Aldol chiral Lewis bases

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. 

Boron enolates bearing menthol-derived chiral ligands have been found to exhibit excellent diastereo- and enantio-control on reaction with aldehydes34 and imines.35 Highly diastereo- and enantio-selective aldol additions of geometrically defined trichlorosilyl ketone enolates (31) and (32) have been achieved by promoting the reactions with chiral Lewis bases, of which (,S., S )-(33) proved to be the most effective.36 Moderate enantiomeric excesses have been achieved by using chiral ammo alcohols as catalysts for the Baylis-Hillman condensation of aldehydes with methyl vinyl ketone the unexpected pressure effect on the reaction has been rationalized.37... 

Modern Aldol Reactions contains several pertinent reviews (i) catalytic enantiose-lective aldols with chiral Lewis bases 97 (ii) the aldol-Tishchenko reaction 98 (iii) titanium—enolate aldols 99 (iv) crossed aldols mediated by boron and silicon enolates 100 (v) amine-catalysed aldols 101 and (vi) aldols catalysed by antibodies.102... 

Ester Enolate Aldol Additions to Aldehydes. Among the first examples of aldol additions employing chiral Lewis bases as catalysts were the additions of trichlorosilyl ketene acetals to aldehydes. Silyl ketene acetal 7 could be generated by metathesis of methyl tributylstannylacetate with SiCL. Treatment of 7 with benzaldehyde and 10 mol % of a phosphoramide in CH2CI2 at —78°C afforded aldol products in good to high yields with moderate enantioselectivities for all phosphoramides employed. Reaction of 7 with pivalaldehyde provided aldol products in similar yields and with slightly improved enantioselectivities. The increase in stereoselection is presumably attributed to a less com-... 

In recent years the synthetic potential and mechanistic aspects of asymmetric catalysis with chiral Lewis base have been investigated. Aldol addition reactions between trichlorosilyl enolates with aldehydes have been also intensively studied. Now, full investigations of the trichlorosilyl enolates derived from achiral and chiral methyl ketones, in both uncatalysed and catalysed reactions with chiral and achiral aldehyde acceptors have been reported. The aldol addition is dramatically accelerated by the addition of chiral phosphoramides, particularly (137) and proceed with good to high enantioselectivity with achiral enolates and aldehydes (Scheme 34). ... 

The first catalytic, diastereoselective and enantioselective cross-aldol reactions of aldehydes have also been documented. Geometrically defined trichlorosilyl enolate derivatives of aldehydes undergo diastereoselective addition to a wide range of aldehyde acceptors with good enantioselectivity. The use of chiral Lewis base (138) was critical for achieving useful enantioselectivity. ... 

Denmark, S. E., Stavenger, R. A. Asymmetric Catalysis of Aldol Reactions with Chiral Lewis Bases. Acc. Chem. Res. 2000, 33, 432-440. 

Denmark et al. used non-linear effects to identify a higher order molecularity of the catalyst with respect to substrate in one of the pathways for a chiral Lewis base-catalyzed aldol addition reaction [60]. The reaction generates mainly a syn or an anti aldol, according to the catalysts used (A or B, Scheme 9). It was proposed that the formation of the anfi-adduct involved two molecules of a chiral phosphoramide A (the catalyst) bound to a cationic sihcon intermediate. In contrast, only one molecule of the more bulky catalyst B can bind to silicon, favoring the formation of the syw-adduct. This interpretation is in agreement with the NLE curve observed for catalyst A and the linear behavior observed with catalyst B. 

Trichlorosilyl triflate and a chiral Lewis base catalyse direct aldols in high de and... 

Demnark SE, Stavenger RA (2000) Asymmetric catalysis of aldol reactions with chiral lewis bases. Ace Chem Res 33 432-440... 

Demnark SE, Fujimori S (2004) Catalytic, enantioselective aldol reactions with chiral lewis bases. In Mahrwald R (ed) Modem aldol reactions. Wiley-VCH, Weinheim... 

Denmark SE, Pham SM (2000) Kinetic analysis of the divergence of reaction pathways in the chiral lewis base promoted aldol addition of trichlorosilyl enolates a rapid injection NMR study. Helv Chim Acta 83 1846-1853... 

The concept of Lewis base activation of Lewis acids was developed by Denmark, and it takes advantage of the fact that the Lewis acidity of silicon is increased when the coordination sphere is enlarged. If chiral Lewis bases are provided, here chiral phosphoramides and bisphosphoramide, SiCl can be efficiently employed in asymmetric Mukaiyama aldol reactions. The Lewis base activation can be performed on trichlorosilyl enolates (24), which can be generated in situ by mercury-mediated trans-silylalion of a TMS silyl enol ether (18) in the presence of SiCl. Generation of the hypervalent silicon species produces a more Lewis acidic silicon moiety, which acts to coordinate and activate the aldehyde that has to be brought to reaction (Scheme 2.128) [48]. 

Accounts of Chemical Research, 33, 432 (b) Denmark, S.E., Fujimori, S. (2004) Catalytic enan-tioselective aldol additions with Chiral Lewis bases, in Modem Aldol Reactions, (ed. R. Mahrwald), Wiley-VCH, Weinheim, Germany, Vol. 2, Chap. 7, p. 229. 

This class of chiral Lewis base catalysts was also applicable to the enantioselective aldol reactions of trichlorosilyl enol ethers (Scheme 7.14) [24, 25). As included in Scheme 7.14, Denmark devised chiral bipyridine N.N -dioxide 8 and demonstrated that it smoothly catalyzed the aldol addition of methyl acetate-derived trichlorosilyl ketene acetal to a series of ketones with good to high enantioselectivi-ties [25],... 

The potential of 9 as a chiral Lewis base catalyst was further demonstrated by application to the aldol reaction of trichlorosilyl enol ethers of ketones with aldehydes, which proceeded with high diastereo- and enantioselectivity [32], The observed stereospecificity suggested the intervention of a six-membered cyclic transition state (Scheme 7.17). Notably, enoHzation of cyclohexanone derivatives and aliphatic aldehydes appeared feasible by SiCLt with the assistance of amine base and 9, leading to the estabhshment of a new protocol for direct aldol-type reactions between ketones and aldehydes or two aldehydes (Scheme 7.18) [33]. 

With the current emphasis on enantioselective synthesis, it is not surprising that numerous, highly successful asymmetric versions of aldol reaction have been developed. Noncatalytic methods involve the use of stoichiometric amounts of a chiral auxiliary in diastereoselective aldol reactions. Small-molecule-catalyzed aldol reactions typically would involve the use of a chiral Lewis acid for aldehyde activation or a chiral Lewis base for donor... 

The asymmetric catalysis of aldol reactions with chiral Lewis bases is an important method to form C-C bonds [130-139], The emergence of Lewis base-activated Lewis acid catalysis is pioneered by the Denmark group [140-142], They used a variety of chiral phosphoramides as catalysts for the enantioselective intermolecular aldol reactions (Scheme 7,20),... 

Summary of the Relationship between Diastereoselectivity and the Transition Structure. In this section we considered simple diastereoselection in aldol reactions of ketone enolates. Numerous observations on the reactions of enolates of ketones and related compounds are consistent with the general concept of a chairlike TS.35 These reactions show a consistent E - anti Z - syn relationship. Noncyclic TSs have more variable diastereoselectivity. The prediction or interpretation of the specific ratio of syn and anti product from any given reaction requires assessment of several variables (1) What is the stereochemical composition of the enolate (2) Does the Lewis acid promote tight coordination with both the carbonyl and enolate oxygen atoms and thereby favor a cyclic TS (3) Does the TS have a chairlike conformation (4) Are there additional Lewis base coordination sites in either reactant that can lead to reaction through a chelated TS Another factor comes into play if either the aldehyde or the enolate, or both, are chiral. In that case, facial selectivity becomes an issue and this is considered in Section 2.1.5. 

Recently, novel bifunctionalized zinc catalysts have been developed (compounds (N) and (P), Scheme 55). They have both Lewis-acid and Lewis-base centers in their complexes, and show remarkable catalytic activity in direct aldol reactions.233-236 A Zn11 chiral diamine complex effectively catalyzes Mannich-type reactions of acylhydrazones in aqueous media to afford the corresponding adducts in high yields and selectivities (Scheme 56).237 This is the first example of catalytic asymmetric Mannich-type reactions in aqueous media, and it is remarkable that this chiral Zn11 complex is stable in aqueous media. 

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. 

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. 

In the following a few examples of the asymmetric aldol reaction are given. Silyl enol ethers (0-Si) resemble very much allylsilanes (C-Si) in terms of structure and mode of action. That is why Lewis base catalyzed aldol reactions of silyl enol ethers have been extensively studied. The first example of Lewis base catalyzed asymmetric aldol reaction of trichlorosilyl enol ether with chiral phosphoramide [80-91] was reported by Denmark et al. (Scheme 24). 

Next to the above presented use of SiCl for the in situ preparation of a Lewis acid catalyst with a Lewis base for the aldol reaction, it is possible to apply this compound as a reagent in the ring opening of epoxides leading to chlorinated alcohols. Denmark [104] reported that the chiral phosphoramide 38 catalyzed the asymmetric ring opening reaction of meso-epoxides in the presence of tetrachlo-rosilane. Similar examples were provided by Hashimoto in 2002 [105], applying the A -oxide 39 as catalyst (Scheme 30). 

Asymmetric aldol additions of geometrically defined trichlorosilyl enolates of ketones to aliphatic and aromatic aldehydes have been carried out uncatalysed, and with a chiral phosphoramide as Lewis base promoter.54 Significant differences in rates and diastereoselectivities are interpreted in terms of the changeover from a boat-like transition state, with pentacoordinate siliconate, to a chair-like transition state with hexacoordination. 

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. 

The basic principles of the mechanism of this Lewis-base-catalyzed aldol reaction have already been described in Section 6.2.1.1. With regard to the course of the enantio- and diastereoselective formation of aldol adducts with two stereogenic centers, it is proposed that synthesis of anti-products proceeds via a chair-like transition structure. A distinctive feature of the cationic transition state complex is a hexacoordinated silicon atom bearing two chiral phosphoramide molecules as ligands (Scheme 6.30). 

Regio-, enantio-, and diastereo-selective vinylogous aldol additions of silyl dienol ethers to aldehydes use a Lewis base (a chiral bis-BINAP-phosphoramide) to activate a Lewis acid (silicon tetrachloride).139... 

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