Amines racemization

Procedure 1 Synthesis of the Amine Racemization Catalyst Pentamethylcyclopentadienyliridium(III) Iodide Dimer... 

Early examples of amine racemization are particularly inefficient and tend to be very substrate specific, with very few general methods that tolerate a wide variety of functional groups [11], Thermal racemization has been achieved on relatively stable benzylic amines. For example, the isoquinolines shown in Scheme 13.2 were heated at high temperatures under vacuum to effect rapid loss of ee. This is clearly very specific to relatively simple, thermally stable amines. 

The vast majority of early amine racemizations involve an oxidation-reduction approach, with the oxidation of the amine center removing the chirality so that subsequent reduction yields the racemate. The most efficient redox approach is achieved when the oxidized and reduced forms of the substrate are in equilibrium... 

With the use of additives such as ammonia or 2,4-dimethyl-3-pentanol they managed to suppress dimer formation and observed complete amine racemization in 98% conversion. 

Amine racemization has developed markedly over the last 25 years, and a range of complementary techniques from both academic and industrial research laboratories has come to fruition during this time. From early examples testing out the concept of racemization through to the more recent sophisticated catalytic methods, which have been demonstrated in cost-efficient industrial applications, there can be no question that this approach to waste recycling has a future in modern pharmaceutical manufacturing. 

The practical difficulty with carrying out a crystalhzation DTR process is the need to operate under conditions that allow selective crystalhzation of the least soluble diastereomer while permitting the racemization to take place. Amine racemization catalysts, such as SCRAM , Shvo, Pd/C, and Adam s, are more active at higher temperatures, which runs counter to the conditions required for crystaUization. A solution to this problem is to separate the diastereomeric resolution and racemization steps but couple them with a flow engineering design. In this way each reaction can be operated under optimal conditions for example, temperature, concentration and solvent, via an intermediary solvent exchange unit Since the racemization catalyst itself may affect the crystalhzation (or indeed the crystalhzation may affect the catalyst), it is preferred to keep them separate. This can be achieved by having the catalyst or product either permanently or temporarily in a different phase by immobilization, extraction, precipitation, distil-... 

Screening several amine racemization catalysts, we found that the SCRAM and the Shvo catalyst would both racemize the (S)-enantiomer at temperatures above 11() G. Interestingly, no dimeric products were found. The best racemization conditions were found to be using toluene or TBME at 150°C in a pressure vessel with 1 mol% SCRAM or 5 mol% Shvo catalyst over 24 h, providing quantitative conversion. In the presence of (R, R)-dibenzoyltartaric acid the racemization slowed, possibly because of unfavorable coordination of the alkylammonium substrate or acid quenching of the iridium hydride catalyst intermediate. 

Both (R)- and (S)-amino transferase are available forthe synthesis of enantiomerically pure amines from racemic amines. Degrees of conversion were at or close to 50% for resolutions, and enantioselectivities customarily reached > 99% e.e. for the amine product from both resolutions or syntheses from ketones (Stirling, 1992 Matcham, 1996). The donor for resolutions of amine racemates was usually pyruvate whereas either isopropylamine or 2-aminobutane served as donors for reduction of ketones. The products range from i- and D-amino acids such as i-aminobutyric acid (see Section 7.2.2.6) and i-phosphinothricin (see Section 7.4.2) to amines such as (S)-MOIPA (see Section 7.4.2). 

In both instances, the mutarotation velocity with pyrrolidine was faster than with the other amines. When iminazoline synthesis was conducted between alanyliminoether and 2-aminomethylpyrrolidine, excess pyrrolidine in the reaction media probably accelerated the epimerization reaction. Racemization is faster than crystallization of this, diastereomer, which is less soluble than the other diastereomers. In the case of isopropylpropylenediamine, the excess amine racemizes poorly, so the crystallization was faster than the racemization. 

Resolution of racemates by classical separation of diastereomeric salts remains a valid alternative to enantioselective synthesis. A simple but ingenious idea has recently been proposed and shown to work successfully the use of families of resolving agents that would work as a library on the racemate to be resolved, so that the least soluble salt would crystallize out. As a matter of fact, Broxterman [21] has shown that a mixture of acylated tartaric acids like 6a-c of Fig. 8, gave immediate crystallization in 97 out of 100 amine racemates studied, allowing a more rapid choice of resolving agents to be made in a more suitable manner than was previously possible. 

The synthesis of optically pure L-phenylglycine via the deracemization of mandelic acid was reported via three steps (racemization, enantioselective oxidation and stereoselective reductive amination). Racemization by mandelate racemase combined with simultaneous oxidation and reduction reactions with cofactor recycling gave the amino acid in 97% ee and 94% yield (Scheme 4.43) [96]. 

Snell and Rannefeld discovered that when pyridoxal was autoclaved with amino acids, the resultant material had growth-promoting properties similar to those of pyridoxamine. This suggested that pyridoxal might have been converted to pyridoxamine, and this was later confirmed -. The pyridoxal had catalysed the de-amination of the amino acids. It was subsequently shown that pyridoxal catalyses many reactions involving amino acids, including de-amination, racemization, decarboxylation, a/3-elimina-tion and cleavage. Addition of appropriate multivalent metal ions increased the rate of de-amination and a(3-elimination reactions, but inhibited decarboxylation. 

The Wu and Yang group reported a different type of Pd catalyst (Pd/layered double-hydroxide-dodecyl sulfate anion) which showed a good racemization activity at 55 °C [50]. The Li group showed that the use of Pd nanoparticles modified with various alkalic salts improved the selectivity toward the amine racemization [51]. 

Like the DKR of alcohols, the DKR of amines provides an efficient access to enan-tiopure compounds in theoretically 100% yield. In this case amides are the final products obtained after the combination of an adequate acyl donor and a racemi-zation agent [96, 99-101, 219]. Amine racemization usually requires higher temperatures and/or strongly basic media in comparison with alcohol racemization [96] and must be compatible with preserving the enzyme activity. 

The racemization strategies for the DKR of amines can occur mainly through two different pathways. On one hand, the amine racemization can proceed via metal-catalyzed formation of an achiral imine intermediate, which is subsequently hydrogenated in a nonselective fashion to obtain the racemic amine [220]. Alternatively racemization can be achieved by means of the reversible homolytic abstraction of the a-hydrogen atom of the amine, allowing the interconversion of the amine enantiomers via a carbon-centered a-amino radical intermediate. Owing to its high thermal stability, even at 90-100 °C, CAL-B has been the most common hydrolase in the DKR of amines. 

More recently, Backvall and coworkers have described a very effective catalyst for the racemization of amines highly dispersed Pd nanoparticles supported in the large pores of silica-based mesocellular foam (MCF) [104]. This catalyst proved to be a more robust catalyst in amine racemization than any other catalysts reported before and is completely compatible with CALB activity. 

As in the case of sec-alcohols, ruthenium complex has also been investigated as a catalyst in the racemization of primary amines. In fact, Shvo s complex 2 (Figure 14.3) was employed by the Backvall s group as the catalyst of the racemization of amines under transfer hydrogenation conditions [105]. However, temperatures up to 110 °C were required for amine racemization, incompatible with the lipase resolution, and furthermore, side products were formed in the medimn and a hydrogen source was needed. To avoid these drawbacks, the racemization at high temperature was carried out after a first lipase-catalyzed KR, followed by a second KR process, and a hydrogen source such as 2,4-dimethylpentan-3-ol was employed. 

---