Methyl ketones, Mukaiyama aldol reaction

Mukaiyama aldol reactions of various silyl enol ethers or ketene silyl acetals with aldehydes or other electrophiles proceed smoothly in the presence of 2 mol % B(CgF5)3 [151a,c]. The following characteristic features should be noted (i) the products can be isolated as j8-trimethylsilyloxy ketones when crude adducts are worked-up without exposure to acid (ii) this reaction can be conducted in aqueous media, so that the reaction of the silyl enol ether derived from propiophenone with a commercial aqueous solution of formaldehyde does not present any problems (iii) the rate of an aldol reaction is markedly increased by use of an anhydrous solution of B(C6Fs)3 in toluene under an argon atmosphere and (iv) silyl enol ethers can be reacted with chloromethyl methyl ether or trimethylorthoformate hydroxymethyl, methoxy-methyl, or dimethoxymethyl Cl groups can be introduced at the position a to the carbonyl group. These aldol-type reactions do not proceed when triphenylborane is used (Eq. 92). 

The antiviral marine natural product, (-)-hennoxazole A, was synthesized in the laboratory of F. Yokokawa." The highly functionalized tetrahydropyranyl ring moiety was prepared by the sequence of a Mukaiyama aldol reaction, cheiation-controiied 1,3-syn reduction, Wacker oxidation, and an acid catalyzed intramolecular ketalization. The terminal olefin functionality was oxidized by the modified Wacker oxidation, which utilized Cu(OAc)2 as a co-oxidant. Interestingly, a similar terminal alkene substrate, which had an oxazole moiety, failed to undergo oxidation to the corresponding methyl ketone under a variety of conditions. 

The TiCLrmediated Mukaiyama aldol reactions between 7r-allyltricarbonyliron lactone complexes and chiral aldehydes were well documented by Ley and coworkers [37]. (/ )-Trimethylsilyl enol ether 23 (>96% ee) was prepared from the methyl ketone complex 22 by treatment with MesSiOTf/EtsN in CH2CI2 and this was then reacted with (R)- and (5)-2-benzyloxypropanal 24 under the influence of TiCl4 in CH2CI2 at -78 °C. Although the reactions proceeded very slowly and apparent hydrolysis of the silyl enol ether occurred, the aldol products 25 and 26 were isolated in excellent diastereoselectivity in both cases (Scheme 1-8). Interest-... 

Boron-mediated aldol reactions of -oxygenated methyl ketones are normally unselective, and chiral ligands are needed to achieve useful levels of control. However, as shown in Scheme 9-6, a Mukaiyama aldol reaction can be used where induction from silyl enol ether 13 is high, favouring adduct 14 [7, 8]. 

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. 

The utility of BF3-OEt2, a monodentate Lewis acid, for acyclic stereocontrol in the Mukaiyama aldol reaction has been demonstrated by Evans et al. (Scheme 10.3) [27, 28]. The BF3-OEt2-mediated reaction of silyl enol ethers (SEE, ketone silyl enolates) with a-unsubstituted, /falkoxy aldehydes affords good 1,3-anti induction in the absence of internal aldehyde chelation. The 1,3-asymmetric induction can be reasonably explained by consideration of energetically favorable conformation 5 minimizing internal electrostatic and steric repulsion between the aldehyde carbonyl moiety and the /i-substituents. In the reaction with anti-substituted a-methyl-/ -alkoxy aldehydes, the additional stereocontrol (Felkin control) imparted by the a-substituent achieves uniformly high levels of 1,3-anti-diastereofacial selectivity. 

SCHEME 7 Mukaiyama aldol reaction of methyl ketone 10 and aldehyde 9d. 

Retrosynthetically, virgatolide B (2) would be derived from aldol 26 following spiroketalization and phthalide formation via dihydroxylation/carbonyla-tion (Scheme 9). Importantly, the order in which the spiroketal and phthalide structures are constmcted remained flexible in this strategy, enabling late stage adaptation if necessary. Aldol 26 would be constmcted using the Mukaiyama aldol reaction employed for aldol 8, while methyl ketone 27 would be assembled via Suzuki coupling of trifluoroboratoamide... 

Attention now turned to the aldol reaction of methyl ketone 27 with chiral aldehyde 9d. Motivated by our previous success with a Mukaiyama aldol reaction (see Section 2.3), we aimed to employ an analogous procedure with methyl ketone 27. Formation of silyl enol ether 37 was achieved by treatment with tri-methylsilyl triflate and triethylamine. The Lewis acid-mediated aldol reaction proceeded smoothly once more, although full conversion to aldol 26 could not be attained. Reaction of 37 with aldehyde 9d at -78 °C in the presence of boron trifluoride diethyl etherate provided aldol 26 in 58% yield over two steps together with 38% recovered methyl ketone 27 (Scheme 12). In an effort to improve the yield, the reaction time was extended to 3 h. Interestingly, this did not result in any significant increase in the yield of aldol 26 (56% yield). 

Besides the aldol reaction to form y0-hydroxyketone, 1,3-Dipolar Cycloaddition can also form similar molecules. In addition to the Mukaiyama Aldol Reaction, the following are also similar or closely related to the aldol reaction the Claisen-Schmidt Condensation (the aldol reaction between benzaldehyde and an aliphatic aldehyde or ketone in the presence of relatively strong bases to form an o, )0-unsaturated aldehyde or ketone), the Henry Reaction (base-catalyzed addition of nitroalkane to aldehydes or ketones), the Ivanov Reaction (the addition of enediolates or aryl acetic acid to electrophiles, especially carbonyl compounds), the Knoevenagel Reaction (the condensation of aldehydes or ketones with acidic methylene compounds in the presence of amine or ammonia), the Reformatsky Reaction (the condensation of aldehydes or ketones with organozinc derivatives of of-halo-esters), and the Robinson Annulation Reaction (the condensation of ketone cyclohexanone with methyl vinyl ketone or its equivalent to form bicyclic compounds). 

Mukaiyama aldol reaction of a dienolsilane with a ketone, followed by lactone ring closure (Scheme 2.27). Yields and enantiomeric excesses were satisfactory only with aliphatic methyl ketones. 

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. 

In the Mukaiyama aldol additions of trimethyl-(l-phenyl-propenyloxy)-silane to give benzaldehyde and cinnamaldehyde catalyzed by 7 mol% supported scandium catalyst, a 1 1 mixture of diastereomers was obtained. Again, the dendritic catalyst could be recycled easily without any loss in performance. The scandium cross-linked dendritic material appeared to be an efficient catalyst for the Diels-Alder reaction between methyl vinyl ketone and cyclopentadiene. The Diels-Alder adduct was formed in dichloromethane at 0°C in 79% yield with an endo/exo ratio of 85 15. The material was also used as a Friedel-Crafts acylation catalyst (contain-ing7mol% scandium) for the formation of / -methoxyacetophenone (in a 73% yield) from anisole, acetic acid anhydride, and lithium perchlorate at 50°C in nitromethane. 

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. 

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. 

Several examples of the Sc(OTf)3-catalyzed aldol reactions of silyl enolates with aldehydes were examined, and it was found that silyl enolates derived from ketones, thioesters, and esters reacted smoothly with aldehydes in the presence of 5mol% Sc(OTf)3 to afford the aldol adducts in high yields. Sc(OTf)3 was also found to be an effective catalyst in the aldol-type reaction of silyl enolates with acetals. The reactions proceeded smoothly at -78°C or room temperature to give the corresponding aldol-type adducts in high yields without side reaction products. It should be noted that aldehydes were more reactive than acetals (Noyori et al. 1981, Mukai et al. 1990, Mukaiyama et al. 1991). For example, while 3-phenylpropionealdehyde reacted with the ketene silyl acetal of methyl 2-methylpropionate (3) at -78°C to give the aldol adduct in 80% yield, no reaction occurred at —78°C in the reaction of the same ketene silyl acetal with 3-phenylpropionealdehyde dimethylacetal. The acetal reacted with the ketene silyl acetal at 0°C to room temperature to give the aldol-type adduct in 97% yield (scheme 3). 

By 1989 Mukaiyama had already explored the behaviour of phosphonium salts as Lewis acid catalysts. It was possible to show that the aldol-type reaction of aldehydes or acetals with several nucleophiles and the Michael reaction of a,j3-unsatu-rated ketones or acetals with silyl nucleophiles gave the products in good yields with a phosphonium salt catalyst [116]. In addition, the same group applied bisphosphonium salts as shown in Scheme 45 in the synthesis of ]3-aminoesters [117]. High yields up to 98% were obtained in the reaction of A-benzylideneaniline and the ketene silyl acetal of methyl isobutyrate. Various analogues of the reaction parteers gave similar results. The bisphosphonium salt was found to be superior to Lewis acids like TiCl and SnCl, which are deactivated by the resulting amines. 

Pd(OAc)2, combined with DPPE, catalyzes aldol condensation of aldehydes or ketones with ketene silyl acetal (Mukaiyama reaction) under neutral conditions. The ketene silyl acetal of methyl isobutyrate (10) reacted smoothly with methyl pymvate (9) or benzaldehyde (12) in THF or MeCN using 0.1 % of the catalyst. In this reaction the Pd enolate 14 is generated by transmetallation of the ketene silyl acetal with Pd(OAc)2, and the Pd moiety as a Lewis acid activates the carbonyl group to facilitate the attack by the enolate to provide 11 and 13 [2]. 

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