Unified Total Synthesis of Five Gelsedine-Type Alkaloids: (-)-Gelsenicine, (-)-Gelsedine, (-)-Gelsedilam, (-)-14-Hydroxygelsenicine, and (-)-14,15-Dihydroxygelsenicine

Article abstract of DOI:10.1021/acs.orglett.6b02263

The systematic arrangement of a two-carbon unit, hydrogen atom, and oxygen atom on the versatile enal moiety of a non-natural synthetic intermediate successfully led to the unified access to the gelsedine-type alkaloids. The development and use of this ne

Full text of DOI:10.1021/acs.orglett.6b02263

Letter
pubs.acs.org/OrgLett
Unified Total Synthesis of Five Gelsedine-Type Alkaloids:
(−)-Gelsenicine, (−)-Gelsedine, (−)-Gelsedilam, (−)-14-
Hydroxygelsenicine, and (−)-14,15-Dihydroxygelsenicine
Takaaki Harada,† Jun Shimokawa,‡ and Tohru Fukuyama*,‡
†Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
‡Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa, Nagoya, Aichi 464-8601, Japan
S
* Supporting Information
ABSTRACT: The systematic arrangement of a two-carbon unit,
hydrogen atom, and oxygen atom on the versatile enal moiety of a
non-natural synthetic intermediate successfully led to the unified
access to the gelsedine-type alkaloids. The development and use of
this new synthetic hub and an array of site-selective transformations
resulted in the asymmetric synthesis of (−)-gelsenicine, (−)-gelse-
dine, (−)-gelsedilam, (−)-14-hydroxygelsenicine, and (−)-14,15-
dihydroxygelsenicine.
iosynthesis of natural products has been a popular and
inspiring guide for synthetic chemists in designing total
Thus, we launched our synthetic campaign toward the
development of a flexible and unified route to the gelsedine-
type alkaloids. Our target compounds include gelsenicine (1),13
gelsedine (2),14 gelsedilam (3),8e 14-hydroxygelsenicine
(humantenidine) (4),15 and 14,15-dihydroxygelsenicine (5),16
which are characterized by the common spiro-N-methoxyindo-
linone moiety, the oxabicyclo[3.2.2]nonane core skeleton, and
the variably functionalized pyrrolidine moiety (Figure 1). Since
these alkaloids were found in a single species, Gelsemium elegans
Benth,17 they are closely related to each other within the
integrated biosynthetic pathway proposed by Takayama and
Sakai.15b The C21 unit of the parent intermediate gelselegine
(6) was proposed to be oxidatively removed to furnish the
cyclic imine metabolite gelsenicine (1), which would then be
selectively reduced to give gelsedine (2). Oxidation of
gelsenicine (1) on the imine moiety and removal of a two-
carbon unit18 would afford the lactam derivative, gelsedilam
(3). Oxygenation at C14 would give 14-hydroxygelsenicine (4),
and repeated oxygenation at both the C14 and C15 positions
would give 14,15-dihydroxygelsenicine (5), which would afford
gelsemoxonine (7) by sequential ring opening and cyclization.
Within the framework of the current state of organic synthesis,
transformations that emulate this entire biosynthesis, especially
C−H oxidations on C14 and C15, do not seem to be practical.
Thus, we abandoned a biomimetic strategy and envisioned
access to these targets through a single artificial intermediate
bearing a versatile core structure (Scheme 1).19 The ideal
intermediate would be one that would allow regio- and
diastereoselective introduction of different functional groups at
C14 and C15 and flexible manipulation of the terminal two-
B
syntheses. Biomimetic approaches that usually emulate the
transformations developed in nature, however, do not
necessarily represent the most efficient pathways in the realm
of organic synthesis. It is imperative to customize the originally
inspired strategy to follow the logic of modern organic
synthesis. These abiotic approaches would also target a group
of natural products accompanied by many structurally related
congeners. Thus, our attention turned to the unified synthesis
of natural products resembling each other, namely, gelsemium
alkaloids.1 These natural products have attracted a great deal of
attention of synthetic chemists because of their complex
structures, which hardly succumb to conventional synthetic
approaches. These compounds are known as the toxic
principles in the parent plant that has a rich therapeutic history
in traditional Asian medicine over the past thousand years.2
Among their interesting biological activities, we chose to focus
on the prominent cytotoxic activity of the gelsedine-type3
gelsemium alkaloids against A431 epidermoid carcinoma cells.4
In order to obtain a more detailed understanding of the
structure−activity relationship of these natural products and
their congeners, we found it necessary to develop an efficient
and unified strategy for the synthesis of these target molecules.
Earlier synthetic studies of the gelsedine-type alkaloids were
conducted by Baldwin,5 Hamer,6 and Kende.7 Takayama and
Sakai demonstrated remarkable transformations among the
gelsemium alkaloids and reported a comprehensive semisyn-
thesis based on the biogenetic pathway.8 Hiemstra succeeded in
the de novo synthesis of ent-gelsedine.9 Recent achievements
include the synthesis of gelsemoxonine by Fukuyama10 and
Carreira11 and the synthesis of gelsenicine by Ferreira.12
Nevertheless, the biological profiles of these alkaloids remain
unclear, partly because of the lack of a comprehensive library.
Received: July 31, 2016
© XXXX American Chemical Society
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Scheme 2. Asymmetric Synthesis of Gelsedilam
Figure 1. Gelsedine-type alkaloids and plausible biosynthetic relation-
ship.
Scheme 1. Retrosynthetic Analysis of Gelsedine-Type
Alkaloids through the Introduction of an Ethyl Group and
Hydrogen/Oxygen Atoms on the Enal Moiety of the Non-
natural Intermediate 8
redox-neutral isomerization reaction using the TMSCN−DBU
combination.20 Submission of 8 to the reaction conditions
initially formed a TMS cyanohydrin in situ, which subsequently
underwent a double-bond migration to form 9. The stereo-
chemical outcome of the ensuing protonation and acylation
steps, however, varied significantly depending on the reagents
employed. The use of pyrrolidine as a reagent mainly yielded
11 with the desired 15R isomer (15R:15S = 6.5:1). This result
indicated that protonation of the silyl enol ether intermediate 9
preferentially occurred from the less hindered Si face to afford
(15R)-10. Because of the difficulties associated with further
transformations of the pyrrolidine amide, ethanol was
employed next. However, the use of ethanol reversed the
stereoselectivity (15R:15S = 1:2.3), probably as a result of
isomerization of the sterically congested acyl cyanide 10 to the
thermodynamically more stable 15S isomer during the slow
solvolysis stage. To expedite the solvolysis, methanol was
employed as a smaller nucleophile. Methanol indeed gave an
acceptable result (15R:15S = 2.6:1), and the desired 15R
isomer 12 was isolated in 57% yield. Removal of the Cbz group
by TMS iodide and subsequent cyclization under basic
conditions completed the synthesis of (−)-gelsedilam (3).8e
The intriguing stereochemical outcomes obtained here were
consistent with our previous studies of this bicyclic system,10
which could be explained by the fact that the Re face of the
enolate is somewhat blocked by the bulky indolinone moiety.
Other target gelsedine-type alkaloids are characterized by
possessing two additional carbon atoms on the side chain.
Thus, enal 8 was treated with an ethyl Grignard reagent
followed by IBX oxidation to afford ethyl ketone intermediate
13 (Scheme 3a).10 The synthesis of gelsenicine (1) required
reduction of the double bond and deprotection of the amine
carbon unit. We therefore focused on the key intermediate 8,
which we used for the total synthesis of gelsemoxonine.10 This
molecule bears the common spiro-N-methoxyindolinone
moiety and a nitrogen functionality on the oxabicyclo[3.2.2]-
nonane structure, which is also equipped with a versatile enal
functionality. Introduction of the two-carbon unit and
installation of two hydrogen or oxygen atoms on the C−C
double bond could be envisioned through the transformation of
this enal moiety. Ensuing cyclization from the nitrogen
functionality is expected to afford all of the targeted
gelsedine-type alkaloids.
Scheme 2 represents our total synthesis of gelsedilam (3). It
was necessary to introduce two hydrogen atoms on the C14−
C15 double bond as well as to oxidize the aldehyde moiety. A
one-step conversion that might fulfill this requirement is the
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furnished (−)-gelsedine (2). With the successful reduction of
the C−C double bond, we next focused on introduction of the
oxygen functionalities on the double bond (Scheme 3c).
Fortunately, dihydroxylation of 13 with catalytic osmium
tetroxide and NMO occurred smoothly at the desired face to
afford diol 15. Removal of the Cbz group with triethylsilane/
palladium acetate and subsequent desilylation of the resulting
silyl carbamate and partially silylated secondary alcohol caused
the spontaneous dehydrative cyclization, leading to the first
total synthesis of (−)-14,15-dihydroxygelsenicine (5).16 The
last target, 14-hydroxygelsenicine (4), bears an oxygen atom at
C14 and a hydrogen atom at C15. This task might be realized
via the partial reduction of the C14−C15 epoxide (Scheme 3d).
Diastereoselective introduction of the epoxide functionality in
16 was performed by treatment with TBHP and Triton B.10
After removal of the Cbz group by TMS iodide, the reductive
transformation was achieved by treatment with samarium(II)
iodide, which mediated the reduction of the carbon−oxygen
bond adjacent to the carbonyl group23 while keeping the N−O
bond on the indolinone intact. The samarium enolate 17
generated in situ might be protonated from the less hindered Re
face, resulting in the formation of a cyclic imine. In this case
again, rapid epimerization of the ketone cannot be ruled out.
Formal cis hydration of the C14−C15 double bond eventually
afforded (−)-14-hydroxygelsenicine (4).24
Scheme 3. Asymmetric Syntheses of Gelsenicine, Gelsedine,
14,15-Dihydroxygelsenicine, and 14-Hydroxygelsenicine
In summary, five gelsedine-type alkaloids have been
synthesized from a common non-natural intermediate by
manipulating the potentially divergent enal functional group.
For (−)-14-hydroxygelsenicine (4) and (−)-14,15-dihydrox-
ygelsenicine (5), this synthesis unequivocally established the
structure and absolute configuration. The established synthetic
route to a broad range of gelsedine-type alkaloids sets the stage
for the synthesis of structurally similar unnatural analogues that
could potentially stimulate medicinal research based on these
alkaloids.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02263.
Experimental procedures, spectroscopic data, and 1H and
13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: fukuyama@ps.nagoya-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(Scheme 3b). A hydrosilylative transformation was chosen for
this purpose. When 13 was treated with triethylsilane in the
presence of palladium acetate,21 the desired hydrosilylation and
hydrogenolysis of the Cbz group proceeded simultaneously to
give silyl enol ether/silyl carbamate intermediate 14. Sub-
sequent treatment with TBAF liberated the amine and ketone
to smoothly form (−)-gelsenicine (1).8c,22 It is not quite clear
whether the facile formation of the cyclic imine resulted from
exclusive protonation of the enolate from the Si face or rapid
epimerization of the ketone. Catalytic hydrogenation of 1 with
Adams’ catalyst following the report of Takayama and Sakai8c
■
This work was supported by JSPS KAKENHI Grants
23590003, 25221301, 15H05641, and 13J05263 and the
Platform for Drug Discovery, Informatics, and Structural Life
Science from the Ministry of Education, Culture, Sports,
Science and Technology of Japan. T.H. was supported by a
research fellowship from JSPS.
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