Enantioselective Copper‐Catalyzed Conjugate Addition of Trimethylaluminum to β,γ‐Unsaturated α‐Ketoamides: Efficient Access to γ‐Methyl‐Substituted Carbonyl Compounds

Abstract

Vollständig regioselektiv reagieren β,γ‐ungesättigte α‐Ketoamide bei der Umsetzung mit Trimethylaluminium zu den 1,4‐Addukten, die in guten bis ausgezeichneten Ausbeuten und Enantioselektivitäten erhalten werden. Der Aufbau γ‐methylierter Carbonylmotive – Schlüsselbausteine in vielen Naturstoffen – zeigt die Anwendungsmöglichkeiten des Verfahrens in der Synthese. Binap=2,2′‐Bis(diphenylphosphanyl)‐1,1′‐binaphthyl, TC=Thiophencarboxylat.

Rhodium‐Catalyzed Asymmetric Arylation of β,γ‐Unsaturated α‐Ketoamides for the Construction of Nonracemic γ,γ‐Diarylcarbonyl Compounds

“…Alexakis et al. used the highly reactive AlMe 3 as the Michael donor to achieve a remarkable Cu‐catalyzed asymmetric 1,4‐addition to β,γ‐unsaturated α‐ketoesters,8a as well as β,γ‐unsaturated α‐ketoamides 8b. However, these substrates are particularly challenging for rhodium‐catalyzed asymmetric conjugate additions, owing to the high reactivity of the α‐keto moiety, which promotes 1,2‐addition 9.…”

“…We have previously demonstrated that chiral sulfinylphosphine ligands effectively promoted Rh‐catalyzed arylation of arylboronic acids to nitro‐styrenes and chalcones, and provide chiral gem ‐diarylalkanes in high yield and enantiomeric excess 10. To examine the feasibility of this strategy, phenylboronic acid 2 a was added to the β,γ‐unsaturated α‐ketoamides ( 1 a – c )8b and ligand L1 11 with [{Rh(C 2 H 4 ) 2 Cl} 2 ] as catalyst, in the presence of aqueous KOH in dichloromethane (DCM) at 40 °C (Table 1, entries 1–3). Amides ( 1 a – c ) provide the 1,4‐adduct 3 as product in more than 86 % yield with excellent 1,4‐selectivity (93/7 to 94/6) and enantioselectivities (92–93 % ee ).…”

“…In this reaction, no 1,6‐addition product was observed. Note, this methodology also provided a general route for the synthesis of enantiomerically enriched γ‐alkyl‐γ‐aryl (particularly, γ‐methyl‐γ‐aryl) carbonyl compounds from γ‐alkyl‐β,γ‐unsaturated α‐ketoamides 8a,b. 16 For example, the reaction between phenylboronic acid 2 a and γ‐methyl‐ and γ‐propyl‐β,γ‐unsaturated α‐ketoamides ( 1 q and 1 r ) proceeded smoothly in the rhodium‐catalyzed 1,4‐arylation to provide 3 qa and 3 ra in good yields and in enantiomeric excess.…”

“…The utility of this methodology is demonstrated in a concise formal synthesis2a–c of sertraline (Scheme ), an important pharmaceutical agent for the treatment of depression. The 1,4‐adduct 3 na (98 % ee ) was converted into 1,3‐dithiolane 7 and then reduced8b, 17 to form γ,γ‐diarylamide 8 , without the loss of enantiomeric excess 18. The amide 8 was hydrolyzed by heating under reflux in concentrated HCl for 20 hours to afford 9 .…”