NHC‐Catalyzed Enantioselective [4+3] Cycloaddition of Ortho‐Hydroxyphenyl Substituted Para‐Quinone Methides with Isatin‐Derived Enals

Abstract

The first enantioselective cycloaddition of ortho‐hydroxyphenyl substituted para‐quinone methides has been established by employing isatin‐derived enals as suitable 3C‐synthons under chiral N‐heterocyclic carbene catalysis. By using this strategy, biologically important ϵ‐lactones have been prepared in good yields (up to 89%) and excellent asymmetric inductions (up to >99% ee, >20:1 dr). Notably, this methodology opens a direct [4+3] annulation entry for the asymmetric synthesis of spirobenzoxopinones bearing an oxindole moiety connected through the spirocenter.magnified image

Recent Advances in the Catalytic Enantioselective Reactions of para‐Quinone Methides

“…The first enantioselective [4+3] cycloaddition of ortho ‐hydroxyphenyl‐substituted para ‐quinone methides mediated by a chiral N‐heterocyclic carbene was established by Li′s group (Scheme ) . They employed isatin‐derived enals 73 as suitable three‐carbon synthons for the reaction with ortho ‐hydroxyphenyl‐substituted p ‐QMs 72 in the presence of NHC C20 .…”

“…The first enantioselective [4+ +3] cycloaddition of ortho-hydroxyphenyl-substituted para-quinone methides mediated by a chiral N-heterocyclic carbene was established by Li'sg roup (Scheme23). [28] They employed isatin-derivede nals 73 as suitable three-carbon synthons for the reaction with ortho-hydroxyphenyl-substituted p-QMs 72 in the presence of NHC C20.A ddition of the chiral carbenet ot he isatin-derived enal generated aB reslow intermediate, which,i ni ts mesomeric form, constituteda na zolium homoenolate intermediate. Next, 1,6-addition of the homoenolate equivalent to the p-QM afforded an acyl azolium intermediate.…”

N-Heterocyclic Carbene-Catalyzed 1,6-Addition of Homoenolate Equivalent Intermediates: Asymmetric Synthesis of Nonspirocyclic Quaternary Oxindoles

“…Since then, numerous NHC-catalyzed reactions, via homoenolate equivalent intermediates with activated double bonds have been developed by several groups. 28,39 Surprisingly, although there are significant advances in cycloaddition reactions of homoenolate equivalent intermediates with Michael acceptors, [51][52][53][54][55][56][57][58][59][60][61][62] the corresponding linear processes via homoenolate additions are largely unexplored (Scheme 1b). Currently, only two types of 1,4-Michael additions have been reported.…”

Access to Enantioenriched Spiro‐ϵ‐Lactam Oxindoles by an N‐Heterocyclic Carbene‐Catalyzed [4+3] Annulation of Flexible Oxotryptamines with Enals

“…and 99 % ee (entries [8][9][10][11][12]. Increasing the loading of base, oxidant and 2a improved the product yield considerably without any loss in d.r.a nd ee,r espectively (entries [13][14][15]. To our delight, the use of the Br-substituted aminoindanol-derived triazolium pre-catalyst C [21] could furtheri mproved iastereoselectivity up to 4.6:1( entry 16).…”

“…[3] Since the groups of Ye [4] and Scheidt [5] in 2013 independently pioneered NHC-catalyzed [ 4 + +3] annulation for the synthesis of e-lactone,c onsiderable effort has been devotedt ot his area, and some elegant catalytic approaches for the synthesis of enantioenriched seven-membered heterocycles have been successfully developed by NHC-catalyzed formal [4+ +3] and [5+ +2] annulations by the groups of Glorius, [6] Ye, [7] Zhao, [8] Enders, [9] Chi, [10] Hui, [11] Du, [12] andL i. [13] Notably, the aforementioned methods have to rely on the use of sub-stratesw ith ar igid structurea st he synthons to overcome high ring strain and transannulari nteractions (Scheme 1). In contrast, synthesis of seven-membered heterocyclesbased on substratesw ith af lexible alkyl chain under NHC organocatalysis still remains elusive and underexplored.T hus, the development of an ovel methodb ased on more challenging flexible substratesp romoted by NHC, meanwhile constructiono fn ovel structurally diverse seven-membered rings is highly desirable.…”