Imines chiral silyl ketene acetals

Diastereoselective Additions of Chiral Silyl Ketene Acetals to Imines... 

Chiral silyl ketene acetals derived from (lS,2/ )-yV-methylephedrine (168), known to exhibit high levels of syn-anti and diastereofacial selectivities in the aldol condensation, have been used by Gennari et al. in TiCU-mediated imine condensations for the asymmetric synthesis of 3-lactams (Scheme 34) 32. 33 p.j mino esters (169) are produced in these reactions, and are characterized by their sub-... 

Table V. Ratio of Diastereoisomers in the TiCl4 Mediated Reaction of Chiral Silyl Ketene Acetals with Imines. > ...

Scheme 27 Addition of nitronates, enolates and silyl ketene acetals to chiral a-amino imines and iminium ions...

A titanium catalyst 20 that incorporates binaphthyl chirality along with imine and phenolic (salen) donors is highly active in addition of silyl ketene acetals to aldehydes.160... 

TiCl, on the silyl ketene acetal however, other data suggest that metal enolates may not be involved (73b). In subsequent studies, this reaction has been extended to chiral imines (81,82). 

Since then, efficient catalytic asymmetric methods have been developed for the addition of silyl enol ethers or silyl ketene acetals to imines with chiral metal catalysts [29-34], Recently, direct catalytic asymmetric Mannich reactions which do not require preformation of enolate equivalents have appeared. 

Fu has demonstrated that acetate anion attack on the silicon center of the silyl ketene acetal, as well as formation of an acyl pyridinium salt, contribute towards the promotion of these reactions [62]. Additionally, silyl ketene imines have also been shown to participate in analogous asymmetric C-acylation reactions to yield chiral quaternary nitriles, and this method was employed as a key step in the synthesis of verapamil [65]. 

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. 

Asymmetric Mannich-type reactions provide useful routes for the synthesis of enantiomerically enriched P-amino ketones or esters [48a, 48b]. For the most part, these methods involve the use of chirally modified enolates or imines. Only a handful of examples has been reported on the reaction of imines with enolates of carboxylic acid derivatives or silyl ketene acetals in the presence of a stoichiometric amount of a chiral controller [49a, 49b, 49c]. Reports describing the use of a substoichiometric amount of the chiral agent are even more scarce. This section contains some of the most recent advances in the field of catalytic enantioselective additions of lithium enolates and silyl enol ethers of esters and ketones to imines. 

Largely stimulated by the synthesis of 3-lactam antibiotics, there have been widespread investigations into the stereochemical aspects of imine condensations, mainly involving reactions of enolates of carboxylic acid derivatives or silyl ketene acetals. In analogy to the aldol condensation, stereoselectivity of imine condensations will be discussed in terms of two types in this chapter (i) simple dia-stereoselectivity or syn-anti selectivity, when the two reactants are each prochiral (equation 12) and (ii) diastereofacial selectivity, when a new chiral center is formed in the presence of a pre-existing chiral center in one of the reactants (e.g. equation 13). The term asymmetric induction may be used synonymously with diastereofacial selectivity when one of the chiral reactants is optically active. For a more explicit explanation of these terms, see Heathcock s review on the aldol condensation. ... 

Acylhydrazones, R CH=N-NHCOR , undergo stereoselective Mannich reactions with silyl ketene acetals to give j8-hydrazido esters, using activation by a chiral silicon Lewis acid. Alternatively, the use of silyl ketene imine gives a /3-hydrazido nitrile. Enantioselective (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) hydrazone alkylation of aldehydes and ketones is the subject of a computational study, providing a useful screening method for possible new candidates. " ... 

A chiral boron reagent, derived from equimolar amounts of (R)-or (5)-binaphthol and triphenyl borate, promotes the condensation of chiral imines with t-butyl acetate silyl ketene acetal in high diastereomeric excess (eq 12). ... 

TiCU-mediated additions of silyl ketene acetal (98) to chiral imines (99) and (100) (R = Et, Pr", Bu", Bu ) are described in equations (33) and (34) good diastereoisomeric ratios were obtained using imines (100), derived from (S)-valine methyl ester, which form with TiCU the chelated complex (101). Znh-catalyzed additions of acetate-derived silyl ketene acetals to chiral a. -dialkoxy nitrones (102 R = H) were reported to proceed with good yield (86-100%) and high diastereofacial selectivity ca, 90 10) in favor of the anti isomer (103 R = H, R = CHPh , R = Bu ) or of the syn isomer (104 R = H, R = CH2Ph, R- = Me) depending on the steric hindrance of R and (Scheme 8). Addition to nitrone (102 R = Me) gave the anti isomer (103 R Me, R = CHMePh, R = Me) in quantitative yield and 100% diastereofacial selectivity. This material was further elaborated to A/-benzoyl-L-daunosamine (Scheme S). ... 

It must be noted that chiral thiourea catalysts have been used earlier to catalyze the asymmetric Mannich reaction. Jacobsen and Wenzel reported the enantioselective synthesis of A-Boc-protected p-amino acids from silyl ketene acetals and A-Boc-protected imines using the thiourea catalyst 123 (Scheme 11.24). Here, the chiral thiourea-derived Brpnsted acid catalyst (the application of chiral Brpnsted acids in the... 

As outlined in the previous paragraph, chiral Brpnsted base organocatalysts appear to be most effective when equipped with an additional Brpnsted acidic moiety, for example, hydrogen bond donors like (thio)urea. Apparently, both functionalities catalyze the asymmetric Mannich reaction in a cooperative fashion, that is, simultaneous activation of both the nucleophile and the electrophile. However, activation of the electrophile can also be accomplished with a single, enantiomerically pure Brpnsted acid. In this respect, readily available chiral phosphoric acids are most commonly applied [88-90]. In 2004, the groups of Akiyama and Terada independently from each other reported the first asymmetric Mannich reaction of silyl ketene acetals or acetyl acetone with imines utilizing chiral phosphoric acid catalysts, which... 

The imines 12 (X = 4-CH3-QH4-SO2 (Ts), Ar, C02R, COR, etc.) preformed or generated in situ from N,0- or N,N-acetals or hemiacetals are another important class of Mannich reagents frequently used for diastereo- and/or enantioselective aminoalkylation reactions catalyzed by chiral Lewis acids (usually copper or palladium BINAP complexes such as 13). Among other things excellent results were obtained in the aminoalkylation of silyl enol ethers or ketene acetals [24], A typical example is the synthesis of Mannich bases 14 depicted in Scheme 5 [24b], Because of their comparatively high electrophilicity imines 12 could even be used successfully for the asymmetric aminoalkylation of unactivated alkenes 15 (ene reactions, see Scheme 5) [24h, 25], and the diastereo- and/or enantioselective aminoalkyla-... 

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). 

The chiral-modified binaphthol complex (23) has been prepared (Eq. 10) and shown to be an efficient catalyst for enantioselective Memnich-type reactions [9]. The reaction of imine (24) with ketene silyl acetal in the presence of the catalyst 23 with NMI afforded /3-amino acid derivatives 25 and 26 in high enantioselectivity (Eq. 11). 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones or esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [1-6]. While several diastereoselective Mannich reactions with chiral auxiliaries have been reported, very little is known about enantioselective versions. In 1991, Corey et al. reported the first example of the enantioselective synthesis of p-amino acid esters using chiral boron enolates [7]. Yamamoto et al. disclosed enantioselective reactions of imines with ketene silyl acetals using a Bronsted acid-assisted chiral Lewis acid [8]. In all cases, however, stoichiometric amounts of chiral sources were needed. Asymmetric Mannich reactions using small amounts of chiral sources were not reported before 1997. This chapter presents an overview of catalytic asymmetric Mannich reactions. 

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