A Highly Enantio‐ and Diastereoselective Synthesis of Spirocyclic Dihydroquinolones via Domino Michael Addition‐Lactamization of ortho‐Quinone Methide Imines

Abstract

Spirocyclic dihydroquinolones have been obtained with good yields and excellent diastereoselectivity (> 20:1 d.r.), and enantioselectivity (up to 99:1 e.r.) from in situ generated ortho-quinone methide imines and cyclic b-oxo esters. This one-step domino Michael addition-lactamization processf eatures mild reactionc onditions, easily accessible startingm aterials, and products with two adjacent chiral centers one of whichi sq uaternary.M echanistic studies revealedthe in situ generatedc hiralm agnesium phosphate salt rather than the free phosphoric acid to be the more reactive catalystfor this reaction.

Recent Advances in the Synthesis of Spiro‐β‐Lactams and Spiro‐δ‐Lactams

“…Spiro‐δ‐lactams 220 were prepared from ortho ‐quinone methide imines, generated in situ from propargylic alcohols 217 , and cyclic β‐oxo esters 218 (Scheme 59). [75] The reaction was catalyzed by chiral BINOL‐based phosphoric acid 219 and comprised a one‐step domino Michael addition‐lactamization process. The products were obtained in moderate to high yields (32–98%) with excellent stereoselectivities (up to >20:1 dr and up to >99:1 er).…”

Relay Cu(I)/Brønsted Base Catalysis for Phospha‐Michael Addition/5‐exo‐dig Cyclization/Isomerization of in situ Formed aza‐Alkynyl o‐quinone methides with P(O)−H compounds to C3‐Phosphorylated Indoles

“…Hydroamination triggered reactions have been well documented in which A undergoes 5‐ exo ‐ dig or 6‐ endo ‐ dig cyclization to form indoles [1] or quinolines [2] (Scheme 1a). However, reactions that proceed through prior dehydration to generate carbocation [5a] or aza ‐alkynyl o ‐quinone methides ( N ‐ o ‐AQMs) [5b–c] are much less common. Very recently, our group have reported the first example of carbocation formation initiated tandem phosphorylative allenylation/5‐ exo ‐ dig cyclization of 1‐( o ‐aminophenyl)prop‐2‐ynols to afford C2‐phosphorylmethylindoles (Scheme 1b) [5a] …”

The Use of Domino Reactions for the Synthesis of Chiral Rings

“…Another chiral magnesium catalyst derived from MgSO 4 and a chiral phosphoric acid ligand 60 was applied by Schneider and Hodik in 2018 to develop a synthesis of chiral spirocyclic dihydroquinolones 61 through the reaction of ortho-quinone methide imines 58 with cyclic -oxo esters 59 (Scheme 15). 25 This one-step process evolved through successive addition and lactamization reactions, affording spirocyclic dihydroquinolones 61 with good yields (39-98%) and both moderate to excellent diastereo-(50 to >90% de) and enantioselectivities (66-98% ee).…”