Enantioselective Total Synthesis of Lycoposerramine-Z Using Chiral Phosphoric Acid Catalyzed Intramolecular Michael Addition

Abstract

A new enantioselective total synthesis of phlegmarine-type Lycopodium alkaloid lycoposerramine-Z (1) has been accomplished, using one-pot chemoselective sequential additions of two different Grignard reagents to the bis-Weinreb-amide intermediate and an efficient construction of the fully fuctionalized cyclohexanone intermediate with a chiral phosphoric acid catalyzed enantioselective intramolecular Michael addition.

Decahydroquinoline Ring 13C NMR Spectroscopic Patterns for the Stereochemical Elucidation of Phlegmarine-Type Lycopodium Alkaloids: Synthesis of (−)-Serralongamine A and Structural Reassignment and Synthesis of (−)-Huperzine K and (−)-Huperzine M (Lycoposerramine Y)

“…(4aR,7S,8aS)-7-Methyl-5-oxo-1-(4-methylphenylsulfonyl)decahydroquinoline (25). To a cooled (0 °C) stirred solution of the above mixture of 24 and its epimer (630 mg, 3.8 mmol) in identical to those reported for the racemic compound.…”

Phosphoric Acid Based Heterodimers in Asymmetric Catalysis

“…58 Furthermore, a Brønsted acid catalyzed intramolecular Michael reaction of ketones to enones was recently employed to elegantly build the cyclohexanone core of the Lycopodium alkaloid, lycoposerramine-Z (Scheme 17d). 59 Numerous other classes of compounds, which have traditionally been activated by bases, may in the future be activated as nucleophiles by Brønsted acids (e.g., linear ketones, amides, esters). Exciting discoveries can be expected in this new area.…”

Recent Applications of Asymmetric Organocatalytic Methods in Total Synthesis

“…Further elaboration of 463 afforded lycoposerramine‐Z ( 469 ) via a multistep sequence that included reductive amination, hydrogenolysis, mesylation, and nitrone formation reaction (Scheme 50). [97] …”

“…[96] In 2016, Yang, Yao, and co-workers reported an enantioselective total synthesis of lycoposerramine-Z (469, Scheme 50). [97] To obtain the key intermediate 463, they carried out an asymmetric intramolecular Michael addition of α,β-unsaturated ketone 461 using chiral phosphoric acid 462 as the catalyst. The reaction led to the formation of the desired highly substituted cyclohexanone 463 in high stereoselectivities after optimizations.…”

“…Further elaboration of 463 afforded lycoposerramine-Z (469) via a multistep sequence that included reductive amination, hydrogenolysis, mesylation, and nitrone formation reaction (Scheme 50). [97] In 2015, Higuchi, Kawasaki, and co-workers reported the enantioselective total synthesis of (+)-melodinine E (479) and (À )-leuconoxine (480) (Scheme 51). [98] The desymmetrization of a prochiral diester 470 under the catalysis of the chiral phosphoric acid 471 led to the formation of an optically active lactam derivative 472, which underwent further transformations to afford (+)-melodinine E (479) via a multistep sequence that included NaBH 4 reduction/deoxygenation, azidation, Staudinger reduction, indole oxidation, and lactamization with Bestmann's ylide (478).…”