Enantioselective Chemoenzymatic Synthesis of cis- and trans-2,5-Disubstituted Morpholines

Abstract

A versatile synthesis of enantiomerically pure cis- and trans-2,5-disubstituted morpholines is described. Hydroxynitrile lyase-mediated cyanide addition onto aldehydes provided cyanohydrins in virtually quantitative yield and excellent enantioselectivity. Subsequent formation of diastereomerically pure amino esters via a three-step, one-pot reduction-transimination-reduction sequence followed by reduction and simultaneous protection provided cyclization precursors. Finally, cyclization and SmI(2)-mediated reductive detosylation completed the synthesis of cis- and trans-2,5-disubstituted morpholines in good yields and excellent diastereoselectivities.

Biocatalytic and Chemo-Enzymatic Approaches for the Synthesis of Heterocycles

“…Due to their chemical instability, the optically active cyanohydrins 50 were immediately protected at the hydroxy group as 2-methoxy-isopropyl (MIP) ethers 51, which were converted into the desired morpholines 52 via a multistep chemo-synthesis (Scheme 12). 24 Scheme 12 Chemo-enzymatic synthesis of enantiopure morpholines…”

Enantioselective synthesis of cyanohydrins catalysed by hydroxynitrile lyases – a review

“…40,41 Scheme 5 Chemo-enzymatic synthesis of D-and L-(2-cyano-2-hydroxy/acetoxy)mannosides. 42,43 Organic & Biomolecular Chemistry Review [45][46][47] Aziridines are known to be highly reactive and they occur in a number of natural products which show antibiotic and antitumor activities due to their ability to cross-link DNA. trans-2,3-Disubstituted aziridines 32 (Scheme 7) were obtained in a five-step procedure via the formation of anti-amino alcohols 30 using a one-pot Grignard addition-reduction sequence.…”

“…53 The stereospecific Suzuki crosscoupling of alkyl α-cyanohydrin triflates 53 with a range of aryl and alkenyl boronic acids 54 was achieved, under mild reaction conditions with moderate to excellent yields and excellent Scheme 7 Cyanohydrins as key intermediates in the synthesis of N'-containing heterocycles. [45][46][47] Organic & Biomolecular Chemistry Review enantioselectivities. Triflate 53 has been synthesised chemically with a Lewis base-Lewis acid based approach using TMSCN followed by basic protection with TfO 2 (Scheme 11), but is equally accessible via HNL-catalysis.…”

Racemization-Free Synthesis of Morpholinone Derivatives from α-Amino Acids

“…Chiral morpholine derivatives have been synthesized from naturally occurring amino acids, 4 amino alcohols, 5 epoxides, 6 small-ring azaheterocycles, 7 olefins, 8 carbohydrates, 9 or vinylsulfonium salts. 2d,10 Asymmetric hydrogen-transfer reactions 11 and metal-catalyzed cyclization reactions 12 are also important routes to chiral morpholines. There are only a few reports on syntheses of chiral morpholinone derivatives.…”