Bidentate Phosphoramidite Research Articles

Design and synthesis of new bidentate phosphoramidite ligands for enantioselective copper-catalyzed conjugate addition of diethylzinc to enones

Several thioaryl- and phosphino-phosphoramidite ligands have been synthesized from commercially available β-aminoalcohols. This new family of bidentate ligands are highly active in the enantioselective copper-catalyzed conjugate addition of diethylzinc to both cyclic and acyclic enones showing moderate to good enantiomeric excesses of up to 81%.

Enantioselective 1,4-addition of arylboronic acids to α,β-unsaturated carbonyl compounds catalyzed by rhodium(I)-chiral phosphoramidite complexes

A chiral bidentate phosphoramidite ( 5a) was synthesized from Shibasaki’s linked-( R)-BINOL and P(NMe 2) 3 as a new ligand for rhodium(I)-catalyzed asymmetric 1,4-addition of arylboronic acids to α,β-unsaturated carbonyl compounds. The effects of 5a and Feringa’s monodentate phosphoramidite ( 4, R 1, R 2 = Et) on the yields and enantioselectivities were fully investigated. The reaction was significantly accelerated in the presence of a base such as KOH and Et 3N, allowing the reaction to be completed at the lower temperatures than 50 °C. The addition to cyclic enones such as 2-cyclopentenone, 2-cyclohexenone and 2-cycloheptenone at 50 °C in the presence of an [Rh(coe) 2Cl] 2- 4 (R 1, R 2 = Et) complex resulted in enantioselectivities up to 98%, though it was less effective for acyclic enones (0–70% ee). On the other hand, a complex between [Rh(nbd) 2]BF 4 and 5a completed the addition to cyclic enones within 2 h at room temperature in the presence of Et 3N with 86–99% yields and 96–99.8% ee. This catalyst was also effective for acyclic enones, resulting in 62–98% yields and 66–94% ee. The 1,4-additions of arylboronic acids to unsaturated lactones and acyclic esters with rhodium(I)-phosphoramidites complexes were also investigated.

Chiral Phosphites and Phosphoramidites Based on the Tropane Skeleton and Their Application in Catalysis

Chiral BINOL phosphorochloridites were esterified and amidated with enantiopure 6-hydroxytropinone [6-hydroxy-8-azabicyclo[3.2.1]octan-3-one] cyclic acetal to yield chiral bidentate and monodentate phosphite-phosphoramidite ligands for copper-catalyzed asym. conjugate addn. of diethylzinc to cyclic enones. Condensation of N-protected pyrrole with tetrabromoacetone with subsequent acetalization and asym. hydroboration gave (6S)-6-hydroxy-8-azabicyclo[3.2.1]octan-3-one ethylene glycol acetal (8), which was treated with (2S)- and (2R)-BINOL phosphorochloridite esters (7a,b), affording chiral bidentate phosphite-phosphoramidite ligands, (S,S)-9a and (R,R)-9a; their octahydro analogs (S,S)-9b and (R,R)-9b were also prepd. Monodentate chiral phosphoramidite (6S)-6-methoxymethoxy-N-[(2S)-BINOL-phosphino]-8-azabicyclo[3.2.1]octan-3-one acetal [(S)-13] and 8-(2-methylthioethyl)-substituted tropinone acetal (2S)-BINOL phosphite esters (11a, b) were prepd. by phosphination of the corresponding N- or O-protected 8 with BINOL- or octahydro-BINOL phosphorochloridites. When applied to Cu-catalyzed asym. 1,4-addns. of dialkylzinc to cyclic enones, ranging from 2-cyclopentenone to 2-cyclooctenone (14a-d) and acyclic enones RCH:CHCOR1 (16a-d; R = Bu, Ph, 2-thienyl; R1 = Me, Ph), the bidentate phosphoramidite (S,S)-9a bearing two (S)-binaphthol units worked selectively in most cases affording the alkylation products with up to 90% ee. Ligand (S,S)-9a was also tested in Rh-mediated asym. hydrogenation of di-Me itaconate and Me acetamidocinnamate, exhibiting 85% ee and 95% ee selectivity superior to the majority of other ligands. In both reactions, a matched/mismatched case was obsd. for (S,S)-9a and its diastereomer (R,R)-9a.

Catalytic enantioselective synthesis of prostaglandin E(1) methyl ester using a tandem 1,4-addition-aldol reaction to a cyclopenten-3,5-dione monoacetal.

Conjugate addition reactions are among the most important carbon-carbon bond formation reactions in organic synthesis, and considerable progress has been made in the development of asymmetric Michael additions and 1,4-additions of organometallic reagents. Recently, highly enantioselective copper-catalyzed conjugate addition reactions of diorganozinc reagents to enones have been reported. Among the various chiral ligands introduced for this purpose phosphoramidite 4, developed in our laboratories, shows nearly complete stereocontrol in the reaction of (functionalized) dialkylzinc (R2Zn) reagents with six-, sevenand eightmembered cycloalkenones. On the basis of this methodology, catalytic routes are now available to enantiomerically pure products, embedding cyclohexane and larger rings in their structure. In contrast, the catalytic enantioselective 1,4-addition to 2-cyclopentenone is a major challenge, particularly because chiral cyclopentane structures are ubiquitous in natural products. Employing TADDOL-based phosphoramidite ligands we obtained up to 62% ee when the Et2Zn addition to 2-cyclopentenone was run in the presence of molecular sieves. Furthermore, with using chiral bidentate phosphoramidite ligands, the enantioselectivity improved to 83%. Chan reached 89% ee using a diphosphite ligand, whereas Pfaltz enhanced the enantioselectivity in this addition to 94%. Recently Hoveyda reported ee values up to 97% using a chiral peptide-based phosphine ligand in the 1,4addition of diethylzinc to 2-cyclopentenone. Although these catalysts give excellent enantioselectivities, the isolated yields for the 3-substituted cyclopentanones are often moderate. Possible reasons are the lower reactivity of 2-cyclopentenone in comparison with other cyclic enones, the side-reactions of the resulting zinc enolate with the starting material and the high volatility of the 1,4-addition product. Performing the reaction in the presence of an aldehyde increases the yield considerably.