Oxazolidines as Intermediates in the Asymmetric Synthesis of 3-Substituted and 1,3-Disubstituted Tetrahydroisoquinolines

Abstract

A diastereoselective mercury(II)-promoted intramolecular cyclization of unsaturated aldehyde via an oxazolidine to prepare C-3-substituted tetrahydroisoquinoline is disclosed. The C-3 stereogenic center is subsequently exploited to create the C-1 stereocenter by coordination of the nucleophilic reagent to the oxygen atom of oxazolidine. Both cis- and trans-1,3-disubstituted tetrahydroisoquinolines can be readily prepared. In addition, when a cationic rhodium complex was used, intramolecular hydroamination was effected, thus avoiding mercury(II) salts and demercuration. The reaction is general and works well using aliphatic and aromatic aldehydes.

Studies towards the Synthesis of (+)‐Lochnerine

“…The next step called for the stereoselective creation of the C3 stereocenter. Reaction of compound 7 with allylmagnesium bromide cleanly afforded the C3/C5 anti ‐diastereomer 16 as the sole isomer,as expected from our earlier study, by coordination of the Grignard reagent to the oxazolidine oxygen and delivery from the same face.…”

“…The earlier reported synthesis rely on Pictet‐Spengler reaction for the introduction of the C‐ring. Herein, we disclose our efforts towards the synthesis of lochnerine, based on our recent report, using an oxazolidine, prepared from an unsaturated aldehyde, to stereoselectively create the C−N bond and subsequently the C−C bond in the C‐ring. The retrosynthesis is depicted in Scheme .…”

Probing the Reactivity of Cyclic N,O-Acetals versus Cyclic O,O-Acetals with NaBH4 and CH3MgI

“…6 Unlike cyclic O,O-acetals, cyclic N,O-acetals are ring-opened with hydride and Grignard reagents, and the C−O bond of oxazolidines is cleaved selectively to afford the corresponding substituted 2-amino-1-alkanols. 3 Most likely this is due to a hyperconjugative effect exerted by the nitrogen atom that weakens the C−O bond. The reaction is thought to proceed via an iminium ion intermediate formed upon C−O bond rupture, possibly subsequent to chelation with a Lewis acid, if one is present (Figure 1).…”

“…Nonaromatic N - and O -heterocycles display a rich and diverse chemistry . Many examples, both natural and synthetic, include well-known pharmaceuticals and other physiologically active compounds, synthetic building blocks, , and chiral ligands for asymmetric catalysis . Students in introductory undergraduate organic chemistry courses are typically introduced to nonaromatic heterocycles through epoxidation of alkenes and acid-catalyzed conversion of aldehydes and ketones to their corresponding five- and six-membered cyclic O , O -acetals (substituted 1,3-dioxolanes and 1,3-dioxanes, respectively) (Scheme ).…”

“…Unlike cyclic O , O -acetals, cyclic N , O -acetals are ring-opened with hydride and Grignard reagents, and the C–O bond of oxazolidines is cleaved selectively to afford the corresponding substituted 2-amino-1-alkanols . Most likely this is due to a hyperconjugative effect exerted by the nitrogen atom that weakens the C–O bond.…”