Enantio- and Diastereoselective Synthesis of Spiro-epoxyoxindoles

Abstract

An asymmetric synthesis of epoxyoxindoles from isatins has been developed by employing chiral sulfur ylides generated in situ from camphor-derived sulfonium salts. This reaction allows an efficient access to enantioenriched spiro-epoxyoxindoles under mild reaction conditions, featuring high yields and excellent enantio- and diastereoselectivities.

Chemoselective Addition of Halomethyllithiums to Functionalized Isatins:A Straightforward Access to Spiro‐Epoxyoxindoles

“…In recent years, the synthesis of spiro‐epoxyoxindoles represented a significant challenge for the synthetic community and, in this sense the elegant work from the laboratories of Metzner and Brière opened the field to access them in a stereoselective fashion through Darzens‐type processes carried out on an isatin derivative 4. Further developments came from the work of Lu, Xiao and co‐workers who achieved impressive levels of enantio‐ and diastereoselection by employing chiral sulfur ylides as methylene donors 5. Moreover, truly asymmetric Darzens reactions between N ‐protected isatins and phanacyl bromides have been disclosed by Feng in the presence of chiral N,N′ ‐dioxide–Co(acac) 2 complexes 6.…”

Asymmetric Synthesis of Spirooxindoles via Nucleophilic Epoxidation Promoted by Bifunctional Organocatalysts

“…Indeed, the oxirane ring easily undergoes several stereoselective chemical transformations into a variety of multi-functionalized compounds that directly led to advanced precursors of both natural products and biologically active molecules [ 2 , 3 , 4 , 5 , 6 , 7 ]. Among them, spiro-epoxyoxindoles, featured with a spiro-carbon and unstable oxirane motif, have piqued the interest of a growing number of research groups [ 8 , 9 , 10 ]. Such striking allure is mainly due not only to their recognised medicinal effectiveness [ 11 , 12 , 13 , 14 , 15 , 16 , 17 ], but also to their role providing direct access to architecturally complex heterocycles [ 18 , 19 , 20 , 21 , 22 ].…”

“…For instance, since the seminal work of Brière and Metzner [ 23 ], stereoselective Darzen-type processes have been the object of several investigations. In 2014 Xiao et al succeeded in the synthesis of epoxyoxindoles from isatines [ 8 ]. Likewise, Feng and co-workers investigated a Co(acac) 2 - N,N ′-dioxide-catalyzed Darzens reaction to afford benzyl-substituted trans -spirooxirane-oxindoles [ 10 ], while, more recently, Wong has focused his efforts on the use of (R)-BINOL and Ti(iOPr) 4 as catalysts reaching a high level of stereoselectivity involving chiral sulfur ylides in situ generated from camphor-derived sulfonium salts [ 24 ].…”

Stereoselective Synthesis of Trisubstituted Epoxides Marks the Route to Chiral Building Blocks with Quaternary Centers

“…The asymmetric epoxidation of aldehydes employing sulfur ylides constitutes an excellent tool that has been well studied and applied in synthetic organic chemistry . In contrast, and despite the fact that the epoxidation reaction of ketones was reported by Corey and Chaykovsky in 1962, only a couple of reports dealing with asymmetric epoxidation of ketones have enriched the chemistry literature , . In particular, a general asymmetric epoxidation of ketones yielding trisubstituted epoxides (Scheme b) remains unprecedented , .…”

“…In contrast, and despite the fact that the epoxidation reaction of ketones was reported by Corey and Chaykovsky in 1962, only a couple of reports dealing with asymmetric epoxidation of ketones have enriched the chemistry literature , . In particular, a general asymmetric epoxidation of ketones yielding trisubstituted epoxides (Scheme b) remains unprecedented , . Having a quaternary carbon vicinal to another chiral center in optically active epoxides bequeaths important stereogenic properties to these building blocks as well as to the small molecules emanating from them and therefore calls for the development of an easy and efficient access to these small heterocycles.…”