Enantioselective scalability

Greenberg, W.A., Varvak, A., Hanson, S.R. el ai (2005) Development of an efficient, scalable, aldolase-catalyzed process for enantioselective synthesis of statin intermediates. Proceedings of the National Academy of Sciences of the United States of America, 101, 5788-5793. 

Development of an efficient, scalable, aldolase-catalyzed process for enantioselective synthesis of statin intermediates. Proc Natl Acad Sci USA 101 5788-5793... 

Although many methods have been developed for enantioselective carbon-carbon construction, not all of these are robust and scalable. A promising recent addition has been the development of protocols for the enantioselective construction of allylic carbon-carbon bonds. 

In 2006, Ley reported the application of a continuous flow-through platform for the preparation of the neolignan natural product Grossamide (Scheme 8.48) [63], This was the first report of the enantioselective total synthesis of Grossamide utilizing a fully automated and scalable flow reactor with supported-reagents and scavengers. This principle has a wider impact on multiple step assembly of libraries and natural products. 

The c/s-dihydroxylation reaction catalyzed by these dioxygenases is typically highly enantioselective (often >98% ee) and, as a result, has proven particularly useful as a source of chiral synthetic intermediates (2,4). Chiral cis-dihydrodiols have been made available commercially and a practical laboratory procedure for the oxidation of chlorobenzene to IS, 2S)-3-chlorocyclohexa-3,5-diene-l,2-c diol by a mutant strain of Pseudomonas putida has been published (6). Transformation with whole cells can be achieved either by mutant strains that lack the second enzyme in the aromatic catabolic pathway, cw-dihydrodiol dehydrogenase (E.C. 1.3.1.19), or by recombinant strains expressing the cloned dioxygenase. This biocatalytic process is scalable, and has been used to synthesize polymer precursors such as 3-hydroxyphenylacetylene, an intermediate in the production of acetylene-terminated resins (7). A synthesis of polyphenylene was developed by ICI whereby ftie product of enzymatic benzene dioxygenation, c/s-cyclohexa-3,5-diene-1,2-diol, was acetylated and polymerized as shown in Scheme 2 (8). 

P.S. (2012) Scalable enantioselective total synthesis of taxanes. Nat. Chem., 4, 21-25. 

Foo K, Usui I, Gotz DCG, Werner EW, Holte D, Baran PS (2012) Scalable, enantioselective synthesis of gcmnacrenes and related sesquiterpenes inspired by terpene cyclase phase logic. Angew Chem Int Ed 51 11491-11495... 

The first enantioselective total synthesis of the 2-aryl-2,3-dihydro-3-benzofuran-carboxyamide neolignan grossamide was also developed using a fully automated and scalable fiow reactor [39]. 

Most recently, Komiyama et al. [233] applied an oxo-tethered ruthenium(ll) complex for an efficient and scalable enantioselective synthesis of the intermediate for a p2-adrenergic receptor antagonist. The intermediate, (/f)-2-amino-l-oxyethyl-l,2-dihydroquinolin-2-one derivative, was obtained with 71 % yield and 98.6 % ee on large-scale production. 

The nitro-Mannich reaction has been reviewed (266 references), covering a variety of its manifestations simple nitroalkane versus more functionalized nitro compounds, non-catalytic, metal ion- and organo-catalytic, conjugate and cycloadditions and so on. 0 New chiral modular bifimctional iminophosphorane superbase organocatalysts allow 0 metal-free enantioselective addition of nitromethane to otherwise unreactive ketone-derived imines. The readily scalable reaction yields -nitroamines (20) with a fully 0 substituted carbon atom, in up to 95% ee. 

The easy scalability of enantioselective HPLC can be demonstrated for the separation of omeprazole [29], one of the blockbuster drugs for the treatment of ulcers (see Fig. 17). The (S)-enantiomer, esomeprazole with the trade name Nexium, is used as an improved active pharmaceutical ingredient against inflammation and ulcers of the oesophagus (reflux oesophagitis), heartburn/ pyrosis (gastrooesophagal reflux), and ulcers of the duodenum after infection with helicobacter pylori. 

In general, the scalable route is quite distinct from the discovery route. In our case, it was decided that this second route should be highly enantioselective... 

In this context, Backvall and coworkers employed complex 8 in combination with CALB in the DKR of l-(6-chlorop5n-idin-3-yl)ethanol 16. This DKR process is presented as the key step of an innovative and scalable route to prepare chiral Me-imidacloprid (S)-17, a chloronicotinyl insecticide (Figure 14.7) [62]. DKR parameters were optimized, reaching maximum conversion and ee at 50 °C in toluene after 36 h. Although the ruthenium catalyst works at room temperature, increasing the temperature enhances the reaction rate and the enantioselectivity. 

Biocatalysis in organic synthesis has a longstanding history and wide applicability in the enantioselective reduction of ketones (150, 151], Many enzymatic protocols provide reliable, scalable, and inexpensive routes to optically active alcohols consequently, such transformations have been extensively employed in industrial applications. A few representative examples of enzymatic reductions of ketones on large scale, giving hydroxy acids 243 [147, 152) and 245 (153) with exceptional enantioselectivities and yields, are shown below (Equations 18 and 19). 

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