Total synthesis of (-)-corynantheidine by nickel-catalyzed carboxylative cyclization of enynes

Article abstract of DOI:10.1002/ejoc.201100147

The total synthesis of (-)-corynantheidine has been achieved through Ni⁰-mediated carboxylative cyclization as the key reaction step with incorporation of CO₂, and this cyclization was also successfully expanded to the catalytic reac

Full text of DOI:10.1002/ejoc.201100147

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100147
Total Synthesis of (–)-Corynantheidine by Nickel-Catalyzed Carboxylative
Cyclization of Enynes
Takashi Mizuno,[a] Yoshihiro Oonishi,[a] Masanori Takimoto,[a][‡] and Yoshihiro Sato*[a]
Keywords: Carbon dioxide fixation / Nickel / Total synthesis / Enynes
The total synthesis of (–)-corynantheidine has been achieved
through Ni0-mediated carboxylative cyclization as the key
reaction step with incorporation of CO2, and this cyclization
was also successfully expanded to the catalytic reaction by
using Et2Zn in the presence of an excess amount of DBU.
dergoes insertion of CO2 at the Csp3–nickel bond under an
atmosphere of CO2 to give nickelacycle II. After hydrolysis
of II, the corresponding carboxylic acid 2 was produced
along with CO2 incorporation.
Introduction
Carbon dioxide (CO2) has attracted much attention as
an abundant carbon resource. Thus, the development of re-
actions that utilize CO2 as a C1 unit is one of the important
challenges in synthetic organic chemistry.[1] However, the
utilization of CO2 as a C1 unit is limited due to its chemical
stability. It is known that transition metals can activate the
C=O bond of CO2, and various reactions that incorporate
CO2 into organic molecules by employing transition-metal
complexes have been reported.[2,3] In this context, we have
recently reported the nickel-mediated carboxylative cycliza-
tion of enynes, and the reaction mechanism is shown in
Scheme 1.[4,5]
Results and Discussion
Since plants produce various organic compounds using
CO2 as a carbon source through photosynthesis, the synthe-
sis of natural products, especially those derived from plants
such as alkaloids, by a CO2 incorporation reaction is a stim-
ulating objective. Thus, we decided to utilize the above-
mentioned nickel-mediated carboxylative cyclization of en-
ynes for the synthesis of (–)-corynantheidine.[6,7] The retro-
synthetic plan is shown in Scheme 2. (–)-Corynantheidine
would be derived from 3, which would be synthesized from
Scheme 1. Ni0-mediated carboxylative cyclization of enynes.
Enyne 1, having an electron-withdrawing group on the
terminus of the alkene, reacts with a zero-valent nickel com-
plex to form oxanickelacyclopentene I. Nickelacycle I un-
[a] Faculty of Pharmaceutical Sciences, Hokkaido University,
Sapporo 060-0812, Japan
Fax: +81-11-706-4982
E-mail: biyo@pharm.hokudai.ac.jp
[‡] Current address: Organometallic Chemistry Laboratory,
RIKEN Advanced Science Institute,
Hirosawa 2-1, Wako, Saitama 351-0198, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100147.
Scheme 2. Retrosynthetic analysis of (–)-corynantheidine.
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Total Synthesis of (–)-Corynantheidine
enyne 4 by nickel-mediated carboxylative cyclization ac-
companied by CO2 incorporation. Chiral enyne 4 would be
formed from tetrahydro-β-carboline 5, which would be ac-
cessed from l-tryptophan methyl ester and aldehyde 6 by a
cis-selective Pictet–Spengler reaction.[8]
Initially, cis-selective Pictet–Spengler reaction of l-tryp-
tophan methyl ester (7) and aldehyde 8 was investigated
(Scheme 3). As a result, two tetrahydro-β-carboline prod-
ucts were produced, and they could be easily separated by
silica gel chromatography to give the major product in 74%
yield and the minor product in 18% yield. As expected, the
stereochemistry of the major product was unambiguously
assigned to have the cis configuration by comparison of its
13C NMR spectrum with that of the minor product, in
which the 13C carbon signals for C1 and C3 of the major
product [cis-9: δ = 53.2 (C1), 56.8 (C3) ppm] were downfield
relative to those of the minor product [trans-9: δ = 48.9
(C1), 52.1 (C3) ppm].[9]
Scheme 4. Synthesis of enyne 16 from cis-9.
selectively formed from 16 and the Ni0 complex. On the
other hand, product 18 would be directly formed from III
without CO2 incorporation.
Scheme 3. cis-Selective Pictet–Spengler reaction.
Desired enyne 16 was readily synthesized from cis-9 in
an optically active form in good yield through a sequence
of usual transformations: N-propargylation of cis-9 with 10,
protection of 11 with Boc, followed by hydrolysis of the
ester moiety, decarboxylation by using the Barton reaction,
deprotection of the TBDSP group, and oxidation with
Dess–Martin periodinane followed by Wittig reaction
(Scheme 4).
With substrate 16 in hand, we turned our attention to
the construction of the fourth ring in (–)-corynantheidine
by a nickel-mediated carboxylative cyclization. According
to the optimal conditions previously reported by us,[4] treat-
ment of enyne 16 with a stoichiometric amount of Ni-
(cod)2 and DBU (2 equiv.) as a ligand in the presence of
4 Å molecular sieves (MS) in dioxane at 40 °C under an
atmosphere of gaseous CO2 (1 atm) gave crude materials.
The crude materials were treated with diazomethane, re-
sulting in desired product 17 in 73% yield as a single isomer
along with 18 in 2% yield (Scheme 5). Apparently, CO2 in-
corporation product 17 was produced via nickelacycles
III[10] and IV; the former was formed from 16 and the Ni0
complex through oxidative cycloaddition, and the latter was
formed by insertion of CO2 between the Csp3–nickel bond
Scheme 5. Ni0-mediated carboxylative cyclization of 16.
It is noteworthy that carboxylative cyclization of 16 also
in III. The stereochemistry of the ring junction in 17 was proceeded by using a catalytic amount of Ni(cod)2 (20 mol-
unequivocally determined to be in the syn configuration by %) in the presence of an excess amount of DBU (6.4 equiv.)
an NOE experiment between Ha and Hb (see V in and Et2Zn (3.0 equiv.) to give desired product 17 in 58%
Scheme 5), which means that nickelacycle IV was stereo- yield (Scheme 6).[11]
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T. Mizuno, Y. Oonishi, M. Takimoto, Y. Sato
SHORT COMMUNICATION
ine have been successfully conducted according to the litera-
ture, giving (–)-corynantheidine in 47% yield (two steps).
The spectroscopic data, including the sign and value of
[α]D, for our synthetic (–)-corynantheidine agreed with
those reported in the literature.[7c]
Scheme 6. Ni0-catalyzed carboxylative cyclization of 16.
The possible mechanism of the catalytic carboxylative cy-
clization of 16 is shown in Scheme 7. As mentioned above,
nickelacycles III and IV would be successively formed from
substrate 16 and Ni0 complex. Then, transmetalation be-
tween nickelacycle IV and Et2Zn would occur to give com-
plex 19, and β-elimination from the ethyl group on nickel
metal in 19 would produce nickel–hydride complex 20 along
with the evolution of ethylene. Reductive elimination from
20 gives zinc–carboxylate 21 along with regeneration of a
zero-valent nickel complex. Then, methyl ester 17 is ob-
tained through hydrolysis of 21 by acidic workup followed
by methylation with diazomethane. It is known that the use
of an excess amount of DBU is important in the catalytic
reaction because DBU can coordinate to both the Ni0 com-
plex and the zinc reagent as a ligand.
Scheme 8. Synthesis of (–)-corynantheidine from 17.
Conclusions
In summary, the total synthesis of (–)-corynantheidine
has been achieved through Ni0-mediated carboxylative cy-
clization as the key reaction step with incorporation of
CO2. We have also succeeded in expanding the Ni0-medi-
ated reaction of enynes to the catalytic reaction by using
Et2Zn as a transmetalation reagent in the presence of an
excess amount of DBU. The present results indicate that
CO2 is one of the useful carbon resources in synthetic or-
ganic chemistry, and further studies for development of new
reactions accompanied by CO2 incorporation and their ap-
plications are now in progress.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, characterization data, and 1H and 13C
NMR spectra for key compounds.
Acknowledgments
Scheme 7. Mechanism of Ni0-catalyzed carboxylative cyclization of
16.
This work was financially supported by a Grand-in-Aid for Scien-
tific Research on Priority Areas from the Ministry of Education,
Culture, Sports, Science and Technology, Japan (No. 18032003,
“Creation of Biologically Functional Molecules”) and also by the
Fugaku Foundation. We thank Prof. J.M. Cook for kindly provid-
Key synthetic intermediate 17 was converted into (–)-co-
rynantheidine by the following four steps (see Scheme 8).
Deprotection of the Boc group in 17 by treatment with for-
mic acid produced 22 in 93% yield, which was reduced with
DIBALH (1.5 equiv.) to give Z-geissoschizinene (23) in
58% yield along with recovery of unreacted 22 in 35%
yield. Conversion of (Ϯ)-Z-geissoschizinene into (Ϯ)-coryn-
antheidine has already been reported by Lounasmaa.[6g]
Thus, the final two steps from 23 toward (–)-corynantheid-
1
ing H and 13C NMR spectra of their synthetic (–)-corynantheid-
ine.
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Total Synthesis of (–)-Corynantheidine
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Received: February 1, 2011
Published Online: March 15, 2011
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