Aldol reaction chiral Lewis acids

The stereogenic centers may be integral parts of the reactants, but chiral auxiliaries can also be used to impart facial diastereoselectivity and permit eventual isolation of enantiomerically enriched product. Alternatively, use of chiral Lewis acids as catalysts can also achieve facial selectivity. Although the general principles of control of the stereochemistry of aldol addition reactions have been well developed for simple molecules, the application of the principles to more complex molecules and the... 

Scheme 2.8 gives some examples of chiral Lewis acids that have been used to catalyze aldol and Mukaiyama reactions. 

Chiral boron Lewis-acid complexes have been successfully used in Diels-Alder and aldol reactions. Representative chiral Lewis-acidic boron compounds are shown in Figure 2.297-301... 

A lead(II) triflate-crown ether complex functions as a chiral Lewis-acid catalyst for asymmetric aldol reactions in aqueous media (Scheme 86).352 This is the first example of a chiral crown-based Lewis acid that can be successfully used in catalytic asymmetric reactions. 

Annual Volume 71 contains 30 checked and edited experimental procedures that illustrate important new synthetic methods or describe the preparation of particularly useful chemicals. This compilation begins with procedures exemplifying three important methods for preparing enantiomerically pure substances by asymmetric catalysis. The preparation of (R)-(-)-METHYL 3-HYDROXYBUTANOATE details the convenient preparation of a BINAP-ruthenium catalyst that is broadly useful for the asymmetric reduction of p-ketoesters. Catalysis of the carbonyl ene reaction by a chiral Lewis acid, in this case a binapthol-derived titanium catalyst, is illustrated in the preparation of METHYL (2R)-2-HYDROXY-4-PHENYL-4-PENTENOATE. The enantiomerically pure diamines, (1 R,2R)-(+)- AND (1S,2S)-(-)-1,2-DIPHENYL-1,2-ETHYLENEDIAMINE, are useful for a variety of asymmetric transformations hydrogenations, Michael additions, osmylations, epoxidations, allylations, aldol condensations and Diels-Alder reactions. Promotion of the Diels-Alder reaction with a diaminoalane derived from the (S,S)-diamine is demonstrated in the synthesis of (1S,endo)-3-(BICYCLO[2.2.1]HEPT-5-EN-2-YLCARBONYL)-2-OXAZOLIDINONE. 

Asymmetric Aldol Reactions Catalyzed by Chiral Lewis Acids... 

The aldol reaction between enolsilanes and aldehydes mediated by chiral Lewis acids may be considered the most notable achievement in the area of asymmetric aldol reactions. However, the design of new catalyst systems to tolerate... 

Several other chiral Lewis acids have also been reported to effect asymmetric aldol reactions. Kruger and Carreira59 reported a catalytic aldol addition of silyl dienolate to a range of aldehydes in the presence of a bisphosphanyl-Cu(II) fluoride complex generated in situ from (iS )-Tol-BINAP, Cu(OTf)2, and (Bu4N)Ph3SiF2. Aromatic, heteroaromatic, and a,/ -unsaturated aldehydes provided the aldol adducts with up to 95% ee and 98% yield (Scheme 3-33). 

This chapter will begin with a discussion of the role of chiral copper(I) and (II) complexes in group-transfer processes with an emphasis on alkene cyclo-propanation and aziridination. This discussion will be followed by a survey of enantioselective variants of the Kharasch-Sosnovsky reaction, an allylic oxidation process. Section II will review the extensive efforts that have been directed toward the development of enantioselective, Cu(I) catalyzed conjugate addition reactions and related processes. The discussion will finish with a survey of the recent advances that have been achieved by the use of cationic, chiral Cu(II) complexes as chiral Lewis acids for the catalysis of cycloaddition, aldol, Michael, and ene reactions. 

The addition of an enolsilane to an aldehyde, commonly referred to as the Mukaiyama aldol reaction, is readily promoted by Lewis acids and has been the subject of intense interest in the field of chiral Lewis acid catalysis. Copper-based Lewis acids have been applied to this process in an attempt to generate polyacetate and polypropionate synthons for natural product synthesis. Although the considerable Lewis acidity of many of these complexes is more than sufficient to activate a broad range of aldehydes, high selectivities have been observed predominantly with substrates capable of two-point coordination to the metal. Of these, benzy-loxyacetaldehyde and pyruvate esters have been most successful. 

Denmark utilized chiral base promoted hypervalent silicon Lewis acids for several highly enantioselective carbon-carbon bond forming reactions [92-98]. In these reactions, a stoichiometric quantity of silicon tetrachloride as achiral weak Lewis acid component and only catalytic amount of chiral Lewis base were used. The chiral Lewis acid species desired for the transformations was generated in situ. The phosphoramide 35 catalyzed the cross aldolization of aromatic aldehydes as well as aliphatic aldehydes with a silyl ketene acetal (Scheme 26) [93] with good yield and high enantioselectivity and diastereoselectivity. 

Enantioselective condensation of aldehydes and enol silyl ethers is promoted by addition of chiral Lewis acids. Through coordination of aldehyde oxygen to the Lewis acids containing an Al, Eu, or Rh atom (286), the prochiral substrates are endowed with high electrophilicity and chiral environments. Although the optical yields in the early works remained poor to moderate, the use of a chiral (acyloxy)borane complex as catalyst allowed the erythro-selective condensation with high enan-tioselectivity (Scheme 119) (287). This aldol-type reaction may proceed via an extended acyclic transition state rather than a six-membered pericyclic structure (288). Not only ketone enolates but ester enolates... 

Recently, highly enantioselective Mukaiyama-type aldol reactions using a substoichiometric amount of chiral Lewis acid have been reported from three research groups. Mukaiyama et al. 

The mechanism A very detailed mechanistic study of this phosphoramide-catalyzed asymmetric aldol reaction was conducted by the Denmark group (see also Section 6.2.1.2) [59, 60], Mechanistically, the chiral phosphoramide base seems to coordinate temporarily with the silicon atom of the trichlorosilyl enolates, in contrast with previously used chiral Lewis acids, e.g. oxazaborolidines, which interact with the aldehyde. It has been suggested that the hexacoordinate silicate species of type I is involved in stereoselection (Scheme 6.15). Thus, this cationic, diphosphoramide silyl enolate complex reacts through a chair-like transition structure. 

Aldol reactions enjoy great recognition as a useful tool for the synthesis of building blocks in natural product and drug synthesis [42, 182]. The stereochemistry of the stereogenic centers formed can be controlled by various means. Besides chiral auxiliaries, catalytic methods with chiral Lewis acids, organocatalysts, or catalytic antibodies were established for stereochemical control [183-187]. 

Kiyooka S-i (1997) Development of a chiral lewis acid-promoted asymmetric aldol reaction using oxaborolidinone. Rev Heteroatom Chem 17 245-270... 

Catalytic, enantioselective addition of silyl ketene acetals to aldehydes has been carried out using a variant of bifunctional catalysis Lewis base activation of Lewis acids.145 The weakly acidic SiCU has been activated with a strongly basic phor-phoramide (the latter chiral), to form a chiral Lewis acid in situ. It has also been extended to vinylogous aldol reactions of silyl dienol ethers derived from esters. 

Dihydropyran-4-ones are formed with good enantiomeric excess by a chiral Lewis acid catalysed reaction of aldehydes with Danishefsky s diene and cyclisation of the initial aldol product. The overal process equates to a hetero-Diels-Alder cycloaddition (95JOC5998). Lactams also react with the electron rich diene under the influence of a Lewis acid, yielding 7-aza-l-oxaspiroalkenones (95JOC7724). 

Mukaiyama and co-workers developed a chiral Lewis acid complex 15 consisting of tin (II) triflate and a chiral diamine. An aldol reaction of enol silyl ether 16 and octanal is promoted by 15 to give 17 in a highly diastereo-and enantioselective manner. The enantioface of the aldehyde is selectively activated by coordination with 15. This method is similar to method 3, in that an aldehyde-chiral Lewis acid complex can be regarded as a chiral electrophile. An advantage of method 4 over method 3 is the possible catalytic use of a chiral Lewis acid. In the reaction of Scheme 3.6, 20 mol% of 15 effects the aldol reaction in 76% yield with excellent selectivity.9... 

In the Mukaiyama aldol reaction an aldehyde (1) reacts with a silyl enol ether (3) under Lewis-acid catalysis to yield the aldol adduct (4). The use of a chiral Lewis acid (L offers the opportunity to perform the reaction in an a.sym-metric manner (Scheme 1) [5]. 

Scheme 3. Catalytic asymmetric aldol reaction with aluminum- and tin-containing chiral Lewis acids a) Reetz and b) Mukaiyama.

A chiral Lewis acid derived from Sn(OTf)2 and the proline derivative 17 has proven to catalyze the aldol reaction effectively. As Mukaiyama et al. [7J demonstrated, a high degree of enantio-selectivity was achieved (Scheme 3b). 

OMe Scheme 5. Catalytic, asymmetric aldol reaction with titanium containing chiral Lewis acids a) Mikami and b) Carreira. 

C2-Symmetric tridentate bis(oxazolinyl)pyri-dine-Cu(Il) complexes, introduced by Evans et al., can function as effective chiral Lewis acid catalysts in the Diels-Alder reaction [15a]. When applied to catalytic asymmetric aldol reactions [15], remarkable results were achieved (Scheme 8) [15a]. Only 0.5 mol % of catalyst 48 was needed for the reaction of 30 with the silylketene thioacetal 47 to yield after deprotection 49 in 99 % chemical yield. The ee values were determined to be 99 %. Today, catalysts... 

A useful synthetic alternative to the Mukaiyama aldol addition is the carbonyl-ene reaction [17], This reaction of an aldehyde 51 with an enol ether 55, bearing at least one hydrogen atom in the allylic position, under Lewis-acid catalysis, yields a ff-hydroxy-enol ether of type 56 (Scheme 10). By use of a chiral Lewis acid (L ) enantioselectivity can be achieved. For the... 

The remarkable affinity of the silver ion for hahdes can be conveniently applied to accelerate the chiral palladium-catalyzed Heck reaction and other reactions. Enantioselectivity of these reactions is generally increased by addition of silver salts, and hence silver(I) compounds in combination with chiral ligands hold much promise as chiral Lewis acid catalysts for asymmetric synthesis. Employing the BINAP-silver(I) complex (8) as a chiral catalyst, the enantioselective aldol addition of tributyltin enolates (9) to aldehydes (10) has been developed." This catalyst is also effective in the promotion of enantioselective allylation, Mannich, ene, and hetero Diels-Alder reactions. 

As above (eq 1), a major drawback of this reagent is the lack of a readily available enantiomer. There are many alternative methods for the enantioselective propionate aldol reaction. The most versatile chirally modified propionate enolates or equivalents are N-propionyl-2-oxazolidinones, a-siloxy ketones, boron enolates with chiral ligands, as well as tin enolates. Especially rewarding are new chiral Lewis acids for the asymmetric Mukaiyama reaction of 0-silyl ketene acetals. Most of these reactions afford s yw-aldols good methods for the anri-isomers have only become available recently. ... 

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. 

Copper Lewis acids have found many applications in the last decade in a variety of organic transformations and more notably in enantioselective reactions. In particular, Cu(OTf)2 and Cu(SbFg)2 in conjunction with chiral bisoxazolines are the chiral Lewis acids of choice for cycloadditions, aldol reactions, ene reactions, and other selective transformations. Moderately Lewis acidic copper salts are also reagents for transesterifications, dehydrations, and hydrolysis. The thiophilic nature of copper makes them ideal for selective deprotection of thio acetals and thioesters and offer practical advantages over mercury salts. 

The BINAP silver(I) complex can be further applied as a chiral catalyst in the asymmetric aldol reaction. Although numerous successful methods have been developed for catalytic asymmetric aldol reaction, most are the chiral Lewis acid-catalyzed Mukaiyama aldol reactions using silyl enol ethers or ketene silyl acetals [32] and there has been no report which includes enol stannanes. Yanagisawa, Yamamoto, and their colleagues found the first example of catalytic enantioselective aldol addition of tributyltin enolates 74 to aldehydes employing BINAP silver(I) complex as a catalyst (Sch. 19) [33]. 

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