Acetals aldol-type reactions

Nagao, Y., Hagiwara, Y., Kumagai, T., Ochiai, M., Inoue, T., Hashimoto, K., and Fujita, E. (1986). New C4-chiral l,2-thiazolidine-2-thiones Excellent chiral auxiliaries for highly diastereocontrolled aldol-type reactions of acetic acid and a,b-unsaturated aldehydes. J. Org. Chem. 51, 2391-2393. 

Chiral bis-phosphine acylplatinum complex 210 with a strong acid such as TfOH serves as an effective enantio-selective catalyst for aldol-type reactions of aldehydes with ketene silyl acetals (Equation (127)).486 The presence of water and oxygen in the catalyst preparation step is required to obtain the highly enantioselective catalyst. The intermediacy of a C-bound platinum enolate was suggested by IR and 31P NMR spectroscopies. 

Alkoxy ketones. These ketones can be prepared by an aldol-type reaction of enol ethers with acetals catalyzed by a trityl salt. Methoxymethyl (MOM) enol ethers are more reactive than methyl enol ethers. 

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 synthesis in aldol-type reaction involving magnesium ester or lactone enolates has also been reported. Enolate of (—)-menthyl or (-l-)-bornyl acetate reacts with substituted benzophenones or a-naphtophenones to yield, upon hydrolysis of the resulting esters, optically active /3-hydroxyacids. Although these results are interpreted in terms of a steric factor. Prelog s rules are not applicable to these reactions (equation 88). 

A direct enantioselective cross-aldol-type reaction of acetonitrile with an aldehyde (RCHO) has been reported, giving /3-cyano alcohol product, R-CH (OH)-CH2-CN, (7e) in up to 77% ee.148 CH3CN, acting as an acetate surrogate, is chemoselectively activated and deprotonated using a soft metal alkoxide (CuO-Bu1) in a strong donor solvent (HMPA), with a bulky chiral diphosphine as auxiliary. 

Asymmetric aldol-type reactions.1 This chiral diamine (1) in combination with tin(II) triflate and tributyltin fluoride (15, 314-315) effects a highly enantioselective aldol-type reaction between ketene silyl acetals and aldehydes. A tentative structure (2) has been suggested for the promotor. 

Aldol-type reaction of acetals with alkenes. Mildly activated alkenes can undergo addition reactions with acetals in the presence of ClSi(CH3)3 and SnCl2, as in the reaction with dihydropyran. However, the corresponding reaction with styrene requires a full equivalent of ClSi(CH3)3 and a catalytic amount of SnCl2 for a satisfactory yield. 

Aldol reaction,6 This triflate is an effective catalyst for an aldol-type reaction between silyl enol ethers and acetals at -78°. The reaction shows moderate to high svn-selectivity regardless of the geometry of the enol ether. 

For catalytic asymmetric aldol-type reactions, the transformation of the methylene compounds to a silyl enolate or a silyl ketene acetal was at one time necessary. Recently, the aldol reaction of aldehydes with non-modified ketones was realized by use of the lanthanum-Li3-trisf(/ )-bi-naphthoxidej catalyst 22 [18]. According to the proposed catalytic cycle, after abstraction of an a-proton from the ketone, the reaction between the lithium-enolate complex and the aldehyde... 

Aldol-type reactions. Trityl perchlorate catalyzes an aldol-type reaction between silyl enol ethers and acetals or ketals to give p-alkoxy ketones. The yields are comparable to those obtained with TiCU (6, 594). The iyn-aldol is formed predominantly ( 4 1). 

This condensation is essentially an aldol-type reaction of an aldehyde with the methylene group of an anhydride. The sodium salt may be replaced by other basic catalysts such as potassium carbonate oi tertiary amines. If the acid residue in the anhydride is not the same as that in the sodium salt, an equilibrium between these substances may occur before condensation. Thus, a mixture of acetic anhydride and sodium butyrate or a mixture of butyric anhydride and sodium acetate gives cinnamic acid and a-ethylcinnamic acid in the same ratio. ... 

A catalytic asymmetric aldol-type reaction of ketene silyl acetals with achiral aldehydes also proceeds with the CAB catalyst (2), which can furnish syn-p-hydroxy esters with high enantioselectivity (eq 6). 

Ruthenium hydride-catalyzed carbon-carbon double bond migration is applicable to isomerization of allylic acetals and ketals 31 to vinylic ones 32, which undergo selective cross-aldol type reaction by treatment with Bp3-Et20 to yield 33 (Eq. 12.12) [18]. 

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). 

Yamamoto and co-workers found that 27 is an excellent chiral promoter not only for the aza Diels-Alder reaction of aldimines [40] but also for the stereoselective aldol-type reaction of aldimines with ketene silyl acetals [55]. The reaction of (5)-benzyli-dene a-methylbenzylamine with trimethylsilyl ketene acetal derived from terf-butyl acetate in the presence of (R)-27 produces the (R) adduct in > 92 % diastereomeric excess (de), whereas reaction with (5)-27 gives the adduct in 74 % de. In a similar way, (5)-butylidene a-methylbenzylamine, an aliphatic imine, can be converted to the (R)-)3-amino ester in 94 % de by use of (R)-27 (Eq. 73). 

BLA 28 is very useful in the double stereodifferentiation of aldol-type reactions of chiral imines [41], Reaction of (5)-benzylidene-a-methylbenzylamine with trimethyl-silyl ketene acetal derived from tert-butyl acetate in the presence of (R)-28 at -78 °C for 12 h provides the corresponding aldol-type adduct in 94 % de (Eq. 78). Including phenol in the reaction mixture does not influence the reactivity or the diastereoselec-tivity. The aldol-type reaction using yellow crystals of (R)-28.(5)-benzylidene-a-methylbenzylamine PhOH proceeds with unprecedented (> 99.5 0.5) diastereoselec-tivity (Eq. 79). In general, 28 is a more efficient chiral Lewis acid promoter than 27. 

On the basis of these results, we have developed the first method for the enantiose-lective synthesis of chiral /3-amino acid esters from achiral imines and ketene silyl acetals using BLA 28. The enantioselectivity of the aldol-type reaction is dramatically increased by using sterically bulky A-substituents. Condensation of the imine derived from benzhydrylamine occurs with high enantioselectivity (90 % ee) (Eq. 80). Furthermore, the best result (96 % ee) is achieved by use of a 1 1 (v/v) mixture of toluene and dichloromethane as solvents. Thus, excellent enantioselectivity (95 % ee or better) has been achieved in reactions of aromatic aldehyde-derived imines... 

Soloshonok and Hayashi applied chiral ferrocenylphosphine-gold(I) complexes to asymmetric aldol-type reactions of fluorinated benzaldehydes with methyl isocyano-acetate (27) and A, A/-dimethyl-a-isocyanoacetamide (95). It is noteworthy that successive substitution of hydrogen atoms by fluorine in the phenyl ring of benzaldehyde causes gradual increase of both the cis selectivity and the ee of cw-oxazolines [53]. 

Several examples of Sc(OTf)3-catalyzed aldol reactions of silyl enolates with aldehydes were been examined. Silyl enolates derived from ketones, thioesters, and esters reacted smoothly with different types of aldehyde in the presence of 5 mol % Sc(OTf)3 to afford the aldol adducts in high yields. Sc(OTf)3 was also found to be an effective catalyst in aldol-type reactions of silyl enolates with acetals. The reactions proceeded smoothly at -78 °C or room temperature to give the corresponding aldol-typc adducts in high )delds without side-reaction products. It should be noted that aldehydes were more reactive than acetals. For example, while 3-phenylpropionalde-hyde reacted with the ketene silyl acetal of methyl isobutyrate at -78 °C to give the aldol adduct in 80 % yield, no aldol-type adduct was obtained at -78 °C in the reaction of the same ketene silyl acetal with 3-phenylpropionaldehyde dimethyl acetal. The acetal reacted with the ketene silyl acetal at 0 °C to room temperature to give the... 

Aldol-type reactions of PSSEEs with acetals have been successfully performed using Sc(OTf)3 as a catalyst (Eq. 24) [88]. The reactions were performed at room temperature and the adducts were cleaved from the polymer supports by use of LiBH4 to give 1,3-dioI monoethers. The SR-MAS NMR technique was also us JKhh effect in the development the reactions. l. NaOMe/MeOH-THF n i... 

Another possibility to obtain thioamides from thioamides is via electrophilic attack in the a-position (Scheme 6). Thus, aldol-type reactions are feasible and proceed with high erythro selectivity providing (30), or even allowing optically active products (c/. Volume 2, Chapter 1.6). Heating with a form-amide 0,V-acetal gives an a,3-unsaturated thioamide (31) in a sequence of electrophilic attack and elimination. ... 

For benzoic acid acceleration in Yb(OTf)3-catalyzed allylation of aldehydes in acetonitrile, (a) As-pinall, H.C. Greeves, N. Mclver, E. G. Tetrahedron Lett. 1998, 39, 9283. For acetic acid acceleration in Yb(fod)3-catalyzed ene reaction of aldehydes with alkyl vinyl ethers, ene reaction of aldehydes with alkyl vinyl ethers, (b) Deaton, M. V. Ciufolini, M.A. Tetrahedron Lett. 1993, 34, 2409. Yamamoto et al. reported Brpnsted acid-assisted chiral Lewis acids and Lewis acid-assisted Brpnsted acids which were used for catalytic asymmetric Diels-Alder reactions and protonations and stoichiometric asymmetric aza Diels-Alder reactions, aldol-type reactions of imines, and an aldol reaction, (c) Ishihara, K. Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 1561. (d) Ishihara, K. Kurihara, H. Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 3049. (e) Ishihara, K. Nakamura, S. Kaneeda, M. Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854. (f) Ishihara, K. Miyata, M. Hattori, K. Tada, T. Yamamoto, H. J. Am. Chem. Sc c. 1994, 116, 10520. (g) Yamamoto, H. J. Am. Chem. Soc 1994, 116, 10520. (h) ishihara, K. Kurihara, H. Matsumoto, M. Yamamoto Ishihara, K. Kurihara, H. Matsumoto, M. Yamamoto, H. J. Am. Chem. Soc 1998, 120, 6920. 

The original methods for directed aldol and aldol-type reactions of aldehydes and acetals with silyl enolates required a stoichiometric amount of a Lewis acid such as TiCh, Bl i-OI y, or SnCl.j [18]. Later studies have introduced many Lewis acids which accelerate these processes with a catalytic quantity (vide infra). In addition, it has been found that fluoride ion sources also work as effective catalysts of the aldol reaction [19]. In the last decade, much attention has been paid for the development of diastereo- and enantioselective aldol reactions [20, 21], aqueous aldol reactions using water-stable Lewis acids [22], and novel types of silyl enolate with unique reactivity. 

SbF6)2 [61], and an oxovanadium(IV) complex [62] are effective catalysts. Matsuda et al. recenfly reported that a cationic Ir complex generated in situ from [Ir(COD) (PPh3)2]OTf and H2 catalyzes aldol and aldol-type reactions of aldehydes and acetals with silyl enolates in CH2CI2 [63]. 

Kobayashi et al. have reported fhat Sc(OTf)3 works as an effective and reusable Lewis acid catalyst of fhe aldol and aldol-type reactions of aldehydes and acetals wifh silyl enolates in CH2CI2 [69]. The activities of Sc(OTf) ), and ofher rare earth triflates (Y(OTf)3 and Yl)(() l f) () were evaluated in the reaction of cyclohexanone TMS enolate wifh benzaldehyde (Scheme 10.21). The results clearly indicate that Sc(OTf)3 is more active fhan Y(OTf)3 and Yb(OTf)3. 

Chiral auxiliary-bound substrates have also been used for the asymmetric process. The aldol reaction of chiral pyruvates such as 46 is a reliable method for highly enantioselective synthesis of functionalized tertiary alcohols (Scheme 10.38) [112]. The Lewis acid-catalyzed aldol-type reactions of chiral acetals with silyl enolates are valuable for the asymmetric synthesis of -alkoxy carbonyl compounds ]113, 114]. 

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]. 

Unexpectedly, the trienyl silyl ketene acetal (122) reacts with p-dimethylaminobenzoyl chloride and zinc bromide at the a-position to give the ester (123) as the only isolable product.It is not known at this time whether such a-selectivity is general for other aldol-type reactions of (122) or limited to acylations. ... 

Although the development of a range of catalytic asymmetric aldol-type reactions has proven to be a valuable contribution to asymmetric synthesis [35—37], in all of these reactions pre-conversion of the ketone moiety to a more reactive species such as an enol silyl ether, enol methyl ether, or ketene silyl acetal has been an unavoidable necessity. However, quite recently Shibasaki et al. reported that a direct catalytic asymmetric aldol reaction, which is known in enzyme chemistry, is also possible in the presence of heterobimetallic lanthanoid catalysts [38]. Using fR)-LLB (20 mol%), which shows both Lewis acidity and Bron-sted basicity similar to the corresponding aldolases, the desired optically active aldol adducts were obtained with up to 94% ee. A variety of aldehydes and unmodified ketones can be used as starting materials (Scheme 11). 

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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