Aldol reactions Mukaiyama-type

Aldol and Related Condensations As an elegant extension of the PTC-alkylation reaction, quaternary ammonium catalysts have been efficiently utilized in asymmetric aldol (Scheme 11.17a)" and nitroaldol reactions (Scheme ll.lTb) for the constmction of optically active p-hydroxy-a-amino acids. In most cases, Mukaiyama-aldol-type reactions were performed, in which the coupling of sUyl enol ethers with aldehydes was catalyzed by chiral ammonium fluoride salts, thus avoiding the need of additional bases, and allowing the reaction to be performed under homogeneous conditions. " It is important to note that salts derived from cinchona alkaloids provided preferentially iyw-diastereomers, while Maruoka s catalysts afforded awh-diastereomers. 

During the past decades, the scope of Lewis acid catalysts was expanded with several organic salts. The adjustment of optimal counter anion is of significant importance, while it predetermines the nature and intensity of catalytic Lewis acid activation of the reactive species. Discovered over 100 years ago and diversely spectroscopically and computationally investigated [131-133], carbocations stiU remain seldom represented in organocatalysis, contrary to analogous of silyl salts for example. The first reported application of a carbenium salt introduced the trityl perchlorate 51 (Scheme 49) as a catalyst in the Mukaiyama aldol-type reactions and Michael transformations (Scheme 50) [134-142]. 

The silatropic ene pathway, that is, direct silyl transfer from an silyl enol ether to an aldehyde, may be involved as a possible mechanism in the Mukaiyama aldol-type reaction. Indeed, ab initio calculations show that the silatropic ene pathway involving the cyclic (boat and chair) transition states for the BH3-promoted aldol reaction of the trihydrosilyl enol ether derived from acetaldehyde with formaldehyde is favored [60], Recently, we have reported the possible intervention of a silatropic ene pathway in the catalytic asymmetric aldol-type reaction of silyl enol ethers of thioesters [61 ]. Chlorine- and amine-containing products thus obtained are useful intermediates for the synthesis of carnitine and GABOB (Scheme 8C.26) [62],... 

A unique condensation is observed between 1,3-dimethoxy-l-trimethylsiloxybuta-diene (35) and cinnamaldehyde (36) producing the acyclic adduct 37 in 72 % yield when catalyzed by Ag(fod) (Sch. 8). In contrast, when Eu(fod)3 or Yb(fod)3 is used as the catalyst, a hetero-Diels-Alder reaction takes place exclusively [17]. The acyclic adduct 37 is believed to be formed by a [2 -i- 2] cycloaddition via an oxetane rather than through a six-membered ring transition state (Mukaiyama aldol type reaction). 

The first use of rare earth metals in the aldol reaction began in the case of cerium enolate (198). Subsequently, Kagan and Kobayashi groups reported systematically the use of rare earth metalscatalyzed for the Mukaiyama aldol-type reaction of silyl enol ethers with aqueous formaldehyde solution (199,200). The efficiency of rare earth metals in a Mukaiyama aldol reaction of 1-trimethylsiloxycyclohexene with benzaldehyde was examined in aqueous THF (Scheme 52). Of the rare earth metal trifiates screened, catalytic efficiency was increased in the order of Yb (91%) > Gd (89%) > Lu (88%) > Nd (83%) > Dy (73%) > Er (52%) > Ho(47%) > Sm (46%) > Eu (34%) > Tm (20%) > La (8%) > Y (trace) (201,202). For different aldol or aldol-type reactions, every rare earth metal occupied its special position in the aldol reaction with distinctive catalytic activity. There were several reviews concerning the rare earth metals catalyzed aldol reactions (203,204). New progress in this context will be discussed herein according to rare earth metals catalysis especially for the past 10 years. 

The influence of the presence of carbohydrate solutes had been previously briefly explored by Lubineau and Scherrmann in the case of the Mukaiyama aldol-type reaction of silylenol ethers with aldehydes, which had been found to be accelerated with effects on the syn-anti selectivity similar to what is observed under high pressure. Favoring the syn aldol product was clearly consistent with its smaller transition state volume as compared to the anti one. When this reaction was studied in the presence of carbohydrate solutes, a moderate yield increase was observed, in the same ty -directed selectivity. This effect was however ascribed to slower competitive hydrolysis of the silylenol ether, probably related to a limitation of water activity in the medium, responsible for this undesired side reaction. ... 

Addition of carbon-based nucleophiles to acetals activated with TBDMS triflate has been reported. In a Mukaiyama aldolization-type reaction, oxygen-, sulfur-, and nitrogen-based heterocyclic silyloxydienes add to chiral electrophilic species derived from the same building blocks (eq 32). All nine possible combinations of nucleophile and electrophile have been achieved. ... 

Bismuth tris-trifluoromethanesulfonate has been found to be an efficient catalyst for the Mukaiyama aldol-type reactions (Equation (8.14)). The catalytic activity of this catalyst is higher than the one reported for the rare earth triflates M(OTf)3 (M = Sc, Ln). In its presence the mechanism involves a transmetallation step [33]. The catalyst s water stability allows the recovery and recycling. 

The conditions used for the Mukaiyama-aldol type reactions employing InCh (see Section 8.2) were found by Loh et al. to be useful in Michael-type additions of silyl enol ethers to a,P-unsaturated carbonyl compounds [49] (Figure 8.25). 

Carbocations were discovered over 100 years ago and have been investigated in diverse ways both spectroscopically and computationally [86-88]. Although as cations they can possess strong Lewis acidic character, carbocations remain seldom represented in organocatalysis, unlike the analogous of silyl salts, for example, discussed above. The first catalytic application of a carbenium salt, the trityl perchlorate 35 (Figure 16.7), was reported for Mukaiyama aldol-type reactions and Michael transformations (Scheme 16.29) [89-97]. 

Recent developments of aldol-type reactions with titanium enolates include the a- and /3-C-glycosidation of glycals73 and the diastereoselective addition to 2-acetoxytetrahydrofurans.74 Mukaiyama and co-workers have developed a one-pot procedure for the preparation of unsymmetrical double aldols.75... 

T. Mukaiyama, K Narasaka, T. Banno, New Aldol Type Reaction Chern Lett 1973,1011-1014. 

As can be seen from Fig. 19, the activation energy of the reaction in the presence of the 1-naphthyl substituted TADDOL catalyst was reduced by 10.2 kcal mol, in comparison with the uncatalyzed reaction (20.2 kcal moF ). The reaction proceeds via a concerted but asynchronous pathway, and no zwitterionic intermediate or transition state corresponding to a stepwise Mukaiyama-aldol type pathway could be located. 

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. 

Asymmetric Aldol-Type Reaction. CAB complex (2) is an excellent catalyst for the Mukaiyama condensation of simple achiral enol silyl ethers of ketones with various aldehydes. The CAB-catalyzed aldol process allows the formation of adducts in a highly diastereo- and enantioselective manner (up to 96% ee) under mild reaction conditions (eqs 4 and 5). The reactions are catalytic 20 mol % of catalyst is sufficient for efficient conversion, and the chiral auxiliary can be recovered and reused. 

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). 

CAB 2, R = H, derived from monoacyloxytartaric acid and diborane is also an excellent catalyst (20 mol %) for the Mukaiyama condensation of simple enol silyl ethers of achiral ketones with various aldehydes. The reactivity of aldol-type reactions can, furthermore, be improved, without reducing the enantioselectivity, by use of 10-20 mol % of 2, R = 3,5-(CF3)2C6H3, prepared from 3,5-bis(trifluoromethyl)phenyl-boronic acid and a chiral tartaric acid derivative. The enantioselectivity could also be improved, without reducing the chemical yield, by using 20 mol % 2, R = o-PhOCgH4, prepared from o-phenoxyphenylboronic acid and chiral tartaric acid derivative. The CAB 2-catalyzed aldol process enables the formation of adducts in a highly diastereo- and enantioselective manner (up to 99 % ee) under mild reaction conditions [47a,c]. These reactions are catalytic, and the chiral source is recoverable and re-usable (Eq. 62). 

Mukaiyama and Kobayashi et al. have developed the use of Sn(OTf)2 in diastereose-lective and enantioselective aldol-type reactions [26,27]. Initially, the stereoselective aldol reactions were performed with a stoichiometric amount of Sn(OTf)2 [28], The reaction between 3-acylthiazolidine-2-thione and 3-phenylpropionaldehyde is a representative example of a diastereoselective syn-aldol synthesis (Eq. 17). 

Mukaiyama, T., Narasaka, K., Banno, K. New aldol type reaction. Chem. Lett. 1973,1011-1014. 

The activation of the carbonyl group by Lewis acids was another leap made in the 1960s as typified by Mukaiyama-aldol reaction. In sharp contrast to the conventional carbonyl addition reactions that had been run under basic conditions, this new method allowed the addition of various nucleophiles under acidic conditions with high chemo- and stereocontrol and, consequently, the scope of the carbonyl addition reaction was extensively expanded. The Lewis acid-promoted ally-lation with allylmetals and ene reaction also received as much attention as the aldol-type reaction. It should be further pointed out that the catalytic versions of asymmetric reactions, which represent one of the most exciting topics in recent synthetic chemistry, owe their development strongly to the Lewis acid activation protocol. The design of a variety of chiral ligands for metals has produced luxuriant fruits in this field. 

The titanium(IV) chloride-promoted reactions of enol silyl ethers with aldehydes, ketones, and acetals, known as Mukaiyama reaction, are useful as aldol type reactions which proceed under acidic conditions (eq (23)) [20], Enol silyl ethers also undergo the Michael type reactions with enones or p.y-unsaturated acetals (eq (24)) [21]. Under similar reaction conditions, enol silyl ethers are alkylated with reactive alkyl halides such as tertiary halides or chloromethyl sulfides (eq (25)) [22], and acylated with acid halides to give 1,3-diketones (eq (26)) [23]. 

The Mukaiyama reaction is an aldol-type reaction between a silyl enol ether and an aldehyde in the presence of a stoichiometric amount of titanium chloride. The reaction, which displays a negative volume of activation, could be performed without acidic promoter under high pressure [58]. In this case, the major product is the syn hydroxy ketone, not as for the TiCl4-promoted reactions which lead mostly to the anti addition product. Since the syn or anti selectivity is the result of two transition states with different activation volumes (AV n < AVfnti), it was of great interest to investigate the aldol reaction in water. Indeed, the reaction of the silyl enol ether of cyclohexanone with benzaldehyde in aqueous medium was shown to proceed without any catalyst and under atmospheric pressure, with the same syn... 

It was reported that TMSOTf selectively activated acetals rather than aldehydes in the aldol-type reaction of silyl enolates (a) Noyori R,Murata S, Suzuki M (1981) Tetrahedron 37 3899 (b) Mukai C, Hashizume S, Nagami K, Hanaoka M (1990) Chem Pharm Bull 38 1509. (c) Murata S, Suzuki M, Noyori R (1980) J Am Chem Soc 102 3248. Selective activation of acetals or aldehydes under certain non-basic conditions are now under investigation in our group cf. (d) Mukaiyama T, Ohno T, Han JS, Kobayashi S (1991) Chem Lett 949... 

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