Development of a Divergent Synthetic Route to the Erythrina Alkaloids: Asymmetric Syntheses of 8-Oxo-erythrinine, Crystamidine, 8-Oxo-erythraline, and Erythraline

Article abstract of DOI:10.1002/anie.201602650

A general synthetic methodology toward the erythrina alkaloids has been developed. Inspired by a proposed biosynthetic mechanism, the medium-sized chiral biaryl lactam was asymmetrically transformed into the common core A-D rings by a stereospecific singlet oxygen oxidation of the phenol moiety, followed by a transannular aza-Michael reaction to the dienone functionality. The late-stage manipulation of the oxidation and oxygenation states of the functional groups on the peripheral moieties enabled the flexible syntheses of the erythrina alkaloids. Then there were four: The fixed atropisomeric stereochemistry of a medium-sized biaryl intermediate was fully transferred to the central point chirality of a helical intermediate as a result of singlet oxygen oxidation and transannulation. This finding enabled the asymmetric synthesis of a common intermediate, which is amenable to a variety of oxidation-reduction transformations, thus giving rise to the first asymmetric syntheses of four erythrina alkaloids.

Full text of DOI:10.1002/anie.201602650

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International Edition: DOI: 10.1002/anie.201602650
German Edition: DOI: 10.1002/ange.201602650
Total Synthesis
Development of a Divergent Synthetic Route to the Erythrina
Alkaloids: Asymmetric Syntheses of 8-Oxo-erythrinine, Crystamidine,
8-Oxo-erythraline, and Erythraline
Hirotatsu Umihara, Tomomi Yoshino, Jun Shimokawa, Masato Kitamura,* and
Tohru Fukuyama*
¯
Dedicated to Professor Satoshi Omura on the occasion of his 80th birthday
Abstract: A general synthetic methodology toward the eryth-
rina alkaloids has been developed. Inspired by a proposed
biosynthetic mechanism, the medium-sized chiral biaryl lactam
was asymmetrically transformed into the common core A–D
rings by a stereospecific singlet oxygen oxidation of the phenol
moiety, followed by a transannular aza-Michael reaction to the
dienone functionality. The late-stage manipulation of the
oxidation and oxygenation states of the functional groups on
the peripheral moieties enabled the flexible syntheses of the
erythrina alkaloids.
D
ecades of synthetic, biological, and medicinal research
explorations have been devoted to the chemistry of the
erythrina alkaloids. These alkaloids share a common central
structure featuring diverse peripheral oxidation states, such as
those present in the representative members 1–8[1] (Figure 1).
Curare-like paralyzing activity[2] has long been recognized as
a prominent biological activity derived from antagonizing the
nicotinic acetylcholine receptor (nAChR).[3] The erythrina
alkaloid most commonly explored is dihydro-b-erythroidi-
ne[1a] (DHbE; 8), bearing a lactonic D ring. This compound is
commonly used in research as a moderately selective
antagonist of nAChR.[4] An X-ray structural analysis of the
complex formed between 8 and the acetylcholine binding
protein (AChBP) suggested that the A,B ring moiety is
important to the binding interaction, and the bulky C,D rings
are important for site-specific repulsion.[5] These insights
suggest that all the rings (A–D) are necessary for achieving
the antagonist activity. Recent reports indicate that a variety
of aromatic erythrina alkaloids display similar activities with
Figure 1. Representative erythrina alkaloids and their common core
motif. Marked in gray is the periphery which can be differentially
functionalized.
development of novel subtype-selective nAChR antago-
nists.[7]
Since the first pioneering synthetic studies of the erythrina
alkaloids by Belleau,[8] Mondon,[9] and Prelog et al.[10] more
than half a century ago, extensive synthetic studies of these
alkaloids have been pursued by numerous synthetic
groups.[11,12] Among the approaches explored to date, asym-
metric syntheses comprise only a small fraction.[13] This lack of
asymmetric syntheses is probably due to the inherent
difficulties associated with the asymmetric construction of
the central tetrasubstituted stereocenter, especially with the
most widely employed approach of sequential cyclizations.
We thus focused upon the biosynthetic scheme of the
erythrina alkaloid, as it was originally proposed by Bar-
ton[1c,14] and later revised by Zenk.[15] The nine-membered
dibenz[d.f]azonine intermediate 9 undergoes an oxidation of
the phenol moiety by a two-step SET mechanism (Sche-
me 1a). The resulting planar cationic intermediate 10 is then
subject to a transannulation from the amine to give 11,
equipped with a tetrasubstituted C5 center.[16] Subsequent
adjustment of the oxidation state would give, for example,
erythraline (6). Inspired by this biosynthetic sequence, we
envisioned a novel asymmetric synthetic approach by using
different subtype selectivities.[6]
A divergent synthetic
approach to erythrina alkaloid analogues, having a variety
of peripheral functional groups, would therefore enable the
[*] H. Umihara
Graduate School of Pharmaceutical Sciences, University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
T. Yoshino, Dr. J. Shimokawa, Prof. Dr. M. Kitamura,
Prof. Dr. T. Fukuyama
Graduate School of Pharmaceutical Sciences, Nagoya University
Furo-cho, Chikusa, Nagoya, Aichi 464-8601 (Japan)
E-mail: kitamura@os.rcms.nagoya-u.ac.jp
fukuyama@ps.nagoya-u.ac.jp
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201602650.
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Scheme 1. Proposed biosynthesis and our synthetic strategy.
a nine-membered intermediate, which only Teetz and Ito
employed in erythrina alkaloid syntheses.[17] Construction of
the core structure of the tetracyclic moiety was deemed
accessible through the diastereoselective oxidative transfor-
mation of 12 into the dienone 13 (Scheme 1b). Subsequent
intramolecular reaction would form the C5 tetrasubstituted
chiral carbon center in 14. The chirality at the C11 benzylic
oxygen functionality was introduced with the expectation to
bias the stereoinduction during the oxidation. A variety of
erythrina alkaloids with a methylenedioxy moiety on the
D ring could be synthetically derived from 14 through
a combination of elimination, reduction, and oxidation of
the oxygen functionalities. This two-phase synthetic strategy
involving the initial construction of a common core structure
and further functionalization of the late-stage pluripotent
intermediate would facilitate the divergent syntheses of
natural, as well as artificial derivatives of the erythrina
alkaloids.[18]
Scheme 2. Construction of the nine-membered lactam intermediate.
Reagents and conditions: a) H2, Pd/C, EtOH, RT; b) Boc2O, CH3CN,
08C to RT; evap.; 2,2-dimethoxypropane, BF3·OEt2, acetone, 08C, 70%
(2 steps); c) NBS, CH3CN, 508C, 88%; d) SOCl2, CH3OH, 08C to RT,
95%; e) BBr3, CH2Cl2, 08C; f) MsCl, Et3N, CH2Cl2, 08C, 83% (2 steps);
g) [PdCl2(dppf)] (5 mol%), (Bpin)2, KOAc, 1,4-dioxane, 808C, 59%;
h) [PdCl2(dppf)] (10 mol%), Cs2CO3, DME, reflux; i) LiOH·H2O, THF/
H2O (1:1), RT, 90% (2 steps); j) H2O/HCO2H (1:2), 08C to RT;
k) DMT-MM, CH3OH (2.0 mm), RT, 62% (2 steps); l) 2-butanol, 908C,
40 h; m) TBSCl, imidazole, Cl(CH2)2Cl, 408C, 54% (2 steps); n) KOH,
CH3OH, 508C, 91%. Boc=tert-butoxycarbonyl, DME=dimethoxy-
ethane, DMT-MM=4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmor-
pholinium chloride, dppf=1,1’-bis(diphenylphosphanyl)ferrocene,
Ms=methanesulfonyl, NBS=N-bromosuccinimide, pin=pinacol,
TBS=tert-butyldimethylsilyl, THF=tetrahydrofuran.
Our synthesis commenced with the chiral nitro alcohol 15,
which was prepared by using the method reported by Gong
and co-workers[19] (Scheme 2).
A
subsequent three-pot
diastereomers comprising the stable biaryl atropisomers (M)-
21 and (P)-22 in a ratio of 2:1. The source of the inversion
barrier was attributed to the steric repulsion between the
protons on C7 and C11 according to Mislowꢀs pioneering
work on the stereochemical fixation of medium-sized biaryl
rings.[21] This assumption was experimentally supported by the
fact that the ketone 23, lacking a proton on C11, racemized
fairly rapidly (t1/2rac = 2025 sec at 258C[22]).[23] In an attempt to
improve the ratio of (M)-21 and (P)-22, it was found that
these were interconvertible when heated in 2-butanol at 908C.
After 40 hours of heating, the thermodynamically more
favorable (P)-22 was obtained as a major isomer with good
sequence afforded the bromoaryl compound 16 in 62%
overall yield. The coupling partner, the aryl boronate 18, was
synthesized in four steps from the commercially available
carboxylic acid 17. These two substrates were subjected to
Suzuki–Miyaura cross-coupling conditions to afford the biaryl
intermediate 19. Removal of the Boc and acetonide protect-
ing groups gave the amino-acid intermediate 20. Preferential
formation of the nine-membered lactam over the eight-
membered lactone was successfully achieved by means of
DMT-MM[20] as the condensation reagent in methanol.
Interestingly, the products proved to be a mixture of two
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diastereoselectivity [(M)-21/(P)-22 = 1:7].[24] Selective silyla-
synthesized by first treating 28 with Et3SiH under acidic
tion occurred only with (P)-22 and the ensuing demesylation
afforded 24 as a single isomer. The stereochemical config-
uration of the benzylic hydroxy group was thus successfully
transferred to the atropisomeric stereochemistry of the biaryl
moiety.
conditions to afford 30. 8-Oxo-erythraline[12h] (4) was
obtained by a sequence involving Luche reduction and
methylation. Finally, reduction of the amide moiety using
a combination of LiAlH4 and AlCl3[28] afforded erythraline[29]
(6). The first asymmetric total syntheses of these four
alkaloids suggested that our strategy might offer an efficient
route to a broad range of the erythrina alkaloids.
The X-ray structure of 24[25] revealed that the silyloxy
group is pointing toward the phenol moiety (Scheme 3). This
peculiar configuration along with the atropisomeric stereo-
chemistry was thus expected to influence the trajectory of the
incoming reagents. Thus the oxidative transformation of the
phenol moiety of 24 was performed by using singlet-oxygen
oxidation,[26] which actually gave only a single diastereomer
via the transition-state 25, without even forming the unde-
sired orthoquinone derivatives. The C5 position of the
dienone 26 was spontaneously attacked by the amide nitrogen
atom of the intermediate, thus creating the crucial tetrasub-
stituted carbon center. The in situ reduction of the hydro-
peroxide by PPh3 yielded the tertiary alcohol 27 bearing the
C11 oxygen functionality with the desired configuration.[27]
The stereochemistry of the biaryl atropisomer was thus
successfully transferred to the tetrasubstituted point chirality
at C5. The intermediate 27 thus obtained is equipped with the
common core helical architecture containing functional
groups on the A–C rings, which are amenable to further
modifications. The flexibility of 27 was showcased by the
facile transformations into four members of erythrina alka-
loids. Elimination of the tertiary hydroxy group by thionyl
chloride gave 28. Application of the diastereoselective Luche
reduction of the enone moiety[28] led to 29, which was
converted into 8-oxo-erythrinine[1e, 12h] (2) by methylation
and treatment with TBAF. Subsequent elimination of the
hydroxy group under acidic conditions afforded crystamidine
(1).[1f] The other series without a benzylic hydroxy group was
In conclusion, a versatile strategy for the synthesis of the
erythrina alkaloids has been developed by employing the
medium-membered dibenz[d.f]azonine intermediate 24. The
selective formation of the thermodynamically more favorable
biaryl intermediate and the diastereoselective control during
the singlet oxygen oxidation made it possible to construct the
requisite tetrasubstituted C5 center by intramolecular 1,4-
addition of an amide nitrogen atom. Throughout the trans-
formations, the chirality of the benzylic hydroxy group was
transferred to the atropisomeric stereochemistry, which in
turn controlled the point chirality at C5 by exploiting the
chemistry of the nine-membered ring. Manipulation of the
functionalities along the peripheral moieties of the core A–C
structure enabled the syntheses of four chiral erythrina
alkaloids and could potentially give rise to a divergent
synthetic strategy for this class of alkaloids.
Acknowledgements
This work was supported by JSPS (KAKENHI Grant
Numbers 23590003, 20002004, 15H05641, 13J04813) and the
Platform for Drug Discovery, Informatics, and Structural Life
Science from the Ministry of Education, Culture, Sports,
Science and Technology of Japan. The authors thank Mr.
Yusuke Suzuki (Nagoya University) for his support in X-ray
crystallographic analysis.
Scheme 3. Synthesis of the common intermediate and total syntheses of four erythrina alkaloids. Reagents and conditions: a) O2, hn, rose bengal,
PPh3, NaHCO3, CH3CN/H2O (1:1), RT; 77%; b) SOCl2, pyridine, 08C, 84%; c) NaBH4, CeCl3·7H2O, CH3OH, RT, 75%; d) CH3I, NaH, THF, RT;
e) TBAF, THF, RT, 84% (2 steps); f) TsOH·H2O (20 mol%), toluene, reflux, 77%; g) Et3SiH, BF3·OEt2, CH2Cl2, 08C, 74%; h) NaBH4, CeCl3·7H2O,
CH3OH, RT; i) CH3I, KOH, Et4NBr, THF, RT, 86% (2 steps); j) LiAlH4, AlCl3, THF/Et2O (1:1), 08C, 73%.
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Received: March 16, 2016
Published online: May 12, 2016
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