Total Synthesis without Protection: Three‐Step Synthesis of Optically Active Clavicipitic Acids by a Biomimetic Route

Abstract

A three-step synthesis of a mixture of optically active cisand trans-clavicipitic acids 6, which are ergot alkaloids, was achieved, starting from 4-bromoindole (7) and dl-serine (dl-2). This short synthesis was made possible by omitting the protection and deprotection steps from the synthetic route. The key step was the spontaneous cyclization of 4-vinyltryptophan (10) formed from the Heck reaction of 4-bromotryptophan (8) with 2-methyl-3-buten-2-ol (9) in aqueous media.

Chemistry of Unprotected Amino Acids in Aqueous Solution: Direct Bromination of Aromatic Amino Acids with Bromoisocyanuric Acid Sodium Salt under Strong Acidic Condition

“…The ortho- (16) and para-bromophenylalanine (17) were obtained in 36% and 58% yield, respectively (Table 1, run 2). The total yield of mono-brominated products was very high (94%), and separation of each products (16,17) was easy by using the reverse phase (ODS) column chromatography. Furthermore, these products were not racemized despite the strong acidic conditions.…”

“…Most of the synthetic transformations to natural products, pharmaceuticals, and chiral auxiliaries have been performed [12][13][14][15] with protected amino acids to increase solubility in organic solvents and avoid side reactions. We have reported 16,17) a three-step synthesis of optically active clavicipitic acids (6), ergot alkaloids, from 4-bromoindole (1) and dl-serine (2) that involved a reaction of unprotected amino acids in aqueous media as a key step (Chart 1). Thus, Pd-catalyzed reaction of 4-bromotryptophan [S- (3)] with 1,1-dimethylallylalcohol (4) under strong basic conditions selectively yielded the Heck product (5), which spontaneously cyclized to give clavicipitic acids (6) in one pot.…”

Mechanistic Studies for Synthesis of Bis(indolyl)methanes: Pd-Catalyzed C–H Activation of Indole–Carboxylic Acids with Benzyl Alcohols in Water

“…Water activates the benzyl alcohol via hydration of the hydroxyl group for generation of the (η 3 -benzyl)palladium species, which can then undergo innovative direct transformation reactions. We became interested in further expanding the substrate scope of the (η 3 -benzyl)palladium system to water-soluble unprotected indole carboxylic acids 1, since we have been studying the development of synthesis without protecting groups and selective reactions towards various reactive functional groups [29][30][31][32]. In general, synthesis without protecting groups represents a distinct challenge and has been fraught with a number of difficulties such as chemoselectivity [33].…”

Synthesis of VIP-Lipopeptide Using a New Linker to Modify Liposomes: Towards the Development of a Drug Delivery System for Active Targeting

“…Due to our experience developing unprotected synthesis strategies for highly polar compounds such as free amino acids, [14][15][16][17] we attempted the direct introduction of benzyl acetate moiety into unprotected diol 3.…”