-
assigned using 2D NMR spectroscopy, and the structure of 19c
was confirmed by X-ray crystallography. It was found that
silanol 19c was mainly formed from 19a during silica gel
column chromatography.
Once we had synthesized the all-carbon motif of
protoilludane sesquiterpenes, we focused our attention on
the introduction of an endo olefin into the six-membered ring
as the final stage of the synthesis of 2, as shown in Scheme 3.
Scheme 3. Final Steps in Total Synthesis of Paesslerin A: Ar
in 21a, o-Nitrophenyl
oacetate in the presence of Hunig base, to afford 15 in 96%
̈
yield. The C−H insertion reaction of 15 was achieved
smoothly by treatment with Rh2Oct4, to furnish the tetracyclic
ester as a mixture of diastereomers, which was purified after
reduction to the corresponding alcohol 16. The silyl group of
15 not only served as a tether but also masked the hydroxyl
group. Once we had successfully introduced two carbon units
at the C(2) position, we investigated whether the reaction of
diazosulfonate rather than a diazo ester tethered to silicon
would lead to one-carbon insertion at the same position. Tosyl
diazomethane 17 was prepared from 14 in 32% yield (66%,
based on recovered starting material (brsm)) in the same
manner as 15. C−H insertion of diazo tosylate 17, Cu(acac)2
(where acac = acetylacetonate) was found to be superior to
rhodium(II) salts such as Rh2Oct4 and Rh2(esp)2, as a catalyst.
Under the optimal conditions, the tetracyclic compound 18
was obtained as an inseparable diastereomeric mixture. After
desulfonylation of 18 with lithium naphthalenide, isolable
siloxanes 19a and 19b, and silanol 19c were obtained in 32%,
10%, and 15% yields (two steps), respectively. No regioisomer,
which could be produced by an insertion reaction into another
C−H bond, was detected. The relative configurations were
Cleavage of the C−Si bond of 1,2-oxasilolane 19a was
achieved via Tamao−Fleming oxidation, providing diol 20a
in 87% yield. Silanol 19c was also transformed to 20a in high
yield under the modified conditions, using cumene hydro-
peroxide as an oxidant.22 Nishizawa−Grieco dehydration of
20a afforded exo-methylene 22 through the formation of
selenide 21a.23 It is worth noting that the minor diastereomer
of 1,2-oxasilolane, 19b, was converted to 22 by the same
reaction sequence (74% yield in three steps). Therefore, all
three products obtained in the carbene insertion can be
C
DOI: 10.1021/acs.orglett.9b01089
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
converted to 22. Isomerization of exo olefin 22 using acid or
transition-metal catalysts was examined, but we only observed
recovery or decomposition of the starting material. However, a
density functional theory calculation (B3LYP/6-31G*) in-
dicated that the energy level of exo-22 in the ground state is
higher than that of endo-2b (ΔE° = +5.5 kcal/mol).
Encouraged by the result, we continued to examine the
isomeriazation under basic conditions. We speculated that
formation of the allyl anion from 22 would promote
isomerization to the endo olefin, because the countercation
bound to the C(1) atom could be stabilized by chelation with
the anionic oxygen atom generated from the tert-hydroxyl
group. Treatment of 22 with excess KAPA (potassium 3-
aminopropylamide),24 prepared from potassium hydride and
1,3-diaminopropane, successfully promoted isomerization to
the endo cyclic olefin, to give protoilludenol (2b), which was
isolated by Nozoe and co-workers from the mycelium of
Fomitopsis insularis.8 Finally, acetylation of 2b with acetic
anhydride (as the solvent) in the presence of pyridine rendered
2a in 73% yield. The physical properties of ( )-2a (1H and
13C NMR spectra and low-resolution MS) were identical to
those reported for paesslerin A.7
In conclusion, a novel multicomponent reaction involving
three mechanistically distinct Tf2NH-catalyzed reactions[4
+ 2] and [2 + 2] cycloadditions, and isomerizationwas
developed. The reaction cascade enables the assembly of a
skewed 5/6/4 tricyclic motif with migration of the reactive site
with the assistance of the catalyst. We used this process for
rapid construction of the protoilludane skeleton as a key step
in the first total synthesis of the racemic protoilludene
sesquiterpenes, protoilludenol and paesslerin A, in 17 and 18
overall steps, respectively, from 5,5-dimethyl-2-cyclopente-
none. This achievement led to revision of the originally
assigned tricyclic structure of paesslerin A. The synthesis also
features the regioselective C−H insertion of a silicon-tethered
sulfonyl carbenoid and base-promoted isomerization of an exo
olefin to the endo one without decomposition of the unstable
tert-cyclobutanol moiety.
Kiyosei Takasu: 0000-0002-1798-7919
Present Address
¶Graduate School of Pharmaceutical Sciences, Tokushima
University, Shomachi, Tokushima 770−8505, Japan.
Author Contributions
§These authors contributed equally to this manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank JSPS KAKENHI (Grant No. 16H05073), MEXT
KAKENHI (Grant Nos. JP16H01147 and JP18H04406 in
Middle Molecular Strategy), and AMED Platform for
Supporting Drug Discovery and Life Science Research, the
Uehara Memorial Foundation, and the Hoansha Foundation.
REFERENCES
■
(1) Dewick, P. M. Medicinal Natural Products: A Biosynthetic
Approach; Wiley: Chichester, U.K., 2002.
(2) (a) Tietze, L. F. Domino Reactions: Concepts for Organic Synthesis;
Wiley−VCH: Weinheim, Germany, 2014. (b) Nicolaou, K. C.; Chen,
J. S. Chem. Soc. Rev. 2009, 38, 2993−3009. (c) Pellissier, H. Chem.
Rev. 2013, 113, 442−524.
(3) (a) Zhu, J.; Wang, Q.; Wang, M. Multicomponent Reactions in
Organic Synthesis; Wiley−VCH: Weinheim, Germany, 2014. (b) Mu
ler, T. J. J., Ed. Science of Synthesis: Multicomponent Reactions, Vols. 1
̈
l-
́
and 2; Thieme: Stuttgart, Germany, 2014. (c) Toure, B. G.; Hall, D.
G. Chem. Rev. 2009, 109, 4439−4486. (d) Villaume, M. T.; Baran, P.
S. Nature 2014, 513, 324−325. (e) Sahn, J. J.; Granger, B. A.; Martin,
S. F. Org. Biomol. Chem. 2014, 12, 7659−7672.
(4) (a) Vaxelaire, C.; Winter, P.; Christmann, M. Angew. Chem., Int.
Ed. 2011, 50, 3605−3607. (b) Calder, E. D. D.; Grafton, M. W.;
Sutherland, A. Synlett 2014, 25, 1068−1080.
(5) (a) Fogg, D. E.; dos Santos, E. N. Coord. Chem. Rev. 2004, 248,
2365−2379. (b) Shindoh, N.; Takemoto, Y.; Takasu, K. Chem. - Eur.
J. 2009, 15, 12168−12179. (c) Takasu, K. Yuki Gosei Kagaku
Kyokaishi 2014, 72, 770−780.
(6) (a) Inanaga, K.; Takasu, K.; Ihara, M. J. Am. Chem. Soc. 2004,
126, 1352−1353. (b) Takasu, K.; Inanaga, K.; Ihara, M. Tetrahedron
Lett. 2008, 49, 4220−4222.
ASSOCIATED CONTENT
* Supporting Information
■
S
(7) Rodriguez Brasco, M. F.; Seldes, A. M.; Palermo, J. A. Org. Lett.
2001, 3, 1415−1417.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01089.
(8) Nozoe, S.; Kobayashi, H.; Urano, S.; Furukawa, J. Tetrahedron
Lett. 1977, 18, 1381−1384.
(9) Quin, M. B.; Flynn, C. M.; Schmidt-Dannert, C. Nat. Prod. Rep.
2014, 31, 1449−1473.
Experimental procedures and characterization data for
the intermediates (PDF)
Characterization data for the products (PDF)
(10) Abraham, W. R. Curr. Med. Chem. 2001, 8, 583−606.
(11) As a review, see: (a) Siengalewicz, P.; Mulzer, J.; Rinner, U. Eur.
J. Org. Chem. 2011, 2011, 7041−7055. As representative examples,
see: (b) Semmelhack, M. F.; Tomoda, S.; Nagaoka, H.; Boettger, S.
D.; Hurst, K. M. J. Am. Chem. Soc. 1982, 104, 747−759. (c) Rychlet
Elliott, M.; Dhimane, A.-L.; Malacria, M. J. Am. Chem. Soc. 1997, 119,
Accession Codes
CCDC 1906155 and 1906156 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
̈
3427−3428. (d) Kogl, M.; Brecker, L.; Warrass, R.; Mulzer, J. Angew.
Chem., Int. Ed. 2007, 46, 9320−9322. (e) Schwartz, B. D.; Matousova,
E.; White, R.; Banwell, M. G.; Willis, A. C. A. Org. Lett. 2013, 15,
1934−1937. (f) Baumann, A. N.; Eisold, M.; Didier, D. Org. Lett.
2017, 19, 2114−2117.
(12) (a) Pitaval, A.; Leboeuf, D.; Ceccon, J.; Echavarren, A. M. Org.
Lett. 2013, 15, 4580−4583. (b) Hovey, M. T.; Cohen, D. T.; Walden,
D. M.; Cheong, P. H.-Y.; Scheidt, K. A. Angew. Chem., Int. Ed. 2017,
56, 9864−9867.
(13) Inanaga, K.; Ogawa, Y.; Nagamoto, Y.; Daigaku, A.; Tokuyama,
H.; Takemoto, Y.; Takasu, K. Beilstein J. Org. Chem. 2012, 8, 658−
661.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kay-t@pharm.kyoto-u.ac.jp.
ORCID
Hidetoshi Tokuyama: 0000-0002-6519-7727
(14) Jung, M. E.; Ho, D. G. Org. Lett. 2007, 9, 375−378.
D
DOI: 10.1021/acs.orglett.9b01089
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(15) (a) Inanaga, K.; Takasu, K.; Ihara, M. J. Am. Chem. Soc. 2005,
127, 3668−3669. (b) Takasu, K. Synlett 2009, 2009, 1905−1914.
(c) Kurahashi, K.; Yamaoka, Y.; Takemoto, Y.; Takasu, K. React.
Chem. Eng. 2018, 3, 626−630.
(16) (a) Agosta, W. C.; Smith, A. B., III. J. Am. Chem. Soc. 1971, 93,
5513−5520. (b) Cohen, T.; McNamara, K.; Kuzemko, M. A.; Ramig,
K.; Landi, J. J., Jr.; Dong, Y. Tetrahedron 1993, 49, 7931−7942.
(17) Cazeau, P.; Duboudin, F.; Moulines, F.; Babot, O.; Dunogues,
J. Tetrahedron 1987, 43, 2089−2100.
(18) (a) Takasu, K.; Nagao, S.; Ihara, M. Tetrahedron Lett. 2005, 46,
1005−1008. (b) Takasu, K.; Nagamoto, Y.; Takemoto, Y. Chem. -
Eur. J. 2010, 16, 8427−8432. (c) Azuma, T.; Takemoto, Y.; Takasu,
K. Chem. Pharm. Bull. 2011, 59, 1190−1193.
(19) Davies, H. M. L.; Dick, A. R. Top. Curr. Chem. 2009, 292, 303−
3145.
(20) Garner, P.; Anderson, J. T.; Dey, S.; Youngs, W. J.; Galat, K. J.
Org. Chem. 1998, 63, 5732−5733.
(21) (a) Kablean, S. N.; Marsden, S. P.; Craig, A. M. Tetrahedron
Lett. 1998, 39, 5109−5112. (b) Marsden, S. P.; Pang, W.-K.
Tetrahedron Lett. 1998, 39, 6077−6080.
(22) (a) Smitrovich, J. H.; Woerpel, K. A. J. Org. Chem. 1996, 61,
6044−6046. (b) Ventocilla, C. C.; Woerpel, K. A. J. Org. Chem. 2012,
77, 3277−3283.
(23) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
1485−1486.
(24) Brown, C. A. J. Chem. Soc., Chem. Commun. 1975, 222−223.
E
DOI: 10.1021/acs.orglett.9b01089
Org. Lett. XXXX, XXX, XXX−XXX