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Journal of the American Chemical Society
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cleus (Scheme 6).5b We theorized that a ConiaꢀEne type reaction
occurred transforming 27 into desꢀN4ꢀmethyl isodihydrokoumine
ae, Gentianales)—a review of their phytochemistry, pharmacoloꢀ
gy, toxicology and traditional use. J. Ethnopharmacol. 2014, 152,
33–52.
(4) Namjoshi, O.A.; Cook, J.M. Sarpagine and related alkaꢀ
loids. In the alkaloids: Volume 76; Knölker, H.J., Ed.; Elsevier:
2016, 63–169.
(28). A reductive amination reaction furnished the natural product
isodihydrokoumine (8) in a 57% yield.10 (4R)ꢀIsodihydrokoumine
N4ꢀoxide (7) was prepared by oxidizing the N4 nitrogen in 8 with
mCPBA.18 The oxidation produced a 1.8:1 mixture of diastereꢀ
omers favoring the N4 epimer (29) which could be separated from
the natural product (4R)ꢀIsodihydrokoumine N4ꢀoxide (7) by
chromatography.10,19
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(5) (a) Sakai, S.ꢀI.; Takayama, H. Biomimetic chemical transꢀ
formation from simple indole alkaloids to Gelsemium alkaloids.
Pure & Appl. Chem. 1994, 66, 2139–2142. (b) Sakai, S.ꢀI.; Yaꢀ
manaka, E.; Kitajima, M.; Yokota, M.; Aimi, N.; Wongseripatana,
S.; Ponglux, D. Biomimetic synthesis of koumine skeleton: Partial
synthesis of 11ꢀmethoxykoumine (Gelsemiumꢀtype alkaloid) from
18ꢀhydroxygardnerine. Tetrahedron Lett. 1986, 27, 4585–4588.
(c) Takayama, H.; Sakai, S.ꢀI. Chemical conversion of gardnerine
into koumidine by inverting the ethylidene side chain with a palꢀ
ladium catalyst. Chem. Pharm. Bull. 1989, 37, 2256–2257. (d)
Takayama, H.; Kitajima, M.; Wongseripipatana, S.; Sakai, S.ꢀI.
Partial synthesis and the absolute configuration of two new Gel-
semium alkaloids, koumidine and (19Z)ꢀtaberpsychine. J. Chem.
Soc. Perkin. Trans. I. 1989, 0, 1075–1076. (e) Kitajima, M.; Taꢀ
kayama, H.; Sakai, S.ꢀI. Stereoselective transformation of ajmaꢀ
line into three minor Gelsemium alkaloids, koumidine, (19Z)ꢀ
anhydrovobasinediol [(19Z)ꢀtaberpsychine] and Nꢀ
demethoxyrankinidine and their absolute configuration. J. Chem.
Soc. Perkin. Trans. 1. 1991, 0, 1773–1779. (f) Takayama, H.;
Kitajima, M.; Ogata, K.; Sakai, S.ꢀI. The first and biomimetic
construction of the new skeleton of gelselegineꢀtype oxindole
alkaloids. J. Org. Chem. 1992, 57, 4583–4584. (g) Sakai, S.ꢀI.;
Kubo, A.; Katano, K.; Shinma, N.; Sasago, K. Transformation of
indole alkaloids. II. On the C/D ring opening and closing reacꢀ
tions of indole alkaloids and the syntheses of vobasine type alkaꢀ
loids. Yakugaku Zasshi 1973, 93, 1165–1182. (h) Phisalaphong,
C.; Takayama, H.; Sakai, S.ꢀI. A first synthesis of 20ꢀ
hydroxydihydrorankinidine, a new oxindole alkaloid from Gelse-
mium elegans Benth. Tetrahedron Lett. 1993, 34, 4035–4039. (i)
Takayama, H.; Tominaga, Y.; Kitajima, M.; Aimi, N.; Sakai, S.ꢀI.
First synthesis of the novel Gelsemium alkaloids, Gelselegine,
Gelsenicine, and Gelsedine using a biomimetic approach. J. Org.
Chem. 1994, 59, 4381–4385. (j) Liu, C.ꢀT.; Yu, Q.ꢀS. A biomiꢀ
metic transformation of vobasine to koumine. Acta Chimica Sini-
ca 1987, 45, 181–187. (k) Takayama, H.; Kitajima, M.; Sakai, S.ꢀ
I. Biomimetic synthesis of koumine by the palladiumꢀcatalyzed
intramolecular coupling reaction of 18ꢀhydroxytaberpsychine (18ꢀ
hydroxyanhydrovobasinediol). Heterocycles 1990, 30, 325–327.
(6) Kitajima, M.; Watanabe, K.; Maeda, H.; Kogure, N.; Takaꢀ
yama, H. Asymmetric total synthesis of sarpagineꢀrelated indole
alkaloids hydroxygardnerine, hydroxygardnutine, gardnerine, (E)ꢀ
16ꢀepiꢀnormacusine B, and koumine. Org. Lett. 2016, 18, 1912–
1915.
In summary, the first total syntheses of the natural products
isodihydrokoumine and (19Z)ꢀtaberpsychine were completed in
11 steps and isodihydrokoumine N4ꢀoxide in 12 steps (longest
linear sequence) from commercially available starting materials.
In addition, a formal total synthesis of koumine has been realized.
Modification of hydroxylamine 19 or aldehyde 20 will allow for
rapid analogue preparation, which highlights the modularity of
this synthesis. The brevity of these routes was made possible by
an intramolecular [3+2] nitrone cycloaddition to set the stereoꢀ
chemistry of the piperidine ring central to these natural products.
The ability to produce acetal 24 on a gram scale will allow us to
prepare suitable quantities of these natural products for biological
testing to potentially unearth new uses for these natural product
scaffolds.
ASSOCIATED CONTENT
Supporting Information
Experimental Procedures, and characterization, and spectral data
for all compounds are in a single PDF file
Crystallographic data for the hydrogen oxalate salt of 33 is in a
CIF file
AUTHOR INFORMATION
Corresponding Author
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We would like to thank the Natural Sciences and Engineering
Research Council of Canada for funding. Jeff K. Kerkovius is the
recipient of an NSERC CGSM award. We are grateful to Doug
Hairsine of the University of Western Ontario Mass spectrometry
facility for performing MS analysis. We would like to thank Dr.
Paul Boyle for Xꢀray crystallographic analysis, and Dr. Mat Wilꢀ
lans for NMR spectroscopy assistance. We would graciously like
to thank Dr. Schmalz, and Julia Westphal for providing a sample
of ligand L8 (see SI for details) for our screening studies. We are
also grateful to Dr. Wang Lei for providing us a copy of the NMR
spectra of natural isodihydrokoumine (8).
(7) (a) Magnus, P.; Mugrage, B.; DeLuca, M.; Cain, G.A. Total
synthesis of (+)ꢀkoumine, (+)ꢀtaberpsychine, and (+)ꢀkoumidine.
J. Am. Chem. Soc. 1989, 111, 786–789. (b) Magnus, P.; Mugrage,
B.; DeLuca, M.R.; Cain, G.A. Studies on Gelsemium alkaloids.
Total synthesis of (+)ꢀkoumine, (+)ꢀtaberpsychine, and (+)ꢀ
koumidine. J. Am. Chem. Soc. 1990, 112, 5220–5230.
(8) Cao, H.; Yu, J.; Wearing, X.Z.; Zhang, C.; Liu, X.; Desꢀ
champs, J.; Cook, J.M. The first enantiospecific synthesis of (ꢀ)ꢀ
koumidine via the intramolecular palladiumꢀcatalyzed enolate
driven cross coupling reaction. The stereospecific introduction of
the 19ꢀ(Z) ethylidene side chain. Tetrahedron Lett. 2003, 44,
8013–8017.
(9) Ponglux, D.; Wongseripiatana, S.; Subhadhirasakul, S.; Taꢀ
kayama, H.; Yokota, M.; Ogata, K.; Phisalaphong, C.; Aimi, N.;
Sakai, S.ꢀI. Studies on the indole alkaloids of Gelsemium elegans
(Thailand): Structure elucidation and proposal of biogenetic route.
Tetrahedron 1988, 44, 5075–5094.
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