Asymmetric Total Synthesis of Hispidanin A

Article abstract of DOI:10.1002/anie.201700958

Asymmetric total synthesis of the dimeric diterpenoid hispidanin A was accomplished by non-catalytic Diels–Alder cycloaddition at room temperature. The synthesis relies on iron-catalyzed coupling to construct a Z-configured trisubstituted alkene, an iron-catalyzed radical cascade to generate a labdane-type diene, and both Yamamoto cationic polyene cyclization and palladium-catalyzed Stille coupling to generate a totarane-type dienophile.

Full text of DOI:10.1002/anie.201700958

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International Edition: DOI: 10.1002/anie.201700958
German Edition: DOI: 10.1002/ange.201700958
Total Synthesis Hot Paper
Asymmetric Total Synthesis of Hispidanin A
Heping Deng, Wei Cao, Rong Liu, Yanhui Zhang, and Bo Liu*
Abstract: Asymmetric total synthesis of the dimeric diterpe-
noid hispidanin A was accomplished by non-catalytic Diels–
Alder cycloaddition at room temperature. The synthesis relies
on iron-catalyzed coupling to construct a Z-configured
trisubstituted alkene, an iron-catalyzed radical cascade to
generate a labdane-type diene, and both Yamamoto cationic
polyene cyclization and palladium-catalyzed Stille coupling to
generate a totarane-type dienophile.
I
n 2014, the Jiang group isolated four dimeric diterpernoids
named hispidanins A–D (1–4) from the rhizomes of Isodon
[1]
hispida, a medicinal plant in southwest China. Hispidanins
are toxic to several tumor cell lines, including SGC7901,
SMMC7721, and K562, with IC50 values ranging from 9.8 to
1
3.7 mM. The corresponding labdane diterpenoids 5 and 6
Figure 1. Structures of compounds 1–7 and their biogenetic relation-
ships.
[2]
were recently isolated from Isodon yuennanensis, and their
structures inspired the biogenetic hypothesis that hispidanins
arise from Diels–Alder cycloaddition between a labdane-type
[1]
diene (5/6) and a totarane-type dienophile (7). The complex
structure and intriguing bioactivity of hispidanins led us to
attempt their synthesis. Herein we report our progress on
asymmetric total synthesis of hispidanin A (1) as well as its
natural precursor 5.
Taking inspiration from the biosynthetic hypothesis
proposed in Figure 1, we reasoned that hispidanin A could
be retrosynthetically generated from 8 by reduction of ketone
and acetylation; 8 can be synthesized by Diels–Alder cyclo-
addition of 5 and 9 (Scheme 1). The totarane-type 9 is an
analogue of 7 but with greater dienophilicity because of its
more electron-deficient alkene. Although we recently accom-
[3]
plished the semi-synthesis of 5 from (3aR)-(+)-sclareolide,
a total synthesis was highly anticipated since it could be
extended to numerous bicyclic, tricyclic, and tetracyclic
[
4]
diterpenoids functionalized at C involving ent-kaurane
2
0
[
5]
and abietane compounds with intriguing bioactivities such
[6]
as carnosol and carnosic acid. Therefore we sought to
synthesize 5 via nucleophilic attack of a methyl anion on the
ketone 10, accessible from the diene surrogate 11 and 12.
Compound 12 could be elaborated from chiral 13, which in
turn could be generated with a trans-fused decalin skeleton by
Scheme 1. Retrosynthetic analysis of hispidanin A.
catalytic asymmetric radical cascade cyclization of polyene
[
7]
14. Alternatively, chiral 13 could be generated in a sub-
strate-controlling fashion via radical polycyclization of 15 and
subsequent dehydroxylation. We opted for this latter
approach to 13 because of the challenge of achieving
[
*] H. Deng, W. Cao, R. Liu, Y. Zhang, Prof. Dr. B. Liu
Key Laboratory of Green Chemistry & Technology of the Ministry of
Education, College of Chemistry, Sichuan University
[
8]
a catalytic asymmetric radical cascade with 14. Achieving
3 from 14 or 15 through other mechanisms might be
29 Wangjiang Rd., Chengdu, Sichuan 610064 (China)
1
E-mail: chembliu@scu.edu.cn
inefficient owing to difficulty in initiation of an anionic
polycyclization and instability of a carbocation adjacent to an
ester in cationic polycyclization process. Therefore we
explored the synthetic efficacy of a radical cascade with 15,
which could be assembled from the easily available starting
materials 16–19. The lactone of dienophile 9 could be
installed through transition metal-catalyzed cross-coupling
Prof. Dr. B. Liu
State Key Laboratory of Natural Medicines
China Pharmaceutical University
24 Tong Jia Xiang, Nanjing 210009 (China)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201700958.
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of 20 and 21. Compound 21 could be generated by routine
functionalization of 22, which could be prepared by enantio-
conformation. Although the possibility of direct transforma-
tion from 27 to 29 through a concerted mechanism cannot be
completely ruled out, we reasoned that neither SOMO–
LUMO nor SOMO–HOMO interactions would support fast
radical trapping because of the electron-deficient character of
both the tertiary radical and the alkene as radical acceptor in
[9]
selective cationic polyene cyclization.
Biomimetic polyene cyclization to trans-decalin by a cat-
[
10]
ionic cascade has been known for decades, and asymmetric
[
9]
versions have been developed. Although radical cascade
[
15]
cyclization of normal polyene toward trans-decalin has been
28. In this way, 28 should be a relatively stable intermediate,
ensuring diastereoselectivity of the final radical cyclization to
afford 29 with trans-decalin architecture either as a radical or
as an anion. This anion could be generated by reducing the
radical in the presence of [FeH] species in the system.
Quenching 29 with oxygen or silane would deliver, respec-
tively, 13a or 13b with a cis-fused 5/6 bicycle motif. Using
a five-membered unsaturated lactone could minimize forma-
tion of a trans-fused 5/6 bicycle, which is less favorable than
[10c]
achieved through single-electron transfer
and conven-
[
11]
tional direct radical generation, it has rarely been achieved
for polyene substrates bearing electron-withdrawing groups,
which would be useful for generating diterpenoid- or
triterpenoid-like molecules with angular esters or formyl
groups.
Along these lines, the Zoretic and the MacMillan groups
reported elegant radical polycyclizations of unsaturated
nitriles leading to 6/6/6/6 trans-fused polycycles (Sche-
[
16]
the cis-fused bicycle,
making this radical cascade more
[
12]
me 2A). This approach of radical polycyclization may not
efficient.
We initiated our total synthesis by conducting epoxide-
opening of 30, an enantiomeric antipode of a known com-
[
17]
pound, with alkynyl lithium. Subsequent silyl protection of
the resulting secondary alcohol afforded 31 in 47% overall
yield; furthermore, 32 was produced during workup and
purification in 5% overall yield (Scheme 3). To circumvent
facile formation of a five-membered lactone under other
conditions such as catalysis with HgCl , HCl, AuCl , and
2
3
[18]
Sc(OTf)3,
we developed a mild hydration method to
transform 31 into 32 using 0.5 mol% of Au(PPh )Cl without
3
silver salt, which is a rare case of gold catalysis without
[19]
promotion by silver.
A formyl group was introduced
proximal to the ester in 32, and the intermediate was
converted into enol tosylate 33 in the Z-configuration using
[20]
the procedure developed by Tanabe et al. In the presence
of iron(III) chloride catalyst, 33 was coupled with the
Grignard reagent 34 to afford 35 with retention of the
Scheme 2. Radical cascade transformation of polyene into a 6/6
bicycle.
provide adequate diastereoselectivity to deliver trans-fused
polycycles if the starting material is an unsaturated ester.
Indeed, the only example of such polycyclization, reported by
[13]
the Pattenden group,
showed that the reaction with 25
delivered only cis-isomer 26 as the isolable product. This may
reflect that esters show more severe steric repulsion during
cyclization than unsaturated nitrile. Unfortunately, the
cyclized intermediate with an angular ester is more attractive
than the corresponding intermediate with angular nitrile,
because it can be transformed to other functionalities in
a more straightforward way. This indicated the challenge to
engineer appropriate stereoselectivity into our devised rad-
ical cascade involving an unsaturated ester.
Inspired by the recently published metal-catalyzed reduc-
[14]
tive radical addition of alkene, we devised a radical cascade
triggered by hydrogen atom transfer (HAT) (Scheme 2B).
The gem-disubstituted terminal alkene in 15, which features
the least steric hindrance and greatest electronic density,
would generate a tertiary radical (27) in the presence of metal
catalyst and silane. After intramolecular capture of the
radical, 28 would form via a transition state in a chair
Scheme 3. Synthesis of 5.
2
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[
20]
double-bond configuration. Our attempts to construct the
trisubstituted alkene in 35 directly by the Wadsworth–
Horner–Emmons reaction afforded an inseparable 1:1 Z/E
with MOMCl and Stille cross-coupling with the tin reagent 44
afforded 45. Final deprotection and base-promoted lactoni-
zation produced the dienophile 9, which is labile and was thus
used directly in the next step without purification.
[
21]
mixture. Oxidative elaboration of furan followed by acid-
mediated rearrangement delivered 36. We then attempted
to set up a radical cascade with 36 using different metal
catalysts and phenylsilane as hydrogen source. No cycliza-
tion product was detected with Co(acac) or Mn(dpm) as the
catalyst in the presence of oxygen; this likely reflects the
failure of radical initiation at the gem-disubstituted alkene.
To our delight, HAT-triggered radical cascade polycyclization
in the Fe-catalyzed conditions and subsequent silyl depro-
tection generated the tricyclic compound 37 with proper
stereochemistry in 45% isolated yield over two steps. It also
generated an inseparable mixture of another three diastereo-
mers in 19% combined yield over two steps. This cascade
simultaneously afforded two carbocycles and four contiguous
stereogenic centers. Then the secondary alcohol in 37 was
[
22]
Diels–Alder cycloaddition between 5 and 9 produced 8
and its diastereomer as endo-cycloadducts in 81% combined
yield in a 10:1 ratio. Although Diels–Alder cycloaddition has
been well applied in organic synthesis and natural product
[
23]
2
3
[
32]
synthesis, this cycloaddition proceeded surprisingly well at
room temperature. Such a spontaneous process is uncom-
[24]
[
33]
mon, suggesting that this reaction may participate in the
real biosynthesis of hispidanin A through a nonenzymatic
pathway, even though the biosynthetic hypothesis from the
[
25]
[
1]
Jiang group does not involve cycloaddition between 5 and 9.
Diastereoselective reduction of ketone and then acid-pro-
moted acetylation completed the total synthesis of hispida-
nin A (1), for which characterization data matched those of
[
26]
[1]
a natural sample.
[
27]
removed by a radical process, affording 38. Partial reduc-
tion of the lactone and subsequent elimination generated 39.
Oxidative cleavage of the double bond and base-promoted
elimination delivered the enone 40. Michael addition of
compound 11 and pyrolysis of the resulting intermediate
released one molecule of SO2 and generated 41. Finally,
nucleophilic addition of methyl lithium to the ketone,
followed by lactone formation, afforded the diene 5.
In conclusion, we have accomplished the asymmetric total
synthesis of the dimeric diterpenoid hispidanin A. The syn-
thesis involves 1) stereoselective construction of Z-alkene in
35 via Tanabeꢀs iron catalysis; 2) HAT-triggered and iron-
catalyzed radical polyene cyclization to generate the trans-
decalin architecture of the natural diterpenoid 5; 3) Yama-
motoꢀs cationic polyene cyclization to construct the basic
skeleton of the dienophile fragment; 4) site-selective bromi-
nation with TBCO and Stille cross-coupling to afford the
dienophile 9; and 5) a final step of bioinspired Diels–Alder
connection of the two diterpenoid monomers. The radical
polycyclization involving electron-deficient alkenes described
herein can likely be extended to total synthesis of other
diterpenoids functionalized at position C20.
We then began synthesizing the dienophile 9 from
[28]
compound 22 (Scheme 4), which was prepared in 90% ee
using Yamamotoꢀs enantioselective polyprenoid cycliza-
[
29]
[30]
tion.
Benzylic oxidation of 22
and basic hydrolysis
afforded 42. Site-selective bromination with 2,4,4,6-tetrabro-
mocyclohexa-2,5-dienone (TBCO) could be smoothly ach-
[31]
ieved to afford 43, once the reaction was timely quenched
to prevent formation of dibrominated product and other
byproducts. Other brominating reagents, such as NBS, Acknowledgements
bromine and TBAB, led to either complex mixture or an
unfavorable product brominated at the para-position of
We acknowledge financial support from the NSFC (21672153
and 21290180) and the Open Fund of State Key Laboratory of
Natural Medicines in China Pharmaceutical University
[
26b]
ketone on phenyl ring.
Subsequent protection of phenol
(SKLNMKF201601).
Conflict of interest
The authors declare no conflict of interest.
Keywords: diterpenoids · labdane · radical cascade ·
total synthesis · totarane
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Final Article published: && &&, &&&&
4
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Communications
Total Synthesis
H. Deng, W. Cao, R. Liu, Y. Zhang,
B. Liu*
&&&& — &&&&
Asymmetric Total Synthesis of
Hispidanin A
Radical is radical: Asymmetric total syn-
thesis of a dimeric diterpenoid, hispida-
nin A, has been accomplished through
spontaneous [4+2] cycloaddition without
catalysis at room temperature. Construc-
tion of the diene fragment features
a designed radical polyene cyclization
triggered by metal-catalyzed hydrogen
atom transfer, while subsequent asym-
metric cationic polyene cyclization gen-
erates the dienophile fragment.
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
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www.angewandte.org
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