Asymmetric Total Synthesis of Sarpagine-Related Indole Alkaloids Hydroxygardnerine, Hydroxygardnutine, Gardnerine, (E)-16-epi-Normacusine B, and Koumine

Article abstract of DOI:10.1021/acs.orglett.6b00661

Sarpagine-related indole alkaloids (-)-hydroxygardnerine, (+)-hydroxygardnutine, (-)-gardnerine, (+)-(E)-16-epi-normacusine B, and (-)-koumine were divergently synthesized via a common intermediate possessing a piperidine ring with an exocyclic (E)-ethylidene side chain, which was constructed by a gold(I)-catalyzed 6-exo-dig cyclization strategy.

Full text of DOI:10.1021/acs.orglett.6b00661

Letter
pubs.acs.org/OrgLett
Asymmetric Total Synthesis of Sarpagine-Related Indole Alkaloids
Hydroxygardnerine, Hydroxygardnutine, Gardnerine, (E)‑16-epi-
Normacusine B, and Koumine
Mariko Kitajima, Keisuke Watanabe, Hiroyuki Maeda, Noriyuki Kogure, and Hiromitsu Takayama*
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
S
* Supporting Information
ABSTRACT: Sarpagine-related indole alkaloids (−)-hydrox-
ygardnerine, (+)-hydroxygardnutine, (−)-gardnerine, (+)-(E)-
16-epi-normacusine B, and (−)-koumine were divergently
synthesized via a common intermediate possessing a piperidine
ring with an exocyclic (E)-ethylidene side chain, which was
constructed by a gold(I)-catalyzed 6-exo-dig cyclization
strategy.
e have recently developed a stereoselective gold(I)-
catalyzed 6-exo-dig cyclization reaction of silyl enol ether
having an internal alkyne, which affords a piperidine derivative
with an exocyclic (E)-ethylidene side chain (Figure 1), and
droxygelselegine,5c,d and gelselegine.5a Further, the partial
synthesis of koumine6 and 11-methoxykoumine was achieved
by the chemical conversion of natural hydoxygardnerine (2)7 in
our laboratory.8 The total synthesis of several sarpagine-type
alkaloids was accomplished by Cook’s group, using mainly
tryptophan derivatives as the starting material.2b,9 Herein we
report an asymmetric total synthesis of sarpagine-related
alkaloids, which involves the first total synthesis of
(−)-hydroxygardnerine (2), (+)-hydroxygardnutine (3),4 and
(−)-koumine (34) with natural absolute configuration10 by
applying the gold-catalyzed 6-exo-dig cyclization reaction.
Our retrosynthetic analysis of sarpagine-type alkaloids
gardnerine (1), (−)-hydroxygardnerine (2), and (+)-(E)-16-
epi-normacusine B (4)11 is shown in Scheme 1. Alkaloids 1, 2,
and 4 and compound 5 are obtained from tricyclic ketone 6,
which could be a common intermediate for the divergent
synthesis of various sarpagine-type alkaloids, by manipulation of
the indole nucleus having various substituents on the benzene
part and preservation/removal of the allylic hydroxyl group.
The piperidine ring with an (E)-ethylidene side chain in
tricyclic ketone 6 could be constructed by the gold(I)-catalyzed
6-exo-dig cyclization of alkynyl silyl enol ether 7. Silyl enol ether
7 would be derived by alkylation of keto amine 8, which could
be synthesized from known (+)-9-azabicyclo[3.3.1]nonane-2,6-
diol derivative 9.12
W
Figure 1. Gold(I)-catalyzed 6-exo-dig cyclization reaction and
structures of gardnerine (1), hydroxygardnerine (2), hydroxygardnu-
tine (3), and (E)-16-epi-normacusine B (4).
Employing azabicyclononane 9, which was prepared from
1,5-cyclooctadiene in four steps, as the starting material, we
initially prepared alkynyl silyl enol ether 10 for use as the
substrate in the gold(I)-catalyzed cyclization (Scheme 2).
Swern oxidation of 9 and subsequent partial reduction of the
resultant diketone by treatment with BH3·THF gave mono-
alcohol 11. After acetylation of the hydroxyl group in 11 and
deprotection of the benzyl group in acetate 12, the resultant
accomplished the total synthesis of conolidine and apparicine
by using this product.1 The piperidine ring with an exocyclic
(E)-ethylidene side chain exists in many sarpagine-type
monoterpenoid indole alkaloids2 isolated from several genera,
such as Gardneria, Rauwolfia, Alstonia, and Gelsemium.3
Gardnerine (1),4 one of the representative sarpagine-type
indole alkaloids, was utilized for biomimetic chemical trans-
formation into several Gelsemium alkaloids,5 such as gelsenici-
ne,5a des-Na-methoxyhumantenirine,5b 11-methoxy-19(R)-hy-
Received: March 15, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00661
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Letter
Scheme 1. Retrosynthetic Analysis of Alkaloids 1, 2, and 4
Scheme 3. Gold(I)-Catalyzed 6-Exo-Dig Cyclization of
Alkynyl Silyl Enol Ethers 10 and 19
having a trityl ether was prepared from 12 via alkylation of 8
with alkyne 20 and silyl enol etherification of 21. As expected,
the gold(I)-catalyzed cyclization of 19 with Au catalyst 16 (3
mol %) and AgBF4 (3 mol %) in MeCN−H2O at 80 °C gave
predominantly 6-exo-dig-cyclized product 22 in 85% yield along
with 7-endo-dig-cyclized product 23 in 15% yield.
Thus, obtained cyclized product 22 was deacetylated, and the
C1 unit corresponding to C-17 was introduced by treating
ketone 24 with Tebbe reagent in the presence of pyridine in
THF in 72% yield (Scheme 4). Swern oxidation of exo olefinic
compound 25 followed by deprotection of the trityl group in
26 gave ketone 27, the substrate for the indole synthesis.
Scheme 2. Synthesis of Alkynyl Silyl Enol Ethers 10 and 19
Scheme 4. Synthesis of Ketone 27
Next, we turned our attention to the synthesis of gardnerine
(1)14 and hydroxygardnerine (2) (Scheme 5). After protection
of allyl alcohol in ketone 27 with an acetyl group, Fischer
indole synthesis of ketone 28 with phenylhydrazine 29 in the
presence of pyridine·HCl in pyridine15 was conducted to give
desired 11-methoxyindole 30 in 79% yield together with 9-
methoxy isomer in 15% yield. The regio- and diastereoselective
introduction of a hydroxyl group at the C-17 position was
achieved by hydroboration of 30 by 9-BBN followed by
oxidation14 in 67% yield. Finally, deprotection of the benzyl
group on Na in 31 by the Birch reduction at −78 °C gave
hydroxygardnerine (2) in 63% yield. When the Birch reduction
was carried out at −30 °C, gardnerine (1) was selectively
obtained in 77% yield via deoxygenation at C-18 position and
debenzylation.10 Hydroxygardnerine (2) was oxidized with
DDQ in THF16 to afford hydroxygardnutine (3).
keto amine 8 was alkylated with alkyne 13 in the presence of
K2CO3 in MeCN to afford alkyne ketone 14. The primary
alcohol in 14 was protected by MOM ether, and treatment of
ketone 15 with TIPSOTf in the presence of Et3N in CH2Cl2
gave alkynyl silyl enol ether 10.
Next, we carried out the gold(I)-catalyzed cyclization of
alkynyl silyl enol ether 10 (Scheme 3). Treatment of 10 with
Au catalyst 1613 (10 mol %) and AgBF4 (10 mol %) in
MeCN−H2O (10:1) at 80 °C gave the desired 6-exo-dig-
cyclized product 17 in 50% yield, together with undesired 7-
endo-dig cyclized product 18 in 32% yield. To improve the
selectivity of the cyclization mode, i.e., 6-exo-dig vs 7-endo-dig,
the protecting group of alcohol in the alkyne part was changed
from MOM to a bulky trityl group. Alkynyl silyl enol ether 19
B
DOI: 10.1021/acs.orglett.6b00661
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Scheme 5. Synthesis of Gardnerine (1), Hydroxygardnerine
(2), and Hydroxygardnutine (3)
Scheme 6. Synthesis of (E)-16-epi-Normacusine B (4) and
Koumine (34)
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.6b00661.
According to the above-mentioned procedure, ketone 27 was
converted into (E)-16-epi-normacusine B (4)17 having a
nonsubstituted indole A ring in three steps: indole synthesis
by using 1-benzyl-1-phenylhydrazine; hydroboration/oxidation
of indole 32; and the Birch reduction of 33 at −30 °C to yield 4
(Scheme 6). On the other hand, the Birch reduction of 33 at
−78 °C selectively afforded 5 in 90% yield. Then, using
compound 5, the synthesis of (−)-koumine (34) was achieved
in four steps according to a previously reported method8 that
featured the C/D ring opening of 5 to give 35 and the
intramolecular coupling reaction between C-7 and C-20
positions in 37 using palladium catalysis.
In conclusion, we have succeeded in the asymmetric total
synthesis of sarpagine-related indole alkaloids, including the
first total synthesis of (−)-hydroxygardnerine (2), (+)-hydrox-
ygardnutine (3), and (−)-koumine (34) with natural absolute
configuration. The divergent synthesis of sarpagine-type
compounds features the gold(I)-catalyzed 6-exo-dig cyclization
to furnish a piperidine ring having an exocyclic (E)-ethylidene
side chain, the construction of an indole nucleus having various
substituents on the benzene ring, and the preservation/removal
of the allylic hydroxyl group by temperature control in the
Birch reduction. Further synthetic study of other sarpagine-
related alkaloids is underway in our laboratory.
Experimental procedures for the preparation of com-
pounds 1−5, 8, 10−12, 14, 15, 17−28, and 30−37 and
1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: takayamah@faculty.chiba-u.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by JSPS KAKENHI Grant Nos.
25293023 and 26293023.
■
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