Efficient Solvent‐Free Robinson Annulation Protocols for the Highly Enantioselective Synthesis of the Wieland–Miescher Ketone and Analogues

Abstract

A highly efficient (93% overall yield) and enantioselective (94% ee) synthesis of the WielandMiescher ketone (10-g scale) through a solvent-free Robinson annulation procedure is reported. The process involves only 1 mol% triethylamine as the base in the initial Michael process and the organocatalyst N-tosyl-(S a )-binam-l-prolinamide (2 mol%) and benzoic acid (0.5 mol%) for the intramolecular aldol process. This green protocol is applied to a wide range of valuable building block analogues of the Wieland-Miescher ketone (10 examples). Among these, a noteworthy compound for terpene synthesis is the 8a-allyl derivative, which is prepared in 93% yield and 97% ee in a process allowing the recovery and reutilization of the organocatalyst. Furthermore, a one-pot, two-step process has also been developed.

Mechanistic Study on the Asymmetric Synthesis of the Wieland‐Miescher Ketone and Analogs

“…The relative energy of the different TSs is: 0.0, 0.4, 2.5 and 3.2 kcal.mol −1 , for TS4anti/reA , TS4anti/reB , TS4syn/siA and TS4syn/siB respectively. Considering again these four TSs leads to an ee value of 97.9 %, very consistent with the experimental result (97 % ee) . The main difference between the TS4anti/reA and TS4anti/reB is in the relative orientation of SO 2 R group.…”

“…Experimental details : General procedure for synthesis of Wieland‐Miescher ketone 1 (using catalysts 3 – 10 ) In a standard glass vial (10×3 cm) with stirrer bar was added triketone 2 (R=Me) followed by the corresponding catalyst and the acid. The resulting mixture darkened and was stirred for the indicated time.…”

Synthetic and DFT Studies Towards a Unified Approach to Phlegmarine Alkaloids: Aza‐Michael Intramolecular Processes Leading to 5‐Oxodecahydroquinolines

“…tonaldehyde under a range of conditions [25] gave low yields of the corresponding Michael adduct (not shown). Michael addition of the carbamate-and sulfonamide-tethered b-keto esters 10 a-d to cro-Scheme 3.…”

Prolinamide‐Catalysed Asymmetric Organic Transformations

“…Initially, in the Michael addition to methyl vinyl ketone of compound 126 to the butanone for the preparation of triketone 127 was carried out in the presence of 1 mol% triethylamine. The N‐tosyl‐(Sa) binam – L‐prolinamide 128 (2.5 mol%) was used as an organocatalyst for the intramolecular aldol reaction in the presence of benzoic acid (1 mol%) and the corresponding intramolecular aldol product of 2‐allyl −2‐(3‐oxobutyl)‐1,3 cyclohexanediones 129 was obtained in 93% yield with 97% ee (Scheme ) …”