Chiral Bispidines

Abstract

Chiral bispidines are characterized by a modified 3,7-diazabicyclo[3.3.1]nonane framework. Their structural diversity is broad, reaching from simple bicyclic derivatives with chiral substituents at the nitrogen atoms to sophisticated tetracyclic ones like (-)-sparteine. This review focuses on the stereoselective preparation of chiral bispidines and on their applications in selected asymmetric transformations, thus showing the tremendous progress achieved in both areas over the last 15 years.

The First Modular Route to Core‐Chiral Bispidine Ligands and Their Application in Enantioselective Copper(II)‐Catalyzed Henry Reactions

“…There was another surprising observation within this context. From the sense of stereoinduction reached with 1 and 2 ,4, 5, 25 a preference for the S ‐configured product ( S )‐ 43 was expected in the lithiation–silylation of 42 . This product enantiomer was indeed obtained in 52 % ee with 10 b as the chiral ligand, while the formation of ( R )‐ 43 (7 % ee ) was slightly favored in the presence of 10 a ,56 although the very same quadrant is blocked in both diamines by the chirality‐transferring pyrrolidine moiety.…”

“…The chirality transfer abilities of the tricyclic, pyrrolidinef used bispidines 10 a and 10 b were first studied in asymmetric deprotonation-electrophilic trapping reactions. As model reac-tions servedt he lithiation-silylation of NBoc pyrrolidine (42) , [4,5,25] which requires an (over)stoichiometric amount of the chiral diamine, and the enantiotopos-selective lithiation-benzophenone trapping of the dimethylphosphine borane 44, [13e] for which ac atalytic amount of the chiral diamine can be used (Table 3). Acceptable to good yields were achieved in these reactions with the two bispidines 10 a and 10 b as the chiral ligands,b ut the enantioselectivities (< 52 % ee)w ere mediocre as comparedt ot he excellent values (up to 98 % ee for 43 and up to 82 % ee for 45)r eached with sparteine (1)a nd the 25] This result is not surprising for the unsubstituted derivative 10 a since quantum chemical calculations by O'Brien, Wiberga nd Bailey had predicted al ow stereoinduction with this diamine.…”

“…There was another surprising observation within this context. From the sense of stereoinduction reached with 1 and 2, [4,5,25] ap reference for the S-configured product (S)-43 was expected in the lithiation-silylationo f 42.T his product enantiomer was indeed obtainedi n5 2% ee with 10 b as the chirall igand, while the formation of (R)-43 (7 % ee)w as slightly favored in the presence of 10 a, [56] althought he very same quadrant is blockedi nb oth diamines by the chirality-transferring pyrrolidine moiety. These results clearly demonstrate the high susceptibility of enantioselective deprotonation reactions to even smallg eometricc hanges in the bispidine and, fort he first time, prove the eminent importance of the 2-endo,N-fused pyrrolidine ring in 1 and 2.…”

“…Amongc hiral diaminel igands, the natural bisquinolizidine alkaloid [1] (À)-sparteine (1)a nd the synthetic [2] (+ +)-sparteine surrogate 2 (Figure 1) have received particular attentionb ecause of their unique effectivenessi nm any asymmetric transformations. [3][4][5] In combination with the strong base sBuLi, they are the ligandso fc hoice [6] in all kind of enantioselective deprotonation-electrophilic trapping reactions of weakly CÀHa cidic compounds. [7] Since the pioneering work of Hoppe [8] and Beak [9] on the (À)-sparteine mediated lithiationo fa-methylene groups in O-alkyl and N-alkyl carbamates, this new principle has been extended to many other substrates, including allylic, [10] benzylic, [11] and aromatic [12] protons, and prochiral methyl groups in phosphine boranes.…”

Investigation of bispidines as the stoichiometric ligand in the two-ligand catalytic asymmetric deprotonation of N-boc pyrrolidine

“…1,2 In this context, (-)-sparteine is the most widelyinvestigated diamine 3 following the pioneering work by Hoppe 4 and Beak. 5 Indeed, reagents comprising organolithium reagents (e.g.…”