Abstract
A proof of concept for a novel approach towards enantiomerically highly enriched acyclic secondary amines and β-aminothiols as non-cyclic target molecules when starting from 3-thiazolines as heterocycles is presented. Starting from 2,2,4,5,5-pentamethyl-3-thiazoline, we demonstrated this chemoenzymatic pathway to both of these types of amine molecules, which were isolated as urea derivatives with a non-optimized yield of up to 20%. As a substrate, 2,2,4,5,5-pentamethyl-3-thiazolidine, which was obtained with an enantiomeric excess (ee) of 99% in a biotransformation from the corresponding 3-thiazoline according to a recently developed protocol, was used. For the reductive desulfurization of this substrate leading to a sulfur-free secondary amine, in situ formed Ni2B turned out to be a suitable reducing reagent. However, when using lithium aluminum hydride as a reducing agent, β-aminothiol was obtained.
Highlights
Starting from 2,2,4,5,5-pentamethyl-3-thiazoline, we demonstrated this chemoenzymatic pathway to both of these types of amine molecules, which were isolated as urea derivatives with a non-optimized yield of up to 20%
Friedrich Asinger, a professor of Technical Chemistry at RWTH Aachen, is the discoverer of a sulfur-based multi-component condensation reaction leading in an elegant fashion to 3-thiazoline heterocycles [1,2,3]
Following our recently developed protocol [12] for the biocatalytic reduction of 3-thiazolines in the presence of the recombinant imine reductase IRED8 from Mycobacterium smegmatis [25] and a glucose dehydrogenase from Bacillus subtilis [26] (utilized as our designed recombinant Escherichia coli (E. coli) whole-cell catalyst with a concentration of 2 mg/mL) [12] as well as a cofactor in catalytic amount and d-glucose as the reducing agent added in stoichiometric amount, we transformed this 3-thiazoline 1 into the thiazolidine (S)-2 on a 20 mM substrate concentration and on a 10 mL scale with a high conversion of >95% and an excellent enantioselectivity of 99% ee
Summary
Friedrich Asinger, a professor of Technical Chemistry at RWTH Aachen, is the discoverer of a sulfur-based multi-component condensation reaction leading in an elegant fashion to 3-thiazoline heterocycles [1,2,3]. The Asinger group members, Offermanns and Scherberich, introduced the Asinger synthesis at Degussa AG after joining this company and at Degussa AG this synthetic route was expanded towards an industrial process for the production of d-pencillamine [4], underlining the power of heterocyclic chemistry for the preparation of non-cyclic industrial chemicals on a large scale Inspired by this success in the chemical industry, in the following decades, numerous further efficient transformations of the 3-thiazoline heterocycle by addition of suitable nucleophiles have been reported, e.g., the pioneer achievements by Martens at Degussa AG and later accomplishments by his group at Oldenburg University with, in part, collaboration partners on the use of malonates (leading use of malonates (leading to β-amino acid derivatives) [5], isocyanides (within the Ugi reaction leaditnogβt-oamtoitnaollyacpirdotdeecrtievdatαiv-aems)in[5o],aicsiodcsy) a[6n,i7d]easn(dwpithhoinspthhieteUs g(lieraedaicntgiotno lαe-aadminingotophtootsaplhlyonparotetse)ct[e8d– 1α1-]a.mAilntohoaucigdhs)m[6o,s7t] oafntdhpesheosmpehtihteosd(slegaidvienrgatcoemα-iacmpirnoodpuhctoss[p5h–o7n],aitteiss) n[8o–t1e1w].oArtlhtyhotuhagthMmaorstteonfs,thSehsiebmaestahkoidasngdivtheeriarcceomwicorpkreordsudcetsm[o5n–7st]r,aitteids nthoatetwthoertlhayttethrattraMnasfroternmsa, tSiohnibwasaaskiaabnledttohebier ccoonwdourckteerds edveemnoinnsatrnataesdymthmatetthreiclafattsehriotrnanlesafodrinmgattoiohniwghasenaabnletitoosebleecctoinvidtuiecstefodretvheenfoinrmanataiosynmomf tehterircefsauslhtiinogn αle-aadminingotophhoigsphheonnaantteisos[9e–le1c1t]i.vAitiseas floorngth-leasfotirnmgacthioanlleonfgteheforresduelctaindgesα, -tahme i(nenoapnhtioosspehleocntiavtee)s r[e9d–u11c]-. Addressing these challenges, in the following, we present a novel conceptual approach to such non-cyclliiccttaarrggeettmmoolleeccuulelessbbyystsatartritninggfrformomhehteetreorcoyccylcelse.sI.nIdnedtaeitla, iwl,ewreproerptotrhtethperoporfoooffcoofncoenpct efoprt aforhiaghliyghelynaenntaionsteiolescetlievcetivcheecmheomenozeynmzyamticatpicatphawthawy atyo tboobthothtytpyepsesofofmmoolelecuculelsessstatarrtitninggffrroomm a 3-thiazoline, ccoonnssiissttiinnggooffaannininitiitaial lbbioiocactaatlaylytitcicrerdeudcutciotinonofoefaesailsyilayccaecscseisbsliebl3e-t3h-itahzioalzinoleinfoellfoowlloewd ebdy bdyiffdeirfefnertecnhtecmhiecmalicreadl ruecdtiuvcetitveechtencohlongoileosg.ies
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