Total synthesis of (+)-lysergic acid

Abstract

A total synthesis of (+)-lysergic acid, which features the C-C bond formation between C10 and C11 via cleavage of an aziridine ring, was accomplished.

Methods of Lysergic Acid Synthesis—The Key Ergot Alkaloid

“…Strategy IV . The Fukuyama team’s recent work deviates from the idea of using the Heck reaction and instead proposes the formation of a C–C bond between C10 and C11 by aziridine ring cleavage [ 91 ]. The reaction begins with the preparation of the substrate—an indoline derivative [ 92 ].…”

Migraine drugs

“…To increase step economy, Hendrickson considered the assembly of the framework [313,314]. However, also some recent formal syntheses of lysergic acid [315][316][317][318] as well as Peter Vollhardt's total synthesis of racemic LSD in 1994, starting from commercial 4-bromoindole in just seven steps and 1.1% overall yield, might also be appreciated [319] a Ring construction/introduction sequence [320] 1976 AB→C→D (+/-) 19 1.5 Oppolzer [321] 1981 AB→CD (+/-) 17 0.9 Ninomiya [322] 1982 AB→C→D (+/-) 20 0.03 Rebek [323] 1983 AB→C→D (+/-) 14 4.4 Kurihara [324] 1986 AB→C→D (+/-) 14 2.0 Ortar [325] 1988 AB→C→D (+/-) 12 1.3 Hendrickson e [326] 2004 AB→D→C (+/-) 9 14.5 Szántay [327] 2004 AB→C→D (+) 15 0.7 Fujii, Ohno [328] 2008 AB→DC (+/-) 21 3.1 Fukuyama [329] 2009 D→A→BC (+) 34 0.9 Fukuyama [330] 2009 D→AB→C (+) 24 0.08 Fujii, Ohno [331] 2011 AB→ DC (+) 16 5.9 Fujii, Ohno [332] 2011 AB→ DC (+) 17 1.8 Jia [333] 2011 AB→D→C (+) 20 5.1 Fukuyama [334] 2013 AB→D→C (+) 19 12.0 Jia [335] 2013 D→AB→C (+) 12 1.0 Fukuyama [336] 2018 A→B→C→D (+) 30 0.07 Smith [337] 2022 AB→D→C (+/-) 6 12.0 from readily available indole and nicotinic acid starting materials as the most efficient route and avoided also the initial reduction of the indole, which was frequently performed in previous syntheses (Scheme 4). The first key step in Hendrickson's lysergic acid synthesis is a Suzuki coupling of indole-4-boronic acid and 3-chloro-pyridine-2,5-dicarboxylic acid diethyl ester, obtained in few steps from 4-bromoindole and 6-carboxynicotinic acid, respectively.…”

Overview of the synthetic approaches to lysergic acid as a precursor to the psychedelic LSD

“…The Fukuyama group also completed another approach using this ring formation strategy. [26] The Bisai group also used a C and D-ring cyclisation synthetic approach to the lysergic acid related compounds (+)-lysergol and (+)-isolysergol. In this report an asymmetric nitronate addition onto an α,β-unsaturated ester aza-Michael addition is used to construct the C-ring while a 6-endo-trig cyclisation is used to install the D-ring.…”