Synthesis of Bicyclo[2.1.1]hexan‐5‐ones via a Sequential Simmons‐Smith Cyclopropanation and an Acid‐Catalyzed Pinacol Rearrangement of α‐Hydroxy Silyl Enol Ethers

Abstract

A synthetic strategy involving a Simmons‐Smith cyclopropanation, followed by an acid‐catalyzed pinacol rearrangement, was developed to transform α‐hydroxy silyl enol ethers into 1‐substituted bicyclo[2.1.1]hexan‐5‐ones. These bicyclic ketones underwent further synthetic manipulations to generate various 1,5‐disubstituted bicyclo[2.1.1]hexanes, which could serve as potential bioisosteres of ortho‐substituted arenes.

(Bio)isosteres of ortho- and meta-substituted benzenes

“…Furthermore, 1,5-BCH (±)-64 was synthesised as a bioisostere of the fungicide fluxapyroxad from amine (±)-63 , which was itself accessed via Curtius rearrangement of the corresponding 1,5-BCH ( Scheme 5C ) [ 42 ]. In 2023, Yoo and co-workers reported the synthesis of 1,5-BCHs by derivatization of 5-oxo-BCHs (±)-67 ( Scheme 5D ) [ 43 ]. They accessed the 5-oxo-BCHs by Simmons–Smith cyclopropanation [ 44 ] (to (±)-66 ) of α-hydroxy silyl enol ethers (±)-65 followed by an acid-catalysed pinacol rearrangement to (±)-67 .…”

“…C: Application of the Mykhailiuk and co-workers’ synthesis for the synthesis of a fluxapyroxad bioisostere [ 42 ]. D: Yoo and co-workers’ synthesis of 1,5-BCHs [ 43 ].…”

“…C: Application of the Mykhailiuk and co-workers' synthesis for the synthesis of a fluxapyroxad bioisostere [42]. D: Yoo and co-workers' synthesis of 1,5-BCHs [43]. 1,2-Disubstituted BCHeps (1,2-BCHeps) have been proposed as isosteres of ortho-benzenes [46], but no exit vector comparison has thus far been reported in the literature (Figure 13).…”