Synthesis of (+)-Lysergol and Its Analogues to Assess Serotonin Receptor Activity

Article abstract of DOI:10.1021/acs.orglett.6b03779

An efficient synthesis of ergot alkaloid lysergol and its analogues is described, providing compounds for functional evaluation at the human 5-HT_1A, 5-HT_2A, 5-HT_2B, or 5-HT_2C receptors. Key features of the synthesis include the development of a tandem reaction to construct the multifunctionalized piperidine skeleton and use of a rhodium-catalyzed [3 + 2] annulation in the late-stage indole formation.

Full text of DOI:10.1021/acs.orglett.6b03779

Letter
pubs.acs.org/OrgLett
Synthesis of (+)-Lysergol and Its Analogues To Assess Serotonin
Receptor Activity
†
†
,†,‡
Haosen Yuan, Zhixian Guo, and Tuoping Luo*
†
Key Laboratory of Bioorganic Chemistry and Molecular Engineering, Ministry of Education, Beijing National Laboratory for
‡
Molecular Science, College of Chemistry and Molecular Engineering, and Peking-Tsinghua Center for Life Sciences, Academy for
Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
*
S Supporting Information
ABSTRACT: An efficient synthesis of ergot alkaloid lysergol
and its analogues is described, providing compounds for
functional evaluation at the human 5-HT , 5-HT , 5-HT ,
1
A
2A
2B
or 5-HT2C receptors. Key features of the synthesis include the
development of a tandem reaction to construct the multi-
functionalized piperidine skeleton and use of a rhodium-
catalyzed [3 + 2] annulation in the late-stage indole formation.
5
he total synthesis of small-molecule natural products
psychiatric, and neurodegenerative disorders. For instance,
T
provides a reliable method for making deep-seated and
flexible structural changes of a targeted chemotype, leading to
valuable analogues that are inaccessible from semisynthesis or
agonists against 5-HT1 have been heralded as a new class of
A
6
antidepressant drugs, while 5-HT agonists have the potential
2A
7
for enhancing cognition. Herein, we describe a new synthesis
1
of (+)-lysergol (1) in a concise and enantioselective manner
that will facilitate the study of structure−activity relationships.
Even though the chemical synthesis of the ergot alkaloids has
been intensively investigated over the last six decades, most
approaches either used substituted indoles as the starting
materials or constructed the indole ring in the early stage of the
synthetic biology. We have therefore embarked on a synthetic
program to assemble a collection of natural products and their
analogues for biological evaluation, which ensures the
reproducible and comparable data. Lysergol (1) and lysergic
acid (2) are prototypes of ergot alkaloids that have important
2
3
pharmacological properties that engage various serotonin G
protein-coupled receptors (Figure 1). Among the serotonin
8
synthesis. In a previous report, we delineated the synthesis of
4
lysergine (3) via a radical cyclization/fragmentation strategy,
(5-HT) receptors, 5-HT1A and 5-HT have been the most
9
2
also starting from an indole fragment. In order to prepare
studied due to their involvement in emotional, neuro-
ergot alkaloid analogues with substituents on the phenyl ring to
optimize their affinity and selectivity at 5-HT receptor
10
subtypes, we investigated the potential of forging the indole
ring at a late stage in the synthesis. An intramolecular
dearomatizing [3 + 2] annulation reaction to furnish 3,4-
fused indole skeletons developed by Murakami and co-workers
attracted our attention, which has been used for the synthesis of
11
racemic Uhle’s ketone, a precursor for ergot alkaloids. We
envisaged that this reaction could be used to construct 4, a late-
stage intermediate for the synthesis of (+)-lysergol (1), if a
highly substituted tetrahydropyridine (5a) could be readily
prepared (Figure 1). Moreover, introduction of the phenyl
group to the highly substituted tetrahydropyridine 5a by Pd-
catalyzed cross-coupling with bromide 6a would allow easy
variation of the substituents on the phenyl ring for analogue
generation. We proposed that the ring-opening of gem-
12
dibromocyclopropane 9 would give rise to iminium 7,
which could be trapped in situ by allenyltributyltin 8 to
produce 6a. Intermediate 9 could in turn be prepared through
cyclopropanation of the simple monocyclic enamine 10.
Received: December 19, 2016
Figure 1. Retrosynthetic analysis of (+)-lysergol (1).
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03779
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
We commenced our studies by making chiral alcohol 11
from (R)-Garner’s aldehyde following the reported procedures,
which took five steps with 48% overall yield (Scheme 1).
Table 1. Optimization of the Ring-Opening/Nucleophilic
Substitution Cascade Reaction
8p
Scheme 1. Synthesis of 5a and 5b
a
b
entry Lewis acid (equiv) conditions
time (h) yield (%) (13a/13b)
c
1
2
3
4
5
6
7
8
9
Sc(OTf) (1.1)
THF, rt
1
trace
3
c
c
c
d
AgOTf (1.1)
THF, rt
1
50 (2:1)
38 (5:3)
60 (5:3)
83 (5:3)
ZnCl (1.1)
THF, rt
1
2
ZnCl (0.1)
THF, rt
2
2
ZnCl (0.1)
THF, rt
2
2
d
ZnCl (0.1)
THF, 0 °C
MeCN, rt
DCM, rt
toluene, rt
5
7 (5:3)
2
d
d
d
ZnCl (0.1)
1.5
2
53 (3:1)
65 (2:1)
85 (2:1)
2
ZnCl (0.1)
2
ZnCl (0.1)
3
2
a
The reaction was carried out with 0.15 mmol of 10; 1.5 mL of solvent
b
was used in the second step. Isolated yield after flash chromatog-
raphy. 1.3 equiv of 12 was used. 2.0 equiv of 12 was used.
c
d
of a similar N-sulfonyliminium intermediate with carbon-based
16
nucleophiles.
The mixture of 13a and 13b underwent Suzuki coupling with
phenylboronic acid to provide 14a and 14b in excellent yield.
Fortunately, after the redox manipulation and Seyferth−Gilbert
homologation using Bestmann−Ohira reagent 15, a pair of C5
epimers, alkynes 5a and 5b, could be readily separated by flash
chromatography. After the stereochemistry of 5a and 5b was
assigned by extensive 2D-NMR experiments (see the
Supporting Information), the next step was to convert them
to lysergol (1) and isolysergol (19), respectively (Scheme 2).
To this end, N-sulfonyl-1,2,3-triazole 16 was first prepared
Protecting the primary alcohol of 11 with TBS followed by
silver-catalyzed 5-endo-dig cyclization afforded 10 in 85% yield
1
3
over two steps. The reaction of 10 with dibromocarbene
14
proceeded smoothly in petroleum ether at −30 °C, but the
product was not stable and was therefore subjected to the
propargylation reaction without flash chromatography. This
procedure eventually gave rise to a pair of inseparable
diastereomers 6a and 6b (ratio 3:2) using 1.1 equiv of
Scheme 2. Synthesis of (+)-Lysergol (1) and (−)-Isolysergol
Sc(OTf) and 3 equiv of allenyltributyltin 8 in the second step.
3
(
19)
Unfortunately, a variety of Pd-catalyzed coupling reactions,
including Suzuki, Stille, and Negishi reactions, failed to provide
the desired tetrahydropyridines (5a/5b). The presence of a
neighboring alkyne to the alkenyl bromide may have caused
complications as the 4-exo-dig cyclocarbopalladation has been
15
well-documented for this structure feature.
To overcome this synthetic hurdle, we switched to silyl
ketene acetal 12 as the nucleophile and further optimized the
conditions to furnish 13a and 13b (Table 1). Interestingly, only
a trace amount of product was obtained when Sc(OTf) was
3
used as the Lewis acid (entry 1). When the ring-enlargement/
nucleophilic addition reaction was promoted by 1.1 equiv of
AgOTf, 13a and 13b were obtained in 50% overall yield with a
2
:1 ratio (entry 2). Even though 1.1 equiv of ZnCl gave a low
2
yield (38%, entry 3), reducing the amount of Lewis acid to 0.1
equiv significantly improved the reaction efficiency (60%, entry
4
), indicating the decomposition of 12 in the presence of the
Lewis acid could be an issue in this cascade transformation. We
were delighted to find that increasing the amount of C-
nucleophile 12 afforded 13a and 13b in 83% overall yield with a
5:3 ratio (entry 5). However, lowering the reaction temperature
to 0 °C essentially shut down the reaction (entry 6). Several
solvents were also examined (entries 7−9), revealing that
toluene behaved slightly better than THF (entry 9). The
preference for 1,2-addition over 1,4-addition is consistent with
the observation made by Rutjes and co-workers for the reaction
B
DOI: 10.1021/acs.orglett.6b03779
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
using a copper-catalyzed [3 + 2] cycloaddition. A subsequent
rhodium-catalyzed intramolecular dearomatizing [3 + 2]
annulation reaction followed by oxidative aromatization and
deprotection of the TBS group furnished compound 4 in 67%
yield over two steps. Eventually, deprotection of Ts groups and
reductive amination completed the total synthesis of
Table 2. Agonist Properties of Lysergol and Analogues at
Serotonin Receptors
EC50 ± SEM (nM)
compd
5-HT1A
11 ± 2
73 ± 6
342 ± 23
481 ± 31
424 ± 27
5-HT2A
5-HT2B
0.071 ± 0. 010
>10000
5-HT2C
5-HT
0.96 ± 0.14
1.6 ± 0.5
2.7 ± 1.6
0.14 ± 0.03
a
b
(+)-lysergol (1). In parallel, subjecting 5b to the same
(+)-1
6.6 ± 1.4
c
d
e
sequence of transformations afforded (−)-isolysergol (19).
Interestingly, the [3 + 2] annulation/rearomatization tandem
reaction gave a better yield of the corresponding indole product
(±)-3
(−)-19
(+)-26
145 ± 54
>10000
>10000
103 ± 9
>10000
>10000
f
12 ± 3
>10000
a
b
c
(
4
18) in this scenario. It is noteworthy that both enantiomers of
5
1% max 5-HT stimulation. 43% max 5-HT stimulation. 57% max
d
e
and 18 have been prepared via an elegant Pd-catalyzed
5-HT stimulation. 36% max 5-HT stimulation. 42% max 5-HT
stimulation. 17% max 5-HT stimulation.
8p
f
domino reaction by the group of Fujii and Ohno. The
spectroscopic data of the synthesized samples of 1, 4, 18, and
1
9 were in good agreement with those reported in the
8j,o,p,17
literature.
Encouraged by the synthesis of (+)-lysergol (1) and
−)-isolysergol (19), we moved on to prepare an analogue of
at both 5-HT2A and 5-HT2C receptors with single-digit
nanomolar EC50. In comparison, (+)-13-fluorolysergol (26),
substituting a fluoride for the C13 hydrogen of 1, exhibited
substantially lower potency (12 nM vs 1.6 nM) and efficacy
(
lysergol with the C13 hydrogen substituted by fluorine (26,
Scheme 3). To this end, 3,5-difluorophenylboronic acid 20 was
(
17% vs 51% Emax) at the 5-HT2A receptor and lost the ability
to activate the 5-HT2c receptor. (−)-Isolysergol (19), the
Scheme 3. Synthesis of (+)-13-Fluorolysergol (26)
8o,p,17
enantiomer of (+)-isolysergol synthesized previously,
only
activated the 5-HT1A receptor, implying the importance of the
C5 stereogenic center in (+)-lysergol (1). Even though further
investigation is required, the preliminary data for racemic
lysergine (3) suggest that the hydroxyl group in (+)-lysergol
(
1) plays a role in interacting with the 5-HT receptors.
In summary, we have achieved the synthesis of (+)-lysergol
1) in 13 steps and 11% overall yield starting from enantiopure
(
1
1. More importantly, the dramatically different properties
resulting from a single atom change to lysergol reinforces the
value of total synthesis in studying the biological activities of
natural products. Our strategy of preparing highly function-
alized piperidines and substituted indoles could be further
applied to the synthesis of various alkaloids, which is ongoing in
our group and will be reported in due course.
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.6b03779.
Detailed experimental procedures, compound character-
ization data, and biological assay protocols (PDF)
used in the Suzuki coupling reaction with bromides 13a and
1
3b. Following the same protocols, tetrahydropyridine 22a was
AUTHOR INFORMATION
Corresponding Author
■
*
isolated in 41% yield through the redox manipulations and
homologation and was further converted to N-sulfonyl-1,2,3-
triazole 23 in high yield. In this case, the rhodium-catalyzed
intramolecular dearomatizing [3 + 2] annulation reaction was
followed by the addition of excess TEA to facilitate the
elimination of the hydrogen fluoride of intermediate 24. The
subsequent TBS deprotection provided 25 in 32% yield over
two steps. Removal of the Ts groups and reductive amination
eventually lead to (+)-26 in 68% yield over two steps.
E-mail: tuopingluo@pku.edu.cn.
ORCID
Tuoping Luo: 0000-0003-2156-3198
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The agonist properties of compounds 1, 3, 19, and 26 were
■
evaluated in a calcium flux assay using CHO-K1 cells expressing
This work was supported by generous start-up funds from the
National “Young 1000 Talent Plan” Program, College of
Chemistry and Molecular Engineering, Peking University,
Peking-Tsinghua Center for Life Sciences, and the National
Science Foundation of China (Grant Nos. 21472003,
31521004, and 21672011).
5
-HT , 5-HT , 5-HT , or 5-HT with serotonin as the
1A 2A 2B 2C
18
positive control (Table 2 and Figures S1−4). All four
compounds demonstrated full agonism at the 5-HT receptor,
1
A
with (+)-lysergol (1) being over 5-fold more potent than the
other three. (+)-Lysergol (1) also proved to be a partial agonist
C
DOI: 10.1021/acs.orglett.6b03779
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
12) (a) Lantos, I.; Bhattacharjee, D.; Eggleston, D. S. J. Org. Chem.
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