Proline Derived Bicyclic Derivatives through Metal Catalysed Cyclisations of Allenes: Synthesis of Longamide B, Stylisine D and their Derivatives

Abstract

Annulations of allene‐substituted proline derivatives promoted by transition metals have been investigated as a general way to access bicyclic structures with a bridgehead nitrogen. Two processes, Pd‐ and Ag‐catalysed cyclisations, have been employed complementary to control the substitution pattern of the product. The investigated methodologies afforded the bicyclic derivatives in comparable yields, while Ag‐catalysis showed higher level of diastereoselectivity. Both processes have been utilized in the synthesis of naturally occurring pyrroles longamide B, stylisine D and their derivatives.

Marine Pyrrole Alkaloids

“…At this point, the stereoselective synthesis of (−)-stylisine D ( 334 ) reported by Petkovic and Savic in 2019 should be mentioned ( Scheme 20 ) [ 288 ]. The synthesis commenced with an N-protection and propargylation followed by routine transformations to generate allene 337 in 55% yield over three steps.…”

Stereoselective synthesis of 3,4‐dihydropyrrolo[1,2‐a]pyrazin‐1(2H)‐one derivatives as PIM kinase inhibitors inspired from marine alkaloids

“…Based on these results, a stereoselective synthesis was designed. Literature data reported stereoselective approach to the pyrrolo[1,2-a]pyrazine bicycle for the synthesis of longamide 20,34,35 and (À)-stylisine D. 21 Based on this precedent, a pathway starting from the aspartic acid dimethyl esters was envisioned. The retrosynthesis depicted in Scheme 2 is very versatile as the functional group transformations involved are in principle compatible with any amino acid, resulting in a wide chemo-and stereo-diversification of the scaffold.…”

“…[15][16][17] Heterocyclic compounds containing the 3,4-dihydropyrrolo [1,2-a]pyrazin-1(2H)-one moiety occur in a number of natural products of marine origin. 18 This intriguing chemical architecture of annellated pyrroles was investigated by several teams involved in the total synthesis of natural products, [19][20][21] but its potential as an innovative scaffold in medicinal chemistry is still overlooked even though the role of natural products as an inspiration for chemical templates in drug discovery programs is quite established. Structural features of natural products such as the presence of elements of asymmetry might be advantageous in exploring demanding biological targets.…”

A Review of the Synthetic Strategies toward Dihydropyrrolo[1,2-a]Pyrazinones

“…Earlier attempts to aromatize 127 with 2,3-dichloro 5,6-dicyano-1,4-benzoquinone (DDQ) gave a lower yield (20-30%) and was accompanied by difficult purification [107]. Recently, the proline-derived compound 129 was oxidized to the pyrrole 130 with MnO2 in THF at 85 °C without effecting the vinyl or dihydropyra zinone parts [123] (Scheme 35).…”

“…Earlier attempts to aromatize 127 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) gave a lower yield (20-30%) and was accompanied by difficult purification [107]. Recently, the proline-derived compound 129 was oxidized to the pyrrole 130 with MnO2 in THF at 85 °C without effecting the vinyl or dihydropyrazinone parts [123] (Scheme 35). The condensation of N-(2-aminoethyl)aziridine with two equivalents of diethyl acetylenedicarboxylate gave the triester 131, the same compound that could be obtained through the ring transformation of the furan tetraester 132 and 1,2-diaminoethane [124] (Scheme 36).…”