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

Abstract

Efficient access to diverse screening compounds with desirable, lead‐like properties can be a bottleneck in early drug discovery and chemical biology. Herein we present an efficient, rapid route to three structurally distinct classes of compounds (A–C) from a single precursor, which in turn is available through a one‐pot Petasis 3‐component reaction/Diels–Alder cascade reaction. We demonstrate the versatility of the approach through the synthesis of 35 exemplary compounds from the three classes, as well as by the production of 2188 final compounds, which have been included in the Joint European Compound Library of the European Lead Factory.

Reactivity and Synthetic Applications of Multicomponent Petasis Reactions

“…102 A cascade using α-hydroxylated aldehydes, Bn-protected allyl amine, and 5-Boc-amine-substituted fur-2-ylboronic acids gave the PR/IMDA products 197 , which were applied for small-molecule library synthesis (Scheme 51). 163…”

“…162 The PR/IMDA allyl product 209 obtained via the PR/IMDA cascade using an allyl-substituted furan-2-boronic acid was subjected to a ROM/RCM sequence to give the tricyclic tetrahydropyridine 210 (Scheme 54). 163…”

“…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. − …”

“…102 A cascade using α-hydroxylated aldehydes, Bnprotected allyl amine, and 5-Boc-amine-substituted fur-2ylboronic acids gave the PR/IMDA products 197, which were applied for small-molecule library synthesis (Scheme 51). 163 Nielsen and coworkers developed a PR/IMDA/oxidative cleavage sequence starting from salicylaldehyde, Bn-protected allyl amine, and furan-2-boronic acid to give phenol 198 as the PR/IMDA cascade product. Following the oxidative cleavage of phenol 198 using catalytic K 2 OsO 4 and NMO as the oxidants with the subsequent treatment of NaIO 4 yielded key dialdehyde intermediates 199, which were reduced to give the diols 200 in the presence of NaBH 4 .…”

Reaction of Aroylpyrrolobenzothiazinetriones with Electron‐Rich Dienophiles

“…The Diels‐Alder reaction is a powerful synthetic tool for assembling various complex three‐dimensional molecules, since it can enable installation of up to four stereogenic centers in a regio‐ and stereoselective manner via a single step [4b,5] . 4‐Acyl‐1 H ‐pyrrole‐2,3‐diones I are well‐known to be prone to react as oxo‐dienes with electron‐rich dienophiles II to afford pyrano[4,3‐ b ]pyrroles III (Scheme 1).…”