The synthetic utility and potential power of the Diels–Alder (D–A) reaction in organic chemistry is evident. These significances have been extended to the synthesis of a plethora and wide variety of heterocyclic compounds via [4 + 2] cycloaddition reactions, the so called hetero Diels–Alder (HDA) reaction. In this work we try to focus on the scope and preparative synthetic applications of the HDA reaction as a key step in the total synthesis of natural products.

Recent applications of the hetero Diels–Alder reaction in the total synthesis of natural products

CHAPTER 14 – Dissociation Constants

Enantioselective total synthesis of the biologically important indole alkaloids (+)-lysergol, (+)-isolysergol, and (+)-lysergic acid is described. Key features of these total synthesis include (1) a facile synthesis of a chiral 1,3-amino alcohol via the Pd(0)- and In(I)-mediated reductive coupling reaction between l-serine-derived 2-ethynylaziridine and formaldehyde; (2) the Cr(II)/Ni(0)-mediated Nozaki−Hiyama−Kishi (NHK) reaction of an indole-3-acetaldehyde with iodoalkyne; and (3) Pd(0)-catalyzed domino cyclization of an allene bearing amino and bromoindolyl groups. This domino cyclization enabled direct construction of the C/D ring system of the ergot alkaloids skeleton, as well as the creation of the C5 stereogenic center with transfer of the allenic axial chirality to the central chirality.

Enantioselective Total Synthesis of (+)-Lysergic Acid, (+)-Lysergol, and (+)-Isolysergol by Palladium-Catalyzed Domino Cyclization of Allenes Bearing Amino and Bromoindolyl Groups

(±)-Lysergic acid (1) has been synthesized from 4-hydroxymethyl-1-tosylindole (2) by a sequence of 9 steps. The crucial thermolysis 9 10 involves the in situ-generation of the transient diene III which undergoes an intramolecular cycloaddition to a C, N-double bond at 200° and at low stationary concentration of III.

Total Synthesis of (±)-Lysergic Acid by an Intramolecular Imino-Diels-Alder Reaction. Preliminary communication

Ergot alkaloids is a group of natural biologically active compounds belonging, according to the general alkaloid classification, to the class of indole derivatives. Ergot alkaloids are found in largest amounts in the fungal species of Claviceps genus, the most widely occurring source of these substances being purple ergot (Claviceps purpurea Fr. Tul.) [1 – 6]. Another well-known fungal species producing alkaloids of the clavine series is Claviceps paspali [1, 3, 4, 6 – 8]. Ergot alkaloids are rarely encountered in higher plants; examples are offered by the Ipomoea genus of the Convolvulaceae family occurring in Central America [4, 9, 10]. The life cycle of ergot consists of three sequential stages, including the (i) conidial stage of sphacelia, (ii) sclerotium (resting stage), and (iii) sephalated stroma with perithecium. The alkaloids are obtained from ergot sclerotium called “spurred rye” (Secale cornutum) [4 – 6, 11]. The ergot sclerotium contains up to 30 – 40% of fatty oils and up to 2% of alkaloids. The other components of sclerotium are free amino acids, ergosterin, choline, acetylcholine, betaine, ergothionine, uracil, guanidine, free aromatic and heterocyclic amines (tyramine, histamine, agmatine), and alkylamines (the natural representatives of which were originally found in ergot). The outer shell of sclerotium contains acid pigments belonging to anthraquinolinic acid derivatives, including orange-red (endocrocin, clavorubin) and light-yellow (ergochromes, ergochrysins). These pigments impart to the sclerotium shell the characteristic grayish-brown-violet color [6, 12 – 15]. Also encountered are the albino ergot strains incapable of producing pigments [16]. Investigation of the wild-growing Cl. purpurea species revealed the existence of numerous geographic types differing in both qualitative and quantitative composition of alkaloids. To the present, ergot strains were specially selected that are capable of producing predominantly a single alkaloid or a certain group of alkaloids: ergotamine, ergotoxin, ergocristine, etc. [3, 4, 6, 16 – 27]. Owing to a high biological activity and broad spectrum of pharmacological effects, ergot alkaloids are of considerable importance for medicine. These compounds are now obtained both by methods of artificial parasitic cultivation on rye [11, 14, 19 – 22, 25 – 30] and by saprophytic growth techniques [31 – 35]. The most widely known pharmacological effect of ergot alkaloids is the ability to induce uterine contraction. Ergot extracts were officially used for the first time in gynecology. The best known drugs of this type are ergotamine and ergometrine. As the chemical structure and pharmacological properties of ergot alkaloids were studied, the scope of their application considerably expanded. Ergot alkaloids exhibit a complicated action upon the organism, which accounts for a variety of possible therapeutic applications. Dihydroxy derivatives of ergotoxin alkaloids produce -adrenoblocking and “venotonic” action. These compounds are administered in cases of hypertension, cerebral vasospasms, peripheral circulation disorders, etc. [36 – 39]. Many ergot alkaloids produce a more or less pronounced dopaminergic effect. Specific dopamine agonists are 2-Brand 2-Br-ergocryptines, which influence the secretion of hypophyseal anterior hormones and produce a hypotensive action upon the CNS, sympathetic nerve endings, and smooth vascular muscles. The drug abergin (Russia) [36, 37] or parlodel (bromergon, bromocriptine mesylate) are used for the treatment of a wide spectrum of disorders, including galactorrhea, acromegalia, mastites, prolactinomas, amenorrhea, and infertility and for the suppression of lactation, Cushing’s disease, some hormonal tumors, etc. [1, 36 – 44].

The Chemistry of Peptide Ergot Alkaloids. Part 1. Classification and Chemistry of Ergot Peptides

Die Aufhebung des Asymmetriezentrums am Kohlenstoffatom 8 durch β-Aminocarbonsaure-Spaltung ergibt ein identisches Lactam aus Lysergsaure und Isolysergsaure, was zur Formulierung dieser Isomeren als Diastereomere fuhrt. Ihre hydrierbare Doppelbindung wird auf Grund des Vergleichs der Absorptionsspektren in Δ9-10 festgelegt. Der Hofmann'sche Abbau, die Decarboxylierung und die Hydrierung von Lysergsaure und Isolysergsaure werden in Ubereinstimmung mit dieser Auffassung formuliert. Fur den Mechanismus der reversiblen Lysergsaure-Isolysergsaure-Umlagerung wird eine Erklarung gegeben.

A. Stoll

Papers

Über die Isomerie von Lysergsäure und Isolysergsäure. 14. Mitteilung über Mutterkornalkaloide