Enantioselective Synthesis of a Key Intermediate in a New Process for Orlistat Using Asymmetric Hydrogenation and a Grignard Reagent Promoted Lactone Cyclization

Abstract

A new enantioselective synthesis of Orlistat suitable for largescale preparation is described. Therein, the first isolated key intermediate (R)-3-hexyl-5,6-dihydro-4-hydroxy-6-undecyl-2Hpyran-2-one (12) is prepared via (a) the asymmetric hydrogenation of methyl 3-oxotetradecanoate to (S)-3-hydroxytetradecanoate (9); (b) the acylation of 9 with 2-bromooctanoyl halide (bromide/chloride) to (R)-3-[(2-bromo-1-oxooctyl)oxy]-tetradecanoic acid methyl ester (11) and finally (c) the tert-butyl magnesium chloride promoted cyclization of 11 to the single enantiomer 12. The single enantiomer intermediate 12, previously published as a mixture of enantiomers 2, has been carried on through several steps to Orlistat (1) without any process changes.

Development of Chiral Spiro P‐N‐S Ligands for Iridium‐Catalyzed Asymmetric Hydrogenation of β‐Alkyl‐β‐Ketoesters

“…When the catalyst loading was further reduced to 0.0002 mol %( S/C = 500 000), the conversion was 71 %( turnover number = 355 000), and (R)-9b was obtained with 93 % ee (entry 16). Hydrogenation product (R)-9e,w hich has al ong chain (R = C 11 H 23 ), and product (R)-9i,which has atrifluorobenzyl group,are critical intermediates in the syntheses of the chiral antiobesity drug orlistat [11] and the antidiabetes drug sitagliptin, [12] respectively. [8] Aw ide range of b-alkyl-b-ketoester substrates (8a-m)c ould be hydrogenated under the optimal reaction conditions ( Table 2).…”

“…These results demonstrate that (R)-5k is one of the most active chiral catalysts reported to date for the asymmetric hydrogenation of b-alkyl-b-ketoesters. Catalyst (R)-5ktolerated various functional groups,including ad ouble bond (8j), an ether (8k), and an amide (8l), in the substrate,a ffording chiral b-hydroxyesters (R)-9j,( R)-9k, and (S)-9l,w hich are key intermediates in the syntheses of natural products brefeldin A [13] and dolabelides [14] and the chiral drug carnitine, [15] respectively,i nh igh yields with excellent enantioselectivities (entries [10][11][12]. Catalyst (R)-5k showed high yields (91-98 %) and excellent enantioselectivities (95-99.9 % ee)f or all the tested substrates,r egardless of the electronic and steric properties of the alkyl group (entries 1-13).…”

Development of Chiral Spiro P‐N‐S Ligands for Iridium‐Catalyzed Asymmetric Hydrogenation of β‐Alkyl‐β‐Ketoesters

“…Catalyst (R)-5k showed high yields (91-98 %) and excellent enantioselectivities (95-99.9 % ee)f or all the tested substrates,r egardless of the electronic and steric properties of the alkyl group (entries 1-13). Hydrogenation product (R)-9e,w hich has al ong chain (R = C 11 H 23 ), and product (R)-9i,which has atrifluorobenzyl group,are critical intermediates in the syntheses of the chiral antiobesity drug orlistat [11] and the antidiabetes drug sitagliptin, [12] respectively. Catalyst (R)-5ktolerated various functional groups,including ad ouble bond (8j), an ether (8k), and an amide (8l), in the substrate,a ffording chiral b-hydroxyesters (R)-9j,( R)-9k, and (S)-9l,w hich are key intermediates in the syntheses of natural products brefeldin A [13] and dolabelides [14] and the chiral drug carnitine, [15] respectively,i nh igh yields with excellent enantioselectivities (entries [10][11][12].…”

Fully Diastereoselective Synthesis of Polysubstituted, Functionalized Piperidines and Decahydroquinolines Based on Multicomponent Reactions Catalyzed by Cerium(IV) Ammonium Nitrate

“…Catalyst ( R )‐ 5 k showed high yields (91–98 %) and excellent enantioselectivities (95–99.9 % ee ) for all the tested substrates, regardless of the electronic and steric properties of the alkyl group (entries 1–13). Hydrogenation product ( R )‐ 9 e , which has a long chain (R=C 11 H 23 ), and product ( R )‐ 9 i , which has a trifluorobenzyl group, are critical intermediates in the syntheses of the chiral antiobesity drug orlistat11 and the antidiabetes drug sitagliptin,12 respectively. Catalyst ( R )‐ 5 k tolerated various functional groups, including a double bond ( 8 j ), an ether ( 8 k ), and an amide ( 8 l ), in the substrate, affording chiral β‐hydroxyesters ( R )‐ 9 j , ( R )‐ 9 k , and ( S )‐ 9 l , which are key intermediates in the syntheses of natural products brefeldin A13 and dolabelides14 and the chiral drug carnitine,15 respectively, in high yields with excellent enantioselectivities (entries 10–12).…”