ABSTRACT
Sulfoximines have gained considerable recognition as an important structural motif in drug discovery of late. In particular, the clinical kinase inhibitors for the treatment of cancer, roniciclib (pan-CDK inhibitor), BAYâ 1143572 (P-TEFb inhibitor), and AZDâ 6738 (ATR inhibitor), have recently drawn considerable attention. Whilst the interest in this underrepresented functional group in drug discovery is clearly on the rise, there remains an incomplete understanding of the medicinal-chemistry-relevant properties of sulfoximines. Herein we report the synthesis and inâ vitro characterization of a variety of sulfoximine analogues of marketed drugs and advanced clinical candidates to gain a better understanding of this neglected functional group and its potential in drug discovery.
Subject(s)
Drug Design , Protein Kinase Inhibitors/chemistry , Sulfoxides/chemistry , Aminopyridines/chemical synthesis , Aminopyridines/chemistry , Aminopyridines/metabolism , Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors , Ataxia Telangiectasia Mutated Proteins/metabolism , Cyclin-Dependent Kinases/antagonists & inhibitors , Cyclin-Dependent Kinases/metabolism , Estradiol/analogs & derivatives , Estradiol/chemical synthesis , Estradiol/chemistry , Estradiol/metabolism , Fulvestrant , Imatinib Mesylate/chemical synthesis , Imatinib Mesylate/chemistry , Imatinib Mesylate/metabolism , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/metabolism , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Purines/chemical synthesis , Purines/chemistry , Purines/metabolism , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/metabolism , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/metabolism , Sulfoxides/chemical synthesis , Sulfoxides/metabolism , Vardenafil Dihydrochloride/chemical synthesis , Vardenafil Dihydrochloride/chemistry , Vardenafil Dihydrochloride/metabolismABSTRACT
The palladium-catalyzed allylation of N-tert-butanesulfinyl imines with allylic alcohols in the presence of InI as reducing reagent takes place with high diastereoselectivity in reasonable yields. The reaction with crotyl alcohol is totally regioselective, leading to the anti-diastereomer as the main reaction product.
ABSTRACT
The diastereoselective addition of an allylic indium intermediate to chiral o-bromophenyl sulfinyl imine 4 proceeded with good levels of diastereoselectivity. The resulting homoallylic amine derivatives were transformed into lactams 7 and 12, which upon copper-mediated intramolecular N-arylation led to the formation of benzo-fused 1-azabicyclo[j.k.0]alkanes 8 and 13. Benzo-fused 2-allyl-substituted heterocycles 14 could also be prepared by means of a palladium-catalyzed N-arylation of the corresponding free amines. The synthesis of the alkaloid (−)-angustureine was easily accomplished from (S)-2-allyltetrahydroquinoline (14b).
Subject(s)
Benzazepines/chemical synthesis , Imines/chemistry , Indoles/chemical synthesis , Lactams/chemistry , Quinolines/chemical synthesis , Sulfhydryl Compounds/chemistry , Alkanes/chemistry , Benzazepines/chemistry , Copper/chemistry , Indoles/chemistry , Molecular Structure , Quinolines/chemistry , StereoisomerismABSTRACT
Indium-mediated allylation of N-tert-butanesulfinyl ketimines afforded in high yields and diastereoselectivities homoallylic amine derivatives with the nitrogen atom bonded to a quaternary stereocenter.
