Iridium‐Catalyzed Enantioselective Hydrogenation of β,β‐Disubstituted Nitroalkenes

Abstract

Ah ighly efficient, iridium-catalyzed, enantioselective hydrogenation of b,b-disubstituted nitroalkenesh as been developed. Using ac omplex consisting of iridium and (S,S)-f-spiroPhos as the catalyst, av ariety of b,b-disubstituted nitroalkenes were successfully hydrogenated to the corresponding chiral nitroalkanes with excellent enantioselectivities (up to 98% ee)a nd high turnover numbers (TON = 1000).Keywords: asymmetric catalysis; enantioselectivity; hydrogenation;i ridium;n itroalkenes Asymmetric hydrogenation represents one of the most economicala nd industrially revalvent synthetic methodsf or the production of enantiomerically pure chiral compounds. [1,2] Chiralf unctional groups can be transformed into various importantm oieties present in pharmaceuticals and biologically active molecules.[1] Thea symmetric hydogenation of b,b-disubstituted nitroalkenesr esults in chiral nitroalkanes, ac lass of important intermediates in the synthesiso f pharmacueticals.[3] It is wellk nown that nitro groups can be easily transformed into av ariety of functional groups including amines,a ldehydes,c arboxylica cids, nitrile oxides,a nd denitrated compounds.[4] These building blocks,s uch as chiral carboxylic acids and amines,a re present in manyd ifferent commercial pharmaceuticals including the well-known non-steroidal anti-inflammatory drug (NSAID), (+ +)-ibuprofen, [5] and the muscle relaxant, baclofen. [6] Due to the utility of chiral nitroalkanesi nc hemical synthesis, av ariety of synthetic methodst op roduce chiral nitroalkanes starting from nitroalkenes has been developed, such as asymmetric conjugate addition, [7] transfer hydrogenation, [8] biocatalysis.[9] However, the direct asymmetric hydrogenation of b,b-disubstituted nitroalkenesh as been relatively less explored. One recent example of ar hodium-catalyzed asymmetric hydrogenation of b,b-disubstituted nitroalkenes hasb een reported by Zhang et al, ande xcellent enantioselectivitiesw ere achieved. However, beside the high catalyst loading (e.g.,3mol% catalyst), it wass hown that the catalytic system wass ensitive to sterich indrance,a nd thus for substrates having as ubstituent in the ortho-position of the phenylr ing it resulted in poor to moderate conversion or enantioselectivity.[3] It hasb eens hownt hat iridium-based catalysts are more active to the asymmetric hydrogenation of certain classes of compoundsincluding unfunctionalized olefins, [2b,f] ketones, [10] unsaturated carboxylic acids [11] and imines. [12] We have also previously shown that the asymmetric hydrogenation of b-acylamino nitroolefins and a,b-unsaturated nitriles catalyzed by the Ir-o rR h-(S,S)-f-spiroPhos complexr esulted in enantioselectivitieso fu pt o9 8% ee and 99.9% ee,r espectively.[13] However, to the best of our knowledge,a ne fficient iridium catalyst for the asymmetrich ydrogenation of nitroalkenesw ithout any additional chelating groups has not yet been reported. When we evaluated the hydrogenation of b,b-disubstituted nitroalkenesw ith the Ir-(S,S)-f-spiroPhosc a...

Enantioselective Hydrogenation of β,β-Disubstituted Unsaturated Carboxylic Acids under Base-Free Conditions

“…Recently, Ding and co-workers developed a Rh catalyst containing a chiral monodentate phosphine (SPO) ligand and an achiral Ph 3 P ligand, which exhibited excellent enantioselectivity for the asymmetric hydrogenation of β,β-diarylacrylic acids and β-CF 3 -substituted acrylic acids. , Whereas in most of the reported cases of the asymmetric hydrogenation of unsaturated acrylic acids, a base additive (NEt 3 or morpholine) was required to achieve high efficiency and enantioselectivity. − Accordingly, the development of more efficient catalysts for the asymmetric hydrogenation of β,β-disubstituted acrylic acids is highly desirable. Inspired by the excellent performance of the chiral diphosphine ligand f-spiroPhos in Rh- or Ir-catalyzed asymmetric hydrogenations of α,β-unsaturated nitriles and nitroolefins, we evaluated this ligand for the hydrogenation of β,β-disubstituted unsaturated acrylic acids, including sterically similar β,β-diaryl unsaturated acrylic acids, and found that its Rh complex showed excellent enantioselectivities (up to 99.3% ee) under mild reaction conditions without any additive (Scheme ).…”

N‐tert‐Butylsulfinyl‐3,3,3‐trifluoroacetaldimine: Versatile Reagent for Asymmetric Synthesis of Trifluoromethyl‐Containing Amines and Amino Acids of Pharmaceutical Importance

“…Related chemistry, dealing with addition to keto analogues of imine 7, is presented in Scheme 4. In this case, the reactions between ketimines (R)-13 and various Ar-Li derivatives occurred with very high yields and diastereoselectivity, [29] allowing preparation of interesting amines 15 and amino acids 16, each containing a quaternary stereogenic carbon atom. The generality of these addition reactions could be extended to include CHF 2 , CClF 2 , and perfluoroalkyl groups, as well as alkyl-Li reagents.…”

“…[26,27] The absolute stereochemistry of the newly created stereogenic center in the additions of (S)-7 was determined to be S; however, the mechanistic explanation for the preferential for-mation of diastereomers 11 was rather vague, [27] with a reference to a "non-chelated transition-state model". [28] Under the standard conditions [29] compounds 11 were easily deprotected to afford the target CF 3 -amines 12.…”

Asymmetric cross-coupling of racemic α-bromo esters with aryl Grignard reagents catalyzed by cyclopropane-based bisoxazolines cobalt complexes

“…10 Although there are some successful asymmetry syntheses of (S)-ibuprofen reported, the main enantioselective synthetic approaches include hydrogenation of b,b-disubstituted nitroalkenes, 11 hydrocarboxylation of olefins, 12 Grignard cross-coupling of vinyl bromide, 13 protonation of silyl enol ethers, 14 iron-bisphosphine-catalyzed cross-coupling of a-chloropropanoate, 2 hydrogenation of aldehydes, 15 and hydrocyanation of vinylarenes, 16 more efficient and convenient asymmetric syntheses of this drug still remain highly desirable.…”