Asymmetric homogeneous hydrogenations at scale

Abstract

Asymmetric hydrogenations are increasingly being used to introduce stereogenic centres into products used in the life sciences industries. There are a number of potential pitfalls when moving from a laboratory reaction to a manufacturing process, not least of which is safety. Time-to-market pressure leads to short development times, which in the past could be a large barrier for the implementation of catalytic steps; now there are new ways to minimise this problem. The potential problems associated with impurities and other methods that can shut down the hydrogenation reactions are highlighted in this critical review (353 references).

Asymmetric NaBH4 1,4‐Reduction of C3‐Disubstituted 2‐Propenoates Catalyzed by a Diamidine Cobalt Complex

“…Asymmetric hydrogenation has been the major approacht ot his reduction since 1987, when the first success using Ru(OCOCH 3 ) 2 (binap) (binap = 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) was reported. [2,3] Two years later,P faltz and co-workers reported an excellent chiral Co semicorrin catalyst affecting asymmetric 1,4-reduction of a,b-unsaturated carboxylic esters by NaBH 4 ; [4] however,t his development did not result in as ignificant advance in the field. [5] This may be due to the lower atom efficiency,a sw ell as the higher Ef actor,o fN aBH 4 compared with that of the H 2 system.…”

Iron/Brønsted Acid Catalyzed Asymmetric Hydrogenation: Mechanism and Selectivity‐Determining Interactions

“…[ 1 , 2 ] A well-known example is the enantioselective iridium-catalysed hydrogenation leading to the synthesis of the herbicide (S)-metolachlor, representing one of the largest scale hydrogenations employed industrially. [2] A similarly well-known example is the first industrially implemented protocol for L-DOPA synthesis, which involved a rhodiumdiphosphine-catalysed hydrogenation step. [2] The majority of catalysts employed in asymmetric hydrogenation reactions are based on precious metals such as rhodium, [1] iridium, [ 3 ] and ruthenium.…”

“…[2] A similarly well-known example is the first industrially implemented protocol for L-DOPA synthesis, which involved a rhodiumdiphosphine-catalysed hydrogenation step. [2] The majority of catalysts employed in asymmetric hydrogenation reactions are based on precious metals such as rhodium, [1] iridium, [ 3 ] and ruthenium. [ 4 ] The cost of precious metals has fuelled academic and industrial research into alternative hydrogenation catalysts involving abundant base metals such as cobalt and iron.…”

8.17 Homogeneous Catalytic Hydrogenation of CåC and CåC

“…205 Comparison with literature precedent or experimental screening is usually used to determine which type of catalyst system is to be used in a specific application. Many catalysts, when first developed, are tried with 'standard' substrates.…”