Total Synthesis of Paralemnolide A

Article abstract of DOI:10.1021/acs.orglett.7b03038

The first total synthesis of tricyclic bisnorsesquiterpene paralemnolide A, isolated from the soft coral Paralemnalia thyrsoides, was achieved. This synthesis features the lactonization of the cyclohexene derivative having a tert-butyl ester via stereosel

Full text of DOI:10.1021/acs.orglett.7b03038

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Total Synthesis of Paralemnolide A
Hideki Abe,*,†,‡ Yuta Ogura,† Toyoharu Kobayashi,† and Hisanaka Ito*,†
†School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan
‡Department of Chemical and Biological Sciences, Faculty of Science, Japan Women’s University, Bunkyo-ku, Tokyo 112-8681, Japan
S
* Supporting Information
ABSTRACT: The first total synthesis of tricyclic bisnorses-
quiterpene paralemnolide A, isolated from the soft coral
Paralemnalia thyrsoides, was achieved. This synthesis features
the lactonization of the cyclohexene derivative having a tert-
butyl ester via stereoselective epoxidation followed by
treatment with a Brønsted acid and construction of the novel
tricyclic skeleton by an intramolecular Reformatsky−Honda reaction.
embers of the soft coral genus Paralemnalia are rich
Scheme 1. Synthetic Scheme for Paralemnolide A, 1
M
sources of biologically active natural products.1 In 2012,
Duh and co-workers reported the isolation of bisnorsesqui-
terpene paralemnolide A 1, from the soft coral Paralemnalia
thyrsoides.1b The unique tricyclic structure of 1, including its
peculiar ring system, was assigned using 2D NMR as shown in
Figure 1. In addition, the absolute configuration of 1 was
Figure 1. Structures of paralemnolide A, 1, and paralemnolin A, 2.
determined as 1R, 2S, 4aR, 5S, 8S, and 8aS using a modified
Mosher method involving the hydroxyl group at the C5
position. The biological activity of paralemnolide A 1 reported
moderate cytotoxicity (ED50 = 3.8 μg/mL) against the P-388
cell line, but no cytotoxic activity against the A549 and HT-29
cell lines, and antiviral activity against human cytomegalovirus.
Norsesquiterpene paralemnolin A 2 containing a chlorine atom
was isolated from the same soft coral in 2005 by Sheu and co-
workers.1h The unusual tricyclic structure of 2 was assigned
using 2D NMR spectroscopic analysis and X-ray crystallo-
graphic analysis as depicted in Figure 1. Its absolute
stereochemistry was established using the Flack parameter for
the X-ray diffraction analysis. Although these small and complex
molecules are challenging targets for total synthesis, no studies
of their total synthesis have been reported.
Interest in the structural features of these novel tricyclic
natural products prompted a synthetic study based on the
intramolecuar Reformatsky−Honda reaction. The present
report describes the stereoselective total synthesis of paral-
emnolide A in 14 steps starting from 2,3-dimethylcyclohexanol.
The strategy for the total synthesis of paralemnolide A 1 is
outlined in Scheme 1. The target natural compound would be
synthesized from tricyclic compound 3 via transformations that
included stereochemistry inversion of the hydroxyl group at the
C5 position. Tricyclic lactone 3 containing the principal
framework of 1 would be constructed through intramolecular
Reformatsky−Honda reaction of the α-bromolactone 4 tether-
ing aldehyde group. Precursor 4 would be derived from lactone
5 by α-bromination of the carbonyl group and oxidative
Received: September 28, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03038
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Organic Letters
Letter
cleavage of the carbon−carbon double bond. The bicyclic
lactone 5 would be obtained through stereoselective
epoxidation of cyclohexene derivative 7 followed by treatment
of epoxide 6 with a Brønsted acid. The cyclohexene derivative 7
would be synthesized from 2,2,3-trisubstituted cyclohexanone 8
via introduction of an alkenyl side chain through Kumada
coupling. The cyclohexene derivative 8 would be easily
prepared from commercially available 2,3-dimethylcyclohexanol
(9) as the starting material.
Kumada coupling of vinyl triflate 11 with butenylmagnesium
bromide in the presence of PdCl2(dppf) in THF under reflux
for 1 h furnished the coupling product 7 in 92% yield.
Stereoselective epoxidation of cyclohexene derivative 7 with m-
chloroperbenzoic acid (mCPBA) gave an inseparable mixture of
epoxide 6 and its diastereomer in a 2:1 ratio as a crude product.
This crude product was treated immediately with a Brønsted
acid, 1 M hydrochloric acid, to afford the bicyclic lactone 5 in
63% yield in two steps. Related configurations of bicyclic
lactone 5 were confirmed using X-ray crystallography of the p-
bromobenzoate 12,6 derived from 5 by esterification with p-
bromobenzoyl chloride. The stereochemical configuration of all
substituted groups of the bicyclic lactone, two types of methyl
groups, the butenyl side chain, and the hydroxyl group was syn,
which indicates that epoxidation of cyclohexene derivative 7
with mCPBA proceeded from the opposite side of the tert-
butoxycarbonylmethyl group, which is the most bulky group of
7, and that lactonization of epoxide 6 under acidic conditions
involved 5-exo-cyclization of the ester carbonyl group with the
more cationic carbon of the epoxide portion that was activated
by protonation.
This synthetic study began with the preparation of
cyclohexene derivative 7, the precursor for epoxidation, from
2,3-dimethylcyclohexanol, as shown in Scheme 2. Oxidation of
Scheme 2. Stereoselective Synthesis of Bicyclic Lactone 5
After synthesis of bicyclic lactone 5, the tricyclic skeleton of
the target molecule was constructed, as shown in Scheme 3.
Scheme 3. Stereoselective Synthesis of Tricyclic Compound
16
2,3-dimethylcyclohexanol (9) with PCC gave 2,3-dimethyl-
cylcohexanone (10) in high yield.2 After treatment of 2,3-
dimethylcyclohexanone (10) with potassium hydride and
triethylborane in THF at 60 °C according to a procedure by
Negishi,3 alkylation of the thermodynamically more stable
boron enolate with tert-butyl bromoacetate afforded the desired
product 8 in 52% yield (dr = 10:1). Introduction of a butenyl
side chain at the C1 position of 8 was realized by a metal-
catalyzed Kumada coupling reaction4 of vinyl triflate 11
prepared from ketone 8, with butenylmagnesium bromide.
Enolization of ketone 8 with LHMDS, followed by trapping of
the enolate anion with N-phenylbis(trifluoromethanesulfone)-
amide yielded the corresponding vinyl triflate 11. After the
screening of metal catalysts for the Kumada coupling reaction,
PdCl2(dppf)5 was found suitable for this reaction. Thus,
Upon protection of the hydroxyl group of 5 with TBS, many
different reaction conditions for α-bromination of 13 were
investigated, including different bases (LDA and LHMDS) and
brominating agents (NBS, CBr4, and N-phenyltrimethyl-
ammonium tribromide). The combination of LHMDS and
CBr4 in THF at −78 °C gave the best results to afford 14a and
14b in 62% yield in a 1.7:1 ratio.7 The stereochemistry of the
bromolactone 14b was confirmed by X-ray crystallographic
analysis.8 Ozonolysis of the mixture of bromides 14a and 14b
produced a mixture of aldehydes 15a and 15b (Reformatsky−
Honda reaction precursors) in 76% yield. To construct the rigid
tricyclic framework,9 which was the key feature of this project,
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Letter
an intramolecular Reformatsky−Honda reaction10 using
Wilkinson’s catalyst and diethylzinc of the mixture of α-
bromolactones 15a and 15b produced the cyclized product 16
in moderate yield as the sole product. The relative
configuration of the tricyclic compound 16 was confirmed
from X-ray crystallographic analysis of its p-bromobenzoate
derivative 1711 obtained by esterification of 16.
The intramolecular Reformatsky−Honda reaction of 15
proceeded via the six-membered ring transition state of zinc
enolate A10a as shown in Scheme 4 to afford the α-hydroxyl
cyclized product 16 as a single isomer.
spectral data for synthetic sample 1 were completely identical
with those for natural product 1.
In conclusion, the first total synthesis of tricyclic
bisnorsesquiterpene paralemnolide A was accomplished. This
synthesis features the formation of a lactone ring via
epoxidation followed by acid treatment of the resulting epoxide
tether tert-butyl ester portion, and construction of the novel
tricyclic skeleton by intramolecuar Reformatsky−Honda
reaction. This methodology can be extended to the synthesis
of the related natural product, paralemnolin A. Related
investigations are now underway.
ASSOCIATED CONTENT
* Supporting Information
Scheme 4. Possible Mechanism of the Reformatsky−Honda
Reaction of 15
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03038.
Experimental procedures, spectral data (PDF)
Crystallographic data for compound 12 (CIF)
Crystallographic data for compound 14b (CIF)
Crystallographic data for compound 17 (CIF)
Upon obtaining tricyclic compound 16, the final stage of the
synthesis was performed. After attaching an acetyl group to the
hydroxyl group of 16, cleavage of the TBS group of the
resulting 18 with TBAF gave alcohol 19 in 81% yield (Scheme
5). Inversion of the stereochemical configuration at the C1
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: abehi@fc.jwu.ac.jp (H.A.).
*E-mail: itohisa@toyaku.ac.jp (H.I.).
ORCID
Scheme 5. Total Synthesis of 1
Hideki Abe: 0000-0002-3608-7123
Toyoharu Kobayashi: 0000-0002-7362-1129
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Platform for Drug Discovery,
Informatics, and Structural Life Science from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
REFERENCES
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D
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