A Concise and Malleable Synthesis of (±)-Lysergic Acid

Abstract

This Letter describes a concise synthesis of lysergic acid from simple aromatic precursors. The successful strategy relies on the coupling, dearomatization, and cyclization of a halopyridine with a 4-haloindole derivative in 6 total synthetic steps from commercial starting materials. In addition to highlighting the advantages of employing dearomative retrosynthetic analysis, the design is practical and anticipated to enable the synthesis of novel neuroactive compounds.

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“…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.…”