Total Synthesis of (+)-Lysergic Acid

Abstract

We report the enantioselective total synthesis of (+)-lysergic acid using two different strategies, which featured three metal-catalyzed reactions for the construction of the BCD three rings, involving Pd-catalyzed indole synthesis for the construction of the B ring, a ring-closing metathesis reaction for the formation of the D ring, and an intramolecular Heck reaction to forge the C ring. In synthetic strategy I, the synthesis was achieved in 20 steps following the ring construction sequence of BDC. In synthetic strategy II, the synthetic route was shortened to only 12 steps by following the ring construction sequence of DBC and using a 4-chlorotryptophan derivative for the intramolecular Heck reaction. Moreover, we also discussed an unsuccessful synthetic strategy.

Synthesis of 2-substituted tryptophans via a C3- to C2-alkyl migration

“…Facile access to tryptophan and unnatural tryptophan derivatives is of general interest because tryptophans are found in many naturally occurring compounds and are an important component of biologically active compounds [1–7]. Tryptophan and tryptophan analogs also have applications in chemical biology thanks to the highly environment-sensitive fluorescence properties of the indole ring [8–17] and when incorporated into peptides, they lead to compounds with increased resistance to enzymatic degradation and modification [18–25].…”

Total Synthesis of Dictyodendrins B and E, and Formal Synthesis of Dictyodendrin C

“…5‐Bromoindole intermediate 7 could be rapidly prepared by Friedel–Crafts alkylation at the C‐2 position of indole 9 with the corresponding electrophile, followed by site‐selective bromination at the C‐5 position. Finally, common indole intermediate 9 should be easily obtained by the palladium‐catalysed annulation reaction of o ‐iodoaniline 12 and the corresponding aldehyde, followed by N ‐alkylation with bromide 10 16,9a–9e…”

Applications of Morita-Baylis-Hillman Reaction to the Synthesis of Natural Products and Drug Molecules

“…Based on DYKAT process, Trost et al developed the total synthesis of furaquinocin E (67) from the MBH derivative 62 (Scheme 8) which was prepared from the MBH adduct 60 [24,25]. They elegantly extended the scope of their strategy by developing the synthesis of furaquinocin A (68) analogues of furaquinocin E [26], thereby demonstrating the modular property of the strategy. Dialkylation of 2-iodoresorcinol with the allylic carbamate (62) prepared from the MBH adduct gave 63 in excellent yield and high stereoselectivity.…”

“…(+)-Lysergic acid (241), a member of pharmacologically important Ergot alkaloids, was isolated from the fungus Claviceps purpurea. Very recently, Jia and co-workers reported two different enantioselective strategies featuring metal-catalyzed reactions to achieve the total synthesis of (+)-lysergic acid [68]. In one of their approaches they used the allyl bromide 238, prepared from the MBH adduct of formaldehyde, to generate the precursor 239 for RCM reaction (Scheme 35).…”