Enantioselective Total Synthesis of (+)-Dihydro-β-erythroidine

Article abstract of DOI:10.1021/jacs.9b04626

Erythrina alkaloids represent a rich source of complex polycyclic, bioactive natural products. In addition to their sedative and hypotensive effect, their curare-like activity and structural framework have made them attractive targets for synthetic and medicinal chemists. (+)-Dihydro-β-erythroidine (DHβE), the most potent nicotine acetylcholine receptor antagonist (nAChR) of the Erythrina family, is synthesized for the first time in 13 steps from commercially available material.

Full text of DOI:10.1021/jacs.9b04626

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Enantioselective Total Synthesis of (+)-Dihydro-#-erythroidine.
Sebastian Clementson, Mikkel Jessing, Henrik Pedersen, Paulo Vital, and Jesper L. Kristensen
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 23 May 2019
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Enantioselective Total Synthesis of (+)-Dihydro-β-erythroidine.
Sebastian Clementson,†,‡ Mikkel Jessing, Henrik Pedersen, Paulo Vital,* and Jesper L. Kristensen*
‡
#
,‡
,†
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†
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen,
Universitetsparken 2, 2100 Copenhagen, Denmark.
‡
Molecular Discovery and Innovation, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark
#
Compound Management and Analytical Chemistry, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark
Supporting Information Placeholder
A
ABSTRACT: Erythrina alkaloids represent a rich source of
complex polycyclic, bioactive natural products. In addition to their
sedative and hypotensive effect, their curare-like activity and
structural framework have made them attractive targets for
synthetic and medicinal chemists. (+)-Dihydro-β-Erythroidine
Alkenoid type
Dienoid type
O
O
N
N
Non-
aromatic
(lactonic)
O
O
H
H
MeO
MeO
(DHβE), the most potent nicotine acetylcholine receptor antagonist
()-Dihydro--erythroidine (1)
()--Erythroidine (2)
(nAChR) of the Erythrina family is synthesized for the first time in
13 steps from commercially available material.
MeO
MeO
O
Aromatic
N
N
O
H
H
MeO
MeO
The Erythrina alkaloids were first characterized at the end of the
1
9th century. Today, more than 100 members of the erythrinanes
()-Erythramine
()-Erysotrine
have been isolated from specimens collected throughout the
1
,2
B
tropical and subtropical regions of the world. These alkaloids
possess unique structural attributes, with a tetracyclic, α-tertiary
spiroamine scaffold that connects the A, B and C rings in a
dextrorotatory (S) fashion, see Figure 1B. Depending on the nature
of the D-ring, they are categorized into aromatic and non-aromatic

-tertiary amine
HO
HO
D
C
Tetracyclic spiroamine
> 100 members
HN
Nature
N
5
B
7
H
A
6
O
1
MeO
Neuromuscular
blocking effect
2
(lactonic) alkaloids. Further subdivision can also be made
O
depending on the presence of a conjugated unsaturation in the A
and B ring at the C-1, C-2, C-6 and C-7 carbons, or a double bond
in the A ring at the C-1 and C-6 carbons (Figure 1 B).
C
O
O
O
1
,3
12
MeO
MeO
O
[
D-ring]
[C-ring]
N
N
N
The structure of (+)-Dihydro-β-erythroidine (DHβE (1), Figure
1A) was first elucidated back in 1953 and it can be found in the
seeds of the Erythrina Americana family of Mexican coral plants.
TfO
13
O
14 13
H
MeO
H
H
6
Dieckmann
condensation
Decarboxylative
1
MeO
MeO
MeO
1
-cyanation
3
4
4
,5
DHβE (1) is one of the most potent nicotine acetylcholine
receptor (nAChR) antagonists described to date (IC50(α4β2):
[A-ring]
RCM
6
,7
0
.11µM) and it has been used in a vast number of studies both in
8–12
vitro and in vivo.
DHβE (1) has been demonstrated to have
Asymmetric
allylation
OMe
OMe
O
2
Boc
3
Boc
N
antidepressant-like activities in various preclinical assays, and was
used as a muscle relaxant several years ago in the treatment of
Parkinson’s disease to relieve tetanus and spastic disorders.
Importantly, DHβE (1) is effective when administered perorally
Boc
AAA
4
N
5
N
O
MeO
MeO
7
O
O
6
O
5
Figure 1. A) Representative members and categorization of the alkaloid
family. B) Erythrina alkaloids; proposed biosynthesis and properties. C)
Key transforms in the retrosynthetic analysis.
8
,12,13
demonstrating its excellent drug-like properties.
Several other
Erythrina alkaloids have been shown to possess an antidepressant
like neuromuscular blocking effect and many of them have been
5
used as sedatives and hypnotics in traditional Mexican medicine.
3
spiroamine skeleton (Figure 1B). Given the interesting structural
features and numerous applications, Erythrina alkaloids have been
popular targets for total synthesis. The majority of synthetic work
has been devoted to the aromatic erythrinan subclass of
compounds,
Thus, the Erythrina alkaloids are an interesting source of new
chemical leads for drug discovery.
The biogenesis of Erythrina alkaloids is not fully biochemically
elucidated, but envisioned to be the condensation of two molecules
of 3,4-dihydroxyphenylalanine to give an indoline nucleus, which
then undergoes further oxidative manipulations to furnish the
2,6,14
whereas only a few synthetic approaches to the
15a-f
non-aromatic alkaloids have been reported.
Hatakeyama group published an enantioselective synthesis of (+)-
In 2006, the
β- Erythroidine (β-E) (2) in 26 steps.
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Scheme 1. 13-Step Total Synthesis of (+)-DHβE (1)a
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3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
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3
3
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3
3
4
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5
5
5
5
5
6
Me
Me
MeO
H Me
OMe
e.
OMe
O
O
12
OH
Boc
Boc
a. [PdCl(allyl)]2, K2CO3,
Boc
Boc
N
B
3
b. OsO4, NMO, then NaIO4
N
MeO
N
MeO
N
OAc 8
O
c. CH(OMe) , CSA
O
HCl (aq.)
3
H
MeO
O
O
87%
67%, [2 steps]
60% of
13 (major diastereomer)
4% total yield
O
X
O
9
7
9
6
10: X = O
11: X = CH2
13
d. MePPh3Br, KOtBu, 52%
9
5% ee
1.8:1 d.r. at C3
Ph2P
NH HN
PPh2
f. Me3OBF4,
Proton-Sponge
O
O
89%
MesN
Cl
g.
NMes
14
h. TFA, then
NaBH3CN,
O
O
12
O
O
Ru
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MeO
MeO
OMe
AcOH
MeO
Cl
OMe
Boc
N
1
6
NOE
Ph
O
Boc
PCy3

N
i. KOtBu, 
N
HO 13
H
OMe
N
H
H
3
MeO
O
MeO
96%
MeO
95%
1
7
4
15
99% ee
MeO
[
steps a-h,
gram scale]
5
>
[enantioenrichment]
j. NaH, Tf2O
62%, [2 steps]
O
[
13 steps]
O
MeO
TfO
CN 19
k. Dibal-H
KO
O
TBSO
TfO
H
TBSO
NC
then
l. TBSCl, imidazole
m. [PdCl(allyl)]2, S-Phos, 
HCl, MeOH/H O, 
N
N
3
N
N
2
O
H
H
74%, [2 steps]
H
54%, [one pot]
MeO
)-DHE (1)
MeO
MeO
18
MeO
20
(
aReagents and conditions: a) [PdCl(allyl)]
0.04 equiv), NMO (1.3 equiv), THF:H O, room temperature, 12 h, then NaIO
equiv), toluene, room temperature, 2 h, 67% for two steps; d) MePPh Br (2.1 equiv), KOtBu (2 equiv), THF, 30 C, 10 h, 52%; e) 12 (1.2 equiv), HCl (1
equiv), DCM: H O, room temperature, 8 h, 60% for 13, 94% total yield, d.r. 1.8:1; f) Me OBF (3 equiv), Proton-Sponge (3 equiv), DCM, room temperature,
3 h, 89%; g) 14 (0.075 equiv), toluene, 80 C, 2 h, 95%, >99% ee; h) TFA:DCM, room temperature, 30 min, then 16 (2 equiv), AcOH (3 equiv), NaBH CN
(3 equiv), THF:MeOH, room temperature, 5 h, 96%; i) KOtBu (2.3 equiv), toluene, 95 C, 1 h; j) NaH (4 equiv), Tf O (2 equiv), THF:Et O, room temperature,
h, 62% for two steps; k) Dibal-H (3 equiv), DCM, -78 – 0 C, 1.5 h; l) TBSCl (2 equiv), imidazole (3.2 equiv), DCM, room temperature, 2 h, 74% for two
steps; m) 19 (3 equiv), [PdCl(allyl)]
(0.025 equiv), 9 (0.05 equiv), K
CO
(1.05 equiv), 8 (1.05 equiv), DMF, -40 – 0 C, 2.5 h, 87%, 95% ee; b) OsO
(2 equiv), DCM, room temperature, 4 h; c) CH(OMe) (1.1 equiv), CSA (0.1
2
2
3
4
(
2
4
3
3
2
3
4
3
2
2
1
2
(0.2 equiv), S-Phos (0.4 equiv), mesitylene, 110 C, 30 min, then HCl:H O, 85 C, 30 min, 54%. CSA = camphorsulfonic
2
acid, DCM = dichloromethane, Dibal-H = diisobutylaluminium hydride, DMF = N,N-dimethylformamide, NMO = N-methylmorpholine N-oxide, S-Phos =
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, TFA = trifluoroacetic acid, THF = tetrahydrofuran.
Later that year the Funk group published a synthesis of the same
natural product in a total of 20 steps giving access to racemic
material; an approach which was used to synthesize several other
congeners of β-E (2) with similar synthetic efficiency. Herein, we
wish to report the first total synthesis of DHβE (1).
the sterically encumbered ketone with a wide range of titanium
to no success (see SI Table 2). Peterson and
Grignard reagents reacted selectively with the ester and Boc-
group respectively. Eventually, Wittig methenylation proved
superior and provided the desired olefin 11 in 52% yield.
Subsequently, hydrolysis followed by in situ allylation of the
1
9a-g
20
carbenoids,
2
1
2
2
The first key transform in our retrosynthetic analysis of DHβE
1) would rely on a late-stage palladium catalyzed enolate
23
aldehyde with (+)-allylboronic acid pinanediol ester (12)
(
provided allylic alcohol 13 as the major component of a 1.8:1
mixture of diastereoisomers. Several other reagents were
investigated in an attempt to improve the selectivity, however they
were all inferior to the boronic ester 12 (see SI Table 3 and Figure
S5).
coupling-lactonization, initiated by the construction of the C13-
C14 bond, thereby forming the D-ring (see Figure 1C). The C-ring
would be assembled by a Dieckmann-condensation and a reductive
amination, providing the spiroamine scaffold with the desired
oxidation states. A ring-closing metathesis (RCM) and an
asymmetric allylation would furnish the C1-C6 double bond and
the C2-C3 bond respectively, closing the A-ring and establishing
the alkenoid core structure 4. The synthesis would commence with
the installment of the α-tertiary-amine stereogenic center at C5,
using a Tsuji-
The diastereomers of the resulting allylic alcohol 13 were, at this
time, inseparable and they were thus carried through until the
formation of the bicyclic system 15 in the following way:
methylation of the alcohol gave methyl ether 5, which underwent
2
4a,b
RCM
in excellent yield, delivering the bicyclic ester 15, bearing
the A-B-alkenoid architecture of the Erythrina alkaloids. At this
point, the desired diastereomer was readily separated from the
unwanted diastereomer by column chromatography and it could
also be further enantioenriched, using chiral chromatography. The
relative configuration at C-3 was established by the noticeable
presence of a through-space coupling between the methine proton
at C-3 and the methyl ester (Scheme 1) in the NMR-spectra. Taking
inspiration from Hatakeyama and coworkers, deprotection and
reductive alkylation of the secondary amine using aldehyde 16
provided bis-ester 4, which set the stage for the assembly of the C-
ring at C12-C13 via an intramolecular Dieckmann condensation.
Spiroamine 17, which resided almost exclusively as its enol
tautomer in aprotic solvents, was immediately subjected to sodium
Trost asymmetric allylic alkylation (AAA). This approach would
allow for a rapid assembly of the tetracyclic erythrinan framework.
In the forward sense, the key aza-tertiary stereocenter was
installed by subjecting commercially available prolinone 7
(Scheme 1) to a Tsuji-Trost AAA
Screening of different ligands, bases and solvents (see SI Table 1)
identified ligand 9 in combination with allyl acetate 8, potassium
carbonate and allylpalladium chloride dimer as an ideal
combination, which delivered allyl prolinone 6 in 87% yield and
5% ee. Upjohn dihydroxylation followed by periodate mediated
oxidative cleavage
1
6a,b
on multigram scale.
1
5a
17
9
1
8a,b
of the terminal olefin gave the
corresponding, unstable aldehyde that was isolated as the dimethyl
acetal 10. With acetal 10 in hand we then attempted to methenylate
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Journal of the American Chemical Society
hydride and triflic anhydride to give enol triflate 3 in 62% yield
over two steps.
(4) Boekelheide, V.; Weinstock, J.; Grundon, M. F.; Sauvage, G. L.;
Angello, E. J. The Structure of β-Erythroidine and its Derivatives. J. Am.
Chem. Soc. 1953, 75, 2550.
1
2
3
4
5
6
7
8
9
Moving forward, reduction of the ester and subsequent TBS-
protection furnished silyl ether 18. Silyl protection was necessary,
since the corresponding alcohol was unstable. We envisioned that
the final two carbons of the lactone ring would be installed via an
enolate coupling, however it was quickly realized that base-
(5) García-Mateos, R.; Soto-Hernández, M.; Vibrans, H. Erythrina
Americana Miller ("Colorin"; Fabaceae), a versatile resource from Mexico:
a review. Econ. Bot. 2001, 55, 391.
(6) Majinda, R.R. An Update of Erythrinan Alkaloids and Their
Pharmacological Activities. In Progress in the Chemistry of Organic
Natural Products; Kinghorn, D. A.; Falk, H.; Gibbons, S.; Kobayashi, J.;
Asakawa, Y.; Liu, J.-K., Ed.; Springer, Cham, 2018, pp 95–152.
dependent procedures, described by Hartwig, Buchwald and
25a-d
others,
were ineffective as the coupling precursor 18, rapidly
(7) Jensen, A. A.; Frølund, B.; Liljefors, T.; Krogsgaard-Larsen, P.
decomposed when exposed to basic conditions under slightly
elevated temperatures (see SI Table 4). We then turned to the
Neuronal Nicotinic Acetylcholine Receptors: Structural Revelations,
Target Identifications, and Therapeutic Inspirations. J. Med. Chem. 2005,
2
6
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9
0
chemistry developed by Liu and coworkers, which allowed us to
circumvent this issue by installing the final two carbons using a
base-free decarboxylative coupling of cyanoacetate 19 to furnish α-
alkenyl nitrile 20. This is, to the best of our knowledge, the first
employment of this chemistry on an alkenyl system as well as in a
target-oriented synthesis. Ultimately, a process was developed in
which the cross coupling was telescoped with an acid mediated
hydrolysis, deprotection and lactonization-cascade, delivering (+)-
DHβE (1) in 13 steps from commercially available prolinone 7.
4
8, 4705.
(8) Shapiro, S.; Baker, A. B. Treatment of Paralysis Agitans with
Dihydro-beta-erythroidine. Am. J. Med. 1950, 8, 153.
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with d-Tubocurarine Chloride in Peanut Oil with Myricin. Anesthesiology
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10) Williams, M.; Robinson, J. Binding of the Nicotinic Cholinergic
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(
1
(
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(11) Badio, B.; Shi, D.; Martin, H. M.; Daly J. W. Antinociceptive
Effects of the Alkaloid Epibatidine: Further Studies on Involvement of
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In summary, we have developed an enantioselective synthetic
route to the alkenoid family of non-aromatic Erythrina alkaloids
and the first total synthesis of (+)-DHβE (1). It is envisioned that
several intermediates from this synthetic sequence (in particular 15
and 17) will serve as versatile platforms from which structurally
diverse DHβE-congeners can be accessed. Such endeavors, will
serve to explore the structural requirements for nAChR-antagonism
and probe the potential of such derivatives in drug discovery.
Furthermore, the application of the current methodology to the
synthesis of other lactonic Erythrina alkaloids will also be
investigated.
(12) Andreasen, J.; Olsen, G.; Wiborg, O.; Redrobe, J. Antidepressant-
like Effects Antagonists, but Not Agonists, of Nicotinic Acetylcholine
Receptor in the Mouse Forced Swim and Mouse Tail Suspension Tests. J.
Psychopharmacol. 2009, 23, 797.
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Hydrochloride for Spastic and Dystonic States. Arch. Neurol. Psychiatry
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(14) Heller, S. T.; Kiho, T.; Narayan, A. R. H.; Sarpong, R. Protic-
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Propargylic Alcohols: Syntheses of (±)-3-Demethoxyerythratidinone and
(±)-Cocculidine. Angew. Chem. Int. Ed. 2013, 52, 11129.
(
15) a) Fukumoto, H.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. Total
ASSOCIATED CONTENT
Supporting Information
Synthesis of (+)-β-Erythroidine. Angew. Chem. Int. Ed. 2006, 45, 2731. b)
He, Y.; Funk, R. L. Total Syntheses of (±)-β-Erythroidine and (±)-8-oxo-
β-Erythroidine by an Intramolecular Diels−Alder Cycloaddition of a 2-
Amidoacrolein. Org. Lett. 2006, 8, 3689. c) Kawasaki, T.; Onoda, N.;
Watanabe, H.; Kitahara, T. Total Synthesis of (±)-Cocculolidine.
Tetrahedron Lett. 2001, 42, 8003. d) Funk, R. L.; Belmar, J. Total synthesis
of (±)-Isophellibiline. Tetrahedron Lett. 2012, 53, 176. e) Jepsen, T. H.;
Glibstrup, E.; Crestey, F.; Jensen, A. A.; Kristensen, J. L. A Strategic
Approach to [6,6]-Bicyclic Lactones: Application Towards the CD
Fragment of DHβE. Beilstein J. Org. Chem. 2017, 13, 988. f) Jepsen, T. H.;
Jensen, A. A.; Lund, M. H.; Glibstrup, E.; Kristensen, J. L. Synthesis and
Pharmacological Evaluation of DH β E Analogs as Neuronal Nicotinic
Acetylcholine Receptor Antagonists. ACS Med. Chem Lett. 2014, 5, 766.
The Supporting Information is available free of charge on the ACS
Publications website at DOI: .
Experimental section including characterization (PDF)
AUTHOR INFORMATION
Corresponding Authors
*
*
PJVV@Lundbeck.com
jesper.kristensen@sund.ku.dk
(16) a) Trost, B. M.; Schäffner, B.; Osipov, M.; Wilton, D. A. A.
Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of β-
ketoesters: An Unusual Counterion Effect. Angew. Chem. Int. Ed. 2011, 50,
3
548. b) Trost, B. M.; Crawley, M. L. Asymmetric Transition-Metal-
ACKNOWLEDGMENT
Catalyzed Allylic Alkylations: Applications in Total Synthesis. Chem. Rev.
2
003, 103, 2921.
This research was financially supported by the Innovation Fund
Denmark (Case no. 7038-00149B) and H. Lundbeck A/S. We thank
the Medicinal Chemistry department at H. Lundbeck A/S for
valuable resources and inputs. We would also like to thank Emil
Märcher-Rørsted for chromatographic aid.
(17) Vanrheenen, V.; Kelly, R. C.; Cha, D. Y. An Improved Catalytic
4
Oxidation of Olefins to Cis-1,2-Glycols Using Tertiary Amine Oxides
OsO
as the Oxidant. Tetrahedron Lett. 1976, 17, 1973.
18) a) Pappo, R.; Allen, D. S.; Lemieux, R. U.; Johnson, W. S. Osmium
Tetroxide-Catalyzed Periodate Oxidation of Olefinic Bonds. J. Org. Chem.
956, 21, 478. b) Li, W.; Chen, Z.; Yu, D.; Peng, X.; Wen, G.; Wang, S.;
(
1
Xue, F.; Liu, X.-Y.; Qin, Y. Asymmetric Total Syntheses of the
Akuammiline Alkaloids (-)-Strictamine and (-)-Rhazinoline. Angew. Chem.
Int. Ed. 2019, 58, 6059.
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TOC:
Me
Me
()-Dihydro--erythroidine
O
H
Me
O
O
CN
B
KO
N
O
O
H
OMe
H
Boc
-
13 steps
N
MeO
O
- Asymmetric
O
O
OAc
O
OMe
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