Asymmetric Synthesis of Lysergic Acid via an Intramolecular (3+2)

Dipolar Cycloaddition/Ring-Expansion Sequence

Upendra Rathnayake and Philip Garner*

Department of Chemistry, Washington State University, Pullman, Washington 99164- 4630, United
States

The ergot alkaloid family is a rich source of bioactive

natural products that is produced by Claviceps fungi.
Two examples of ergot alkaloids are ergotamine
(a naturally occurring ergot 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 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.
Análisis retrosintético
Síntesis de 6, precursor de 4, a partir de 4-bromoindol S1
Síntesis de 4 a partir de 6
J. Org. Chem. 2016, 81, 2744−2752.
 Oxidación con IBX
(Ácido 2-Iodoxibenzoico)
 Síntesis del precursor 2 del Ácido Lisérgico a partir de 4 y 5

(1R)
Cicloadición 1,3-dipolar

S R
Síntesis del precursor 16 del Ácido Lisérgico a partir de 2
Síntesis formal del Ácido Lisérgico

J. Org. Chem. 2004, 69,

5993-6000.
Mecanismo propuesto para la expansión del anillo
Seguimiento de la expansión del anillo por RMN