Petasis/Diels–Alder/Cyclization Cascade Reactions for the Generation of Scaffolds with Multiple Stereogenic Centers and Orthogonal Handles for Library Production

Abstract

A new effective strategy for the synthesis of sp3‐rich small molecules for library production is presented. The key steps to generate complexity involve a Petasis three‐component reaction followed by an intramolecular Diels–Alder and cyclization to generate a densely enriched tricyclic or tetracyclic scaffolds with 3–4 stereocenters and three handles for decoration. The strategy was used for the production of 143 molecules for the European Lead Factory.

Reactivity and Synthetic Applications of Multicomponent Petasis Reactions

“…Diols 204 could be further cyclized to yield tricyclic pyrrolidinones 205 and 206 with a diversified handle at the 2-position of the octahydro-6 H -furo[2,3- c ]pyrrolo[3,4- b ]pyrrol-6-one core scaffold (Scheme 53). 165…”

“…The obtained compounds 201 , 202 , 205 , 206 , and 208 – 210 all shared a densely functionalized polycyclic core structure bearing at least three stereogenic centers as well as at least three handles for further derivatization and are attractive scaffolds for the establishment of natural-product-like small-molecule libraries. − …”

“…Diols 204 could be further cyclized to yield tricyclic pyrrolidinones 205 and 206 with a diversified handle at the 2-position of the octahydro-6H-furo[2,3-c]pyrrolo [3,4-b]pyrrol-6-one core scaffold (Scheme 53). 165 A second allyl group can be incorporated into the PR/ IMPDA product by choosing the corresponding substrates to achieve a PR/IMDA−ROM/RCM sequence. In the PR/ IMDA cascade, the replacement of the glycolaldehyde dimer with a masked α-hydroxypent-4-enal as the carbonyl component led to the formation of the hexahydroepoxyisoindole 207 with an allyl handle.…”

Generation of a Heteropolycyclic and sp3‐Rich Scaffold for Library Synthesis from a Highly Diastereoselective Petasis/Diels–Alder and ROM–RCM Reaction Sequence

“…We recently published the synthesis of an sp 3 ‐rich library based on a 3‐component Petasis/Diels–Alder strategy . This sequence in combination with ring opening/ring closing metathesis (ROM/RCM) cascade reactions enabled us to access different, diverse and sp 3 ‐rich scaffolds.…”

Petasis/Diels–Alder/Cyclization Cascade Reactions for the Generation of Scaffolds with Multiple Stereogenic Centers and Orthogonal Handles for Library Production

“…In the original article, we omitted to cite the following work by Norsikian and Beau et al, who first reported this combination of reactions in 2014. Later, we explored this reaction further , …”