Enantio‐ and Diastereoconvergent Cyclocondensation Reactions: Synthesis of Enantiopure cis‐Decahydroquinolines

Abstract

Up to four stereocenters with a well-defined configuration are generated in a single synthetic step by cyclocondensation of (R)-phenylglycinol or (1S,2R)-1-amino-2-indanol with stereoisomeric mixtures (racemates, meso forms, diastereoisomers) of cyclohexanone-based δ-keto acid and δ-keto diacid derivatives in enantio-and diastereoconvergent processes that involve dynamic kinetic resolution and/or desymmetrization of enantiotopic groups. A detailed analysis of the stereochemical outcome of the process is presented. The methodology provides easy access to enantiopure 8-and 6,8-substituted cis-decahydroquinolines, including alkaloids of the myrioxazine group.

Enantioselective Synthesis of Lepadins A–D from a Phenylglycinol‐Derived Hydroquinolone Lactam

“…In previous work, we have developed straightforward procedures for the enantioselective synthesis of cis ‐DHQs bearing substituents at the 2‐, 5‐, and 6‐positions, for instance, the dendrobatid alkaloid (−)‐pumiliotoxin C, using phenylglycinol‐derived oxazoloquinolone lactams A as enantiomeric scaffolds (Scheme ) 12. These lactams are easily accessible by a stereoselective cyclocondensation reaction between ( R )‐phenylglycinol and appropriate cyclohexenone‐derived δ‐keto esters 13…”

“…[12] These lactams are easily accessible by astereoselective cyclocondensation reaction between (R)-phenylglycinol and appropriate cyclohexenone-derived d-keto esters. [13] We envisaged tricyclicl actams A as suitable synthetic precursors of lepadins AÀCand D, E, H, belonging to two different stereochemical series. Startingf rom al actam B (A;R 1 = CH 2 OProt, R 2 = H), bearing an oxidized one-carbon substituent at the quinoline C5 position, after stereoselective hydrogenation of the CÀCd ouble bond and reductive removal of the oxazolidine ring, the stereoselectivei ntroduction of the methyl and hydroxy substituents, taking advantage of the lactam functionality,w ould give rise to a cis-DHQ C,w hich was visualized as ac ommon intermediate en route to lepadins AÀEa nd H( Scheme 2).…”

Studies on the Synthesis of Phlegmarine-Type Lycopodium Alkaloids: Enantioselective Synthesis of (−)-Cermizine B, (+)-Serratezomine E, and (+)-Luciduline

“…As a consequence of their widespread distribution and different biogenetic origins, DHQ-containing alkaloids are structurally diverse in their substitution pattern and stereochemistry, which has stimulated the development of general methodologies and unified synthetic strategies for the stereoselective synthesis of substituted DHQ derivatives . In this context, in previous work, we have used tricyclic aminoalcohol-derived oxazoloquinolone lactams as multipurpose enantiopure scaffolds for diastereoselective transformations into a variety of diversely substituted cis -decahydroquinolines, including the DHQ alkaloids (−)-pumiliotoxin C, (−)-lepadins A-C, (+)-lepadin D, (+)-myrioxacin A, and (+)-gephyrotoxin 287C (Scheme ).…”

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

“…Chiral aminoalcohol-derived tricyclic lactams have proven to be excellent optically enriched scaffolds for the synthesis of cis-decahydroquinolines (DHQs) and cisand trans-octahydroindoles. [1][2][3][4][5] In previous work we have reported the enantioselective synthesis of a variety of natural products, such as α-lycorane, [1] Myrioneuron alkaloids, [2] pumiliotoxin C, [3] ent-2-epi-pumiliotoxin C, [3b] cermizine B, [4] and the marine alkaloids lepadins A-D, [5] from chiral tricyclic lactams, thus demonstrating their value in the field of total synthesis. One of the key steps in the above transformations is the removal of the phenylethanol moiety of the chiral inductor.…”

“…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.…”