Phosphoramides chiral

Allylic trichlorosilanes have shown promise in the development of methods for enantioselective reactions by use of chiral phosphoramides such as C. 

Two patterns are possible in the activation mechanism by simple chiral Lewis base catalysts. One is through the activation of nucleophiles such as aUyltrichlorosilanes or ketene trichlorosilyl acetals via hypervalent silicate formation using organic Lewis bases such as chiral phosphoramides or A-oxides. " In this case, catalysts are pure organic compounds (see Chapter 11). The other is through the activation of nucleophiles by anionic Lewis base conjugated to metals. In this case, transmetal-lation is the key for the nucleophile activation. This type of asymmetric catalysis is the main focus of this section. 

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. 

Stereo specific generation and reactions of allylic alkali and alkaline earth metals have been reviewed121 and solvent-mediated allylation of carbonyl compounds with allylstannanes has been explored.122 Chiral phosphoramides derived from (5 )-proliiie have been used to catalyse asymmetric allylation of aromatic aldehydes by allylic trichlorosilanes.123... 

Chiral phosphoramides have been developed as catalysts for asymmetric addition of allylic trichlorosilanes to aldehydes.176 Although some des were high, ees were modest. Kinetic studies suggest dual mechanisms, and thus a route to the design of more highly selective catalysts. 

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. 

It should be noted that in the absence of the organocatalyst the E enolate affords mainly the syn adduct (syn/anti ratio 49 1, 92% yield, reaction temperature 0 °C [82, 84]) whereas in the presence of (S,S)-52 by dramatic reversal in diastereoselectivity the anti-aldol product anti-53 is preferentially formed (anti/syn ratio 50 1 anti 93% ee) [84], Other types of chiral phosphoramide, e.g. based on optically active 1,2-cyclohexyldiamine, had less satisfactory catalytic properties. 

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). 

Denmark et al. employed the chiral phosphoramide 74 (Scheme 13.37) as nucleophilic activator [75]. As summarized in Scheme 13.37, the best enantiomeric excess was observed for cis-stilbene oxide (87%). The study revealed that enantioselectivity was highly dependent on the ring size (cyclohexene oxide cyclopentene oxide > cyclooctene oxide). 

Denmark introduced an array of efficient chiral phosphoramides as nucleophilic activators (Fig. 7.3) for the enantioselective C-C bond formation, and also carried out a detailed mechanistic investigation [56, 59, 60]. Bidentate (e.g., 60) and smaller monodentate catalysts (58) have been shown by Denmark to react via a cationic chair-like transition state 56 with octahedral extracoordinate silicon (Scheme 7.10). Following this manifold, (Z)-enol ethers 55b and 55c produced syn-adducts 57b and 57c, whereas (E)-derivatives 55a and 55d furnished anti-diastereoisomers 57a and 57d. By contrast, with a bulky monodentate activator (e.g., 59), where coordination of the second catalyst molecule is precluded by steric factors, the reaction exhibits opposite diastereoselectivity, presumably due to the cationic boat-like transition state, where silicon is pentacoordinate. Along this manifold, cyclohexanone-derived enol ether 55d with the fixed (E)-... 

Chiral phosphoramidates attached to polystyrene have also been reported to exhibit asymmetric induction in the allylation of PhCHO with AllylSiCl3 (< 63% ee) Oyama, T., Yoshioka, H., Tomoi, M., Chem. Commun. 2005, 1857. 

The reaction of simple cyclic vinyl aziridines with organozinc reagents typically provides the 1,4-addition product <2003TL8559>. Several binaphthyl phosphoramidate ligands were examined. In all cases, the /ra r-product 159a was the major product. When no catalyst was used a roughly 1 1 mixture of the trans. cis product was obtained. The use of the chiral phosphoramidate catalyst provided 159a with moderate % ee values (Equation 43). 

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). ... 

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. 

Lewis Basic Phosphoramides. In a series of elegant investigations, Denmark has documented an aldol process that utilizes trichlorosilyl enolates such as 101 and 105 in catalytic, enantioselective addition reactions (Eqs. (8.28) and (8.29)) [45]. These unusual enoxysilanes are prepared by treatment of the corresponding tribu-tylstannyl enolates with SiCl4. Trichlorosilyl enolates are sufficiently reactive to add to aldehydes at -78 °C, but their addition can be substantially accelerated by the addition of Lewis basic phosphoramides. The use of catalytic amounts of chiral phosphoramides leads to the formation of optically active products. Thus, treatment of the cyclohexanone or propiophenone-derived trichloroenolsilanes 101 and 105 with a variety of aldehydes afforded adducts displaying high levels of simple diastereoselectivity and up to 96% ee. On the basis of the stereochemical outcome of the reaction, Denmark has postulated that the reaction proceeds through an or-... 

In their initial disclosure on the chiral phosphoramide-catalyzed allylation of aldehydes with allyltrichlorosilanes, Denmark also reported that allyltrichlorostan-nanes were effective, albeit in significantly lower yield and selectivity (cf. Scheme 10-31 51% yield, 16% ee) [55]. 

In 1994, Denmark et al. found that chiral phosphoramides such as 58 may act as Lewis base in the enantioselective addition of trichloroallylsilane and aldehydes [64] (Table 10). 

Denmark et al. have extended this study to the enantioselective ring opening of meso-epoxides with silicon tetrachloride catalyzed by chiral phosphoramide 71 (Table 11). In this case, enantiomerically enriched chlorohydrins have been synthesized in enantiomeric excesses varying from 7 to 87 depending on the structure of the considered substrate [68]. 

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-... 

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