PhanePhos

As expected initial examination of the hydrogenation of this substrate revealed its relatively low activity compared to dehydroamino acids that provide 3-aryl-a-amino acids. By carrying out the hydrogenation at an elevated temperature, however, the inherent low activity could be overcome. A screen of the Dowpharma catalyst collection at S/C 100 revealed that several rhodium catalysts provided good conversion and enantioselectivity while low activity and selectivity was observed with several ruthenium and iridium catalysts. Examination of rate data identified [(l )-PhanePhos Rh (COD)]Bp4 as the most active catalyst with a rate approximately... 

Although the asymmetric hydrogenation route to 3,3-diphenylalanine via this modified substrate preparation was not developed further, Dowpharma had a requirement to rapidly develop and scale up the manufacture of a related 3,3-diarylalanine product. The work to 3,3-diphenylalanine centred around substrate preparation and removal of impurities leading to high activity associated with the PhanePhos catalyst system allowed for a facile transfer from laboratory scale experiments to the commercial manufacture of the related diphenylalanine derivative by a robust, reproducible and scaleable procedure. 

Manufacture of ruthenium precatalysts for asymmetric hydrogenation. The technology in-licensed from the JST for the asymmetric reduction of ketones originally employed BINAP as the diphosphine and an expensive diamine, DAIPEN." Owing to the presence of several patents surrounding ruthenium complexes of BINAP and Xylyl-BINAP, [HexaPHEMP-RuCl2-diamine] and [PhanePHOS-RuCl2-diamine] were introduced as alternative catalyst systems in which a cheaper diamine is used. Compared to the BINAP-based systems both of these can offer superior performance in terms of activity and selectivity and have been used in commercial manufacture of chiral alcohols on multi-100 Kg scales. 

Catalyst screen at 90 psi hydrogen at r.t. and 60 °C for 20 h - No product detected Pfaltz-lr-BARF-cat, (Et-Duphos)Rh(COD)BF4,(BINAP)Ru(ll)CI2, Phanephos/(COD)2RhBF4, Josiphos SL-J009-1/(COD)RhCI,... 

More recent work employing diphosphine ligands has focused on both new substrates for hydroboration and also new hydroborating agents. Specifically, Gevorgyan has successfully employed cyclopropenes 56 as substrates, with pinacolboranes 13 as the borane source.20 Impressive enantioselectivities were obtained with a range of diphosphines, for example, with rhodium complexes of NORPHOS (>99% ee), PHANEPHOS (97% ee), BINAP (94% ee), and Tol-BINAP (96% ee), all with near perfect m-selectivity (see Scheme 8). 

The use of the diphosphine PHANEPHOS (see Scheme 1.24) permitted Bar-gon, Brown and colleagues to detect and characterize a dihydrido intermediate in the hydrogenation of the enamide MAC by a rhodium-based catalyst The PH IP NMR technique was employed, and showed one of the hydrogen atoms to be agostic between the rhodium center and the /1-carbon of the substrate [85]. By using the same diphosphine and technique it was also possible to detect two diastereomers of the dihydride depicted in Scheme 1.25, which may also be detected using conventional NMR measurements [86]. 

DIPAMP-Rh complex to give the corresponding chiral a-amino acid derivative in over 98% ee. The chiral product has been used for the synthesis of (S)-(-)-ac-romelobic acid [88]. Hydrogenation of a tetrahydropyrazine derivative catalyzed by a PHANEPHOS-Rh complex at -40"C gives an intermediate for the synthesis of Crixivan in 86% ee [82a]. Hydrogenation of another tetrahydropyrazine carboxamide derivative catalyzed by an (R)-BINAP-Rh catalyst leads to the chiral product in 99% ee [89]. 

Further hydrogenations of a variety of C=C substrates depicted in Figure 37.22 range from a pilot process to several feasibility studies. Of special interest are PhanePhos, originally reported by Merck, an unsymmetrically substituted phos-pholane developed by Pfizer, and the rare case of an Ir-diphosphine complex active for the hydrogenation of a C=C bond. Nevertheless, the catalyst performances of most processes summarized in Figure 37.22 are probably not (yet) sufficient for manufacturing purposes. Indeed, several of the reports explicitly mention that further development was stopped, either because another route proved to be superior or because the compound was abandoned. 

The hydrogenation of a number of aromatic ketones is shown in Figure 37.30. Noyori s very effective Ru-diphosphine-diamine technology was developed by several companies. It is not clear on which scale the processes developed by Takasago (dm-binap = 3,5-xylyl-binap) [16] and Dow/Chirotech [109-111] for the reduction of substituted acetophenones are actually applied commercially. Using the Xyl-PhanePhos-dpen catalyst, a highly efficient bench-scale process was developed for the hydrogenation of p-fluoroacetophenone (ee 98%, TON 100000, TOF 50000 IT1 at r.t., 8 bar) [109]. Ru-P-Phos (licensed to Johnson Matthey [112]) achieved ee-values >99.9% and TON up to 100000 for sev-... 

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