Review

. 2022 Oct 28;27(21):7322.

doi: 10.3390/molecules27217322.

Methods of Lysergic Acid Synthesis-The Key Ergot Alkaloid

Michał K Jastrzębski¹, Agnieszka A Kaczor^{1

2}, Tomasz M Wróbel^{1

3}

Affiliations

¹ Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki St., PL-20093 Lublin, Poland.
² School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, FI-70211 Kuopio, Finland.
³ Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.

PMID: 36364148
PMCID: PMC9654825
DOI: 10.3390/molecules27217322

Review

Methods of Lysergic Acid Synthesis-The Key Ergot Alkaloid

Michał K Jastrzębski et al. Molecules. 2022.

. 2022 Oct 28;27(21):7322.

doi: 10.3390/molecules27217322.

Authors

Michał K Jastrzębski¹, Agnieszka A Kaczor^{1

2}, Tomasz M Wróbel^{1

3}

Affiliations

¹ Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki St., PL-20093 Lublin, Poland.
² School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, FI-70211 Kuopio, Finland.
³ Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.

PMID: 36364148
PMCID: PMC9654825
DOI: 10.3390/molecules27217322

Abstract

Ergot is the spore form of the fungus Claviceps purpurea. Ergot alkaloids are indole compounds that are biosynthetically derived from L-tryptophan and represent the largest group of fungal nitrogen metabolites found in nature. The common part of ergot alkaloids is lysergic acid. This review shows the importance of lysergic acid as a representative of ergot alkaloids. The subject of ergot and its alkaloids is presented, with a particular focus on lysergic acid. All methods of total lysergic acid synthesis-through Woodward, Hendrickson, and Szantay intermediates and Heck coupling methods-are presented. The topic of biosynthesis is also discussed.

Keywords: biosynthesis; ergot alkaloids; lysergic acid; total synthesis.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

**Figure 2**
Structural formulas of the 5 main groups of ergot alkaloids: (a) clavine alkaloids and (b) 6,7-secoergolenes (alkaloids with an open D ring), (c) lysergic acid derivatives, (d) peptide alkaloids, and (e) lactam ergot alkaloids.

**Figure 3**
Structural formulas of endogenous amines and lysergic acid.

**Figure 4**
Ergot alkaloid derivatives.

**Figure 7**
Four stereoisomeric forms of lysergic acid.

**Figure 8**
Equilibrium between the forms of lysergic acid, explaining the racemization mechanism.

**Scheme 1**
Retrosynthetic analysis leading to substrate in the Woodward strategy.

**Figure 9**
Indole scaffold (red) in the lysergic acid molecule.

**Figure 10**
Structural formulas of amine derivatives (9 and 10).

**Scheme 3**
Derivative products strategies implemented.

**Scheme 7**
Reaction of the substitution of bromine 4 with ketal.

**Scheme 8**
Woodward pathway to the deprotected key intermediate 2.

**Scheme 9**
Woodward pathway to lysergic acid.

**Figure 11**
Woodward intermediate 31 and deprotected compound 2.

**Scheme 10**
Beginning of the synthesis proposed by Baillarge team.

**Scheme 11**
Synthesis of the protected Woodward’s intermediate.

**Scheme 12**
First part of the Ramage synthesis.

**Scheme 13**
Second part of the Ramage synthesis.

**Scheme 14**
Obtained epimers of dihydrolysergic acid derivatives 2.

**Scheme 15**
Preparation of the Rebek substrate 44.

**Scheme 16**
The first part of Rebek synthesis.

**Scheme 17**
The second part of Rebek synthesis.

**Scheme 18**
The first part of Kiguchi synthesis.

**Scheme 19**
The second part of Kiguchi synthesis.

**Scheme 20**
The third part of Kiguchi synthesis.

**Scheme 21**
The last part of Kiguchi synthesis.

**Scheme 22**
Additional Kiguchi research.

**Scheme 23**
A new method for the synthesis of compound 51.

**Scheme 24**
Coupling reaction leading to a tricyclic system 65.

**Scheme 25**
Obtaining Hendickson’s intermediate.

**Scheme 26**
Synthesis of lysergic acid ester proposed by Hendrickson.

**Scheme 27**
Structural formula of the product obtained in the literature procedure repeated by Bekkam.

**Scheme 28**
Coupling reaction leading to a protected tricyclic system 74.

**Scheme 29**
Synthetic path leading to the Henrickson’s intermediate, as postulated by Yigang.

**Scheme 30**
Beginning of the synthesis proposed by Beaundry.

**Scheme 31**
Ending of the synthesis proposed by Beaundry.

**Scheme 32**
Beginning of the synthesis proposed by Szantay.

**Scheme 33**
Preparation of the carbonyl α,β-unsaturated system 82.

**Scheme 34**
Obtaining Szantay’s intermediate.

**Scheme 35**
Synthesis of lysergic acid proposed by Szantay.

**Figure 12**
Structural formulas of compounds obtained in further works of Szantay’s research group.

**Scheme 36**
Beginning of the synthesis proposed by Garner.

**Scheme 37**
Preparation of a tetracyclic derivative 95 with a camphor substituent.

**Scheme 38**
Synthesis of lysergic acid proposed by Garner.

**Scheme 39**
Preparation of a tricyclic system by Heck coupling as the source of the D-ring.

**Scheme 40**
Synthesis of lysergic acid ester 51 proposed by Ortar.

**Scheme 41**
Preparation of a tricyclic system by Kurihara, analogous to that of Ortar.

**Scheme 42**
Preparation of a lysergic acid protected ester **(R)-31** by the Kurihara strategy.

**Scheme 43**
Synthesis of dihydropyridine **112**.

**Scheme 44**
Protection of the tetrahydropyridine with a nosyl group.

**Scheme 45**
Synthesis of tricyclic alcohol **117**.

**Scheme 46**
Preparation of ester **120**.

**Scheme 47**
Preparation of lysergic acid in Fukuyama strategy I.

**Scheme 48**
Synthesis of cyclic acetate-enamine **124**.

**Scheme 49**
Introducing an allylic system into molecule **126**.

**Scheme 50**
Preparation of nitroolefin **129**.

**Scheme 51**
Forming the B and C rings in Fukuyama strategy II.

**Scheme 52**
Preparation of a protected lysergic acid ester **135** by Fukuyama strategy II.

**Scheme 53**
Deprotection and methylation of lysergic acid ester 51.

**Scheme 54**
Retrosynthetic analysis leading to substrates in Fukuyama strategy III.

**Scheme 55**
Preparation of the hemiaminal **136**.

**Scheme 56**
Preparation of allylamine **142**.

**Scheme 57**
Reaction of allylamine **142** and the hemiaminal **136**, along with reduction by Grubbs catalyst II.

**Scheme 58**
Preparation of lysergic acid in Fukuyama strategy III.

**Scheme 59**
Beginning of the synthesis according to Fukuyama strategy IV.

**Scheme 60**
Preparation of alkyne 154.

**Scheme 61**
Synthesis of aziridine **157** in the Mitsunobu reaction.

**Scheme 62**
Closing the D-ring in Fukuyama strategy IV.

**Scheme 63**
Preparation of lysergic acid in Fukuyama strategy IV.

**Scheme 64**
Beginning of the synthesis of lysergic acid from D-glutamic acid **163**.

**Scheme 65**
Introducing of two terminal double bonds into molecule **166** in strategy I.

**Scheme 66**
Method of obtaining lysergic acid proposed by Liu and Jia.

**Scheme 67**
Introducing two terminal double bonds into the molecule **173** in strategy II.

**Scheme 68**
Synthesis of the ABD tricyclic system in Liu and Jia’s strategy.

**Scheme 69**
Preparation of lysergic acid precursor **171**.

**Scheme 70**
C and D rings closing strategy in the Diels–Alder reaction.

**Scheme 71**
Introduction of a masked diene system into the molecule **184**.

**Scheme 72**
Preparation of lysergic acid by the Oppolzer procedure.

**Scheme 73**
Synthesis of thioacetal **190** from bromoindole.

**Scheme 74**
Enolate ether **192** synthesis.

**Scheme 75**
Obtaining allene in strategy I.

**Scheme 76**
Preparation of lysergic acid ester 51 proposed by Inuki, Iwata, and Ohno.

**Scheme 77**
Synthesis of materials for the coupling in strategy II.

**Scheme 78**
Reaction leads to an asymmetric alcohol **204**.

**Scheme 79**
Obtaining allene in strategy II.

**Scheme 80**
Obtaining intermediate **196** in strategy II.

**Scheme 81**
Synthesis of enyne **210** from bromoindole.

**Scheme 82**
Obtaining allene in strategy III.

**Scheme 83**
Retrosynthetic analysis proposed by Padwa.

**Scheme 84**
Beginning of the synthesis proposed by Padwa.

**Scheme 85**
Continuation of the synthesis proposed by Padwa.

**Scheme 86**
Parsons group synthetic strategies.

**Scheme 87**
The first stages of lysergic acid biosynthesis.

**Scheme 88**
Biomechanism proposed by Metzger.

**Scheme 89**
Enzymatic cyclization of the D-ring.

**Scheme 90**
Preparation of lysergic acid from agroclavine.

**Scheme 91**
Lysergic acid biosynthesis strategy proposed by Zhu.

See this image and copyright information in PMC

References

1. Ochodzki P., National Research Institute . Zapobieganie Zagrożeniom Związanym z Występowaniem w Ziarnie Zbóż Alkaloidów Pasożytniczego Grzyba Buławinki Czerwonej (Sporysz)—Prevention of Risks Associated with the Presence of Alkaloids in the Cereal Grain Parasitic Fungus of Ergot. Expertise; Radzików, Poland: 2015.
1. Schiff P.L. Ergot and Its Alkaloids. Am. J. Pharm. Educ. 2006;70:98. doi: 10.5688/aj700598. - DOI - PMC - PubMed
1. Smakosz A., Kurzyna W., Rudko M., Dąsal M. The Usage of Ergot (Claviceps Purpurea (Fr.) Tul.) in Obstetrics and Gynecology: A Historical Perspective. Toxins. 2021;13:492. doi: 10.3390/toxins13070492. - DOI - PMC - PubMed
1. Krska R., Crews C. Significance, Chemistry and Determination of Ergot Alkaloids: A Review. Food Addit. Contam. Part A. 2008;25:722–731. doi: 10.1080/02652030701765756. - DOI - PubMed
1. Berde B., Schild H.O., editors. Ergot Alkaloids and Related Compounds. Springer; Berlin/Heidelberg, Germany: 1978.

Publication types

Actions

MeSH terms

Actions
Actions
Actions

Substances

Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- The Lens - Patent Citations Database

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Methods of Lysergic Acid Synthesis-The Key Ergot Alkaloid

Affiliations

Methods of Lysergic Acid Synthesis-The Key Ergot Alkaloid

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources