Rh(iii)-Catalyzed diastereoselective transfer hydrogenation: an efficient entry to key intermediates of HIV protease inhibitors

Abstract

A highly efficient diastereoselective transfer hydrogenation of α-aminoalkyl α′-chloromethyl ketones catalyzed by a tethered rhodium complex was developed and successfully utilized in the synthesis of the key intermediates of HIV protease inhibitors.

Bifunctional Homogeneous Catalysts Based on Ruthenium, Rhodium and Iridium in Asymmetric Hydrogenation

“…The method allowed to prepare the key intermediates for the synthesis of HIV protease inhibitors (up to 99% yield, up to 99:1 dr). 152 Overall, the results above clearly demonstrate that tethering the Cp* and diamine ligands is a suitable strategy for the design of rhodium-based catalysts for enantioselective reactions.…”

“…Wills and co-workers 42,[143][144] followed by Ratovelomanana-Vidal, Phansavath and co-workers [145][146][147][148][149][150][151][152] developed rhodium catalysts displaying a benzyl tether between the cyclopentadienyl and TsDPEN units, for applications in the ATH of ketones. The rhodium catalysts developed by Wills and co-workers proved to be very efficient for the reduction of a series of ketones, especially in aqueous solutions (Scheme 29).…”

“…Ratovelomanana-Vidal and co-workers developed the synthesis of a series of new ligands closely related to the Wills ligands, by introducing a substituent on the aromatic unit of the tether (Me, OMe, F, CH3). [145][146][147][148][149][150][151][152] These ligands provided tethered rhodium(III) catalysts efficient in the ATH of alkyl,arylketones [145][146] and in the DKR/ATH of -amino--ketoesters, leading to functionalized alcohols with high syn/anti ratios and ee. 147 The DKR/ATH of -methoxy--keto esters in water/cetyltrimethylammonium bromide was carried out then by using a tethered rhodium(III) complex that displays a N-C6F5SO2 substituted DPEN ligand.…”

Tethered Rh(III)-N-(p-Tolylsulfonyl)-1,2-Diphenylethylene-1,2-Diamine Complexes: Efficient Catalysts for Asymmetric Transfer Hydrogenation

“…10 The ATH of -keto--acetal enamides 15 has been studied with complex (R,R)-B and the HCO 2 H/Et 3 N (5:2) azeotropic mixture delivering a wide range of enantioenriched -hydroxy--acetal enamides 16 with a high chemoselectivity observed toward the reduction of the carbonyl group over the C=C bond, yields up to quantitative and enantioselectivities up to 99% (Table 1, F). 11 The same catalytic system was used to access 1,2,3,4tetrahydroquinolin-4-ols 18 conveniently through ATH of 4-quinolone derivatives 17 with excellent enantioselectivi-(F) ATH of -keto--acetal enamides 11 -Access to -hydroxy--acetal enamides -Mild conditions -Low catalyst loading -Excellent chemo-and enantioselectivities (G) ATH of Quinolone Derivatives 12 -Efficient and practical access to 1,2,3,4-tetrahydroquinolin-4-ols -Catalytic ATH cascade reaction -Mild conditions -Excellent enantiofacial discrimination (H) ATH/DKR of 3-Benzylidene Chromanones 13 -One-pot ATH cascade protocol to access cis-benzyl-chromanols -Low catalyst loading -2 stereogenic centers controlled in a single step -Excellent diastereo-and enantioselectivities (I) ATH/KR of 2-Aryl-2,3-dihydroquinolin-4(1H)-ones 14 -Synthesis of 2-aryl-2,3-dihydroquinolin-4(1H)-ones and 2-aryl tetrahydro-4quinolols -Efficient kinetic resolution -Excellent enantioselectivities (J) ATH of -Aminoalkyl ′-Chloromethyl Ketones 15 -Access to both diastereomers of 3-amino-1-chloro-2-hydroxy-4-phenylbutanes -Low catalyst loading -Excellent yields and high diastereoselectivities -Key building blocks for pharmaceutical intermediates -Broad scope (K) ATH/DKR of -Substituted -Keto Carbonitriles 16 -Efficient access to -substituted -hydroxy carbonitriles -Building blocks for biologically active pharmaceuticals -Excellent yields -High diastereoselectivities and excellent enantioselectivities -Rationalization of the diastereoselectivity by DFT calculations -Wide substrate scope…”

“…14 The ATH of -aminoalkyl ′-chloromethyl ketones 24 using (R,R)-B or (S,S)-B afforded a series of chiral 3-amino-1-chloro-2-hydroxy-4-phenylbutanes 25 or 26 in excellent yields and diastereoselectivities, with both diastereomers of the reduced products available (up to 99% yield, up to 99:1 dr, Table 1, J). 15 -Substituted -keto carbonitriles 27 and 28 were efficiently reduced with (R,R)-B and HCO 2 H/Et 3 N (5:2) to the corresponding -substituted -hydroxy carbonitriles 29 and 30 in excellent enantio-and diastereoselectivities (up to >99% ee, up to >99:1 dr) through a DKR process offering rapid access to key intermediates of biologically active pharmaceuticals (Table 1, K). 16 Rh-tethered complexes (R,R)-B-(R,R)-E have been developed and used in the ATH of a wide range of functionalized ketones exhibiting excellent activities and selectivities.…”