Asymmetric Hydrogenation of α,β‐Unsaturated Carboxylic Esters with Chiral Iridium N,P Ligand Complexes

Abstract

Enantioselective conjugate reduction of a wide range of α,β-unsaturated carboxylic esters was achieved using chiral Ir N,P complexes as hydrogenation catalysts. Depending on the substitution pattern of the substrate, different ligands perform best. α,β-Unsaturated carboxylic esters substituted at the α position are less problematic substrates than originally anticipated and in some cases α-substituted substrates actually reacted with higher enantioselectivity than their β-substituted analogues. The resulting saturated esters with a stereogenic center in the α or β position were obtained in high enantiomeric purity.

Chiral auxiliary recycling in continuous flow: automated recovery and reuse of Oppolzer's sultam

“… 9 This procedure uses enantiopure camphorsultam (Oppolzer's Sultam) as a chiral auxiliary to control the diastereoselectivity in the reduction step prior to auxiliary cleavage, giving the final product in 95 : 5 to 98 : 2 enantiomeric ratio. Since this report in 1986, catalytic hydrogenations to access similar β-chiral acids and esters have been developed, for instance by the groups of Noyori, 10 Buchwald, 11 and Pfaltz; 12 however, none have been able to achieve the generality and high enantiomeric ratios of the chiral auxiliary system when the two β-substituents are simple alkyl groups. 13 …”

SpinPhox/Iridium(I)‐Catalyzed Asymmetric Hydrogenation of Cyclic α‐Alkylidene Carbonyl Compounds

“…[1] An attractive synthetic route to these compounds would be the catalytic asymmetric hydrogenation (AH) of the C = C bonds in the exocyclic a,b-unsaturated cyclic carbonyls, by virtue of the high efficiency, atom-economy, and cost-effectiveness of the methodology. While a great number of chiral catalysts have been developed over the years for AH of various acyclic and endocyclic unsaturated carbonyl compounds, [2] documented examples which are especially effective for the AH of the exocyclic C = C bonds of a-alkylidene lactams, [3] lactones, [4] and/or cyclic ketones [5] are still quite rare. The difficulty associated with this type of substrate in asymmetric hydrogenation is probably due to the exocyclic nature of the C=C bond which may hamper substrate bonding to the metal center, and has been assumed to be a key factor in achieving high activity and good stereocontrol in the rhodium-or ruthenium-catalyzed AH.…”

“…[6] The iridium complexes of chiral P,N ligands are particularly noteworthy in overcoming these limitations, [7] and demonstrated excellent enantioselectivities in the AH of a wide range of largely unfunctionalized olefins, [8] including olefins with weakly coordinating groups [9] and tetrasubstituted olefins. [11] Nevertheless, challenges still remain in the AH of exocyclic a,b-unsaturated cyclic carbonyls with regard to the limited substrate scope, and the enantioselectivities are often strongly dependent on the ring size of the substrates in the AH of a-alkylidene lactams and lactones, [3][4][5] as indicated by BiphPhox/Ir I catalysts ( Figure 2). [11] Nevertheless, challenges still remain in the AH of exocyclic a,b-unsaturated cyclic carbonyls with regard to the limited substrate scope, and the enantioselectivities are often strongly dependent on the ring size of the substrates in the AH of a-alkylidene lactams and lactones, [3][4][5] as indicated by BiphPhox/Ir I catalysts ( Figure 2).…”

“…[10] In this context, a few excellent iridium catalysts have been developed recently for AH of C=C bonds in a,b-unsaturated carbonyl compounds as well, as exemplified by the independent pioneering studies of the groups of Bolm, Hou, and Zhou. [11] Nevertheless, challenges still remain in the AH of exocyclic a,b-unsaturated cyclic carbonyls with regard to the limited substrate scope, and the enantioselectivities are often strongly dependent on the ring size of the substrates in the AH of a-alkylidene lactams and lactones, [3][4][5] as indicated by BiphPhox/Ir I catalysts ( Figure 2). [12] We previously reported a class of chiral iridium(I) complexes, SpinPhox/Ir I (Figure 2), with spiro P,N ligands [13] for efficient AH of ketimines, a,b-unsaturated carboxylic acids, and Weinreb amides, as well as a,a'-bis(2- [*] X.…”

“…The hydrogenation of a range of N-Boc-protected alklidenecaprolactams having various aryl substituents was further carried out with (R,S)-1 c as the catalyst under the optimized reaction conditions mentioned above, and the results are shown in the right column of Table 2. All the reactions proceeded smoothly at room temperature under 5 atm of H 2 to afford the corresponding chiral caprolactams 5 a-q with full conversion of the substrates and excellent ee values (95-98 %; entries [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. For these substrates, it appears that the reactions are quite general and less influenced by the electronic nature or the steric bulk of the aryl substituents in the substrates.…”