Rhodium‐Catalyzed Enantioselective Arylation of Aliphatic Imines

Abstract

Chiral rhodium(I)-catalyzed highly enantioselective arylation of aliphatic N-sulfonyl aldimines with arylboronic acids has been developed. This transformation is achieved by the use of a rhodium/bis(phosphoramidite) catalyst to give enantiomerically enriched α-branched amines (up to 99% ee). In addition, this system enables efficient synthesis of (+)-NPS R-568 and Cinacalcet which are calcimimetic agents.

Bifunctional Brønsted Base Catalyzed Mannich Reaction of β‐Alkoxy α‐Keto Amides: Stereocontrolled Entry to Functionalized Amino Diols

“…Diisopropyl a-keto amide 1c reacted with both aromatic and aliphatic p-nosyl N-protected imines to produce the corresponding Mannich adducts 12 and 13 with high diastereoselectivity, albeit with moderate enantioselectivity for the aliphatic adduct 13.I nterestingly,t he methodology resulted also compatible [b] d.r. [c] ee with morpholine derived a-keto amide 1d to produce the enantioenriched adducts 14-16.L ikewise, modificationi nt he nature of the alkoxym oiety did not substantially affect either reactivity or selectivity (adducts [17][18][19], confirming the high versatility of the method. As noted above, the stereochemical outcome of the stereoselectiver eduction of the Mannicha dducts,promoted by K-Selectride,c ould be inverted (Scheme 2) to efficiently produce, under treatment with Et 3 B/NaBH 4 ,a12:88 mixture of anti,syn:syn,syn diastereoisomers from which the major syn,syn adduct 20 was isolated in 58 %y ield.…”

“…As noted above, the stereochemical outcome of the stereoselective reduction of the Mannich adducts, promoted by K‐Selectride, could be inverted (Scheme ) to efficiently produce, under treatment with Et 3 B/NaBH 4 , a 12:88 mixture of anti , syn : syn , syn diastereoisomers from which the major syn , syn adduct 20 was isolated in 58 % yield. On the other hand, the cleavage of the p ‐nosyl protecting group was efficiently promoted in the presence of thiophenol and potassium carbonate, to afford the corresponding amino diol 21 in high yield . An interesting feature of nosyl protected amines is that they can be easily transformed in secondary amines through alkylation followed by deprotection .…”

“…On the other hand, the cleavage of the p-nosyl protecting group was efficiently pro-moted in the presence of thiophenol and potassium carbonate, to afford the correspondinga minod iol 21 in high yield. [18] An interesting feature of nosyl protected amines is that they can be easily transformedi ns econdary aminest hrough alkylation followed by deprotection. [19] Methylation of adduct 11 a, and subsequent p-nosyl cleavage, produced the corresponding secondary amine 22 in 50 %o verall yield.…”

Direct Asymmetric Arylation of Imines

“…This transformation was achieved by the use of a rhodium/bis(phosphoramidite) catalyst to give enantiomerically enriched α-branched amines (up to 99% ee). [112] This method was also applicable to saccharinderived ketimine affording the corresponding product in 80% yield with > 99% ee (Scheme 94). This new chiral bidentate phosphoramidite ligand (N-Me-BI-PAM) was found to be highly efficient for asymmetric arylation of both N-tosyl and N-nosylaryl imines with aryl boronic acids.…”

Enantioselective synthesis of (R)‐Cinacalcet via cobalt‐catalysed asymmetric Negishi cross‐coupling

“…(R)‐cinacalcet (Figure ) is a clinical drug to regulate calcium levels in the treatment of hyperparathyroidism . The reported syntheses mainly based on the resolution of racemic cinacalcet, asymmetric reductive amination of ketones, enantioselective arylation of aliphatic imines, chemoenzymatic approaches, and the application of (R)‐tert‐butanesulfinamide . Furthermore, Bijukumar and Tewari prepared cinacalcet from commercial (R)‐1‐(1‐naphthyl) ethyl amine, which can be purchased from a number of companies in its pure form.…”