Total Synthesis of the Diterpenoid (+)-Harringtonolide

Article abstract of DOI:10.1002/anie.201605879

Described herein is the first asymmetric total synthesis of (+)-harringtonolide, a natural diterpenoid with an unusual tropone imbedded in a cagelike framework. The key transformations include an intramolecular Diels–Alder reaction and a rhodium-complex-c

Full text of DOI:10.1002/anie.201605879

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201605879
German Edition: DOI: 10.1002/ange.201605879
Natural Product Synthesis
Total Synthesis of the Diterpenoid (+)-Harringtonolide
Hai-Jun Zhang+, Lin Hu+, Zhiqiang Ma, Ruining Li, Zhen Zhang, Cheng Tao, Bin Cheng,
Yun Li, Huifei Wang, and Hongbin Zhai*
In memory of Nanjun Sun and Puzhu Cong
Abstract: Described herein is the first asymmetric total
synthesis of (+)-harringtonolide, a natural diterpenoid with
an unusual tropone imbedded in a cagelike framework. The
key transformations include an intramolecular Diels–Alder
reaction and a rhodium-complex-catalyzed intramolecular
[3+2] cycloaddition to install the tetracyclic core as well as
a highly efficient tropone formation.
centers, a bridged lactone, and a tetrahydrofuran ring.
(+)-Harringtonolide (1) was shown to inhibit the growth of
tobacco and beans and to be antineoplastically and antivirally
active. In addition, it was found to have potent cytotoxic
activities with an IC50 = 43 nm for KB tumor cells and to cause
necrosis under certain conditions.[2] In contrast, 2 was
biologically inactive,[2,3] thus suggesting that the THF ring in
1 might play a decisive role in its biological activity. The
chemical relationship between the two natural products was
investigated, as exemplified by a biomimetic transformation
of 2 into 1 through an oxidation process promoted by lead
tetraacetate, though the yield was not given in the literature.[4]
Owing to their intriguing architecture and outstanding
biological activities, 1 and its derivatives have attracted
considerable attention from the synthetic community. Many
synthetic efforts have been devoted to 1 since its isolation.[5–8]
In 1998, Manderꢀs group demonstrated a groundbreaking
total synthesis of (ꢀ)-hainanolidol, which constituted
a formal synthesis of 1.[6g] The elegant strategy featured
arene cyclopropanation and a subsequent ring expansion for
the construction of the tropone moiety, though the formation
of the THF ring of the natural product at an early stage
proved to be unfavorable.[6d–f] More recently, Tang et al.
reported an efficient total synthesis of 1 through an intra-
molecular oxidopyrylium-based [5+2] cycloaddition to
assemble the tetracyclic carbon skeleton.[9] Nevertheless, the
asymmetric synthesis of this molecule has not been accom-
plished to date. As part of our long-term efforts on stream-
lining efficient synthetic strategies for complex natural
products, we present herein the first enantioselective total
synthesis of (+)-harringtonolide (1).
The retrosynthetic analysis is outlined in Scheme 1. We
envisioned that the construction of the tropone, the lactone,
and the ether ring moieties in 1 could be achieved by
a sequence of late-stage functionalizations from the oxapen-
tacyclic derivative 3. In a key synthetic step, 3 could be
constructed through an intramolecular [3+2] cycloaddition of
the intermediate 4, generated in situ from the diazo inter-
mediate 5 and a rhodium(II) catalyst.[10] The diazo 5, with
correct configuration of the stereochemical centers and all
associated functional groups, may be obtained from the
compound 6, having 6-6 cis-fused rings, which in turn could be
derived from the ester 7 through an intramolecular Diels–
Alder reaction. Finally, 7 could be disconnected into the
known compound 8.[11]
T
he structurally unique diterpenoid (+)-harringtonolide (1;
Figure 1) was first isolated from the seeds of Cephalataxus
harringtonia by Buta and co-workers in 1978,[1a] and subse-
quently from the bark of the Chinese species Cephalotaxus
hainanensis by Sun et al. in 1979, yet under the name of
hainanolide.[1b] Hainanolidol (2), the structural congener of
hainanolide was also isolated.[1b] The cagelike diterpenoid
1 contains an unusual tropone ring, a compact cis-fused
tricyclic ring system carrying seven contiguous stereogenic
Figure 1. The cephalotaxus norditerpenes 1 and 2.
[*] H.-J. Zhang,[+] Z. Zhang, C. Tao, Dr. B. Cheng, Dr. Y. Li,
Prof. Dr. H. Zhai
The State Key Laboratory of Applied Organic Chemistry
College of Chemistry and Chemical Engineering
Lanzhou University
222 Tianshui South Road, Lanzhou 730000 (China)
E-mail: zhaihb@pkusz.edu.cn
Dr. H. Wang, Prof. Dr. H. Zhai
Guangdong Provincial Key Laboratory of Nano-Micro Materials
Research, Key Laboratory of Chemical Genomics
Shenzhen Graduate School of Peking University
Shenzhen 518055 (China)
Dr. L. Hu,[+] Dr. Z. Ma, Dr. R. Li, Prof. Dr. H. Zhai
CAS-Key Laboratory of Synthetic Chemistry of Natural Substances
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences, Shanghai 200032 (China)
Prof. Dr. H. Zhai
Collaborative Innovation Center of Chemical Science and Engineer-
ing, Tianjin, Tianjin 300071 (China)
[+] These authors contributed equally.
As delineated in Scheme 2, our synthesis began with the
enone 9, a known compound accessible from 3-methoxyben-
zoic acid in three steps (see the Supporting Information).
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201605879.
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sorbic acid afforded ester 7. To our delight, the key intra-
molecular Diels–Alder reaction and the subsequent sponta-
=
neous C C bond shift proceeded smoothly at 1808C in the
presence of the polymerization inhibitor BHT to afford
a diastereomeric mixture of 10 and 10’ in a 2.5:1 ratio.[12]
However, the major endo compound 10 in the mixture cannot
be separated by either column chromatography or recrystal-
lization at this stage. Thus, 6 was obtained by treatment of the
diastereomers with LDA and HMPA at ꢁ788C followed by
quenching with AcOH.[13] Selective partial reduction of the
lactone moiety in 6 with Dibal-H afforded a mixture of
hemiacetals (11) in 97% yield. The chemoselectivity for this
step presumably arose from the sterically hindered environ-
ment of the methoxycarbonyl functionality. After extensive
screening of the nucleophilic reagents, it was found that
treatment of the above mixture with 1-propynylmagnesium
bromide in refluxing THF furnished the propargyl alcohol 12
as a 1:1 diastereomeric mixture. Efforts on optimizing the
diastereomeric ratio proved unsuccessful. The hydroxy group
at the propargyl position was then protected selectively and
the two epimers, 14 and 14’, were readily separated after
oxidation of the unprotected hydroxy group. The configura-
tion of the propargyl alcohol in 14 was in agreement with that
of the natural product by the X-ray crystallographic analyses
of several advanced intermediates (in the racemic form, see
the Supporting Information for details). Although it was
difficult to convert 14’ into 14 in this case, the former (14’)
could be transformed into intermediate 19 in a similar way.
Next, the bicycle 14 was employed to investigate the
intramolecular [3+2] cycloaddition (i.e., 5!3, Scheme 3).
Preliminary studies[14,15] suggested that the carbon–carbon
double bond in 14 should be converted prior to the cyclo-
addition into a chlorohydrin moiety, and could be used to
construct the lactone and THF rings present in the target
molecule at a late stage. Thus, 14 was treated with (CONCl)3
(trichloroisocyanuric acid)[16] to afford the chlorohydrin 15
stereo- and regioselectively. The Cl+ species generated in situ
approached the carbon–carbon double bond from the convex
face of the 6-6 cis-fused rings, and the reactive intermediate
thus formed, having a three-membered ring, was subse-
quently opened up by nucleophilic attack of water from the
a-face.
Scheme 1. Retrosynthetic analysis of (+)-harringtonolide (1). PG=pro-
tecting group.
Protection of the hydroxy group in 15 by TBS led to 16.
The side-chain in acyldiazo 5 was constructed through
a reaction sequence including alkylation of 16, saponification
of 17, and activation of 18 followed by reaction with freshly
prepared CH2N2.[10] It is worth mentioning that only about
half of 17 underwent the saponification to yield 18, and the
reaction conditions need to be controlled rigorously, other-
wise isomerization of the 6-6 cis-fused rings would occur and
the number of byproducts would increase substantially.[17] As
the stereogenic centers in 5 were in agreement with the
natural product, the following key intramolecular [3+2]
cycloaddition was carried out to assemble the tetracyclic
carbon backbone of the natural product. According to the
procedure reported by Schmalz and co-workers,[10] the [Rh2-
(OAc)4]-catalyzed [3+2] cycloaddition took place smoothly in
refluxing toluene, thus furnishing the oxapentacycle 3 in 81%
yield. The structure was partially confirmed by an X-ray
Scheme 2. Synthesis of the intermediates 14 and 14’. BHT=2,6-di-tert-
butyl-p-cresol, DCC=dicyclohexylcarbodiimide, DCM=dichlorome-
thane, Dibal-H=diisobutylaluminum hydride, DMAP=4-(N,N-dime-
thylamino)pyridine, DMP=Dess–Martin periodinane, HMPA=hexa-
methylphosphoramide, LDA=lithium diisopropylamide, “RuII”=[RuCl-
(p-cymene){(S,S)-Ts-DPEN}], TBS=tert-butyldimethylsilyl, THF=tetra-
hydrofuran.
Asymmetric reduction of 9 was achieved by a hydride transfer
hydrogenation catalyzed by [RuCl(p-cymene){(S,S)-Ts-
DPEN}], thus providing the corresponding allylic alcohol 8
in up to 94% ee and 97% yield.[11] Condensation of 8 and
2
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Scheme 4. Completion of the total synthesis of (+)-harringtonolide
(1).
(adjacent to the tertiary carbenium at C5), and dehydration
involving the hydroxy group at C2 would generate the
tropone moiety. In our case, treatment of 22 with Me2AlCl
led to a diene compound.[19] We speculated that preferential
ꢁ
elimination of C6 H would eventually favor the tropone
formation. Therefore, the carbonyl group within the seven-
membered ring had better be converted into an enol ether to
ꢁ
further activate the C6 H bond. Based upon the above
analysis, exposure of 22 to TBSOTf and Et3N furnished the
silyl enol ether 23, which was used directly in the next step
without further purification. Gratifyingly, the tropone unit
was smoothly constructed and the natural product (+)-har-
ringtonolide (1) was obtained as the major product upon
treatment of the unpurified 23 with Me2AlCl.[20] The spectro-
Scheme 3. Construction of the oxapentacycle 19 from 14. TBAF=tetra-
n-butylammonium fluoride, Tf=trifluoromethanesulfonyl.
crystallographic analysis of (ꢀ)-3.[21] Desilylation of 3 with
TBAF generated the diol 19. Similar to bicycle 14, the epimer
14’ was also utilized to construct 19 (see the Supporting
Information for more details).
scopic data (HRMS; H and 13C NMR) were fully consistent
1
with those reported for the natural product.[1,9]
In summary, we have developed a novel and concise
strategy for the enantioselective total synthesis of (+)-har-
ringtonolide (1) in 20 steps from the known alcohol 8.[11] The
key transformations include an asymmetric transfer hydro-
genation, an intramolecular Diels–Alder reaction, selective
functionalization of the olefin in the presence of an acetylenic
group, a rhodium-complex-catalyzed intramolecular [3+2]
cycloaddition, and formation of the tropone via a silyl enol
ether.
With 19 secured, the remaining tasks for the total
synthesis of 1 were to install the THF ring, the lactone, and
the tropone moiety (Scheme 4). The diol 19 was subjected to
a NaH-mediated SN2 reaction, thus furnishing the desired
cyclic ether 20 as the major product.[18] To close the lactone
ring, the configuration of the remaining hydroxyl group in 20
had to be inverted. Mitsunobu reaction resulted in the
recovery of the starting material, possibly because of the
steric hindrance present in the molecule. Thus, a redox
protocol was employed instead. The compound 20 was
oxidized to the dione 21, reduction and subsequent lactoni-
zation of which was realized in a one-pot fashion. Oxidation
of the remaining hydroxy group led to the compound 22, an
intermediate possessing the desired skeleton of the natural
product.
Acknowledgments
We thank the NSFC (21272105; 21290183), Shenzhen
Science
and
Technology
Innovation
Committee
(JCYJ20150529153646078), Program for Changjiang Scholars
and Innovative Research Team in University (PCSIRT:
IRT_15R28), and “111” Program of MOE for financial
support. We are grateful to Prof. Fayang Qiu of GIBH for
enlightening discussions.
The endgame for the total synthesis of 1 was the formation
of the tropone unit. According to the literature procedure,[10c]
ꢁ
cleavage of the C5 O bond, elimination of the proton at C6
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Keywords: asymmetric synthesis · cycloaddition ·
natural products · terpenoids · total synthesis
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Received: June 17, 2016
Published online: && &&, &&&&
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Communications
Natural Product Synthesis
H.-J. Zhang, L. Hu, Z. Ma, R. Li, Z. Zhang,
C. Tao, B. Cheng, Y. Li, H. Wang,
H. Zhai*
&&&& — &&&&
Total Synthesis of the Diterpenoid
(+)-Harringtonolide
Ever more rings: The first asymmetric
total synthesis of the diterpenoid
(+)-harringtonolide is described. The key
features include an asymmetric transfer
hydrogenation, an intramolecular Diels–
Alder reaction, chemoselective function-
alization of an olefin in the presence of an
acetylenic group, a rhodium-catalyzed
intramolecular [3+2] cycloaddition, and
efficient formation of the tropone.
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5
These are not the final page numbers!