Phosphoramides aldol reaction

Based on the same strategy, Denmark and coworkers developed a vinylogous aldol reaction using enolate activation with a catalyst derived from SiCl4 and dimeric phosphoramide 47 [24,25]. This strategy relies on the observation that not all Lewis acid - Lewis base interactions diminish the Lewis acidity [26-28]. Due to the formation of a pentacoordinated silicon cation (48), both the enolate and the substrate can be assembled in a closed transition state, giving rise to the observed high selectivities (Scheme 19) [29,30]. 

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 phosphoramides, Denmark reported an axially chiral A -oxide to catalyze the asymmetric aldol reaction of trichlorosilyl enol ethers with ketones [99]. Hashimoto reported an aldol reaction with 3 mol% of another axially chiral A -oxide [100] which gave good yields and enantioselectivities. 

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). 

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 using phosphoramides as organocatalysts The organic base-catalyzed asymmetric intermolecular aldol reaction with ketone-derived donors can be successfully applied to the construction of aldol products with two stereogenic centers [82-86]. Trichlorosilyl enolates of type 51 have been used as nucleophiles. Such enolates are strongly activated ketone derivatives and react spontaneously with several aldehydes at —80 °C. A first important result was that in the aldol reaction of 51 catalytic amounts of HMPA led to acceleration of the rate of reaction. After screening several optically active phosphoramides as catalysts in a model reaction the aldol product anti-53 was obtained with a diastereomeric... 

The Denmark phosphoramide organocatalyst has recently been applied in the first catalytic, diastereoselective, and enantioselective crossed-aldol reaction of aldehydes [86]. It is worthy of note that such controlled stereoselective selfcondensation of aldehydes has previously found no general application, because of many side-reactions, e.g. polyaldolization, and dehydration of the products. Several previously developed solutions have limitations. In a first step the Denmark group developed a procedure for generation of stereodefined trichlorosilyl enolates of aldehydes with high geometrical purity. Use of these geometrically pure (Z) and... 

The phosphoramide-catalyzed cross-aldol reaction tolerates a broad variety of... 

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). 

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-... 

Denmark further applied this concept of chiral diamine-derived phosphoramide bases to catalytic diastereo- and enantioselective aldol reactions (Sch. 60) [103] and enantioselective ring opening of epoxides (Sch. 61) [104]. For instance, catalytic 84 effectively promotes aldol coupling of aldehydes and enoxytrichlorosilane at -78 °C with predominant formation of anti or syn aldols from ( )- or (Z)-enolates, respee-tively. 

On the basis of NLE studies coupled with kinetic analyses, Denmark has disclosed that the mechanism of the rate acceleration by chiral phosphoramides in asymmetric aldol reactions of trichlorosilyl enolates with aldehydes stemmed from the ionization of the enolate by the basic phosphoramides (Eq. (7.8)) [26]. Steri-cally demanding phosphoramides (R=Ph) exhibit a linear relationship, through binding to the enolate in a 1 1 fashion and the resulting pentacoordinated cationic siliconate. In contrast, sterically less demanding pho.sphoramides (R=Me) with (-e)-NLE can bind in a 2 1 fashion to result in the hexacoordinated cationic. siliconate. 

This concept of Lewis base catalysis has been widely developed by Denmark and coworkers in the asymmetric aldol additions of trichlorosilyl enolates on aldehydes. These reactions were shown to be highly susceptible to acceleration by catalytic quantities of chiral phosphoramides [69-77]. In particular, a phos-phoramide derived from (S,S)-stilbenediamine was remarkably effective not only in accelerating the reaction but also in modulating the diastereoselectivity and in providing the aldol addition products in good to excellent enantioselec-tivity. For example, trichlorosilyl enolate 61 reacts with benzaldehyde in very high enantio- and diastereoselectivity with 10 mol% of phosphoramide 62 in favor of the anti diastereomer (antifsyn 60/1). The catalyzed aldol reaction depends on the bulkiness and loading of the catalyst. On the other hand, the hindered phosphoramide (S,S)-63 afforded the syn aldol product in excellent diastereoselectivity (anti syn 1/97) but with modest enantioselectivity. 

The formation of 64 using catalyst (S,S)-62 exhibits a positive nonlinear effect, fitting well with Kagan s two ligand model [78] whereas the more hindered catalyst (S,S)-63 led to a perfect linear asymmetric induction suggesting that the product arose from a transition structure involving only one chiral phosphoramide. The kinetic study of this aldol reaction is in accordance with these re-... 

Chiral phosphoramides, particularly C2-symmetric examples, are widely used in asymmetric synthesis (see section 3.2). One example is the asymmetric catalysis of Aldol reactions, where the phosphoramide catalyst is used in combination with a Lewis base. A solid state and solution study of the structure of chiral phosphoramide-tin complexes used in such reactions has now been reported. A number of chiral, non-racemic cyclic phosphoramide receptors (387) have been synthesised and their interactions with homochiral amines studied using electrospray ionisation MS. Although (387) bind the amines strongly, no evidence of chiral selectivity was found. Evidence from a combination of its X-ray structure, NMR, and ab initio calculations suggests that the cyclen phosphorus oxide (388) has an N-P transannular interaction in the solid state. A series of isomers of l,3,2-oxazaphosphorino[4,3-a]isoquinolines(389), containing a novel ring-system, have been prepared and their stereochemistry and conformation studied by H, C, and P NMR spectroscopy and X-ray crystallography... 

Phosphoramide ligands represei lation and aldol reaction. Their pref Aldol reaction with L-proline as crating anri-diols. Transition state catalyzed by Et2Zn-PhjPS in the p dazolidinones serve as chiral aux zolidinones. In employing 4-/-but equiv of a base leads to syn product... 

Phosphoramide ligands represented by 47 are valuable for Lewis base-catalyzed ally-lation and aldol reaction. Their preparations are detailed. ... 

Trichlorosilyl enol ethers. The reaction of tributylstannyl enol ethers with SiCl results in trichlorosilyl analogs that are highly reactive as donors in aldol reactions without catalysts. Asymmetric synthesis in the presence of chiral phosphoramides is realized. 

An alternate strategy for catalysing the aldol reaction is by the use of Lewis bases that activate the donor. Denmark and coworkers have applied phosphoramide... 

Chiral AT-oxides have also been employed as catalysts to promote aldol reactions but their true potential remains to be realised. Catalysis by N-oxides follows the same general trends that were established for the phosphoramide activators, though with reduced enantioselectivity. Thus, Nakajima has demonstrated that the reaction of aldehydes 21.4 with silyl enol ethers 21.97, catalysed by bidentate bis-iV-oxides 21.17 and 21.105 [3 mol% of the catalyst, 1 equivalent of (z-Pr2)NEt, dichloromethane, -78 °C], proceeds via a chair-like transition state 21.98, resulting in high diastereoselectivity and moderate-to-good enantioselectivity (<82% ee). On the other hand, aldol reaction of cyclic silyl enol ethers of type 21.97e with aromatic aldehydes, catalysed by bulky mono-oxides 21.27 and 21.106, displayed syn-selectivity, consistent with participation of the boat-like transition state 21.101. The enantioselectivity remained rather modest in the latter case (up to 72% enantiomeric excess). ... 

With the synergistic effect of Lewis base and Lewis acid, Denmark and coworkers have established several successful organic catalyst systems based on the strategy of Lewis acid activated Lewis base or Lewis base activation of Lewis acid, in which chiral phosphoramides expressed excellent diastereo- and stereoselectivity for the aldol reaction of silyl enolates and aldehydes (Scheme 65) (311-313). 

Scheme 7.37 Domino intramolecular hydrosilojgrlation-Mukaiyama aldol reaction catalysed by chiral phosphoramide catalysis and gold catalysis.

Denmark SE, Bui T (2004) Chiral phosphoramide-catalyzed, enantioselective, directed cross-aldol reactions of aldehydes. Proc Natl Acad Sd USA 101 5439-5444... 

Since 1973, many Lewis acid-catalyzed aldol reactions have been studied, as described above. There have, however, been few examples of Lewis base-catalyzed aldol reaction using special silyl enolates, e.g. phosphoramide-catalyzed aldol reactions of trichlorosilyl enolates 69 (Eq. (36)) [47] and CaCh-catalyzed reactions of dimethylsilyl enolates 72 in aqueous DMF (Eq. (37)) [56]. 

After the first reports of the above-mentioned highly eflident catalytic enantioselective aldol reaction, some groups independently reported catalytic symmetric aldol reactions of silicon enolates vith aldehydes using chiral boron [72], titanium [73], zirconium [74], and copper Le vis acids [75], or by transmetalation to chiral Pd(II) enolates [44]. Chiral phosphoramide-promoted aldol reactions of trichlorosilyl enol ethers have been reported as Le vis base-catalyzed asymmetric aldol reactions [76]. 

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]. 

In 1996, Denmark introduced chiral phosphoramide 1, which could be readily synthesized from the parent commercially available (R)-2,2 -diamino-l,l-binaphthalene, as an effective catalyst for the aldol reaction of the preformed trichlorosilyl enol ether of methyl acetate with aldehydes under mild conditions (Scheme 7.1) (2). 

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