Key Elements - Over the course of previous decades, worldwide research has continued to be focused on increasingly sophisticated novel methods for the development of chiral building blocks. These compounds are now a key element in the synthesis routes selection for the manufacture of active pharmaceutical ingredients.

In principle, three routes to these chiral building blocks can be described (fig. 1):

All three of these routes - asymmetric synthesis, synthesis using the chiral pool (reservoir of enantiomerically pure natural products) and the resolution of racemates - are used and offered by Saltigo as customized contract synthesis methods for its customers. As shown in fig. 1, there is therefore initially a variety of possible ways of obtaining a specific building block. The resultant chiral building blocks are then converted into active ingredients, such as quinolone antibiotics, statins and many others, either in-house at Saltigo or by the customer.

For example, S,S-cis-pyrrolopiperidine can be prepared by enzymatic resolution of the isomers. However, a further variant that is also available is chemical resolution via a salt, which in the end gives the same result. Furthermore, chromatographic separation may make sense on an industrial scale and certainly can be applied. Which of the methods is in conclusion used in order to enable the preparation of this building block on a multi ton scale is ultimately decided by economic efficiency. Once a process has been established for a specific chiral building block, it is also important to continue work on further optimization over the entire life cycle of this building block. This has a positive effect on the cost of goods for the customer and consequently on the duration of the business relationship.

A Saltigo example is access to chiral polyalcohols and amino alcohols by the reduction of cheap hydroxy acids and natural amino acids by metal-catalyzed hydrogenation in order to avoid the use of expensive complex hydrides, such as lithium aluminum hydride. For instance, L lactic acid, L malic acid and L tartaric acid can be hydrogenated easily using hydrogen at 200 bar with a ruthenium/ rhenium catalyst. The advantage of the optimized ruthenium/rhenium catalyst compared with ruthenium alone is that the reaction can be carried out at low pressures and temperatures without racemization. The ruthenium/rhenium catalyst achieves an ee value of virtually 100% in this reaction at a reaction temperature of only 60 °C with a yield of 80 %, use of the ruthenium catalyst alone is not able to achieve even approximately this yield and this ee value under any of the reaction conditions selected. It is even possible to re-use the catalyst a number of times. The use of the ruthenium/rhenium catalyst can also be easily extended to the preparation of chiral amino alcohols by simply using natural amino acids in the reaction. The advantages of the ruthenium/rhenium catalyst in such reactions are clear:

• • It is cheaper to use than the complex hydrides (LiAlH₄, .....)
• • No racemization takes place, in contrast to with ruthenium
• • High yields are obtained
• • A broad range of starting materials is available
• • Aromatic amino acids, such as L phenylalanine, yield the cycloaliphatic amino alcohols in one step.

This simple optimization work achieves two important aims in one: high economic efficiency and broad applicability.

Enantioselective Synthesis is Most Significant

Besides these routes to chiral building blocks which use the natural chiral pool directly, enantioselective synthesis has by far the greatest significance in the modern chemical industry. This can be used to generate a new, artificial chiral pool, which then represents the basis for ever newer and better active ingredients. It is also worthwhile investing in optimization work and new developments here in order to be able to offer chiral building blocks successfully on the market and in addition to stand out from competitors.

On the one hand, the Juliá-Colonna epoxidation, a hydrogen peroxide oxidation in basic medium induced by polyamino acids, should be mentioned at this point. The optically active compounds from these enantioselective epoxidations are particularly suitable for obtaining precursors of a large number of bioactive compounds. At Saltigo, epoxides are produced, inter alia, by a process variant using a phase-transfer catalyst in order to actually ensure a corresponding conversion in an acceptable time and a high ee value in the three-phase system under Juliá-Colonna conditions. The range of applications of this reaction is very broad, the best results being achieved in the reaction of aromatic enones, with base-sensitive starting materials tending to undergo side reactions.

On the other hand, enantioselective hydrogenation is worthy of mention as a milestone in enantioselective synthesis on an industrial scale. For example, β keto esters can be hydrogenated in excellent yields and selectivities by means of suitable catalysts and corresponding chiral ligands. These are used such as building blocks for the preparation of statins. New chiral ligands, which are finally responsible for the selectivity of the reaction, have been and still are being developed for this purpose. Fig. 2 only shows a very small selection intended to show briefly that many colleagues throughout the world are working specifically on this topic, and many novel, interesting derivatives and even entirely new ligand families are in the meantime again already available.

Saltigo can also develop high-performance ligands and then to make them available for commercial purposes, i.e. in the event multiton production campaigns, by up-scaling the syntheses. Cl-MeOBipheb is only one example of the few ligands that are also available on the market in multikilogram quantities and gives analogous to better results compared with a standard ligand, such as BINAP. The synthesis of Cl-MeOBipheb has been developed and optimized very successfully for up-scaling and gives the two isomers in >99% ee and good yields - only ten kilograms of ligand can give approximately 30 90 metric tons of the hydrogenation product (s/c 15,000 30,000:1; MW of product 150 200 g/mol). The commitment and hard work shown both during development and also during industrial-scale implementation were extremely profitable, since it is only the high economic efficiency that has made enantioselective hydrogenation attractive on an industrial scale and as a commercial tool for customers.