Natural Product-Derived Chiral Pyrrolidine-2,5-diones, Their Molecular Structures and Conversion to Pharmacologically Important Skeletons

Abstract

The versatility of the natural products (2S,3S)- and (2S,3R)-3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylic acids (1 and 2), isolated in large amounts from tropical plant sources, has been demonstrated by the construction of 3-substituted and 3,4-disubstituted chiral pyrrolidine-2,5-diones. The absolute configurations of chiral pyrrolidine-2,5-diones have been ascertained using chiroptical spectroscopic methods and/or single-crystal XRD data. A combination of different reaction strategies delivering a diverse matrix of fused heterocyclic ring systems is presented. The pyrrolo­[2,1-a]­isoquinoline alkaloid (+)-crispine A possesses a wide range of pharmacological activities including antidepressant, antiplatelet, antileukemic, and anticancer activities. The analogues of indolizino­[8,7-b]­indole alkaloids (+)- and (−)-harmicine show strong antileishmanial, antinociceptive, PDE5-inhibitory, antimalarial, and antiviral activities. The bicyclic furo­[2,3-b]­pyrrolo skeleton is present in many natural products. Thus, the uniqueness of relatively cheap, naturally occurring chiral 2-hydroxycitric acid lactones as chirons has been demonstrated by the construction of some important molecular skeletons that are otherwise difficult to synthesize.

Phosphine‐Catalyzed Enantioselective (3+2) Annulation of Vinylcyclopropanes with Imines for the Synthesis of Chiral Pyrrolidines

“…To demonstrate the practicality of our method, a convenient gram‐scale (3+2) annulation was performed using standard reaction conditions, furnishing 3 a in high yield with excellent ee and dr values (Scheme 6a). We developed a synthetic route to convert pyrrolidine 3 a to γ‐lactam 4 b , a structural scaffold of biological significance [16] . Ketoester 4 a , obtained from ozonolysis of 3 a , was treated with m ‐CPBA to trigger a Baeyer–Villiger oxidation to yield 4 a′ .…”

“…We developed a synthetic route to convert pyrrolidine 3 a to γ-lactam 4 b, a structural scaffold of biological significance. [16] Ketoester 4 a, obtained from ozonolysis of 3 a, was treated with m-CPBA to trigger a Baeyer-Villiger oxidation to yield 4 a'. Subsequent reaction with TFA led to fragmentation and formed iminium 4a'', Scheme 3.…”

Synthesis of Pyrrolo[2,1‐a]isoquinoline Class of Natural Product Crispine A

“…Again, the same three-step strategy was employed for the synthesis of (+)-Crispine A analog in 2020 (Scheme 47). [83] The NaBH 4 -mediated reductive cyclization of chiral pyrrolidine-2,5dione ester 175 in acidic conditions affords (+)-crispine A analog 176 in 85 % yield. Hence, using this chiral pool strategy, diastereomeric natural products 171 and 172 are conveniently converted to desirable enantiomers of Crispine A.…”

Desymmetrization of meso-Dicarbonatecyclohexene with β-Hydrazino Carboxylic Esters via a Pd-Catalyzed Allylic Substitution Cascade

“…(Figure ). For this reason, much effort has been devoted to their preparation, and a series of useful methodologies have been developed and applied generally in the organic and medicinal chemistry fields . Compared with cinnolines, hydrocinnolines remain relatively unfamiliar in modern-day organic chemistry, and their construction has been considerably less exploited.…”

“…Compared with cinnolines, hydrocinnolines remain relatively unfamiliar in modern-day organic chemistry, and their construction has been considerably less exploited. Furthermore, most of the existing synthetic methods are racemic. , Therefore, the development of synthetic approaches for the efficient construction of novel chiral hydrocinnoline derivatives is greatly important.…”