Lysergic acid total synthesis

Ninomiya, L, Hashimoto, C., Kiguchi, T, Naito, T. (1985) Photocyclisation ofEnamides. Part 24. Total Synthesis of ( )-Isofumigaclavine B and ( )-Lysergic Acid. Journal of the Chemical Society Perkin Transactions I, 941-948. 

Oppolzer, W., Francotte, E., Battig, K. (1981) Total Synthesis of ( )-Lysergic Acid by an Intramolecular Imino-Diels-Alder Reaction. Helvetica ChimicaActa, 64, 478 81. 

The following methods all proceed from lysergic acid (I). Methods 1, 2, 4, and 6 give less than 20% iso-LSD in the product but methods 2, 5, and 9 seem to have the highest total yield (about 80%) of LSD plus iso-LSD. Since unreacted lysergic acid can be recovered and run through the synthesis again, and iso-LSD isomerized to LSD as described here, it is probably best to use the simplest methods. These comparative yields come mostly from the reference to method 9. 

Of the many attempts at the total synthesis of lysergic acid from simple starting materials, only two have been successful (JACS 78,3087(1956), which is very complicated, and CA 74,3762 (1970), which follows). However, it is very likely that some of the intermediates in each attempt are psychedelic. In fact, this is one of... 

The decomposition of 368 catalysed by Rh perfluorobutyrate and subsequent intramolecular cycloaddition give 370 in high yield (93%) as the key step in the total synthesis of lysergic acid (371), and is believed to involve the intramolecular reaction of the ylide intermediate 369 at the alkene. No C—H insertion takes place [122], Another elegant example is the efficient construction of the aspidosperma alkaloid skeleton 374. The Rh-catalysed domino cyclization cycloaddition of diazo irnide 372 afforded cycloadduct 374 in 95% yield as a single diastereomer via the dipole 373, and desacetoxy-4-oxo-6,7-dihydrovindorosine (375) has been synthesized from 374 [123]. 

To begin with the more classic transformations, the total synthesis of a clavine alkaloid, (+ )-isosetoclavine (24) reported by Kornfeld and Bach (27) deserves mention. Using the same tetracyclic ketone (23) as starting material as in their famous synthesis (28) of lysergic acid (43) (cf. Vol. VIII) 24 was built up stereospecifically in two steps as demonstrated below. 

As the resolution of the racemic lysergic acid into its optical antipodes and the synthesis of ergometrine had been described earlier by Stoll and Hofmann (25, 66), this meant that not only had the synthesis of d-lysergic acid been achieved but also the first total synthesis of an ergot alkaloid. 

Conversion of isomer Lilia with lysergic acid chloride hydrochloride (IVa) in chloroform, with the addition of tributylamine, yielded a compound whose chemical, physical, and pharmacological properties were identical with those of the natural alkaloid ergotamine. Thus, the total synthesis of this alkaloid was accomplished, lysergic acid having already been synthesized at an earlier date (50). 

For such electron-rich dienophiles, Diels-Alder reactions with unfavorable electron demand become possible when assisted by intramolecularity and high dilution, as in Oppolzer s total synthesis of lysergic acid (Scheme 66), where the labile transient diene is set free by cycloreversion. 

In the laboratory of A. Padwa, a novel synthetic approach to the fully functionalized core of lysergic acid was developed utilizing an intramolecular isomunchone cycloaddition pathway. The key cycloaddition precursor diazo imide was prepared using the standard Regitz diazo tranter conditions. The diazo imide then was heated with catalytic amouts of rhodium(ll)-perfluorobutyrate in dichloromethane to afford the desired cycloadduct as a single diastereomer and in excellent yield. The only reason the authors were not able to complete the total synthesis of lysergic acid was that they could not affect the isomerization of the double bond between the two six-membered rings. 

Glycidic acid—>a,p-unsaturated aldehyde. In the course of a total synthesis of lysergic acid, Kornfeld et al. " treated the glycidic acid sodium salt (1) in acetonitrile solution successively with Py+HBr, and then semicarbazide. The free aldehyde (4) was then obtained by exchange of the semicarbazide residue to pyruvic acid. 

Scheme 31. Formal total synthesis of ( )-lysergic acid...

Kurihara, T., Terada, T., Satoda, S., and Yoneda, R., Studies on indenopyridine derivatives and related compounds. Part 6. Synthesis and stereochemistry of ethyl 9,9-dimethyl-l,2,3,9a-tetrahydro-9//-indeno[2,l-fc]pyridine-3-carboxylate as a possible intermediate for the total synthesis of lysergic acid, Chem. Pharm. Bull., 34, 2786, 1986. 

An unsuccessful attempt was made to apply this methodology to a total synthesis of the Ergot alkaloid lysergic acid (Scheme 19) [42]. Therefore, aldehyde olefin 107 was prepared and was exposed to the Kresze conditions with the... 

In another example, 2 mol of base were used in the production of the enolate the resulting enolate product was then trapped as the diazo ketone (Scheme 6) A comparative study was provided by the work of Kurihara et al. in their approaches to the total synthesis of lysergic acid (equation 8). ... 

Oppolzer et al. devised a clever total synthesis of lysergic acid (40) that has as its key step an intramolecular imino Diels-Alder reaction (Scheme... 

Kornfeid, E.C. et al. 1954. Xhe total synthesis of lysergic acid and ergonovine Journal of the. American Chemical Society 76 5256-5257. 

Oppolzer et al. devised a clever total synthesis of lysergic acid (40) that has as its key step an intramolecular imino Diels-Alder reaction (Scheme 2-XIII). A thermal retro-Diels-Alder reaction of 39 liberating cyclopen-tadiene was used to afford a diene oxime ether which cyclized to give a tetracyclic indole as a 3 2 mixture of diastereomers. Three additional steps served to convert this adduct to ( )-lysergic acid (40). Of particular interest here is the fact that simple oximino compounds are not normally reactive dienophUes, and the intramolecularity of the conversion is apparently crucial to the success of this transformation. 

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