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org/OrgLett Letter

A Short Synthesis of Ergot Alkaloids and Evaluation of the 5‑HT1/2

Receptor Selectivity of Lysergols and Isolysergols
Nikhil R. Tasker and Peter Wipf*
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ABSTRACT: Key transformations in a four-step synthesis of the ergot

alkaloid scaffold include a novel cesium carbonate-mediated hydrogen
Downloaded via KING'S COLLEGE LONDON on January 10, 2024 at 09:45:32 (UTC).

autotransfer alkylation to generate the C(3)−C(4) bond and an

intramolecular Heck reaction that directly establishes the C(9)−C(10)
alkene of methyl lysergate. An ester reduction and a streamlined
experimental procedure establish a readily scalable, expedient total
synthesis of all four stereoisomers of lysergol and isolysergol, including
the previously unknown (−)-lysergol, for pharmacological evaluation at
5-HT1A and 5HT2A,B,C receptors. A bicyclic scaffold is also characterized for the first time in the intramolecular Heck coupling.

S ynthetic and pharmacological investigations of ergot

alkaloids have been pursued for more than a century,
inspired by their striking biological properties and the potential
of these natural products to treat migraine, mood disorders,
and cognitive ailments. Recent clinical results have renewed
the interest in D-lysergic acid diethylamide (D-LSD), first
marketed as Delysid by Sandoz Ltd. in 1947, as a medication
for depression, anxiety, neurodegeneration, and substance
abuse disorders.1 However, given the strong hallucinogenicity
and adverse side effects associated with D-LSD, establishing
effective dosing regimens in a controlled clinical environment
has remained a challenge.2−4 In comparison to investigations
of lysergic acid amides, the therapeutic potential of many other
ergot alkaloids has remained underutilized, in spite of their
frequently more selective dopamine and serotonin receptor
binding profiles.5,6 For example, (+)- and (−)-cycloclavine
were found to show increased selectivity for dopamine D3 and
serotonin 5-HT1A and 5-HT2A central nervous system (CNS)
receptors,7,8 and indole fluorination of (+)-lysergol enhanced
selectivity among 5-HT receptors compared to D-LSD.9
Selective agonism at 5-HT1−7 receptors is a target profile for
the treatment of neuropsychiatric conditions, with the
potential to yield new classes of therapeutics.10,11 Furthermore,
structural modifications of ergot alkaloids may deliver more
effective therapeutic agents compared to the available portfolio
of natural products and lysergate amides and avoid ergotism, a
disease causing convulsions and gangrene.
Several of the less thoroughly studied clavine alkaloids have
been synthesized,12−14 but most of these reports showcase
novel reaction methods without exploring analogue develop-
ment and are limited in scope by the availability of starting
materials, synthesis length, and stability of intermediates.
Strategies for rapidly accessing the ergoline scaffold would
accelerate drug discovery and empower medicinal chemists to
expand structure−activity relationship (SAR) analyses in this
field. After completing an eight-step synthesis of cyclo-
clavine,7,8 we now report the shortest synthesis to date of
methyl lysergates, direct precursors to lysergic acid amides, and
the syntheses of lysergol (1) and isolysergol (2). We also
investigate the scope and mechanism of a metal-free indole
C(3) alkylation using pyridine carbinols and use our route to
compare the affinity of all four lysergol stereoisomers at
serotonin 5-HT receptors.
We envisioned that a rapid construction of the ergoline core
would commence via a hydrogen autotransfer (HA) reaction of
commercially available pyridyl alcohol 3a to alkylate 4-
bromoindole (4) at C(3),15 followed by an intramolecular
Heck coupling at C(4) of the indole (Scheme 1). A
conventional approach to effect the former step would be to
oxidize alcohol 3a to the aldehyde, perform an aldol reaction,
and then reduce the addition product,16 but this method has
proven to be more difficult than anticipated.17 Alternatively,
alkylation at C(3) in 4 can be realized in a two-step acylation/
reduction sequence18,19 or with an SN2 displacement of a
suitable electrophile. HA reactions conveniently allow for a
combination of these methods into one all-encompassing
process to increase step economy and facilitate material
throughput.20,21
The proposed HA alkylation at C(3) of 4-bromoindole (4)
was first investigated with 2-pyridyl carbinol (3b) and various
transition metal catalysts. However, control reactions indicated
that this reaction proceeded effectively in the absence of
Received: July 29, 2022
Published: August 22, 2022

© 2022 American Chemical Society https://doi.org/10.1021/acs.orglett.2c02569

7255 Org. Lett. 2022, 24, 7255−7259
Organic Letters pubs.acs.org/OrgLett Letter

Scheme 1. Representative Ergot and Clavine Alkaloids and
Retrosynthetic Analysis of Lysergol and Isolysergol
Featuring Hydrogen Autotransfer (HA) and Heck Coupling
(entries 4−6, respectively). The optimized reaction conditions
used 4 as the limiting reagent, with 3 equiv of 3b and 1.1 equiv
of Cs2CO3 at 110 °C under neat conditions for 24 h (entry 1).
To confirm the absence of trace transition metals, the reaction
was also performed with transition metal-free grade Cs2CO3
(entry 7) and without a stir bar22 (entry 11). Additionally, all
optimization and control reactions were performed in new
one-dram vials and with Teflon-coated stir bars to minimize
the possibility of trace metal cross-contamination. Concen-
trated solutions in MeOH (entry 8) or PhMe (entry 9)
resulted in similarly high yields but still required the use of 3
equiv of 3b; otherwise, the yield diminished (entry 10). Air
was crucial for the reaction to proceed (entry 12); however,
radical inhibitors did not interfere with the progress of the
reaction (entry 13). Moreover, catalytic amounts of
picolinaldehyde (6) initiated the reaction under anaerobic
conditions (entry 14).
Mechanistically, the reaction is proposed to start with
deprotonation of enol tautomer 3b′ and chelation-assisted air
oxidation of small amounts of 3b′ to aldehyde 6 (Scheme 2),

Scheme 2. Proposed Mechanism for the Reductive

Alkylation of 4

transition metals and required only stoichiometric amounts of

Cs2CO3 to produce 5b in high yield (Table 1, entries 1−3).
K2CO3, K3PO4, and Hünig’s base were far less effective

Table 1. Transition Metal-Free HA Alkylation of 4-

Bromoindole (4) Using Alcohol 3ba

as previously proposed.23 This hypothesis is further supported

entry solvent base (equiv) modifications yield (%)
by (1) detection of trace 6 when 3b was heated to 110 °C with
Cs2CO3 under an air atmosphere and (2) the need for oxygen
1 − Cs2CO3 (1.1) − 89
or catalytic aldehyde for the reaction to progress. Con-
2 − − − <5
densation of indole 4 with 6 furnishes conjugated imine 7.
3 − Cs2CO3 (0.2) − 16
Hydride transfer23−25 from another equivalent of Cs-3b
4 − K2CO3 (1.1) − 31
provides tautomer 5b′ and final product 5b as well as an
5 − K3PO4 (1.1) − 26
equivalent of 6 to continue the chain process. Previous studies
6 − EtN(i-Pr)2 (1.1) − <5
required additives to promote the MPV-type reduction of
7 − Cs2CO3 (1.1) b 88
intermediate adducts.24−26 However, the reaction seems to
8 MeOH Cs2CO3 (1.1) c 85
proceed catalytically using oxygen in air as the initial oxidant.
9 PhMe Cs2CO3 (1.1) c 86
Further mechanistic studies and investigations of the scope and
10 MeOH Cs2CO3 (1.1) c, d 68
limitations of the Cs2CO3-mediated HA reaction are currently
11 PhMe Cs2CO3 (1.1) c, e 90
in progress.
12 − Cs2CO3 (1.1) f 9
For an extension to the lysergic acid scaffold, the HA
13 − Cs2CO3 (1.1) g 70
reaction of methyl nicotinate analogue 3a with indole 4 was
14 − Cs2CO3 (1.1) f, h 54
used. Interestingly, this electronically deactivated substrate
a
Experiments were performed on a ≥0.5 mmol scale. bTransition required an increase in reaction temperature to 185 °C to
metal-free grade Cs2CO3 was used. cA 2.0 M solution with respect to proceed in high yield (Scheme 3). Partial in situ saponification
4. dWith 1.5 equiv 3b. eNo stir bar. fThe reaction mixture was of the ester in 3a under these conditions caused a solidification
deoxygenated and kept under N2. gTEMPO (5 equiv) was added. of the reaction mixture, but a larger amount of 4, which serves
h
With 15 mol % aldehyde 6. as a solvent, and higher temperatures maintained a
7256 https://doi.org/10.1021/acs.orglett.2c02569
Org. Lett. 2022, 24, 7255−7259
Organic Letters pubs.acs.org/OrgLett
Scheme 3. Preparation of Lysergates, Lysergols, and Novel Bicyclic Analogue 9 with Its CPK X-ray Structure Shown (CCDC
2101977)
homogeneous solution. An acidic workup in MeOH afforded
the desired condensation product 5a.
All attempts to promote the six-membered ring closure of 5a
and closely related analogues, with catalyst tuning or pyridine
activation through N-alkylation, failed to proceed. Typically,
starting material or protodebrominated products were isolated
instead. An intramolecular Heck coupling of a tetrahydro
analogue was then pursued to circumvent the poor reactivity of
the pyridine. Treatment of 5a with MeI at 50 °C provided the
methylpyridinium ion quantitatively. Without isolation, sub-
sequent regioselective reduction of this intermediate with
NaBH4 provided tetrahydropyridine 8 in 90% yield.27
Attempts to perform a direct γ-functionalization or tandem
isomerization Heck reaction of 8 also failed to deliver the fused
ergoline tetracycle. Instead, bridged methyl lysergate analogue
9 was consistently isolated as the sole product and obtained in
the highest yield in the presence of PdCl2[P(o-tol)3]2 and Et3N
in MeCN at 100 °C in a sealed tube. Interestingly, the
preparation and characterization of the unnatural bridged
bicyclic scaffold 9 have not previously been recorded in any
detail.28 For the synthesis of the desired lysergate targets,
deprotonation of 8 with LiTMP followed by a kinetically
controlled α-protonation of the ester dienolate with the
sterically hindered 2,6-di-tert-butylphenol formed deconju-
gated alkene 10 in 80% yield as a mixture of diastereomers,19
with the remaining mass balance consisting of recovered
starting material. Unlike past efforts,19,28 an indole protective
group was not needed for this deconjugative isomerization, a
substrate modification that was likely to influence the
mechanistically surprising orientation of the double bond in
conjugation with the indole ring in the Heck reaction (vide
infra).
Initially, the use of standard Heck reaction conditions such
as Pd(PPh3)4 or Herrmann’s catalyst failed to convert alkene
10 to the tetracyclic ergoline. NHC, bulky phosphine, and
bidentate ligands were similarly unsuccessful.29 Fortunately,
treatment of 10 under the optimized conditions used for the
conversion of isomer 8 to bicycle 9 provided a diastereomeric
mixture of β,γ-unsaturated methyl lysergates 11 and 12 in 28%
overall yield from 3a. The intramolecular Heck coupling
proceeded rapidly and was stopped after 3 h upon
consumption of the starting material, because prolonged
reaction times reduced yields. Notably, all reactions up to
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Letter
this point were performed on a >1 g scale, establishing robust
access to lysergic acid derivatives. Contrary to previous reports
of related Heck reactions,19,28,30 the α,β-unsaturated ester
analogue of 11 was never observed. Typically, isomerization of
the α,β-conjugated ester is performed in tandem with
saponification to lysergic acid, but these paths provide limited
access to clavine alkaloids with varying oxidation states. In the
synthesis presented here, methyl lysergates 11 and 12 were
generated in situ, possibly by a post-Heck coupling alkene
isomerization, and likely facilitated by the absence of an
electron-withdrawing protective group on the indole nitrogen.
A cyclization involving a Pd radical would also be a feasible
pathway from 10 to 11 and 12.31 Irrespective of the specific
mechanism for the annulation of the piperidine ring, this
experimental outcome, combined with increased yields
compared to those of previous approaches, offers an entry to
several clavine alkaloids (Scheme 1) without requiring a
discrete alkene isomerization step. Moreover, treatment of
methyl lysergates 11 and 12 with LiAlH4 provided (±)-lysergol
(1) and (±)-isolysergol (2) in 48% and 34% yields from 11
and 12, respectively. While we were unable to identify
conditions for an enantioselective reduction of 5a to 8,
chromatographic resolution of 1 and 2 readily furnished
enantiomerically pure (+)-lysergol and (−)-lysergol, the
previously unknown antipode of natural D-lysergol, as well as
(+)- and (−)-isolysergols (Table 2 and the Supporting
Information).32
Telescoping synthetic procedures can greatly improve the
efficiency of a preparative route by reducing workup
manipulations and solvent use.33,34 In particular, eliminating
chromatographic purifications of intermediates is environ-
mentally beneficial and accelerates material throughput.35,36
We were able to expedite the short sequence to methyl
lysergates 11 and 12 further by treating the HA reaction
mixture with MeI to provide pyridinium ion 13, which was
precipitated and used without further purification (Scheme 4).
Reduction, isomerization, and Heck reactions then afforded
methyl lysergates 11 and 12 in 15% overall yield after a single
chromatographic purification of the final products.
This short synthetic route to all four lysergol and isolysergol
stereoisomers allowed us to compare the properties of their
binding to 5-HT receptors. Previously, the Luo group
evaluated synthetic (+)-lysergol, (−)-isolysergol, and (+)-13-
https://doi.org/10.1021/acs.orglett.2c02569
Org. Lett. 2022, 24, 7255−7259
Organic Letters
Table 2. Percent Inhibition of the Binding of a Specific
Agonist Radioligand at Serotonin Receptors by Lysergols
and Isolysergolsa
compd 5-HT1A (%)b 5-HT2A (%)b 5-HT2B (%)b 5-HT2C (%)b
(+)-1 94 (99) 96 (97) 96 (99) 97 (99)
(−)-1 27 (67) 12 (62) 34 (87) 41 (86)
(+)-2 96 (99) 92 (99) 90 (93) 91 (97)
(−)-2 9 (19) 0 (20) 3 (16) 5 (44)
a
CNS receptor assays were performed in duplicate at human
receptors at Eurofins Cerep Panlabs. bPercent inhibition at 100 nM
(percent inhibition at 1.0 μM in parentheses).
Scheme 4. Streamlined Synthesis of Methyl Lysergates
fluorolysergol for activity at these receptors.9 Hofmann et al.
also disclosed binding information about N1-alkyl lysergols,37
and the Pertz group studied the effect of natural clavines on rat
tail artery contractions.5,6 To the best of our knowledge,
however, a comparison of the binding profiles of all lysergol
stereoisomers to serotonin receptors was not yet available in
the literature. Accordingly, we evaluated (+)- and (−)-lysergols
as well as (+)- and (−)-isolysergols for their ability to compete
with known standards for specific binding at 5-HT1A, 5-HT2A,
5-HT2B, and 5-HT2c receptors (Table 2).
As expected, (+)-lysergol [(+)-1] with the naturally
occurring (R,R)-configuration bound strongly to all 5-HT
receptors, exceeding 90% displacement of the agonist radio-
ligand even at 100 nM. In contrast, the enantiomeric
(−)-lysergol [(−)-1] showed significant binding potency
only at 1.0 μM with a slight preference for 5-H2B and 5-
HT2C receptors. The diminished affinity of (−)-1 for serotonin
5-HT1A and 5-HT2A receptors suggests that this stereoisomer
would likely produce reduced hallucinogenic and euphoric
effects.38 In contrast to (−)-lysergol, (+)-isolysergol [(+)-2]
was also highly potent at all four serotonin receptors at 100
nM, suggesting that the configuration at C(8) of the ergoline
scaffold had a weak effect on receptor binding if paired with
the (R)-configuration at C(5). Furthermore, supporting the
dominant influence of the (R)-configuration at C(5),
(−)-isolysergol [(−)-2] was insignificantly active at these 5-
HT receptors. Overall, these data suggest that the (R)-
configuration at C(5) of the ergoline scaffold is necessary and
sufficient for potent nanomolar serotonin receptor binding
affinity, especially at 5-HT1A and 5-HT2A. We are currently
evaluating the extent to which the configuration at C(8) plays
a role in the agonistic properties of these stereoisomers at 5-
HT receptors, as well as the receptor profile of novel bridged
scaffold 9 and its derivatives.
In conclusion, we have developed a short, scalable four-step
synthesis of methyl lysergates from commercial starting
pubs.acs.org/OrgLett Letter
materials in 28% overall yield, which can provide a convenient
general access to ergot alkaloids. The key HA segment coupling
process proceeds efficiently on the functionalized substrates in
the absence of transition metals, requiring only stoichiometric
Cs2CO3. An intramolecular Heck coupling was optimized to
generate a streamlined synthetic route. Lysergols and
isolysergols were thus obtained in five total steps and
chromatographically resolved. Binding studies of all stereo-
isomers, including the previously unknown (−)-lysergol,
against representative 5-HT receptors provided an SAR profile
that highlighted the significance of the (R)-configuration at
C(5) and suggested that future analogue development of
clavine alkaloids can yield highly potent lead structures.
Ongoing work is focused on the introduction of structural
modifications based on this synthetic route, with the goal of
expanding the SAR for the development of clinical candidates
with distinct serotonin receptor profiles.
■
*
ASSOCIATED CONTENT
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.2c02569.
Experimental details and 1H and 13C NMR spectra for
new synthetic intermediates and products, trace metal
analysis of Cs2CO3, HPLC chromatograms, in vitro
serotonin 5-HT receptor binding assay conditions, and
X-ray diffraction data (PDF).
(PDF)
Accession Codes
CCDC 2101977 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
■ AUTHOR INFORMATION
Corresponding Author
Peter Wipf − Department of Chemistry, University of
Pittsburgh, Pittsburgh, Pennsylvania 15260, United States;
orcid.org/0000-0001-7693-5863; Email: pwipf@
pitt.edu
Author
Nikhil R. Tasker − Department of Chemistry, University of
Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.2c02569
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
The authors thank S. J. Geib (University of Pittsburgh) for
determining the X-ray structure of 9 (CCDC 2101977), D.
Crocker, M. Liang, and T. Maskrey (University of Pittsburgh)
for administrative and technical support, and the University of
Pittsburgh for a Mellon Fellowship (to N.R.T.). Discretionary
funding of this work by Boehringer-Ingelheim Pharmaceuticals
Inc. (Ridgefield, CT) is gratefully acknowledged.
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Org. Lett. 2022, 24, 7255−7259
Organic Letters pubs.acs.org/OrgLett Letter

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