A Practical Synthetic Route to Enantiopure 6-Substituted cis-Decahydroquinolines

Abstract

Starting from 4-substituted cyclohexanones, a practical synthetic route to enantiopure 6-substituted cis-decahydroquinolines has been developed, the key steps being a stereoselective cyclocondensation of an unsaturated δ-keto ester derivative with (R)-phenylglycinol and the stereoselective hydrogenation of the resulting tricyclic oxazoloquinolone lactams.

Studies on the Regioselectivity of the Cyclization of Tryptophanol‐Derived Oxazolopiperidone Lactams

“…Taking advantage of the functionalization present in the oxazolopiperidone lactam, an electrophilic cyclization on the indole 2‐position can involve either the hemiaminal ether carbon via an N ‐acyliminium cation (Scheme , via a ) [1a–1d,2] or the lactam carbonyl through a Bischler–Napieralski type reaction (Scheme , via b ),1e,3 leading to regioisomeric indolo[2,3‐ a ]quinolizidines (when R 1 ≠ H). Additionally, by choosing the appropriate reaction conditions, intramolecular α‐amidoalkylation allows the stereocontrolled generation of C‐12b epimeric derivatives.…”

“…However, the desired cyclization on the lactam carbonyl can be satisfactorily performed under nonacidic conditions by a modified Bischler–Napieralski procedure via a (benzylthio)iminium intermediate 1e. In the only example reported to date of a successful POCl 3 ‐promoted Bischler–Napieralski cyclization from a tryptophanol‐derived oxazolopiperidone lactam,3 the hemiaminal ether carbon incorporates an additional substituent, which, for steric reasons, seems to hamper the intramolecular α‐amidoalkylation reaction.…”

Unexpected Cascade Reactions of Ortho‐Hydroxyenaminones and β,γ‐Unsaturated α‐Ketoesters to Access Hydrogenated Benzoxazolepolycycles and Pyrrole−Phenol Atropisomers

“…[1] In addition, they also constitute the key intermediates for the construction of biologically interesting molecules. [2] In view of the synthetic importance and medicinal relevance, not surprisingly, considerable attention has been devoted to the assembly of such useful skeletons and some elegant approaches have been achieved, including C3-functionalization/cyclization sequence of tryptophols and indole derivatives, [3] [3 + 2] cycloaddition of indoles with phenols [4] and oxaziridines, [5] cascade cyclization of β,γ-unsaturated α-ketoesters with alkyl amides [6] and cyclic enamines, [7] N,O-acetalization of 2-hydroxybenzamide with aldehydes, [8] and others. [9] Although substantial advances have been made, some of them still suffer from limitations of multistep procedures, substrate availability and expensive metal catalysts and are often unsatisfactory in yield and generality.…”

Removal of the Chiral Inductor from Phenylglycinol-derived Tricyclic Lactams. Unexpected Generation of Chiral trans-Hydrochromene Lactones

“…Under these conditions, enantiopure lactone 14 was obtained in 60% yield (Scheme 7). Taking into account that we have previously developed a general procedure for the preparation of (R)-phenylglycinolderived tricyclic lactams, by cyclocondensation of this amino alcohol with appropriate cyclohexanone-based δ-keto esters, [2][3][4][5][6]12] we envisaged these lactams as general synthetic precursors of enantiopure trans-hydrochromene lactones. Thus, following the above procedure, lactam 15, prepared by desilylation (TBAF) of the corresponding TBDMS derivative, [5b] was satisfactorily converted to enantiopure trans-lactone 16.…”