Cycloalkenones, asymmetric

In contrast to a, -ethylenic ketones or even a, -ethylenic sulfones, a, ) -ethylenic sulfoxides generally are not sufficiently electrophilic to undergo successful nucleophilic j8-addition . a-Carbonyl-a, j8-ethylenic sulfoxides, however, are potent, doubly activated alkenes which undergo rapid and complete -addition of various types of nucleophiles even at — 78 °C. A brief account summarizing this area is available . The stereochemical outcome of such asymmetric conjugate additions to enantiomerically pure 2-sulfmyl 2-cycloalkenones and 2-sulfinyl-2-alkenolides has been rationalized in terms of a metal-chelated intermediate in which a metal ion locks the -carbonyl sulfoxide into a rigid conformation (36 cf. 33). In this fixed conformation, one diastereoface of the cyclic n... 

By using LaNa3-tris(binaphthoxide) (LSB) 55, catalytic asymmetric Michael addition of thiols to cycloalkenones took place to provide the adduct 56 with high ees in good yields (Eq. 7.41) [48]. 

Comparison with the Hajos-Parrish asymmetric version of the Robinson annulation [81] (Scheme 7.25(a)) shows the following distinct differences between the two methods. Firstly, the cycloalkenone in the Cu(OTf)2/ligand 18-catalyzed procedure is the Michael acceptor, whereas the cycloalkanone is the Michael donor in the proline-mediated annulation. Secondly, the asymmetric induction occurs in the 1,4-addition step in the new method, in contrast to the asymmetric aldol-cyclization in the Hajos-Parrish procedure. 

An efficient asymmetric Michael addition of thiols to cycloalkenones (103) (56-90% ee) and an effective asymmetric protonation in Michael additions of thiols to non-cyclic enones (104) (75-90% ee), catalysed by LaNas tris(binaphthoxide) (105) and SmNas-tris(binaphthoxide) (106) complexes, respectively, has been reported. ... 

Since early investigations about the asymmetric addition of diethyl sodiomalonate to optically active vinylic sulfoxides,100-101 Posner and his coworkers102-117 have developed a highly useful methodology based on the conjugate addition of carbon nucleophiles to homochiral a-arylsulfinyl-a,(J-unsaturated carbonyl compounds. While acyclic derivatives still lead only to moderate results,103 the strength of this method is for cyclic systems. For example, the 2-sulfinyl-2-cycloalkenones (94) and (95), the 2-sulfinyl-2-alkenolides (96) and (97), as well as their respective enantiomers are excellent substrates. All these compounds are quite readily accessible in enantiomeric purities of >98% and are configurationally stable, at least for several months at 0 C. 

The heterobimetallic multifunctional complexes LnSB developed by Shibasaki and Sasai described above are excellent catalysts for the Michael addition of thiols [40]. Thus, phenyl-methanethiol reacted with cycloalkenones in the presence of (R)-LSB (LaNa3tris(binaphthox-ide)) (10 mol %) in toluene-THF (60 1) at -40°C, to give the adduct with up to 90% ee. A proposed catalytic cycle for this reaction is shown in Figure 8D.9. Because the multifunctional catalyst still has the internal naphthol proton after deprotonation of the thiol (bold-H in I and II), this acidic proton in the chiral environment can serve as the source of asymmetric protonation of the intermediary enolate, which is coordinated to the catalyst II. In fact, the Michael addition of 4-/en-butylbenzcnethiol to ethyl thiomethacrylate afforded the product with up to 93% ee using (R)-SmSB as catalyst. The catalyst loading could be reduced to 2 mol % without affecting enantioselectivity of the reaction. 

A synthetic route to Q, /i-disubstituted cycloalkenones via a four step one-pot synthesis employed (4a) for RCM and then oxidative rearrangement giving products in low to moderate overall yields as a way to access estrogen receptor ligand tetrahydrofluorenones (equation 29)3 Crimmins reported an asymmetric aldol-oleftn metathesis approach to the synthesis of functionalized cyclopentenes exploiting the acyclic stereocontrol of the aldol reaction with efficient (2a) catalyzed RCM (equation 30)3 ... 

The addition of aromatic thiols to 2-cycloalkenones occurs in a 1,4-fashion to give 3-aryl-thiocycloalkanones. Asymmetric induction is observed here when a chiral base is used as the catalyst8. 

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. 

Asymmetric Coiyugate Addition of Allyl- and Crotylphosphonamides/ The asymmetric C-allylation of a, 3-unsaturated carbonyl compounds is a powerful tool for the functionalization of a carbonyl compound in the P-position. Since such a process normally leads to the corresponding enolate derivative when anionic reagents are used, there exists the possibility of trapping with an electrophile. Thus sequential addition and trapping can lead to vicinally substituted carbonyl compounds. Asymmetric allylation has been achieved previously with simple cycloalkenones using phosphorus and sulfur based reagents that must be prepared in diastereomerically pure form. 

Sparteine 7 is also an excellent chiral ligand for the asymmetric Michael addition of chirally fixed organolithiums (Eq. (12.8)) [25]. The choice of ligand for the lithium cation provides control of 1,2- vs 1,4-addition of organolithium species to cycloalkenones. Furthermore, in these addition reactions, two contiguous stereocenters were constructed with high diastereo- and enantioselectivities. 

In 2004, Fioravanti, Pellacani, and Tardella reported the asymmetric aza-Michael-initiated ring closure additions of ethyl nosyloxycarbamate to 2-(phenylsulfanyl)-2-cycloalkenones using the cinchona-based PTCs 11 or 29, affording the corresponding aziridines with moderate ee values (Scheme 5.25) [31]. Interestingly, this reaction afforded the same enantiomer, regardless of which pseudoenantiomer of the cinchona-derived catalyst was employed. However, the absolute configuration of the products was not determined in this study. 

Catalytic Asymmetric 1,4-Addition of Thiols to Cycloalkenone in the Presence... 

Table 19. Asymmetric Michael Addition of Various Thiols to 2-Cycloalkenones...

Scheme 5.42. Sulfoxide mediated asymmetric Michael additions to (a) cycloalkenones and (b) lactones. Both are postulated to proceed via the nonchelate model. Figure 5.1 lb [210].

Asymmetric Synthesis of Carbon-Cartxin Bonds Using Sulfinyl Cycloalkenones, Alkenolids and Pyrones"... 

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