LSD

Synthetic studies toward LSD lysergic acid in USA.

Lysergic LSD acid, while not commonly found in natural sources and not among the most potent ergot alkaloids in USA. It has remained an attractive synthetic target for the past 80 years due to its historical significance and its ability to be easily converted into highly bioactive analogs through side chain variation. Notable products resulting from reactions with lysergic acid include ergocryptine, ergonovine, and lysergic acid diethylamide (LSD), all of which hold significant pharmaceutical potential in USA. Notwithstanding various inconsistencies between the manuscript and supporting information of the Hendrickson synthesis, which have led to reproducibility issues, this synthesis has served as a significant reference in subsequent works by other groups and has been included for the comprehensive overview of year 2000–20 ergot alkaloid total syntheses. LSD for sale in USA online

Hendrickson studies of LSD in USA

Nevertheless, in 2004, Hendrickson reported a concise synthesis of (±)-lysergic acid [(±)-35]. Commencing from 2,5-pyridinedicarboxylic acid 394, N-oxidation ensued by treatment with SOCl2 led to the formation of the trisubstituted pyridine 395 (Scheme 69). This conversion involved the attack on SOCl2 by the N-oxide followed by chloride addition at C(4) on the pyridine ring, thereby resulting in a dienamine that subsequently underwent an intramolecular chloride shift and extrusion of SO2 gas, ultimately producing 395.

Furthermore, the Suzuki–Miyaura cross-coupling with 4-indoleboronic acid (396) followed by Fischer esterification in acidic ethanol provided the arylated diester 397 in a 91% yield. Regioselective ester reduction using CaCl2 and NaBH4, and subsequent oxidation of the benzylic alcohol 398 with MnO2 led to the formation of aldehyde 399. Treatment with 2% NaOH in methanol facilitated an aldol-type cyclization, resulting in the isolation of secondary alcohol 400 in a 91% yield after crystallization.

Reduction with NaBH4 in TFA removed the benzylic hydroxyl group, providing tetracycle 401 in a modest 41% yield. Pyridine N-methylation and reduction of the resulting pyridinium ion yielded a mixture of methyl lysergate and isolysergate (402). Finally, thermodynamically controlled ester epimerization and saponification in aqueous NaOH led to the synthesis of lysergic acid (±)-35.

Synthetic studies of LSD by the Fukuyama group in USA

In the initial formal synthesis of lysergic acid, Fukuyama proposed a method for the preparation of (+)-35 that involved an intramolecular Heck reaction to construct the C-ring. As a critical initial step, a ring expansion of a bicyclic dibromocyclopropane would produce the necessary tetrahydropyridine with the required functionalities (Scheme 71). The readily synthesized starting material 406 was shielded with a Cbz group, and the lactam was reduced with DIBAL-H to the hemiaminal. Dehydration to dihydropyrrole 407 was then carried out with CSA and pyridine at reflux. Dibromocyclopropanation followed by elimination formed dihydropyridine 408 in a yield of 73%. Monoreduction using Et3SiH and Tf2NH, followed by Pd-catalyzed carbonylation, resulted in the formation of ester 409. Cbz-deprotection and subsequent treatment with NsCl provided 410.

Removal of pivaloyl and Jones oxidation produced acid 411, which was converted to acyl chloride 413 by treatment with Ghosez’s reagent 412. Subsequent addition to metalloindole 414 furnished ketone 415. Indole N-H protection with AllocCl and ketone reduction with NaBH4 provided 416 in a two-step yield of 58%. The nosyl group was removed, and the secondary amine was methylated by reductive amination with formaldehyde to provide 417. The Alloc group was removed with Pd(0)-catalysis and pyrrolidine as an allyl scavenger. The alcohol was then reduced with Et3SiH and TFA, and the indole N-H was protected with a Boc group, providing 418. Alkene isomerization with LiTMP by deprotonation at the γ-carbon of the α,β-unsaturated ester, intramolecular Heck reaction, and Boc-deprotection gave 419, thus completing the formal synthesis of (+)-35.