Asymmetric Total Synthesis of Cerorubenic Acid-III

Article abstract of DOI:10.1021/jacs.8b12647

The first asymmetric total synthesis of the highly strained compound cerorubenic acid-III is reported. A type II intramolecular [5 + 2] cycloaddition allowed efficient and diastereoselective construction of the synthetically challenging bicyclo[4.4.1] ring system with a strained bridgehead (anti-Bredt) double bond in the final product. A unique transannular cyclization installed the vinylcyclopropane moiety with retention of the desired stereochemistry.

Full text of DOI:10.1021/jacs.8b12647

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Asymmetric Total Synthesis of Cerorubenic Acid-III
Xin Liu, Junyang Liu, Jianlei Wu, Guocheng Huang, rong liang, Lung Wa Chung, and Chuang-Chuang Li
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 05 Feb 2019
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Asymmetric Total Synthesis of Cerorubenic Acid-III
,§,
, ,
Xin Liu,† # Junyang Liu,† ‡ # Jianlei Wu,† Guocheng Huang,† Rong Liang,† Lung Wa Chung,† and Chuang-
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Chuang Li*,†
†Shenzhen Grubbs Institute, Department of Chemistry, Southern University of Science and Technology, Shenzhen 518055, China
‡SUSTech Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen 518055, China
§Institute of Chinese Medical Sciences, University of Macau, Macau, China
Supporting Information Placeholder
not yet been reported, and the catalytic asymmetric synthesis of 1
has not been achieved. In our continuing efforts towards the
synthesis of biologically active natural products,11 we herein
describe the first asymmetric total synthesis of 1, based on a type
II intramolecular [5+2] cycloaddition.
ABSTRACT: The first asymmetric total synthesis of the highly
strained compound cerorubenic acid-III is reported. A type II
intramolecular [5+2] cycloaddition allowed efficient and
diastereoselective construction of the synthetically-challenging
bicyclo[4.4.1] ring system with a strained bridgehead (anti-
Bredt) double bond in the final product. A unique transannular
cyclization installed the vinylcyclopropane moiety with
retention of the desired stereochemistry.
Sesterterpenoids continue to play a significant role in synthetic
organic chemistry and drug discovery, owing to their intriguing and
broad range of biological activities and complicated, diverse
structures.1,2 Cerorubenic acid-III (1, Fig. 1), a sesterterpenoid with
a
novel tetracyclo[8.4.1.0.0]pentadecane skeleton, was first
isolated by Naya and coworkers in 1983 from secretions of the
scale insect Ceroplastes rubens Maskell.3 This compound plays an
important role in insect communication,4 although the relative
scarcity of 1 from natural sources has impeded a more systematic
evaluation of its biological activity. Therefore, the development of
an efficient synthesis of 1 and its analogs is highly desirable.
Structurally, 1 comprises a sterically compact 6/3/7/6 tetracyclic
skeleton, with a unique bridged bicyclo[4.4.1]undecene ring
system5 (highlighted in red in 1) and a vinylcyclopropane fragment
(highlighted in blue in 2). In particular, 1 possesses a strained
bridgehead (anti-Bredt) double bond at C6–C7,6a,6b as is also found
in the well-known natural drug Taxol.6c This double bond is
unstable in air, as it oxidizes to give the corresponding epoxide.3
These unique structural features of 1 make it highly strained.7
Moreover, 1 has seven contiguous stereocenters, including an all-
carbon quaternary stereocenter on the cyclopropane moiety.
Therefore, 1 presents a formidable synthetic challenge.
Despite this difficulty, the promising pharmacological properties
and unusual structural motifs of 1 have resulted in interest from the
synthetic community.8-10 In particular, a campaign that crossed
more than 10 years in the Paquette group has led to several reported
approaches to 1.8 In 1998, Paquette and coworkers developed an
elegant synthetic approach for cerorubenic acid-III methyl ester (2),
in which an anionic oxy-Cope rearrangement and a 6-exo radical
cyclization are key steps. The asymmetric synthesis of unnatural 2
based on the optical resolution8b of its precursor requires 30 steps
in 0.3% overall yield.10 However, synthesis of 1 from 2 was
unknown. According to previous studies,8 hydrolysis of the ester
group in 2 under basic or acidic conditions would be potentially
problematic, due to the instability of the bridgehead
vinylcyclopropane double bond. To date, a total synthesis of 1 has
Figure 1. Naturally-occurring cerorubenic acid-III (1) and the
synthetic unnatural methyl ester (2).
Using a retrosynthetic approach (Scheme 1), we expected that 1
could be obtained from 3 via chemoselective cross-metathesis (CM)
with methacrylic acid.12 The tetracyclo[8.4.1.0.0]pentadecane core
of 3 would be produced from 4 through transannular cyclization to
install the cyclopropane moiety,13 followed by a series of functional
group interconversion (FGI). Compound 4 would be synthesized
from 5 by selective reductive cleavage of the C–O bond14 and
additional functional group modifications. In turn, the
bicyclo[4.4.1] ring system with the bridgehead double bond in 5
would be synthesized from 6 using type II intramolecular [5+2]
cycloaddition,15,16 while 6 would be prepared from 7 using an
Achmatowicz reaction.17 It was envisaged that 7, which would
contain almost all the carbons of 1, would be assembled via a one-
step process based on a cascade 1,4-addition-aldol reaction,18
starting with the readily available compounds vinylstannane (8),
furan-aldehyde (9) and enone (10). Finally, 10 would be
synthesized from the commercially-available starting material (S)-
citronellal (11) by organocatalytic enantioselective Michael
addition19 with methyl vinyl ketone (MVK), followed by aldol
condensation and dehydration.
Our synthesis began with the asymmetric preparation of 10
(Scheme 2a) using
a previously reported procedure with
modifications.19b The organocatalytic Michael addition of 11 to
MVK was promoted by employing the proline-derived catalyst 12
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(5 mol%) together with ethyl 3,4-dihydroxybenzoate (13) as a
Charge neutralization of the dipolar precursor intermediate and the
formation of the two strong C-C bonds in the [5+2] cycloaddition
should provide a strong thermodynamically driving force.
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cocatalyst (20 mol%). Subsequent intramolecular aldol
condensation and dehydration (using LiOH and i-PrOH) gave 10 in
72% overall yield with 93% de (on a 20 g scale). The Cu(I)-
catalyzed 1,4-addition of an organolithium reagent (generated from
820 via Sn-Li exchange) to 10 and quenching with TMSCl, gave the
silyl enol ether. The silyl enol ether reacted with BuLi, followed by
trapping the resulting enolate with the aldehyde 920 in the presence
of ZnBr2, furnished 7 (see the structure in Scheme 1). This product
was too unstable to be isolated, and so the ketone group in 7 was
reduced in situ using DIBAL-H to give the more stable diol 14 in
an overall yield of 50% from 10 (10 g scale). Treatment of 14 with
TsOH in acetone followed by addition of TBAF afforded 15 in 85%
yield. The oxidative rearrangement of 15 using VO(acac)2 and
TBHP in DCM, followed by one-pot Ac-protection of the anomeric
hydroxyl group, produced the key precursor 6 in 71% yield.
Scheme 2. a. Catalytic asymmetric synthesis of 5; and b. the
computed free energy profile of the two possible [5+2]
cycloaddition pathways by the M06-2X/6-31G* method.
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Scheme 1. Retrosynthetic analysis of cerorubenic acid-III (1).
Having obtained 6, we explored the possibility of performing a
type II intramolecular [5+2] cycloaddition to prepare 5. Based on
our previous synthetic study,15 a type II [5+2] cycloaddition
reaction was expected to give a bicyclo[4.4.1]undecene ring system
with endo selectivity, with the stereochemistry at the allylic
position of the dienophile alkene group being critical in terms of
controlling the diastereoselectivity. However, it was difficult to
predict the diastereoselective outcome of the reaction using the
complex precursor 6. That is, it was uncertain whether the product
5 or the undesired product 5a would be obtained. Density function
theory (DFT) calculations showed that the reaction of 6 via the 1,3-
dipole intermediate TS5 to give 5 is both kinetically (by ~4.9
kcal/mol) and thermodynamically more favorable than the reaction
to form 5a (see Scheme 2b and SI for computational details).
Consistent with the DFT results (Scheme 2a), the type II [5+2]
cycloaddition of 6 was realized using TMP as a base in a sealed
tube with heating, giving 5 as a single diastereomer in 72% yield
(1.5 g scale). The structure of 5 was confirmed by the X-ray
crystallographic analysis of its derivative (17, Fig. 2), obtained
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from 5 by reduction to give 16 followed by subsequent
Having synthesized 16, we proceeded to the next stage of our
proposed synthesis of 1 (Scheme 3). The initial efforts involved the
double reductive cleavages of the C4-O and C5-O bonds, even
though it was challenging to control the chemoselectivity during
this process due to the presence of the additional allylic C24-O
bond. To the best of our knowledge, there have been very few
instances of the efficient reductive cleavage of double C-O bonds
in the ring system of 8-oxabicyclo[3.2.1]oct-2-ene (highlighted in
red in 16).21 After several unproductive methods were evaluated
(see SI for more details), the following solution was identified. The
C5-hydroxyl group in 16 was converted to the corresponding
bromide using a nucleophilic substitution strategy to give 18 in 67%
yield (3.7 g scale). Compound 18 was treated with sodium
naphthalenide21e in THF and H2O at 25 °C to give the diol 20 in 78%
(2.7 g scale), likely proceeding via the intermediate 19, which
could be isolated in anhydrous condition. Notably, Na-
naphthalenide played various roles in this reaction, including (i)
selectively reductive eliminating the C4–O bond in 18, (ii)
removing the Bn group, and (iii) unusually reducing the less
sterically hindered C4-C5 double bond of the diene in 19.
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esterification. This synthetic route represented a facile means of
obtaining a suitable quantity (20 g) of 5, highlighting the robust
nature of this synthetic approach. Notably, this type II [5+2]
cycloaddition enabled the efficient and diastereoselective
construction of the desired core in 5, supplying the synthetically-
challenging bicyclo[4.4.1] ring system and bridgehead double bond.
Scheme 3. Asymmetric total synthesis of cerorubenic acid-III.
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Figure 2. ORTEP diagram of 17 and 23a
We subsequently examined transannular cyclization as a means
of installing the vinylcyclopropane moiety in 4 (Scheme 3). This
was challenging, as there have been few reports concerning the
complete retention of stereochemistry (such as R configuration at
C24) during such cyclizations.13,22 The formation of an all-carbon
quaternary stereocenter at C3 on the strained cyclopropane ring is
especially difficult. Initially, we attempted to synthesize the
aldehyde 21 with an activated sulfonate at C24 for cyclization, by
regioselective oxidation followed by tosylation, although this
approach was unsuccessful. In subsequent work, temporary TBS-
protection of the primary hydroxyl group in 20, followed by
tosylation of the C24-OH group and removal of the TBS group in
a one pot sequence and DMP oxidation, gave 21 in 55% overall
yield. Extensive trials found that the desired transannular
cyclization of 21 using t-BuOK22b in t-BuOH afforded
cyclopropyl-aldehyde 4 diastereoselectively in 78% yield (2.1 g
scale). The reaction presumably proceeded through a cationic
pathway via intermediate 22, with the enolate attacking the C24
cation stabilized by the adjacent vinyl group. The structure of 4 was
confirmed by X-ray crystallographic analysis of its derivative 23a
(Fig. 2, see SI for more details). Huang’s modification of the
Wolff–Kishner reduction23 was used to convert the formyl group
of 4 to a methyl moiety, followed by in situ deprotection using
AcOH to generate the diol 23 (1.2 g scale). Chemoselective
acetylation of the less sterically hindered hydroxyl group in 23,
followed by DMP oxidation using a one-pot process and
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(3) Tempesta, M. S.; Iwashita, T.; Miyamoto, F.; Yoshihara, K.; Naya,
subsequent base-mediated elimination, gave the enone 24 in an 80%
overall yield.
Y. A New Class of Sesterterpenoids from the Secretion of Ceroplastes
Rubens (Coccidae). J. Chem. Soc., Chem. Commun. 1983, 1182-1183.
(4) (a) Noda, T.; Kitamura, C.; Takahashi, S.; Tagaki, K.; Kashio, T.;
Tanaka, M. Host Selection Behavior of Anicetus Beneficus Ishii Et
Yasumatsu (Hymenoptera : Encyrtidae). 1. Ovipositional Behavior for the
Natural Host Ceroplastes Rubens Maskell (Hemiptera : Coccidae). Appl.
Ent. Zool. 1982, 3, 350-357. (b) Takahashi, S.; Takabayashi, J. Host
Selection Behavior of Anicetus Beneficus Ishii Et Yasumatsu
(Hymenoptera : Encyrtidae). 2. Bioassay of Oviposition Stimulants in
Ceroplastes Rubens Maskell (Hemiptera : Coccidae). Appl. Ent. Zool. 1984,
19, 117-119. (c) Takahashi, S.; Takabayashi, J. Host Selection Behavior of
Anicetus Beneficus Ishii Et Yasumatsu (Hymenoptera : Encyrtidae). 3.
Presence of Ovipositional Stimulants in the Scale Wax of the Genus
Ceroplastes. Appl. Entomol. Zool. 1985, 20, 173-178.
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The final stage of the synthesis was accomplished via cross-
metathesis to obtain the sole oxygenated side chain. The 1,4-
reduction of 24 using NaBH4 and NiCl224 and the Wittig olefination
of the carbonyl group provided the triene 3. While the reaction of
3 with methacrylic acid gave none of the expected 1 when using a
Grubbs II catalyst, reaction with methacrylaldehyde using this
same catalyst in DCM was possible.12b This was followed by in situ
Ag2O oxidation to give 125 in 27% overall yield from 24,
completing the asymmetric total synthesis (see SI for more details).
Cerorubenic acid-III methyl ester (2) was synthesized from 1 with
TMS-diazomethane in 95% yield
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In summary, this work demonstrated the first asymmetric total
synthesis of the highly strained compound cerorubenic acid-III.
Notably, a type II intramolecular [5+2] cycloaddition enabled
efficient and diastereoselective construction of the synthetically-
(5) For related reviews, see: (a) Kuwajima, I.; Tanino, K. Total Synthesis
of Ingenol. Chem. Rev. 2005, 105, 4661-4670. (b) Kim, S.; Winkler, J. D.
Approaches to the Synthesis of Ingenol. Chem. Soc. Rev. 1997, 26, 387-399.
(6) (a) Bredt, J. Steric Hindrance in the Bridge Ring (Bredt’s Rule) and
the Meso-Trans-Position in Condensed Ring Systems of the
Hexamethylenes. Justus Liebigs Ann. Chem. 1924, 437, 1-13. For an
excellent review about natural products with anti-bredt and bridgehead
double bonds, see: (b) Mak, J. Y. W.; Pouwer, R. H.; Williams, C. M.
Natural Products with Anti-Bredt and Bridgehead Double Bonds. Angew.
Chem., Int. Ed. 2014, 53, 13664-13688. Taxol represents the most
prominent example with a bridgehead double bond, see: (c) Nicolaou, K.
C.; Dai, W.-M.; Guy, R. K. Chemistry and Biology of Taxol. Angew. Chem.,
Int. Ed. 1994, 33, 15-44.
(7) For selected recent examples of total synthesis of natural products
with high strain, see: (a) Burns, N. Z.; Krylova, I. N.; Hannoush, R. N.;
Baran, P. S. Scalable Total Synthesis and Biological Evaluation of
Haouamine A and Its Atropisomer. J. Am. Chem. Soc. 2009, 131, 9172-
9173. (b) Matveenko, M.; Liang, G.; Lauterwasser, E. M. W.; Zubiꢀ,
E.;Trauner, D. A Total Synthesis Prompts the Structure Revision of
Haouamine B. J. Am. Chem. Soc. 2012, 134, 9291-9295. (c) Pronin, S. V.;
Shenvi, R. A. Synthesis of Highly Strained Terpenes by Non-Stop Tail-to-
Head Polycyclization. Nat. Chem. 2012, 4, 915-920. (d) Jørgensen, L.;
McKerrall, S. J.; Kuttruff, C. A.; Ungeheuer, F.; Felding, J.; Baran, P. S.
14-Step Synthesis of (+)-Ingenol from (+)-3-Carene. Science 2013, 341,
878-882. (e) Hu, P.; Snyder, S. A. Enantiospecific Total Synthesis of the
Highly Strained (-)-Presilphiperfolan-8-ol via a Pd-Catalyzed Tandem
Cyclization. J. Am. Chem. Soc. 2017, 139, 5007-5010.
(8) (a) Paquette, L. A.; Hormuth, S.; Lovely, C. J. Studies Directed
toward the Total Synthesis of Cerorubenic Acid-III. 4. Exploration of an
Organometallic Approach to Construction of the Eastern Sector. J. Org.
Chem. 1995, 60, 4813-4821. (b) Paquette, L. A.; Deaton, D. N.; Endo, Y.;
Poupart, M.-A. Studies Directed toward the Total Synthesis of Cerorubenic
Acid-III. 3. A Convergent Enantioselective Approach Involving New
Arrangements for the Actuation of Ring-D Cyclization. J. Org. Chem. 1993,
58, 4262-4273. (c) Paquette, L. A.; Lassalle, G. Y.; Lovely, C. J. Studies
Directed toward the Total Synthesis of Cerorubenic Acid-III. 2. Analysis of
the Inability to Realize D-Ring Formation by Means of Extraannular
Robinson Annulation. J. Org. Chem. 1993, 58, 4254-4261. (d) Paquette, L.
A.; Poupart, M.-A. Studies Directed toward the Total Synthesis of
Cerorubenic Acid-III. 1. Expedient Construction of the Tetracyclic Core by
Oxyanionic Sigmatropy. J. Org. Chem. 1993, 58, 4245-4253. (e) Paquette,
L. A.; Poupart, M.-A. Rapid Construction of the Tetracyclic Nucleus of
Cerorubenic Acid-III by Oxyanionic Cope Chemistry. Tetrahedron Lett.
1988, 29, 273-276.
(9) Rigby, J. H.; Ateeq, H. S. Synthetic Studies on Transition-Metal-
Mediated Higher Order Cycloaddition Reactions: Highly Stereoselective
Construction of Substituted Bicyclo[4.4.1]undecane Systems. J. Am. Chem.
Soc. 1990, 112, 6442-6443.
(10) Paquette, L. A.; Dyck, B. Y. Studies Directed toward the Total
Synthesis of Cerorubenic Acid-III. 5. A radical Cyclization Route Leading
to the Methyl Ester of the Natural Isomer. J. Am. Chem. Soc. 1998, 120,
5953-5960.
(11) (a) Cheng, M.-J.; Cao, J.-Q.; Yang, X.-Y.; Zhong, L.-P.; Hu, L.-J.;
Lu, X.; Hou, B.-L.; Hu, Y.-J.; Wang, Y.; You, X.-F.; Wang, L.; Ye, W.-C.;
Li, C.-C. Catalytic Asymmetric Total Syntheses of Myrtucommuacetalone,
Myrtucommuacetalone B, and Callistrilones A, C, D and E. Chem. Sci.
2018, 9, 1488-1495. (b) Chen, B.; Liu, X.; Hu, Y.; Zhang, D.; Deng, L.; Lu,
J.; Min, L.; Ye, W.-C.; Li, C.-C. Enantioselective Total Synthesis of (-)-
Colchicine, (+)-Demecolcinone and Metacolchicine: Determination of the
Absolute Configurations of the Latter Two Alkaloids. Chem. Sci. 2017, 8,
4961-4966. (c) Han, J. C.; Li, F.; Li, C.-C. Collective Synthesis of
Humulanolides Using a Metathesis Cascade Reaction. J. Am. Chem. Soc.
challenging bicyclo[4.4.1] ring system having
a strained
bridgehead anti-Bredt double bond in 1. A unique cascade
reduction of 8-oxabicyclo[3.2.1]octene in 18 was achieved
chemoselectively using sodium naphthalenide, and an unusual
transannular cyclization installed the vinylcyclopropane moiety
with retention of the desired stereochemistry. This approach could
be extended to the asymmetric synthesis of other cerorubenic acids
and their analogs to allow further biological studies. Such work is
ongoing and the results will be reported in due course.
ASSOCIATED CONTENT
Supporting
Information.
Detailed
experimental
and
1
computational procedure, H NMR and 13C NMR spectra, DFT
results as well as X-ray data information are available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
ccli@sustc.edu.cn
# These authors contributed equally to this work.
ORCID
Chuang-Chuang Li: 0000-0003-4344-0498
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This paper is dedicated to Professor Leo Paquette on the occasion
of his 84th birthday. This work was supported by the Natural
Science Foundation of China (Grant nos. 21602100, 21522204 and
21472081) and the Shenzhen Science and Technology Innovation
Committee (Grant nos. JCYJ20170817110130636). We would also
like to thank Prof. N. Burns at Stanford and Prof. T. Maimone at
Berkeley for helpful discussions.
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(20) For synthesis of 8 and 9, see the Supporting Information for details.
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