Preparation and use of C2-symmetric bis(phospholanes): production of .alpha.-amino acid derivatives via highly enantioselective hydrogenation reactions

Abstract

A new class of chiral Cz-symmetric bis(phospho1ane) ligands has been prepared and used in rhodium-catalyzed asymmetric hydrogenation reactions. We describe a practical, one-pot procedure which utilizes enantiomerically pure 1,4-diol cyclic sulfates 4 for the preparation of a homochiral series of 1,2-bis(phospholano)ethanes 1 and 1,2-bis-(phospho1ano)benzenes (DuPHOS) 2. Cationic rhodium complexes bearing these new ligands behave as very efficient catalyst precursors for the asymmetric hydrogenation of a broad range of a-(N-acy1amino)acrylate (enamide) substrates 5. Significantly, a variety of unnatural and nonproteinaceous a-amino acid derivatives 6 were obtained directly with enantioselectivities approaching 100% ee when using the DuPHOS ligands 2. Substrate-to-catalyst ratios of 10 000 were routinely used, and ratios as high as 50 000 were demonstrated in these reactions. Details of the DuPHOS-Rh-catalyzed hydrogenations are discussed.Asymmetric phosphine ligands have played a dominant role in the development of novel transition-metal-catalyzed enantioselective syntheses.' Notwithstanding the high selectivities observed in certain applications using some of the more successful asymmetric phosphines such as DIPAMP,Z CHIRAPHOS,3 and BINAP: there are many reactions of interest where catalysts bearing these phosphines perform rather poorly in terms of efficiency and enantioselectivity. Such failure indicates the need for alternative asymmetric ligands and/or catalysts.Toward this goal, our research has been focused on the design of new chiral ligands for use in transition-metal-based asymmetric catalysis. We recently outlined our approach and described the synthesis of new electron-rich Cz-symmetric bis(phospho1ane) and C3-symmetric tris(phospho1ane) ligands-' These studies indicated the potential utility of Cz-symmetric 1 ,2-bis(phospholano)ethane ligands of type 1. The reported ligand preparation, however, was inefficient for cases other than the dimethylsubstituted diphospholane (Le., la, R = Me). We herein report details of an improved synthetic procedure that allows facile preparation of the homochiral series of Cz-symmetric 1,2-bis-(phospho1ano)ethanes 1 (BPE, R = Me, Et, Pr, and i-Pr). The evolutionary nature of our ligand design subsequently led us to prepare the analogous homochiral series of 1 ,2-bis(phospholano)benzene ligands 2 (DuPHOS, R = Me, Et, Pr, and i-Pr).sWe have found that the new ligands 1 and 2 afford efficient catalysts for the highly enantioselective hydr0genation5-~ and t Present address: hydrosilylation1° of various unsaturated substrates. In particular, enantioselectivities approaching 100% ee have been observed in the Rh-catalyzed hydrogenation of a wide range of a-(N-acy1amino)acrylates. Importantly, the high efficiency, selectivity, and substrate generality exhibited by these catalysts provide a practical route to a variety of enantiomerically pure unnatural and nonproteinaceous a-amino acid derivatives. The details of these hydrogenation studies are described herein. Results and Disc...

Efficient asymmetric hydrogenation with rhodium complexes of C1-symmetric 2,5-dimethylphospholane-diphenylphosphines

“…Dried, nitrogen-saturated solvents were collected from a Grubbs system 15 18 and the Nacetyl--arylenamide substrates. 19 1-Bromo-2-diphenylphosphinobenzene was prepared using the palladium-catalysed cross-coupling reaction reported by Stille et al 20 With the enamide substrates F-H, it was noted that the hydrogenations with 3a as catalyst were completed much more rapidly than with [Rh(nbd)(Duphos)][BF 4 ] and therefore, we monitored the reaction progress more closely. Fig.…”

“…Fig. 2 4 ] was screened and shown to be more than five times slower than 3a. Thus it appears that the unsymmetrical catalyst 3a is significantly more efficient than either of its symmetrical analogues.…”

Synthesis of Chiral Building Blocks for Use in Drug Discovery

“…The advantage of this catalyst is that it is predictable. The relative stereochemistry of the product is determined by the chiral catalyst ie [(COD)Rh((S,S)-Et-DuPHOS)] + will always give the (S)-enantiomer and [(COD)Rh((R,R)-EtDuPHOS)] + gives the corresponding (R)-enantiomer [1,2]. In addition, the double bond geometry of the starting alkene, whether it be E or Z gives the same absolute configuration in high enantiomeric excess.…”

Solid-Phase Synthesis and Catalytic Screening of Polystyrene Supported Diphosphines

“…Polystyrene-Br (50-100 mesh, 2.17 mmol g -1 , 2 % cross-linked DVB) was obtained from Sigma-Aldrich. Cyclic sulfates are prepared according to literature: 1,3-propadiol cyclic sulfate i [47], l,4-butanediol cyclic sulfate ii [48], (2R,4R)-2,4-pentanediol cyclic sulfate iii [41], (2R,5R)-2,5-hexanediol cyclic sulfate iv [49], (2S,5S)-2,5-hexanediol cyclic sulfate v [49], (3R,3R)-3,6-octadiol cyclic sulfate vi [50]. See ESM for detailed synthetic procedures and characterisation of the ligands.…”