Cycloalkenones chiral

Another chiral cuprate that shows high diastereoselectivity on addition to cycloalkcnones is the dihydropyrazine derivative 12. The adducts 13 were obtained in good chemical yield with diastereoselectivities exceeding 90% A Lower diastereoselectivities resulted on addition of 12 to /(-substituted cycloalkenones or to acyclic ( )-enones. 

Highly diastereoface selective Michael additions to chiral cycloalkenones and lactones have been developed264. The selectivity is, in general, due to the shielding of one of the diastereotopic faces by a substituent R at the stereogenic center in the y- or -position (steric effect). 

Posner and coworkers have published a series of papers in which they described a successful application of the Michael reaction between a variety of carbanionic reagents and chiral cycloalkenone sulphoxides 557 to the synthesis of chiral organic compounds (for reviews see References 257, 649, 650). In several cases products of very high optical purity can be obtained. Subsequent removal of the sulphinyl group, serving as a chiral adjuvant, leads to optically active 3-substituted cycloalkenones 558 (equation 356 Table 27). 

TABLE 27. Michael additions to chiral cycloalkenone sulphoxides 557... 

Recently, the use of chiral carbanionic ligands as non-transferable ligands has received attention. Gais and BoBhammer have successfully applied cyclic ct-sulfonimidoyl carbanion 24 in the conjugate addition of alkylcuprates to cycloalkenones (Scheme 14).30... 

A different approach towards titanium-mediated allene synthesis was used by Hayashi et al. [55], who recently reported rhodium-catalyzed enantioselective 1,6-addition reactions of aryltitanate reagents to 3-alkynyl-2-cycloalkenones 180 (Scheme 2.57). In the presence of chlorotrimethylsilane and (R)-segphos as chiral ligand, alle-nic silyl enol ethers 181 were obtained with good to excellent enantioselectivities and these can be converted further into allenic enol esters or triflates. In contrast to the corresponding copper-mediated 1,6-addition reactions (Section 2.2.2), these transformations probably proceed via alkenylrhodium species (formed by insertion of the C-C triple bond into a rhodium-aryl bond) and subsequent isomerization towards the thermodynamically more stable oxa-jt-allylrhodium intermediates [55],... 

Since allyl sulfoxides may quite easily undergo racemization at the sulfur atom via a reversible [2,3] sigmatropic process, the configurationally more stable chiral allylic phosphine oxides were also investigated.201 Compounds (184) and (185), prepared as a 1 1 mixture from allylphosphonyl dichloride and (-)-ephedrine, were shown to add to cycloalkenones with reasonably high diastereoselectivities. Ozono-lysis of the initially formed 1,4-adducts affords the respective optically active ketoaldehydes (Scheme 67). With a / /-isopropyl-substituted derivative even higher selectivities (88-98% ee) could be obtained. 

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. 

These results are analogous to the pioneering work of Posner, who initially developed highly stereoselective conjugate additions of carbon nucleophiles to chiral 2-(arylsulfinyl)-2-cycloalkenones.25 This methodology has been extended to include novel diastereomer differentiating radical (3-additions in which the two... 

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. 

Chiral Ligand for other Stereoselective Reactions. The effect of the addition of dihydroquinidine-derived alkaloids on the product enantioselectivity has also been investigated in the addition reaction of Diethylzinc to aldehydes, in the addition of aromatic thiols to conjugated cycloalkenones, and in the heterogeneous hydrohalogenation of a,a-dichlorobenzazepinone-2. In these cases, the dihydroquinidine derivatives were not the optimal ligands. 

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. 

The breakthrough in the stoichiometric reaction was brought about by Leyen-decker in 1983 by using hydroxyprolinol-derived sulfide 20 bearing three coordinating sites, as shown in 21 [50]. The reaction of dimethylcopper lithium with chalcone gave the product in 94% ee (Eq. (12.24)). In 1991, Alexakis introduced chiral phosphines, e.g. 22, as the ligands in the reaction of the medium order cuprate with cycloalkenones in the presence of lithium bromide to afford the product in 76-95% ee (Eq. (12.25)) [51]. 

Based on the reaction of diorganozinc with cycloalkenone catalyzed by N-monosubstituted sulfonamide and copper(I) [69], the effect of chiral sulfonamide 33 was examined. It was found that catalytic amounts of both sulfonamide and copper(I) are necessary to catalyze the reaction, but ee was at most 32% [70]. 

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

The success is attributed to the use of copper triflate as the copper source. The ligand catalyzes not only the reaction of cycloalkenone but also that of acyclic enones. The chiral thiazolidinone 23 (Scheme 14) was also developed as a chiral ligand to afford the product in 63% ee [57]. 

The Lewis acid mediated cyclopentadiene addition to cycloalkenone 12. derived from a chiral sulfoxide, has been reported38. Virtually complete diastereoselection and formation of a separable endoiexo mixture in good yield was observed. In contrast, the quinone89 15 undergoes exclusive endo addition to the less substituted double bond with lower diastereoselection due to a greater distance between the reaction site and the stereogenic center. 

For sulfoxides attached to a cycloalkenone, e.g., formation of 12 and 13, a detailed procedure which can also serve as a model for the reaction of other enolates with chiral sulfinates has been published3. Such compounds are not only useful as chiral dienophiles, but have found applications as chiral Michael acceptors and for other purposes6. A chiral quinone 14 was obtained by the same technique14. 

The ketophosphonate chemistry briefly discussed above indicates that the cycloalkenones 23 can be easily functionalized and, therefore, can serve as synthetic intermediates in the synthesis of bioactive products. Having this in mind, Altenbach and Holzapfel [35] devised an elegant and short synthesis of natural (+)-terrein (21) from the protected ethyl ester of (+)-(l)-tartaric acid 24. Upon reaction of 24 with diethyl lithiomethanephosphonate in the presence of acetic acid under strictly controlled reaction conditions a mixture of two cyclic products 25 and 26 was formed. The first of them, readily separated chromatograph-ically, was the desired product of an intramolecular Horner-Wittig reaction of the transiently formed bis-jS-ketophosphonate. Introduction of the unsaturated side chain was achieved via Horner-Wittig reaction with acetaldehyde. Subsequent deprotection of the chiral diol moiety with fluoride ion gave (+)-terrein (21) in 26% overall yield (Scheme 12). 

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