Methyl ketones, asymmetric aldol

Pride of place here must go to the asymmetric Robinson annelation, discovered as long ago as 1974, but not appreciated at the time for the landmark that it undoubtedly was.17 The normal Robinson annelation (text chapter 36) is first a Michael addition to produce an achiral triketone 82 which cyclises when the enol of the methyl ketone adds, aldol fashion, to the syn face of either of the other ketones to give 83, and hence the enone 84, the north east corner of a steroid. 

Acetoxy-l,7-octadiene (40) is converted into l,7-octadien-3-one (124) by hydrolysis and oxidation. The most useful application of this enone 124 is bisannulation to form two fused six-membered ketonesfl 13], The Michael addition of 2-methyl-1,3-cyclopentanedione (125) to 124 and asymmetric aldol condensation using (5)-phenylalanine afford the optically active diketone 126. The terminal alkene is oxidi2ed with PdCl2-CuCl2-02 to give the methyl ketone 127 in 77% yield. Finally, reduction of the double bond and aldol condensation produce the important intermediate 128 of steroid synthesis in optically pure form[114]. 

By the use of chiral oxazolidines derived from a chiral norephedrine and methyl ketones, an asymmetric aldol reaction proceeds in a highly enantioselective manner. In the case of ethyl or a-methoxy ketones, the corresponding anti aldol products were obtained with high diastereo- and enantioselectivities. A chiral titanium reagent, generated from... 

The development of enantioselective aldol reactions has been widely studied in conjunction with the synthesis of natural products. Highly enantioselective aldol reactions have been achieved by employing chiral enolates of ethyl ketones and propionic acid derivatives.(1) On the other hand, achieving high asymmetric induction in the asymmetric aldol reaction of methyl ketones is still a problem.(2)... 

Based on this assumption, the asymmetric aldol reaction of chiral 1,3-oxazolidines 1 of methyl ketones was examined. It was found that the corresponding aldol products were obtained in good optical purity when divalent tin chloride was used as an additive metal salt. 

Table 1. Asymmetric Aldol Reaction of Methyl Ketones...

Dialkylboron trifluoromethanesulfonates (triflates) are particularly useful reagents for the preparation of boron enolates from carbonyl compounds, including ketones, thioesters and acyloxazolidinones.4 Recently, the combination of dicylohexylboron trifluoromethanesulfonate and triethylamine was found to effect the enolization of carboxylic esters.5 The boron-mediated asymmetric aldol reaction of carboxylic esters is particularly useful for the construction of anti (3-hydroxy-a-methyl carbonyl units.6 The present procedure is a slight modification of that reported by Brown, et al.2... 

Yamamoto has recently described a novel catalytic, asymmetric aldol addition reaction of enol stannanes 19 and 21 with aldehydes (Eqs. 8B2.6 and 8B2.7) [14]. The stannyl ketones are prepared solvent-free by treatment of the corresponding enol acetates with tributyltin methoxide. Although, in general, these enolates are known to exist as mixtures of C- and 0-bound tautomers, it is reported that the mixture may be utilized in the catalytic process. The complexes Yamamoto utilized in this unprecedented process are noteworthy in their novelty as catalysts for catalytic C-C bond-forming reactions. The active complex is generated upon treatment of Ag(OTf) with (R)-BINAP in THF. Under optimal conditions, 10 mol % catalyst 20 effects the addition of enol stannanes with benzaldehyde, hydrocinnamaldehyde, or cinnamaldehyde to give the adducts of acetone, rerf-butyl methyl ketone (pinacolone), and acetophenone in good yields and 41-95% ee (Table 8B2.3). 

Asymmetric induction is reported in the addition of enolates of methyl ketones to aldehydes.55 Double stereo-differentiation—in which simultaneous 1,3-control can be obtained hi the aldehyde moiety—is shown to be achievable with proper selection of the aldol type. 

Asymmetric aldol reactions.4 The borane complex 3 can also serve as the Lewis acid catalyst for the aldol reaction of enol silyl ethers with aldehydes (Mukaiyama reactions).5 Asymmetric induction is modest (80-85% ee) in reactions of enol ethers of methyl ketones, but can be as high as 96% ee in reactions of enol ethers of ethyl ketones. Moreover, the reaction is syn-selective, regardless of the geometry of the enol. However, the asymmetric induction is solvent-dependent, being higher in nitroethane than in dichloromethane. 

Recent success was achieved in carrying out direct catalytic asymmetric aldol reactions of aldehydes with unmodified ketones [22]. No preconversion of the ketone moiety to a more reactive species such as an enol silyl ether or enol methyl ether is necessary. 

Another route to (+)-19-nortestosterone (73) started firom 2-methyl-l,3 cyclopentanedione (74). The asymmetric aldol condensation of the Michael adduct using L-phenylalanine produced the opticaUy active enone (75). The PdCh-catalyzed oxidation yielded crystalline trione (76) in 77% ee, which was recrystallized as an optically pure form. Reduction of the double bond and aldol condensation afforded the desired cd tratu-fused ketone (77). The construction of the A-ring was carried out by alkylation with... 

Enolboration of Ketones and Opening of meso-Epoxides. Methyl alkyl ketones have been successfully enolized by IpciBX (X = OTf or Cl) in the presence of a tertiary amine. The corresponding enolborinates have been used in asymmetric aldol condensations (eq 5). The reagent has also been applied to the enantioselective opening of mcj o-epoxides to form the corresponding nonracemic chlorohydrins (eq 6). ... 

Aldol additions to methyl pyruvate by silyl ketene thioacetals have been shown to proceed in high yield and with excellent asymmetric induction (Eq. 28). This process is an uncommon example of catalytic, asymmetric aldol additions to ketones, providing access to synthetically useful compounds. The remarkable ability of the catalyst to differentiate between subtle steric differences of substituents flanking a 1,2-diketone has been elegantly demonstrated in highly enantioselective additions to 2,3-pentane-dione (Eq. 29). Tlie aldol adduct of 5-ferr-butyl thiopropionate derived silyl ketene acetal afforded 2,3-anh-aldol adduct (>99 1 antilsyn) in 98 % ee and 97 3 chemoselec-tivity for the methyl ketone. 

The same group further developed the asymmetric aldol reaction of A -methoxy-A -methyl-a-isocyanoacetamide (a-isocyano Weinreb amide) with aldehydes (Sch. 25). The reaction of the Weinreb amide 96 with acetaldehyde in the presence of 86c Au(I) catalyst gives the optically active tram-oxazoline 98 (E = CON(Me)OMe R = Me) with high diastereo- and enantioselectivities similar to those of 95 [49], The oxazoline can be transformed into A,0-protected /3-hydroxy-a-amino aldehydes or ketones. 

Having developed an efficient catalytic asymmetric nitroaldol reaction, we next applied our attention to a direct catalytic asymmetric aldol reaction. The aldol reaction is generally regarded as one of the most powerful carbon-carbon bond-forming reactions. The development of a range of catalytic asymmetric aldol-type reactions has proven to be a valuable contribution to asymmetric synthesis. In all these catalytic asymmetric aldol-type reactions, however, preconversion of the ketone moiety to a more reactive speeies such as an enol silyl ether, enol methyl ether or ketene silyl... 

Stereoselective reduction of a-alkyl-3-keto acid derivatives represents an attractive alternative to stereoselective aldol condensation. Complementary methods for pr uction of either diastereoisomer of a-alkyl-3-hydroxy amides from the corresponding a-alkyl-3-keto amides (53) have been developed. Zinc borohydride in ether at -78 C gave the syn isomer (54) with excellent selectivity ( 7 3) in high yield via a chelated transition state. A Felkin transition state with the amide in the perpendicular position accounted for reduction with potassium triethylborohydride in ether at 0 C to give the stereochemi-cally pure anti diastereoisomer (55). The combination of these methods with asymmetric acylation provided an effective solution to the asymmetric aldol problem (Scheme 6). In contrast, the reduction of a-methyl-3-keto esters with zinc borohydride was highly syn selective when the ketone was aromatic or a,3-unsaturated, but less reliable in aliphatic cases. Hydrosilylation also provided complete dia-stereocontrol (Scheme 7). The fluoride-mediated reaction was anti selective ( 8 2) while reduction in trifluoroacetic acid favored production of the syn isomer (>98 2). No loss of optical purity was observed under these mild conditions. 

In recent years the synthetic potential and mechanistic aspects of asymmetric catalysis with chiral Lewis base have been investigated. Aldol addition reactions between trichlorosilyl enolates with aldehydes have been also intensively studied. Now, full investigations of the trichlorosilyl enolates derived from achiral and chiral methyl ketones, in both uncatalysed and catalysed reactions with chiral and achiral aldehyde acceptors have been reported. The aldol addition is dramatically accelerated by the addition of chiral phosphoramides, particularly (137) and proceed with good to high enantioselectivity with achiral enolates and aldehydes (Scheme 34). ... 

Denmark, S. E., Stavenger, R. A., Wong, K.-T. Lewis Base-Catalyzed, Asymmetric Aldol Additions of Methyl Ketone Enolates. J. Org. Chem. 1998, 63, 918-919. 

Given this problem, the attachment of the butanone synthon to aldehyde 74 prior to the methyl ketone aldol reaction was then addressed. To ovenide the unexpected. vTface preference of aldehyde 74, a chiral reagent was required and an asymmetric. syn crotylboration followed by Wacker oxidation proved effective for generating methyl ketone 87. Based on the previous results, it was considered unlikely that a boron enolate would now add selectively to aldehyde 73. However, a Mukaiyama aldol reaction should favour the desired isomer based on induction from the aldehyde partner. In practice, reaction of the silyl enol ether derived from 87 with aldehyde 73, in the presence of BF3-OEt2, afforded the required Felkin adduct 88 with >97%ds (Scheme 9-29). This provides an excellent example of a stereoselective Mukaiyama aldol reaction uniting a complex ketone and aldehyde, and this key step then enabled the successful first synthesis of swinholide A. 

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