Chemoenzymatic Synthesis of Chiral 1‐Benzyl‐5‐(hydroxymethyl)‐2‐piperidone Enabled by Lipase AK‐Mediated Desymmetrization of Prochiral 1,3‐Diol and Its Diacetate

Abstract

General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/pure/about/ebr-terms FULL PAPER Abstract:The synthesis of (R)-1-benzyl-5-(hydroxymethyl)-2-piperidone 1 from key synthon monoacetate (R)-3 has been accomplished conveniently in 6 steps with 93% ee and in 44% overall yield. The key step involved lipase AK desymmetrization of diol 4 to produce monoacetate (R)-3 in 93% ee and 93% yield. Lipase AK desymmetrization of diacetate 5 provided ready access to monoacetate (S)-3 in 93% ee and 54% yield.

Desymmetrisation of 1,3-diols and their diacetates under enzymatic heterogeneous catalysis and synthesis of 1,3-diols under continuous flow conditions

“…Lipase AK was also established to be best for the hydrolysis of diacetate 53. [97] Due to the obvious advantages of immobilisation of enzymes as mentioned in section 3, lipase AK will be immobilised on three different nanomaterials -Fe3O4 magnetic nanoparticles, [106] covalent triazinepiperazine linked polymer (CTPP-1) [107] and silica nanospheres (KCC-1) [108] to identify the most suitable support material. The optimum conditions for immobilisation of lipase AK on these nanomaterials will be tested by varying the method of immobilisation, temperature, pH of buffer used for immobilisation, concentration of cross-linking agent, etc.…”

“…We have developed a chemo-enzymatic approach for the synthesis of chiral piperidone 39 (Scheme 17) using tert-butyl acrylate 47, and dimethyl malonate 48 as the starting material. [97] The key step in this synthetic route is the enzymatic desymmetrisation of diol 52 and diacetate 53. Using only lipase AK, we have demonstrated that both enantiomeric products (R)-54 and (S)-54 monoacetates can be prepared effectively with 93% ee.…”

“…Using only lipase AK, we have demonstrated that both enantiomeric products (R)-54 and (S)-54 monoacetates can be prepared effectively with 93% ee. [97] Scheme 16: Synthesis of important biologically active compounds from chiral piperidone 39 Scheme 17: Chemo-enzymatic approach for the synthesis of chiral piperidone 39 [97] Although lipases are present in several organisms and can be used for catalysis, microbial lipases are particularly attractive because they do not need any coenzymes. [9] Since diol 52 is a synthetic substrate, in order to identify the optimal lipase for the acetylation of diol 52, we attempted its desymmetrisation with vinyl acetate in THF using different lipases that have been used extensively Yield [b] (%) ee [c] (%) Yield [b] (%) (Table 1).…”

“…[9] Since diol 52 is a synthetic substrate, in order to identify the optimal lipase for the acetylation of diol 52, we attempted its desymmetrisation with vinyl acetate in THF using different lipases that have been used extensively Yield [b] (%) ee [c] (%) Yield [b] (%) (Table 1). [97] Lipase AK is an alkaline lipase obtained from the Gram-negative, rod-shaped bacterium Pseudomonas fluorescens AK102. [98] Since lipases display the same prochiral selectivity for acetylation and hydrolysis, desymmetrisation of diacetate 53 in phosphate buffer solution was also performed using lipase AK.…”

“…However, monoacetate (S)-54 was obtained with a maximum yield and enantioselectivity of 54% and 91% ee respectively. [97] The use of immobilised lipase AK is expected to improve its stability and therefore enhance its catalytic ability. In addition, immobilisation also offers significant purification and recycling advantages.…”