This account focuses on the application
of ω-transaminases,
lyases, and oxidases for the preparation of amines considering mainly
work from our own lab. Examples are given to access α-chiral
primary amines from the corresponding ketones as well as terminal
amines from primary alcohols via a two-step biocascade. 2,6-Disubstituted
piperidines, as examples for secondary amines, are prepared by biocatalytical
regioselective asymmetric monoamination of designated diketones followed
by spontaneous ring closure and a subsequent diastereoselective reduction
step. Optically pure tert-amines such as berbines
and N-methyl benzylisoquinolines are obtained by
kinetic resolution via an enantioselective aerobic oxidative C–C
bond formation.
Deracemization, that is, the transformation of a racemate into a single product enantiomer with theoretically 100 % conversion and 100 % ee, is an appealing but also challenging option for asymmetric synthesis. Herein a novel chemo-enzymatic deracemization concept by a cascade is described: the pathway involves two enantioselective oxidation steps and one non-stereoselective reduction step, enabling stereoinversion and a simultaneous kinetic resolution. The concept was exemplified for the transformation of rac-benzylisoquinolines to optically pure (S)-berbines. The racemic substrates were transformed to optically pure products (ee>97 %) with up to 98 % conversion and up to 88 % yield of isolated product.
(S)-Strictosidine
represents the first key intermediate
in the biosynthesis of several pharmaceutically relevant monoterpenoid
indole alkaloids. Optically pure C3-methyl-substituted strictosidine
derivatives were prepared by setting up the two stereogenic centers
at the β-carboline core via two enzymatic steps catalyzed by
the enzymes transaminase and strictosidine synthase in a one-pot cascade
fashion. The two enzymatic steps were performed simultaneously as
well as in a stepwise fashion. The amination of the prochiral ketones
led to optically pure amines with up to >98% enantiomeric excess.
Depending on the enzyme used, the (S)- and (R)-enantiomers were prepared in most cases. Selected amines
were then condensed with secologanin in a Pictet–Spengler reaction
catalyzed by strictosidine synthase leading to diastereomerically
pure products (>98% diastereomeric excess).
Stereoselective methods for the synthesis of tetrahydro‐ß‐carbolines are of significant interest due to the broad spectrum of biological activity of the target molecules. In the plant kingdom, strictosidine synthases catalyze the C−C coupling through a Pictet–Spengler reaction of tryptamine and secologanin to exclusively form the (S)‐configured tetrahydro‐ß‐carboline (S)‐strictosidine. Investigating the biocatalytic Pictet–Spengler reaction of tryptamine with small‐molecular‐weight aliphatic aldehydes revealed that the strictosidine synthases give unexpectedly access to the (R)‐configured product. Developing an efficient expression method for the enzyme allowed the preparative transformation of various aldehydes, giving the products with up to >98 % ee. With this tool in hand, a chemoenzymatic two‐step synthesis of (R)‐harmicine was achieved, giving (R)‐harmicine in 67 % overall yield in optically pure form.
Deracemisation of benzylisoquinoline alkaloids was performed employing a recently developed variant of monoamine oxidase from Aspergillus niger (MAO-N variant D11).
Transaminases are valuable enzymes for industrial biocatalysis and enable the preparation of optically pure amines. For these transformations they require either an amine donor (amination of ketones) or an amine acceptor (deamination of racemic amines). Herein transaminases are shown to react with aromatic β‐fluoroamines, thus leading to simultaneous enantioselective dehalogenation and deamination to form the corresponding acetophenone derivatives in the absence of an amine acceptor. A series of racemic β‐fluoroamines was resolved in a kinetic resolution by tandem hydrodefluorination/deamination, thus giving the corresponding amines with up to greater than 99 % ee. This protocol is the first example of exploiting the catalytic promiscuity of transaminases as a tool for novel transformations.
Transaminases are valuable enzymes for industrial biocatalysis that enable the preparation of optically pure amines. For these transformations they require either an amine donor (amination of ketones) or an amine acceptor (deamination of racemic amines).
N-Dealkylation methods are well described for organic chemistry and the reaction is known in nature and drug metabolism; however, to our knowledge, enantioselective N-dealkylation has not been yet reported. In this study, exclusively the (S)-enantiomers of racemic N-ethyl tertiary amines (1-benzyl-N-ethyl-1,2,3,4-tetrahydroisoquinolines) were dealkylated to give the corresponding secondary (S)-amines in an enantioselective fashion at the expense of molecular oxygen. The reaction is catalyzed by the berberine bridge enzyme, which is known for CC bond formation. The dealkylation was demonstrated on a 100 mg scale and gave optically pure dealkylated products (ee>99 %).
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