Enantioselective Synthesis of Spiroindenes by Enol‐Directed Rhodium(III)‐Catalyzed CH Functionalization and Spiroannulation

Abstract

Chiral cyclopentadienyl rhodium complexes promote highly enantioselective enol-directed C(sp 2 )-H functionalization and oxidative annulation with alkynes to give spiroindenes containing all-carbon quaternary stereocenters. High selectivity between two possible directing groups,aswell as control of the direction of rotation in the isomerization of an O-bound rhodium enolate into the C-bound isomer,appear to be critical for high enantiomeric excesses.Cyclopentadienyl rhodium(III) complexes are well-established as highly active and versatile precatalysts in ad iverse array of CÀHf unctionalization reactions.[1] However, enantioselective variants of these reactions only became possible with the development of chiral C 2 -symmetric cyclopentadienyl ligands by Ye and Cramer, [2] and an artificial Rh III -containing metalloenzyme by Ward, Rovis,and co-workers. [3] To date,ahandful of catalytic enantioselective Rh III -catalyzed CÀHf unctionalizations have been described, [2][3][4][5] but there is ac ompelling need to develop new processes to access novel classes of enantioenriched products. [6] We recently reported Ru-and Pd-catalyzed oxidative annulations of a-aryl cyclic 1,3-dicarbonyl compounds (or their enol tautomers) with alkynes that provide achiral or racemic spiroindenes. [7] Given that indenes appear in several biologically active compounds, [8,9] theability to prepare chiral spiro-fused indenes 4 by asymmetric C À Hf unctionalization would be valuable.[4d, 10] Because we also found that [{Cp*RhCl 2 } 2 ]i sa ne ffective precatalyst, [7a,11] chiral cyclopentadienyl rhodium complexes 3 appeared to be highly promising for investigation. However,i nc ontrast to existing enantioselective Rh III -catalyzed CÀHf unctionalizations, which all rely upon aryl C(sp 2 )-H activation of substrates containing as ingle directing group (Scheme 1a), [2][3][4][5] the substrates 1 required for our proposed study contain two potential directing groups (Scheme 1b). Within the accepted model for enantioinduction using complexes 3, [2b, 5] cyclorhodation can generate up to four species,w hich differ in which directing group participates in cyclometallation, and/or the orientation of the rhodacycle within the chiral pocket (Scheme 2). This situation contrasts with existing processes, [2][3][4][5] including the dearomatizing oxidative spiroannulations of Youand co-workers, [4d] in which only two conformations of one rhodacycle need to be considered. Given the possibility of other reaction pathways with potentially different stereochemical outcomes,t he development of ah ighly enantioselective process was far from certain. Herein, we report the successful realization of asymmetric [3+ +2] spiroannulations to give adiverse range of spiroindenes in up to 97 % ee. Scheme 2. Possible species to consider upon cyclorhodation.[*] Dr

Catalytic Enantioselective Transformations Involving C–H Bond Cleavage by Transition-Metal Complexes

“…Later that same year, Lam and co-workers employed a similar strategy to realize an asymmetric spiroannulation of enols 226 with internal alkynes 227. 158 In this case either Cat-1 or Cat-6 served as precatalyst and furnished spiroindenes 228 with high levels of enantiocontrol.…”

Chiral Aluminum Complex Controls Enantioselective Nickel‐Catalyzed Synthesis of Indenes: C−CN Bond Activation

“…(3)], and though an aryl C À H bond was still used as the starting point, an enolate trapping step was devised to replace the dearomization step. [11] Despite these elegant works, the synthesis of easy-to-modify indenes bearing all-carbon quaternary stereocenters from readily available arenes is still in high demand. Herein, we report a new domino process that uses the C À C bond as a starting point for the first time to prepare chiral non-spiro-indenes in 32-91 % yield and up to 98 % ee [Scheme 1 b, Eq.…”

Enantiodivergent Desymmetrization in the Rhodium(III)‐Catalyzed Annulation of Sulfoximines with Diazo Compounds

“…[6] Very recently,P erekalin and co-workers applied ar eduction/nucleophilic addition approach to rhodium fulvene complexes to access planar-chiral Cp X Rh III catalysts. [9] With regard to desymmetrization, Cramer and Sun reported an oxidative [4+ +2] annulation between phosphinamides and alkynes [10] where the desymmetrization was enabled by ac hiral Cp X Rh III catalyst (Scheme 1a). [9] With regard to desymmetrization, Cramer and Sun reported an oxidative [4+ +2] annulation between phosphinamides and alkynes [10] where the desymmetrization was enabled by ac hiral Cp X Rh III catalyst (Scheme 1a).…”

“…[7] In these asymmetric catalytic systems,t he stereodetermining process is the CÀHa ctivation (in desymmetrization), the migratory insertion process, [4a,b,8] or the reductive elimination. [9] With regard to desymmetrization, Cramer and Sun reported an oxidative [4+ +2] annulation between phosphinamides and alkynes [10] where the desymmetrization was enabled by ac hiral Cp X Rh III catalyst (Scheme 1a). In principle,t he desymmetrizing CÀHa ctivation of an arene may be realized by using an achiral Rh III catalyst and achiral carboxylic acid where the chiral carboxylic acid renders the Rh III center chiral in aCMD mechanism.…”

“…Indeed, the e.r. generally decreased or was even inverted when as terically hindered benzoic acid was applied, as in the case of various 2,6-disubstituted benzoic acids (entries [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. Although the electronic effect of the acid is also convoluted, there is no direct correlation of this effect with the enantioselectivity of the reaction.…”