Bioinspired Total Synthesis of (±)-Chaetophenol C Enabled by a Pd-Catalyzed Cascade Cyclization

Article abstract of DOI:10.1021/acs.orglett.7b02124

A novel Pd(II)-catalyzed cascade reaction has been developed that consists of a highly regio- and stereoselective oxa [4 + 2] cycloaddition reaction of o-alkynylbenzaldehydes and an intramolecular carboxylic group quenching of the in situ generated oxonium ion. This new reaction provides a one-step construction of the tetracyclic core structure of chaetophenol C from two simple starting materials. The developed chemistry was successfully applied to the first total synthesis of chaetophenol C and dozens of its analogues.

Full text of DOI:10.1021/acs.orglett.7b02124

Letter
pubs.acs.org/OrgLett
Bioinspired Total Synthesis of ( )-Chaetophenol C Enabled by a Pd-
Catalyzed Cascade Cyclization
Yun Li,*,†,‡ Qingyu Zhang,† Hongyu Wang,† Bin Cheng,† and Hongbin Zhai*,⊥
†State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou
730000, China
‡State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, China
⊥Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking
University, Shenzhen 518055, China
S
* Supporting Information
ABSTRACT: A novel Pd(II)-catalyzed cascade reaction has
been developed that consists of a highly regio- and
stereoselective oxa [4 + 2] cycloaddition reaction of o-
alkynylbenzaldehydes and an intramolecular carboxylic group
quenching of the in situ generated oxonium ion. This new
reaction provides a one-step construction of the tetracyclic
core structure of chaetophenol C from two simple starting
materials. The developed chemistry was successfully applied to
the first total synthesis of chaetophenol C and dozens of its analogues.
haetophenol C (1; Scheme 1) was isolated in 2013 from
apparently is a prerequisite for the formation of the lactone
Cepigenetic manipulated Chaetomium indicum by Oshima functionality because the subsequent trapping reaction would
and co-workers.1 The structure of 1 is particularly striking in
be possible only when the carboxylate group and the oxonium
ion were accessible to one another in the intermediate 2
(Scheme 1B).
that it contains a rigid polycyclic core with a pentasubstituted γ-
lactone to bridge the [2.2.2] ring system. To the best of our
knowledge, no synthetic study on such a molecule has ever
been reported to date. This, together with the inability to
acquire sufficient quantities of chaetophenol C for further
biomedical studies, makes it warranted to develop a facile access
to the polycyclic core structure of such an interesting molecule.
In this paper, we report a novel cascade reaction along with the
first total synthesis of chaetophenol C in 10 steps.
o-Alkynylbenzaldehydes (I, Scheme 1 A) are known to
readily undergo transition-metal-catalyzed cycloisomerization
to generate benzopyrilium species2 (II, Scheme 1 A), which
may serve as a heterodiene2c,m,k,3 in [4 + 2] or a 1,3-dipole
equivalent4 in [3 + 2] cycloaddition reactions. Therefore, we
speculated that chaetophenol C might be accessible according
to the retrosynthetic analysis in Scheme 1 B: The [2.2.2] ring
system was expected to be accessed by a stereoselective [4 + 2]
cycloaddition reaction of the isochromenylium species 2
(Scheme 1 B) with an enol ether, while the lactone motif
could be installed by a subsequent trapping of the in situ
generated oxonium intermediate with a carboxylate properly
located within the same molecule. This prospective high
efficiency of the so far unexplored route to chaetophenol C
promoted us to believe that it would be a worthy synthetic
endeavor. However, challenges did exist: (1) the competition
between [4 + 2] and [3 + 2] cycloaddition reactions and (2)
the stereoselectivity of the desired [4 + 2] pathway (endo vs
exo). A [4 + 2] cycloaddition with the desired stereoselectivity
Oshima1a has postulated that chaetophenol C is biogeneti-
cally generated by the condensation of chaetophenol A (3,
Scheme 1B) with pyruvic acid in the living system while the
stereochemical fidelity over this condensation is governed by
enzyme(s). Enlightened by this biosynthetic hypothesis, we
began our explorations of the desired cascade cyclization with
o-alkynylbenzaldehyde 4a and pyruvic acid. However, initial
results were disappointing; no desired product could be
detected under a variety of conditions tested.5 This observation
led us to examine other dienophiles instead of pyruvic acid, and
eventually trimethylsilyl 2-[(trimethylsilyl)oxy] acrylate 5 was
found to be effective in the presence of a catalytic amount of
AgOTf (Table 1, entry 1). The reaction gave the desired
polycyclic product 6a6 as a single diastereoisomer, with the
chemical structure and relative configuration being secured by
X-ray crystallographic analysis.7 A brief screening of catalysts
reveals that Pd(OAc)2 gave the highest yield (entry 2) of
product. AuCl3, Zn(OTf)2, and PtCl2−CO were relatively less
effective (entry 4−7). Increasing the catalyst loading of
Pd(OAc)2 to 10 mol % did not show further improvement of
the isolated yield (entry 8). Other solvents such as toluene and
THF (entries 9 and 10) gave inferior results compared with
dichloromethane.
Received: July 12, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02124
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Organic Letters
Letter
substrates (4b−p) examined, leading to the expected products
(6b−p) in good to excellent yields.
Scheme 1. Reactivities of Benzopyrilium Ion and the
Synthetic Strategy for Chaetophenol C
a
Scheme 2. Analogues of Chaetophenol C
Table 1. Catalyst Screening and Condition Optimization of
a
the Cascade Cyclization
b
entry
catalyst
solvent
time (h)
yield (%)
1
2
3
4
5
AgOTf
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1,4-dioxane
CH2Cl2
toluene
THF
24
24
24
48
48
24
24
24
24
24
58
Pd(OAc)2
Cu(OTf)2
AuCl3
75
59
6
Zn(OTf)2
PtCl2/CO
PtCl2/CO
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
5
a
c
The reactions were performed by adding Pd(OAc)2 (5 mol %) to a
6
14
d
solution of 4 (1 equiv) and 5 (12 equiv) in CH2Cl2 (c = 0.05 M) at
ambient temperature and stirring for 10−40 h until TLC showed full
7
e
complex
8
56
51
8
b
consumption of 4. With Pd(TFA)2 (5 mol %) as the catalyst.
9
10
The substituents on the phenyl ring showed only a negligible
influence on the cyclization compared with the groups attached
to the alkyne motif. Butyl substituted substrates (4f, 4g) gave as
good yields as 4a. However, when the substituent R1 contained
an ethereal subunit (4i−l) or was an aryl group (4m−p), the
reactivity of the substrates was significantly reduced; the
starting o-alkynylbenzaldehydes could not be fully consumed,
presumably because of additional coordination to the palladium
and/or the increased steric crowding. Interestingly, it was found
that when Pd(TFA)2, a more cationic palladium(II) salt, was
used as the catalyst instead of Pd(OAc)2, substrates 4i−p all
afforded the corresponding products 6i−p in satisfactory yields.
The structure of 6m was further confirmed by X-ray
crystallographic analysis.7 However, it is worth mentioning
that substrate 4a, which reacted well when using Pd(OAc)2 as
a
The reactions were performed by adding the catalyst (5 mol %) to a
solution of 4a (1 equiv) and 5 (12 equiv) in solvent (c = 0.05 M) at
ambient temperature and stirring the mixture for 10−40 h until TLC
showed full consumption of 4a. Isolated yield based on 4a. 10 mol %
of PtCl2 was used under 1 atm of CO. The reaction was performed at
80 °C under 1 atm of CO, with 10 mol % of PtCl2 as the catalyst. 10
b
c
d
e
mol % of Pd(OAc)2 was used.
With optimized conditions in hand, we next examined the
scope of the cascade reaction, which amazingly allowed for the
formation of four new bonds, three rings and four stereocenters
(including two quaternary ones) in a one-flask manner with a
range of o-alkynylbenzaldehydes. As illustrated in Scheme 2,
this reaction proceeded very well at ambient temperature for all
B
DOI: 10.1021/acs.orglett.7b02124
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Total Synthesis of Chaetopenol C
the catalyst, only gave 46% yield under the Pd(TFA)2
conditions, along with significant amounts of unidentified side
products. A substrate with a terminal alkyne (4h) gave a much
lower yield of the polycyclic product even under the milder
Pd(OAc)2 conditions, presumably because the highly reactive
4h was prone to other undesired transformations in the
presence of the palladium catalyst.
Table 2. Screening of Conditions for the Direct Prenylation
Reaction
a
To demonstrate the utility of this newly developed
methodology, the total synthesis of chaetophenol C was then
attempted. As outlined in Scheme 3, the synthesis commenced
with the commercially available phenol 7. Benzoyl protection
and oxime formation of 7 were carried out to produce the O-
methyloxime 8 in 67% combined yield over two steps.
Subsequent bromination at the C-6 of compound 8 was
initially achieved through a five-step sequence (i.e., nitration at
the C-5, hydrogenation, bromination, nitrosylation, and
reduction) according to a previously reported protocol.3d,8
Strategically, the ortho-directed C−H functionalization appa-
rently offers quick access to desired C-6 bromination.9 To this
end, Fabis’ condition10 was first tested, which was indeed
feasible. However, the reaction only gave 52% yield of 9
together with a mass of unreacted 8 as an inseparable mixture.
Then, after extensive examinations, we eventually found that
1,3-dibromo-5,5-dimethylhydantoin (DBDMH) was much
superior to NBS as in Fabis’ original protocol, which delivered
the desired product 9 in 77% yield. To the best of our
knowledge, this is the first report on the utilization of DBDMH
as the brominating reagent in C−H bromination.
b
entry
catalyst
solvent
H2O
yield (%)
1
2
formic acid
complex
Amberlyst 15
CH2Cl2
(CH2Cl)2
CH2Cl2
CH2Cl2
CCl4
NR
c
3
Cu−Al−KIT-5
NR
d
4
5
6
7
PMA
14 (35); 17 (0)
14 (48); 17 (10)
14 (20)
NR
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
1,4-dioxane
CH2Cl2
e
8
14 (67)
a
The reactions were performed by adding the catalyst (0.1 equiv) to a
solution of 12 (0.1 mmol) and 13 (0.25 mmol) in 0.5 mL of solvent at
0 °C and stirring the mixture for 10−40 h at ambient temperature.
Isolated yield based on 12. Performed at 80 °C. PMA =
phosphormolybdic acid. 0.2 equiv of BF3·Et2O was used with a
concentration [12] = 0.1 M.
b
c
d
e
Among them, BF3·Et2O gave the best results under a much-
diluted concentration (entry 8).
With compound 14 in hand, the two hydroxyl groups were
then converted to corresponding bis-TBS ether 15 in decent
yield. The resulting alkynylbenzaldehyde 15 was subjected to
the optimal conditions for the cascade cyclization. To our
gratification, the reaction proceeded smoothly and delivered the
desired polycyclic compound 16 in 60% yield. It is noteworthy
that the cascade cyclization reaction did not work when
diphenol 14 was directly used as the substrate. We suspect that
the intramolecular hydrogen bonding might be responsible for
the failure of the desired cyclization. Subsequent removal of the
TBS protection of 16 with TBAF buffered with acetic acid16
gave chaetophenol C in 87% yield, with all spectroscopic data
identical to those reported by Oshima.1a
In summary, we have developed a palladium-catalyzed
cascade cycloaddition/cyclization reaction of o-alkynylbenzal-
dehydes giving products containing the [2.2.2] bicyclic lactone
core structural unit found in chaetophenol C. The efficacy of
this process was showcased by the ease with which novel, highly
composite scaffolds could be assembled from steadily available
materials in one chemical step. The practicality of the
transformation was also demonstrated in the first total synthesis
After removing the benzoyl and oxime group in 9, the
propynyl group was then installed onto aldehyde 10 through a
modified Suzuki coupling.11 It is noteworthy that Sonogashra
reaction was inapplicable here because of the high volatility of
propyne. Considering the hindrance at C5 position of
compound 12, an intramolecular reaction was believed to be
more feasible for the following functionalization at C5. Thus,
phenol 12 was initially converted to its allylic ether 4e and
various Claisen rearrangement conditions were attempted for
the C5 allylation. However, the desired transformation did not
proceed under dozens of classical conditions. These negative
results forced us to seek other alternatives.
Enlightened by Manners’ report,12 which employed 2-
methylbut-3-en-2-ol (13) as the prenylation reagent for a
biogenetic-type synthesis of o-isopentenylphenols, an array of
catalysts were evaluated in this prenylation reaction (see Table
2, entries 1−7) including formic acid,12 Amberlyst 15,13 Cu−
Al−KIT-5,14 phosphormolybdic acid (PMA), and BF3·Et2O.15
C
DOI: 10.1021/acs.orglett.7b02124
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Organic Letters
Letter
F. Chem. Commun. 2016, 52, 13405. (f) Hu, Z. L.; Qian, W. J.; Wang,
S.; Wang, S. Z.; Yao, Z. J. Org. Lett. 2009, 11, 4676. (g) Asao, N.;
Takahashi, K.; Lee, S.; Kasahara, T.; Yamamoto, Y. J. Am. Chem. Soc.
2002, 124, 12650. (h) Asao, N.; Sato, K.; Menggenbateer; Yamamoto,
Y. J. Org. Chem. 2005, 70, 3682. (i) Hsu, Y.-C.; Ting, C.-M.; Liu, R.-S.
J. Am. Chem. Soc. 2009, 131, 2090. (j) Hojo, D.; Noguchi, K.; Tanaka,
K. Angew. Chem., Int. Ed. 2009, 48, 8129.
(4) (a) Cao, Z.; Zhu, H.; Meng, X.; Tian, L.; Sun, X.; Chen, G.; You,
J. Chem. - Eur. J. 2016, 22, 9125. (b) Shin, S.; Gupta, A. K.; Rhim, C.
Y.; Oh, C. H. Chem. Commun. 2005, 4429. (c) Oh, C. H.; Yi, H. J.;
Lee, J. H.; Lim, D. H. Chem. Commun. 2010, 46, 3007. (d) Ishida, K.;
Kusama, H.; Iwasawa, N. J. Am. Chem. Soc. 2010, 132, 8842.
(e) Kusama, H.; Ishida, K.; Funami, H.; Iwasawa, N. Angew. Chem., Int.
Ed. 2008, 47, 4903. (f) Ito, K.; Hara, Y.; Mori, S.; Kusama, H.;
Iwasawa, N. Chem. - Eur. J. 2009, 15, 12408. (g) Kusama, H.; Funami,
H.; Shido, M.; Hara, Y.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc.
2005, 127, 2709.
(5) Most Bronsted acids gave a complex mixture, while the Lewis
acids such as Pd(OAc)2, CoCl2, and Cu(OTf)2 gave small amounts of
hydrolyzed methyl ketone (18) as the product. In addition, we also
tested the reaction of methyl ketone 18 and pyruvic acid according to
the Oshima biosynthetic proposal for chaetophenol C. However,
complex mixtures were observed ether under the presence of protic
acids (TFA, TsOH) or Lewis acids such as Pd(OAc)2 and Cu(OTf)2.
of chaetophenol C, which was accomplished in 10 steps from a
commercially available starting material.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02124.
1
Synthetic procedures; H and 13C NMR spectra for all
organic products (PDF)
X-ray data for compound 6a (ZIP)
X-ray data for compound 6m (ZIP)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: liyun@lzu.edu.cn
*E-mail: zhaihb@pkusz.edu.cn
ORCID
Yun Li: 0000-0003-2236-9880
Bin Cheng: 0000-0002-8276-6653
Hongbin Zhai: 0000-0003-2198-1357
Notes
The authors declare no competing financial interest.
(6) A H+ source for the protonolysis of the bridgehead Pd−C bond
might comes from the moisture contained in trimethylsilyl 2-
[(trimethylsilyl)oxy] acrylate, which was used as it crude form in the
cyclization.
(7) CCDC 1546892 and CCDC 1552890 contain the supplementary
crystallographic data for compound 6a and 6m, respectively. These
data can be obtained free of charge from the Cambridge Crystallo-
graphic Data Centre.
(8) Wei, W.-G.; Zhang, Y.-X.; Yao, Z.-J. Tetrahedron 2005, 61, 11882.
(9) (a) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int.
Ed. 2009, 48, 9792. (b) Rouquet, G.; Chatani, N. Angew. Chem., Int.
Ed. 2013, 52, 11726. (c) Lyons, T. W.; Sanford, M. S. Chem. Rev.
2010, 110, 1147.
ACKNOWLEDGMENTS
■
This research was supported by the National Natural Science
Foundation of China (21572089), Program for Changjiang
Scholars and Innovative Research Team in University
(PCSIRT: IRT_15R28), and FRFCU (lzujbky-2016-52,
lzujbky-2016-ct02). We thank Prof. Chun-An Fan of Lanzhou
University for enlightening discussions.
REFERENCES
■
(1) (a) Asai, T.; Yamamoto, T.; Shirata, N.; Taniguchi, T.; Monde,
K.; Fujii, I.; Gomi, K.; Oshima, Y. Org. Lett. 2013, 15, 3346. (b) Asai,
T.; Morita, S.; Taniguchi, T.; Monde, K.; Oshima, Y. Org. Biomol.
Chem. 2016, 14, 646.
(10) Dubost, E.; Fossey, C.; Cailly, T.; Rault, S.; Fabis, F. J. Org.
Chem. 2011, 76, 6414.
(2) (a) Asao, N.; Chan, C. S.; Takahashi, K.; Yamamoto, Y.
Tetrahedron 2005, 61, 11322. (b) Asao, N.; Nogami, T.; Takahashi, K.;
Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 764. (c) Dyker, G.;
Hildebrandt, D.; Liu, J. H.; Merz, K. Angew. Chem., Int. Ed. 2003, 42,
4399. (d) Iwasawa, N.; Shido, M.; Kusama, H. J. Am. Chem. Soc. 2001,
123, 5814. (e) Kim, N.; Kim, Y.; Park, W.; Sung, D.; Gupta, A. K.; Oh,
C. H. Org. Lett. 2005, 7, 5289. (f) Kusama, H.; Funami, H.; Takaya, J.;
Iwasawa, N. Org. Lett. 2004, 6, 605. (g) Patil, N. T.; Pahadi, N. K.;
Yamamoto, Y. J. Org. Chem. 2005, 70, 10096. (h) Patil, N. T.;
Yamamoto, Y. J. Org. Chem. 2004, 69, 5139. (i) Teng, T.-M.; Liu, R.-S.
J. Am. Chem. Soc. 2010, 132, 9298. (j) Beeler, A. B.; Su, S.; Singleton,
C. A.; Porco, J. A. J. Am. Chem. Soc. 2007, 129, 1413. (k) Asao, N.;
Kasahara, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2003, 42, 3504.
(l) Hu, Z.-L.; Yang, Z.-Y.; Wang, S.; Yao, Z.-J. Chem. - Eur. J. 2011, 17,
1268. (m) Malhotra, D.; Liu, L.-P.; Mashuta, M. S.; Hammond, G. B.
Chem. - Eur. J. 2013, 19, 4043. (n) Barluenga, J.; Vazquez-Villa, H.;
Ballesteros, A.; Gonzalez, J. M. J. Am. Chem. Soc. 2003, 125, 9028.
(o) Kotera, A.; Uenishi, J. i.; Uemura, M. J. Organomet. Chem. 2010,
695, 2180. (p) Tovar, J. D.; Swager, T. M. J. Org. Chem. 1999, 64,
6499. (q) Saxena, A.; Perez, F.; Krische, M. J. Angew. Chem., Int. Ed.
2016, 55, 1493.
(11) (a) Fananas, F. J.; Mendoza, A.; Arto, T.; Temelli, B.; Rodriguez,
F. Angew. Chem., Int. Ed. 2012, 51, 4930. (b) Molander, G. A.; Katona,
B. W.; Machrouhi, F. J. Org. Chem. 2002, 67, 8416.
(12) Jurd, L.; Stevens, K.; Manners, G. Tetrahedron Lett. 1971, 12,
2275.
(13) Das, B.; Veeranjaneyulu, B.; Krishnaiah, M.; Balasubramanyam,
P. Synth. Commun. 2009, 39, 1929.
(14) Varghese, S.; Anand, C.; Dhawale, D.; Mane, G. P.; Wahab, M.
A.; Mano, A.; Raj, G. A. G.; Nagarajan, S.; Vinu, A. ChemCatChem
2013, 5, 899.
(15) Ravada, S. R.; Emani, L. R.; Garaga, M. R.; Meka, B.; Golakoti,
T. Am. J. Infect. Dis. 2009, 5, 83.
(16) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 3090.
(3) (a) Asao, N.; Nogami, T.; Lee, S.; Yamamoto, Y. J. Am. Chem.
Soc. 2003, 125, 10921. (b) Selvi, T.; Srinivasan, K. Org. Biomol. Chem.
2013, 11, 2162. (c) Liu, L.-P.; Hammond, G. B. Org. Lett. 2010, 12,
4640. (d) Zhu, J. L.; Germain, A. R.; Porco, J. A. Angew. Chem., Int. Ed.
2004, 43, 1239. (e) Arto, T.; Fernandez, P.; Fananas, F. J.; Rodriguez,
D
DOI: 10.1021/acs.orglett.7b02124
Org. Lett. XXXX, XXX, XXX−XXX