Enantioselective Mukaiyama-aldol

Oxamborolidenes. There are noteworthy advances in the design, synthesis, and study of amino acid-derived oxazaborolidene complexes as catalysts for the Mukaiyama aldol addition. Corey has documented the use of complex 1 prepared from A-tosyl (S)-tryptophan in enantioselective Mukaiyama aldol addition reactions [5]. The addition of aryl or alkyl methyl ketones 2a-b proceeded with aromatic as well as aliphatic aldehydes, giving adducts in 56-100% yields and up to 93% ee (Scheme 8B2.1, Table 8B2.1). The use of 1-trimethylsilyloxycyclopentene 3 as well as dienolsilane 4 has been examined. Thus, for example, the cyclopentanone adduct with benzaldehyde 5 (R = Ph) was isolated as a 94 6 mixture of diastereomers favoring the syn diastereomer, which was formed with 92% ee, Dienolate adducts 6 were isolated with up to 82% ee it is important that these were shown to afford the corresponding dihydropyrones upon treatment with trifuoroacetic acid. Thus this process not only allows access to aldol addition adducts, but also the products of hetero Diels-Alder cycloaddition reactions. 

Significant efforts have extended the scope of catalytic enantioselective Mukaiyama aldol addition reactions beyond the acetate and propionate enoxysilanes and have been used traditionally. Recent reports describe novel addition reactions of silyl dienolates along with isobutyrate-derived enol silanes. 

A clear two step formation of a pyrone by an enantioselective Mukaiyama-aldol and acid catalysed aldol dihydropyrone annulation using aliphatic and aromatic aldehydes and l-methoxy-3-trimethylsilyloxy-l,3-butadiene in the presence of a tryptophan-derived oxazaborolidine was described by Corey et al. [115]. The resulting pyrone which could be assigned as a formal Diels-Alder adduct was obtained with a 67-82% ee and 57 -100% yield. 

Aldol Addition. A catalyst generated upon treatment of Cu(OTf)2 with the (5,5)-r-Bu-box ligand has been shown to be an effective Lewis acid for the enantioselective Mukaiyama aldol reaction. The addition of substituted and unsubstituted enolsilanes at -78 °C in the presence of 5 mol % catalyst was reported to be very general for various nucleophiles, including silyl dienolates and enol silanes prepared from butyrolactone as well as acetate and propionate esters. 

Enantioselective Mukaiyama Aldol Reaction Promoted by Chiral Lanthanide Complexes... 

Catalyzed enantioselective Mukaiyama-aldol reactions have been developed extensively [101] and chiral polymer-supported Lewis acids are the catalysts of choice. Polymer-supported chiral A(-sulfonyloxazaborohdinones 86 and 87, prepared by copolymerization of styrene, divinylbenzene, and chiral monomers derived from L-valine and L-glutamic acid, respectively, have been used for aldol reactions [102]. The rates of reaction using the polymeric catalysts were slow and enantioselectivity was lower than was obtained by use of the low-molecular-weight counterpart (88). The best ee obtained by use of the polymeric catalyst was 90 % ee with 28 % isolated yield in the asymmetric aldol reaction of benzaldehyde with 89 (Eq. 27). 

Corey, E. J., Cywin, C. L., Roper, T. D. Enantioselective Mukaiyama-aldol and aldol-dihydropyrone annulation reactions catalyzed by a tryptophan-derived oxazaborolidine. Tetrahedron Lett. 1992, 33, 6907-6910. 

Oxazaborolidenes. Corey has reported the use of a novel oxazaborolidene complex 41 prepared from borane and A-tosyl (5)-tryptophan. This complex functions in a catalytic fashion in enantioselective, Mukaiyama aldol addition reactions (Scheme 8-3) [17]. The addition of ketone-derived enol silanes 42-43 gives adducts in 56-100% yields and up to 93% ee. The use of 1-trimethylsilyloxycyclo-pentene 43 in the addition reactions to benzaldehyde affords adducts 46 as a 94 6 mixture of diastereomers favoring the syn diastereomer in 92% ee. Addition reactions with dienol silanes 44 furnishes products 47 in up to 82% ee. Corey also demonstrated the use of these adducts as important building blocks for the synthesis of corresponding dihydropyrones treatment of 47 with trifluoroacetic acid affords the cyclic product in good yields. 

Recently, Chen has synthesized and resolved chiral suberyl carbenium ions and utilized these as catalysts for enantioselective Mukaiyama aldol addition reactions (Eq. (8.22)) [34]. Thus the reaction of the ethyl acetate-derived silyl ketene acetal with benzaldehyde in the presence of 10-20 mol% of catalyst afforded the corresponding adduct in 50% ee. The enantioselectivity of the process proved sensitive to the nature of the cation, consistent with observations previously highlighted by Denmark in related studies [35]. Although at the current level of development the selectivities are modest, the study documents a novel class of metal-free Lewis acidic agents. 

Enantioselective aldol reactions.-1 The tryptophan-derived oxazaborolidine 1 can also effect enantioselective Mukaiyama-aldol reactions of aldehydes with trimethyl-->ilyl ethers. 

The Cu(n)-catalyzed reaction of silyl enol ethers with oxomalonic esters in the presence of a bis(oxazoline) ligand constitutes the first step of an access to chiral p-hydroxy acids. Enantioselective Mukaiyama aldol reaction performed in the presence of 52, and that in aqueous ethanol has been accomplished to a certain degree of success (32-85% ee). ... 

The reaction can be applied to silyl enol esters as well. Good asymmetric induction can be achieved in the Mukaiyama aldol reaction. The reaction of silyl enol thioether 246 and nonanal, for example, gave 247 in 60% yield and in 93% ee when the (/ )-BINOL-titanium catalyst shown was used. In this work, the reaction was also done in supercritical fluoroform and in supercritical carbon dioxide. A similar reaction was reported using catalysts closely related to 244 and dichloromethane as the solvent.Chiral oxazaborolidine catalysts have also been shown to be effective for enantioselective Mukaiyama aldol reactions. 

The first examples of the hydrogen-bond-promoted enantioselective Mukaiyama aldol condensation involving 1-acylphosphonates (472) has been described by Rawal and co-workers. These reactions were catalyzed by commercially available Taddol (474) (a,a,a ,a -tetraaryl-l,3-dioxolane-4,5-dimethanol) and proceeded in good yield and excellent diastereo- and enantioselectivity. This mild and general method produced phosphonates (473) with two chiral centers, one tertiary and one quaternary (Scheme 120). 

Chiral Catalysts Containing Group 11 Metals (Cu, Ag, and Au). The most recent publications on the chiral copper catalysts are mainly dealing with those containing bis(oxazoline)-type ligands (Fig. 22). Cationic [Cu( Bu-BOX)] + complexes with OTf , [SbFe] , counterions catalyze Michael reactions, and various types of cycloadditions (292). Copper(II)-PYBOX complexes have been shown to catalyze enantioselective Mukaiyama aldol reactions (293). Similarly, bisoxa-zoline derivatives serve as ligands in the catalytic system prepared in situ from Cud) salts and are used for asymmetric peroxidation and enantioselective Meer-wein arylation of activated olefins (294). The copper-BOX-triflate complexes have found wide applications in cyclopropanation of alkenes (60), furans (295), and aziridination of alkenes (296). 

Enantioselective Mukaiyama-aldol and Sakurai-Hosomi allylation reactions catalyzed by chiral Lewis acid are currently of great interest because of their utility for the introduction of asymmetric centers and functional groups. 

Given the utility of chiral Cu(II)/bisoxazoline complexes in enantioselective Mukaiyama aldol reactions, a number of reports detailing the development of polymer-bound or dendritic bisoxazoline copper (I I) complexes have been developed. Development of such catalyst systems provides the potential for easy recovery and reuse of the relatively expensive catalyst. To this end, Salvadori and CO workers reported Mukaiyama aldol addition of ketene thioacetal (57) to methyl pyruvate catalyzed by a Cu(OTf)2 complex of polystyrene-supported bisoxazoline (89) (Scheme 17.18) [23]. The enantioselectivity of the addition remained high over eight cycles of the catalyst, however, reactivity was gradually reduced over time. 

C2-symmetric bis(oxazolinyl)pyridine (pybox)-Cu(II)-complexes have been shown to catalyze the enantioselective Mukaiyama aldol reaction between (benzyloxy)acetaldehyde and TMSOF in excellent yield, diastereo- and enantioselectivity (cqS )." ... 

The development of C2-symmetric bis(oxazolinyl)-Cu(lI) complexes 65 and 66 by the Evans group greatly contributed to the advancement of the enantioselective Mukaiyama aldol reaction. In addition, these chiral, non-... 

Masamune and coworkers developed an enantioselective Mukaiyama aldol protocol that is based upon chiral oxazaborolidinones like 183 that are generated from BHj THF and the /lara-toluenesulfonamide of the corresponding a-amino acid. Mediated by 20 mol% of the chiral additive, the reaction of the silyl ketene... 

Scheme 5.62 Enantioselective Mukaiyama aldol additions mediated by titanium-BINOL complexes 196 according to Mikami and Keck. Proposed Zimmerman-Traxler-type transition state model.

Scheme 5.74 Diastereoselective and enantioselective Mukaiyama aldol addition catalyzed by doubly lithiated BINOL 262 proposed transition state model 264.

Silver(I) complexes with Tol-BINAP (270) were used by Yamamoto and coworkers for mediating diastereoselective and enantioselective Mukaiyama aldol additions. According to the authors conclusion, the mechanism does not involve transmetallation to silver enolates but follows the usual carbonyl group activation [135]. Hoveyda and coworkers used silver(II) fluoride in the presence of a dipeptide-type ligand for enantioselective additions of silyl enol ethers to a-keto esters [136]. The reaction of 2-trimethylsilyloxyfuran with aromatic and aliphatic aldehydes was catalyzed with chromium salen complex in the presence of protic additives like isopropanol [137]. Various protocols of enantioselective Mukaiyama aldol reactions that use water as cosolvent have been elaborated ... 

Subsequently, Rawal group disclosed the hydrogen bond catalysis of highly diastereo- and enantioselective Mukaiyama aldol reactions of 0-silyl-N,0-ketene acetals by the use ofTADDOL (22b) as a catalyst (Scheme 1.29) [30d]. The reaction is effective for a range of aldehydes and affords the corresponding adducts in synthetically useful yields with excellent enantioselectivities (up to 98% ee). 

The absolute configuration of the product was assigned by analogy. Scheme 1.29 Enantioselective Mukaiyama aldol reactions catalyzed by TADDOL (22b). 

Highly diastereoselective and enantioselective Mukaiyama aldol reaction was reported by Rawal et al. [140] After screening of the catalyst, a cyclohexylidene derivative (30) gave the best result (Scheme 2.74). 

Reetz and coworkers introduced the cyclic chlorodialkylboron Lewis acid (75) (Equation 48) [46], and Kiyooka and coworkers made use of acyloxyborane (76) (Equation 49) [47] in enantioselective Mukaiyama-aldol reactions that employ stoichiometric amounts of the respective boron Lewis acids. Both species give high enantioselectivity in the formation of the desired aldol adducts. After Kiyooka s report of (76), various boron catalysts derived from chiral amino acids appeared in the literature. As such, Masamune and coworkers introduced (77) and (78) [48], Kiyooka and co workers introduced (79) [49], and Corey and co workers introduced (80) [50] as chiral acyloxy borane catalysts for enantioselective aldol reactions (Figure 5.7). 

The asymmetric catalysis using SiCU and (107) is effective also in enantioselective Mukaiyama aldol reaction of TMS enolates derived from methyl ketones [164]. Addition of i-Pr2NEt improves the yield of adducts. The amine probably acts as a proton scavenger to suppress the protodesilylation of the enolates with adventitious HCl. The reaction of TMS enolates derived from ethyl ketones shows high anti diastereoselectivity as in the case of the TBS enolate of t-butyl propanoate. 

Scheme 10.3 Enantioselective Mukaiyama aldol reaction of 0-silyl-N,0-ketene acetals.

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