Methods of Lysergic Acid Synthesis-The Key Ergot Alkaloid

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.

Figure 1

Structure of ergoline.

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 5

Metergoline.

Figure 6

d-Lysergic acid.

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.

Scheme 2

Obtaining Uhle’s ketone 8.

Figure 10

Structural formulas of amine derivatives (9 and 10).

Scheme 3

Derivative products strategies implemented.

Scheme 4

Diol 19 synthesis.

Scheme 5

Aldehyde 22 synthesis.

Scheme 6

Ketone 25 synthesis.

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.