A highly enantioselective Mannich reaction of aldehydes with cyclic N-acyliminium ions by synergistic catalysis

Abstract

Matched combinations of Brønsted or Lewis acids with suitable pro-electrophiles and secondary amine organocatalysts enable the novel enantioselective syntheses of carbamoyl dihydroquinoline and tetrahydropyridine derivatives with concomitant formation of two stereocenters. A short formal asymmetric synthesis of (2R,2'R)-threo-methylphenidate (Ritalin) is also described.

Organocatalytic alkylation of carbohydrate‐containing aldehydes with dihydroquinoline N,O‐acetals: Absolute configuration of 1,2‐dihydroquinolines

“…In preliminary experiments, we used aldehydes 1c and 1d , containing an ether functionality at different positions as model substrates. In view of the use of particularly valuable glycidic aldehydes 1a,b , the experimental conditions reported in Table make use of half equivalent of this reaction component, whereas in our prior reports, an excess of aldehyde (3.0 equivalents) was generally used . Benzyloxyacetaldehyde ( 1c ) has already been used as the nucleophilic component in highly enantioselective proline‐catalyzed Mannich‐type reactions, but proved to be a challenging substrates for prolinol‐based catalyzed reactions .…”

“…Conversely, a high enantioselectivity was found for the reaction of higher homologous aldehyde 1d , delivering a separable mixture of two diastereoisomeric alcohols 7bd and 8bd (entries 3 and 4). The relative and absolute stereochemistry of compounds 7,8ac and 7,8bd was given on the basis of careful 1 H NMR analysis and comparison with the stereochemical assignments previously obtained for related compounds by means of single crystal X‐ray analysis …”

“…Most approaches for the preparation of chiral 2‐substituted dihydroquinolines in nonracemic form are able to introduce only rather simple organic frameworks making use of sophisticated metal catalysts in strictly anhydrous and/or oxygen‐free reaction conditions . Mannich‐type reactions have recently been reported by us and other research groups using synergistic cooperative metal‐organocatalysis starting from dihydroquinoline N,O‐acetals as proelectrophiles or directly from quinolines . It should be noted that while there are precedents about the use of chiral aldehydes as the electrophilic acceptors in organocatalyzed reactions, we are not aware of reactions in which chiral aldehydes, such as saccharidic aldehydes, have been used as the nucleophilic donor.…”

Direct enantioselective vinylogous Mannich‐type reactions of acyclic enals: New experimental insights into the E/Z‐dilemma

“…All reagents were purchased from commercially available sources. Compounds 1a,b and have been prepared by known procedures . For the preparation of other N,O‐acetals, see ESI.…”

“…In principle, a vinylogous extension of recently reported enantioselective α‐alkylations of aldehydes with N‐acyl quinolinium ions poses several reactivity and selectivity issues . In fact, there are several regioselectivity issues about the nucleophilic addition (α‐selectivity vs γ‐selectivity) of the in situ formed dienamine to the reactive positions of the N‐acylquinolinium ion (α′‐selectivity vs γ′‐ selectivity) (Figure ) .…”