Skeletal Diversification via Heteroatom Linkage Control: Preparation of Bicyclic and Spirocyclic Scaffolds from N-Substituted Homopropargyl Alcohols

Abstract

The discovery and application of a new branching pathway synthesis strategy that rapidly produces skeletally diverse scaffolds is described. Two different scaffold types, one a bicyclic iodo-vinylidene tertiary amine/tertiary alcohol and the other, a spirocyclic 3-furanone, are each obtained using a two-step sequence featuring a common first step. Both scaffold types lead to intermediates that can be orthogonally diversified using the same final components. One of the scaffold types was obtained in sufficiently high yield that it was immediately used to produce a 97-compound library.

Synthesis of a Family of Spirocyclic Scaffolds: Building Blocks for the Exploration of Chemical Space

“…The sequence began with the N -Boc protected spirocyclic 3-furanones 23-25 which were prepared from N -Boc protected cyclic 2-aminoketones 1-3 as previously reported by this laboratory. 12 The 3-furanones were converted to their corresponding tosylhydrazones (not shown) which were obtained as mixtures of geometric isomers. These were treated with base to give the enol ethers 26 , 27 and 28 , which were isolated in the indicated overall yields.…”

“…The synthetic plan for spiro-DHF containing scaffolds is shown in Scheme . The sequence began with the N -Boc protected spirocyclic 3-furanones 23 – 25 which were prepared from N -Boc protected cyclic 2-aminoketones 1 – 3 as previously reported by this laboratory . The 3-furanones were converted to their corresponding tosylhydrazones (not shown) which were obtained as mixtures of geometric isomers.…”

Four-Membered Ring-Containing Spirocycles: Synthetic Strategies and Opportunities

“…The synthetic route for the synthesis of 2,6-diazaspiro [3.3]heptane is similar to that described for 2-thia-6-aza-spiro [3.3]heptane. The reaction of 3,3-bis(tosylmethyl)-or 3,3-bis(bromomethyl)-azetidine (93) with benzylamine effects closure of the second azetidine ring, giving 132 (Scheme 31). A series of differentially protected homospiropiperazines, such as Boc-protected example 133, has been used in a number of drug discovery programs.…”

Oxa-spirocycles: synthesis, properties and applications

“… 15 In 2013, Santini described the gold-catalyzed oxidative cyclization of propargyl alcohols into oxa-spirocyclic amines ( Scheme 1 ). 16 In the same year, Santini also developed an alternative approach to oxa-spirocyclic amines via oxidative intramolecular hydroxycyclization of alkenes. 17 Subsequently, Cocotos realized an organocatalytic version of that method ( Scheme 1 ).…”