Cyclohexenone asymmetric phenylation

Scheme 12.4 Stoichiometric stepwise exploration of the catalytic cycle in the asymmetric phenylation of cyclohexenone.

Hayashi and co-workers established the catalytic cycle of the asymmetric conjugate addition in 2002 [16]. An example is outlined in Scheme 3.4 for the reaction of phenylboronic acid 2m with 2-cyclohexenone la. The reaction has three main intermediates hydroxo-rhodium (A), phenylrhodium (B), and oxa- j-allylrhodium (C) complexes. They are related in the catalytic cycle by (1) transmetallation of a phenyl group from boron to hydroxo-... 

Nagasawa and co-workers reported the use of a chiral bis-thiourea catalyst (108) for the asymmetric MBH reactions of cyclohexenone with aldehydes [95]. Since others had already shown that thioureas form hydrogen bonds with both aldehydes and enones, it was hypothesized that the inclusion of two thiourea moieties in close proximity on a chiral scaffold would organize the two partners of the MBH reaction and lead to enantiofacial selectivity. Initial studies showed that the achiral 3,5-bis-(trifluoromethyl)phenyl-substituted urea increased the rate of MBH reaction between benzaldehyde and cyclohexenone. These authors then showed that chiral 1,2-cyclohexyldiamine-linked bis-thiourea catalyst 108, used at 40 mol% loading in the presence of 40 mol% DMAP, promoted the MBH reactions of cyclohexenone with various aliphatic and aromatic aldehydes (40) to produce allylic alcohols in moderate to high yields (33-99%) and variable enantio-selectivities (19-90% ee Table 6.33). 

Despite the obvious advantages the catalytic methods suffer from some limitations. A considerably lesser degree of regioselectivity was observed in the oxyamination reactions of terminal alkenes and asymmetrically disubstituted alkenes, such as 1-phenyl-1-propenes, with respect to the comparable results from stoichiometric reactions (cf. Tabic 5 and 6). Furthermore, reduced reactivity was observed, In fact, neither method (A or B) was successful with tetramethylethylene, cholesteryl acetate, diethyl ( )-2-butenedioate, 2-cyclohexenone, 1-acetoxycyclohexene or 1-phenylcyclohexene73. 

Catalytic, Enantioselective Addition of Arylboronic Acids to Cycloalkenones. A complex between ligand 1 and a rhodium(I) salt was found to catalyze the asymmetric 1,4-addition reaction of arylboronic acids to cyclohexenone and cyclohep-tenone. The reaction proceeds with high enantiocontrol and excellent yields (eq 4). Lower enantiomeric excesses were observed with cyclopentenone (83% ee), but a variety of substituted phenyl-boronic acids could be used. 

R = Me, Et, Pr, vinyl, phenyl Scheme 4,17. Asymmetric addition of Grignards to cyclohexenones [166]. 

A number of BINOL-based bifunctional organocatalysts, for example (7.171-7.173), containing both Bronsted acidic and Lewis basic sites have been used to good effect in the asymmetric MBH reaction. The amine-thiourea (7.171) promotes the MBH reaction of aliphatic aldehydes with 2-cyclohexenone with ees ranging from 80 to 94% while both the (pyridinylaminomethyl)BINOL (7.172) and phosphine (7.173) catalyse the aza-Bayhs-Hilhnan reaction of simple a,p-carbonyls such as MVK and phenyl acrylate with N-tosyl arylaldmines with similar levels of enantioselectivity. 

An a,p-unsaturated ketone can contribute as both a Michael donor and a Michael acceptor at the same time. There are cases in which a PTC catalyst has served for the enantioselective dimerisation of a,(3-unsaturated ketones under phase-transfer conditions. In 2004, Corey and coworkers demonstrated a simple and practical pathway to chiral a-alkyl-ated y-keto acids, which are important intermediates for the preparation of peptide isosteres by dimerisation, through a Michael reaction of 1-phenyl-2-buten-l-one (57) with itself. Subsequently, the Bella group reported the asymmetric dimerisation of cyclohexenone (60), catalysed by the newly prepared PTC catalyst 7f with good enantioselectivity (up to 92% enantiomeric excess), and no byproducts or regioisomers were observed (Scheme 16.18). ... 

---