Synthesis of 12-epi-Protopanaxadiol and Formal Synthesis of Ginsenoside Chikusetsusaponin-LT8

Article abstract of DOI:10.1002/ejoc.201901031

In the context of the total synthesis of protopanaxadiol, two strategies were explored. One strategy from an optically active trienic epoxide, possessing a 5-membered ring, prepared from (S)-epoxy-limonene and (S)-epoxyfarnesol, which was submitted to Ti-(III)-mediated radical cascade to afford an original tetracyclic structure resulting from a 6-endo-trig 6-endo-trig 8-endo-trig process. A second strategy, starting from a Wieland-Miescher-type ketone, using a “ring-by-ring” synthesis allowed the synthesis of 12-epi-protopanaxadiol. In this latter strategy, an efficient sequence of reactions to install the two vicinal C8–C14 quaternary centers involves: i) a Barbier type reaction; ii) an oxidative allylic transposition and iii) a nickel-catalyzed addition of trimethylaluminium. By using this second strategy, 20-hydroxydammar-24-ene-3,12-dione was synthesized which represents a formal synthesis of chikusetsusaponin-LT₈, isolated from Panax japonicus.

Full text of DOI:10.1002/ejoc.201901031

A Journal of
Accepted Article
Title: Synthesis of 12-epi-protopanaxadiol and formal synthesis of
ginsenoside chikusetsusaponin-LT8
Authors: Laurent Evanno, Damien Belotti, Edmond Toromanoff, and
Janine Cossy
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10.1002/ejoc.201901031
European Journal of Organic Chemistry
FULL PAPER
Synthesis of 12-epi-protopanaxadiol and formal synthesis of
ginsenoside chikusetsusaponin-LT8
Laurent Evanno,[a],[b] Damien Belotti,[a] Edmond Toromanoff[a] and Janine Cossy*[a]
Abstract: In the context of the total synthesis of protopanaxadiol, two
strategies were explored. One strategy from an optically active trienic
epoxide, possessing a 5-membered ring, prepared from (S)-epoxy-
limonene and (S)-epoxyfarnesol, which was submitted to
Ti-(III)-mediated radical cascade to afford an original tetracyclic
structure resulting from a 6-endo-trig 6-endo-trig 8-endo-trig process.
A second strategy, starting from a Wieland-Miescher-type ketone,
using a “ring-by-ring” synthesis allowed the synthesis of 12-epi-
protopanaxadiol. In this latter strategy, an efficient sequence of
reactions to install the two vicinal C8-C14 quaternary centers involves:
i) a Barbier type reaction; ii) an oxidative allylic transposition and iii) a
nickel-catalyzed addition of trimethylaluminium. By using this second
strategy, 20-hydroxydammar-24-ene-3,12-dione was synthesized
which represents a formal synthesis of chikusetsusaponin-LT8,
isolated from Panax japonicus.
have realized the synthesis of dammarenediol II 5 using a bio-
inspired cascade cyclization (17 and 21 steps respectively).[8] To
chemically access to protopanaxadiol 2, strategies allowing the
construction of the carbon skeleton, the introduction of the
hydroxyl at C12 as well as methods for the highly challenging
control of two adjacent quaternary centers, have to be
developed.[9] In this context, two strategies were evaluated: i) a
radical bio-inspired strategy designed for a one-step construction
of the tetracyclic-core; ii) an efficient “ring-by-ring” construction of
the complete framework as well as an efficient control of the C8-
C14 adjacent quaternary centers.
Introduction
Ginsenosides constitute a family of triterpene glycosides isolated
from different species of ginseng (Panax spp.) (Scheme 1).[1]
Specifically Panax ginseng is used in Asian traditional medicine
as a stimulant, and an anti-aging supplement. Regularly, reviews
are summarizing the plethora of pharmacological properties of
ginsenosides[2] and, among the properties, positive effects on the
central nervous system against stress, tiredness, and for the
improvement of cognitive performance were reported.[2]
Ginsenosides, (for example 1) are constituted by a (20S)-
dammarane-type aglycone [protopanaxadiol 2 or protopanaxatriol
3], biosynthetically originating from a cationic cascade cyclization
of (S)-2,3-epoxy-squalene
4
in
a
chair-chair-chair-boat
arrangement,[3] followed by further hydroxylations at C12 and
C6.[4] The structure of the aglycone was solved more than 60
years ago, and since 1962,[5] more than 16 000 articles are related
to ginsenosides.[6] Despite their importance for the scientific
community, ginsenosides are only available by extraction from
Scheme 1. Structure and biosynthesis of protopanaxadiol and ginsenosides.
plants and just
a few synthetic approaches toward the
dammarane-core are described. In the 1970’s, Tanaka et al.
reported a semi-synthetic route from hopanoids triterpenes,[7] and
in the late 1990’s, Corey et al. and Bartlett et al. independently
Results and Discussion
To construct the tetracyclic core of 2, a bio-inspired cascade
cyclization of 12 was considered.[10] Polyene 12 containing a D-
ring precursor substituted by an (S)-epoxy-farnesyl side chain
was elaborated in a straightforward sequence from (S)-epoxy-
limonene 6 (Scheme 2). The 6-membered ring of 6 was
contracted to a 5-membered ring (compound 8)[11] and then
converted in two steps into sulfone 9. The sequence was
completed by the alkylation of sulfone 9 by (S)-10,11-epoxy
farnesyl bromide 11, and 12 was produced in 68% yield (from
10).[12] To access the tetracyclic compound 13, epoxy-triene 12
was treated under several acidic conditions (ex: MsOH, PTSA,
[a]
[b]
Dr. Damien Belotti, Dr. Edmond Toromanoff and Pr. Janine Cossy
Molecular, Macromolecular Chemistry and Materials
ESPCI Paris, CNRS, PLS
10 rue Vauquelin 75231 Paris Cedex 05, France
E-mail: janine.cossy@espci fr
www.lco.espci.fr
Dr. Laurent Evanno
current address: BioCIS, Univ. Paris-Sud, CNRS, Université Paris-
Saclay, 92290, Châtenay-Malabry, France
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201901031
European Journal of Organic Chemistry
FULL PAPER
H2SO4). However, under these conditions, no cascade reaction
occurred and only the epoxide opening, and partial A-ring closing
was observed. When 12 was submitted to Ti-(III) (Cp2TiCl2, Mn,
TMSCl, collidine, THF),[13] a radical cascade reaction took place
and, after desilylation, compounds 14 (23%) and 15 (20%) were
isolated but 13 was not observed. To explain the formation of 14,
one can envisage that the cascade cyclization was aborted by an
intramolecular hydrogen transfer. Concerning the formation of
compound 15, the cascade proceeds via a very uncommon 8-
endo-trig process favored over a 6-endo-trig process.
reaction under sonication to afford the allylic alcohol 21.[17] The
oxidative allylic transposition of 21, induced by PCC, led to the
Michael acceptor 22 bearing the required ketone at C12, and
being suitable for the introduction of the C30-methyl group by a
conjugated addition. Despite an extensive screening of conditions,
it was not possible to prepare 23 using an organocopper reagent.
Only the Flemming addition [18] of AlMe3 ([Ni(acac)3, THF] to the
hindered Michael acceptor furnished 23 (quantitative yield). The
reaction sequence was completed by the cleavage of the ketals
under acidic conditions with a concomitant aldolization to deliver
the complete A/B/C/D tetracyclic core of 2.[19] The reaction
sequence from 20 is quite satisfying as it allows the highly
challenging installation of the C8-C14 vicinal quaternary centers
and the D-ring construction in very good yields (57%, 4 steps).
To install the C20-C27 aliphatic fragment, an isopropenyl side
chain was introduced by
a conjugated addition of an
organocopper reagent (C3H5Li, CuCN, LiCl)[20] onto enone 24
which was activated by BF3.OEt2.[21] Adduct 25 revealed to be
unstable and was immediately reduced (compound 26). Because
of the conformation of the tetracyclic compound 25 (Figure 1), the
reduction only resulted in the 3β,12α-diol 25 instead of the
targeted 3β,12β-epimer.[22] All attempts for the epimerization
performed under the Mitsunobu conditions (DEAD, PPh3, PhMe,
benzoic or nitro-benzoic acids) led to a dehydration. Nevertheless,
the construction of C20-C27 side chain was completed. The
hydroxyl groups were protected as silyl ethers and the isopropenyl
side chain was cleaved by ozonolysis to produce ketone 27. The
C22-C27 fragment was introduced, with complete control of the
diastereoselectivity,[8,23] by addition of an organolithium reagent
which deliver the complete triterpene framework. Deprotection of
the hydroxyl groups afforded 12-epi-protopaxadiol 28 after 19
steps with an overall 1.0% yield. Diol 28 was further oxidized into
diketone 29,[24] but attempts to reduce this ketone (e.g. sodium
borohydride,[25] or metallic sodium[26] in toluene/isopropanol or
Birch conditions) did not afford protopanaxadiol 2 but regenerate
3β,12α-diol 28 as the sole product. It is worth mentioning that
diketone 29 has already been described by Atopkina and
Denisenko for the semi-synthetic preparation of ginsenoside
glycosides[27] and, in addition, our strategy allows the formal total
synthesis[22] of chikusetsusaponin-LT8 30, a bioactive ginsenoside
isolated from Panax japonicus.[28]
Scheme 2. Synthesis and cyclization of polyene 12.
As the bio-inspired strategy did not afford the valuable
intermediate, we have envisaged a “ring-by-ring” sequence to
form the tetracyclic skeleton of protopanaxadiol (Scheme 3). The
B/C-ring system has been prepared by the annulation of
2-methylcyclohexa-1,3-dione (16) using ethyl vinyl-ketone to
afford a Wieland-Miescher-type ketone,[14] which was further
reduced into alcohol 17. A second annulation using the ethyl vinyl-
ketone, followed by a reductive Birch-alkylation, completed the
construction of the A/B/C-ring system of protopanaxadiol
(compound 18)[15],[16] It is worth mentioning that compound 18 can
be obtained with a good ee by utilizing an enzymatic resolution.[16]
To progress toward the D-ring, the ketone at C3 was protected as
a dioxolane,[16] and the C9-C11 double bond was hydrogenated
over PtO2 in acetic acid. The C14-hydroxyl group in 19 was then
oxidized to enone 20 using Dess-Martin periodinane (DMP),
followed by a selenylation/selenoxide elimination sequence.[15] At
this stage, the C15-C17-fragment was introduced by a Barbier
Figure 1. Geometry optimization of 25 (MMFF94 Avogadro® Software).
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10.1002/ejoc.201901031
European Journal of Organic Chemistry
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Scheme 3. Synthesis of 12-epi-protopanaxadiol (28) and formal synthesis of chikusetsusaponin-LT8 (30).
12-epi-protopanaxiol 28 was oxidized into a diketone, allowing the
formal total synthesis of chikusetsusaponin-LT8 30, a minor
ginsenoside, isolated from Panax japonicus.
Conclusion
To summarize, a bio-inspired sequence toward protopanaxadiol
was explored. When epoxy-triene 12 was submitted to Ti-(III), a
radical cascade reaction took place to afford an original 6/6/8/5
tetracyclic structure, compound 15. Notably, this structure is
highly similar to bioactive sesterpenes containing a 8-membered
ring (asperterpenol A, fusicoauritone, variecolin…).[29] This
original cascade might be an original synthetic approach to this
family of natural products. In addition, a “ring-by-ring” strategy
allows the synthesis of the complete dammarane-type triterpene
Supporting Information
(see footnote on the first page of this article): experimental procedures and
copy of the NMR spectrum.
framework. An efficient strategy to install the two adjacent Acknowledgements
quaternary centers (C8 and C14) and the D-ring was developed.
This strategy may be exemplified for the synthesis of other
triterpene frameworks bearing such adjacent quaternary centers
(oleanoids, hopanoids, lupanoids…) However, the obtained final
Novipharma Synergis is gratefully acknowledged for financial
support. Thomas Aubineau and Claude Chassagnard are
gratefully acknowledged for NMR assistance.
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10.1002/ejoc.201901031
European Journal of Organic Chemistry
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[18] S. Flemming, J. Kabbara, K. Nickisch, H. Neh, J. Westermann, Synthesis,
1995, 317-320.
Keywords: ginsenoside • protopanaxadiol • total synthesis •
dammarane • glycoside
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Entry for the Table of Contents (Please choose one layout)
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In the context of the total synthesis of
protopanaxadiol, two strategies were
explored. One strategy from an optically
active trienic epoxide was submitted to
Ti-(III)-mediated radical cascade to afford
an original 6/6/8/5 tetracyclic structure. A
second strategy, using a “ring-by-ring”
synthesis allowed the synthesis of 12-epi-
Total synthesis
Laurent Evanno, Damien Belotti,
Edmond Toromanoff
Janine Cossy*
Page No. – Page No.
Synthesis of 12-epi-protopanaxadiol
and formal synthesis of ginsenoside
chikusetsusaponin-LT8
protopanaxadiol.
In
addition,
20-
hydroxydammar-24-ene-3,12-dione was
synthesized which represents a formal
synthesis of chikusetsusaponin-LT8,
isolated from Panax japonicus.
Layout 2:
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Key Topic*
Author(s), Corresponding Author(s)*
((Insert TOC Graphic here; max. width: 11. 5 cm; max. height: 2. 5 cm; NOTE: the
final letter height should not be less than 2 mm. ))
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