Highly Enantioselective Copper-Phosphoramidite Catalyzed Kinetic Resolution of Chiral 2-Cyclohexenones

Abstract

Chiral 2-cyclohexenones are attractive building blocks for the synthesis of a variety of natural products. A limited number of naturally occurring optically active cyclohexenones such as pulegone, piperitone, and carvone are cheap, readily available, and widely used for this purpose. [1] The development of routes to other optically active 2-cyclohexenones includes the preparation of nonnatural cyclohexenones from naturally occurring ones; for example, 4-methyland 5-methylcyclohexenone can be derived from pulegone and carvone. [2] Recently the groups of Corey and Sato introduced elegant methods for the synthesis of enantiomerically pure 2-cyclohexenones which can easily be converted into a variety of other chiral 2-cyclohexenones. [3] Although both methods are widely applicable they consist of multistep syntheses to obtain the desired 2-cyclohexenone synthons. On the other hand a variety of racemic 2-cyclohexenones is readily accessible. This encouraged us to develop a general method towards optically active 2-cyclohexenones by kinetic resolution of racemic 2-cyclohexenones based on the copper ± phosphoramidite catalyzed 1,4-addition to enones [Eq. (1)]. [4] It was anticipated that the high enantioselectivity obtained with these catalysts in the 1,4-addition of diethylzinc to 2-cyclohexenone (b 98 % ee, [Eq. (1)]), [4] combined with the high trans-diastereoselectivity generally found in the addition of organometallic reagents to, for example, 5-alkyl-substituted 2-cyclohexenones, [5] should provide high selectivity in the kinetic resolution of such compounds [Eq. (2)]. [6,7] To check the viability of this new approach we tested the ligands L1 ± L5 in the kinetic resolution of racemic 5-substituted 2-cyclohexenones 1 a ± d under the conditions typical for the asymmetric 1,4-addition as shown in Scheme 1. By using [Cu(OTf) 2 ] (1 mol %), (S,R,R)-L1 (2 mol %), and Et 2 Zn (0.8 equiv) in toluene at À 40 8C for the resolution of (AE)-5methyl-2-cyclohexenone (1 a) on a 1 mmol scale, an ee of 88 % Scheme 1. Kinetic resolution of racemic 5-substituted 2-cyclohexenones 1 a ± d under the conditions typical for asymmetric 1,4-addition.was reached at 48 % conversion indicating a selectivity (s) of 120 (Table 1, entry 1). [8±10] Accordingly after 20 min 53 % conversion had taken place and unreacted 1 a with 99 % ee was found. This high selectivity makes the resolution synthetically applicable. [11] Based on the expected trans-diastereoselectivity and the fact that the 1,4-addition of Et 2 Zn to 2-cyclohexenone in the presence of L1 produces (S)-3-ethylcyclohexanone we predicted the unreacted enantiomer to be (R)-1 a which turned out to be correct. [4d, 5, 12] A good correlation was observed between the results with the ligands L1 ± L5 in the 1,4-addition of diethylzinc to 2-cyclohexenone and the results in the kinetic resolution (Table 1, entries 1 ± 9). The most successful ligands in the 1,4addition, namely (S,R,R)-L1, (S,R)-and (S,S)-L2 (Table 1, entries 3 and 4), and (S,R,R)-L3 (Table 1, entry 5), also give the highest ...

N‐Heterocyclic Carbene Catalyzed [4+2] Annulation of Enals via a Double Vinylogous Michael Addition: Asymmetric Synthesis of 3,5‐Diaryl Cyclohexenones

“…One typical approach relies on the intramolecular aldol condensation reaction, which has been successfully established via amine and phosphoric acid catalysis (Scheme , path a). Another approach involves the kinetic resolution of the corresponding cyclohexenones via copper catalysis (path b). Despite this progress, the asymmetric synthesis of enantioenriched 3,5‐diaryl cyclohexenones is still a challenge .…”