Asymmetric Synthesis of Lysergic Acid via an Intramolecular (3+2) Dipolar Cycloaddition/Ring-Expansion Sequence

Article abstract of DOI:10.1021/acs.orglett.1c02337

An effective, potentially scalable asymmetric synthesis of lysergic acid, a core component of the ergot alkaloid family, is reported. The synthesis features the strategic combination of an intramolecular azomethine ylide cycloaddition and Cossy-Charette r

Full text of DOI:10.1021/acs.orglett.1c02337

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Letter
Asymmetric Synthesis of Lysergic Acid via an Intramolecular (3+2)
Dipolar Cycloaddition/Ring-Expansion Sequence
Upendra Rathnayake and Philip Garner*
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ABSTRACT: An effective, potentially scalable asymmetric syn-
thesis of lysergic acid, a core component of the ergot alkaloid
family, is reported. The synthesis features the strategic combina-
tion of an intramolecular azomethine ylide cycloaddition and
Cossy−Charette ring expansion to assemble the target’s C- and D-
rings. Simple functional group manipulation produced a compound
that had been converted to lysergic acid in four steps, thus
constituting a formal synthesis of the natural product. The strategy
may be used to prepare novel ergot analogues that include
unnatural antipodes and may be more amenable to analogue generation relative to prior approaches.
he ergot alkaloid family is a rich source of bioactive
Scheme 1. Retrosynthetic Plan
T
natural products that is produced by Claviceps fungi.1,2
Many of these natural products serve as drugs themselves or
provide a starting point for the development of semisynthetic
analogues. Although humankind’s first experience with ergot
alkaloids was probably negative (ergot poisoning resulting
from eating moldy rye), ergot alkaloids can be used to treat a
variety of human diseases. They are particularly useful for the
treatment of neurological disorders such as Parkinson’s disease,
migraine headaches, and senile dementia and certain
psychological conditions. Two examples of ergot alkaloids
are shown in Figure 1, ergotamine (a naturally occurring ergot
Figure 1. Structures of two representative ergot alkaloids.
syntheses have delivered this natural product in enantiomeri-
cally pure form.4−11 Herein, we report a novel asymmetric
synthesis of lysergic acid.
alkaloid used to treat migraines) and LSD (a synthetic
compound known for its illicit recreational use but now being
evaluated as a treatment for anxiety, depression, and
addiction). Lysergic acid (Scheme 1) is a core constituent of
these drugs. Although it is available on an industrial scale via
hydrolysis of naturally occurring peptidic ergot alkaloids, this
chiral tetracyclic molecule has remained a popular synthetic
target ever since Woodward first reported its total synthesis in
1954.3 It has been used to showcase both synthetic
methodology and synthetic strategy. Seven of the resulting
Received: July 13, 2021
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Our retrosynthetic analysis is shown in Scheme 1. The
synthesis of 1 features the strategic use of two key reactions: an
intramolecular azomethine ylide cycloaddition12 that may also
be described as a tethered asymmetric [C+NC+CC] cyclo-
addition paired with the ring expansion of a functionalized
pyrroline to construct the target’s C- and D-rings. The
asymmetric [C+NC+CC] cycloaddition is a robust multi-
component reaction that enables the synthesis of highly
functionalized pyrrolidines in enantiomerically pure form via
the staged one-pot combination of an aldehyde (C-
component), a chiral glycylsultam (NC-component), and a
dipolarophile (CC-component) (a brief overview of this
multicomponent reaction is provided in the Supporting
Information). This application of the asymmetric [C+NC
+CC] cycloaddition using an alkyne dipolarophile not only
provides an enantiomerically pure pyrroline (the D-ring
precursor) but also installs a synthetic handle for the
subsequent ring-expansion reaction.
TBS protecting group followed by oxidation of primary alcohol
10 using 2-iodoxybenzoic acid (IBX) gave aldehyde 4, which
served as the CC−tether−C construct. The overall yield of 4
from 6 was 60%.
Assembly of the ergoline structure (Scheme 3) commenced
with the Ag(I)-catalyzed reaction of 4 and 5 to give
Scheme 3. Asymmetric Synthesis of Lysergic Acid
Significantly, the plan allows for potential structural
modification of the ergoline core that would expand ergot
alkaloid structural space. For example, the C-ring may be
enlarged by simply modifying the tether connecting the “C”
and “CC” components. Our strategy may also be applied to the
synthesis of the antipode of 1 and related analogues. Such
deep-seated variation in molecular structure is not found in the
natural ergot alkaloids. The resulting diversification of three-
dimensional structure space could prove useful for targeting
specific receptor subtypes employing fragment-based drug
design strategies. The use of an intramolecular azomethine
ylide cycloaddition to construct the C-ring and (pre)D-ring of
1 was inspired by Brewer’s synthesis of ( )-cycloclavine.13 The
ring-expansion reaction finds precedent in the work of Cossy14
and Charette.15
The synthesis of 1 began with the known16 trisubstituted
indole 6 (Scheme 2), itself prepared in five steps from
cycloadduct 3 in good yield on a multigram scale. On the
basis of our prior experience, this reaction was expected to
proceed through concerted pre-TS 11. It is unlikely that a
stepwise Michael addition/Mannich ring closure is involved
because the observed regioselectivity would be disfavored in
that case. The structure of 3 was confirmed by extensive NMR
analysis of intermediate 12 (see the Supporting Information)
as well as the eventual correlation with lysergic acid (1). It is
worth noting that attempted cycloaddition using an alkynyl
aldehyde structurally related to 4 but lacking the activating
sulfonyl group failed. Treatment of 3 with lithium borohydride
resulted in reductive removal of the auxiliary as well as
conjugate reduction of the α,β-unsaturated sulfone to give a
mixture of saturated sulfone 12 along with elimination product
13. Intermediate 12 could be converted to 13 by treating the
crude product with sodium hydride. The sulfonyl group thus
not only activates the dipolarophile but also enables
installation of the target’s double bond. Presumably, both the
conjugate reduction and sulfinate elimination reaction proceed
with the help of the hydroxyl moiety. The removal of the
sulfone group under nonreducing conditions was crucial
because it allowed the retention of the toluenesulfonyl indole
protecting group. At this point, the pyrroline was N-
methylated via reductive amination to give β-aminoalcohol 2
in 27% overall yield from cycloadduct 3 (an average of 65%
yield for each operation). Because the protons α to the
acylsultam and γ to the sulfone in 3 are potentially
epimerizable, we decided to assess the enantiomeric purity of
2. The enantiomer of 2 (ent-2) was prepared by the same
sequence of reactions but using ent-5 as the NC component.
Scheme 2. Synthesis of Disubstituted Indole 9
commercially available 4-bromoindole (Supporting Informa-
tion). Sonogashira coupling of trimethylsilyl acetylene and aryl
bromide 6 gave alkyne-substituted indole 7 in excellent yield.
Removal of the trimethylsilyl group produced terminal
acetylene 8, which reacted with the in situ-generated
phenylsulfonyl radical to produce alkynyl sulfone 9.17 The
sulfone moiety serves to activate the alkyne for the dipolar
cycloaddition but is readily removed afterward. This three-step
route from 6 to 9 was necessitated by the reluctance of 6 to
couple directly with ethynyl phenyl sulfone. Removal of the
B
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Chiral HPLC showed these antipodes to be >99% pure (see
the Supporting Information).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02337.
■
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Treatment of 2 with methanesulfonyl chloride followed by
exposure to aqueous NaOH produced ring-expanded secon-
dary alcohol 14. The structure of this compound was based on
NMR coupling data and conformational analysis (see the
Supporting Information). The details of this pivotal trans-
formation deserve further comment (Scheme 4). Mesylation of
General experimental information, detailed procedures,
and NMR and MS data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Scheme 4. Proposed Ring-Expansion Mechanism
Philip Garner − Department of Chemistry, Washington State
University, Pullman, Washington 99164-4630, United
States; orcid.org/0000-0002-6503-9550; Email: ppg@
wsu.edu
Author
Upendra Rathnayake − Department of Chemistry,
Washington State University, Pullman, Washington 99164-
4630, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02337
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by National Science
Foundation Grant CHE-1665274. The authors thank Dr.
Zach Heiden (Washington State University) for helpful
discussions regarding the Sonogashira coupling, Prof. Jin Cha
(Wayne State University, Detroit, MI) for insight regarding the
ring expansion, and Dr. Vindi Jayasinghe Arachchige (UNT
Health Science Center, Fort Worth, TX) for assistance with
the conformational analysis of 12 and 14.
2 at 0 °C resulted in the clean formation of primary mesylate
17, which appeared to be relatively stable at this temperature.
However, when the compound was warmed to rt, a rapid
equilibrium between 17 and 20 was established [followed by
NMR (see the Supporting Information)], favoring 20. On the
basis of a literature precedent,18 we believe that the
rearrangement proceeds through aziridinium 18 or synchron-
ized transition state 19. Alkaline hydrolysis of the crude
product resulted in alcohol 14. The fact that mesylate
hydrolysis occurred with retention of configuration suggests
the intermediacy of 18. It is also possible that hydroxide
attacks the sulfonyl moiety in 20.
Reductive removal of the indole protecting group (Mg/
MeOH) gave compound 15. Oxidation of the allylic alcohol to
produce the enone proved to be delicate, presumably due to
overoxidation leading to a 3-oxidopyridinium species.19
However, IBX/DMSO cleanly produced the desired enone
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