New development in the enantioselective synthesis of spiro compounds

Abstract

The enantioselective synthesis of spirocycles has long been pursued by organic chemists. Despite their unique 3D properties and presence in several natural products, the difficulty in their enantioselective synthesis makes them underrepresented in pharmaceutical libraries. Since the first pioneering reports of the enantioselective construction of spirosilanes by Tamao et al., significant effort has been devoted towards the development of new promising asymmetric methodologies. Remarkably, with the advent of organocatalysis, particularly over six years, the reported methodologies for the synthesis of spirocycles have increased exponentially. The aim of this review is to summarize the latest trends and developments in the enantioselective synthesis of spirocompounds during these last six years.

Catalyst-free formal [4+1]/[4+2] cyclization cascade sequence of isocyanides with two molecules of acylketene formed in situ from thermal-induced Wolff rearrangement of 2-diazo-1,3-diketones

“…Spirocyclic compounds featuring with a spiro center connecting to both heteroatoms of two heterocycles are common and significant tools for developing new pharmaceutically relevant compounds [1][2][3][4][5], materials [6][7][8] and ligands [9][10][11][12][13] owing to their inherent structural rigidity and capacity to orient distinct groups in defined spatial arrangements. Two representative scaffolds are O,O-spiroketal (type I: X,X-spiro structure) and N,Ospirohemiaminal (type II: X,Y-spiro structure), which have attracted much research interest from chemists because of their functional irreplaceability (Fig.…”

Cycloaddition Strategies for the Synthesis of Diverse Heterocyclic Spirocycles for Fragment‐Based Drug Discovery

“…Regio‐ and stereo‐control is difficult to achieve and, historically, has required multiple alkylation steps followed by intramolecular coupling. Furthermore, these routes have suffered from functional group incompatibility which, in turn, has greatly limited the incorporation of functional handles for late‐stage modification and fragment elaboration . Moreover, these strategies tend to involve long linear sequences, and are therefore of limited use in the optimisation of fragment hits …”

Bimetallic Catalytic Asymmetric Tandem Reaction of β‐Alkynyl Ketones to Synthesize 6,6‐Spiroketals

“…Chiral spiroketals are key structural motifs in am ass of natural and synthetic bioactive compounds. [5,6] Among the family of spiroketals,6 ,6-spiroketal behaves as ac rucial pharmacophore in many natural products, [7] and also as an important skeleton in chiral ligands applied in various transition-metal-catalyzed asymmetric reactions (Scheme 1b). [8] In previous works,t he common strategy was to deliver chiral 6,6-spiroketal through intramolecular nucleophilic addition of alcohol to oxocarbenium ion intermediate or carbonyl group catalyzed by chiral Brønsted acids [9] or chiral iridium complexes.…”